KR20230128271A - HER3 radioimmunotherapy for the treatment of solid cancers - Google Patents
HER3 radioimmunotherapy for the treatment of solid cancers Download PDFInfo
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Abstract
방사성핵종, 예컨대 225Ac, 177Lu, 131I, 90Y, 213Bi, 211At, 213Bi, 227Th, 또는 212Pb로 표지된 HER3-표적화제의 유효량을, 단독으로 또는 다른 치료제 또는 치료 양식과 조합하여 투여함으로써 대상체에서 고형 암, 예컨대 HER3-양성 종양을 치료하기 위한 조성물 및 방법이 제공된다. 방사성표지된 HER3-표적화제의 유효량은 단일 볼루스로 투여되거나 또는 함께 최대 허용 용량과 동일한 분할 용량으로 투여되는 최대 허용 용량일 수 있다.radionuclides such as 225 Ac; in a subject by administering an effective amount of a HER3-targeting agent labeled with 177 Lu, 131 I, 90 Y, 213 Bi, 211 At, 213 Bi, 227 Th, or 212 Pb, alone or in combination with another therapeutic agent or treatment modality. Compositions and methods for treating solid cancers, such as HER3-positive tumors, are provided. An effective amount of the radiolabeled HER3-targeting agent can be the maximum tolerated dose administered as a single bolus or together in divided doses equal to the maximum tolerated dose.
Description
관련 출원에 대한 상호 참조CROSS REFERENCES TO RELATED APPLICATIONS
본 출원은 2021년 10월 22일에 출원된 국제 출원 번호 PCT/US21/56259 및 그의 우선권 출원인, 2021년 9월 30일에 출원된 미국 가출원 번호 63/250,725 및 2021년 7월 28일에 출원된 미국 가출원 번호 63/226,699; 2020년 11월 25일에 출원된 미국 가출원 번호 63/118,181; 및 2020년 11월 20일에 출원된 미국 가출원 번호 63/116,225를 각각 우선권 주장하며, 전술한 출원 각각은 그 전체 내용이 본원에 참조로 포함된다.This application claims International Application No. PCT/US21/56259, filed on October 22, 2021, and its priority applicant, U.S. Provisional Application No. 63/250,725, filed on September 30, 2021, and filed on July 28, 2021. US Provisional Application No. 63/226,699; US Provisional Application No. 63/118,181, filed on November 25, 2020; and U.S. Provisional Application No. 63/116,225, filed on November 20, 2020, each of which is incorporated herein by reference in its entirety.
서열 목록sequence listing
본 출원은 ASCII 형식으로 전자적으로 제출된 서열 목록을 함유하며, 그 전체 내용이 본원에 참조로 포함된다. 2021년 11월 22일에 생성된 상기 ASCII 카피는 ATNM-010PCT_SL_ST25.txt로 명명되며, 그 크기는 191,107바이트이다.This application contains a sequence listing submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. Said ASCII copy, created on November 22, 2021, is named ATNM-010PCT_SL_ST25.txt and is 191,107 bytes in size.
발명의 분야field of invention
본 발명은 방사선치료 분야에 관한 것이다.The present invention relates to the field of radiation therapy.
ErbB3/HER3는 티로신 키나제 수용체 (EGFR, HER2, HER3 및 HER4)의 적혈모구 종양유전자 B (ErbB) 패밀리의 구성원인 유형 I 막횡단 당단백질이다. HER3를 통한 신호전달은 리간드-의존적 또는 리간드-비의존적 방식으로 활성화될 수 있다. 리간드의 부재 하에서는, HER3 수용체 분자가 수용체 이량체화를 방지하는 입체형태를 가진 단량체로서 세포 표면에서 정상적으로 발현된다. 이러한 입체형태에서, 서브도메인 II의 이량체화 루프는 서브도메인 IV 상의 포켓과 분자내 접촉을 만든다. 세포외 영역의 서브도메인 I 및 III에 대한 HER3 리간드, 예컨대 뉴레굴린 (NRG), 예를 들어 NRG1 (헤레굴린, HRG로서 공지되기도 함) 또는 NRG2의 결합은 서브도메인 II의 이량체화 루프의 노출을 초래하는 입체형태적 변화를 일으켜 수용체 이량체화 및 신호전달을 용이하게 한다. HER3에서의 특정 암-연관 돌연변이는 서브도메인 II와 IV 간의 이러한 상호작용, 즉 불활성 '폐쇄' 입체형태의 형성에 필요한 상호작용을 방해하고, 이에 따라 리간드 결합의 부재 하에서 이량체화 루프의 구성적 제시 및 HER3-매개 신호전달의 활성화를 야기한다.ErbB3/HER3 is a type I transmembrane glycoprotein that is a member of the erythroblast oncogene B (ErbB) family of tyrosine kinase receptors (EGFR, HER2, HER3 and HER4). Signaling through HER3 can be activated in a ligand-dependent or ligand-independent manner. In the absence of ligand, the HER3 receptor molecule is normally expressed on the cell surface as a monomer with a conformation that prevents receptor dimerization. In this conformation, the dimerization loop of subdomain II makes intramolecular contact with a pocket on subdomain IV. Binding of HER3 ligands such as neuregulin (NRG), eg NRG1 (also known as heregulin, HRG) or NRG2, to subdomains I and III of the extracellular domain results in exposure of the dimerization loop of subdomain II. resulting in conformational changes that facilitate receptor dimerization and signaling. Certain cancer-associated mutations in HER3 disrupt this interaction between subdomains II and IV, an interaction required for the formation of an inactive 'closed' conformation, thus constitutive presentation of a dimerization loop in the absence of ligand binding. and activation of HER3-mediated signaling.
HER3를 표적으로 하는 항체는 특이적 암 세포, 특히 특정 고형 암을 표적으로 하기 위해 이용될 수 있다. HER3는 여러 유형의 암, 예컨대 유방암, 위장암 및 췌장암에서 과다발현된다. HER2/HER3의 발현과 이들 암의 비-침습적 단계에서 침습적 단계로의 진행 간의 상관관계가 나타났다. HER3-매개 신호전달을 방해하는 작용제, 예컨대 항-HER3 항체는 종래의 요법을 사용해서는 부적절할 수 있는 암 세포에 대한 강력한 면역 반응의 확립을 가능하게 할 수 있다.Antibodies that target HER3 can be used to target specific cancer cells, particularly certain solid cancers. HER3 is overexpressed in several types of cancer, such as breast, gastrointestinal and pancreatic cancer. A correlation has been shown between the expression of HER2/HER3 and the progression of these cancers from non-invasive to invasive stages. Agents that interfere with HER3-mediated signaling, such as anti-HER3 antibodies, can allow the establishment of robust immune responses against cancer cells that may be inappropriate using conventional therapies.
따라서, 본원에 의해 개시된 발명의 하나의 목적은 HER3-양성 암의 치료를 위한 것과 같은 치료상 유효한 방사성표지된 HER3 표적화제를 제공하는 것이다. 본원에 의해 개시된 발명의 관련 목적은 이러한 방사성표지된 HER3 표적화제를, 단독으로 또는 하나 이상의 부가의 치료제와 조합하여 투여하는 것을 포함하는 치료 방법을 제공하는 것이다.Accordingly, one object of the invention disclosed herein is to provide therapeutically effective radiolabeled HER3 targeting agents, such as for the treatment of HER3-positive cancers. A related object of the invention disclosed herein is to provide a method of treatment comprising administering such a radiolabeled HER3 targeting agent, alone or in combination with one or more additional therapeutic agents.
본 발명은 방사성동위원소로 표지된, HER3을 표적으로 하는 HER3 표적화제, 예컨대 모노클로날 항체, 펩티드, 또는 소분자, 및 방사성표지된 HER3 표적화제를 사용하여 HER3-양성 (HER3-발현) 암을 진단 및/또는 치료하는 방법을 제공한다.The present invention uses a radioisotope-labeled, HER3-targeting agent that targets HER3, such as a monoclonal antibody, peptide, or small molecule, and a radiolabeled HER3-targeting agent to treat HER3-positive (HER3-expressing) cancers. Methods of diagnosis and/or treatment are provided.
본 발명의 특정 측면에 따르면, 진단 목적에 유용한 방사성표지된 HER3 표적화제는 방사성동위원소, 예컨대 111In, 68Ga, 64Cu, 89Zr, 또는 177Lu를 포함하는 항-HER3 항체, 펩티드, 또는 소분자일 수 있다.According to certain aspects of the invention, radiolabeled HER3 targeting agents useful for diagnostic purposes are anti-HER3 antibodies, peptides, or anti-HER3 antibodies comprising radioisotopes such as 111 In, 68 Ga, 64 Cu, 89 Zr, or 177 Lu. It may be a small molecule.
특정의 다른 측면에 따르면, 치료적 개입에 유용한 방사성표지된 HER3 표적화제는 방사성동위원소, 예컨대 131I, 125I, 123I, 90Y, 177Lu, 186Re, 188Re, 89Sr, 153Sm, 32P, 225Ac, 213Bi, 213Po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137Cs, 212Pb, 또는 그의 조합을 포함하는 항-HER3 항체, 펩티드, 또는 소분자일 수 있다. 특정의 바람직한 측면에 따르면, 방사성표지된 HER3 표적화제는 131I, 90Y, 177Lu, 225Ac, 213Bi, 211At, 227Th, 또는 212Pb를 포함할 수 있다.According to certain other aspects, the radiolabeled HER3 targeting agent useful for therapeutic intervention is a radioisotope such as 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm. , 32 P, 225 Ac, 213 Bi, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, or a combination thereof; or a small molecule. According to certain preferred aspects, the radiolabeled HER3 targeting agent may comprise 131 I, 90 Y, 177 Lu, 225 Ac, 213 Bi, 211 At, 227 Th, or 212 Pb.
특정 측면에 따르면, HER3-양성 암은 고형 종양일 수 있다.According to certain aspects, the HER3-positive cancer may be a solid tumor.
본원에 의해 개시된 발명의 치료 방법은 일반적으로 방사성표지된 HER3 표적화제의 치료 유효량을 환자에게 투여하는 것을 포함한다. 특정 측면에 따르면, 방사성표지된 HER3 표적화제의 유효량은 최대 허용 용량 (MTD)일 수 있거나, 또는 분할 용량일 수 있으며, 여기서 분할 용량으로 투여되는 방사선의 총량은 MTD이다.The treatment methods of the invention disclosed by this application generally comprise administering to a patient a therapeutically effective amount of a radiolabeled HER3 targeting agent. According to certain aspects, the effective amount of the radiolabeled HER3 targeting agent can be a maximum tolerated dose (MTD) or can be divided doses, wherein the total amount of radiation administered in divided doses is the MTD.
특정 측면에 따르면, HER3 표적화제의 방사성표지된 분획 및 비-방사성표지된 분획을 포함하는 HER3 표적화제의 조성물 또는 양이 제공 및/또는 사용된다. 이와 같이, HER3 표적화제의 유효량은 100 mg 미만, 예컨대 5 mg 내지 60 mg, 또는 5 mg 내지 45 mg의 총 단백질 용량을 포함할 수 있다. 특정 측면에 따르면, 총 단백질 용량은 0.001 mg/ kg 내지 3 mg/kg (대상체의 체중), 예컨대 0.005 mg/kg 내지 2 mg/kg (대상체의 체중)일 수 있다. 특정 측면에 따르면, 총 단백질 용량은 2 mg/kg 미만, 또는 1 mg/kg 미만, 0.5 mg/kg 미만, 또는 심지어 0.1 mg/kg 미만일 수 있다. 총 단백질 용량의 일부분은 표시된 바와 같이 방사성표지 (즉, 방사성 접합)되며, 여기서 방사성표지된 HER3 표적화제의 유효량은 선택된 특이적 방사성동위원소에 따라 달라질 수 있다. 치료적 개입을 위한 바람직한 방사성동위원소는 225Ac, 177Lu, 131I, 90Y, 213Bi, 211At, 227Th, 또는 212Pb를 포함한다. 따라서, HER3 표적화제는 방사성표지된 분획 및 비표지된 분획을 포함할 수 있다.According to certain aspects, a composition or amount of a HER3 targeting agent comprising a radiolabeled fraction and a non-radiolabeled fraction of the HER3 targeting agent is provided and/or used. As such, an effective amount of a HER3 targeting agent may include a total protein dose of less than 100 mg, such as 5 mg to 60 mg, or 5 mg to 45 mg. According to certain aspects, the total protein dose may be between 0.001 mg/kg and 3 mg/kg of the subject's body weight, such as between 0.005 mg/kg and 2 mg/kg of the subject's body weight. According to certain aspects, the total protein dose may be less than 2 mg/kg, or less than 1 mg/kg, less than 0.5 mg/kg, or even less than 0.1 mg/kg. A portion of the total protein dose is radiolabeled (ie, radioconjugated) as indicated, wherein the effective amount of the radiolabeled HER3 targeting agent may vary depending on the specific radioisotope selected. Preferred radioisotopes for therapeutic intervention include 225 Ac, 177 Lu, 131 I, 90 Y, 213 Bi, 211 At, 227 Th, or 212 Pb. Thus, the HER3 targeting agent may include a radiolabeled fraction and an unlabeled fraction.
특정 측면에 따르면, 방사선 용량의 관점에서 HER3 표적화제, 즉 그의 방사성표지된 부분, 예컨대 225Ac-항-HER3 항체, 펩티드, 또는 소분자의 유효량은 0.1 내지 20 μCi/kg (대상체의 체중)의 용량, 예컨대 0.1 내지 10 μCi/kg 또는 0.1 내지 5 uCi/kg (대상체의 체중)의 용량, 또는 0.5 내지 20 μCi/kg 또는 1 내지 10 uCi/kg (대상체의 체중)의 용량을 포함할 수 있다.According to certain aspects, an effective amount of a HER3 targeting agent, i.e., a radiolabeled portion thereof, such as a 225 Ac-anti-HER3 antibody, peptide, or small molecule, in terms of radiation dose, is a dose of 0.1 to 20 μCi/kg of subject's body weight. , such as a dose of 0.1 to 10 μCi/kg or 0.1 to 5 uCi/kg (body weight of the subject), or a dose of 0.5 to 20 μCi/kg or 1 to 10 uCi/kg (body weight of the subject).
특정 측면에 따르면, HER3 표적화제, 즉 그의 방사성표지된 부분, 예컨대 225Ac-항-HER3 항체, 펩티드, 또는 소분자의 유효량은 표적화제의 구성, 즉 완전한 길이의 항체 또는 항원-결합 항체 단편 (예를 들어, Fab, Fab2, 미니바디, 나노바디 등), 예컨대 본원에 개시된 것들 중 임의의 것에 의존할 수 있다. 예를 들어, HER3 표적화제가 완전한 길이의 항체인 225Ac-항-HER3 항체를 포함하는 경우, 용량은 5 uCi/kg (대상체의 체중) 미만, 예컨대 0.1 내지 5 uCi/kg (대상체의 체중)일 수 있다. 대안적으로, HER3 표적화제가 단편인 225Ac-항-HER3 항체를 포함하는 경우, 용량은 5 uCi/kg (대상체의 체중) 초과, 예컨대 5 내지 20 uCi/kg (대상체의 체중)일 수 있다.According to certain aspects, an effective amount of a HER3 targeting agent, i.e., a radiolabeled portion thereof, such as a 225 Ac-anti-HER3 antibody, peptide, or small molecule, is a component of the targeting agent, i.e., a full-length antibody or antigen-binding antibody fragment (eg eg, Fab, Fab 2 , minibodies, nanobodies, etc.), such as any of those disclosed herein. For example, if the HER3 targeting agent comprises a full-length antibody, 225 Ac-anti-HER3 antibody, the dose is less than 5 uCi/kg of the subject's body weight, such as between 0.1 and 5 uCi/kg of the subject's body weight. can be Alternatively, if the HER3 targeting agent comprises a fragment 225 Ac-anti-HER3 antibody, the dose may be greater than 5 uCi/kg of the subject's body weight, such as between 5 and 20 uCi/kg of the subject's body weight. .
특정 측면에 따르면, HER3 표적화제는 항-HER3 항체, 예컨대 모노클로날 항체 또는 그의 항원 결합 단편, 예컨대 IgG 또는 그의 항원 결합 단편, 예컨대 다이이치 산쿄(Daiichi Sankyo)로부터의 파트리투맙, 메리맥 파마슈티칼즈(Merrimack Pharmaceuticals)로부터의 세리반투맙 (MM-121), 로슈(Roche)로부터의 룸레투주맙, 노바티스(Novartis)로부터의 엘젬투맙, 글락소스미스클라인(GlaxoSmithKline)으로부터의 GSK2849330, 셀덱스 테라퓨틱스(Celldex Therapeutics)의 CDX-3379, 메디파마(MediPharma)로부터의 EV20 및 MP-RM-1, 이수 앱지스 캄파니(Isu Abxis Co.)로부터의 ISU104, 허밍버드 바이오사이언스(Hummingbird Bioscience) Pte.로부터의 HMBD-001 (10D1F), 리제네론 파마슈티칼즈(Regeneron Pharmaceuticals)로부터의 REGN1400 및/또는 아베오 온콜로지(AVEO Oncology)로부터의 AV-203에 의해 인식되는 HER3의 에피토프와 결합하는 것이다. 특정 측면에 따르면, 항-HER3 항체는 파트리투맙, 세리반투맙, 룸레투주맙, 엘젬투맙, AV-203, CDX-3379, 또는 GSK2849330 중 하나 이상으로부터 선택된다.According to certain aspects, the HER3 targeting agent is an anti-HER3 antibody, such as a monoclonal antibody or antigen-binding fragment thereof, such as an IgG or antigen-binding fragment thereof, such as patritumab from Daiichi Sankyo, Merrimack Pharma Serivantumab (MM-121) from Merrimack Pharmaceuticals, rumletuzumab from Roche, elgemtumab from Novartis, GSK2849330 from GlaxoSmithKline, Celdex Thera CDX-3379 from Celldex Therapeutics, EV20 and MP-RM-1 from MediPharma, ISU104 from Isu Abxis Co., Hummingbird Bioscience Pte. and/or by HMBD-001 (10D1F) from Regeneron Pharmaceuticals, REGN1400 from Regeneron Pharmaceuticals, and/or AV-203 from AVEO Oncology. According to certain aspects, the anti-HER3 antibody is selected from one or more of patritumab, ceribantumab, rumletuzumab, elgemtumab, AV-203, CDX-3379, or GSK2849330.
특정 측면에 따르면, HER3 표적화제는 치료 기간 전체에 걸쳐 7일, 10일, 12일, 14일, 20일, 24일, 28일, 35일, 및 42일마다 1회 투여로 이루어진 군으로부터 선택된 투여 스케줄에 따라 투여될 수 있으며, 여기서 치료 기간은 적어도 2회 투여를 포함한다.According to certain aspects, the HER3 targeting agent is selected from the group consisting of administration once every 7 days, 10 days, 12 days, 14 days, 20 days, 24 days, 28 days, 35 days, and 42 days throughout the treatment period. It may be administered according to an administration schedule, wherein the treatment period includes at least two administrations.
특정 측면에 따르면, HER3 표적화제는 치료 기간의 제1일과 제5일, 제6일, 제7일, 제8일, 제9일, 또는 제10일의 2회 투여, 또는 치료 기간의 제1일과 제8일의 2회 투여를 포함하는 투여 스케줄에 따라 투여될 수 있다.According to certain aspects, the HER3 targeting agent is administered in two doses on
특정 측면에 따르면, HER3 표적화제는 단일 대상체 특이적 용량으로 단일 볼루스 또는 주입으로서 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be administered as a single bolus or infusion in a single subject specific dose.
특정 측면에 따르면, 상기 방법은 하나 이상의 추가 치료제, 예컨대 화학요법제, 소분자 약물, 항염증제, 면역억제제, 면역조정제, 항골수종제, 시토카인, 또는 그의 조합의 투여를 추가로 포함할 수 있다. 예시적인 화학요법제는 방사성표지된 HER3 표적화제와 상승작용할 수 있는 적어도 방사선증감제, 예컨대 테모졸로미드, 시스플라틴 및/또는 플루오로우라실을 포함한다.According to certain aspects, the method may further comprise administration of one or more additional therapeutic agents, such as chemotherapeutic agents, small molecule drugs, anti-inflammatory agents, immunosuppressive agents, immunomodulatory agents, antimyeloma agents, cytokines, or combinations thereof. Exemplary chemotherapeutic agents include at least radiosensitizers that can synergize with radiolabeled HER3 targeting agents, such as temozolomide, cisplatin and/or fluorouracil.
특정 측면에 따르면, 상기 방법은 하나 이상의 면역 체크포인트 요법의 투여를 추가로 포함할 수 있다. 예시적인 면역 체크포인트 요법은 CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, OX40, GITR, CD137, CD40, CD40L, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4, CD160, CGEN-15049에 대한 항체, 또는 그의 임의의 조합을 포함한다. 특정 측면에 따르면, 면역 체크포인트 요법은 PD-1, PD-L1, PD-L2, CTLA-4, CD137에 대한 항체, 및 그의 조합으로 이루어진 군으로부터 선택된 면역 체크포인트 단백질에 대한 항체를 포함할 수 있다.According to certain aspects, the method may further include administration of one or more immune checkpoint therapies. Exemplary immune checkpoint therapies include CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, OX40, GITR, CD137, CD40, CD40L, CD27, HVEM, PD-L1, PD -L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4, CD160, CGEN-15049 antibodies, or any combination thereof. According to certain aspects, the immune checkpoint therapy may include an antibody to an immune checkpoint protein selected from the group consisting of antibodies to PD-1, PD-L1, PD-L2, CTLA-4, CD137, and combinations thereof. there is.
특정 측면에 따르면, 면역 체크포인트 요법은 유효량, 예컨대 0.1 mg/kg 내지 50 mg/kg (환자 체중), 예컨대 0.1-5 mg/kg, 또는 5-30 mg/kg의 용량으로 대상체에게 투여될 수 있다.According to certain aspects, an immune checkpoint therapy can be administered to a subject in an effective amount, such as a dose of 0.1 mg/kg to 50 mg/kg of patient body weight, such as 0.1-5 mg/kg, or 5-30 mg/kg. there is.
특정 측면에 따르면, 상기 방법은 하나 이상의 DNA 손상 반응 억제제 (DDRi)의 투여를 추가로 포함할 수 있다. 예시적인 DDRi 작용제는 폴리(ADP-리보스) 폴리머라제를 표적으로 하는 하나 이상의 항체 또는 소분자 (즉, 폴리(ADP-리보스) 폴리머라제 억제제 또는 PARPi)이다. PARPi는 예를 들어, 올라파립, 니라파립, 루카파립, 탈라조파립, 또는 그의 임의의 조합을 포함할 수 있다. 특정 측면에 따르면, PARPi는 0.1 mg/일 - 1200 mg/일, 예컨대 0.100 mg/일 - 600 mg/일, 또는 0.25 mg/일 - 1 mg/일을 포함한 대상체 유효량으로 제공될 수 있다. 예시적인 대상체 유효량은 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 및 1000 mg을 포함하며, 하루에 1회 또는 2회 경구 투여된다.According to certain aspects, the method may further include administration of one or more DNA damage response inhibitors (DDRi). Exemplary DDRi agonists are one or more antibodies or small molecules that target poly(ADP-ribose) polymerase (ie, poly(ADP-ribose) polymerase inhibitors or PARPi). PARPi can include, for example, olaparib, niraparib, rucaparib, thalazoparib, or any combination thereof. According to certain aspects, PARPi can be given in a subject effective amount including 0.1 mg/day - 1200 mg/day, such as 0.100 mg/day - 600 mg/day, or 0.25 mg/day - 1 mg/day. Exemplary subject effective amounts are 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, and 1000 mg, administered orally once or twice daily.
또 다른 예시적인 DDRi는 돌연변이된 모세혈관확장성 운동실조증 (ATM), 돌연변이된 및 Rad-3 관련된 모세혈관확장성 운동실조증 (ATR), 또는 Wee1의 억제제를 포함한다. ATM의 예시적인 억제제는 KU-55933, KU-59403, 워트만닌, CP466722 및 KU-60019를 포함한다. ATR의 예시적인 억제제는 적어도 쉬잔드린 B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20 및 AZD6738을 포함한다. Wee1의 예시적인 억제제는 AZD-1775 (즉, 아다보세르팁)를 포함한다.Another exemplary DDRi includes mutated telangiectatic ataxia (ATM), mutated and Rad-3 related telangiectatic ataxia (ATR), or an inhibitor of Weel. Exemplary inhibitors of ATM include KU-55933, KU-59403, wortmannin, CP466722 and KU-60019. Exemplary inhibitors of ATR include at least Schizandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20 and AZD6738. Exemplary inhibitors of Weel include AZD-1775 (ie, Adavosertip).
특정 측면에 따르면, 상기 방법은 하나 이상의 CD47 차단제의 투여를 추가로 포함할 수 있다. CD47 차단제는 CD47이 SIRPα와 결합하는 것을 방지하거나 그렇지 않으면 CD47의 면역억제 활성을 차단하거나 하향조절하는 모노클로날 항체, SIRPα-Fc 융합 단백질 또는 다른 분자, 예컨대 마그롤리맙, 렘조파를리맙, AO-176, AK117, IMC-002, IBI-188, IBI-322, BI 766063, ZL-1201, AXL148, RRx-001, ES004, SRF231, SHR-1603, TJC4, TTI-621, 또는 TTI-622를 포함할 수 있다. CD47 차단제에 대한 예시적인 유효 용량은 0.05 내지 5 mg/kg (환자 체중)을 포함한다. CD47 차단제는 또한 CD47 및/또는 SIRPα의 발현을 조정하는 작용제, 예컨대 핵산 접근 방식, 예를 들어 안티센스, RNAi 또는 μRNA 접근 방식을 포함할 수 있다. 예시적인 CD47 차단제는 또한 CD47의 번역을 차단하는 포스포로디아미데이트 모르폴리노 올리고머 (PMO), 예컨대 MBT-001을 포함한다.According to certain aspects, the method may further comprise administration of one or more CD47 blockers. CD47 blockers include monoclonal antibodies, SIRPα-Fc fusion proteins or other molecules that prevent CD47 from binding to SIRPα or otherwise block or downregulate the immunosuppressive activity of CD47, such as magnolimab, remzoparlimab, AO Includes -176, AK117, IMC-002, IBI-188, IBI-322, BI 766063, ZL-1201, AXL148, RRx-001, ES004, SRF231, SHR-1603, TJC4, TTI-621, or TTI-622 can do. Exemplary effective doses for CD47 blockers include 0.05 to 5 mg/kg of patient body weight. CD47 blockers may also include agents that modulate the expression of CD47 and/or SIRPα, such as nucleic acid approaches such as antisense, RNAi or μRNA approaches. Exemplary CD47 blockers also include phosphorodiamidate morpholino oligomers (PMOs) that block translation of CD47, such as MBT-001.
특정 측면에 따르면, 상기 방법은 추가 치료제의 조합의 투여를 추가로 포함할 수 있다. 예시적인 조합은 적어도 하나 이상의 DDRi 및/또는 하나 이상의 면역 체크포인트 요법 및/또는 하나 이상의 CD47 차단제 및/또는 하나 이상의 화학요법제 및/또는 하나 이상의 소분자 항암 약물 및/또는 상이한 암-연관 항원에 대하여 유도된 하나 이상의 표적화제를 포함한다.According to certain aspects, the method may further include administration of a combination of additional therapeutic agents. Exemplary combinations are directed against at least one or more DDRi and/or one or more immune checkpoint therapies and/or one or more CD47 blockers and/or one or more chemotherapeutic agents and/or one or more small molecule anticancer drugs and/or different cancer-associated antigens. Including one or more targeting agents that have been derived.
특정 측면에 따르면, 방사성표지된 HER3 표적화제 및 하나 이상의 추가 치료제는 동시에 또는 순차적으로 투여될 수 있다. 하나 초과의 부가의 치료제가 투여되는 경우, 이러한 치료제는 동시에 또는 순차적으로 투여될 수 있다.According to certain aspects, the radiolabeled HER3 targeting agent and one or more additional therapeutic agents may be administered simultaneously or sequentially. When more than one additional therapeutic agent is administered, these therapeutic agents may be administered simultaneously or sequentially.
본 발명의 특정 측면에 따르면, 방사성표지된 HER3 표적화제는 적어도 하나의 부분이 HER3을 인식하는 다중특이적 표적화제, 예컨대 다중특이적 항체 또는 이중특이적 항체일 수 있다. 따라서, 상기 방법은 유효량의 다중특이적 항체를 대상체에게 투여하는 것을 포함할 수 있으며, 여기서 다중특이적 항체는 HER3의 에피토프와 특이적으로 결합하는 제1 표적 인식 성분, 및 제1 표적 인식 성분과 상이한 HER3의 에피토프와 특이적으로 결합하거나 또는 상이한 항원, 예컨대 상이한 암-연관 항원의 에피토프와 특이적으로 결합하는 제2 표적 인식 성분을 포함한다. 특정 측면에 따르면, HER3 표적화제는 HER3의 제1 에피토프 및 HER3의 적어도 제2 에피토프에 대한, 또는 HER3 및 적어도 제2 (상이한) 항원에 대한 다중특이적 항체이다. 본 발명에 따른 진단 및/또는 치료 용도를 위해 방사성표지될 수 있는 예시적인 다중특이적 항체는 HER3/HER2에 대한 이중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-111 또는 메루스(Merus) N.V.로부터의 MCLA-128; 또는 IGF-1R/HER3에 대한 이중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-141 (즉, 이스티라투맙); 또는 EGFR/HER3에 대한 이중특이적 항체, 예컨대 로슈로부터의 MEHD7945A (즉, 둘리고투맙) 또는 진게니아 인크.(Zyngenia Inc.)로부터의 세툭시맙-기반 이중특이적 또는 다중특이적 자이보디 중 임의의 것을 포함한다.According to certain aspects of the invention, the radiolabeled HER3 targeting agent may be a multispecific targeting agent, such as a multispecific antibody or a bispecific antibody, wherein at least one portion recognizes HER3. Accordingly, the method may comprise administering to a subject an effective amount of a multispecific antibody, wherein the multispecific antibody comprises a first target recognition component that specifically binds an epitope of HER3, and a first target recognition component and and a second target recognition component that specifically binds an epitope of a different HER3 or that specifically binds an epitope of a different antigen, such as a different cancer-associated antigen. According to certain aspects, the HER3 targeting agent is a multispecific antibody directed against a first epitope of HER3 and at least a second epitope of HER3, or against HER3 and at least a second (different) antigen. Exemplary multispecific antibodies that can be radiolabeled for diagnostic and/or therapeutic use according to the present invention include bispecific antibodies to HER3/HER2, such as MM-111 from Merrimack Pharmaceuticals or Merus ( Merus) MCLA-128 from N.V.; or a bispecific antibody to IGF-1R/HER3 such as MM-141 from Merrimac Pharmaceuticals (ie istiratumab); or a bispecific antibody to EGFR/HER3, such as MEHD7945A from Roche (i.e. duligotumab) or a cetuximab-based bispecific or multispecific zybody from Zyngenia Inc. including any
특정 측면에 따르면, HER3 표적화제, 예컨대 HER3에 대한 항체와 하나 이상의 추가 표적화제, 예컨대 하나 이상의 상이한 암 연관 항원을 표적으로 하고/이러한 항원에 대한 항체의 혼합물을 포함하는 조성물이 제공되며, 여기서 HER3 표적화제 및 다른 표적화제(들) 중 하나 이상은 임의의 조합으로 방사성표지되거나 비-방사성표지될 수 있다. 항체 혼합물을 포함한 예시적인 항체 조성물은 EGFR (HER1), HER2 및 HER3에 대한 6개의 모노클로날 항체를 갖는 심포젠(Symphogen)으로부터의 적어도 Sym013을 포함한다. 한 측면에서, Sym013의 항체 중 하나 이상은 임의의 조합으로, 예컨대 적어도 HER3 항체와 EGFR 및 HER2에 대한 항체가 없거나 또는 이러한 항체의 하나 이상으로 방사성표지될 수 있다.According to certain aspects, there is provided a composition comprising a mixture of a HER3 targeting agent, such as an antibody to HER3, and one or more additional targeting agents, such as antibodies targeting/to one or more different cancer-associated antigens, wherein the HER3 One or more of the targeting agent and the other targeting agent(s) may be radiolabeled or non-radiolabeled in any combination. Exemplary antibody compositions comprising antibody mixtures include at least Sym013 from Symphogen with 6 monoclonal antibodies against EGFR (HER1), HER2 and HER3. In one aspect, one or more of the antibodies of Sym013 can be radiolabeled in any combination, eg, with at least a HER3 antibody and no antibodies to EGFR and HER2, or with one or more of these antibodies.
본 발명의 부가의 특색, 장점 및 측면은 하기 상세한 설명, 존재하는 경우 도면, 및 청구범위를 고려하여 설명되거나 명백해질 수 있다. 더욱이, 본 발명의 전술한 요약 및 하기의 상세한 설명 모두는 예시적인 것이며, 청구된 본 발명의 범위를 제한하지 않고 추가적인 설명을 제공하기 위한 것으로 이해되어야 한다.Additional features, advantages and aspects of the present invention may be described or made apparent in consideration of the following detailed description, drawings, if any, and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and are intended to provide further explanation without limiting the scope of the claimed invention.
도 1은 본 발명의 다양한 측면에서 구현될 수 있는 HER3 모노클로날 항체의 중쇄 및 경쇄의 N-말단 영역, 상보성 결정 영역 및 가변 영역의 아미노산 서열을 제공한다.
도 2는 본 발명의 다양한 측면에서 구현될 수 있는 HER3 모노클로날 항체의 리더 서열이 있거나 없는 완전한 길이의 중쇄 및 경쇄의 아미노산 서열을 제공한다.
도 3은 비변형된 항-HER3 항체 및 비특이적 항체 (IgG)와 비교한 Ac225 표지된 DOTA-접합된 항-HER3 모노클로날 항체의 ELISA 검정 결합 특징을 나타내며, 이는 그러한 변형이 HER3에 대한 면역 반응성에 실질적으로 영향을 미치지 않다는 것을 입증해준다.
도 4는 HER3-양성 NCI-H1975 세포 (인간 폐 선암종, NSCLC) 및 BxPC-3 세포 (인간 췌장 선암종)에 대한 225Ac-HER3-ARC, 비변형된 항-HER3 mAb, 비특이적 항체 대조군 (IgG) 및 2차 항체 단독 대조군의 결합을 조사한 유동 세포계수법 검정 결과를 보여주는 그래프이다.
도 5는 HER3-양성 세포주 NCI-H1975에 대한 225Ac-HER3-ARC의 시험관내 세포독성 효과를 방사선 용량에 따른 함수로서 나타낸 그래프이다.
도 6A는 225Ac-HER3-ARC가 NCI-H1975 세포에서 세포 표면 칼레티쿨린 (CRT)을 상향조절한다는 것을 보여주는 그래프이다.
도 6B는 225Ac-HER3-ARC가 NCI-H1975 세포 상에서 CD47을 상향조절한다는 것을 보여주는 그래프이다.
도 7A는 225Ac-HER3-ARC와 항-CD47 차단 항체의 조합이 어느 하나의 처리 단독에 비해 BxPC-3 세포의 식세포작용을 향상시켰다는 것을 입증하는 식세포작용 검정의 결과를 나타내는 그래프이다.
도 7B는 225Ac-HER3-ARC와 항-CD47 차단 항체의 조합이 어느 하나의 처리 단독에 비해 NCI-H1975 세포의 식세포작용을 향상시켰다는 것을 입증하는 식세포작용 검정의 결과를 나타내는 그래프이다.
도 8은 인간 종양 (NCI-H1975 세포) 마우스 이종이식편 모델에서, 상이한 방사선 용량에서 225Ac-HER3-ARC를 항-CD47 차단 항체와 조합하여 종양 성장에 미치는 효과를 나타내는 그래프이다.
도 9는 도 8에 기재된 실험의 대상체에 대한 시간 경과에 따른 체중을 나타내는 그래프이다.
도 10은 도 8에 기재된 실험의 실험 군 대상체에 대한 시간 경과에 따른 생존 확률을 나타내는 그래프이다.
도 11은 HER2-양성 SK-OV3 인간 난소암 세포주를 사용한 NGS 마우스 이종이식편 모델에서 비히클 (대조군), CD47 차단 항체 마그롤리맙 단독, 225Ac-트라스투주맙 단독, 및 마그롤리맙과 225Ac-트라스투주맙의 조합의 종양 성장에 대한 비교 효과를 나타내는 그래프이다.
도 12는 SK-OV3 인간 난소암 세포주를 사용한 NGS 마우스 이종이식편 모델에서 비히클 (대조군), 마그롤리맙 단독, 177Lu-트라스투주맙 단독, 및 마그롤리맙과 177Lu-트라스투주맙의 조합의 종양 성장에 대한 비교 효과를 나타내는 그래프이다. 1 provides amino acid sequences of N-terminal regions, complementarity determining regions, and variable regions of heavy and light chains of HER3 monoclonal antibodies that can be implemented in various aspects of the present invention.
2 provides amino acid sequences of full-length heavy and light chains, with or without leader sequences, of HER3 monoclonal antibodies that can be implemented in various aspects of the present invention.
FIG. 3 shows the ELISA assay binding characteristics of Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibodies compared to unmodified anti-HER3 antibodies and non-specific antibodies (IgG), indicating that such modifications are immunoreactive to HER3. proves that it has no real effect on
Figure 4 shows 225Ac-HER3-ARC, unmodified anti-HER3 mAb, non-specific antibody control (IgG) and BxPC-3 cells (human pancreatic adenocarcinoma) on HER3-positive NCI-H1975 cells (human lung adenocarcinoma, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma). A graph showing the results of a flow cytometry assay examining the binding of the secondary antibody only control.
5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC on the HER3-positive cell line NCI-H1975 as a function of radiation dose.
6A is a graph showing that 225Ac-HER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells.
6B is a graph showing that 225Ac-HER3-ARC upregulates CD47 on NCI-H1975 cells.
7A is a graph showing the results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC with an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells compared to either treatment alone.
7B is a graph showing the results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC with an anti-CD47 blocking antibody enhanced phagocytosis of NCI-H1975 cells compared to either treatment alone.
8 is a graph showing the effect of 225Ac-HER3-ARC in combination with an anti-CD47 blocking antibody on tumor growth at different radiation doses in a human tumor (NCI-H1975 cell) mouse xenograft model.
9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8 .
10 is a graph showing survival probability over time for subjects in the experimental group of the experiment described in FIG. 8 .
Figure 11 shows vehicle (control), CD47 blocking antibodies Magrolimab alone, 225Ac-Trastuzumab alone, and Magrolimab and 225Ac-Trastuzumab in an NGS mouse xenograft model using the HER2-positive SK-OV3 human ovarian cancer cell line. It is a graph showing the comparative effect of combinations of zumab on tumor growth.
Figure 12 : Tumor growth of vehicle (control), magnolimab alone, 177Lu-trastuzumab alone, and the combination of magnolimab and 177Lu-trastuzumab in an NGS mouse xenograft model using the SK-OV3 human ovarian cancer cell line. It is a graph showing the comparative effect on
한 측면에서, 본원에 의해 개시된 발명은 HER3을 발현하는 암, 즉 HER3-양성 암을 치료하기 위한 조성물 및 방법을 제공한다. 이러한 측면은 일반적으로 치료를 필요로 하는 포유동물 대상체, 예컨대 인간 환자에게 방사성표지된 HER3 표적화제, 예컨대 HER3에 표적화된 방사성표지된 항체, 펩티드, 또는 소분자의 유효량을 단독으로 또는 하나 이상의 부가의 치료제 및/또는 치료 양식/치료와 조합하여 투여하는 것을 포함한다.In one aspect, the invention disclosed by the present application provides compositions and methods for treating cancers that express HER3, ie, HER3-positive cancers. This aspect generally relates to the administration of an effective amount of a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide, or small molecule targeted to HER3, alone or in one or more additional therapeutic agents, to a mammalian subject in need of treatment, such as a human patient. and/or administration in combination with a treatment modality/treatment.
사용될 수 있는 부가의 치료제 및 치료 양식은, 예를 들어, 적어도 하나 이상의 면역 체크포인트 요법 및/또는 DNA 손상 반응 경로의 성분의 하나 이상의 억제제 (즉, DNA 손상 반응 억제제, DDRi, 예컨대 폴리(ADP-리보스) 폴리머라제에 대한 하나 이상의 작용제, 즉 PARPi) 및/또는 하나 이상의 CD47/SIRPα 축 차단제 및/또는 하나 이상의 화학요법제, 예컨대 방사선증감제, 및/또는 하나 이상의 소분자 종양학 약물, 예컨대 티로신 키나제 억제제, 및/또는 상이한 항원에 대한 하나 이상의 표적화제를 포함한다. Additional therapeutic agents and treatment modalities that may be used include, for example, at least one or more immune checkpoint therapies and/or one or more inhibitors of components of the DNA damage response pathway (i.e., DNA damage response inhibitors, DDRi, such as poly(ADP- ribose) polymerase, i.e. PARPi) and/or one or more CD47/SIRPα axis blockers and/or one or more chemotherapeutic agents such as radiosensitizers, and/or one or more small molecule oncology drugs such as tyrosine kinase inhibitors , and/or one or more targeting agents to different antigens.
본원에 의해 개시된 발명은 대상체에서 HER3-양성 암을 확인, 영상화 및/또는 진단하는 방법을 추가로 제공한다. 본원에 의해 개시된 발명은 대상체에서 HER3-양성 암을 확인, 영상화 및/또는 진단한 후, 본원에 개시된 방법 중 임의의 것에 따라 상기 대상체를 치료하는 방법을 추가로 제공한다.The invention disclosed herein further provides methods for identifying, imaging and/or diagnosing HER3-positive cancer in a subject. The invention disclosed by the present application further provides methods of identifying, imaging and/or diagnosing a HER3-positive cancer in a subject, and then treating the subject according to any of the methods disclosed herein.
정의 및 약어Definitions and Abbreviations
단수 형태는 문맥상 명백하게 달리 지시하지 않는 한 복수 지시대상을 포함한다. 따라서, 예를 들어, 항체에 대한 언급은 단일 항체와 복수 개의 상이한 항체 둘 다를 포함한다.The singular form includes the plural referent unless the context clearly dictates otherwise. Thus, for example, reference to an antibody includes both a single antibody and a plurality of different antibodies.
본 명세서 및 청구범위에서 사용된 바와 같은 단어 "포함하는" 및 단어 "포함하는"의 형태뿐만 아니라 단어 "포함한" 및 단어 "포함한"의 형태는, 그것이 지칭된 것 이상의 요소의 포함을 제한하지 않는다. 부가적으로, 본 개시내용 전반에 걸쳐 그의 다양한 측면 또는 요소가 "포함한" 또는 "포함하는"의 관점에서 기재되지만, "~로 본질적으로 이루어지는" 또는 "~로 이루어지는"의 관점에서 기재된 그의 상응하는 측면 또는 요소가 유사하게 개시된다. 예를 들어, 본 발명의 특정 측면이 방사성표지된 표적화제를 투여하는 것을 "포함한" 또는 "포함하는" 방법의 관점에서 기재되었지만, 그 대신에 방사성표지된 표적을 투여하는 것으로 "본질적으로 이루어지는" 또는 "이루어지는"으로 나열된 상응하는 방법이 또한 상기 측면의 범위 내에 있고 본 개시내용에 의해 개시된다.As used in this specification and claims, the word "comprising" and the forms of the word "comprising" as well as the forms of the word "comprising" and "comprising" do not limit the inclusion of elements beyond those with which they are recited. . Additionally, throughout this disclosure various aspects or elements thereof are described in terms of “comprising” or “comprising”, but their corresponding counterparts described in terms of “consisting essentially of” or “consisting of”. Aspects or elements are similarly disclosed. For example, while certain aspects of the invention have been described in terms of a method that “comprises” or “comprises” administering a radiolabeled targeting agent, it instead “consists essentially of” administering a radiolabeled target. or corresponding methods listed as “consisting of” are also within the scope of this aspect and are disclosed by this disclosure.
용어 "약"은, 예를 들어, 온도, 시간, 양 및 농도를 특정 범위의 설명에 포함하여 기재하는 데 있어서, 수치적 명칭 또는 값과 연계해서 본 개시내용에서 사용될 때, ±10%의 분산을 나타내고, 그 더 큰 분산 내에서, 수치적 명칭 또는 값의 ±5% 또는 ±1%의 분산을 나타낸다.The term "about", when used in this disclosure in conjunction with numerical designations or values, to describe, for example, temperature, time, amount, and concentration, including in the description of a particular range, a variance of ±10%. , and, within that larger variance, represents a variance of ±5% or ±1% of the numerical designation or value.
본원에 사용된 바와 같은, 표적화제, 예컨대 항체, 항체 단편, Fab 단편, 또는 앱타머와 관련하여 "투여하다"는 항체 전달에 적합한 임의의 공지된 방법을 통해 대상체의 신체에 상기 작용제를 전달하는 것을 의미한다. 구체적 투여 방식은 정맥내, 경피, 피하, 복강내, 척수강내 및 종양내 투여를 포함하며, 이에 제한되지 않는다. 항체에 대한 예시적인 투여 방법은 본원에 참고로 포함된 국제 공개 번호 WO 2016/187514에 실질적으로 기재된 바와 같을 수 있다.As used herein, “administering” in reference to a targeting agent, such as an antibody, antibody fragment, Fab fragment, or aptamer, means delivering the agent to the body of a subject via any known method suitable for antibody delivery. means that Specific modes of administration include, but are not limited to intravenous, transdermal, subcutaneous, intraperitoneal, intrathecal and intratumoral administration. Exemplary methods of administration for the antibody may be substantially as described in International Publication No. WO 2016/187514, incorporated herein by reference.
또한, 본 발명에서, 항체는 예를 들어, 하나 이상의 일상적으로 사용되는 제약상 허용되는 담체 및 부형제를 사용하여 제형화될 수 있다. 이러한 담체 및 부형제는 관련 기술분야의 통상의 기술자에게 널리 공지되어 있다. 예를 들어, 주사용 약물 전달 시스템은 용액, 현탁액, 겔, 미소 구체 및 중합체성 주사제를 포함하고, 부형제, 예컨대 용해도-변경제 (예를 들어, 에탄올, 프로필렌 글리콜 및 수크로스) 및 중합체 (예를 들어, 폴리카프릴락톤 및 PLGA)를 포함할 수 있다.Also in the present invention, antibodies may be formulated using, for example, one or more routinely used pharmaceutically acceptable carriers and excipients. Such carriers and excipients are well known to those skilled in the art. For example, injectable drug delivery systems include solutions, suspensions, gels, microspheres, and polymeric injectables, and include excipients such as solubility-altering agents (e.g., ethanol, propylene glycol, and sucrose) and polymers (e.g., ethanol, propylene glycol, and sucrose). For example, polycapryllactone and PLGA) may be included.
본원에 사용된 바와 같은, 용어 "항체"는 (a) 2개의 중쇄 및 2개의 경쇄를 포함하고 항원을 인식하는 이뮤노글로불린 분자; (b) 폴리클로날 및 모노클로날 이뮤노글로불린 분자; (c) 그의 1가 및 2가 단편, 예컨대 Fab, 디-Fab, scFv, 디아바디, 미니바디, 및 나노바디 (sdAb); (d) 자연적으로 발생하는 및 비-자연적으로 발생하는, 예컨대 완전 합성 항체, IgG-Fc-침묵 및 키메라; 및 (e) 그의 이중특이적 및 다중특이적 형태를 포함하며, 이에 제한되지 않는다. 이뮤노글로불린 분자는 IgA, 분비성 IgA, IgG 및 IgM을 포함하나 이에 제한되지는 않는, 통상적으로 공지된 클래스 중 임의의 것으로부터 유래될 수 있다. IgG 서브클래스는 또한 관련 기술분야의 통상의 기술자에 널리 공지되어 있으며, 인간 IgG1, IgG2, IgG3 및 IgG4를 포함하나 이에 제한되지는 않는다. 각각의 쇄의 N-말단은 항원 인식을 주로 담당하는 약 100개 내지 110개 또는 그 초과의 아미노산의 "가변 영역"을 규정한다. 용어 가변 경쇄 (VL) 및 가변 중쇄 (VH)는 각각 경쇄 및 중쇄의 이들 영역을 지칭한다. 항체는 인간, 인간화 또는 비인간일 수 있다. 본원에 의해 개시된 발명의 구체적 측면이 "항체"를 지칭하거나 이를 나열하는 경우, 명백하게 달리 나타내지 않는 한, 본원에 개시된 완전한 길이의 항체 또는 그의 단편 중 임의의 것을 언급하는 것으로 생각된다.As used herein, the term “antibody” refers to (a) an immunoglobulin molecule comprising two heavy chains and two light chains and recognizing an antigen; (b) polyclonal and monoclonal immunoglobulin molecules; (c) monovalent and bivalent fragments thereof, such as Fabs, di-Fabs, scFvs, diabodies, minibodies, and nanobodies (sdAbs); (d) naturally occurring and non-naturally occurring, such as fully synthetic antibodies, IgG-Fc-silencing and chimeras; and (e) bispecific and multispecific forms thereof. Immunoglobulin molecules may be derived from any of the commonly known classes including, but not limited to, IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3 and IgG4. The N-terminus of each chain defines a “variable region” of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these regions of the light and heavy chains, respectively. Antibodies may be human, humanized or non-human. Where a specific aspect of the invention disclosed herein refers to or lists an “antibody,” it is intended to refer to any of the full-length antibodies or fragments thereof disclosed herein, unless expressly indicated otherwise.
"인간화" 항체는 비-인간 항체의 CDR 도메인 외부의 일부, 대부분 또는 모든 아미노산이 인간 이뮤노글로불린으로부터 유래된 상응하는 아미노산으로 대체되는 항체를 지칭한다. 인간화 형태의 항체의 한 실시양태에서, CDR 도메인 외부의 아미노산의 일부, 대부분 또는 전부는 인간 이뮤노글로불린으로부터의 아미노산으로 대체된 반면, 하나 이상의 CDR 영역 내의 일부, 대부분 또는 모든 아미노산은 변하지 않는다. 아미노산의 작은 부가, 결실, 삽입, 치환 또는 변형은 특정한 항원과 결합할 수 있는 항체의 능력을 저해하지 않는 한 허용된다. "인간화" 항체는 원래 항체와 유사한 항원 특이성을 유지한다.A “humanized” antibody refers to an antibody in which some, most or all amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of the humanized form of the antibody, some, most or all of the amino acids outside the CDR domains are replaced with amino acids from human immunoglobulin, while some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible so long as they do not interfere with the antibody's ability to bind a particular antigen. A “humanized” antibody retains similar antigenic specificity to the original antibody.
"키메라 항체"는 가변 영역이 하나의 종으로부터 유래되고 불변 영역이 또 다른 종으로부터 유래되는 항체, 예컨대 가변 영역이 마우스 항체로부터 유래되고 불변 영역이 인간 항체로부터 유래되는 항체를 지칭한다.A "chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
"상보성 결정 영역" 또는 "CDR"은 천연 이뮤노글로불린 결합 부위의 가변 영역의 결합 친화도 및 특이성을 함께 규정하는 아미노산 서열을 지칭한다. 항체의 경쇄 및 중쇄 각각에 3개의 CDR이 있다."Complementarity determining region" or "CDR" refers to an amino acid sequence that together defines the binding affinity and specificity of the variable region of a native immunoglobulin binding site. There are three CDRs in each of the light and heavy chains of the antibody.
"프레임워크 영역" 또는 "FR"은 CDR 사이에 스캐폴드로서 작용하는, 전형적으로 보존된 CDR 사이에 개재된 아미노산 서열을 지칭한다.“Framework regions” or “FRs” refer to amino acid sequences intervening between typically conserved CDRs that act as a scaffold between the CDRs.
"불변 영역"은 항체의 특정 클래스에 대해 일치하고 경쇄 및 중쇄의 유형에 의해 규정되는 항체 분자의 일부분을 지칭한다. 예를 들어, 경쇄 불변 영역은 카파 또는 람다 쇄 유형일 수 있고 중쇄 불변 영역은 알파, 델타, 엡실론, 감마 또는 뮤의 5가지 쇄 이소형 중 하나일 수 있다. 이러한 불변 영역은 일반적으로, 항체에 의해 나타나는 이펙터 기능을 부여할 수 있다. 다양한 서브클래스의 중쇄 (예컨대 중쇄의 IgG 서브클래스)는 주로 상이한 이펙터 기능을 담당한다."Constant region" refers to the portion of an antibody molecule that is consistent for a particular class of antibody and is defined by the type of light and heavy chains. For example, the light chain constant region can be of kappa or lambda chain type and the heavy chain constant region can be of one of five chain isotypes: alpha, delta, epsilon, gamma or mu. Such constant regions are generally capable of conferring effector functions exhibited by the antibody. The different subclasses of heavy chains (such as the IgG subclass of heavy chains) are primarily responsible for different effector functions.
본원에 사용된 바와 같은, HER3 표적화제는 예를 들어, 본원에 정의된 바와 같은 항체, 예를 들어 HER3, 예컨대 인간 HER3의 임의의 이용 가능한 에피토프와 높은 면역반응성으로 결합하는 완전한 길이의 항체, 미니바디 또는 나노바디일 수 있다.As used herein, a HER3 targeting agent includes, for example, an antibody as defined herein, e.g., a full-length antibody that binds with high immunoreactivity to any available epitope of HER3, such as human HER3, mini It can be a body or a nanobody.
본원에 사용된 바와 같은, "면역반응성"은 특이적 항원을 인식하고 이와 결합할 수 있는 이뮤노글로불린의 능력의 척도를 지칭한다. "특이적 결합" 또는 "특이적으로 결합하다" 또는 "결합하다"는, 예를 들어 관련 맥락 내에서, 예컨대 포유동물 대상체, 예컨대 인간 환자의 신체 내에서, 다른 항원에 대한 것보다 더 큰 친화도로 항원 또는 항원 내의 에피토프와 결합하는 항체를 지칭한다. 본 발명의 다양한 측면에서 구현되거나 사용될 수 있는 항체는 예를 들어, 약 1x10-8 M 이하의 평형 해리 상수 (KD), 예를 들어 약 1x10-9 M 이하, 약 1x10-10 M 이하, 약 1x10-11 M 이하, 또는 약 1x10-12 M 이하, 전형적으로 비특이적 항원 (예를 들어, BSA, 카세인)에 대한 결합에 대한 그의 KD보다 적어도 100배 낮은 KD로 항원 또는 항원 내의 에피토프와 결합할 수 있다. 해리 상수는 표준 절차를 사용하여 측정될 수 있다. 그러나, 항원 또는 항원 내의 에피토프와 특이적으로 결합하는 항체는 다른 관련 항원, 예를 들어 다른 종, 예컨대 인간 또는 원숭이, 예를 들어 마카카 파스시쿨라리스(Macaca fascicularis ) (시노몰구스, cyno), 판 트로글로디테스(Pan troglodytes) (침팬지, chimp) 또는 칼리트릭스 자쿠스(Callithrix jacchus ) (코먼 마모셋, 마모셋)로부터의 동일한 항원 (상동체)에 대해 교차 반응성을 가질 수 있다.As used herein, "immunoreactivity" refers to a measure of the ability of an immunoglobulin to recognize and bind to a specific antigen. “Specific binding” or “specifically binds” or “binds” means a greater affinity than for another antigen, e.g., within a relevant context, such as within the body of a mammalian subject, such as a human patient. It also refers to an antibody that binds an antigen or an epitope within an antigen. Antibodies that may be implemented or used in various aspects of the invention may have, for example, an equilibrium dissociation constant (K D ) of about 1x10 -8 M or less, eg about 1x10 -9 M or less, about 1x10 -10 M or less, about Binds to an antigen or epitope within an antigen with a K D of 1x10 -11 M or less, or about 1x10 -12 M or less, typically at least 100-fold lower than its K D for binding to a non-specific antigen (eg BSA, casein) can do. Dissociation constants can be determined using standard procedures. However, an antibody that specifically binds an antigen or an epitope within an antigen is another related antigen, for example another species, such as human or monkey, for example Macaca fascicularis ( Macaca fascicularis ) (cynomolgus, cyno) , Pan troglodytes (chimpanzee, chimp) or Callithrix jacchus ) (common marmoset, marmoset) to the same antigen (homolog).
"에피토프"는 표적화제, 예컨대 항체, 항체 단편, Fab 단편 또는 앱타머에 의해 인식되고 이에 의해 결합될 수 있는 표적 분자 부위 (예를 들어, 항원의 적어도 일부분)를 지칭한다. 예를 들어, 단백질 항원의 경우, 이는 항체에 의해 결합되는 단백질 영역 (즉, 아미노산, 및 특히 그의 측쇄)을 지칭할 수 있다. 중첩 에피토프는 적어도 1개 내지 5개의 공통 아미노산 잔기를 포함한다. 항체의 에피토프를 확인하는 방법은 관련 기술분야의 통상의 기술자에게 공지되어 있고, 예를 들어 문헌 [Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988)]에 기재된 것을 포함한다.“Epitope” refers to a site on a target molecule (eg, at least a portion of an antigen) that can be recognized by and bound by a targeting agent, such as an antibody, antibody fragment, Fab fragment or aptamer. For example, in the case of a protein antigen, this can refer to the protein region (ie amino acids, and particularly side chains thereof) bound by the antibody. Overlapping epitopes contain at least 1 to 5 common amino acid residues. Methods for identifying epitopes of antibodies are known to those skilled in the art and include, for example, those described in Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Ed Harlow and David Lane (1988). .
본원에 개시된 바와 같은 방사성표지된 HER3 표적화제는 HER3-양성, 즉 HER3-발현 암 또는 전암성 병태, 예컨대 고형 종양을 치료하는데 사용될 수 있다. "HER3-양성" 또는 "HER3-발현"은 환자 내의, 예컨대 종양 내의 암 세포의 적어도 일부가 HER3를 발현하거나 과다발현한다는 것을 의미한다.Radiolabeled HER3 targeting agents as disclosed herein can be used to treat HER3-positive, ie, HER3-expressing cancers or precancerous conditions, such as solid tumors. “HER3-positive” or “HER3-expressing” means that at least some of the cancer cells in a patient, such as in a tumor, express or overexpress HER3.
본원에 사용된 바와 같은, 용어 "증식성 장애" 및 "암"은 상호 교환 가능하게 사용될 수 있고 고형 암 (예를 들어, 종양) 및 전암성 증식성 장애를 포함할 수 있으며 이에 제한되지 않는다. 본 발명의 다양한 측면에 의해 치료될 수 있고 HER3-양성일 수 있는 "고형 암"은 골암, 췌장암, 피부암, 두경부암, 피부 또는 안구내 악성 흑색종, 자궁암, 난소암, 전립선암, 직장암, 항문암, 위암, 고환암, 자궁암, 나팔관암, 자궁내막암, 자궁경부 암종, 질 암종, 외음부 암종, 식도암, 소장암, 내분비계암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 소아 종양, 방광암, 신장 또는 요관암, 신우 암종, 중추 신경계 (CNS)의 신생물, 원발성 CNS 림프종, 종양 혈관신생, 척추축 종양, 뇌간 신경교종, 뇌하수체 선종, 카포시 육종, 유표피암, 편평 세포암, 석면에 의해 유발된 암을 포함한 환경적으로 유발된 암을 포함하며, 이에 제한되지 않는다. 이러한 암은 전이성 또는 비전이성일 수 있다.As used herein, the terms “proliferative disorder” and “cancer” may be used interchangeably and include, but are not limited to, solid cancers (eg, tumors) and precancerous proliferative disorders. "Solid cancers" that may be HER3-positive and which may be treated by various aspects of the present invention include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, prostate cancer, rectal cancer, anal cancer. , gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, children tumor, bladder cancer, kidney or ureter cancer, renal pelvic carcinoma, neoplasia of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermal cancer, squamous cell carcinoma, cancers caused by the environment including, but not limited to, cancers caused by asbestos. These cancers may be metastatic or non-metastatic.
특정 측면에 따르면, 본 발명의 다양한 측면에 의해 치료될 수 있고 HER3-양성일 수 있는 고형 암은 유방암, 예컨대 타목시펜-감수성 유방암, 타목시펜-저항성 유방암, HER2-양성 유방암, HER2-음성 유방암 또는 삼중 음성 유방암 (TNBC), 위암, 방광암, 자궁경부암, 자궁내막암, 피부암, 예컨대 흑색종, 위암, 고환암, 식도암, 세기관지폐포암, 전립선암, 예컨대 거세 저항성 전립선암 (CRPC), 결장직장암, 난소암, 자궁경부 유표피암, 간암, 예컨대 간세포 암종 (HCC) 또는 담관암종, 췌장암, 폐암, 예컨대 비소세포 폐 암종 (NSCLC), 신장암, 두경부암, 예컨대 두경부 편평 세포암, 암종, 육종, 또는 그의 임의의 조합일 수 있다. 이러한 암은 전이성 또는 비전이성일 수 있다.According to certain aspects, the solid cancer that can be treated by various aspects of the present invention and which can be HER3-positive is breast cancer, such as tamoxifen-sensitive breast cancer, tamoxifen-resistant breast cancer, HER2-positive breast cancer, HER2-negative breast cancer or triple negative breast cancer. (TNBC), stomach cancer, bladder cancer, cervical cancer, endometrial cancer, skin cancer such as melanoma, stomach cancer, testicular cancer, esophageal cancer, bronchioloalveolar cancer, prostate cancer such as castration-resistant prostate cancer (CRPC), colorectal cancer, ovarian cancer, uterus Cervical epidermal cancer, liver cancer such as hepatocellular carcinoma (HCC) or cholangiocarcinoma, pancreatic cancer, lung cancer such as non-small cell lung carcinoma (NSCLC), kidney cancer, head and neck cancer such as head and neck squamous cell carcinoma, carcinoma, sarcoma, or any combination thereof. can be These cancers may be metastatic or non-metastatic.
특정 측면에 따르면, HER3 표적화제는 방사성동위원소/방사성핵종으로 표지될 수 있다. 본원에 사용된 바와 같은, "방사성동위원소" 또는 "방사성핵종"은 알파 방출 동위원소, 베타 방출 동위원소 및/또는 감마 방출 동위원소일 수 있다. HER3 표적화제 또는 다른 표적화제를 표지하는데 사용될 수 있는 예시적인 방사성핵종은 하기를 포함한다: 131I, 125I, 123I, 90Y, 177Lu, 186Re, 188Re, 89Sr, 153Sm, 32P, 225Ac, 213Bi, 213Po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137Cs, 212Pb, 103Pd, 134Ce, 43Sc, 44Sc, 47Sc, 55Co, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 66Ga, 67Ga, 68Ga, 82Rb, 86Y, 87Y, 89Zr, 97Ru, 105Rh, 109Pd, 111In, 117mSn, 149Pm, 149Tb, 153Sm, 177Lu, 199Au, 201Tl, 및 203Pb. 단백질, 예컨대 항체 또는 항체 단편에 방사성동위원소를 부착시키는 (즉, 방사성동위원소로 단백질을 "표지화하는") 방법은 관련 기술분야에 널리 공지되어 있다. 표지화하기 위한 구체적 조성물 및 방법은, 예를 들어, 국제 공개 번호 WO 2017/155937 및 2019년 12월 9일에 출원된 미국 가출원 번호 63/042,651 및 2020년 11월 30일에 "부위-특이적 방사성접합체의 제조를 위한 조성물 및 방법"이란 발명의 명칭으로 출원된 미국 가출원 번호 63/119,093에 기재되어 있으며, 이들 각각은 본원에 참조로 포함된다. 하나 이상의 시스테인 잔기를 함유하는 HER3 표적화제 및 다른 표적화제, 예컨대 펩티드, 단백질, 항체 및 단백질 항체 모방체는 예를 들어, 방사성핵종 표지화를 위한 "단백질 또는 항체의 부위-선택적 바이오접합을 위한 시약"이란 발명의 명칭의 미국 특허 11,000,604에 개시된 킬레이터-보유, 예컨대 DOTA-보유, 안정한 링커 중 임의의 것과 화학적으로 접합될 수 있다.According to certain aspects, the HER3 targeting agent may be labeled with a radioisotope/radionuclide. As used herein, a “radioisotope” or “radionuclide” may be an alpha emitting isotope, a beta emitting isotope, and/or a gamma emitting isotope. Exemplary radionuclides that can be used to label HER3 targeting agents or other targeting agents include: 131 I, 125 I, 123 I, 90 Y, 177 Lu, 186 Re, 188 Re, 89 Sr, 153 Sm, 32 P, 225 Ac, 213 Bi, 213 Po, 211 At, 212 Bi, 213 Bi, 223 Ra, 227 Th, 149 Tb, 137 Cs, 212 Pb, 103 Pd, 134 Ce, 43 Sc, 44 Sc, 47 Sc , 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 97 Ru , 105 Rh , 109 Pd, 111 In, 117m Sn, 149 Pm, 149 Tb, 153 Sm, 177 Lu, 199 Au, 201 Tl, and 203 Pb. Methods for attaching radioisotopes to proteins, such as antibodies or antibody fragments (ie, "labeling" proteins with radioisotopes) are well known in the art. Specific compositions and methods for labeling are described, for example, in International Publication No. WO 2017/155937 and US Provisional Application No. 63/042,651 filed on December 9, 2019 and on November 30, 2020, "Site-specific radioactivity "Compositions and Methods for the Preparation of Conjugates" are disclosed in US Provisional Application Serial No. 63/119,093, filed in the name of the invention, each of which is incorporated herein by reference. HER3 targeting agents and other targeting agents containing one or more cysteine residues, such as peptides, proteins, antibodies and protein antibody mimetics, are "reagents for site-selective bioconjugation of proteins or antibodies", for example for radionuclide labeling. It may be chemically conjugated with any of the chelator-containing, such as DOTA-containing, stable linkers disclosed in U.S. Patent 11,000,604 entitled Iran Invention.
특정 측면에 따르면, HER3 표적화제는 225Ac로 방사성표지된 ("225Ac-표지된") 항체, 펩티드 또는 소분자일 수 있으며, 유효량은 예를 들어, 50.0 μCi/kg 이하 (즉, 대상체에게 투여된 225Ac의 양이 대상체의 체중 킬로그램당 50.0 μCi 미만의 방사선 용량을 전달하는 경우)일 수 있다. 특정 측면에 따르면, HER3 표적화제가 225Ac-표지된 경우, 유효량은 50 μCi/kg, 40 μCi/kg, 30 μCi/kg, 20 μCi/kg, 10 μCi/kg, 5 μCi/kg, 4 μCi/kg, 3 μCi/kg, 2 μCi/kg, 1 μCi/kg, 또는 0.5 μCi/kg 미만이다. 특정 측면에 따르면, HER3 표적화제가 225Ac-표지된 경우, 유효량은 적어도 0.05 μCi/kg, 또는 0.1 μCi/kg, 0.2 μCi/kg, 0.3 μCi/kg, 0.4 μCi/kg, 0.5 μCi/kg, 1 μCi/kg, 2 μCi/kg, 3 μCi/kg, 4 μCi/kg, 5 μCi/kg, 6 μCi/kg, 7 μCi/kg, 8 μCi/kg, 9 μCi/kg, 10 μCi/kg, 12 μCi/kg, 14 μCi/kg, 15 μCi/kg, 16 μCi/kg, 18 μCi/kg, 20 μCi/kg, 30 μCi/kg, 또는 40 μCi/kg이다. 특정 측면에 따르면, 225Ac-표지된 항체는 본원에 기재된 바와 같은 상한 및 하한의 임의의 조합을 포함하는 용량, 예컨대 적어도 0.1 μCi/kg 내지 5 μCi/kg 이하, 또는 적어도 5 μCi/kg 내지 20 μCi/kg 이하로 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be an antibody, peptide or small molecule that is radiolabeled with 225 Ac (" 225 Ac-labeled"), and the effective amount is, for example, 50.0 μCi/kg or less (i.e., administered to a subject where the amount of 225 Ac delivered delivers a radiation dose of less than 50.0 μCi per kilogram of the subject's body weight). According to certain aspects, when the HER3 targeting agent is 225 Ac-labeled, the effective amount is 50 μCi/kg, 40 μCi/kg, 30 μCi/kg, 20 μCi/kg, 10 μCi/kg, 5 μCi/kg, 4 μCi /kg, 3 μCi/kg, 2 μCi/kg, 1 μCi/kg, or less than 0.5 μCi/kg. According to certain aspects, when the HER3 targeting agent is 225 Ac-labeled, the effective amount is at least 0.05 μCi/kg, or 0.1 μCi/kg, 0.2 μCi/kg, 0.3 μCi/kg, 0.4 μCi/kg, 0.5 μCi/kg, 1 μCi/kg, 2 μCi/kg, 3 μCi/kg, 4 μCi/kg, 5 μCi/kg, 6 μCi/kg, 7 μCi/kg, 8 μCi/kg, 9 μCi/kg, 10 μCi/kg, 12 μCi/kg, 14 μCi/kg, 15 μCi/kg, 16 μCi/kg, 18 μCi/kg, 20 μCi/kg, 30 μCi/kg, or 40 μCi/kg. According to certain aspects, the 225 Ac-labeled antibody is administered at a dose comprising any combination of the upper and lower limits as described herein, such as from at least 0.1 μCi/kg up to 5 μCi/kg, or from at least 5 μCi/kg to 20 μCi/kg. It can be administered in μCi/kg or less.
특정 측면에 따르면, HER3 표적화제는 225Ac-표지되는 항체, 펩티드 또는 소분자일 수 있고, 유효량은 2 mCi 이하일 수 있다 (즉, 여기서 225Ac는 체중에 기반하지 않은 투여량으로 대상체에게 투여된다). 특정 측면에 따르면, 225Ac-표지된 HER3 표적화제의 유효 용량은 1 mCi 미만, 예컨대 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 μCi, 80 μCi, 70 μCi, 60 μCi, 50 μCi, 40 μCi, 30 μCi, 20 μCi, 10 μCi, 또는 5 μCi일 수 있다. 225Ac-표지된 HER3 표적화제의 유효량은 적어도 2 μCi, 예컨대 적어도 5 μCi, 10 μCi, 20 μCi, 30 μCi, 40 μCi, 50 μCi, 60 μCi, 70 μCi, 80 μCi, 90 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, 1 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, 또는 1.5 mCi일 수 있다. 특정 측면에 따르면, 225Ac-표지된 HER3 표적화제는 본원에 기재된 바와 같은 상한 및 하한의 임의의 조합을 포함하는 용량, 예컨데, 적어도 2 μCi 내지 1 mCi 이하, 또는 적어도 2 μCi 내지 250 μCi 이하, 또는 75 μCi 내지 400 μCi 이하로 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be a 225 Ac-labeled antibody, peptide or small molecule, and the effective amount can be 2 mCi or less (i.e., wherein the 225 Ac is administered to the subject in a non-weight based dose). . According to certain aspects, the effective dose of the 225 Ac-labeled HER3 targeting agent is less than 1 mCi, such as 0.9 mCi, 0.8 mCi, 0.7 mCi, 0.6 mCi, 0.5 mCi, 0.4 mCi, 0.3 mCi, 0.2 mCi, 0.1 mCi, 90 μCi, 80 μCi, 70 μCi, 60 μCi, 50 μCi, 40 μCi, 30 μCi, 20 μCi, 10 μCi, or 5 μCi. An effective amount of 225 Ac-labeled HER3 targeting agent is at least 2 μCi, such as at least 5 μCi, 10 μCi, 20 μCi, 30 μCi, 40 μCi, 50 μCi, 60 μCi, 70 μCi, 80 μCi, 90 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, 1 mCi, 1.1 mCi, 1.2 mCi, 1.3 mCi, 1.4 mCi, or 1.5 mCi. According to certain aspects, the 225 Ac-labeled HER3 targeting agent is at a dose comprising any combination of the upper and lower limits as described herein, e.g., at least 2 μCi up to 1 mCi, or at least 2 μCi up to 250 μCi; or between 75 μCi and up to 400 μCi.
특정 측면에 따르면, 225Ac-표지된 HER3 표적화제는 12 Gy 미만, 또는 8 Gy 미만, 또는 6 Gy 미만, 또는 4 Gy 미만, 또는 2 Gy 미만, 예컨대 2 Gy 내지 8 Gy의 용량을 대상체에게, 예컨대 주로 표적화된 고형 종양에 전달하는 단일 용량을 포함한다.According to certain aspects, the 225 Ac-labeled HER3 targeting agent is administered to a subject at a dose of less than 12 Gy, or less than 8 Gy, or less than 6 Gy, or less than 4 Gy, or less than 2 Gy, such as from 2 Gy to 8 Gy; eg single doses delivered primarily to targeted solid tumors.
특정 측면에 따르면, HER3 표적화제는 177Lu로 방사성표지된 ("177Lu-표지된") 항체, 펩티드, 또는 소분자일 수 있으며, 유효량은 예를 들어, 1 mCi/kg 미만일 수 있다 (즉, 대상체에게 투여된 177Lu-표지된 항체의 양이 대상체의 체중 킬로그램당 1000 μCi 미만의 방사선 용량을 전달하는 경우). 특정 측면에 따르면, 항체가 177Lu-표지된 경우, 유효량은 900 μCi/kg, 800 μCi/kg, 700 μCi/kg, 600 μCi/kg, 500 μCi/kg, 400 μCi/kg, 300 μCi/kg, 200 μCi/kg, 150 μCi/kg, 100 μCi/kg, 80 μCi/kg, 60 μCi/kg, 50 μCi/kg, 40 μCi/kg, 30 μCi/kg, 20 μCi/kg, 10 μCi/kg, 5 μCi/kg, 또는 1 μCi/kg 미만이다. 특정 측면에 따르면, 177Lu-표지된 항체의 유효량은 적어도 1 μCi/kg, 2.5 μCi/kg, 5 μCi/kg, 10 μCi/kg, 20 μCi/kg, 30 μCi/kg, 40 μCi/kg, 50 μCi/kg, 60 μCi/kg, 70 μCi/kg, 80 μCi/kg, 90 μCi/kg, 100 μCi/kg, 150 μCi/kg, 200 μCi/kg, 250 μCi/kg, 300 μCi/kg, 350 μCi/kg, 400 μCi/kg 또는 450 μCi/kg이다. 특정 측면에 따르면, 177Lu-표지된 항체는 본원에 기재된 바와 같은 상한 및 하한의 임의의 조합을 포함하는 용량, 예컨대 적어도 5 mCi/kg 내지 50 μCi/kg 이하, 또는 적어도 50 mCi/kg 내지 500 μCi/kg 이하로 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be an antibody, peptide, or small molecule that has been radiolabeled with 177 Lu (“ 177 Lu-labeled”), and the effective amount can be, for example, less than 1 mCi/kg (i.e., where the amount of 177 Lu-labeled antibody administered to the subject delivers a radiation dose of less than 1000 μCi per kilogram of the subject's body weight). According to certain aspects, when the antibody is 177 Lu-labeled, the effective amount is 900 μCi/kg, 800 μCi/kg, 700 μCi/kg, 600 μCi/kg, 500 μCi/kg, 400 μCi/kg, 300 μCi/kg , 200 μCi/kg, 150 μCi/kg, 100 μCi/kg, 80 μCi/kg, 60 μCi/kg, 50 μCi/kg, 40 μCi/kg, 30 μCi/kg, 20 μCi/kg, 10 μCi/kg , 5 μCi/kg, or less than 1 μCi/kg. According to certain aspects, the effective amount of the 177 Lu-labeled antibody is at least 1 μCi/kg, 2.5 μCi/kg, 5 μCi/kg, 10 μCi/kg, 20 μCi/kg, 30 μCi/kg, 40 μCi/kg, 50 μCi/kg, 60 μCi/kg, 70 μCi/kg, 80 μCi/kg, 90 μCi/kg, 100 μCi/kg, 150 μCi/kg, 200 μCi/kg, 250 μCi/kg, 300 μCi/kg, 350 μCi/kg, 400 μCi/kg or 450 μCi/kg. According to certain aspects, the 177 Lu-labeled antibody is administered at a dose comprising any combination of the upper and lower limits as described herein, such as from at least 5 mCi/kg up to 50 μCi/kg, or from at least 50 mCi/kg to 500 μCi/kg. It can be administered in μCi/kg or less.
특정 측면에 따르면, HER3 표적화제는 177Lu-표지된 항체일 수 있고, 유효량은 45 mCi 미만, 예컨대 40 mCi, 30 mCi, 20 mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, 800 μCi, 600 μCi, 400 μCi, 200 μCi, 100 μCi, 또는 50 μCi 미만일 수 있다. 177Lu-표지된 HER3 표적화제의 유효량은 적어도 10 μCi, 예컨대 적어도 25 μCi, 50 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, 30 mCi일 수 있다. 특정 측면에 따르면, 177Lu-표지된 항체는 본원에 기재된 바와 같은 상한 및 하한의 임의의 조합을 포함하는 용량, 예컨대 적어도 10 mCi 내지 30 mCi 이하, 또는 적어도 100 μCi 내지 3 mCi 이하, 또는 3 mCi 내지 30 mCi 이하로 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be a 177 Lu-labeled antibody, and the effective amount is less than 45 mCi, such as 40 mCi, 30 mCi, 20 mCi, 10 mCi, 5 mCi, 3.0 mCi, 2.0 mCi, 1.0 mCi, less than 800 μCi, 600 μCi, 400 μCi, 200 μCi, 100 μCi, or 50 μCi. An effective amount of 177 Lu-labeled HER3 targeting agent is at least 10 μCi, such as at least 25 μCi, 50 μCi, 100 μCi, 200 μCi, 300 μCi, 400 μCi, 500 μCi, 600 μCi, 700 μCi, 800 μCi, 900 μCi, It may be 1 mCi, 2 mCi, 3 mCi, 4 mCi, 5 mCi, 10 mCi, 15 mCi, 20 mCi, 25 mCi, or 30 mCi. According to certain aspects, the 177 Lu-labeled antibody is administered at a dose comprising any combination of the upper and lower limits as described herein, such as from at least 10 mCi up to 30 mCi, or from at least 100 μCi up to 3 mCi, or up to 3 mCi to 30 mCi or less.
특정 측면에 따르면, HER3 표적화제는 131I로 방사성표지된 ("131I-표지된") 항체, 펩티드, 또는 소분자일 수 있고, 유효량은 예를 들어, 1200 mCi 미만일 수 있다 (즉, 대상체에게 투여된 131I의 양이 체중에 기반하지 않은 용량으로 1200 mCi 미만의 총 체내 방사선 용량을 전달하는 경우). 특정 측면에 따르면, 131I-표지된 표적화제의 유효량은 1100 mCi 미만, 1000 mCi 미만, 900 mCi 미만, 800 mCi 미만, 700 mCi 미만, 600 mCi 미만, 500 mCi 미만, 400 mCi 미만, 300 mCi 미만, 200 mCi 미만, 150 mCi 미만 또는 100 mCi 미만일 수 있다. 특정 측면에 따르면, 131I-표지된 표적화제의 유효량은 200 mCi 미만, 예컨대 190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, 110 mCi, 100 mCi, 90 mCi, 80 mCi, 70 mCi, 60 mCi, 또는 50 mCi 미만일 수 있다. 특정 측면에 따르면, 131I-표지된 표적화제의 유효량은 적어도 1 mCi, 예컨대 적어도 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi, 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi, 190 mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, 500 mCi일 수 있다. 특정 측면에 따르면, 131I-표지된 표적화제는 본원에 기재된 바와 같은 상한 및 하한의 임의의 조합을 포함하는 용량, 예컨대 적어도 1 mCi 내지 100 mCi 이하, 또는 적어도 10 mCi 내지 200 mCi 이하로 투여될 수 있다.According to certain aspects, the HER3 targeting agent can be an antibody, peptide, or small molecule that has been radiolabeled with 131 I (" 131 I-labeled"), and the effective amount can be, for example, less than 1200 mCi (i.e., to a subject if the amount of 131 I administered delivers a total body radiation dose of less than 1200 mCi in a dose that is not based on body weight). According to certain aspects, the effective amount of the 131 I-labeled targeting agent is less than 1100 mCi, less than 1000 mCi, less than 900 mCi, less than 800 mCi, less than 700 mCi, less than 600 mCi, less than 500 mCi, less than 400 mCi, less than 300 mCi. , less than 200 mCi, less than 150 mCi or less than 100 mCi. According to certain aspects, the effective amount of the 131 I-labeled targeting agent is less than 200 mCi, such as 190 mCi, 180 mCi, 170 mCi, 160 mCi, 150 mCi, 140 mCi, 130 mCi, 120 mCi, 110 mCi, 100 mCi, It may be less than 90 mCi, 80 mCi, 70 mCi, 60 mCi, or 50 mCi. According to certain aspects, the effective amount of the 131 I-labeled targeting agent is at least 1 mCi, such as at least 2 mCi, 3 mCi, 4 mCi, 5 mCi, 6 mCi, 7 mCi, 8 mCi, 9 mCi, 10 mCi, 20 mCi , 30 mCi, 40 mCi, 50 mCi, 60 mCi, 70 mCi, 80 mCi, 90 mCi, 100 mCi, 110 mCi, 120 mCi, 130 mCi, 140 mCi, 150 mCi, 160 mCi, 170 mCi, 180 mCi , 190 It may be mCi, 200 mCi, 250 mCi, 300 mCi, 350 mCi, 400 mCi, 450 mCi, or 500 mCi. According to certain aspects, the 131 I-labeled targeting agent can be administered at a dose comprising any combination of the upper and lower limits as described herein, such as between at least 1 mCi and up to 100 mCi, or between at least 10 mCi and up to 200 mCi. can
선택 방사성핵종이 본원에 상세히 논의되긴 했지만, 본원에 개시된 임의의 것과 같은 임의의 방사성핵종이 방사성표지된 표적화제, 예컨대 본원에 개시된 바와 같은 방사성표지된 HER3 표적화제에 사용될 수 있다.Although selected radionuclides are discussed in detail herein, any radionuclide, such as any disclosed herein, may be used with a radiolabeled targeting agent, such as a radiolabeled HER3 targeting agent as disclosed herein.
본원에 사용된 바와 같은, HER3 표적화제를 포함하는 조성물은 방사성핵종 표지된 부분 및 비표지된 부분 모두를 포함하는 "환자 특이적 조성물"을 포함한다. 본 발명의 특정 측면에 따르면, HER3 표적화제가 방사성동위원소로 표지되는 경우, 환자에게 투여되는 표적화제 (항체, 항체 단편 등)의 대다수는 비표지된 표적화제로 이루어질 수 있고, 소수는 방사성표지된 표적화제이다. 표지된 표적화제 대 비표지된 표적화제의 비율은 공지된 방법을 사용하여 조정될 수 있다. 본 발명의 특정 측면에 따르면, 환자 특이적 조성물은 약 0.01:10 내지 1:1, 예컨대 0.1:10 내지 1:1 표지:비표지의 표지된 HER3 표적화제:비표지된 HER3 표적화제의 비율로 HER3 표적화제를 포함할 수 있다.As used herein, a composition comprising a HER3 targeting agent includes a "patient specific composition" comprising both a radionuclide labeled and unlabeled portion. According to certain aspects of the present invention, when the HER3 targeting agent is labeled with a radioisotope, the majority of the targeting agent (antibody, antibody fragment, etc.) administered to the patient may consist of unlabeled targeting agent, and a minority may consist of radiolabeled targeting agent. It is a targeting agent. The ratio of labeled to unlabeled targeting agent can be adjusted using known methods. According to certain aspects of the present invention, the patient specific composition comprises a ratio of about 0.01:10 to 1:1, such as 0.1:10 to 1:1 labeled:unlabeled labeled HER3-targeting agent:unlabeled HER3-targeting agent. HER3 targeting agents.
본 발명의 특정 측면에 따르면, HER3 표적화제는 최대 100 mg, 예를 들어 최대 60 mg, 예컨대 5 mg 내지 45 mg의 총 단백질 또는 펩티드 양, 또는 0.001 mg/kg (환자 체중) 내지 3.0 mg/kg (환자 체중), 예컨대 0.005 mg/kg (환자 체중) 내지 2.0 mg/kg (환자 체중), 또는 0.01 mg/kg (환자 체중) 내지 1 mg/kg (환자 체중), 또는 0.1 mg/kg (환자 체중) 내지 0.6 mg/kg (환자 체중), 또는 0.3 mg/kg (환자 체중), 또는 0.4 mg/kg (환자 체중), 또는 0.5 mg/kg (환자 체중), 또는 0.6 mg/kg (환자 체중)의 총 단백질 양으로 제공될 수 있다.According to certain aspects of the invention, the HER3 targeting agent is in a total protein or peptide amount of at most 100 mg, eg at most 60 mg, such as 5 mg to 45 mg, or 0.001 mg/kg (patient body weight) to 3.0 mg/kg (patient body weight), such as 0.005 mg/kg (patient body weight) to 2.0 mg/kg (patient body weight), or 0.01 mg/kg (patient body weight) to 1 mg/kg (patient body weight), or 0.1 mg/kg (patient body weight) body weight) to 0.6 mg/kg (patient body weight), or 0.3 mg/kg (patient body weight), or 0.4 mg/kg (patient body weight), or 0.5 mg/kg (patient body weight), or 0.6 mg/kg (patient body weight) ) can be provided with a total protein amount of
항체 또는 다른 표적화제의 방사성표지된 분획과 비표지된 분획의 본 발명의 조합은 조성물이 특이적 환자에게 맞춤화될 수 있게 하며, 여기서 항체 또는 다른 표적화제의 방사선 용량 및 단백질 용량 각각은 적어도 하나의 환자-특이적 파라미터에 기초하여 그 환자에게 개인 맞춤형이 된다. 이와 같이, 조성물의 각각의 바이알은 특이적 환자를 위해 제조될 수 있으며, 여기서 바이알의 전체 함량은 단일 용량으로 그 환자에게 전달된다. 치료 요법이 다수의 용량을 요구하는 경우, 각각의 용량은 바이알 내에서 환자 특이적 용량으로서 제형화되어 "단일 용량"으로서 환자에게 투여될 수 있다 (즉, 바이알의 전체 내용물이 한 번에 투여된다). 후속 용량은 유사한 방식으로 제형화될 수 있으며, 이에 따라 요법 내의 각각의 용량은 단일 용량 용기에 환자 특이적 용량을 제공한다. 이러한 조성물의 장점 중 한 가지는 의료진에 의해 폐기되거나 취급될 필요가 있는 잔여 방사선이 없을 것이라는 점, 예를 들어, 환자에 대한 용량을 얻기 위한 희석 또는 다른 조작이 없을 것이라는 점이다. 단일 용량 용기에 제공되는 경우, 그 용기는 환자에게 주입하기 위해 주입 튜빙 세트에 인라인으로 간단히 배치될 수 있다. 더욱이, 용적을 표준화하여 의료 오류 (즉, 조성물의 전체 용적이 1회의 주입으로 투여되어야 하기 때문에, 부정확한 용량의 전달)의 가능성을 크게 감소시킬 수 있다.The present combination of radiolabeled and unlabeled fractions of an antibody or other targeting agent allows compositions to be tailored to a specific patient, wherein each of the protein dose and the radiation dose of the antibody or other targeting agent is at least one It is personalized to that patient based on patient-specific parameters. As such, each vial of the composition can be prepared for a specific patient, wherein the entire contents of the vial are delivered to that patient in a single dose. When a treatment regimen calls for multiple doses, each dose may be formulated as a patient specific dose in a vial and administered to the patient as a “single dose” (i.e., the entire contents of the vial are administered at one time). ). Subsequent doses may be formulated in a similar manner, such that each dose in the regimen provides a patient specific dose in a single dose container. One of the advantages of such a composition is that there will be no residual radiation that needs to be discarded or handled by medical personnel, eg, no dilution or other manipulations to obtain a dose for a patient. When provided in a single dose container, the container can simply be placed in-line with a set of infusion tubing for infusion into a patient. Furthermore, volume can be standardized to greatly reduce the possibility of medical error (ie, delivery of an incorrect dose, since the entire volume of the composition must be administered in one infusion).
따라서, 특정 측면에 따르면, HER3 표적화제는 특이적 환자에게 맞춤화될 수 있는 단일 용량 조성물로서 제공될 수 있으며, 여기서 조성물 중의 방사성표지된 및 비표지된 HER3 표적화제의 양은 환자 체중, 연령, 성별, 질환 상태 및/또는 건강 상태 중 하나 이상, 예컨대 국제 공개 번호 WO 2016/187514 및 미국 특허 번호 10,736,975에 상세히 기재된 것에 따라 달라질 수 있다. 특정 측면에 따르면, HER3 표적화제는 다중 용량 치료제로서 제공될 수 있으며, 여기서 치료 요법 중의 각각의 용량은 환자 특이적 조성물로서 제공된다. 환자-특이적 조성물은 방사성표지된 및 비표지된 HER3 표적화제를 포함하며, 여기서 각각의 양은 환자 체중, 연령, 성별, 질환 상태 및/또는 건강 상태 중 하나 이상에 따라 달라진다.Thus, according to certain aspects, the HER3 targeting agent can be provided as a single dose composition that can be tailored to a specific patient, wherein the amount of radiolabeled and unlabeled HER3 targeting agent in the composition is dependent on the patient's weight, age, sex, One or more of the disease state and/or health condition, such as those detailed in International Publication No. WO 2016/187514 and US Patent No. 10,736,975. According to certain aspects, the HER3 targeting agent may be provided as a multi-dose therapeutic, wherein each dose in the treatment regimen is provided as a patient specific composition. The patient-specific composition comprises radiolabeled and unlabeled HER3 targeting agents, wherein the amount of each varies according to one or more of the patient's weight, age, sex, disease state, and/or health condition.
본원에 사용된 바와 같은, 용어 "대상체" 및 "환자"는 상호 교환 가능하며, 포유동물, 예컨대 인간, 비인간 영장류, 개, 고양이, 말, 양, 염소, 소, 토끼, 돼지, 래트 및 마우스를 포함하며 이에 제한되지 않는다. 대상체가 인간인 경우, 그러한 대상체는 임의의 연령일 수 있다. 예를 들어, 대상체는 60세 이상, 65세 이상, 70세 이상, 75세 이상, 80세 이상, 85세 이상 또는 90세 이상일 수 있다. 대안적으로, 대상체는 50세 이하, 45세 이하, 40세 이하, 35세 이하, 30세 이하, 25세 이하 또는 20세 이하일 수 있다. 암에 걸린 인간 대상체의 경우, 그러한 대상체는 새로 진단되거나, 재발성 및/또는 불응성이거나, 또는 관해 상태에 있을 수 있다.As used herein, the terms “subject” and “patient” are interchangeable and refer to mammals such as humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, rats and mice. Including, but not limited to. Where the subject is a human, such subject may be of any age. For example, the subject may be 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, 80 years of age or older, 85 years of age or older, or 90 years of age or older. Alternatively, the subject may be under 50 years old, under 45 years old, under 40 years old, under 35 years old, under 30 years old, under 25 years old, or under 20 years old. In the case of a human subject with cancer, such subject may be newly diagnosed, relapsed and/or refractory, or in remission.
본원에 사용된 바와 같은, 암에 걸린 대상체를 "치료하는 것"은 (i) 암의 진행을 늦추거나, 중지시키거나 또는 역전시키는 것, (ii) 암 증상의 진행을 늦추거나, 중지시키거나 또는 역전시키는 것, (iii) 암 재발의 가능성을 감소시키는 것, 및/또는 (iv) 암 증상의 재발 가능성을 감소시키는 것을 포함하며 이에 제한되지 않는다. 특정의 바람직한 측면에 따르면, 암에 걸린 대상체를 치료하는 것은 (i) 이상적으로는 암을 제거하는 지점까지 암의 진행을 역전시키는 것, 및/또는 (ii) 이상적으로는 증상을 제거하는 지점까지 암 증상의 진행을 역전시키는 것, 및/또는 (iii) 재발 가능성을 감소시키거나 제거하는 것 (즉, 이상적으로는 남아 있는 임의의 암 세포의 파괴를 초래하는 통합)을 의미한다.As used herein, "treating" a subject suffering from cancer refers to (i) slowing, stopping or reversing the progression of cancer, (ii) slowing, stopping or reversing the progression of symptoms of cancer. or reversing, (iii) reducing the likelihood of cancer recurrence, and/or (iv) reducing the likelihood of cancer symptoms recurring. According to certain preferred aspects, treating a subject suffering from cancer (i) reverses the progression of the cancer, ideally to the point of eliminating the cancer, and/or (ii) ideally to the point of eliminating the symptoms. reversing the progression of cancer symptoms, and/or (iii) reducing or eliminating the likelihood of recurrence (i.e., integration ideally resulting in destruction of any remaining cancer cells).
본 발명의 맥락에서 "화학요법제"는 성장하는 세포를 억제하거나 사멸시키고 암 치료에 사용될 수 있거나 사용이 승인된 화학적 화합물을 의미한다. 예시적인 화학요법제는 핵 분열 또는 세포 혈장 분열 수준에서 세포 분열을 방지, 교란, 방해 또는 지연시키는 세포증식 억제제를 포함한다. 이러한 작용제, 예컨대 탁산, 특히 도세탁셀 또는 파클리탁셀, 및 에포틸론, 특히 에포틸론 A, B, C, D, E 및 F는 미세소관을 안정화시킬 수 있거나, 또는 예컨대 빈카 알칼로이드, 특히 빈블라스틴, 빈크리스틴, 빈데신, 빈플루닌 및 비노렐빈은 미세소관을 불안정하게 할 수 있다. 예시적인 화학요법제, 예컨대 테모졸로미드, 시스플라틴 및/또는 플루오로우라실은 또한 방사성표지된 HER3과 상승작용할 수 있는 방사선증감제를 포함한다.A “chemotherapeutic agent” in the context of the present invention means a chemical compound that inhibits or kills growing cells and can be used or is approved for use in the treatment of cancer. Exemplary chemotherapeutic agents include cytostatic agents that prevent, disrupt, hinder or retard cell division at the level of nuclear division or cell plasma division. Such agents, such as taxanes, especially docetaxel or paclitaxel, and epothilones, especially epothilones A, B, C, D, E and F, can stabilize microtubules, or, such as vinca alkaloids, especially vinblastine, vincristine , Vindesine, vinflunine and vinorelbine can destabilize microtubules. Exemplary chemotherapeutic agents such as temozolomide, cisplatin and/or fluorouracil also include radiosensitizers that can synergize with radiolabeled HER3.
"치료 유효량" 또는 "유효량"은 원하는 치료 결과를 달성하는 데 필요한 투여량 및 기간 동안 유효한 양을 지칭한다. 치료 유효량은 개체의 질환 상태, 연령, 성별 및 체중, 및 개체에서 원하는 반응을 유도할 수 있는 치료제 또는 치료제 조합의 능력과 같은 요인에 따라 달라질 수 있다. 유효한 치료제 또는 치료제 조합의 예시적인 지표는 예를 들어, 환자의 웰빙 개선, 종양 부담의 감소, 종양의 정지 또는 둔화된 성장, 및/또는 암세포가 신체 내의 다른 부위로 전이되는 것의 부재를 포함한다. 특정 측면에 따르면, "치료 유효량" 또는 "유효량"은 단독으로 사용되거나 또는 다른 작용제 및/또는 치료 양식과 조합하거나 연계해서 사용될 때, HER3을 발현하는 세포의 전체 수를 고갈시키거나 그의 감소를 유발할 수 있고/있거나 HER3을 발현하는 세포의 성장을 억제할 수 있는 방사성표지된 HER3 표적화제의 양을 지칭한다.“Therapeutically effective amount” or “effective amount” refers to an amount effective at dosages and for periods of time necessary to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or therapeutic combination include, for example, improved patient well-being, reduced tumor burden, stopped or slowed growth of tumors, and/or absence of metastasis of cancer cells to other sites in the body. According to certain aspects, a "therapeutically effective amount" or "effective amount", when used alone or in combination or conjunction with other agents and/or treatment modalities, is capable of depleting or causing a decrease in the total number of cells expressing HER3. and/or capable of inhibiting the growth of cells expressing HER3.
본원에 사용된 바와 같은, HER3을 발현하는 세포와 관련하여 "고갈시키는 것"은 HER3을 발현하거나 과다발현하는 적어도 하나의 유형의 세포 (예를 들어, 고형 종양에서 또는 대상체의 혈액에서 순환하는 HER3-양성 세포)의 집단을 낮추는 것을 의미한다. 본 발명의 특정 측면에 따르면, 감소는 HER3 표적화제에 의한 치료의 개시 전 및 후에, 대상체의 혈액 또는 조직 생검 중의, 예컨대 고형 종양으로부터의 HER3-양성 세포의 수의 비교에 의해 결정된다. 따라서, 예를 들어, 대상체의 HER3-양성 세포는 그 집단이 적어도 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 또는 99% 만큼 감소되는 경우, 고갈된 것으로 간주될 수 있다.As used herein, “depleting” with respect to cells that express HER3 means at least one type of cell that expresses or overexpresses HER3 (e.g., HER3 circulating in a solid tumor or in the blood of a subject). -positive cells) to lower the population. According to certain aspects of the invention, the reduction is determined by comparing the number of HER3-positive cells in a blood or tissue biopsy of the subject, such as from a solid tumor, before and after initiation of treatment with the HER3 targeting agent. Thus, for example, a subject's HER3-positive cells are reduced in that population by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%. , can be considered depleted.
"성장을 억제하다"는 치료제 또는 치료제 또는 약물의 조합과 접촉될 때의 시험관내 또는 생체내 악성 세포 또는 조직 (예를 들어, 종양)의 성장이, 치료제 또는 치료 약물의 조합의 부재 하에서 동일한 세포 또는 조직의 성장에 있어서의 감소 또는 지연과 비교할 때, 측정 가능하게 감소 또는 지연되는 것을 지칭한다. 시험관내 또는 생체내 악성 세포 또는 조직의 성장 억제는 적어도 약 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 또는 100%일 수 있다."Inhibit growth" means that the growth of malignant cells or tissues (eg, tumors) in vitro or in vivo when contacted with a therapeutic agent or combination of therapeutic agents or drugs, in the absence of the therapeutic agent or combination of therapeutic drugs, inhibits the growth of the same cells or a measurable decrease or retardation when compared to a decrease or retardation in the growth of a tissue. Inhibition of growth of malignant cells or tissues in vitro or in vivo by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97% , 98%, 99%, or 100%.
용어 "면역 체크포인트 요법"은 암 세포에 대한 면역 반응을 촉진하는 데 있어서 면역 체크포인트 단백질의 기능을 양성 또는 음성 방식으로 조정할 수 있는 분자를 지칭한다. 용어 "면역 체크포인트"는 정상적인 생리학적 조건 하에서 비제어된 면역 반응을 방지하여 자기-관용 및/또는 조직 보호를 유지하기 위해 작용하는 면역 경로에 직접 또는 간접적으로 관여하는 단백질을 지칭한다.The term “immune checkpoint therapy” refers to a molecule capable of modulating, in a positive or negative manner, the function of an immune checkpoint protein in promoting an immune response against cancer cells. The term "immune checkpoint" refers to proteins involved directly or indirectly in immune pathways that act to prevent uncontrolled immune responses under normal physiological conditions to maintain self-tolerance and/or tissue protection.
본 발명의 맥락에서, 면역 체크포인트 요법은 억제성 면역 체크포인트 (길항제)의 기능을 적어도 부분적으로 하향조절할 수 있는 항체 및/또는 자극성 면역 체크포인트 (효능제)의 기능을 적어도 부분적으로 상향조절할 수 있는 항체와 같은 요법을 포괄한다. 예를 들어, 면역 체크포인트 요법은 특정 암에서 상향조절될 수 있는 면역 체크포인트 억제제 (ICI)에 대한 항체를 지칭할 수 있으며, 따라서 ICI의 기능을 억제할 수 있다.In the context of the present invention, an immune checkpoint therapy can at least partially upregulate the function of an antibody and/or a stimulatory immune checkpoint (agonist) that can at least partially downregulate the function of an inhibitory immune checkpoint (antagonist). It encompasses therapies such as antibodies in For example, immune checkpoint therapy can refer to antibodies against immune checkpoint inhibitors (ICIs) that can be upregulated in certain cancers and thus inhibit the function of ICIs.
용어 "DDRi"는 DNA 손상 반응 경로 단백질의 억제제를 지칭하며 PARPi가 그 예이다. 용어 "PARPi"는 폴리(ADP-리보스) 폴리머라제의 억제제를 지칭한다. 본 발명의 맥락에서, 용어 PARPi는 폴리(ADP-리보스) 폴리머라제와 결합하여 그의 기능을 억제할 수 있는 분자, 예컨대 항체, 펩티드 또는 소분자를 포괄한다.The term “DDRi” refers to inhibitors of DNA damage response pathway proteins, eg PARPi. The term “PARPi” refers to inhibitors of poly(ADP-ribose) polymerase. In the context of the present invention, the term PARPi encompasses molecules capable of binding to and inhibiting the function of poly(ADP-ribose) polymerase, such as antibodies, peptides or small molecules.
용어 "CD47 차단제"는 SIRPα에 대한 CD47 결합을 방지하는 작용제, 예컨대 CD47 또는 SIRPα 중 어느 하나와 결합하는 차단제, 또는 CD47 또는 SIRPα의 발현을 조정하는 차단제, 또는 그렇지 않으면 CD47/SIRPα 축을 억제하는 차단제를 지칭한다. 제한 없이, CD47 차단제는 적어도 CD47과 결합하는 항체, 예컨대 마그롤리맙, 렘조파를리맙, 및 AO-176, SIRPα 융합 단백질, 예컨대 TTI-621 및 TTI-622, CD47 및/또는 SIRPα의 발현을 조정하는 작용제, 예컨대 CD47의 번역을 차단하는 포스포로디아미데이트 모르폴리노 올리고머 (PMO), 및 소분자 작용제, 예컨대 RRx-001을 포괄한다.The term "CD47 blocker" refers to an agent that prevents CD47 binding to SIRPα, such as a blocker that binds either CD47 or SIRPα, or a blocker that modulates the expression of CD47 or SIRPα, or a blocker that otherwise inhibits the CD47/SIRPα axis. refers to Without limitation, CD47 blockers modulate the expression of antibodies that bind at least CD47, such as magrolimab, remzoparlimab, and AO-176, SIRPα fusion proteins such as TTI-621 and TTI-622, CD47 and/or SIRPα. agents that block the translation of CD47, such as phosphorodiamidate morpholino oligomers (PMOs), and small molecule agents, such as RRx-001.
본원에 사용된 바와 같은, HER3 표적화제와 "연계해서" 하나 이상의 부가의 요법, 예컨대 면역 체크포인트 요법 및/또는 DDRi 및/또는 CD47 차단제 및/또는 방사선증감제 중 하나 이상을 대상체에게 투여하는 것은 HER3 표적화제의 투여 전, 투여 동안 및/또는 투여 후에 부가의 요법을 투여하는 것을 의미한다. 이러한 투여는 하기 시나리오를 포함하며, 그에 제한되지 않는다: (i) 부가의 요법이 첫 번째로 투여되고, HER3 표적화제가 두 번째로 투여되는 것; (ii) 부가의 요법이 HER3 표적화제와 공동으로 투여되는 것 (예를 들어, DDRi는 n일 동안 1일 1회 경구 투여되고, HER3 표적화제는 DDRi 요법의 제2일 내지 제n-1일 중 1일에 단일 용량으로 정맥내 투여된다); (iii) 부가의 요법이 HER3 표적화제와 공동으로 투여되는 것 (예를 들어, DDRi는 1개월 초과의 지속 기간 동안 경구 투여되고, 예컨대 35일, 42일, 49일, 또는 치료 중인 암이 진행되지 않고 DDRi가 허용할 수 없는 독성을 일으키지 않는 더 긴 기간 동안 1일 1회 경구 투여되고, HER3 표적화제는 DDRi 요법의 첫 달 이내에 1일 단일 용량으로 정맥내 투여된다); 및 (iv) HER3 표적화제가 첫 번째로 투여되고 (예를 들어, 단일 용량으로 또는 몇 주의 기간에 걸쳐 복수 개의 용량으로 정맥내 투여된다), 부가의 요법이 두 번째로 투여되는 것 (예를 들어, DDRi는 21일, 28일, 35일, 42일, 49일, 또는 치료 중인 암이 진행되지 않고 DDRi가 허용할 수 없는 독성을 일으키지 않는 더 긴 기간 동안 1일 1회 경구 투여된다). 관련 기술분야의 통상의 기술자에게 명백한 부가의 순열이 가능하며 본원에 의해 청구된 발명의 범위 내에 있다.As used herein, administration of one or more additional therapies, such as immune checkpoint therapy and/or one or more of DDRi and/or CD47 blockers and/or radiosensitizers to a subject "in conjunction with" a HER3 targeting agent It means administering an additional therapy before, during and/or after administration of the HER3 targeting agent. Such administration includes, but is not limited to, the following scenarios: (i) the additional therapy is administered first and the HER3 targeting agent is administered second; (ii) the additional therapy is administered concurrently with the HER3 targeting agent (e.g., DDRi is administered orally once daily for n days, and the HER3 targeting agent is administered on
"제조품"은 본원에 기재된 장애의 치료, 예방 및/또는 진단에 유용한 물질을 함유하는 패키지를 나타낸다. 제조품은 용기; 및 용기 상에 또는 용기와 연합된 라벨 또는 패키지 삽입물을 포함할 수 있다. 적합한 용기는 예를 들어, 병, 바이알, 주사기, IV 용액 봉지 등을 포함한다. 용기는 다양한 재료, 예컨대 유리 또는 플라스틱으로 형성될 수 있다. 용기는 그 자체로 또는 병태를 치료, 예방 및/또는 진단하는데 유효한 또 다른 조성물과 조합되는 조성물을 보유하고, 멸균 접근 포트를 가질 수 있다 (예를 들어, 용기는 정맥내 용액 봉지 또는 피하 주사 바늘에 의해 관통할 수 있는 마개를 갖는 바이알일 수 있다). 조성물 중 적어도 하나의 활성제는 본원에 의해 개시된 발명의 측면에 따라 방사성표지된 HER3 표적화제일 수 있다."Article of manufacture" refers to a package containing materials useful for the treatment, prevention and/or diagnosis of the disorders described herein. Articles of manufacture include containers; and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container may be formed from a variety of materials, such as glass or plastic. The container holds a composition by itself or in combination with another composition effective for treating, preventing and/or diagnosing a condition, and can have a sterile access port (eg, the container can be an intravenous solution bag or a hypodermic needle It may be a vial with a stopper pierceable by). At least one active agent in the composition may be a radiolabeled HER3 targeting agent according to aspects of the invention disclosed herein.
"라벨" 또는 "패키지 삽입물"은 적응증, 사용법, 투여량, 투여, 조합 요법, 금기 사항 및/또는 그러한 치료 제품의 사용에 관한 경고에 대한 정보를 함유하는 치료 제품의 상업용 패키지에 관례적으로 포함된 지침을 지칭하는 데 사용된다. 본원에 사용된 바와 같은, 라벨은 조성물이 HER3-양성 암을 치료하는 데 사용된다는 것을 나타낼 수 있고, 임의로 투여 경로 및/또는 방법을 나타낼 수 있다. 더욱이, 제조품은 (a) HER3 표적화제를 포함하는 조성물이 내부에 함유된 제1 용기; 및 (b) 본원에 의해 개시된 발명의 측면에 따른 추가의 세포독성 또는 다른 치료제를 포함하는 조성물이 내부에 함유된 제2 용기를 포함할 수 있다. 대안적으로 또는 부가적으로, 제조품은 제약상 허용되는 완충액, 예컨대 정균 주사용수 (BWFI), 인산염 완충 식염수, 링거 용액 및 덱스트로스 용액을 포함한 제2 (또는 제3) 용기를 추가로 포함할 수 있다. 이는 다른 완충제, 희석제, 필터, 바늘 및 주사기를 포함하여, 상업적 및 사용자 관점에서 바람직한 다른 재료를 추가로 포함할 수 있다."Labels" or "package inserts" are customarily included in commercial packages of therapeutic products that contain information about indications, directions for use, dosage, administration, combination therapy, contraindications and/or warnings regarding the use of such therapeutic products. It is used to refer to a set of guidelines. As used herein, a label may indicate that the composition is used to treat HER3-positive cancer, and may optionally indicate a route and/or method of administration. Moreover, the article of manufacture may comprise (a) a first container containing therein a composition comprising a HER3 targeting agent; and (b) a second container containing therein a composition comprising an additional cytotoxic or other therapeutic agent according to aspects of the invention disclosed herein. Alternatively or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution. there is. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
본 출원 전반에 걸쳐, 다양한 특허, 특허 출원 및 기타 간행물이 인용되며, 이들 각각은 그 전체 내용이 본원에 참조로 포함된다.Throughout this application, various patents, patent applications and other publications are cited, each of which is incorporated herein by reference in its entirety.
달리 정의되지 않는 한, 본원에 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야의 통상의 기술자에 의해 통상적으로 이해되는 것과 동일한 의미를 갖고 있다. 본원에 기재된 것과 유사하거나 동등한 방법 및 물질이 본원에 기재된 실시 또는 시험에 사용될 수 있지만, 적합한 방법 및 물질이 하기에 기재되어 있다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing described herein, suitable methods and materials are described below.
실험 결과Experiment result
중쇄 서열식별번호 (SEQ ID NO): 77 및 경쇄 서열식별번호: 78로 이루어진 항-HER3 IgG 모노클로날 항체를 제조하고, p-SCN-Bn-DOTA를 사용하여 킬레이터 DOTA와 접합시키고, 악티늄-225로의 킬레이트화를 통해 방사성표지시켜 도 3-11과 연계해서 하기에 기재되는 바와 같이 추가로 조사하였다.An anti-HER3 IgG monoclonal antibody consisting of heavy chain SEQ ID NO: 77 and light chain SEQ ID NO: 78 was prepared, conjugated to the chelator DOTA using p-SCN-Bn-DOTA, and actinium Radiolabeling via chelation to -225 was further investigated as described below in conjunction with Figures 3-11.
도 3은 비변형된 항-HER3 항체 및 비특이적 항체 (IgG)와 비교한 Ac225 표지된 DOTA-접합된 항-HER3 모노클로날 항체 ("HER3-ARC")의 ELISA 검정 결합 특징을 나타내며, 이는 그러한 변형이 HER3에 대한 면역 반응성에 실질적으로 영향을 미치지 않다는 것을 입증해준다.Figure 3 shows the ELISA assay binding characteristics of an Ac225 labeled DOTA-conjugated anti-HER3 monoclonal antibody ("HER3-ARC") compared to an unmodified anti-HER3 antibody and an unspecific antibody (IgG), indicating that such It demonstrates that the modification does not substantially affect immune reactivity to HER3.
225Ac-HER3-ARC의 결합 특성을 ELISA로 평가하였다. 96 웰 플레이트를 인간 재조합 HER3로 밤새 코팅한 다음, 항-HER3, 225Ac-HER3-ARC 및 IgG (이뮤노글로불린 1, 비특이적 IgG1 대조군)의 연속 희석액 (0 - 100 μg/ml)을 실온에서 1시간 동안 인큐베이션하였다. 2차 항체 (염소 항-인간 IgG F(ab')20-HRP)를 부가하고 얼음 위에서 30분 동안 인큐베이션한 다음, HCl 1M을 사용하여 10분 동안 발색하였다. 샘플 흡광도는 450 nm에서 측정되었다. 225Ac-HER3-ARC는 ELISA에 의해 천연 항체와 유사한 결합 특성을 보였다 (HER3-ARC: EC50 = 0.0017 μg/ml, HER3 EC50 = 0.0022 μg/ml).The binding properties of 225Ac-HER3-ARC were evaluated by ELISA. A 96-well plate was coated overnight with human recombinant HER3, followed by serial dilutions (0 - 100 μg/ml) of anti-HER3, 225Ac-HER3-ARC and IgG (
도 4는 HER3-양성 NCI-H1975 세포 (인간 폐 선암종, NSCLC) 및 BxPC-3 세포 (인간 췌장 선암종)에 대한 225Ac-HER3-ARC, 비변형된 항-HER3 mAb, 비특이적 항체 대조군 (IgG) 및 2차 항체 단독 대조군의 결합을 조사한 유동 세포계수법 검정 결과를 보여주는 그래프이다.Figure 4 shows 225Ac-HER3-ARC, unmodified anti-HER3 mAb, non-specific antibody control (IgG) and BxPC-3 cells (human pancreatic adenocarcinoma) against HER3-positive NCI-H1975 cells (human lung adenocarcinoma, NSCLC) and BxPC-3 cells (human pancreatic adenocarcinoma). A graph showing the results of a flow cytometry assay examining the binding of the secondary antibody only control.
225Ac-HER3-ARC의 결합 특성은 HER3+ 세포 (NCI-H1975 및 BxPC3)에서 유동 세포계수법으로 평가되었다. 항-HER3, 225Ac-HER3-ARC 및 IgG (이뮤노글로불린 1, 비특이적 IgG1)의 용액 (100 μg/ml)을 HER+ 세포에 부가하고 실온에서 1시간 동안 인큐베이션하였다. PE 표지된 2차 항체를 부가하고 얼음 위에서 30분 동안 인큐베이션하였다. 샘플 형광을 유동 세포계수기를 사용하여 측정하였다. HER3+ 양성 세포주에 대한 225Ac-HER3-ARC의 결합 특성은 비변형된 항-HER3 mAb의 특성과 유사하였다.The binding properties of 225Ac-HER3-ARC were evaluated by flow cytometry in HER3+ cells (NCI-H1975 and BxPC3). A solution (100 μg/ml) of anti-HER3, 225Ac-HER3-ARC and IgG (
도 5는 HER3-양성 세포주 NCI-H1975에 대한 225Ac-HER3-ARC의 시험관내 세포독성 효과를 방사선 용량에 따른 함수로서 나타낸 그래프이다.5 is a graph showing the in vitro cytotoxic effect of 225Ac-HER3-ARC on the HER3-positive cell line NCI-H1975 as a function of radiation dose.
HER3+ 세포주 NCI-H1975에 대한 225Ac-HER3-ARC의 세포독성 효과는 셀티터(CellTiter) 96® 수성 비-방사성 세포 증식 검정 (MTS)을 사용하는 비색 검정에서 평가되었다. NCI-H1975 세포를 225Ac-HER3-ARC와 함께 37℃에서 24시간 동안 인큐베이션하였다. 이어서, 비결합된 225Ac-HER3-ARC를 제거하고, 세포를 37℃에서 72시간 동안 배양하였다. 490 nm에서의 흡광도를 측정하고 세포 생존율의 %를 계산하였다. 225Ac-HER3-ARC는 HER3+ 세포주 NCI-H1975에 대하여 강력한 시험관내 세포독성을 보였다.The cytotoxic effect of 225Ac-HER3-ARC on the HER3+ cell line NCI-H1975 was evaluated in a colorimetric assay using the CellTiter 96® aqueous non-radioactive cell proliferation assay (MTS). NCI-H1975 cells were incubated with 225Ac-HER3-ARC for 24 hours at 37°C. Unbound 225Ac-HER3-ARC was then removed and the cells were cultured at 37°C for 72 hours. The absorbance at 490 nm was measured and the % of cell viability was calculated. 225Ac-HER3-ARC showed potent in vitro cytotoxicity against the HER3+ cell line NCI-H1975.
도 6A는 225Ac-HER3-ARC가 NCI-H1975 세포에서 세포 표면 칼레티쿨린 (CRT)을 상향조절한다는 것을 보여주는 그래프이고 도 6B는 225Ac-HER3-ARC가 NCI-H1975 세포 상에서 CD47을 상향조절한다는 것을 보여주는 그래프이다.Figure 6A is a graph showing that 225Ac-HER3-ARC upregulates cell surface calreticulin (CRT) in NCI-H1975 cells and Figure 6B shows that 225Ac-HER3-ARC upregulates CD47 on NCI-H1975 cells. This is the graph that shows
HER3+ 세포주 NCI-H1975에 의한 칼레티쿨린 (CRT) 및 CD47의 세포 표면 발현에 대한 225Ac-HER3-ARC의 효과를 유동 세포계수법을 사용하여 조사하였다. 세포를 225Ac-HER3-ARC (100 nCi/ml) 또는 PBS (대조군)로 72시간 동안 처리하였다. 처리 후, 세포를 CRT 및 CD47에 대해 염색하였다. 그 결과는 CRT (도 6A) 및 CD47 (도 6B) 각각이 NCI-H1975 세포에서 225Ac-HER3-ARC에 의해 상향조절된다는 것을 입증해준다.The effect of 225Ac-HER3-ARC on the cell surface expression of calreticulin (CRT) and CD47 by the HER3+ cell line NCI-H1975 was investigated using flow cytometry. Cells were treated with 225Ac-HER3-ARC (100 nCi/ml) or PBS (control) for 72 hours. After treatment, cells were stained for CRT and CD47. The results demonstrate that each of CRT (FIG. 6A) and CD47 (FIG. 6B) is upregulated by 225Ac-HER3-ARC in NCI-H1975 cells.
도 7A는 225Ac-HER3-ARC와 항-CD47 차단 항체의 조합이 어느 하나의 처리 단독에 비해 BxPC-3 세포의 식세포작용을 향상시켰다는 것을 입증하는 식세포작용 검정의 결과를 나타내는 그래프이다. 도 7B는 225Ac-HER3-ARC와 항-CD47 차단 항체의 조합이 어느 하나의 처리 단독에 비해 NCI-H1975 세포의 식세포작용을 향상시켰다는 것을 입증하는 식세포작용 검정의 결과를 나타내는 그래프이다. 동일한 키가 도 7A 및 7B에 적용된다.7A is a graph showing the results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC with an anti-CD47 blocking antibody enhanced phagocytosis of BxPC-3 cells compared to either treatment alone. 7B is a graph showing the results of a phagocytosis assay demonstrating that the combination of 225Ac-HER3-ARC with an anti-CD47 blocking antibody enhanced phagocytosis of NCI-H1975 cells compared to either treatment alone. The same keys apply to Figures 7A and 7B.
시험관내 식세포작용에 대한 225Ac-HER3-ARC와 항-CD47 조합의 효과를 유동 세포계수법으로 평가하였다. BxPC-3 (도 7A) 및 NCI-H1975 (도 7B) 세포를 225Ac-HER3-ARC와 함께 37℃에서 24시간 인큐베이션하기 24시간 전에 6-웰 플레이트에 시딩하였다. 225Ac-HER3-ARC 처리 후, 세포를 37℃에서 72시간 동안 배양하였다.The effect of the combination of 225Ac-HER3-ARC and anti-CD47 on phagocytosis in vitro was evaluated by flow cytometry. BxPC-3 (FIG. 7A) and NCI-H1975 (FIG. 7B) cells were seeded in 6-
BxPC-3 및 NCI-H1975 세포를 비브란트(Vybrant) DiD 세포-표지화 용액으로 염색하고 항-인간 CD47 [바이오 엑스 셀(Bio X Cell), Cat#BE0019] 및 마우스 IgG1 이소형 대조군 (바이오 엑스 셀, Cat#BE0083)으로 37℃에서 1시간 동안 처리하였다. 인간 대식세포는 비브란트 DiO 세포-표지화 용액으로 염색되었다. 표지된 인간 대식세포 및 표적 세포를 37℃에서 2시간 동안 공동 배양하였다. 이중 표지된 세포 (DiD+/DiO+)를 평가함으로써 식세포작용을 평가하였다.BxPC-3 and NCI-H1975 cells were stained with Vybrant DiD cell-labeling solution and stained with anti-human CD47 (Bio X Cell, Cat#BE0019) and mouse IgG1 isotype control (Bio X Cell). , Cat#BE0083) at 37°C for 1 hour. Human macrophages were stained with Vibrandt DiO cell-labeling solution. Labeled human macrophages and target cells were co-cultured at 37°C for 2 hours. Phagocytosis was assessed by evaluating dual labeled cells (DiD+/DiO+).
도 8은 인간 종양 (NCI-H1975 세포) 마우스 이종이식편 모델에서, 상이한 방사선 용량 (100 nCi, 200 nCi, 400 nCi, 600 nCi) 단독 및 200 nCi에서 항-CD47 차단 항체와 조합한 225Ac-HER3-ARC, 비표지된 항-HER3 mAb, 항-CD47 차단 항체 단독, 및 비히클-단독 대조군의 종양 성장에 미치는 효과를 나타내는 그래프이다. 특히, 종양 성장은 각각의 방사선 용량 200 nCi, 400 nCi, 600 nCi에서 225Ac-HER-ARC에 의해 및 225Ac-HER-ARC (200 nCi)와 항-CD47 mAb의 조합에 의해 거의 완전히 억제되었다.Figure 8: 225Ac-HER3- in combination with anti-CD47 blocking antibody at different radiation doses (100 nCi, 200 nCi, 400 nCi, 600 nCi) alone and at 200 nCi in a human tumor (NCI-H1975 cell) mouse xenograft model. A graph showing the effect of ARC, unlabeled anti-HER3 mAb, anti-CD47 blocking antibody alone, and vehicle-only control on tumor growth. In particular, tumor growth was almost completely inhibited by 225Ac-HER-ARC at each radiation dose of 200 nCi, 400 nCi, 600 nCi and by the combination of 225Ac-HER-ARC (200 nCi) with anti-CD47 mAb.
도 9는 도 8에 기재된 실험의 대상체에 대한 시간 경과에 따른 체중을 나타내는 그래프이다.9 is a graph showing body weight over time for the subjects of the experiment described in FIG. 8 .
도 10은 도 8에 기재된 실험의 실험 군 대상체에 대한 시간 경과에 따른 생존 확률을 나타내는 그래프이다.10 is a graph showing survival probability over time for subjects in the experimental group of the experiment described in FIG. 8 .
HER2-ARC 처리 단독 및 CD47 차단제와 조합하여 HER2-양성 종양 성장에 미치는 효과를 조사하는 종양 이종이식편 연구가 또한 수행되었다. 항-HER2 mAb 트라스투주맙은 p-SCN-Bn-DOTA를 사용하여 DOTA와 화학적으로 접합되었고, 이들 실험에 사용하기 위해 킬레이트화를 통해 악티늄-225 또는 루테튬-177로 표지되었다.A tumor xenograft study was also conducted examining the effect of HER2-ARC treatment alone and in combination with a CD47 blocker on HER2-positive tumor growth. The anti-HER2 mAb Trastuzumab was chemically conjugated to DOTA using p-SCN-Bn-DOTA and labeled with actinium-225 or lutetium-177 via chelation for use in these experiments.
도 11은 HER2-양성 SK-OV3 인간 난소암 세포주를 사용한 NGS 마우스 이종이식편 모델에서 비히클 단독 (대조군), 마그롤리맙 단독 (10 mg/kg), 225Ac-트라스투주맙 단독 (0.025 μCi/동물), 및 마그롤리맙 (10 mg/kg)과 225Ac-트라스투주맙 (0.025 μCi/동물)의 조합의 종양 성장에 대한 비교 효과를 나타내는 그래프이다. 각각의 코호트는 8마리의 동물로 이루어졌다.Figure 11 shows vehicle alone (control), magnolimab alone (10 mg/kg), 225Ac-trastuzumab alone (0.025 μCi/animal) in an NGS mouse xenograft model using the HER2-positive SK-OV3 human ovarian cancer cell line. , and Magrolimab (10 mg/kg) and 225Ac-Trastuzumab (0.025 μCi/animal) in combination with comparative effects on tumor growth. Each cohort consisted of 8 animals.
도 12는 HER2-양성 SK-OV3 인간 난소암 세포주를 사용한 NGS 마우스 이종이식편 모델에서 비히클 단독 (대조군), 마그롤리맙 단독 (10 mg/kg), 177Lu-트라스투주맙 단독 (25 μCi/동물), 및 마그롤리맙 (10 mg/kg)과 177Lu-트라스투주맙 (25 μCi/동물)의 조합의 종양 성장에 대한 비교 효과를 나타내는 그래프이다. 각각의 코호트는 8마리의 동물로 이루어졌다.Figure 12 shows vehicle alone (control), magnolimab alone (10 mg/kg), 177Lu-trastuzumab alone (25 μCi/animal) in an NGS mouse xenograft model using HER2-positive SK-OV3 human ovarian cancer cell line. , and Magrolimab (10 mg/kg) and 177Lu-Trastuzumab (25 μCi/animal) are graphs showing comparative effects on tumor growth. Each cohort consisted of 8 animals.
발명의 측면aspect of the invention
HER3-표적화 항체의 투여 후 HER3 수준이 하향조절될 수 있다는 것은 전임상 및 임상 연구 모두에서 문서화가 잘 되어 있다 (Mishra, 2018). 룸레투주맙을 사용한 전임상 모델에서는, 면역조직화학 및 웨스턴 블롯팅 둘 다에 의해 측정된 바와 같이 HER3의 용량-의존적 (1-10 mg/kg) 하향조절이 있었다 (Maneses-Lorenta, 2015; Mirshberger, 2013). 가장 낮은 용량의 룸레투주맙 (0.3 mg/kg)은 HER3 표적 하향조절을 초래하지 않았으며 (문헌 [Maneses-Lorenta, 2015]), 이러한 낮은 수준의 룸레투주맙 (0.1 mg/kg 및 0.3 mg/kg)은 HER3-발현 종양을 제어하는 데 효과적이지 않았다 (Mirshberger, 2013). 룸레투주맙을 사용한 임상 연구에서는, 시험한 모든 용량 수준 (100-2000 mg; 문헌 [Meulendijks, 2016])에 걸쳐 환자의 92%에서 일련의 종양 생검에서 표면 HER3의 하향조절이 관찰되었다. 부가적으로, 총 HER3 수준에서의 감소는 40 mg/kg의 HER3-표적화 항체 LJM716으로 치료받은 환자의 5쌍의 종양 생검 샘플 중 3개에서 관찰되었다 (Reynolds, 2017).It is well documented in both preclinical and clinical studies that HER3 levels can be downregulated following administration of HER3-targeting antibodies (Mishra, 2018). In preclinical models using rumletuzumab, there was a dose-dependent (1-10 mg/kg) downregulation of HER3 as measured by both immunohistochemistry and western blotting (Maneses-Lorenta, 2015; Mirshberger, 2013). The lowest dose of rumletuzumab (0.3 mg/kg) did not result in HER3 target downregulation (Maneses-Lorenta, 2015), and this low dose of rumletuzumab (0.1 mg/kg and 0.3 mg/kg) did not result in downregulation of the HER3 target. kg) was not effective in controlling HER3-expressing tumors (Mirshberger, 2013). In a clinical study with rumletuzumab, downregulation of surface HER3 was observed in serial tumor biopsies in 92% of patients across all dose levels tested (100-2000 mg; Meulendijks, 2016). Additionally, reductions in total HER3 levels were observed in 3 out of 5 paired tumor biopsy samples from patients treated with 40 mg/kg of the HER3-targeting antibody LJM716 (Reynolds, 2017).
HER3의 내재화 및 분해는 HER3의 인산화 및 후속 신호전달 활성을 감소시키는 데 유익할 수 있지만, HER3의 표면 수준의 감소는 종양의 항체 표적화를 방해할 수 있다. 따라서, 효능을 위해 HER3-표적화 항체의 반복 투여가 바람직하거나 필요한 경우, HER3-표적화 항체의 투여는 표적의 하향조절을 초래할 수 있고 재투여를 배제할 수 있다. 본 발명자들은 치료 방법에 유용한 보다 낮은 항체 용량이 HER3 하향조절을 야기하지 않을 수 있기 때문에 항체 방사성접합체 (ARC)를 사용하는 것이 HER3의 용량-의존적 하향조절과 연관된 문제를 회피한다는 것을 발견하였다. 따라서, 본 발명자들은 방사성동위원소를 포함한 HER3 표적화제가 HER3-발현 암 세포, 예컨대 특정 고형 종양의 개선된 종양 표적화 및 사멸을 위한 진단 및 치료제로서 유효하다는 것을 발견하였다. 특히, 다수의 용량의 HER3-표적화제를 포함할 수 있는 치료 방법은 유해한 수준의 HER3 하향조절을 야기하지 않으면서 개선된 종양 표적화 및 사멸을 제공할 수 있다.Internalization and degradation of HER3 can be beneficial in reducing phosphorylation and subsequent signaling activity of HER3, but reduced surface levels of HER3 can interfere with antibody targeting in tumors. Thus, if repeated administration of the HER3-targeting antibody is desired or necessary for efficacy, administration of the HER3-targeting antibody may result in downregulation of the target and preclude re-administration. The inventors have discovered that using an antibody radioconjugate (ARC) avoids the problems associated with dose-dependent downregulation of HER3 because lower antibody doses useful in therapeutic methods may not result in HER3 downregulation. Accordingly, the present inventors have found that HER3 targeting agents including radioisotopes are effective as diagnostic and therapeutic agents for improved tumor targeting and killing of HER3-expressing cancer cells, such as certain solid tumors. In particular, treatment methods that can include multiple doses of HER3-targeting agents can provide improved tumor targeting and killing without causing detrimental levels of HER3 downregulation.
따라서, 본원에 의해 개시된 발명의 특정 측면에 따르면, 방사성표지된 HER3 표적화제를 사용하여 HER3-양성 암을 치료하는 치료 방법이 제공된다. 이러한 방법은 또한, 예를 들어, 고형 종양 내의 또는 환자로부터의 혈액 샘플에서 순환하는 HER3 양성 세포를 확인 및/또는 정량화함으로써, 환자가 HER3-양성 암을 갖는지의 여부 및/또는 어느 정도까지인지의 여부 및/또는 이러한 암의 국재화를 결정하기 위한 진단 단계를 포함할 수 있다.Accordingly, according to certain aspects of the invention disclosed herein, therapeutic methods are provided for treating HER3-positive cancers using radiolabeled HER3 targeting agents. Such methods may also be used to determine whether and/or to what extent a patient has a HER3-positive cancer, for example, by identifying and/or quantifying HER3 positive cells circulating within a solid tumor or in a blood sample from the patient. diagnostic steps to determine whether and/or the localization of such cancer.
특정 측면에 따르면, 치료 방법은 방사성표지된 HER3 표적화제, 예컨대 HER3를 표적으로 하는 방사성표지된 항체, 펩티드 또는 소분자를 단독으로 또는 하나 이상의 부가의 치료제 또는 치료 양식과 조합하여 투여하는 것을 포함한다. 특정 측면에 따르면, 부가의 작용제 또는 양식은 면역 체크포인트 요법, DDRi, CD47 차단제, 화학요법제, 소분자 종양학 약물, 외부 빔 방사선, 및 근접치료 중 어느 하나 이상의 투여일 수 있다.According to certain aspects, the method of treatment comprises administering a radiolabeled HER3 targeting agent, such as a radiolabeled antibody, peptide or small molecule targeting HER3, alone or in combination with one or more additional therapeutic agents or treatment modalities. According to certain aspects, the additional agent or modality may be administration of any one or more of immune checkpoint therapy, DDRi, CD47 blockers, chemotherapeutic agents, small molecule oncology drugs, external beam radiation, and brachytherapy.
특정 측면에 따르면, 방사성표지된 HER3 표적화제는 환자 특이적 조성물로 1회 이상의 용량으로 환자에게 투여될 수 있다.According to certain aspects, the radiolabeled HER3 targeting agent may be administered to a patient in one or more doses in a patient specific composition.
특정 측면에 따르면, 환자는 HER3-양성 세포의 감소를 평가하기 위해 HER3-양성 세포의 존재에 대해 요법 동안 간격을 두고 모니터링될 수 있다. 치료 전의 HER3-양성 세포의 수와 비교 시, HER3 표적화제로 치료한 후에 감소된 수의 HER3-양성 세포를 검출하는 것은, 포유동물 대상체에서 HER3-양성 암을 치료하는데 있어서의 HER3 표적화제의 유효성을 나타낼 수 있다.According to certain aspects, the patient may be monitored at intervals during therapy for the presence of HER3-positive cells to assess a decrease in HER3-positive cells. Detecting a reduced number of HER3-positive cells after treatment with a HER3-targeting agent, as compared to the number of HER3-positive cells prior to treatment, improves the effectiveness of the HER3-targeting agent in treating HER3-positive cancer in a mammalian subject. can indicate
특정 측면에 따르면, 암을 치료하는 방법은 HER3-양성 세포를 확인함으로써 HER3-양성 암을 갖는 환자를 확인하고, 유효량의 HER3 표적화제를 단독으로 또는 부가의 치료 방법과 조합하여 환자에게 투여하는 것을 포함한다. 특정 측면에 따르면, 부가의 치료 방법은 면역 체크포인트 요법, DDRi, CD47 차단제, 화학요법제, 소분자 종양학 약물, 외부 빔 방사선 및 근접치료 중 어느 하나 이상의 투여일 수 있다.According to certain aspects, a method of treating cancer comprises identifying a patient having a HER3-positive cancer by identifying HER3-positive cells, and administering to the patient an effective amount of a HER3 targeting agent, alone or in combination with an additional treatment method. include According to certain aspects, the additional treatment method may be administration of any one or more of immune checkpoint therapy, DDRi, CD47 blockers, chemotherapeutic agents, small molecule oncology drugs, external beam radiation, and brachytherapy.
특정 측면에 따르면, 화학요법제는 방사선증감제이다.According to certain aspects, the chemotherapeutic agent is a radiosensitizer.
특정 측면에 따르면, 방사성표지된 HER3 표적화제는 치료, 예컨대 고형 종양의 전부 또는 일부분을 제거하는 것과 같은 암 치료를 위한 수술을 받은, 예컨대 최근에 받은 환자에게 투여될 수 있다. 따라서, 예를 들어, 방사성표지된 HER3 표적화제는 수술 전에 또는 수술 후에 투여될 수 있다.According to certain aspects, a radiolabeled HER3 targeting agent can be administered to a patient who has undergone, eg, has recently undergone, surgery for treatment, eg, cancer treatment, such as removal of all or part of a solid tumor. Thus, for example, a radiolabeled HER3 targeting agent can be administered before or after surgery.
HER3HER3 표적화제 targeting agent
본원에 의해 개시된 발명의 목적은 HER3-양성 암의 진단 및/또는 치료에서와 같은 진단 용도 및/또는 치료 용도를 위한 방사성표지된 HER3-표적화제, 예컨대 인간 HER3-표적화제를 제공하는 것이다. 방사성표지된 HER3-표적화제는 DNA-손상 이온화 방사선, 예를 들어 이중 가닥 DNA 파손 및 세포 사멸을 유도하는 알파 입자를 세포에 전달하는 것을 통해 치료 반응을 일으킬 수 있다.It is an object of the invention disclosed herein to provide radiolabeled HER3-targeting agents, such as human HER3-targeting agents, for diagnostic and/or therapeutic uses, such as in the diagnosis and/or treatment of HER3-positive cancers. Radiolabeled HER3-targeting agents can elicit a therapeutic response through the delivery of DNA-damaging ionizing radiation, eg, alpha particles to cells that induce double-stranded DNA breakage and cell death.
방사성표지되고 본원에 의해 개시된 발명의 다양한 측면에서 구현되고/되거나 사용될 수 있는 예시적인 항-HER3 항체 (본원에서 "HER3 항체"로서 지칭되기도 함), 예컨대 항-인간 HER3 항체는 하기 항체, 및 항체, 예컨대 이뮤노글로불린 (이에 제한되지는 않음), 예컨대 IgG (이에 제한되지는 않음)를 포함하며 이에 제한되지 않는다: (i) HER3 항체 또는 중쇄의 중쇄 가변 영역을 포함하는 것, (ii) HER3 항체 또는 중쇄의 1개, 2개 또는 3개의 중쇄 CDR (예를 들어, 카바트 정의에 의함) 또는 인용된 것들을 포함하는 것, (iii) HER3 항체 또는 경쇄의 경쇄 가변 영역을 포함하는 것, 및/또는 (iv) HER3 항체 또는 경쇄의 1개, 2개 또는 3개의 경쇄 CDR (예를 들어, 카바트 정의에 의함) 또는 인용된 것들을 포함하는 것. 또한, N-말단 리더 서열을 포함하는 HER3 항체 중쇄 또는 HER3 항체 경쇄가 개시되어 있는 경우, 또한 본 발명의 다양한 측면에서의 실시양태 및 사용을 위해 개시되는 것으로 의도된 것은 리더 서열이 결여된 상응하는 중쇄 및 상응하는 경쇄라는 것을 또한 이해해야 한다.Exemplary anti-HER3 antibodies (also referred to herein as “HER3 antibodies”) that are radiolabeled and can be implemented and/or used in various aspects of the invention disclosed herein, such as anti-human HER3 antibodies, include the following antibodies, and antibodies , such as, but not limited to, immunoglobulins, such as, but not limited to, IgG, including but not limited to: (i) those comprising a heavy chain variable region of a HER3 antibody or heavy chain, (ii) HER3 one, two or three heavy chain CDRs of an antibody or heavy chain (e.g., by the Kabat definition) or those recited, (iii) one comprising the light chain variable region of a HER3 antibody or light chain, and /or (iv) one, two or three light chain CDRs of a HER3 antibody or light chain (eg, according to the Kabat definition) or those recited. Furthermore, where a HER3 antibody heavy chain or HER3 antibody light chain comprising an N-terminal leader sequence is disclosed, it is also intended to be disclosed for embodiments and use in the various aspects of the present invention that the corresponding HER3 antibody lacking a leader sequence is also disclosed. It should also be understood that heavy chains and corresponding light chains.
방사성표지되고 본원에 의해 개시된 발명에서 구현되고/되거나 사용될 수 있는 예시적인 HER3 항체는, 예를 들어 서열식별번호: 9 또는 11에 제시된 바와 같은 아미노산 서열을 갖는 중쇄 및/또는 서열식별번호: 10 또는 12에 제시된 바와 같은 아미노산 서열을 갖는 경쇄를 포함한 HER3에 대한 뮤린 모노클로날 항체, 또는 상기 서열 중 하나 이상으로부터 유래된 인간화 항체와 같은 항체를 포함할 수 있다. 방사성표지되고 본원에 의해 개시된 발명에서 구현되고/되거나 사용될 수 있는 예시적인 HER3 항체는 서열식별번호: 13에 제시된 서열을 갖는 N-말단 영역을 갖는 중쇄 및/또는 서열식별번호: 14에 제시된 바와 같은 서열을 갖는 N-말단 영역을 갖는 경쇄를 포함할 수 있다. 본 발명의 다양한 측면에서 유사하게 구현되거나 사용될 수 있는 HER3 항체는, 예를 들어 서열식별번호: 7에 제시된 바와 같은 아미노산 서열을 갖는 중쇄 가변 영역, 및/또는 서열식별번호: 8에 제시된 바와 같은 아미노산 서열을 갖는 경쇄 가변 영역; 및/또는 서열식별번호: 1-3에 각각 제시된 아미노산 서열을 갖는 CDR1, CDR2 및 CDR3 중 하나 이상을 포함한 중쇄, 및/또는 서열식별번호: 4-6에 각각 제시된 아미노산 서열을 갖는 CDR1, CD2 및 CDR3 중 하나 이상을 포함한 경쇄를 포함할 수 있다. 이들 서열에 대한 추가 설명은 도 1 및 2를 참조한다. 본 발명의 측면 중 임의의 것에서 구현되고/되거나 사용되는 HER3 항체는, 예를 들어 전술한 경쇄 서열 및/또는 중쇄 서열의 임의의 조합을 포함할 수 있다.Exemplary HER3 antibodies that are radiolabeled and can be implemented and/or used in the invention disclosed herein include a heavy chain having an amino acid sequence as set forth in, for example, SEQ ID NO: 9 or 11 and/or SEQ ID NO: 10 or 12, a murine monoclonal antibody to HER3 comprising a light chain having the amino acid sequence as set forth in , or an antibody such as a humanized antibody derived from one or more of the foregoing sequences. Exemplary HER3 antibodies that are radiolabeled and can be implemented and/or used in the invention disclosed herein include a heavy chain having an N-terminal region having the sequence set forth in SEQ ID NO:13 and/or as set forth in SEQ ID NO:14. and a light chain having an N-terminal region having the sequence. HER3 antibodies that can be similarly implemented or used in various aspects of the present invention include, for example, a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:7, and/or an amino acid sequence as set forth in SEQ ID NO:8. a light chain variable region having the sequence; and/or a heavy chain comprising one or more of CDR1, CDR2 and CDR3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, and/or CDR1, CD2 and CDR1 having the amino acid sequences set forth in SEQ ID NOs: 4-6, respectively. and a light chain comprising one or more of the CDR3s. See Figures 1 and 2 for further description of these sequences. A HER3 antibody implemented and/or used in any of the aspects of the present invention may comprise, for example, any combination of light chain sequences and/or heavy chain sequences described above.
예시적인 HER3 항체는 서열식별번호: 15를 포함하는 CDR-H1, 서열식별번호: 16을 포함하는 CDR-H2, 및 서열식별번호: 17을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역, 및/또는 서열식별번호: 18을 포함하는 CDR-L1, 서열식별번호: 19를 포함하는 CDR-L2, 및 서열식별번호: 20을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 21을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 22를 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 23의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 24의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 15, CDR-H2 comprising SEQ ID NO: 16, and CDR-H3 comprising SEQ ID NO: 17 , and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 18, CDR-L2 comprising SEQ ID NO: 19, and CDR-L3 comprising SEQ ID NO: 20; include An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:21 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:22. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:23 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:24.
예시적인 HER3 항체는 서열식별번호: 25를 포함하는 CDR-H1, 서열식별번호: 26을 포함하는 CDR-H2, 및 서열식별번호: 27을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 28을 포함하는 CDR-L1, 서열식별번호: 29를 포함하는 CDR-L2, 및 서열식별번호: 30을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 31을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 32를 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 33의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 34의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 25, CDR-H2 comprising SEQ ID NO: 26, and CDR-H3 comprising SEQ ID NO: 27 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 28, CDR-L2 comprising SEQ ID NO: 29, and CDR-L3 comprising SEQ ID NO: 30. do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:31 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:32. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:33 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:34.
예시적인 HER3 항체는 서열식별번호: 35를 포함하는 CDR-H1, 서열식별번호: 36을 포함하는 CDR-H2, 및 서열식별번호: 37을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 38을 포함하는 CDR-L1, 서열식별번호: 39를 포함하는 CDR-L2, 및 서열식별번호: 40을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 41을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 42를 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 43의 이뮤노글로불린 중쇄 아미노산 서열 및 서열식별번호: 44의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 35, CDR-H2 comprising SEQ ID NO: 36, and CDR-H3 comprising SEQ ID NO: 37 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 38, CDR-L2 comprising SEQ ID NO: 39, and CDR-L3 comprising SEQ ID NO: 40. do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:41 and/or an immunoglobulin light chain variable region comprising SEQ ID NO : 42. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:43 and the immunoglobulin light chain amino acid sequence of SEQ ID NO:44.
예시적인 HER3 항체는 서열식별번호: 45를 포함하는 CDR-H1, 서열식별번호: 46을 포함하는 CDR-H2, 및 서열식별번호: 47을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 48을 포함하는 CDR-L1, 서열식별번호: 29를 포함하는 CDR-L2, 및 서열식별번호: 49를 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 50을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 51을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 52의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 53의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:45, CDR-H2 comprising SEQ ID NO:46, and CDR-H3 comprising SEQ ID NO:47 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:48, CDR-L2 comprising SEQ ID NO:29, and CDR-L3 comprising SEQ ID NO:49. do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:50 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:51. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:52 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:53.
예시적인 HER3 항체는 서열식별번호: 54를 포함하는 CDR-H1, 서열식별번호: 55를 포함하는 CDR-H2, 및 서열식별번호: 56을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 28을 포함하는 CDR-L1, 서열식별번호: 29를 포함하는 CDR-L2, 및 서열식별번호: 30을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 57을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 58을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 59의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 60의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO:54, CDR-H2 comprising SEQ ID NO:55, and CDR-H3 comprising SEQ ID NO:56 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 28, CDR-L2 comprising SEQ ID NO: 29, and CDR-L3 comprising SEQ ID NO: 30. do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:57 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:58. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:59 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:60.
예시적인 HER3 항체는 서열식별번호: 61을 포함하는 CDR-H1, 서열식별번호: 62를 포함하는 CDR-H2, 및 서열식별번호: 63을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 64를 포함하는 CDR-L1, 서열식별번호: 65를 포함하는 CDR-L2, 및 서열식별번호: 66을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 67을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 68을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 69의 이뮤노글로불린 중쇄 아미노산 서열 및 서열식별번호: 70의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 61, CDR-H2 comprising SEQ ID NO: 62, and CDR-H3 comprising SEQ ID NO: 63 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO:64, CDR-L2 comprising SEQ ID NO:65, and CDR-L3 comprising SEQ ID NO:66 do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:67 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:68. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:69 and the immunoglobulin light chain amino acid sequence of SEQ ID NO:70.
예시적인 HER3 항체는 서열식별번호: 71을 포함하는 CDR-H1, 서열식별번호: 72를 포함하는 CDR-H2, 및 서열식별번호: 66을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역; 및/또는 서열식별번호: 28을 포함하는 CDR-L1, 서열식별번호: 29를 포함하는 CDR-L2, 및 서열식별번호: 30을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 73을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 74를 포함하는 이뮤노글로불린 경쇄 가변 영역을 포함한다. 예시적인 HER3 항체는 서열식별번호: 75의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 76의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 71, CDR-H2 comprising SEQ ID NO: 72, and CDR-H3 comprising SEQ ID NO: 66 ; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 28, CDR-L2 comprising SEQ ID NO: 29, and CDR-L3 comprising SEQ ID NO: 30. do. An exemplary HER3 antibody comprises an immunoglobulin heavy chain variable region comprising SEQ ID NO:73 and/or an immunoglobulin light chain variable region comprising SEQ ID NO:74. An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:75 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:76.
예시적인 HER3 항체는 서열식별번호: 77의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 78의 이뮤노글로불린 경쇄 아미노산 서열을 포함한다.An exemplary HER3 antibody comprises the immunoglobulin heavy chain amino acid sequence of SEQ ID NO:77 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO:78.
예시적인 HER3 항체는 서열식별번호: 86, 87, 88, 89, 90 또는 91을 포함하는 이뮤노글로불린 경쇄 가변 영역 및/또는 서열식별번호: 79, 80, 81, 82, 83, 84 또는 85를 포함하는 중쇄 가변 영역을 포함한다.Exemplary HER3 antibodies comprise an immunoglobulin light chain variable region comprising SEQ ID NOs: 86, 87, 88, 89, 90 or 91 and/or SEQ ID NOs: 79, 80, 81, 82, 83, 84 or 85. A heavy chain variable region comprising
예시적인 HER3 항체는 서열식별번호: 92, 94, 95, 98 또는 99를 포함하는 이뮤노글로불린 중쇄 서열 및/또는 서열식별번호: 93, 96, 97, 100 또는 101을 포함하는 이뮤노글로불린 경쇄 서열을 포함한다.An exemplary HER3 antibody comprises an immunoglobulin heavy chain sequence comprising SEQ ID NOs: 92, 94, 95, 98 or 99 and/or an immunoglobulin light chain sequence comprising SEQ ID NOs: 93, 96, 97, 100 or 101 includes
예시적인 HER3 항체는 또한 이수 앱지스 캄파니로부터의 바레세타맙 (ISU104) 및 미국 특허 번호 10,413,607에 개시된 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies also include baresetamab (ISU104) from Isu Abxis Company and any of the HER3 antibodies disclosed in US Pat. No. 10,413,607.
예시적인 HER3 항체는 또한 허밍버드 바이오사이언스 Pte.로부터의 HMBD-001 (10D1F) 및 국제 공개 번호 WO 2019185164 및 WO2019185878, 미국 특허 번호 10,662,241; 및 미국 공개 번호 20190300624, 20210024651, 및 20200308275에 개시된 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies are also described in HMBD-001 (10D1F) from Hummingbird Biosciences Pte. and International Publication Nos. WO 2019185164 and WO2019185878, U.S. Patent Nos. 10,662,241; and any of the HER3 antibodies disclosed in US Publication Nos. 20190300624, 20210024651, and 20200308275.
예시적인 HER3 항체는 또한 메루스 N.V.로부터의 HER2/HER3 이중특이적 항체 MCLA-128 (즉, 제노쿠투주맙); 및 미국 공개 번호 20210206875, 20210155698, 20200102393, 20170058035, 및 20170037145에 개시된, 단일특이적 또는 다중특이적의 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MCLA-128 from Merus N.V. (ie, Genocetuzumab); and any of the monospecific or multispecific HER3 antibodies disclosed in US Publication Nos. 20210206875, 20210155698, 20200102393, 20170058035, and 20170037145.
예시적인 HER3 항체는 또한 HER3 항체 파트리투맙 (U3-1287), 파트리투맙의 쇄로 보고되는 중쇄 서열 서열식별번호: 106 및/또는 경쇄 서열 서열식별번호: 7을 포함하는 항체, 및 미국 특허 번호 9,249,230 및 7,705,130 및 국제 공개 번호 WO2007077028에 개시된 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies also include the HER3 antibody patritumab (U3-1287), an antibody comprising the heavy chain sequence SEQ ID NO: 106 and/or light chain sequence SEQ ID NO: 7 reported as the chain of patritumab, and U.S. Patent No. 9,249,230 and 7,705,130 and International Publication No. WO2007077028.
예시적인 HER3 항체는 또한 HER3 항체 MM-121 및 미국 특허 번호 7,846,440 및 국제 공개 번호 WO2008100624에 개시된 HER3 항체 중 임의의 것을 포함한다. 예시적인 HER3 항체는 또한 EGFR/HER3 이중특이적 항체 DL1 및 미국 특허 번호 9,327,035 및 8,597,652, 미국 공개 번호 20140193414, 및 국제 공개 번호 WO2010108127에 개시된, 단일특이적 또는 다중특이적의 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies also include the HER3 antibody MM-121 and any of the HER3 antibodies disclosed in US Pat. No. 7,846,440 and International Publication No. WO2008100624. Exemplary HER3 antibodies also include the EGFR/HER3 bispecific antibody DL1 and any of the monospecific or multispecific HER3 antibodies disclosed in US Pat. Nos. 9,327,035 and 8,597,652, US Publication No. 20140193414, and International Publication No. WO2010108127. .
예시적인 HER3 항체는 또한 HER2/HER3 이중특이적 항체 MM-111 및 미국 공개 번호 20130183311 및 20090246206 및 국제 공개 번호 W02006091209 및 WO2005117973에 개시된, 단일특이적 또는 다중특이적의 HER3 항체 중 임의의 것을 포함한다.Exemplary HER3 antibodies also include the HER2/HER3 bispecific antibody MM-111 and any of the monospecific or multispecific HER3 antibodies disclosed in US Publication Nos. 20130183311 and 20090246206 and International Publication Nos. W02006091209 and WO2005117973.
특정 측면에 따르면, HER3 표적화제는 다이이치 산쿄로부터의 파트리투맙, 메리맥 파마슈티칼즈로부터의 세리반투맙 (MM-121), 로슈로부터의 룸레투주맙, 노바티스로부터의 엘젬투맙, 글락소스미스클라인으로부터의 GSK2849330, 셀덱스 테라퓨틱스의 CDX-3379, 메디파마로부터의 EV20 및 MP-RM-1, 이수 앱지스 캄파니로부터의 바레세타맙 (ISU104), 허밍버드 바이오사이언스 Pte.로부터의 HMBD-001 (10D1F), 리제네론 파마슈티칼즈로부터의 REGN1400, 및/또는 아베오 온콜로지로부터의 AV-203에 의해 인식된 HER3의 에피토프와 결합하는 항-HER3 항체를 포함한다. 특정 측면에 따르면, 항-HER3 항체는 파트리투맙, 세리반투맙 또는 세리반투맙에 대해 보고되는 중쇄 서열 서열식별번호: 108 및/또는 경쇄 서열 서열식별번호: 109를 포함하는 항체, 룸레투주맙 또는 룸레투주맙에 대해 보고되는 중쇄 서열 서열식별번호: 110 및/또는 경쇄 서열 서열식별번호: 111을 포함하는 항체, 엘젬투맙 또는 엘젬투맙에 대해 보고되는 중쇄 서열 서열식별번호: 112 및/또는 경쇄 서열 서열식별번호: 113을 포함하는 항체, AV-203, CDX-3379, GSK2849330, EV20, MP-RM-1, ISU104, HMBD-001 (10D1F) 및 REGN1400 중 하나 이상으로부터 선택된다. 예시적인 항체가 예시적인 치료 적응증과 함께 또한 표 1에 기재되어 있다.According to certain aspects, the HER3 targeting agent is patritumab from Daiichi Sankyo, cerivantumab (MM-121) from Merrimac Pharmaceuticals, rumletuzumab from Roche, elgemtumab from Novartis, Glaxosmith GSK2849330 from Klein, CDX-3379 from Celdex Therapeutics, EV20 and MP-RM-1 from Medipharma, Baresetamab (ISU104) from Isu Abxis Company, HMBD- from Hummingbird Biosciences Pte. 001 (10D1F), REGN1400 from Regeneron Pharmaceuticals, and/or anti-HER3 antibodies that bind to epitopes of HER3 recognized by AV-203 from Aveo Oncology. According to certain aspects, the anti-HER3 antibody comprises patritumab, cerivantumab or an antibody comprising the heavy chain sequence SEQ ID NO: 108 and/or light chain sequence SEQ ID NO: 109 as reported for cerivantumab, rumletuzumab or antibody comprising heavy chain sequence SEQ ID NO: 110 and/or light chain sequence SEQ ID NO: 111 as reported for rumletuzumab, heavy chain sequence SEQ ID NO: 112 and/or light chain as reported for elgemtumab or elgemtumab An antibody comprising sequence SEQ ID NO: 113, AV-203, CDX-3379, GSK2849330, EV20, MP-RM-1, ISU104, HMBD-001 (10D1F) and REGN1400. Exemplary antibodies are also listed in Table 1 along with exemplary treatment indications.
<표 1><Table 1>
본 개시내용에서 HER3에 대한 또는 임의의 표적에 대한 특이적 항체, 특이적 항체 중쇄 및 특이적 항체 경쇄가 개시되는 곳이면 어디든지, 본 발명의 다양한 측면에서의 실시양태 또는 사용을 위해 개시되는 것으로 또한 의도된 것은 하기를 포함하는 항체, 예컨데 이뮤노글로불린 (이에 제한되지는 않음), 예컨데 IgG (이에 제한되지는 않음)라는 것을 이해해야 한다: (i) 개시된 항체 또는 중쇄의 중쇄 가변 영역을 포함하는 것, (ii) 개시된 항체 또는 중쇄의 1개, 2개 또는 3개의 중쇄 CDR (예를 들어, 카바트 정의에 의함)을 포함하는 것, (iii) 개시된 항체 또는 경쇄의 경쇄 가변 영역을 포함하는 것, 및/또는 (iv) 개시된 항체 또는 경쇄의 1개, 2개 또는 3개의 경쇄 CDR (예를 들어, 카바트 정의에 의함)을 포함하는 것. 또한, 본 개시내용에서 N-말단 리더 서열을 포함하는 항체 중쇄 또는 항체 경쇄가 개시되는 곳이면 어디든지, 본 발명의 다양한 측면에서의 실시양태 또는 사용을 위해 개시되는 것으로 또한 의도된 것은, 리더 서열이 결여된 상응하는 중쇄 및 상응하는 경쇄라는 것을 이해해야 한다.Wherever specific antibodies, specific antibody heavy chains and specific antibody light chains to HER3 or to any target are disclosed in this disclosure, they are considered to be disclosed for embodiment or use in the various aspects of the present invention. It is to be understood that also intended are antibodies such as, but not limited to, immunoglobulins, such as, but not limited to, IgG, including: (i) a antibody comprising a heavy chain variable region of a disclosed antibody or heavy chain; (ii) comprising one, two or three heavy chain CDRs (e.g., by Kabat definition) of a disclosed antibody or heavy chain, (iii) comprising a light chain variable region of a disclosed antibody or light chain. and/or (iv) comprising one, two or three light chain CDRs (eg, according to the Kabat definition) of a disclosed antibody or light chain. Also, wherever an antibody heavy chain or antibody light chain comprising an N-terminal leader sequence is disclosed in this disclosure, it is also intended to be disclosed for embodiments or use in various aspects of the invention, that the leader sequence It should be understood that the corresponding heavy chain and the corresponding light chain are missing.
추가로, 본 발명은 (예를 들어, 도 1 및 2에 열거된 서열식별번호: 1-14 중 임의의 것에서) 정확한 질량을 갖는 하나 이상의 이성질체 아미노산 대체, 예컨대 Ile를 Leu로 대체하거나 그 반대의 경우도 가능한 것이 이루어지는 나열된 아미노산 서열 중 임의의 것의 변형된 버전을 제공한다. 부가적으로, 키메라 이뮤노글로불린 (즉, 키메라 또는 인간화 HER3)을 형성하기 위해 예컨대 인간 이뮤노글로불린으로부터의 관련 부분에 의해 이들 서열의 특정 부분이 치환될 수 있다. 예시적인 치환은 인간 리더 서열의 전부 또는 일부분, 및/또는 인간 IgG1, IgG2 또는 IgG4 중쇄 및/또는 인간 카파 경쇄로부터의 보존된 영역을 포함한다.Additionally, the present invention provides one or more isomeric amino acid replacements having the correct mass (e.g., in any of SEQ ID NOs: 1-14 listed in Figures 1 and 2), such as replacing Ile with Leu or vice versa. Modified versions of any of the listed amino acid sequences are provided, where possible. Additionally, certain portions of these sequences may be substituted, such as by relevant portions from human immunoglobulins, to form chimeric immunoglobulins (ie, chimeric or humanized HER3). Exemplary substitutions include all or part of a human leader sequence and/or conserved regions from a human IgG1, IgG2 or IgG4 heavy chain and/or a human kappa light chain.
인간 HER3, 인간 HER2, 및 인간 EGFR (HER1)의 서열과 구조는 모두 공지되어 있다. 인간 HER3 전구체 단백질 (수용체 티로신-단백질 키나제 erbB-3 이소형 1 전구체 NCBI 참조 서열: NP_001973.2)의 아미노산 서열은 서열식별번호: 115로서 본원에 제공된다. 관련 기술분야의 통상의 기술자는 공지된 표적 단백질 아미노산 서열이 주어지면, 본 발명의 다양한 측면에 사용하기 위해 HER3의 세포외 도메인, 예컨대 인간 HER3의 세포외 도메인에 특이적인 다양한 유형의 적합한 항체 및 항체 모방체가, 관련 기술분야에 널리 확립되어 있는 면역화 및/또는 패닝 및/또는 항체 조작 기술을 사용하여 생산될 수 있다는 것을 쉽게 인지할 것이다.The sequence and structure of human HER3, human HER2, and human EGFR (HER1) are all known. The amino acid sequence of human HER3 precursor protein (receptor tyrosine-protein kinase erbB-3
본 발명의 다양한 실시양태에서 사용하기 위해 방사성표지되는 HER3 표적화제는, 예를 들어, HER3 결합 펩티드, 예컨대 킬레이터-보유 HER3 결합 펩티드, 예컨대 DOTA-보유 HER3 결합 펩티드, 예컨대 미국 공개 번호 20200121814에 개시된 것 중 임의의 것을 포함할 수 있다.A HER3 targeting agent that is radiolabeled for use in various embodiments of the present invention can be, for example, a HER3 binding peptide, such as a chelator-containing HER3 binding peptide, such as a DOTA-containing HER3 binding peptide, such as disclosed in US Publication No. 20200121814. Any of these may be included.
특정 측면에 따르면, HER3 표적화제는 HER3의 제1 에피토프 및 HER3의 적어도 제2 에피토프에 대한, 또는 HER3 및 하나 이상의 상이한 항원, 예컨대 EGFR (HER1), HER2, TROP2, 및 T-세포 수용체 감마 (TCRγ) 쇄 교대 리딩 프레임 단백질 (TRAP) 중 하나 이상에 대한 다중특이적 표적화제, 예컨대 다중특이적 항체를 포함한다/이다. 사용될 수 있는 예시적인 다중특이적 항체는 HER3/HER2에 대한 이중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-111 또는 메루스 N.V.로부터의 MCLA-128 (즉, 제노쿠투주맙); 또는 IGF-1R/HER3에 대한 이중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-141 (즉, 이스티라투맙); 또는 EGFR/HER3에 대한 이중특이적 항체, 예컨대 로슈로부터의 MEHD7945A (즉, 둘리고투맙) 또는 진게니아 인크.로부터의 세툭시맙-기반 이중특이적 또는 다중특이적 자이바디 중 임의의 것을 포함한다.According to certain aspects, the HER3 targeting agent is directed against a first epitope of HER3 and at least a second epitope of HER3, or against HER3 and one or more different antigens, such as EGFR (HER1), HER2, TROP2, and T-cell receptor gamma (TCRγ). ) multispecific targeting agents, such as multispecific antibodies, to one or more of the chain alternating reading frame proteins (TRAPs). Exemplary multispecific antibodies that may be used include bispecific antibodies to HER3/HER2, such as MM-111 from Merrimac Pharmaceuticals or MCLA-128 from Merus N.V. (ie, Xenocutuzumab); or a bispecific antibody to IGF-1R/HER3 such as MM-141 from Merrimac Pharmaceuticals (ie istiratumab); or a bispecific antibody to EGFR/HER3, such as MEHD7945A from Roche (i.e. duligotumab) or cetuximab-based bispecific or multispecific xybodies from Zingenia Inc. .
특정 측면에 따르면, HER3 표적화제, 예컨대 HER3에 대한 항체, 및 하나 이상의 상이한 항원에 대한 하나 이상의 항체의 혼합물을 포함하는 조성물이 제공되고/되거나 사용되며, 여기서 항체 중 하나 이상이 방사성표지된다. 항체 혼합물을 포함하는 예시적인 항체 조성물은 EGFR (HER1), HER2 및 HER3에 대한 6개의 모노클로날 항체를 갖는 심포젠으로부터의 적어도 Sym013을 포함한다. 본 발명의 한 측면에서, Sym013의 항체 중 하나 이상, 예컨대 항-HER3 항체가 방사성표지될 수 있다. 본 발명의 관련 측면은 EGFR (HER1), HER2, 및 HER3에 대한 표적화제, 예컨대 항체를 포함하는 조성물을 제공하며, 여기서 임의의 조합 중 하나 이상 또는 모두가 방사성표지된다.According to certain aspects, compositions comprising a mixture of a HER3 targeting agent, such as an antibody to HER3, and one or more antibodies to one or more different antigens are provided and/or used, wherein one or more of the antibodies are radiolabeled. An exemplary antibody composition comprising an antibody mixture includes at least Sym013 from Symposen with 6 monoclonal antibodies to EGFR (HER1), HER2 and HER3. In one aspect of the invention, one or more of the antibodies of Sym013, such as an anti-HER3 antibody, may be radiolabeled. A related aspect of the invention provides a composition comprising a targeting agent, such as an antibody, to EGFR (HER1), HER2, and HER3, wherein one or more or all in any combination are radiolabeled.
본 발명은 추가로 (i) HER3의 2개 이상의 에피토프에 대한 다중특이적 항체, 또는 HER3의 에피토프와 하나 이상의 부가의 상이한 항원의 에피토프에 대한 다중특이적 항체의 투여, 및/또는 (ii) HER3 표적화제, 예컨대 항체 및 하나 이상의 암 연관 항원에 대하여 유도된 하나 이상의 별개의 표적화제의 투여, 여기서 표적화제, 예컨대 HER3 표적화제 중 하나 이상이 방사성표지되는 것을 포함하는, 증식성 질환 또는 장애를 치료하는 다중특이적 표적화제, 조성물 및 관련 방법을 제공한다. 부가의 상이한 항원은, 예를 들어, 다양한 질환 또는 장애, 예컨대 증식성 장애, 예를 들어, 고형 종양 암, 예컨대 HER3가 또한 상향조절되거나 상향조절될 수 있는 고형 종양 암에 관여하는 세포 상에서 그의 발현이 상향조절되는 항원일 수 있다. 예를 들어, 부가의 상이한 항원은 메소텔린, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL-1, GD2, GD3, B-세포 성숙 항원 (BCMA), Tn Ag, 전립선 특이적 막 항원 (PSMA), ROR1, FLT3, TROP2, T-세포 수용체 감마 (TCRγ) 쇄 교대 리딩 프레임 단백질 (TRAP), 섬유모세포 활성화 단백질 (FAP), 칼레티쿨린, 포스파티딜세린, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, 인터루킨-11 수용체 a (IL-11Ra), PSCA, PRSS21, VEGFR2, 루이스Y, CD24, 혈소판 유래 성장 인자 수용체-베타 (PDGFR-베타), SSEA-4, CD20, 엽산염 수용체 알파 (FRa), ERBB2 (Her2/neu), MUC1, 표피 성장 인자 수용체 (EGFR), EGFRvIII, NCAM, 프로스타제, PAP, ELF2M, 에프린 B2, IGF-I 수용체, CAIX, LMP2, gp100, bcr-abl, 티로시나제, EphA2, 푸코실 GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-아세틸-GD2, 엽산염 수용체 베타, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD 179a, ALK, 폴리시알산, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, 레구마인, HPV E6,E7, MAGE A1, MAGEA3, MAGEA3/A6, ETV6-AML, 정자 단백질 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-관련 항원 1, 프로스테인, 서비빈 및 텔로머라제, PCTA-1/갈렉틴 8, KRAS, MelanA/MART1, Ras 돌연변이체, hTERT, 육종 전위 중단점, ML-IAP, ERG (TMPRSS2 ETS 융합 유전자), NA17, PAX3, 안드로겐 수용체, 사이클린 B1, MYCN, RhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY-TES 1, LCK, AKAP-4, SSX2, RAGE-1, 인간 텔로머라제 역전사효소, RU1, RU2, 장 카르복실 에스테라제, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, GPA7 및 IGLL1을 포함하는 군으로부터 선택될 수 있다.The present invention further relates to administration of (i) a multispecific antibody directed against two or more epitopes of HER3, or a multispecific antibody directed against an epitope of HER3 and an epitope of one or more additional different antigens, and/or (ii) administration of HER3 Treatment of a proliferative disease or disorder comprising administration of a targeting agent, such as an antibody and one or more discrete targeting agents directed against one or more cancer-associated antigens, wherein one or more of the targeting agents, such as a HER3 targeting agent, is radiolabeled Multispecific targeting agents, compositions and related methods are provided. Additional different antigens, e.g., their expression on cells involved in various diseases or disorders, such as proliferative disorders, e.g., solid tumor cancers, such as HER3, are also upregulated or can be upregulated. This may be an antigen that is upregulated. For example, additional different antigens include mesothelin, TSHR, CD19, CD123, CD22, CD30, CD45, CD171, CD138, CS-1, CLL-1, GD2, GD3, B-cell maturation antigen (BCMA), Tn Ag, prostate specific membrane antigen (PSMA), ROR1, FLT3, TROP2, T-cell receptor gamma (TCRγ) chain alternating reading frame protein (TRAP), fibroblast activation protein (FAP), calreticulin, phosphatidylserine, GRP78 (BiP), TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, interleukin-11 receptor a (IL-11Ra), PSCA, PRSS21, VEGFR2, Lewis Y, CD24, platelet-derived growth factor receptor- beta (PDGFR-beta), SSEA-4, CD20, folate receptor alpha (FRa), ERBB2 (Her2/neu), MUC1, epidermal growth factor receptor (EGFR), EGFRvIII, NCAM, protase, PAP, ELF2M, F Lin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, fucosyl GM1, sLe, GM3, DR5, 5T4, TGS5, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/ CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD 179a, ALK, polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY- ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6,E7, MAGE A1, MAGEA3, MAGEA3/A6, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD -CT-2, Fos-associated antigen 1, prostein, subvivin and telomerase, PCTA-1/galectin 8, KRAS, MelanA/MART1, Ras mutant, hTERT, sarcoma potential breakpoint, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, androgen receptor, cyclin B1, MYCN, RhoC, TRP-2, CYP1B 1, BORIS, SART3, PAX5, OY-TES 1, LCK, AKAP-4, SSX2, RAGE- 1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5 , GPA7 and IGLL1.
본 발명에 사용하기 위해 방사성표지되거나, 비표지되거나 또는 약물-접합될 수 있는 예시적인 DR5 (사멸 수용체 5) 표적화제는 모노클로날 항-DR5 항체 마파투무맙, 코나투무맙, 렉사투무맙, 티가투주맙, 드로지투맙, 및 LBY-135를 포함한다. 이러한 DR5 표적화제는, 예를 들어, 난소암, 유방암, 자궁경부 전립선암, 위암, 방광암, 폐암, 흑색종, 결장직장암 및 편평 세포 암종 암 및 본원에 개시된 암 중 임의의 것을 치료하기 위해 방사성표지된 HER3 표적화제와 조합하여 사용될 수 있다.Exemplary DR5 (death receptor 5) targeting agents that may be radiolabeled, unlabeled or drug-conjugated for use in the present invention include the monoclonal anti-DR5 antibodies mapatumumab, conatumumab, lexatumumab, Tigatuzumab, Drozitumab, and LBY-135. Such DR5 targeting agents can be radiolabeled to treat, for example, ovarian, breast, cervical, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein. It can be used in combination with a HER3 targeting agent.
본 발명에 사용하기 위해 방사성표지되거나, 약물-접합되거나 또는 비표지될 수 있는 예시적인 5T4 (영양막 당단백질 (TBPG)) 표적화제는 항-5T4 모노클로날 항체 MED10641, ALG.APV-527, Tb535, H6-DM5, 및 ZV0508 뿐만 아니라 나프투모맙 에스타페나톡스 또는 그의 Fab 부분을 포함한다. 이러한 5T4 표적화제는, 예를 들어, 난소암, 두경부암, 유방암, 전립선암, 위암, 방광암, 폐암, 흑색종, 결장직장암 및 편평 세포 암종 암 및 본원에 개시된 암 중 임의의 것을 치료하기 위해 방사성표지된 HER3 표적화제와 조합하여 사용될 수 있다.Exemplary 5T4 (trophoblast glycoprotein (TBPG)) targeting agents that may be radiolabeled, drug-conjugated or unlabeled for use in the present invention are anti-5T4 monoclonal antibodies MED10641, ALG.APV-527, Tb535 , H6-DM5, and ZV0508 as well as naptumomab estafenatox or the Fab portion thereof. Such 5T4 targeting agents are radioactive to treat, for example, ovarian, head and neck, breast, prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein. It can be used in combination with labeled HER3 targeting agents.
본 발명에 사용하기 위해 방사성표지되거나, 약물-접합되거나 또는 비표지될 수 있는 예시적인 HER2 (ERBB2) 표적화제는 모노클로날 항체 트라스투주맙 및 페르투주맙을 포함한다. 본 출원인들은 트라스투주맙을 p-SCN-DOTA와 성공적으로 접합시키고 조성물을 225Ac 또는 177Lu로 방사성표지하였다. 사용될 수 있는 예시적인 HER2 표적화 ADC는 팜-트라스투주맙 데룩스테칸-nxki [에네르투(Enhertu®); 아스트라제네카(AstraZeneca)/다이이치 산쿄] 및 트라스투주맙 엠탄신 [로슈/제넨테크(Genentech)]을 포함한다. 항-HER2 항체는, 예를 들어, 또한 HER3/HER2의 임의의 이용 가능한 에피토프에 대한 다중특이적 항체, 예컨대 이중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-111 및 MM-141/이스티라투맙, 메루스 NV로부터의 MCLA-128, 및 제넨테크로부터의 MEHD7945A/둘리고투맙일 수 있다. HER2 표적화제는, 예를 들어, HER2-발현 암, 예컨대 난소암, 유방암, 전이성 유방암, 식도암, 폐암, 자궁경부암 및 자궁내막암 (HER2- 및 HER3-양성 모두를 포함하나 이에 제한되지는 않음)의 치료에서 방사성표지된 HER3 표적화제와 조합하여 사용될 수 있다.Exemplary HER2 (ERBB2) targeting agents that may be radiolabeled, drug-conjugated or unlabeled for use in the present invention include the monoclonal antibodies Trastuzumab and Pertuzumab. Applicants successfully conjugated trastuzumab with p-SCN-DOTA and radiolabeled the composition with 225 Ac or 177 Lu. An exemplary HER2 targeting ADC that may be used is pharm-trastuzumab deluxtecan-nxki [Enhertu®; AstraZeneca/Daichi Sankyo] and trastuzumab emtansine [Roche/Genentech]. Anti-HER2 antibodies, for example, also include multispecific antibodies against any available epitope of HER3/HER2, such as bispecific antibodies such as MM-111 and MM-141/ from Merrimac Pharmaceuticals. Istiratumab, MCLA-128 from Merus NV, and MEHD7945A/duligotumab from Genentech. HER2 targeting agents are, for example, HER2-expressing cancers such as ovarian cancer, breast cancer, metastatic breast cancer, esophageal cancer, lung cancer, cervical cancer and endometrial cancer (including but not limited to both HER2- and HER3-positive) It can be used in combination with a radiolabeled HER3 targeting agent in the treatment of .
드럭뱅크 온라인에 의해 보고된 트라스투주맙의 중쇄 및 경쇄의 아미노산 서열은 중쇄 (서열식별번호: 102) 및 경쇄 (서열식별번호: 103)이고, 상기 쇄 중 하나 또는 둘 다를 포함하는 HER2 결합 항체가 본 발명의 다양한 실시양태에서 구현되거나 사용될 수 있다.The amino acid sequences of the heavy and light chains of Trastuzumab reported by Drugbank Online are heavy chains (SEQ ID NO: 102) and light chains (SEQ ID NO: 103), and a HER2-binding antibody comprising one or both of these chains is It can be implemented or used in various embodiments of the present invention.
드럭뱅크 온라인에 의해 보고된 페르투주맙의 중쇄 및 경쇄의 아미노산 서열은 중쇄 (서열식별번호: 104) 및 경쇄 (서열식별번호: 105)이고, 상기 쇄 중 하나 또는 둘 다를 포함하는 HER2 결합 항체가 본 발명의 다양한 실시양태에서 구현되거나 사용될 수 있다.The amino acid sequences of the heavy and light chains of Pertuzumab reported by Drugbank Online are heavy chains (SEQ ID NO: 104) and light chains (SEQ ID NO: 105), and a HER2-binding antibody comprising one or both of these chains is It can be implemented or used in various embodiments of the present invention.
본 발명에 사용하기 위해 방사성표지되거나, 약물-접합되거나, 또는 비표지될 수 있는 예시적인 CD33 표적화제는 모노클로날 항체 린투주맙, 젬투주맙 및 바다스툭시맙을 포함한다. 본원에 개시된 바와 같은 방사성표지된 HER3 표적화제와 조합하여, CD33 표적화 치료제는, 예를 들어, 골수 유래 억제 세포 (MDSC)를 고갈시킴으로써, 예를 들어, 고형 암, 예컨대 난소암, 유방암, 자궁경부 전립선암, 위암, 방광암, 폐암, 흑색종, 결장직장암 및 편평 세포 암종 암 및 본원에 개시된 암 중 임의의 것을 치료하는 데 사용될 수 있다. 한 측면에서, 방사성표지된 HER3 표적화제와 조합하여 사용되는 CD33 표적화제는 225Ac-린투주맙이다. 또 다른 측면에서, 방사성표지된 HER3 표적화제와 조합하여 사용되는 CD33 표적화제는 ADC 젬투주맙 오조가미신 [밀로타르그(Mylotarg®); 화이자(Pfizer)]이다.Exemplary CD33 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the present invention include the monoclonal antibodies lintuzumab, gemtuzumab, and badastuximab. In combination with a radiolabeled HER3 targeting agent as disclosed herein, a CD33 targeting therapeutic can, for example, by depleting bone marrow derived suppressor cells (MDSC), for example, in solid cancers such as ovarian cancer, breast cancer, cervical cancer prostate, gastric, bladder, lung, melanoma, colorectal and squamous cell carcinoma cancers and any of the cancers disclosed herein. In one aspect, the CD33 targeting agent used in combination with the radiolabeled HER3 targeting agent is 225Ac-lintuzumab. In another aspect, the CD33 targeting agent used in combination with the radiolabeled HER3 targeting agent is the ADC gemtuzumab ozogamicin [Mylotarg®; Pfizer].
본 발명에 사용하기 위해 방사성표지되거나, 약물-접합되거나, 또는 비표지될 수 있는 예시적인 CD38 표적화제는 항-CD38 모노클로날 항체, 예컨대 다라투무맙 [다르잘렉스(Darzalex®); 존슨 앤 존슨(Johnson and Johnson)] 및 이사툭시맙 [사르클리사(Sarclisa®); 사노피(Sanofi)] 또는 그의 항원-결합 단편을 포함한다. 이러한 CD38 표적화제는, 예를 들어, CD38-양성 억제 면역 세포로 침윤될 수 있는 고형 종양, 예컨대 난소암, 유방암, 자궁경부 전립선암, 위암, 방광암, 폐암, 흑색종, 결장직장암 및 편평 세포 암종 암 및 본원에 개시된 암 중 임의의 것의 치료에서 방사성표지된 HER3 표적화제와 조합하여 사용될 수 있다.Exemplary CD38 targeting agents that may be radiolabeled, drug-conjugated, or unlabeled for use in the present invention are anti-CD38 monoclonal antibodies such as daratumumab [Darzalex®; Johnson and Johnson] and isatuximab [Sarclisa®; Sanofi] or an antigen-binding fragment thereof. Such CD38 targeting agents can, for example, treat solid tumors that can be infiltrated with CD38-positive suppressor immune cells, such as ovarian cancer, breast cancer, cervical prostate cancer, gastric cancer, bladder cancer, lung cancer, melanoma, colorectal cancer and squamous cell carcinoma. It can be used in combination with a radiolabeled HER3 targeting agent in the treatment of cancer and any of the cancers disclosed herein.
본 발명의 측면에 따라 다중특이적 항체에 의해 표적화될 수 있는 (HER3에 비해) 예시적인 상이한 항원은 적어도 HER1 (EGFR), HER2 및 IGF-1R을 포함한다. 예시적인 HER3 다중특이적 표적화제는 다중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-111 또는 메루스 N.V.로부터의 MCLA-128 (즉, 제노쿠투주맙); 또는 IGF-1R/HER3에 대한 다중특이적 항체, 예컨대 메리맥 파마슈티칼즈로부터의 MM-141 (즉, 이스티라투맙); 또는 EGFR/HER3에 대한 다중특이적 항체, 예컨대 로슈로부터의 MEHD7945A (즉, 둘리고투주맙), 진게니아 인크.로부터의 세툭시맙-기반 이중특이적 자이바디, 및 심포젠으로부터의 다중특이적 항체 조성물 Sym-013을 포함한다. 추가 설명 및 예시적인 적응증에 대해서는 표 2를 또한 참조한다.Exemplary different antigens (relative to HER3) that can be targeted by multispecific antibodies according to aspects of the present invention include at least HER1 (EGFR), HER2 and IGF-1R. Exemplary HER3 multispecific targeting agents include multispecific antibodies such as MM-111 from Merrimac Pharmaceuticals or MCLA-128 from Merus NV (ie, Xenocutuzumab); or a multispecific antibody to IGF-1R/HER3 such as MM-141 from Merrimac Pharmaceuticals (ie istiratumab); or multispecific antibodies against EGFR/HER3, such as MEHD7945A from Roche (i.e., duligotuzumab), cetuximab-based bispecific xybodies from Zingenia Inc., and multispecific antibodies from Symposen. Contains the composition Sym-013. See also Table 2 for further explanation and exemplary indications.
<표 2><Table 2>
본 발명은 또한 HER3의 적어도 하나의 에피토프에 대한 제1 항체의 투여 및 제2 항체의 투여를 포함하는, 증식성 질환 또는 장애를 치료하는 방법을 제공하며, 여기서 제2 항체는 제1 항체와 상이한 HER3의 에피토프에 대한 항체이거나, 또는 상이한 항원, 예컨대 상기 제시된 상이한 항원의 목록으로부터 선택된 하나 이상의 항원의 에피토프에 대한 항체이다. HER3 항체 중 하나 이상이 방사성표지될 수 있다. 상이한 항원에 대한 항체는 예를 들어, 또한 임의의 조합으로 방사성표지될 수 있다.The invention also provides a method of treating a proliferative disease or disorder comprising administering a first antibody to at least one epitope of HER3 and administering a second antibody, wherein the second antibody is different from the first antibody. It is an antibody against an epitope of HER3, or an antibody against a different antigen, such as an epitope of one or more antigens selected from the list of different antigens set forth above. One or more of the HER3 antibodies may be radiolabeled. Antibodies to different antigens may also be radiolabeled, for example in any combination.
상기 나타낸 바와 같은 다중특이적 항체 또는 하나 초과의 모노클로날 항체로서 제시된 이러한 조합은 단독 요법의 부작용을 감소시키면서 HER3에 대한 항체만을 사용한 단독 요법의 유효성에 필적하는 상승적 치료 효과를 전달할 수 있다. 더욱이, 그러한 조합은 단독 요법에 비해 개선된 유효성을 전달할 수 있으며, 이는 예를 들어, 총 종양 세포 수의 감소, 재발되기 까지의 시간 증가, 및 환자 건강의 다른 지표에 의해 측정될 수 있다.Such combinations, presented as multispecific antibodies or more than one monoclonal antibody as indicated above, can deliver a synergistic therapeutic effect comparable to the effectiveness of monotherapy using only antibodies to HER3 while reducing the side effects of monotherapy. Moreover, such combinations may deliver improved efficacy over monotherapy, as measured by, for example, reduction in total tumor cell number, increased time to recurrence, and other indicators of patient health.
상기 방법이 다중특이적 항체의 투여를 포함하는 경우, 제1 표적 인식 성분은, 예를 들어, 제1 완전한 길이의 중쇄 및 제1 완전한 길이의 경쇄, 제1 Fab 단편, 제1 단일 쇄 가변 단편 (scFv), 또는 다른 유형의 항체 중 하나를 포함할 수 있다. 제2 표적 인식 성분은 예를 들어, 제2 완전한 길이의 중쇄 및 제2 완전한 길이의 경쇄, 제2 Fab 단편, 또는 제2 단일 쇄 가변 단편 (scFv) 또는 다른 유형의 항체 중 하나를 포함할 수 있다. 더욱이, 제2 표적 인식 성분은 HER3 항원의 상이한 에피토프로부터 유래될 수 있거나 상기 열거된 항원 중 임의의 것으로부터 유래될 수 있다.Where the method involves administration of a multispecific antibody, the first target recognition component may comprise, for example, a first full-length heavy chain and a first full-length light chain, a first Fab fragment, a first single chain variable fragment (scFv), or other types of antibodies. The second target recognition component may include, for example, a second full-length heavy chain and a second full-length light chain, a second Fab fragment, or a second single chain variable fragment (scFv) or one of the other types of antibodies. there is. Moreover, the second target recognition component may be derived from a different epitope of the HER3 antigen or may be derived from any of the antigens listed above.
HER3 표적화제는 방사성동위원소를 포함할 수 있고, 다른 항원에 대한 임의의 부가의 항체는 임의로 방사성동위원소를 포함할 수 있다. 본 발명의 특정 측면에 따르면, 면역요법이 이중특이적 항체를 포함하는 경우, 제1 표적 인식 성분 및 제2 표적 인식 성분 중 하나 또는 둘 다, 또는 이중특이적 표적화제의 임의의 부분은 방사성동위원소를 포함할 수 있다.The HER3 targeting agent may include a radioisotope, and any additional antibodies to other antigens may optionally include a radioisotope. According to certain aspects of the invention, where the immunotherapy comprises a bispecific antibody, one or both of the first target recognition component and the second target recognition component, or any portion of the bispecific targeting component, is a radioisotope may contain elements.
본 발명의 특정 측면에 따르면, 방사성표지된 표적화제는 대조군 표적화제와 본질적으로 동일한 항원에 대해 면역반응성을 나타낼 수 있으며, 여기서 대조군 표적화제는 방사성표지된 표적화제와 동일한 항원 (즉, HER3)의 에피토프에 대한 네이키드 표적화제 또는 그렇지 않으면 비표지된 표적화제를 포함한다.According to certain aspects of the invention, a radiolabeled targeting agent may be immunoreactive against essentially the same antigen as a control targeting agent, wherein the control targeting agent is immunoreactive against the same antigen (i.e., HER3) as the radiolabeled targeting agent. Naked or otherwise unlabeled targeting agents to the epitope.
본 발명의 특정 측면에 따르면, 표적화제는 225Ac로 표지될 수 있고, 대조군 모노클로날 항체보다 HER3-양성 세포의 세포 사멸을 유발하는 데 적어도 5배 더 유효할 수 있으며, 여기서 대조군 모노클로날 항체는 225Ac 표지된 항체와 동일한 항원 에피토프에 대한 네이키드 또는 비표지된 항체를 포함한다. 예를 들어, 225Ac 표지된 모노클로날 항체는 대조군 모노클로날 항체보다 HER3-양성 세포의 세포 사멸을 유발하는 데 적어도 10배 더 유효하거나, 적어도 20배 더 유효하거나, 적어도 50배 더 유효하거나, 또는 적어도 100배 더 유효할 수 있다.According to certain aspects of the invention, the targeting agent may be labeled with 225 Ac and may be at least 5-fold more effective at inducing cell death of HER3-positive cells than a control monoclonal antibody, wherein the control monoclonal antibody Antibodies include naked or unlabeled antibodies directed against the same antigenic epitope as the 225 Ac labeled antibody. For example, a 225 Ac labeled monoclonal antibody is at least 10-fold more effective, at least 20-fold more effective, at least 50-fold more effective at inducing apoptosis of HER3-positive cells than a control monoclonal antibody, or , or at least 100 times more effective.
본 발명의 특정 측면에 따르면, 상기 방법은 HER3 표적화제, 예컨대 항체, 항체 단편 등의 표지된 분획 및 비표지된 (예를 들어, "네이키드") 분획의 투여를 포함할 수 있다. 예를 들어, 비표지된 분획은 표지된 분획과 동일한 에피토프에 대한 동일한 항체를 포함할 수 있다. 이러한 방식으로, 항체의 전체 방사능은 변할 수 있거나 일정하게 유지될 수 있는 반면, 전체 항체 단백질 농도는 각각 일정하게 유지되거나 변할 수 있다. 예를 들어, 투여되는 비표지된 항체 분획의 총 단백질 농도는 치료될 질환의 정확한 특성, 환자의 연령 및 체중, 모노클로날 항체의 정체, 및 모노클로날 항체의 표지화를 위해 선택된 표지 (예를 들어, 방사성핵종)에 따라 달라질 수 있다.According to certain aspects of the invention, the methods may include administration of labeled and unlabeled (eg, “naked”) fractions of a HER3 targeting agent, such as an antibody, antibody fragment, etc. For example, the unlabeled fraction may contain the same antibodies to the same epitope as the labeled fraction. In this way, the total radioactivity of the antibody can be varied or held constant, while the total antibody protein concentration can be held constant or varied, respectively. For example, the total protein concentration of the unlabeled antibody fraction to be administered depends on the precise nature of the disease being treated, the age and weight of the patient, the identity of the monoclonal antibody, and the marker selected for labeling the monoclonal antibody (e.g. e.g. radionuclides).
본 발명의 특정 측면에 따르면, 항-HER3 항체의 유효량은 항-HER3 항체의 최대 허용 용량 (MTD)이다.According to certain aspects of the invention, the effective amount of the anti-HER3 antibody is the maximum tolerated dose (MTD) of the anti-HER3 antibody.
본 발명의 특정 방법 측면에 따르면, 하나 초과의 항체가 투여될 때, 이들 항체는 동시에 투여될 수 있다. 이와 같이, 본 발명의 특정 측면에 따르면, 항체는 단일 조성물로 제공될 수 있다. 대안적으로, 2개의 항체가 순차적으로 투여될 수 있다. 이와 같이, 방사성표지된 HER3 표적화제는 제2 항체의 투여 전, 제2 항체의 투여 후, 또는 제2 항체의 투여 전 및 후 둘 다에 투여될 수 있다. 더욱이, 제2 항체는 방사성표지된 HER3 표적화제의 투여 전에, 방사성표지된 HER3 표적화제의 투여 후에, 또는 방사성표지된 HER3 표적화제의 투여 전 및 후 둘 다에 투여될 수 있다.According to certain method aspects of the invention, when more than one antibody is administered, these antibodies may be administered simultaneously. As such, according to certain aspects of the invention, the antibody may be provided in a single composition. Alternatively, the two antibodies can be administered sequentially. As such, the radiolabeled HER3 targeting agent can be administered before administration of the second antibody, after administration of the second antibody, or both before and after administration of the second antibody. Moreover, the second antibody can be administered prior to administration of the radiolabeled HER3-targeting agent, after administration of the radiolabeled HER3-targeting agent, or both before and after administration of the radiolabeled HER3-targeting agent.
본 발명의 방법의 특정 측면에 따르면, 방사성표지된 HER3 표적화제는 치료 기간 전체에 걸쳐 7일, 10일, 12일, 14일, 20일, 24일, 28일, 35일, 및 42일마다 1회로 이루어진 군으로부터 선택된 투여 스케줄에 따라 투여될 수 있으며, 여기서 치료 기간은 적어도 2회 투여를 포함한다.According to certain aspects of the methods of the invention, the radiolabeled HER3 targeting agent is administered every 7 days, 10 days, 12 days, 14 days, 20 days, 24 days, 28 days, 35 days, and 42 days throughout the treatment period. It may be administered according to an administration schedule selected from the group consisting of one administration, wherein the treatment period includes at least two administrations.
본 발명의 특정 측면에 따르면, 방사성표지된 HER3 표적화제는 2회 투여, 예컨대 치료 기간의 제1일과 제5일, 제6일, 제7일, 제8일, 제9일 또는 제10일의 투여, 또는 치료 기간의 제1일과 제8일의 투여를 포함하는 투여 스케줄에 따라 투여될 수 있다.According to certain aspects of the invention, the radiolabeled HER3 targeting agent is administered in two doses, e.g., on
본 발명의 방사성표지된 HER3 표적화제의 투여는 다른 치료제에 더하여, 국부적 또는 전신적 치료가 바람직한지 여부 및 치료될 부위에 따라 수많은 방식으로 제공될 수 있다. 투여는 기관내, 비강내, 표피 및 경피, 경구 또는 비경구일 수 있다. 비경구 투여는 정맥내, 동맥내, 피하, 복강내 또는 근육내 주사 또는 주입; 또는 두개내, 예를 들어 척수강내 또는 심실내 투여를 포함한다. 일부 실시양태에서 표적화제(들) 및/또는 다른 치료제를 포함하는 서방형 제제가 투여될 수 있다. 다양한 작용제는 단일 치료로서, 또는 암의 하나 이상의 증상을 감소 또는 완화시키거나 또 다른 바람직한 효과를 달성하는 일정 기간 동안 필요에 따라 지속되는 일련의 치료로서 투여될 수 있다.Administration of the radiolabeled HER3 targeting agent of the present invention can be provided in a number of ways depending on the area to be treated and whether local or systemic treatment is desired, in addition to other therapeutic agents. Administration can be intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, eg intrathecal or intraventricular administration. In some embodiments, a sustained release formulation comprising the targeting agent(s) and/or other therapeutic agent may be administered. The various agents may be administered as a single treatment or as a series of treatments continued as needed for a period of time to reduce or alleviate one or more symptoms of cancer or achieve another desired effect.
용량(들)은, 예를 들어 대상체의 정체, 크기 및 상태에 따라, 추가로 조성물이 투여되는 경로 및 원하는 효과에 따라 달라질 수 있다. 치료제의 적절한 용량은 조정될 발현 또는 활성에 관한 효능에 따라 달라진다. 치료제는 처음에 상대적으로 낮은 용량으로 동물 (예를 들어, 인간)에게 투여될 수 있으며, 적절한 반응이 수득될 때까지 후속적으로 용량이 증가된다.The dose(s) may vary depending, for example, on the identity, size and condition of the subject, further depending on the route by which the composition is administered and the effect desired. Appropriate doses of therapeutic agents depend on the potency with respect to expression or activity to be modulated. A therapeutic agent may be initially administered to an animal (eg, human) at a relatively low dose, with the dose subsequently increased until an adequate response is obtained.
방사성표지된 HER3 표적화제는 하나 이상의 부가의 치료제와 동시에 또는 순차적으로 투여될 수 있다. 더욱이, 하나 초과의 부가의 치료제가 포함되는 경우, 부가의 치료제는 동시에 또는 서로 순차적으로 및/또는 방사성표지된 HER3 표적화제와 함께 투여될 수 있다.The radiolabeled HER3 targeting agent may be administered concurrently or sequentially with one or more additional therapeutic agents. Moreover, when more than one additional therapeutic agent is included, the additional therapeutic agents can be administered simultaneously or sequentially with each other and/or with the radiolabeled HER3 targeting agent.
HER3HER3 표적화제를 targeting agent 방사성표지시키는radiolabeling 것 thing
본원에 개시된 HER3 표적화제 및 다른 표적화제는, 예를 들어, 킬레이터 분자의 접합을 통해, 및 그에 대한 방사성동위원소의 킬레이트화를 통해, 방사성동위원소, 예컨대 베타 방사체 (예를 들어 177Lu) 또는 알파 방사체 (예를 들어, 225Ac)로 표지될 수 있다. 특정 측면에 따르면, 표적화제는 독특한 접합 부위인 글루타민 (즉, Gln-295, Q295)을 발견하여 이작용성 킬레이터 분자와 접합할 수 있도록 하는 목적을 위해, 불변 영역, 예컨대 중쇄 CH2 도메인 내의 아스파라긴-297 (Asn-297, N297; 카바트 넘버)에서 탈글리코실화되는 것에 대한 항체일 수 있다.The HER3 targeting agents and other targeting agents disclosed herein can be used to target a radioisotope, such as a beta emitter (e.g., 177 Lu), for example, via conjugation to a chelator molecule, and via chelation of a radioisotope thereto. or with an alpha emitter (eg 225 Ac). According to certain aspects, the targeting agent is an asparagine- in the constant region, such as the heavy chain CH2 domain, for the purpose of finding a unique conjugation site, glutamine (i.e., Gln-295, Q295) so that it can conjugate with the bifunctional chelator molecule. 297 (Asn-297, N297; Kabat number).
특정 측면에 따르면, 방사선치료제는 환원제를 사용하는 것과 같이 환원된 디술피드 결합을 가질 수 있는 항체일 수 있으며, 이는 이후 이작용성 킬레이터 분자와 접합할 목적으로 데히드로알라닌으로 전환될 수 있다.According to certain aspects, the radiotherapeutic agent may be an antibody that may have reduced disulfide bonds, such as with a reducing agent, which may then be converted to dehydroalanine for conjugation with a bifunctional chelator molecule.
특정 측면에 따르면, 방사선치료제는 그의 디술피드 결합이 환원제를 사용하여 환원된 항체일 수 있으며, 이는 이후 아릴 가교를 통해 이작용성 킬레이터 분자와 접합된다. 예를 들어, 특정 측면에 따르면 링커 분자, 예컨대 3,5-비스(브로모메틸)벤젠을 사용하여 항체 상의 유리 술프히드릴 기를 가교할 수 있다.According to certain aspects, the radiotherapeutic agent may be an antibody whose disulfide bonds have been reduced using a reducing agent, which is then conjugated to a bifunctional chelator molecule via an aryl bridge. For example, according to certain aspects, a linker molecule such as 3,5-bis(bromomethyl)benzene may be used to bridge free sulfhydryl groups on an antibody.
특정 측면에 따르면, 방사선치료제는 특정의 특이적 기존 아미노산이 시스테인(들)으로 대체될 수 있고 이어서 부위-특이적 표지화에 사용될 수 있는 항체일 수 있다.According to certain aspects, the radiotherapeutic agent can be an antibody in which certain specific pre-existing amino acids can be replaced with cysteine(s) and then used for site-specific labeling.
본 발명의 다양한 측면에서 표적화제에 연결될 수 있는 예시적인 킬레이터는 하기를 포함한다: 1,4,7,10-테트라아자시클로도데칸-1,4,7-트리아세트산 (DO3A) 또는 그의 유도체; 1,4,7-트리아자시클로노난-1,4-디아세트산 (NODA) 또는 그의 유도체; 1,4,7-트리아자시클로노난-1,4,7-트리아세트산 (NOTA) 또는 그의 유도체; 1,4,7,10-테트라아자시클로도데칸-1,4,7,10-테트라아세트산 (DOTA) 또는 그의 유도체; 1,4,7-트리아자시클로노난, 1-글루타르산-4,7-디아세트산 (NODAGA) 또는 그의 유도체; 1,4,7,10-테트라아자시클로데칸, 1-글루타르산-4,7,10-트리아세트산 (DOTAGA) 또는 그의 유도체; 1,4,8,11-테트라아자시클로테트라데칸-1,4,8,11-테트라아세트산 (TETA) 또는 그의 유도체; 1,4,8,11-테트라아자비시클로[6.6.2]헥사데칸-4,11-디아세트산 (CB-TE2A) 또는 그의 유도체; 디에틸렌 트리아민 펜타아세트산 (DTPA), 그의 디에스테르 또는 그의 유도체; 2-시클로헥실 디에틸렌 트리아민 펜타아세트산 (CHX-A"-DTPA) 또는 그의 유도체; 데포록사민 (DFO) 또는 그의 유도체; 1,2-[[6-카르복시피리딘-2-일]메틸아미노]에탄 (H2dedpa) 또는 그의 유도체; DADA 또는 그의 유도체; 1,4,7,10-테트라아자시클로도데칸-1,4,7,10-테트라(메틸렌 포스폰산) (DOTP) 또는 그의 유도체; 4-아미노-6-[[16-[(6-카르복시피리딘-2-일)메틸]-1,4,10,13-테트라옥사-7,16-디아자시클로옥타덱-7-일]메틸]피리딘-2-카르복실산 (MACROPA-NH2) 또는 그의 유도체; MACROPA 또는 그의 유도체; 1,4,7,10-테트라키스(카르바모일메틸)-1,4,7,10-테트라아자시클로도데칸 (TCMC) 또는 그의 유도체; {4-[2-(비스-카르복시메틸아미노)-에틸]-7-카르복시메틸-[1,4,7]트리아조난-1-일}-아세트산 (NETA) 또는 그의 유도체; 디암사르 또는 그의 유도체; 1,4,7-트리아자시클로노난-1,4,7-트리스[메틸(2-카르복시에틸)포스핀산 (TRAP, PRP9, TRAP-Pr) 또는 그의 유도체; N,N'-비스(6-카르복시-2-피리딜메틸)에틸렌디아민-N,N'-디아세트산 (H4octapa) 또는 그의 유도체; N,N'-[1-벤질-1,2,3-트리아졸-4-일]메틸-N,N'-[6-(카르복시)피리딘-2-일]-1,2-디아미노에탄 (H2azapa) 또는 그의 유도체; N,N"-[[6-(카르복시)피리딘-2-일]메틸]디에틸렌트리아민-N,N',N"-트리아세트산 (H5decapa) 또는 그의 유도체; N,N'-비스(2-히드록시-5-술포벤질)에틸렌디아민-N,N'-디아세트산 (SHBED) 또는 그의 유도체; N,N'-비스(2-히드록시벤질)에틸렌디아민-N,N'-디아세트산 (HBED) 또는 그의 유도체; 3,6,9,15-테트라아자비시클로[9.3.1]펜타데카-1(15),11,13-트리엔-3,6,9,-트리아세트산 (PCTA) 또는 그의 유도체; 데스페리옥사민 B (DFO) 또는 그의 유도체; N,N'-(메틸렌포스포네이트)-N,N'-[6-(메톡시카르보닐)피리딘-2-일]메틸-1,2-디아미노에탄 (H6phospa) 또는 그의 유도체; 1,4,7,10,13,16-헥사아자시클로헥사데칸-N,N',N",N'",N"",N""'-헥사아세트산 (HEHA) 또는 그의 유도체; 1,4,7,10,13-펜타아자시클로펜타데칸-N,N',N",N'",N""-펜타아세트산 (PEPA) 또는 그의 유도체; 또는 3,4,3-LI(1,2-HOPO) 또는 그의 유도체.Exemplary chelators that can be linked to targeting agents in various aspects of the invention include: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) or a derivative thereof ; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) or a derivative thereof; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) or a derivative thereof; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or a derivative thereof; 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) or a derivative thereof; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) or derivatives thereof; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or a derivative thereof; 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) or a derivative thereof; diethylene triamine pentaacetic acid (DTPA), a diester thereof or a derivative thereof; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A″-DTPA) or a derivative thereof; deforoxamine (DFO) or a derivative thereof; 1,2-[[6-carboxypyridin-2-yl]methylamino] ethane (H 2 dedpa) or a derivative thereof DADA or a derivative thereof 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (DOTP) or a derivative thereof; 4-amino-6-[[16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl ]Pyridine-2-carboxylic acid (MACROPA-NH 2 ) or a derivative thereof; MACROPA or a derivative thereof; 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraaza Cyclododecane (TCMC) or its derivatives {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid (NETA ) or a derivative thereof; Diamsar or a derivative thereof; 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid (TRAP, PRP9, TRAP-Pr) or its N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-diacetic acid (H4octapa) or its derivatives;N,N'-[1-benzyl-1,2, 3-triazol-4-yl]methyl-N,N'-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane (H2azapa) or a derivative thereof; N,N"-[[ 6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N',N"-triacetic acid (H5decapa) or a derivative thereof; N,N'-bis(2-hydroxy-5-sulfo Benzyl)ethylenediamine-N,N'-diacetic acid (SHBED) or a derivative thereof N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) or a derivative thereof 3 ,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA) or its derivatives; B (DFO) or a derivative thereof: N,N'-(methylenephosphonate)-N,N'-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane ( H6phospa) or a derivative thereof; 1,4,7,10,13,16-hexaazacyclohexadecane-N,N',N",N'",N"",N""'-hexaacetic acid (HEHA) or a derivative thereof; 1,4,7,10,13-pentaazacyclopentadecane-N,N',N",N'",N""-pentaacetic acid (PEPA) or a derivative thereof; or 3,4,3-LI(1,2-HOPO) or a derivative thereof.
특정 측면에 따르면, 표적화제는 하나 이상의 방사성핵종을 킬레이트할 수 있는 적합한 이작용성 킬레이터의 화학적 접합을 통해 방사성표지될 수 있다. 사용될 수 있는 예시적인 킬레이터 분자는 p-SCN-Bn-DOTA, NH2-DOTA, NH2-(CH2)1-20-DOTA, NH2-(PEG)1-20-DOTA, HS-DOTA, HS-(CH2)1-20-DOTA, HS-(PEG)1-20-DOTA, 디브로모-S-(CH2)1-20-DOTA, 디브로모-S-(PEG)1-20-DOTA, p-SCN-Bn-DOTP, NH2-DOTP, NH2-(CH2)1-20-DOTP, NH2-(PEG)1-20-DOTP, HS-DOTP, HS-(CH2)1-20-DOTP, HS-(PEG)1-20-DOTP, 디브로모-S-(CH2)1-20-DOTP, 및 디브로모-S-(PEG)1-20-DOTP를 포함한다.According to certain aspects, the targeting agent may be radiolabeled via chemical conjugation of a suitable bifunctional chelator capable of chelating one or more radionuclides. Exemplary chelator molecules that may be used are p-SCN-Bn-DOTA, NH 2 -DOTA, NH 2 -(CH 2 ) 1-20 -DOTA, NH 2 -(PEG) 1-20 -DOTA, HS-DOTA , HS-(CH 2 ) 1-20 -DOTA, HS-(PEG) 1-20 -DOTA, dibromo-S-(CH 2 ) 1-20 -DOTA, dibromo-S-(PEG) 1 -20 -DOTA, p-SCN-Bn-DOTP, NH 2 -DOTP, NH 2 -(CH 2 ) 1-20 -DOTP, NH 2 -(PEG) 1-20 -DOTP, HS-DOTP, HS-( CH 2 ) 1-20 -DOTP, HS-(PEG) 1-20 -DOTP, dibromo-S-(CH 2 ) 1-20 -DOTP, and dibromo-S-(PEG) 1-20 - Includes DOTP.
예를 들어, 킬레이터 분자는 링커 분자를 통해 표적화제에 부착될 수 있다. 예시적인 링커 분자는 하기를 포함한다:For example, a chelator molecule can be attached to a targeting agent through a linker molecule. Exemplary linker molecules include:
-CH2(C6H4)NH2 또는 -CH2(C6H4)NH-X-Y,-CH 2 (C 6 H 4 )NH 2 or -CH 2 (C 6 H 4 )NH-XY;
여기서 X는where X is
-R2-CH2CH2O(CH2CH2O)nCH2CH2-,-R 2 -CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CH 2 -,
-R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O)nCH2CH2-,-R 2 -CH 2 CH 2 NHC(O)CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CH 2 -,
-R2-(CH2)nCH2-,-R 2 -(CH 2 ) n CH 2 -,
-R2-CH2CH2NHC(O)(CH2)nCH2-,-R 2 -CH 2 CH 2 NHC(O)(CH 2 ) n CH 2 -,
-R2-CH(C(O)R3)CH2- (여기서, R3은 -OH 또는 짧은 펩티드 (1-20개 아미노산)이다),-R 2 -CH(C(O)R 3 )CH 2 -, where R 3 is -OH or a short peptide (1-20 amino acids);
-R2-CH2CH2O(CH2CH2O)nCH2C(O)O-, 또는-R 2 -CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 C(O)O-, or
-R2-CH2CH2NHC(O)CH2CH2O(CH2CH2O)nCH2CC(O)O-이며,-R 2 -CH 2 CH 2 NHC(O)CH 2 CH 2 O(CH 2 CH 2 O) n CH 2 CC(O)O-;
여기서 n은 1-20이고,where n is 1-20,
R2는 -C(O)- 또는 -C(S)NH-이고;R 2 is -C(O)- or -C(S)NH-;
Y는 -NH2 또는 -SR4-이며, 여기서 R4는 -H 또는 -CH2-3,5-비스(브로모메틸)벤젠이다.Y is -NH 2 or -SR 4 -, wherein R 4 is -H or -CH 2 -3,5-bis(bromomethyl)benzene.
표적화제, 예컨대 단백질 표적화제, 예를 들어 항체 및 항원-결합 항체 단편, 및 펩티드 표적화제는 예를 들어, 방사성핵종의 킬레이트화를 통해 표적화제를 방사성표지하기 위해 킬레이터와 접합될 수 있다. 예를 들어, 리신(들)을 포함하는 이러한 단백질 또는 펩티드 표적화제는 "p-SCN-Bn-DOTA" [카탈로그 # B205; 매크로사이클릭스, 인크. (Macrocyclics, Inc.; 미국 텍사스주 플래이노)]로서 공지되기도 한 이작용성 작용제인 S-2-(4-이소티오시아나토벤질)-1,4,7,10-테트라아자시클로도데칸 테트라아세트산을 사용하여 DOTA 킬레이트 모이어티에 편리하게 접합될 수 있다. p-SCN-Bn-DOTA는 미국 특허 번호 4,923,985에 충분히 기재된 다단계 유기 합성에 의해 합성될 수 있다. DOTA 모이어티에 의한 방사성핵종의 킬레이트화는 항체와 p-SCN-Bn-DOTA의 화학적 접합 전 및/또는 상기 접합 후에 수행될 수 있다.Targeting agents, such as protein targeting agents such as antibodies and antigen-binding antibody fragments, and peptide targeting agents can be conjugated with chelators to radiolabel the targeting agent, for example through chelation of a radionuclide. For example, such a protein or peptide targeting agent comprising lysine(s) is “p-SCN-Bn-DOTA” [catalog # B205; Macrocyclics, Inc. (Macrocyclics, Inc.; Plano, Texas, USA)], a bifunctional agent also known as S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid. Can be conveniently conjugated to the DOTA chelating moiety using p-SCN-Bn-DOTA can be synthesized by multi-step organic synthesis fully described in U.S. Patent No. 4,923,985. Chelation of the radionuclide by the DOTA moiety can be performed before and/or after chemical conjugation of the antibody with p-SCN-Bn-DOTA.
예시적인 방사성핵종으로 킬레이터-접합된 표적화제를 표지화하는 방법은 실시예 1에 기재되어 있다.A method for labeling chelator-conjugated targeting agents with exemplary radionuclides is described in Example 1.
진단 측면diagnostic aspect
본원에 의해 개시된 방법은 HER3-양성 세포가 존재하는지, 존재하는 정도 및/또는 그들의 국재화를 확인하기 위해 대상체를 진단하는 것을 포함할 수 있다. HER3-양성 세포는 다수의 생물학적 표본, 예컨대 대상체로부터의 혈액 샘플 중의 순환하는 세포 또는 대상체의 생검 내의 종양 세포에 존재할 수 있다. 한 측면에서, 진단 단계는 일반적으로 대상체로부터의 혈액 또는 조직 샘플을 수득하고 그 샘플을 기판 위에 고정시키는 것을 포함할 수 있다. HER3 항원의 존재 또는 부재는 진단 항체, 펩티드 또는 소분자를 사용하여 검출될 수 있으며, 여기서 진단 항체, 펩티드 또는 소분자는 관련 기술분야에 공지된 표준 영상화 표지 중 임의의 것으로 표지된다. 예시적인 표지화제는 예를 들어, 방사성표지, 예컨대 3H, 14C, 32P, 35S, 및 125I; 형광 또는 화학발광 화합물, 예컨대 플루오레세인 이소티오시아네이트, 로다민 또는 루시페린; 및 효소, 예컨대 알칼리성 포스파타제, β-갈락토시다제 또는 서양고추냉이 퍼옥시다제를 포함한다. 이러한 진단 검정에 사용되는 예시적인 HER3 표적화제는 HER3에 대한 인간 또는 인간화 항체를 포함한다.The methods disclosed herein may include diagnosing a subject to determine whether HER3-positive cells are present, the degree to which they are present, and/or their localization. HER3-positive cells can be present in many biological specimens, such as circulating cells in a blood sample from a subject or tumor cells in a biopsy of a subject. In one aspect, the diagnosing step may generally include obtaining a blood or tissue sample from a subject and immobilizing the sample on a substrate. The presence or absence of the HER3 antigen can be detected using a diagnostic antibody, peptide or small molecule, wherein the diagnostic antibody, peptide or small molecule is labeled with any of the standard imaging labels known in the art. Exemplary labeling agents include, for example, radiolabels such as 3 H, 14 C, 32 P, 35 S, and 125 I; fluorescent or chemiluminescent compounds such as fluorescein isothiocyanate, rhodamine or luciferin; and enzymes such as alkaline phosphatase, β-galactosidase or horseradish peroxidase. Exemplary HER3 targeting agents for use in such diagnostic assays include human or humanized antibodies to HER3.
또 다른 측면에서, 상기 방법은 방사성핵종, 예컨대 PET 영상화의 경우에는 18F, 11C, 68Ga, 64Cu, 89Zr, 또는 124I 중 임의의 것, 또는 SPECT 영상화의 경우에는 99mTc 또는 111In으로 표지된 HER3 표적화제를 사용하여 HER3-양성 세포가 존재하는지 확인하기 위해 대상체를 진단하는 것을 포함할 수 있다. 따라서, 상기 방법은 18F, 11C, 68Ga, 64Cu, 89Zr, 124I, 99mTc, 또는 111In 중 하나 이상으로 표지된 HER3 표적화제를 대상체에게 투여하는 것, 및 대상체에 대해 비-침습적 영상화 기술을 수행하는 것, 예컨대 대상체에 대해 PET 또는 SPECT 스캔을 수행하는 것을 포함할 수 있다. 상기 방법은 영상화를 위해 방사성표지된 HER3 표적화제를 대상체에게 투여하는 것, 및 표적화제가 대상체의 조직 내의 표적과 결합하기에 충분한 시간 후에 영상화를 수행하는 것을 포함할 수 있다. 표적화제가 대상체의 조직 내의 표적과 결합하기에 충분한 시간은, 예를 들어, 적어도 20분, 적어도 30분, 적어도 60분, 또는 20분 내지 360분 범위 내의 분의 임의의 수 또는 하위범위일 수 있다. 상기 방법의 특정의 한 측면에 따르면, 방사성표지된 HER3 표적화제는 68Ga, 89Zr, 또는 111In을 포함할 수 있고, 본원에 개시된 방법 중 임의의 것 (예컨대, 실시예 1에 개시된 것)을 사용하여 표지될 수 있다.In another aspect, the method is a radionuclide, such as any of 18 F, 11 C, 68 Ga, 64 Cu, 89 Zr, or 124 I for PET imaging, or 99m Tc or 111 for SPECT imaging. diagnosing the subject to determine if HER3-positive cells are present using a HER3 targeting agent labeled with In. Thus, the method comprises administering to a subject a HER3 targeting agent labeled with one or more of 18 F, 11 C, 68 Ga, 64 Cu, 89 Zr, 124 I, 99m Tc, or 111 In, and - performing an invasive imaging technique, such as performing a PET or SPECT scan on the subject. The method can include administering a radiolabeled HER3 targeting agent to a subject for imaging, and performing imaging after a sufficient time for the targeting agent to bind to a target in a tissue of the subject. The amount of time sufficient for a targeting agent to bind to a target in a tissue of a subject can be, for example, at least 20 minutes, at least 30 minutes, at least 60 minutes, or any number or subrange of minutes within the range of 20 minutes to 360 minutes. there is. According to one particular aspect of the method, the radiolabeled HER3 targeting agent may comprise 68 Ga, 89 Zr, or 111 In, and any of the methods disclosed herein (eg, as described in Example 1) can be labeled using
대상체가, 예를 들어 미리 결정된 또는 미리 선택된 역치 수준을 초과하는 HER3-양성 암 세포, 또는 HER3-양성 암/종양의 다른 적응증을 갖는 경우, 본원에 의해 개시된 발명의 치료 방법이 수행될 수 있는데, 즉 방사성표지된 HER3 표적화제의 치료 유효량을 단독으로 또는 하나 이상의 부가의 치료제와 조합하여 투여하는 것이 수행될 수 있다.If the subject has, for example, HER3-positive cancer cells above a predetermined or pre-selected threshold level, or other indications of HER3-positive cancer/tumor, the treatment methods of the invention disclosed by this application can be performed, That is, administration of a therapeutically effective amount of a radiolabeled HER3 targeting agent alone or in combination with one or more additional therapeutic agents can be performed.
부가의 치료제 및 치료 양식Additional Therapeutics and Treatment Modalities
방사성표지된 HER3 표적화제 치료제를 단독으로 또는 다른 표적화제와 조합하여 투여하는 것을 포함하는 본 발명의 방법은 부가의 치료제 또는 치료 양식의 투여를 추가로 포함할 수 있다. 특정 측면에 따르면, 부가의 작용제는 방사성표지된 HER3 표적화제에 의해 치료 중인 질환 또는 병태와 관련될 수 있다. 이러한 투여는 유효량의 HER3 표적화제의 투여와 동시에, 별개로 또는 순차적일 수 있다. 동시 투여를 위해, 상기 작용제는 하나의 조성물로서 또는 별도의 조성물로서 적절하게 투여될 수 있다.Methods of the invention comprising administering a radiolabeled HER3 targeting agent therapeutic alone or in combination with other targeting agents may further include administration of additional therapeutic agents or therapeutic modalities. According to certain aspects, the additional agent may be associated with a disease or condition being treated by the radiolabeled HER3 targeting agent. Such administration may be concurrent with, separate from, or sequential with administration of an effective amount of the HER3 targeting agent. For simultaneous administration, the agents may be administered as one composition or as separate compositions, as appropriate.
방사성표지된 HER3 표적화제와 조합하여 또는 연계해서 사용될 수 있는 예시적인 부가의 치료제 및 치료 양식은 적어도 화학요법제, 소분자 종양학 약물, 항염증제, 면역억제제, 면역조정제, 면역 체크포인트 요법, DDR 억제제, CD47 차단제, 외부 빔 방사선, 근접치료, 또는 그의 임의의 조합을 포함한다. 단독으로 또는 본원에 개시된 바와 같은 다른 표적화제와 조합되는 방사성표지된 HER3 표적화제와 조합하여 또는 연계해서 사용될 수 있는 예시적인 부가의 작용제 및 치료 양식은 하기에 추가로 기재되어 있다.Exemplary additional therapeutic agents and treatment modalities that can be used in combination or in conjunction with radiolabeled HER3 targeting agents include at least chemotherapeutic agents, small molecule oncology drugs, anti-inflammatory agents, immunosuppressive agents, immunomodulatory agents, immune checkpoint therapies, DDR inhibitors, CD47 blockers, external beam radiation, brachytherapy, or any combination thereof. Exemplary additional agents and treatment modalities that can be used in combination or in conjunction with radiolabeled HER3 targeting agents, either alone or in combination with other targeting agents as disclosed herein, are described further below.
A. 화학요법제 및 기타 A. Chemotherapeutic agents and others 소분자small molecule 작용제 agent
예시적인 화학요법제는 질소 머스타드, 예컨대 메클로르에타민, 시클로포스파미드, 이포스파미드, 멜팔란및 클로람부실을 포함한 알킬화제; 니트로소우레아, 예컨대 카르무스틴 (BCNU), 로무스틴 (CCNU) 및 세무스틴 (메틸-CCNU); 테모달(Temodal™) (테모졸로미드), 에틸렌이민/메틸멜라민, 예컨대 트리에틸렌멜라민 (TEM), 트리에틸렌, 티오포스포르아미드 (티오테파), 헥사메틸멜라민 (HMM, 알트레타민); 알킬 술포네이트, 예컨대 부술판; 트리아진, 예컨대 다카르바진 (DTIC); 엽산 유사체, 예컨대 메토트렉사트 및 트리메트렉세이트, 피리미딘 유사체, 예컨대 5-플루오로우라실 (5FU), 플루오로데옥시우리딘, 젬시타빈, 시토신 아라비노시드 (AraC, 시타라빈), 5-아자시티딘, 2,2'-디플루오로데옥시시티딘, 퓨린 유사체, 예컨대 6-메르캅토퓨린, 6-티오구아닌, 아자티오프린, T-데옥시코포르마이신 (펜토스타틴), 에리스로히드록시노닐아데닌 (EHNA), 플루다라빈 포스페이트 및 2-클로로데옥시아데노신 (클라드리빈, 2-CdA)을 포함한 항대사물질; 항유사분열 약물, 예컨대 파클리탁셀, 빈블라스틴 (VLB), 빈크리스틴 및 비노렐빈을 포함한 빈카 알칼로이드, 탁소테레, 에스트라무스틴 및 에스트라무스틴 포스페이트를 포함한 자연 산물; 피포도필로톡신, 예컨대 에토포시드 및 테니포시드; 항생제, 예컨대 악티노마이신 D, 다우노마이신 (루비도마이신), 독소루비신, 미톡산트론, 이다루비신, 블레오마이신, 플리카마이신 (미트라마이신), 미토마이신 C, 및 악티노마이신; 효소, 예컨대 L-아스파라기나제; 생물학적 반응 조절제, 예컨대 인터페론-알파, IL-2, G-CSF 및 GM-CSF; 백금 배위 착물, 예컨대 옥살리플라틴, 시스플라틴 및 카르보플라틴, 안트라센디온, 예컨대 미톡산트론, 치환된 우레아, 예컨대 히드록시우레아, N-메틸히드라진 (MIH) 및 프로카르바진을 포함한 메틸히드라진 유도체, 부신피질 억제제, 예컨대 미토탄 (o, p-DDD) 및 아미노글루테티미드를 포함한 기타 작용제; 호르몬 및 부신피질스테로이드 길항제, 예컨대 프레드니손 및 등가물, 덱사메타손 및 아미노글루테티미드를 포함한 길항제; 젬자르(Gemzar™) (젬시타빈), 프로게스틴, 예컨대 히드록시프로게스테론 카프로에이트, 메드록시프로게스테론 아세테이트 및 메게스트롤 아세테이트; 에스트로겐, 예컨대 디에틸스틸베스트롤 및 에티닐 에스트라디올 등가물; 항에스트로겐, 예컨대 타목시펜; 테스토스테론 프로피오네이트 및 플루옥시메스테론/등가물을 포함한 안드로겐; 항안드로겐, 예컨대 플루타미드, 고나도트로핀-방출 호르몬 유사체 및 류프롤리드; 및 비스테로이드성 항안드로겐, 예컨대 플루타미드를 포함한 항신생물제를 포함하나, 이에 제한되지는 않는다.Exemplary chemotherapeutic agents include nitrogen mustards such as alkylating agents including mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil; nitrosoureas such as carmustine (BCNU), lomustine (CCNU) and semustine (methyl-CCNU); Temodal™ (temozolomide), ethylenimine/methylmelamine such as triethylenemelamine (TEM), triethylene, thiophosphoramide (thiotepa), hexamethylmelamine (HMM, altretamine); alkyl sulfonates such as busulfan; triazines such as dacarbazine (DTIC); folic acid analogs such as methotrexate and trimetrexate, pyrimidine analogs such as 5-fluorouracil (5FU), fluorodeoxyuridine, gemcitabine, cytosine arabinoside (AraC, cytarabine), 5- Azacytidine, 2,2'-difluorodeoxycytidine, purine analogs such as 6-mercaptopurine, 6-thioguanine, azathioprine, T-deoxycoformycin (pentostatin), erythrohydride antimetabolites including oxynonyladenine (EHNA), fludarabine phosphate and 2-chlorodeoxyadenosine (cladribine, 2-CdA); antimitotic drugs such as paclitaxel, vinblastine (VLB), vinca alkaloids including vincristine and vinorelbine, natural products including taxotere, estramustine and estramustine phosphate; pipodophyllotoxins such as etoposide and teniposide; antibiotics such as actinomycin D, daunomycin (rubidomycin), doxorubicin, mitoxantrone, idarubicin, bleomycin, plicamycin (mitramycin), mitomycin C, and actinomycin; enzymes such as L-asparaginase; biological response modifiers such as interferon-alpha, IL-2, G-CSF and GM-CSF; platinum coordination complexes such as oxaliplatin, cisplatin and carboplatin, anthracenediones such as mitoxantrone, methylhydrazine derivatives including substituted ureas such as hydroxyurea, N-methylhydrazine (MIH) and procarbazine, adrenocortical inhibitors other agents, including mitotane (o, p-DDD) and aminoglutethimide; antagonists including hormone and corticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; Gemzar™ (gemcitabine), progestins such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogens such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogens such as tamoxifen; androgens including testosterone propionate and fluoxymesterone/equivalents; anti-androgens such as flutamide, gonadotropin-releasing hormone analogues and leuprolide; and anti-neoplastic agents including non-steroidal anti-androgens such as flutamide.
(i) 히스톤 데아세틸라제 (HDAC) 억제제, 예컨대 보리노스타트 (수베로일아닐리드 히드록삼산; SAHA), 로미뎁신, 벨리노스타트 (PDX101), 파노비노스타트 (LBH589) 및 투시디노스타트, 탈메틸화제 (예를 들어, 비다자); (ii) LSD1 억제제, 예컨대 세클리뎀스타트, TCP (트라닐시프로민), ORY-1001 (이아다뎀스타트), GSK2879552 (GSK), INCB059872 [이마고 바이오사이언시스(Imago BioSciences)], IMG-7289 (보메뎀스타트; 이마고 바이오사이언시스), ORY-2001 (바피뎀스타트), 및 CC-90011 [셀젠(Celgene)]; 및 (iii) 전사 억제 (ATRA) 요법의 방출을 포함하나 이에 제한되지는 않는 후성유전학적 메카니즘을 표적으로 하는 요법이 또한 본원에 개시된 바와 같이 방사성표지된 HER3 표적화제 및/또는 다른 방사성표지된 표적화제 및 그의 조합과 조합하여 또는 연계해서 사용될 수 있다.(i) histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid; SAHA), romidepsin, belinostat (PDX101), panobinostat (LBH589) and tucidinostat, methylating agents (eg, Vidaza); (ii) LSD1 inhibitors such as seclidemstat, TCP (tranilcypromine), ORY-1001 (iadademstat), GSK2879552 (GSK), INCB059872 (Imago BioSciences), IMG-7289 (Bomedemstat; Imago Biosciences), ORY-2001 (Bapidemstat), and CC-90011 (Celgene); and (iii) therapies targeting epigenetic mechanisms, including but not limited to release of transcriptional repression (ATRA) therapy, can also be performed using radiolabeled HER3-targeting agents and/or other radiolabeled targets as disclosed herein. It can be used in combination or in conjunction with the topic and combinations thereof.
본 발명의 특정 측면에 따르면, 화학요법제는 적어도 방사선증감제, 예컨대 테모졸로미드, 시스플라틴 및/또는 플루오로우라실을 포함한다.According to certain aspects of the invention, the chemotherapeutic agent includes at least a radiosensitizer such as temozolomide, cisplatin and/or fluorouracil.
부가의 작용제는, 예를 들어, bcl-2 억제제, 예컨대 나비토클락스 또는 베네토클락스 [벤클렉스타(Venclexta®); 애브비(Abbvie)]를 포함할 수 있고, 상기 조합은, 예를 들어, 고형 종양, 예컨대 유방암 및 폐암, 예컨대 소세포 폐 암종 (SCLC)의 치료에 사용될 수 있다.Additional agents include, for example, bcl-2 inhibitors such as navitoclax or venetoclax [Venclexta®; Abbvie], and the combination can be used, for example, in the treatment of solid tumors such as breast and lung cancers such as small cell lung carcinoma (SCLC).
부가의 작용제는, 예를 들어, 사이클린 의존성 키나제 CDK4 및 CDK6 억제제, 예컨대 팔보시클립 [아이브런스(Ibrance®); 화이자]을 포함할 수 있으며, 그 조합은, 예를 들어, 아로마타제 억제제를 포함하거나 포함하지 않고, 고형 암, 예컨대 유방암, 예컨대 HR-양성 및 HER2-음성 유방암의 치료에 사용될 수 있다.Additional agents include, for example, cyclin dependent kinase CDK4 and CDK6 inhibitors such as palbociclib [Ibrance®; Pfizer], and the combination can be used, for example, with or without an aromatase inhibitor, for the treatment of solid cancers, such as breast cancer, such as HR-positive and HER2-negative breast cancer.
부가의 작용제는, 예를 들어, 에를로티닙 [타르세바(Tarceva®); 로슈]을 포함할 수 있으며, 그 조합은, 예를 들어, 고형 종양 암, 예컨대 비소세포 폐암 (NSCLC), 예를 들어 표피 성장 인자 수용체 (EGFR)에서의 돌연변이를 갖는 것, 및 췌장암의 치료에 사용될 수 있다.Additional agents include, for example, erlotinib [Tarceva®; Roche], the combination being useful, for example, in the treatment of solid tumor cancers such as non-small cell lung cancer (NSCLC), eg, those having mutations in the epidermal growth factor receptor (EGFR), and pancreatic cancer. can be used
부가의 작용제는, 예를 들어, 시롤리무스 또는 에베롤리무스 [아피니토르(Affinitor®); 노바티스]를 포함할 수 있으며, 그 조합은, 예를 들어, 고형 종양 암, 예컨대 흑색종 및 유방암의 치료에 사용될 수 있다.Additional agents include, for example, sirolimus or everolimus [Affinitor®; Novartis], and the combination can be used, for example, in the treatment of solid tumor cancers such as melanoma and breast cancer.
부가의 작용제는, 예를 들어, 페메트렉시드 [알림타(Alimta®); 일라이 릴리(Eli Lilly)]를 포함할 수 있으며, 그 조합은, 예를 들어, 고형 암, 예컨대 중피종, 예컨대 흉막 중피종 및 폐암, 예컨대 비소세포 폐암 (NSCLC)의 치료에 사용될 수 있다.Additional agents include, for example, pemetrexed [Alimta®; Eli Lilly], and the combination can be used, for example, in the treatment of solid cancers such as mesothelioma, such as pleural mesothelioma and lung cancer, such as non-small cell lung cancer (NSCLC).
부가의 치료제는, 예를 들어, 관련 기술분야에 공지된 임의의 표준 투여 요법에 따라 투여될 수 있다. 예를 들어, 치료제는 1 내지 500 mg/m2 범위의 농도로 투여될 수 있으며, 그 양은 환자 표면적 (m2)의 함수로서 계산된다. 예를 들어, 화학요법제 파클리탁셀의 예시적인 용량은 15 mg/m2 내지 275 mg/m2를 포함할 수 있으며, 도세탁셀의 예시적인 용량은 60 mg/m2 내지 100 mg/m2를 포함할 수 있으며, 에피틸론의 예시적인 용량은 10 mg/m2 내지 20 mg/m2를 포함할 수 있으며, 칼리케아미신의 예시적인 용량은 1 mg/m2 내지 10 mg/m2를 포함할 수 있다. 예시적인 용량이 본원에 열거되어 있지만, 이는 참조용으로만 제공되며 본원에 의해 개시된 발명의 약제의 용량 범위를 제한하려는 의도는 아니다.The additional therapeutic agent may be administered according to any standard dosing regimen known in the art, for example. For example, a therapeutic agent can be administered at a concentration ranging from 1 to 500 mg/m 2 , the amount calculated as a function of patient surface area (m 2 ). For example, an exemplary dose of the chemotherapeutic agent paclitaxel may include 15 mg/m 2 to 275 mg/m 2 , and an exemplary dose of docetaxel may include 60 mg/m 2 to 100 mg/m 2 An exemplary dose of epitilone may include 10 mg/m 2 to 20 mg/m 2 , and an exemplary dose of calicheamicin may include 1 mg/m 2 to 10 mg/m 2 there is. Although exemplary dosages are listed herein, they are provided for reference only and are not intended to limit the dosage ranges of the agents of the invention disclosed herein.
B. 외부 빔 방사선 및/또는 근접치료B. External beam radiation and/or brachytherapy
HER3 표적화제, 및 임의로 본원에 개시된 부가의 치료제 중 임의의 다른 것과 연계해서 투여되는 부가의 치료 양식은 외부 빔 방사선 또는 근접치료을 통해 투여되는 것과 같은 이온화 방사선일 수 있다. 이러한 방사선은 일반적으로 X선, 감마선 또는 하전 입자 (예를 들어, 양성자 또는 전자)를 사용하여 환자의 신체 외부에 배치된 기계 (외부 빔 방사선 요법)에 의해 또는 환자의 신체 내부에 배치된 공급원 (내부 방사선 요법 또는 근접치료)에 의해 전달되는 것과 같은 이온화 방사선을 생성하는 것을 지칭한다.An additional treatment modality administered in conjunction with a HER3 targeting agent, and optionally any other of the additional therapeutic agents disclosed herein, may be ionizing radiation, such as administered via external beam radiation or brachytherapy. Such radiation is usually performed by a machine placed outside the patient's body using X-rays, gamma rays, or charged particles (eg, protons or electrons) (external beam radiation therapy) or from a source (external beam radiation therapy) placed inside the patient's body. refers to producing ionizing radiation, such as delivered by internal radiation therapy or brachytherapy).
외부 빔 방사선 또는 근접치료는 방사성표지된 HER3 표적화제에 의해 전달된 표적화된 방사선 손상을 향상시킬 수 있고, 따라서 HER3 표적화제와 함께 순차적으로, 예컨대 HER3 표적화제의 투여 전 및/또는 후, 또는 HER3 표적화제의 투여와 동시에 전달될 수 있다.External beam radiation or brachytherapy can enhance the targeted radiation injury delivered by a radiolabeled HER3-targeting agent, and thus can be administered sequentially with a HER3-targeting agent, such as before and/or after administration of the HER3-targeting agent, or as a HER3-targeting agent. It can be delivered simultaneously with administration of the targeting agent.
외부 빔 방사선 또는 근접치료는 영상화 기반 기술, 예컨대 컴퓨터 단층촬영 (CT) 및/또는 자기 공명 영상화 (MRI)와 연계해서 계획되고 투여되어 투여될 방사선의 용량과 위치를 정확하게 결정할 수 있다. 예를 들어, 본원에 개시된 방사성표지된 HER3 표적화제 중 임의의 것으로 치료받은 환자는 외부 빔 방사선 또는 근접치료에 의해 투여될 방사선의 용량 및 위치를 결정하기 위해 CT 또는 MRI 중 어느 하나를 사용하여 영상화될 수 있다.External beam radiation or brachytherapy can be planned and administered in conjunction with imaging-based techniques such as computed tomography (CT) and/or magnetic resonance imaging (MRI) to accurately determine the dose and location of the radiation to be administered. For example, patients treated with any of the radiolabeled HER3 targeting agents disclosed herein may be imaged using either CT or MRI to determine the dose and location of radiation to be administered by external beam radiation or brachytherapy. It can be.
다양한 실시양태에서, 방사선 요법은 전신 방사선 요법, 통상적인 외부 빔 방사선 요법, 정위 방사선수술, 정위 신체 방사선 요법, 3-D 입체조형 방사선 요법, 강도 변조 방사선 요법, 영상-유도 방사선 요법, 단층요법 및 근접치료로 이루어진 군으로부터 선택될 수 있다. 특정 측면에 따르면, 방사선 요법은 단일 용량으로서 또는 분할 용량, 예를 들어 2개 이상의 분획으로서 제공될 수 있다. 예를 들어, 용량은 각각의 분획이 2-20 Gy를 포함하도록 투여될 수 있다 (예를 들어, 50 Gy의 방사선 용량은 각각 5 Gy를 포함한 10개의 분획으로 분할될 수 있다). 2개 이상의 분획은 연속 또는 순차적으로, 예컨대 2일에 1회, 3일에 1회, 4일에 1회, 5일에 1회, 6일에 1회, 7일에 1회, 또는 그의 조합으로 투여될 수 있다.In various embodiments, the radiation therapy is whole body radiation therapy, conventional external beam radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, 3-D stereoscopic radiation therapy, intensity modulated radiation therapy, image-guided radiation therapy, tomography, and It may be selected from the group consisting of brachytherapy. According to certain aspects, radiation therapy can be given as a single dose or as divided doses, eg in two or more fractions. For example, doses can be administered such that each fraction contains 2-20 Gy (eg, a radiation dose of 50 Gy can be divided into 10 fractions containing 5 Gy each). Two or more fractions are consecutively or sequentially, such as once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, or combinations thereof. may be administered.
C. 면역 체크포인트 요법C. Immune Checkpoint Therapy
HER3 표적화제와 연계해서 투여되는 부가의 작용제(들)는 면역 체크포인트 요법일 수 있다. 암 세포는 면역 체계의 표준 체크포인트를 회피하는 수단을 개발하였다. 예를 들어, 암 세포는 종양 항원의 발현 감소, MHC 클래스 I 및 II 분자의 하향조절로 인해 종양 항원 제시 감소, 면역억제성 시토카인, 예컨대 TGFb의 분비, 면역억제 세포, 예컨대 조절 T 세포 (Treg) 또는 골수 유래 억제 세포 (MDSC)의 동원 또는 유도, 및 숙주의 기존 항종양 면역을 억제하는 특정 리간드 [예를 들어, 프로그램된 사멸 리간드-1 (PD-L1)]의 과다발현을 통해 면역 감시를 회피하는 것으로 밝혀졌다.The additional agent(s) administered in conjunction with the HER3 targeting agent may be an immune checkpoint therapy. Cancer cells have developed means to circumvent the immune system's standard checkpoints. For example, cancer cells can reduce the expression of tumor antigens, reduce tumor antigen presentation due to downregulation of MHC class I and II molecules, secrete immunosuppressive cytokines such as TGFb, immunosuppressive cells such as regulatory T cells (Tregs) or through recruitment or induction of bone marrow-derived suppressor cells (MDSC) and overexpression of specific ligands [eg, programmed death ligand-1 (PD-L1)] that suppress the host's pre-existing antitumor immunity. turned out to be avoided.
암 세포에 의한 면역 억제의 또 다른 주요 메커니즘은 종양 항원에 대한 만성 노출로 인한 "T-세포 고갈"로서 공지된 프로세스이며, 억제 수용체의 상향조절을 특징으로 한다. 이러한 억제 수용체는 비제어된 면역 반응을 방지하기 위해 면역 체크포인트 역할을 한다.Another major mechanism of immune suppression by cancer cells is a process known as “T-cell depletion” due to chronic exposure to tumor antigens and is characterized by upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune responses.
PD-1 (즉, 프로그램된 세포 사멸 단백질 1) 및 그의 리간드인 PD-L1 및 PD-L2, CTLA-4 (즉, 세포독성 T-림프구 연관 단백질-4) 및 그의 리간드인 CD80 및 CD86, LAG3 (즉, 림프구-활성화 유전자 3), B 및 T 림프구 감쇠기, TIGIT (Ig 및 ITIM 도메인이 있는 T-세포 면역수용체), TIM-3 (즉, T-세포 이뮤노글로불린 및 뮤신-도메인 함유 단백질 3), 및 VISTA (T 세포 활성화의 V-도메인 이뮤노글로불린 억제제)를 포함한, 상이한 수준의 T 세포 면역에서 작용하는 다양한 면역 체크포인트가 문헌에 기재되어 있다.PD-1 (ie programmed cell death protein 1) and its ligands PD-L1 and PD-L2, CTLA-4 (ie cytotoxic T-lymphocyte associated protein-4) and its ligands CD80 and CD86, LAG3 (i.e. lymphocyte-activating gene 3), B and T lymphocyte attenuator, TIGIT (T-cell immunoreceptor with Ig and ITIM domains), TIM-3 (i.e. T-cell immunoglobulin and mucin-domain containing protein 3) ), and VISTA (V-domain immunoglobulin inhibitor of T cell activation), various immune checkpoints that function at different levels of T cell immunity have been described in the literature.
치료적 개입을 통해 면역 체계의 효능을 향상시키는 것은 암 치료에서 특히 흥미로운 발전이다. 표시된 바와 같이, 체크포인트 억제제, 예컨대 CTLA-4 및 PD-1은 자가면역을 예방하고 일반적으로 면역 부수적 손상으로부터 조직을 보호한다. 또한, 자극 체크포인트, 예컨대 OX40 (즉, 종양 괴사 인자 수용체 슈퍼패밀리, 구성원 4; TNFR-SF4), CD137 (즉, TNFR-SF9), GITR (즉, 글루코코르티코이드-유도된 TNFR), CD27 (즉, TNFR-SF7), CD40 (즉, 분화 클러스터 40) 및 CD28은 T 세포의 확장을 활성화 및/또는 촉진시킨다. 이러한 단백질의 억제 또는 과다발현에 의한 면역 체계의 조절은 현재 유망한 연구 분야이다.Improving the efficacy of the immune system through therapeutic intervention is a particularly exciting development in cancer treatment. As indicated, checkpoint inhibitors such as CTLA-4 and PD-1 prevent autoimmunity and generally protect tissues from immune collateral damage. In addition, stimulation checkpoints such as OX40 (ie tumor necrosis factor receptor superfamily,
따라서, 유망한 치료 전략은 본원에 개시된 HER3 표적화제와 조합하여, 암 세포에 의해 활용되는 면역 체계에 대한 특정 차단을 제거할 수 있는 면역 체크포인트 요법를 사용하는 것이다. 예를 들어, 특정 면역 체크포인트 억제제 (ICI)에 대한 항체는 체크포인트 억제제 단백질과 그의 리간드 간의 상호작용을 차단할 수 있으므로, 그렇지 않으면 종양 세포에 대한 면역 반응을 억제할 수 있는 신호전달 이벤트를 방지할 수 있다.Thus, a promising therapeutic strategy is to use immune checkpoint therapies that can eliminate specific blockages to the immune system utilized by cancer cells, in combination with the HER3 targeting agents disclosed herein. For example, antibodies to certain immune checkpoint inhibitors (ICIs) can block interactions between checkpoint inhibitor proteins and their ligands, thus preventing signaling events that might otherwise suppress the immune response to tumor cells. can
더욱이, 방사선이 ICI 항체와 상승작용할 수 있는 능력을 뒷받침하는 전임상 증거가 증가하고 있으며, 이는 다양한 종양 유형 및 ICI 항체 전체에 걸쳐 외부 빔 방사선과 면역 체크포인트 요법의 조합을 평가하는 임상 시험이 증가함에 따라 클리닉에서도 탐구되고 있다 (Lamichhane, 2018). 이러한 조합을 뒷받침하는 임상적 증거가 흑색종에서 생성되었으며, 항-세포독성 T-림프구 연관 단백질 4 (CTLA-4) ICI 항체인 이필리무맙과 조합하여 방사선을 사용하는 임상적 이점을 입증하는 2가지 연구가 있다 (Twyman-Saint Vistor, 2015).Moreover, there is growing preclinical evidence supporting the ability of radiation to synergize with ICI antibodies, as evidenced by a growing number of clinical trials evaluating combinations of external beam radiation and immune checkpoint therapies across a range of tumor types and ICI antibodies. It is also being explored in the clinic (Lamichhane, 2018). Clinical evidence supporting this combination has been generated in melanoma and two studies demonstrating the clinical benefit of using radiation in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) ICI antibody. There are several studies (Twyman-Saint Vistor, 2015).
따라서, 본원에 의해 개시된 발명의 목적은 하나 이상의 면역 체크포인트 요법, 예컨대 ICI 항체와 조합하여 HER3 표적화제를 사용하는 암 치료를 위한 요법을 제공하는 것이다.Accordingly, it is an object of the invention disclosed herein to provide a therapy for the treatment of cancer using a HER3 targeting agent in combination with one or more immune checkpoint therapies, such as an ICI antibody.
본 발명의 면역 체크포인트 요법은 하나 이상의 체크포인트 단백질을 전체적으로 또는 부분적으로 감소, 억제, 간섭 또는 조정하는 분자를 포함한다. 체크포인트 단백질은 T-세포 활성화 또는 기능을 조절한다. 면역 체크포인트 요법은 체크포인트 억제제와 결합하거나 달리 불활성화함으로써 기존의 면역 반응 억제를 차단 해제할 수 있다. 면역 체크포인트 요법은 모노클로날 항체, 인간화 항체, 완전 인간 항체, 항체 단편, 소분자 치료제 또는 그의 조합을 포함할 수 있다.Immune checkpoint therapies of the present invention include molecules that wholly or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins. Checkpoint proteins regulate T-cell activation or function. Immune checkpoint therapy can unblock pre-existing suppression of an immune response by binding to or otherwise inactivating a checkpoint inhibitor. Immune checkpoint therapy can include monoclonal antibodies, humanized antibodies, fully human antibodies, antibody fragments, small molecule therapeutics, or combinations thereof.
예시적인 면역 체크포인트 요법은 체크포인트 단백질, 예컨대 억제 수용체 CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3 및 TIGIT, 및/또는 활성화 수용체 CD28, OX40, CD40, GITR, CD137, CD27 및 HVEM과 특이적으로 결합하여 이를 억제할 수 있다. 부가적으로, 면역 체크포인트 요법은 전술한 체크포인트 단백질, 예컨대 PD-L1, PD-L2, PD-L3 및 PD-L4 (PD-1에 대한 리간드); CD80 및 CD86 (CTLA-4에 대한 리간드); CD137-L (CD137에 대한 리간드); 및 GITR-L (GITR의 리간드) 중 임의의 것의 리간드와 결합할 수 있다. 기타 예시적인 면역 체크포인트 요법은 체크포인트 단백질, 예컨대 CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4 (CD2 패밀리의 분자에 속하며 모든 NK, γδ 및 기억 CD8+ (αβ) T 세포에서 발현됨), CD160 (BY55로서 지칭되기도 함), 및 CGEN-15049와 결합할 수 있다.Exemplary immune checkpoint therapies include checkpoint proteins such as inhibitory receptors CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3 and TIGIT, and/or activating receptors CD28, OX40, CD40, GITR, CD137 , can specifically bind to and inhibit CD27 and HVEM. Additionally, immune checkpoint therapies include checkpoint proteins described above, such as PD-L1, PD-L2, PD-L3 and PD-L4 (ligands for PD-1); CD80 and CD86 (ligands for CTLA-4); CD137-L (ligand for CD137); and GITR-L (ligand of GITR). Other exemplary immune checkpoint therapies include checkpoint proteins such as CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4 (all NK, γδ and memory CD8+ (αβ) T expressed in cells), CD160 (also referred to as BY55), and CGEN-15049.
면역 체크포인트 프로세스의 중심에는 CD137, CTLA-4 및 PD-1 면역 체크포인트 경로가 있다.At the heart of the immune checkpoint process are the CD137, CTLA-4 and PD-1 immune checkpoint pathways.
CTLA-4 및 PD-1 경로는 면역 반응의 상이한 단계에서 작동하는 것으로 생각된다. CTLA-4는 전형적으로 림프절에서 나이브 T-세포 활성화의 초기 단계에서 잠재적으로 자가 반응성 T 세포를 정지시키기 때문에, 면역 체크포인트 억제제 (ICI)의 "리더"로 간주된다. PD-1 경로는 주로 말초 조직에서 면역 반응의 후기 단계에서 이전에 활성화된 T 세포를 조절한다. 더욱이, 진행 중인 암 환자는 종양 세포 또는 종양-침윤 면역 세포에 의한 PD-L1의 상향조절이 부족한 것으로 나타났다. 따라서 PD-1 경로를 표적으로 하는 면역 체크포인트 요법은 이러한 면역 억제 축이 작동하는 종양에서 특히 유효할 수 있으며 면역 보호 환경으로의 균형을 역전시키면 기존의 항종양 면역 반응을 다시 활성화하고 강화할 수 있다. PD-1 차단은 PD-1 또는 그의 리간드인 PD-L1과 결합하는 항체를 포함한 다양한 메커니즘에 의해 달성될 수 있다.The CTLA-4 and PD-1 pathways are thought to operate at different stages of the immune response. CTLA-4 is considered a “leader” of immune checkpoint inhibitors (ICIs) because it typically arrests potentially autoreactive T cells in the early stages of naive T-cell activation in the lymph node. The PD-1 pathway regulates previously activated T cells in the later stages of the immune response, primarily in peripheral tissues. Moreover, patients with advanced cancer have been shown to lack PD-L1 upregulation by tumor cells or tumor-infiltrating immune cells. Thus, immune checkpoint therapies targeting the PD-1 pathway may be particularly effective in tumors where this immunosuppressive axis is at play, and reversing the balance to an immune protective milieu can reactivate and enhance pre-existing antitumor immune responses. . PD-1 blockade can be achieved by a variety of mechanisms, including antibodies that bind to PD-1 or its ligand, PD-L1.
본원에 의해 개시된 발명의 특정 측면에 따르면, 면역 체크포인트 요법은 PD-1 체크포인트의 억제제를 포함할 수 있으며, 이는 PD-1과 그의 결합 파트너, 예컨대 PD-L1 및 PD-L2 중 하나 이상의 상호작용으로부터 발생하는 신호 변환을 감소, 차단, 억제, 폐지 또는 방해할 수 있다. PD-1 체크포인트의 억제제는 항-PD-1 항체, 항원 결합 단편, 융합 단백질, 올리고펩티드, 및 PD-1과 PD-L1 및/또는 PD-L2의 상호작용으로부터 발생하는 신호 변환을 감소, 차단, 억제, 폐지 또는 방해하는 다른 분자일 수 있다. 일부 실시양태에서, PD-1 체크포인트 억제제는 T 림프구 상에서 발현되는 세포 표면 단백질에 의해 또는 이를 통해 매개되는 음성 공동 자극 신호를 감소시켜, 기능 장애 T-세포가 덜 기능 장애가 되도록 한다 (예를 들어, 항원 인식에 대한 이펙터 반응을 향상시킴). 일부 실시양태에서, PD-1 체크포인트 요법은 항-PD-1 항체이다.According to certain aspects of the invention disclosed by this disclosure, an immune checkpoint therapy may include an inhibitor of the PD-1 checkpoint, which interacts with PD-1 and one or more of its binding partners, such as PD-L1 and PD-L2. may reduce, block, inhibit, abolish or interfere with signal transduction resulting from the action. Inhibitors of the PD-1 checkpoint reduce anti-PD-1 antibodies, antigen-binding fragments, fusion proteins, oligopeptides, and signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2; It may be another molecule that blocks, inhibits, abolishes or interferes. In some embodiments, a PD-1 checkpoint inhibitor reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, making dysfunctional T-cells less dysfunctional (e.g., , enhancing effector responses to antigen recognition). In some embodiments, the PD-1 checkpoint therapy is an anti-PD-1 antibody.
따라서, 본 발명의 특정 측면에 따르면, 면역 체크포인트 요법은 면역 체크포인트 억제제 (ICI), 예컨대 CTLA-4, PD-1 또는 PD-L1에 대한 모노클로날 항체를 포함할 수 있다.Thus, according to certain aspects of the invention, an immune checkpoint therapy may include a monoclonal antibody to an immune checkpoint inhibitor (ICI) such as CTLA-4, PD-1 or PD-L1.
특정 측면에 따르면, ICI 항체는 PD-1에 대한 항체일 수 있다. ICI 항체는 항-PD-1 항체, 예컨대 니볼루맙일 수 있다. 예를 들어, PD-1 생물학적 활성 (또는 그의 리간드)의 억제제는 미국 특허 번호 7,029,674에 개시되어 있다. PD-1에 대한 예시적인 항체는 바이오엑스셀로부터의 항-마우스 PD-1 항체 클론 J43 (Cat #BE0033-2); 바이오엑스셀로부터의 항-마우스 PD-1 항체 클론 RMP1-14 (Cat #BE0146); 마우스 항-PD-1 항체 클론 EH12; 머크(Merck)의 MK-3475 항-마우스 PD-1 항체 [케이트루다(Keytruda®), 펨브롤리주맙, 람브롤리주맙]; 및 ANB011로서 공지된 아나프티스바이오(AnaptysBio)의 항-PD-1 항체; 항체 MDX-1106 (ONO-4538); 브리스톨-마이어스 스퀴브(Bristol-Myers Squibb)의 인간 IgG4 모노클로날 항체 니볼루맙 [옵디보(Opdivo®), BMS-936558, MDX1106]; 아스트라제네카의 AMP-514, 및 AMP-224; 및 피딜리주맙 (CT-011), 큐어테크 리미티드(CureTech Ltd.)를 포함한다.According to certain aspects, the ICI antibody may be an antibody to PD-1. The ICI antibody may be an anti-PD-1 antibody, such as nivolumab. For example, inhibitors of PD-1 biological activity (or ligands thereof) are disclosed in US Patent No. 7,029,674. Exemplary antibodies to PD-1 include anti-mouse PD-1 antibody clone J43 from BioXcell (Cat #BE0033-2); anti-mouse PD-1 antibody clone RMP1-14 (Cat #BE0146) from BioXcell; mouse anti-PD-1 antibody clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda®, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody known as ANB011; antibody MDX-1106 (ONO-4538); human IgG4 monoclonal antibody nivolumab from Bristol-Myers Squibb (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514, and AMP-224; and pidilizumab (CT-011), CureTech Ltd.
특정 측면에 따르면, 면역 체크포인트 요법은 PD-L1의 억제제이다. PD-L1의 예시적인 억제제는 항체 (예를 들어, 항-PD-L1 항체, 즉 ICI 항체), RNAi 분자 (예를 들어, 항-PD-L1 RNAi), 안티센스 분자 (예를 들어, 항-PD-L1 안티센스 RNA), 우성 음성 단백질 (예를 들어, 우성 음성 PD-L1 단백질) 및 소분자 억제제를 포함한다. 예시적인 항-PD-L1 항체는 클론 EH12를 포함한다. PD-L1에 대한 예시적인 항체는 제넨테크의 MPDL3280A (RG7446); 바이오엑스셀로부터의 항-마우스 PD-L1 항체 클론 10F.9G2 (Cat #BE0101); 브리스톨-마이어스 스퀴브로부터의 항-PD-L1 모노클로날 항체 MDX-1105 (BMS-936559) 및 BMS-935559; MSB0010718C; 마우스 항-PD-L1 클론 29E.2A3; 및 아스트라제네카의 MEDI4736 (더발루맙)을 포함한다.According to certain aspects, the immune checkpoint therapy is an inhibitor of PD-L1. Exemplary inhibitors of PD-L1 include antibodies (eg, anti-PD-L1 antibodies, i.e., ICI antibodies), RNAi molecules (eg, anti-PD-L1 RNAi), antisense molecules (eg, anti-PD-L1 antibodies). PD-L1 antisense RNA), dominant negative proteins (eg, dominant negative PD-L1 protein) and small molecule inhibitors. Exemplary anti-PD-L1 antibodies include clone EH12. Exemplary antibodies to PD-L1 include Genentech's MPDL3280A (RG7446); anti-mouse PD-L1 antibody clone 10F.9G2 from BioXcell (Cat #BE0101); anti-PD-L1 monoclonal antibodies MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Myers Squibb; MSB0010718C; mouse anti-PD-L1 clone 29E.2A3; and AstraZeneca's MEDI4736 (Durvalumab).
특정 측면에 따르면, 면역 체크포인트 요법은 PD-L2의 억제제이거나 또는 PD-1과 PD-L2 간의 상호작용을 감소시킬 수 있다. PD-L2의 예시적인 억제제는 항체 (예를 들어, 항-PD-L2 항체, 즉 ICI 항체), RNAi 분자 (예를 들어, 항-PD-L2 RNAi), 안티센스 분자 (예를 들어, 항-PD-L2 안티센스 RNA), 우성 음성 단백질 (예를 들어, 우성 음성 PD-L2 단백질), 및 소분자 억제제를 포함한다. 항체는 모노클로날 항체, 인간화 항체, 탈면역된 항체, 및 Ig 융합 단백질을 포함한다.According to certain aspects, the immune checkpoint therapy may be an inhibitor of PD-L2 or reduce the interaction between PD-1 and PD-L2. Exemplary inhibitors of PD-L2 include antibodies (eg, anti-PD-L2 antibodies, i.e., ICI antibodies), RNAi molecules (eg, anti-PD-L2 RNAi), antisense molecules (eg, anti-PD-L2 antibodies). PD-L2 antisense RNA), dominant negative proteins (eg, dominant negative PD-L2 protein), and small molecule inhibitors. Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.
특정 측면에 따르면, 면역 체크포인트 요법은 CTLA-4의 억제제, 예컨대 항-CTLA-4 항체, 즉 ICI 항체일 수 있다. 한 측면에 따르면, ICI 항체는 이필리무맙일 수 있다. 항-CTLA-4 항체는 항원 제시 세포 상에 발현된 CD80 (B7-1) 및/또는 CD86 (B7-2)에 대한 CTLA-4의 결합을 차단할 수 있다. CTLA-4에 대한 예시적인 항체는 브리스톨 마이어스 스퀴브의 항-CTLA-4 항체 이필리무맙 (Yervoy®, MDX-010, BMS-734016 및 MDX-101로서 공지되기도 함); 밀리포어(Millipore)로부터의 항-CTLA4 항체, 클론 9H10; 화이자의 트레멜리무맙 (CP-675,206, 티실리무맙); 및 압캠(Abcam)으로부터의 항-CTLA-4 항체 클론 BNI3을 포함한다. 특정 측면에 따르면, 면역 체크포인트 억제제는 CTLA-4 발현의 핵산 억제제일 수 있다.According to certain aspects, the immune checkpoint therapy can be an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody, ie an ICI antibody. According to one aspect, the ICI antibody can be ipilimumab. Anti-CTLA-4 antibodies can block the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen-presenting cells. Exemplary antibodies to CTLA-4 include Bristol-Myers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 antibody, clone 9H10 from Millipore; Pfizer's Tremelimumab (CP-675,206, Ticilimumab); and anti-CTLA-4 antibody clone BNI3 from Abcam. According to certain aspects, the immune checkpoint inhibitor can be a nucleic acid inhibitor of CTLA-4 expression.
CD137 ("TNF 수용체 슈퍼패밀리 구성원 9"로서 공지되기도 함)은 종양 괴사 인자 수용체 슈퍼패밀리의 공동 자극 수용체 구성원이며, CD28 의존성 및 비의존성 T-세포 공동 자극을 매개한다 (Bartkowiak, 2015). CD137은 T 세포, 자연 살해 (NK) 세포, 수지상 세포 (DC), B 세포, 및 면역 체계의 다른 세포에 의해 유도적으로 발현된다. 단백질은 짧은 N-말단 세포질 부분, 막횡단 영역, 및 3개의 시스테인-풍부 모티프를 보유하는 세포외 도메인을 갖는 255개 아미노산 단백질로 구성된다. 배타적이지는 않지만 주로, 항원 제시 세포 (APC) 상에 발현되는 그의 리간드 CD137L (4-1BBL; TNFSF9)에 의한 CD137의 라이게이션은 다양한 T 세포 반응, 예컨대 세포 확장, 시토카인 분비 증가, 및 활성화-유도된 세포 사멸의 방지를 유발시킨다. 따라서, 이러한 라이게이션은 면역 체계를 활성화시키는 역할을 한다. 그러나, CD137과 CD137L 간의 시스-상호작용은 또한 CD137L의 발현을 강력하게 하향조절한다 (Kwon, 2015). 따라서 CD137 리간드는 CD137 매개 면역 체계 활성화의 정도와 동역학을 제어하는 기능을 한다 (Kwon, 2015). 중요하게도, 인간 NK 세포 상에 발현된 CD137은 종양 세포와 결합된 항-종양 항체와 결합할 때 상향조절된다 (Wei, 2014).CD137 (also known as “TNF receptor superfamily member 9”) is a costimulatory receptor member of the tumor necrosis factor receptor superfamily and mediates CD28-dependent and -independent T-cell costimulation (Bartkowiak, 2015). CD137 is inducibly expressed by T cells, natural killer (NK) cells, dendritic cells (DC), B cells, and other cells of the immune system. The protein consists of a 255 amino acid protein with a short N-terminal cytoplasmic portion, a transmembrane region, and an extracellular domain containing three cysteine-rich motifs. Ligation of CD137 by its ligand CD137L (4-1BBL; TNFSF9), which is primarily, but not exclusively, expressed on antigen-presenting cells (APCs), induces a variety of T cell responses, such as cell expansion, increased cytokine secretion, and activation-induction. induces the prevention of cell death. Thus, this ligation serves to activate the immune system. However, the cis-interaction between CD137 and CD137L also strongly downregulates the expression of CD137L (Kwon, 2015). Thus, CD137 ligand functions to control the extent and kinetics of CD137-mediated immune system activation (Kwon, 2015). Importantly, CD137 expressed on human NK cells is upregulated when combined with anti-tumor antibodies bound to tumor cells (Wei, 2014).
따라서, 본원에 의해 개시된 발명의 특정 측면에 따르면, 면역 체크포인트 요법은 CD137에 대한 항체를 포함할 수 있으며, 이는 면역 체계를 활성화하는 데 사용될 수 있고, 이에 의해 본원에 의해 개시된 HER3 표적화제와 조합하여 암에 대한 요법을 제공할 수 있다. 사용될 수 있는 예시적인 항-CD137 항체는 미국 공개 번호 20140274909; 20130280265; 20130273078; 20130071403; 20120058047; 20110104049; 20110097313; 20080166336; 20080019905; 20060188439; 20060182744; 20060121030; 및 20030223989에 개시되어 있다.Thus, according to certain aspects of the invention disclosed herein, an immune checkpoint therapy may include an antibody to CD137, which may be used to activate the immune system, thereby in combination with a HER3 targeting agent disclosed herein. Thus, therapies for cancer can be provided. Exemplary anti-CD137 antibodies that may be used include US Publication Nos. 20140274909; 20130280265; 20130273078; 20130071403; 20120058047; 20110104049; 20110097313; 20080166336; 20080019905; 20060188439; 20060182744; 20060121030; and 20030223989.
본 발명의 특정 측면에 따르면, 면역 체크포인트 요법은 면역 체크포인트 단백질의 하나 초과의 조정인자를 포함할 수 있다. 이와 같이, 면역 체크포인트 요법은 제1 면역 체크포인트 단백질에 대한 제1 항체 또는 억제제 및 제2 면역 체크포인트 단백질에 대한 제2 항체 또는 억제제를 포함할 수 있다.According to certain aspects of the invention, an immune checkpoint therapy may include more than one modulator of an immune checkpoint protein. As such, an immune checkpoint therapy may include a first antibody or inhibitor against a first immune checkpoint protein and a second antibody or inhibitor against a second immune checkpoint protein.
D. DNA 손상 반응 억제제D. DNA Damage Response Inhibitors
HER3 표적화제와 연계해서 투여되는 부가의 작용제는 하나 이상의 DNA 손상 반응 억제제 (DDRi)일 수 있다. DNA 손상은 내인성 요인, 예컨대 자발적 또는 효소적 반응, 화학적 반응, 또는 복제 오류로 인한 것일 수 있거나, 또는 외인성 요인, 예컨대 UV 또는 이온화 방사선 또는 유전독성 화학물질로 인한 것일 수 있다. 이러한 손상을 극복하는 복구 경로는 집합적으로 DNA 손상 반응 또는 DDR로서 지칭된다. 이러한 신호전달 네트워크는 특정 형태의 DNA 손상, 가장 특히 이중 가닥 파손 및 복제 스트레스에 대한 세포의 반응을 검출하고 조율하는 역할을 한다. 많은 유형의 DNA 손상 약물과 이온화 방사선으로 처리한 후, 세포는 생존을 위해 DDR에 의존한다. DDR의 파괴는 이러한 DNA 손상 물질에 대한 암 세포의 감수성을 증가시킬 수 있고, 따라서 그러한 요법에 대한 환자의 반응을 개선시킬 수 있는 것으로 나타났다.Additional agents administered in conjunction with the HER3 targeting agent may be one or more DNA damage response inhibitors (DDRi). DNA damage can be due to endogenous factors, such as spontaneous or enzymatic reactions, chemical reactions, or replication errors, or it can be due to exogenous factors, such as UV or ionizing radiation or genotoxic chemicals. The repair pathways that overcome this damage are collectively referred to as the DNA damage response or DDR. These signaling networks are responsible for detecting and orchestrating the cell's response to certain forms of DNA damage, most notably double-strand breaks and replication stress. After treatment with many types of DNA-damaging drugs and ionizing radiation, cells depend on DDR for survival. It has been shown that disruption of the DDR can increase the susceptibility of cancer cells to these DNA damaging agents and thus improve the response of patients to such therapy.
DDR 내에는, 염기 절제 복구, 뉴클레오티드 절제 복구, 미스매치 복구, 상동 재조합 복구, 및 비상동 말단 연결을 포함한 여러 DNA 복구 메커니즘이 있다. 대략 450개의 인간 DDR 유전자는 생리학적 프로세스에서 역할을 하는 단백질을 코딩한다. DDR의 조절 장애는 유전적, 신경변성, 면역, 심혈관, 및 대사 질환 또는 장애, 및 암을 포함한 다양한 장애를 유발한다. 예를 들어, 유전자 OGG1 및 XRCC1은 DDR의 염기 절제 복구 메커니즘의 일부이며, 이러한 유전자에서의 돌연변이는 신장암, 유방암 및 폐암에서 발견되는 반면, 유전자 BRCA1 및 BRCA2는 상동 재조합 복구 메커니즘에 관여하고 이러한 유전자에서의 돌연변이는 유방암, 난소암, 전립선암, 췌장암뿐만 아니라 위장암 및 혈액암, 및 흑색종의 위험을 증가시킨다. 예시적인 DDR 유전자는 표 3에 제공된다.Within the DDR, there are several DNA repair mechanisms including base excision repair, nucleotide excision repair, mismatch repair, homologous recombination repair, and non-homologous end joining. Approximately 450 human DDR genes encode proteins that play a role in physiological processes. Dysregulation of the DDR causes a variety of disorders including genetic, neurodegenerative, immune, cardiovascular, and metabolic diseases or disorders, and cancer. For example, the genes OGG1 and XRCC1 are part of the base excision repair mechanism of the DDR, and mutations in these genes are found in renal, breast and lung cancer, whereas the genes BRCA1 and BRCA2 are involved in the homologous recombination repair mechanism and these genes Mutations in β increase the risk of breast, ovarian, prostate, pancreatic, as well as gastrointestinal and hematological cancers, and melanoma. Exemplary DDR genes are provided in Table 3 .
본원에 의해 개시된 발명의 목적은 DDRi와 조합하여 이온화 방사선을 전달하는 방사성표지된 HER3 표적화제를 투여하는 것이다. 따라서, 특정 측면에 따르면, HER3 표적화제와 함께 투여되는 부가의 작용제(들)는 DDR 내의 단백질을 표적화할 수 있어, 즉 DDR 억제제 또는 DDRi이므로, DNA 손상을 최대화하거나 또는 예컨대 G1 및 S-기에서의 손상이 있는 경우 복구를 억제하고/하거나 G2에서의 복구를 방지하여, DNA 손상의 최대량을 유사분열로 가져가 세포 사멸을 초래할 수 있다.It is an object of the invention disclosed herein to administer radiolabeled HER3 targeting agents that deliver ionizing radiation in combination with DDRi. Thus, according to certain aspects, the additional agent(s) administered with the HER3 targeting agent can target proteins within the DDR, i.e., are DDR inhibitors or DDRi, thereby maximizing DNA damage or, for example, in G1 and S-phases. In the presence of damage in , it can inhibit repair and/or prevent repair in G2, bringing the maximum amount of DNA damage to mitosis, resulting in cell death.
<표 3><Table 3>
더욱이, 하나 이상의 DDR 경로는 세포 사멸, 즉 표적화된 암 세포에 대한 치사성을 보장하기 위해 표적화될 수 있다. 예를 들어, BRCA1 및 2 유전자에서의 돌연변이만으로는 세포 사멸을 보장하기에 충분하지 않을 수 있는데, 이는 다른 경로, 예컨대 PARP1 염기 절제 경로가 DNA 손상을 복구하는 역할을 할 수 있기 때문이다. 따라서, 다중 DDRi 억제제의 조합 또는 DDRi와 항혈관신생제 또는 상기에 열거된 것과 같은 면역 체크포인트 억제제의 조합이 가능하며 이는 본원에 의해 개시된 발명의 목적이다.Moreover, one or more DDR pathways can be targeted to ensure cell death, ie lethality to targeted cancer cells. For example, mutations in the BRCA1 and 2 genes alone may not be sufficient to ensure cell death, as other pathways, such as the PARP1 base excision pathway, may play a role in repairing DNA damage. Thus, combinations of multiple DDRi inhibitors or combinations of DDRi with anti-angiogenic agents or immune checkpoint inhibitors such as those listed above are possible and are an object of the invention disclosed herein.
예시적인 exemplary DDRiDDRi - ATM 및 ATR 억제제 - ATM and ATR inhibitors
돌연변이된 모세혈관확장성 운동실조증 (ATM) 및 돌연변이된 및 Rad-3 관련된 모세혈관확장성 운동실조증 (ATR)은 세린/트레오닌 단백질 키나제의 포스파티딜이노시톨 3-키나제 관련 키나제 (PIKK) 패밀리의 구성원이다.Mutated telangiectatic ataxia (ATM) and mutated and Rad-3 related telangiectatic ataxia (ATR) are members of the phosphatidylinositol 3-kinase related kinase (PIKK) family of serine/threonine protein kinases.
ATM은 DNA 이중 가닥 파손에 의해 동원되고 활성화되는 세린/트레오닌 단백질 키나제이다. ATM은 DNA 손상 체크포인트의 활성화를 시작하는 몇 가지 주요 단백질을 인산화하여 세포 주기 정지, DNA 복구 또는 세포성 아폽토시스를 초래한다. p53, CHK2 및 H2AX를 포함한 이러한 표적 중 몇 가지는 종양 억제인자이다. 이러한 단백질은 ATM의 돌연변이로 인해 발생하는 장애인 모세혈관확장성 운동실조증의 이름을 따서 명명되었다. ATM은 포스파티딜이노시톨 3-키나제 관련 키나제 (PIKK)의 슈퍼패밀리에 속하며, 이는 포스파티딜이노시톨 3-키나제 (PI3K)와 서열 유사성을 나타내는 6개의 세린/트레오닌 단백질 키나제를 포함한다.ATM is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. ATM phosphorylates several key proteins that initiate activation of DNA damage checkpoints, resulting in cell cycle arrest, DNA repair or cellular apoptosis. Several of these targets, including p53, CHK2 and H2AX, are tumor suppressors. This protein is named after telangiectatic ataxia, a disorder caused by mutations in ATM. ATM belongs to the superfamily of phosphatidylinositol 3-kinase related kinases (PIKKs), which includes six serine/threonine protein kinases that show sequence similarity to phosphatidylinositol 3-kinases (PI3Ks).
ATM과 마찬가지로, ATR은 DDR에 관여하는 중심 키나제 중 하나이다. ATR은 단일 가닥 DNA 구조에 의해 활성화되며, 이는 예를 들어, 절제된 DNA DSB 또는 지연된 복제 분기점에서 발생할 수 있다. DNA 폴리머라제가 DNA 복제 중에 지연되면, 복제 헬리카제는 복제 분기점보다 먼저 DNA를 계속 풀어서, 길게 이어지는 단일 가닥 DNA (ssDNA)를 생성한다.Like ATM, ATR is one of the central kinases involved in DDR. ATR is activated by single-stranded DNA structures, which can occur, for example, at excised DNA DSBs or delayed replication forks. When DNA polymerase is delayed during DNA replication, the replicating helicase continues to unwind DNA before the replication fork, creating long, single-stranded DNA (ssDNA).
ATM은 화학요법제에 대한 저항성을 제공함으로써 암 세포에 도움이 되는 것으로 밝혀졌으며, 따라서 종양 성장 및 생존을 도와준다. ATM 및/또는 ATR의 억제는 DNA 손상 물질, 예컨대 방사성표지된 HER3 표적화제에 의해 제공된 이온화 방사선에 대한 암 세포 감수성을 현저하게 증가시킬 수 있다. 따라서, 본원에 의해 개시된 발명의 목적은 HER3 표적화제와 조합하여 ATM의 억제제 (ATMi) 및/또는 ATR의 억제제 (ATRi)를 투여하여, 암 세포, 예컨대 HER3을 발현하거나 과다발현하는 암 세포를 억제하거나 사멸시키는 것을 포함한다.ATM has been shown to benefit cancer cells by providing resistance to chemotherapeutic agents, thus helping tumor growth and survival. Inhibition of ATM and/or ATR can significantly increase cancer cell susceptibility to DNA damaging agents, such as ionizing radiation provided by radiolabeled HER3 targeting agents. Accordingly, an object of the invention disclosed herein is to inhibit cancer cells, such as cancer cells that express or overexpress HER3, by administering an inhibitor of ATM (ATMi) and/or an inhibitor of ATR (ATRi) in combination with a HER3 targeting agent. including killing or destroying.
ATM의 억제제 (ATMi) 또는 ATR의 억제제 (ATRi)는 각각 ATM 또는 ATR을 표적으로 하는 항체, 펩티드 또는 소분자일 수 있다. 대안적으로, ATMi 또는 ATRi는 하나 이상의 신호전달 분자, 단백질, 또는 다른 화합물에 의한 ATM 또는 ATR의 활성화를 감소 또는 제거할 수 있거나, 또는 모든 신호전달 분자, 단백질, 또는 다른 화합물에 의한 ATM 또는 ATR 활성화의 감소 또는 제거를 초래할 수 있다. ATMi 및/또는 ATRi는 또한 그들의 발현을 억제하는 화합물 (예를 들어, ATM 또는 ATR 전사 또는 번역을 억제하는 화합물)을 포함한다. 예시적인 ATMi KU-55933은 세포 증식을 억제하고 아폽토시스를 유도한다. 다른 예시적인 ATMi는 적어도 KU-59403, 워트만닌, CP466722 및 KU-60019를 포함한다. 예시적인 ATRi는 적어도 쉬잔드린 B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20 및 AZD6738을 포함한다.An inhibitor of ATM (ATMi) or an inhibitor of ATR (ATRi) may be an antibody, peptide or small molecule that targets ATM or ATR, respectively. Alternatively, the ATMi or ATRi may reduce or eliminate activation of ATM or ATR by one or more signaling molecules, proteins, or other compounds, or ATM or ATR by all signaling molecules, proteins, or other compounds. reduction or elimination of activation. ATMi and/or ATRi also include compounds that inhibit their expression (eg, compounds that inhibit ATM or ATR transcription or translation). Exemplary ATMi KU-55933 inhibits cell proliferation and induces apoptosis. Other exemplary ATMi include at least KU-59403, wortmannin, CP466722 and KU-60019. Exemplary ATRi include at least Schizandrin B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20 and AZD6738.
예시적인 exemplary DDRiDDRi - - Wee1Wee1 억제제 inhibitor
체크포인트 키나제 Wee1은 티로신 15에서 CDK1 (CDC2)과 CDK2 둘 다의 억제 인산화를 촉매하므로, 외부적으로 유도된 DNA 손상에 대한 반응으로 세포 주기를 정지시킨다. 탈조절된 Wee1 발현 또는 활성은 여러 유형의 암에서 병리학의 특징으로 여겨진다. 예를 들어, Wee1은 교모세포종, 악성 흑색종, 간세포 암종, 유방암, 결장 암종, 폐 암종 및 두경부 편평 세포 암종에서 종종 과다발현된다. 게놈 불안정성 수준이 증가한 진행성 종양은 그러한 치명적인 DNA 손상을 복구할 수 있는 기능적 체크포인트가 필요할 수 있다. 이와 같이, 본 발명자들은 Wee1이 그의 억제가 돌이킬 수 없는 DNA 손상을 초래하는 것으로 여겨지는 진행성 종양에서 매력적인 표적을 나타낸다고 믿는다. 따라서, 본원에 의해 개시된 발명의 목적은 HER3 표적화제와 조합하여 Wee1의 억제제를 투여하여, 암 세포, 예컨대 HER3을 발현하거나 과다발현하는 암 세포를 억제하거나 사멸시키는 것을 포함한다.The checkpoint kinase Wee1 catalyzes the inhibitory phosphorylation of CDK1 (CDC2) and both CDK2 on tyrosine 15, thereby arresting the cell cycle in response to externally induced DNA damage. Deregulated Wee1 expression or activity is considered a hallmark of pathology in several types of cancer. For example, Weel is frequently overexpressed in glioblastoma, malignant melanoma, hepatocellular carcinoma, breast cancer, colon carcinoma, lung carcinoma and head and neck squamous cell carcinoma. Advanced tumors with increased levels of genomic instability may require functional checkpoints capable of repairing such lethal DNA damage. As such, we believe that Weel represents an attractive target in advanced tumors where its inhibition is believed to result in irreversible DNA damage. Accordingly, an object of the invention disclosed by the present application includes administering an inhibitor of Weel in combination with a HER3 targeting agent to inhibit or kill cancer cells, such as cancer cells that express or overexpress HER3.
Wee1 억제제는 Wee1을 표적으로 하는 항체, 펩티드 또는 소분자일 수 있다. 대안적으로, Wee1 억제제는 하나 이상의 신호전달 분자, 단백질 또는 기타 화합물에 의한 Wee1 활성화를 감소 또는 제거할 수 있거나, 또는 모든 신호전달 분자, 단백질 또는 기타 화합물에 의한 Wee1 활성화의 감소 또는 제거를 초래할 수 있다. 상기 용어는 또한 Wee1에 의한 하나 이상의 단백질 또는 세포 신호전달 성분의 활성화 또는 불활성화를 감소 또는 제거하는 화합물을 포함한다 (예를 들어, Wee1 억제제는 사이클린 및 Cdk 활성의 Wee1 의존적 불활성화를 감소 또는 제거할 수 있음). Wee1 억제제는 또한 Wee1 발현을 억제하는 화합물 (예를 들어, Wee1 전사 또는 번역을 억제하는 화합물)을 포함한다.Wee1 inhibitors can be antibodies, peptides or small molecules that target Wee1. Alternatively, a Weel inhibitor may reduce or eliminate Wee1 activation by one or more signaling molecules, proteins or other compounds, or may result in reduced or eliminated Weel activation by all signaling molecules, proteins or other compounds. there is. The term also includes compounds that reduce or eliminate activation or inactivation of one or more proteins or cell signaling components by Weel (e.g., Weel inhibitors reduce or eliminate Weel-dependent inactivation of cyclins and Cdk activity). can). Wee1 inhibitors also include compounds that inhibit Wee1 expression (eg, compounds that inhibit Wee1 transcription or translation).
예시적인 Wee1 억제제는 AZD-1775 (즉, 아다보세르팁), 및 억제제, 예컨대 예를 들어, 미국 특허 번호 7,834,019; 7,935,708; 8,288,396; 8,436,004; 8,710,065; 8,716,297; 8,791,125; 8,796,289; 9,051,327; 9,181,239; 9,714,244; 9,718,821; 및 9,850,247; 미국 공개 번호 US 20100113445 및 20160222459; 및 국제 공개 번호 WO2002090360, 2015019037, 2017013436, 2017216559, 2018011569, 및 2018011570에 기재된 것을 포함한다.Exemplary Weel inhibitors include AZD-1775 (ie, adavosertip), and inhibitors such as, for example, US Pat. No. 7,834,019; 7,935,708; 8,288,396; 8,436,004; 8,710,065; 8,716,297; 8,791,125; 8,796,289; 9,051,327; 9,181,239; 9,714,244; 9,718,821; and 9,850,247; US Publication Nos. US 20100113445 and 20160222459; and International Publication Nos. WO2002090360, 2015019037, 2017013436, 2017216559, 2018011569, and 2018011570.
추가의 Wee1 억제제는 피라졸로피리미딘 유도체, 피리도피리미딘, 4-(2-클로로페닐)-9-히드록시피롤로[3,4-c]카르바졸-1,3-(2H,6H)-디온 (CAS No. 622855-37-2), 6-부틸-4-(2-클로로페닐)-9-히드록시피롤로[3,4-c]카르바졸-1,3-(2H,6H)-디온 (CAS No. 62285550-9), 4-(2-페닐)-9-히드록시피롤로[3,4-c]카르바졸-1,3-(2H,6H)-디온 (CAS No. 1177150-89-8), 및 항-Wee1 작은 간섭 RNA (siRNA) 분자를 포함한다.Additional Wee1 inhibitors include pyrazolopyrimidine derivatives, pyridopyrimidines, 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H) -Dione (CAS No. 622855-37-2), 6-butyl-4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H )-dione (CAS No. 62285550-9), 4-(2-phenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3-(2H,6H)-dione (CAS No. 1177150-89-8), and anti-Weel small interfering RNA (siRNA) molecules.
예시적인 exemplary DDRiDDRi - - PARPPARP 억제제 inhibitor
사용될 수 있는 또 다른 예시적인 유형의 DDRi는 폴리(ADP-리보스) 폴리머라제 ("PARP")의 억제제이다. 개별적으로 그리고 총칭하여 "PARPi"로서 지칭된, DNA 복구 단백질 PARP의 억제제는 다양한 고형 종양, 예컨대 특히 BRCA1/2 돌연변이가 있는 환자에서의 유방암 및 난소암에 사용하도록 승인되었다. BRCA1 및 2는 상동 재조합 복구 (HRR)에서 기능한다. 돌연변이가 발생하면, 이들은 DNA 복구 프로세스를 보존적이고 정확한 HRR에서 비-충실 방법, 예컨대 결실 및 삽입을 통해 돌연변이를 생산할 수 있는 DNA 말단 연결로 전환함으로써 게놈 불안정성을 유발시킨다. Another exemplary type of DDRi that may be used is an inhibitor of poly(ADP-ribose) polymerase ("PARP"). Inhibitors of the DNA repair protein PARP, individually and collectively referred to as “PARPi,” have been approved for use in a variety of solid tumors, such as breast and ovarian cancer, particularly in patients with BRCA1/2 mutations. BRCA1 and 2 function in homologous recombination repair (HRR). When mutations occur, they cause genomic instability by shifting the DNA repair process from conservative and precise HRR to DNA end joining that can produce mutations through non-conservative methods such as deletions and insertions.
PARPi는 BRCA1/2 돌연변이체 세포에서 강력한 단일 작용제 활성에 의해 나타난 바와 같이, 합성 치사율을 나타내는 것으로 밝혀졌다. 이것은 본질적으로 단일 가닥 DNA 파손의 복구를 차단한다. HRR은 이러한 종양 세포에서 기능하지 않기 때문에, 세포 사멸이 발생한다. 대부분의 종양은 BRCA1 또는 BRCA2 돌연변이를 보유하고 있지 않기 때문에, 그러한 종양에서의 PARPi의 효능은 훨씬 덜 두드러진다.PARPi was found to exhibit synthetic lethality, as shown by potent single-agent activity in BRCA1/2 mutant cells. This essentially blocks repair of single-stranded DNA breaks. Since HRR does not function in these tumor cells, cell death occurs. Since most tumors do not harbor BRCA1 or BRCA2 mutations, the efficacy of PARPi in such tumors is much less pronounced.
현재까지, FDA는 특히 BRCA1 및 BRCA2 유전자에서의 생식계열 및 체세포 돌연변이가 있는 환자를 대상으로 4가지 PARPi 약물 (올라파립, 니라파립, 루카파립 및 탈라조파립)을 단독 요법제로서 승인하였다. 벨리파립과 함께, 올라파립, 니라파립 및 루카파립은 임상 시험에 들어간 1세대 PARPi에 속한다. 이들의 IC50 값은 나노몰 범위에 있는 것으로 밝혀졌다. 대조적으로, 탈라조파립과 같은 2세대 PARPi는 피코몰 범위의 IC50 값을 갖는다.To date, the FDA has approved four PARPi drugs (olaparib, niraparib, rucaparib, and thalazoparib) as monotherapy specifically for patients with germline and somatic mutations in the BRCA1 and BRCA2 genes. Along with veliparib, olaparib, niraparib and rucaparib are among the first-generation PARPi that have entered clinical trials. Their IC50 values were found to be in the nanomolar range. In contrast, second generation PARPi such as thalazoparib have IC50 values in the picomolar range.
이들 PARPi는 모두 PARP1 및 PARP2의 촉매 도메인에서 보조인자인 b 니코틴아미드 아데닌 디뉴클레오티드 (b-NAD+)의 결합 부위와 결합한다. PARP 패밀리의 효소는 NAD+를 사용하여 폴리(ADP-리보스) (PAR) 쇄를 표적 단백질 상에 공유적으로 부가하는데, 이러한 과정을 "PAR화"라고 한다. PARP1 (가장 많이 연구된 구성원)과 PARP2는 DNA 손상 반응 (DDR) 경로의 중요한 성분이다. PARP1은 단일 가닥 DNA 파손, 및 가능하게 다른 DNA 병변의 복구에 관여한다 (Woodhouse, et al.; Krishnakumar, et al.). PARP1은 그의 아연 핑거 도메인을 통해, 손상된 DNA와 결합한 다음 일련의 DNA 복구 이펙터 단백질을 PAR화하여 니코틴아미드를 부산물로서 방출한다 (Krishnakumar, et al.). 후속적으로, PARP1 자가-PAR화는 DNA로부터의 단백질의 방출을 초래한다. 그러나, 이용 가능한 PARPi는 DNA 상에 PARP1을 포획할 수 있는 능력이 상이하며, 이는 세포독성 및 약물 효능과 상관이 있는 것으로 보인다. 구체적으로, 탈라조파립 및 올라파립과 같은 약물은 벨리파립보다 PARP1 포획에 더 효과적이다 (Murai, et al., 2012; Murai, et al., 2014).All of these PARPi bind to the binding site of b nicotinamide adenine dinucleotide (b-NAD+), a cofactor, in the catalytic domains of PARP1 and PARP2. Enzymes of the PARP family use NAD+ to covalently add poly(ADP-ribose) (PAR) chains onto target proteins, a process called "PARization". PARP1 (the most studied member) and PARP2 are important components of the DNA damage response (DDR) pathway. PARP1 is involved in the repair of single-stranded DNA breaks, and possibly other DNA lesions (Woodhouse, et al.; Krishnakumar, et al.). Through its zinc finger domain, PARP1 binds damaged DNA and then PARates a series of DNA repair effector proteins, releasing nicotinamide as a by-product (Krishnakumar, et al.). Subsequently, PARP1 self-PARylation results in the release of the protein from DNA. However, available PARPi differ in their ability to capture PARP1 on DNA, which appears to correlate with cytotoxicity and drug efficacy. Specifically, drugs such as thalazoparib and olaparib are more effective at capturing PARP1 than veliparib (Murai, et al., 2012; Murai, et al., 2014).
BRCA1 또는 BRCA2 유전자 내에 기능 상실 돌연변이가 있는 난소암 및 유방암 환자에서의 PARPi의 효능은 주로 합성 치사율의 유전적 개념에 기인한다: BRCA 1 및 2의 단백질은 상동 재조합 복구 (HRR)로서 공지된 DNA 복구 프로세스를 매개함으로써 게놈의 무결성을 정상적으로 유지하며; PARPi는 정상적으로 HR에 의해 달리 복구되는 지속적인 DNA 병변을 유발한다. PARPi의 존재 하에, PARP1은 복제 분기점의 진행을 지연시키는 DNA 상에 포획되어 있다. 이러한 지연은 HR 시스템에 의해 적시에 복구되지 않는 한 세포독성이 있다. 효과적인 HR이 결여된 세포에서는, 이러한 DNA 병변을 효과적으로 복구할 수 없으므로, 그 세포는 사멸된다.The efficacy of PARPi in ovarian and breast cancer patients with loss-of-function mutations within the BRCA1 or BRCA2 gene is primarily due to the genetic concept of synthetic lethality: the proteins of
다시 말하지만, BRCA 유전자 및 HRR 시스템 내의 다른 유전자에서의 돌연변이는 많은 암 유형에서 널리 퍼지지 않는다. 따라서, 그러한 암에서 PARPi의 치료 이점을 더 잘 활용하기 위해서는, PARPi를 화학요법 또는 방사선 요법과 페이링함으로써 "인공적인" 합성 치사율을 유도할 수 있다. 전임상 연구에서는 방사선 요법과 PARPi를 조합하면 PARP 억제에 대한 BRCA1/2 돌연변이체 종양 세포의 감수성이 증가될 수 있고 PARP 억제에 대한 비-돌연변이체 BRCA 종양의 감수성이 확장될 수 있는 것으로 입증되었다. 부가의 연구에서는 이온화 방사선 (IR) 자체가 종양 세포에서 PARPi 합성 치사율을 매개할 수 있는 것으로 나타났다.Again, mutations in the BRCA gene and other genes within the HRR system are not prevalent in many cancer types. Thus, to better exploit the therapeutic benefits of PARPi in such cancers, "artificial" synthetic lethality can be induced by pairing PARPi with chemotherapy or radiation therapy. Preclinical studies have demonstrated that combining radiotherapy with PARPi can increase the sensitivity of BRCA1/2 mutant tumor cells to PARP inhibition and expand the sensitivity of non-mutant BRCA tumors to PARP inhibition. Additional studies have shown that ionizing radiation (IR) itself can mediate PARPi synthesis lethality in tumor cells.
따라서, 본원에 의해 개시된 발명의 목적은 PARPi와 조합하여 이온화 방사선을 전달하는 방사성표지된 HER3 표적화제를 투여하는 것이다.Accordingly, an object of the invention disclosed herein is to administer a radiolabeled HER3 targeting agent that delivers ionizing radiation in combination with PARPi.
본 발명의 다양한 실시양태에서, PARPi는 그 기능을 수행하는 임의의 공지된 작용제일 수 있으며, 바람직하게는 FDA에 의해 승인된 것일 수 있다. 바람직하게, PARPi는 올라파립 [린파르자(Lynparza®)], 니라파립 [제줄라(Zejula®)], 루카파립 [루브라카(Rubraca®)] 또는 탈라조파립 [탈젠나(Talzenna®)]이다.In various embodiments of the present invention, PARPi can be any known agent that performs that function, preferably one approved by the FDA. Preferably, PARPi is olaparib [Lynparza®], niraparib [Zejula®], rucaparib [Rubraca®] or thalazoparib [Talzenna®] ]am.
임상적으로, PARPi를 사용한 요법은 난소암, 전립선암, 췌장암 및 삼중 음성 유방암 (TNBC)을 포함한 다양한 암에서 지속적인 항종양 반응을 초래하였다. 한 임상 시험에서, 생식계열 BRCA1/2 돌연변이가 있는 TNBC 환자를 PARPi, 올라파립으로 치료하였다. 이러한 요법은 비-돌연변이체 환자와 비교하여 BRCA1/2 돌연변이체에서 더 높은 질환 안정화율을 명확하게 보여주었지만, 어느 코호트에서도 지속적인 반응이 달성되지 않았다 (Gelmon, 2011).Clinically, therapy with PARPi has resulted in sustained antitumor responses in a variety of cancers including ovarian, prostate, pancreatic and triple negative breast cancer (TNBC). In one clinical trial, TNBC patients with germline BRCA1/2 mutations were treated with PARPi, olaparib. Although this regimen clearly demonstrated higher disease stabilization rates in BRCA1/2 mutants compared to non-mutant patients, no sustained response was achieved in either cohort (Gelmon, 2011).
본 발명자들은 이러한 복구 경로가 PARPi에 의해 차단되는 동안 HER3 표적화제에 의해 제공되는 이온화 방사선에 의해 유도되는 dsDNA 파손의 증가를 통해 PARPi의 효과가 개선될 수 있음을 깨달았다. 예시적인 PARPi는 올라파립, 니라파립, 루카파립 및 탈라조파립을 포함한다.The inventors realized that while this repair pathway is blocked by PARPi, the effect of PARPi can be ameliorated through an increase in dsDNA breakage induced by ionizing radiation provided by HER3 targeting agents. Exemplary PARPi include olaparib, niraparib, rucaparib and thalazoparib.
E. CD47 차단제E. CD47 blockers
HER3 표적화제와 함께 투여되는 부가의 작용제는 CD47 차단제, 예컨대 CD47 또는 SIRPα와의 상호작용을 통해 CD47 (예를 들어, 표적 세포 상에서) 및 SIRPα (예를 들어, 포식 세포 상에서) 간의 활성 및/또는 신호전달을 방해하거나 감소시키는 임의의 작용제일 수 있다. 적합한 CD47 차단제의 비제한적 예는 SIRPα 폴리펩티드, 항-SIRPα 항체, 가용성 CD47 폴리펩티드, 및 항-CD47 항체 또는 항체 단편을 포함하나 이에 제한되지 않는 CD47 및/또는 SIRPα 시약을 포함한다.Additional agents administered with a HER3 targeting agent may inhibit activity and/or signaling between CD47 (eg, on target cells) and SIRPα (eg, on phagocytic cells) through interaction with a CD47 blocker, such as CD47 or SIRPα. It can be any agent that interferes with or reduces delivery. Non-limiting examples of suitable CD47 blocking agents include CD47 and/or SIRPα reagents including, but not limited to, SIRPα polypeptides, anti-SIRPα antibodies, soluble CD47 polypeptides, and anti-CD47 antibodies or antibody fragments.
CD47 차단제의 부가의 예는 CD47 및/또는 SIRPα의 발현을 조정하는 작용제를 포함한다. 예를 들어, 이러한 작용제는 핵산 접근방식, 예컨대 CD47의 번역을 차단하는 포스포로디아미데이트 모르폴리노 올리고머 (PMO) 또는 CD47 발현을 조정, 예를 들어 차단, 억제, 감소, 길항, 중화 또는 달리 방해하는 인간 CD47에 특이적인 항체를 포함할 수 있다. CD47 항체 또는 안티센스 접근방식은 CD47 발현을 억제하거나 (예를 들어, CD47의 세포 표면 발현 억제), 활성 및/또는 신호전달을 억제하거나, 또는 CD47과 SIRPα 간의 상호작용을 방해할 수 있다. 본원에 제공된 작용제는 CD47, 예를 들어 인간 CD47과 결합하거나 달리 상호작용할 때 CD47 발현 또는 활성을 완전히 또는 부분적으로 감소시키거나 달리 조정한다. CD47의 생물학적 기능의 감소 또는 조정은 항체와 인간 CD47 폴리펩티드 및/또는 펩티드 간의 상호작용에 따라 완전하거나, 유의미하거나, 또는 부분적이다. 상기 작용제는 항체의 존재 하에서의 CD47 발현 또는 활성의 수준이, 본원에 기재된 항체와의 상호작용, 예를 들어 결합의 부재 하에서의 CD47 발현 또는 활성의 수준과 비교 시 적어도 50%, 예를 들어, 60%, 70%, 80%, 90%, 95%, 96%, 98%, 99%, 또는 100%만큼 감소되는 경우에 CD47 발현 또는 활성을 억제하는 것으로 간주된다.Additional examples of CD47 blockers include agents that modulate the expression of CD47 and/or SIRPα. For example, such agents modulate, e.g., block, suppress, reduce, antagonize, neutralize, or otherwise modulate CD47 expression or a nucleic acid approach, such as a phosphorodiamidate morpholino oligomer (PMO) that blocks translation of CD47. antibodies specific for human CD47 that interfere with it. A CD47 antibody or antisense approach may inhibit CD47 expression (eg, inhibit cell surface expression of CD47), inhibit activity and/or signaling, or interfere with the interaction between CD47 and SIRPα. An agent provided herein completely or partially reduces or otherwise modulates CD47 expression or activity when it binds or otherwise interacts with CD47, eg, human CD47. The reduction or modulation of a biological function of CD47 is complete, significant, or partial depending on the interaction between the antibody and human CD47 polypeptides and/or peptides. The agent is capable of reducing the level of CD47 expression or activity in the presence of the antibody by at least 50%, e.g., 60%, when compared to the level of CD47 expression or activity in the absence of interaction, e.g., binding, with an antibody described herein. , 70%, 80%, 90%, 95%, 96%, 98%, 99%, or 100% is considered to inhibit CD47 expression or activity.
특정 측면에 따르면, 항-CD47 작용제는 CD47과 특이적으로 결합하고 (즉, 항-CD47 항체), 하나의 세포 (예를 들어, 감염된 세포) 상의 CD47과 또 다른 세포 (예를 들어, 포식 세포) 상의 SIRPα 간의 상호작용을 감소시키는 항체이다. 적합한 항체의 비제한적 예는 클론 B6H12, 5F9, 8B6 및 C3 및 국제 공개 번호 WO2011/143624 및 미국 공개 번호 20210246206에 기재된 것 중 임의의 것을 포함한다. 적합한 항-CD47 항체는 이러한 항체의 완전 인간, 인간화 또는 키메라 버전을 포함한다.According to certain aspects, an anti-CD47 agent specifically binds CD47 (ie, an anti-CD47 antibody) and binds CD47 on one cell (eg, an infected cell) to another cell (eg, a phagocytic cell). ) It is an antibody that reduces the interaction between SIRPα on the. Non-limiting examples of suitable antibodies include clones B6H12, 5F9, 8B6 and C3 and any of those described in International Publication Nos. WO2011/143624 and US Publication No. 20210246206. Suitable anti-CD47 antibodies include fully human, humanized or chimeric versions of such antibodies.
낮은 항원성으로 인해 인간에서의 생체내 적용에 특히 유용한 예시적인 인간 또는 인간화 항체는 적어도 CD47에 대한 모노클로날 항체, 예컨대 Hu5F9-G4, 길리어드(Gilead)로부터 마그롤리맙으로서 입수 가능한 인간화 모노클로날 항체 (문헌 [Sikic, et al. (2019) Journal of Clinical Oncology 37:946]); I-Mab 바이오파마(Biopharma)로부터의 렘조파를리맙 및 TJC4; 아치 온콜로지, 인크.(Arch Oncology, Inc.)로부터의 AO-176; 아케소바이오 호주 법인(Akesobio Australia Pty)으로부터의 AK117; 이노벤트 바이오로직스(Innovent Biologics)로부터의 IMC-002; 지아 랩(Zia Lab)으로부터의 ZL-1201; 장쑤 헝루이 메디신 캄파니(Jiangsu HengRui Medincine Co.)로부터의 SHR-1603; 및 서피스 온콜로지(Surface Oncology)로부터의 SRF231을 포함한다. 이중특이적 모노클로날 항체, 예컨대 CD47과 PD-L1 둘 다를 표적으로 하는 이노벤트 바이오로직스로부터의 IBI-322가 또한 입수 가능하다. SIRPα에 대한 항체, 예컨대 알엑스 온콜로지(Alx Oncology)로부터의 ALX148; OSE로부터의 BI 765063 (OSE-172); 뿐만 아니라 소분자 억제제, 예컨대 에피센트Rx(EpicentRx)로부터의 RRx-001 (1-브로모아세틸-3,3-디니트로아제티딘) 및 아젤니디핀 (CAS 번호 123524-52-7) 또는 그의 제약상 허용되는 염이 또한 가능하다. 예시적인 작용제에 대한 추가의 설명은 표 4를 참조한다.Exemplary human or humanized antibodies that are particularly useful for in vivo application in humans due to their low antigenicity are monoclonal antibodies to at least CD47, such as Hu5F9-G4, a humanized monoclonal available as Magrolimab from Gilead. raw antibodies (Sikic, et al. (2019) Journal of Clinical Oncology 37:946); Remzoparlimab and TJC4 from I-Mab Biopharma; AO-176 from Arch Oncology, Inc.; AK117 from Akesobio Australia Pty; IMC-002 from Innovent Biologics; ZL-1201 from Zia Lab; SHR-1603 from Jiangsu HengRui Medincine Co.; and SRF231 from Surface Oncology. A bispecific monoclonal antibody, such as IBI-322 from Innovent Biologics, which targets both CD47 and PD-L1, is also available. Antibodies to SIRPα such as ALX148 from Alx Oncology; BI 765063 from OSE (OSE-172); as well as small molecule inhibitors such as RRx-001 (1-bromoacetyl-3,3-dinitroazetidine) and azelnidipine (CAS number 123524-52-7) from EpicentRx or their pharmaceutical counterparts. Acceptable salts are also possible. See Table 4 for further description of exemplary agents.
<표 4><Table 4>
AO-176은 CD47-SIRPα 상호작용을 차단하여 종양 식세포작용을 유도하는 것 외에도, 정상 세포 (특히 결합이 무시할 수 있는 경우 RBC)에 비해 종양 세포와 우선적으로 결합하고 정상 세포에 비해 종양을 직접 사멸시키는 것으로 보고되었다.In addition to inducing tumor phagocytosis by blocking the CD47-SIRPα interaction, AO-176 binds preferentially to tumor cells over normal cells (especially RBCs when binding is negligible) and directly kills tumors compared to normal cells. reported to do
특정 측면에 따르면, SIRPα 시약은 정상적으로 신호 서열과 막횡단 도메인 사이에 위치하는, 인식 가능한 친화도로 CD47과 결합하기에 충분한 SIRPα의 부분, 또는 결합 활성을 유지하는 그의 단편을 포함할 수 있다. 적합한 SIRPα 시약은 천연 단백질 SIRPα와 CD47 간의 상호작용을 감소 (예를 들어, 차단, 방지 등)시킨다. 예를 들어, 본 발명의 다양한 측면에서 사용되는 CD47 차단제는 그 안에 개시된 SIRPα-IgG Fc 융합 단백질을 포함하나 이에 제한되지는 않는 미국 특허 번호 9,969,789에 개시된 것 중 임의의 것, 예컨대 TTI-621 및 TTI-622일 수 있으며, 이들 둘 다는 종양 세포 상에서 CD47과 우선적으로 결합하는 동시에 또한 활성화 Fc 수용체를 결합시킨다. 예를 들어, 서열식별번호: 116, 서열식별번호: 117, 또는 서열식별번호: 118의 아미노산 서열을 포함하는 SIRPα-IgG Fc 융합 단백질이 사용될 수 있다.According to certain aspects, a SIRPα reagent may comprise a portion of SIRPα sufficient to bind CD47 with appreciable affinity, normally located between the signal sequence and the transmembrane domain, or a fragment thereof that retains binding activity. A suitable SIRPα reagent reduces (eg, blocks, prevents, etc.) the interaction between the native protein SIRPα and CD47. For example, the CD47 blocker used in various aspects of the present invention is any of those disclosed in U.S. Patent No. 9,969,789, including but not limited to the SIRPα-IgG Fc fusion proteins disclosed therein, such as TTI-621 and TTI -622, both of which preferentially bind CD47 on tumor cells while also binding activating Fc receptors. For example, SEQ ID NO: 116, SEQ ID NO: 117, or a SIRPα-IgG Fc fusion protein comprising the amino acid sequence of SEQ ID NO: 118 can be used.
항-CD47 항체 또는 다른 단백질 CD47 억제제의 치료상 유효 용량은 단백질의 지속적인 혈청 수준을 약 40 μg/ml 이상 (예를 들어, 약 50 ug/ml 이상, 약 60 ug/ml 이상, 약 75 ug/ml 이상, 약 100 ug/ml 이상, 약 125 ug/ml 이상, 또는 약 150 ug/ml 이상)으로 유도하는 용량일 수 있다. CD47 차단제, 예컨대 항-CD47 항체 또는 SIRPα 융합 단백질 또는 소분자의 치료상 유효 용량 또는 투여는 예를 들어, 0.05 - 10 mg/kg (작용제 중량/대상체 체중), 예컨대 적어도 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, 9.0 mg/kg; 또는 10 mg/kg, 9.5 mg/kg, 9.0 mg/kg, 8.5 mg/kg, 8.0 mg/kg, 7.5 mg/kg, 7.0 mg/kg, 6.5 mg/kg, 6.0 mg/kg, 5.5 mg/kg, 5.0 mg/kg, 4.5 mg/kg, 4.0 mg/kg, 3.5 mg/kg, 3.0 mg/kg, 2.5 mg/kg, 2.0 mg/kg, 1.5 mg/kg, 1.0 mg/kg 이하의 양, 또는 이러한 값의 상한 및 하한의 임의의 조합을 포함한다. 본원에 개시된 것과 같은 소분자 CD47 차단제의 치료상 유효 용량은 또한, 예를 들어 0.01 mg/kg 내지 1,000 mg/kg 및 그 안의 mg/kg의 임의의 하위범위 또는 값, 예컨대 0.01 mg/kg 내지 500 mg/kg 또는 0.05 mg/kg 내지 500 mg/kg, 또는 0.5 mg/kg 내지 200 mg/kg, 또는 0.5 mg/kg 내지 150 mg/kg, 또는 1.0 mg/kg 내지 100 mg/kg, 또는 10 mg/kg 내지 50 mg/kg을 포함한다.A therapeutically effective dose of an anti-CD47 antibody or other protein CD47 inhibitor achieves a sustained serum level of the protein of about 40 μg/ml or greater (e.g., about 50 ug/ml or greater, about 60 ug/ml or greater, about 75 ug/ml or greater). ml or more, about 100 ug/ml or more, about 125 ug/ml or more, or about 150 ug/ml or more). A therapeutically effective dose or administration of a CD47 blocker, such as an anti-CD47 antibody or SIRPα fusion protein or small molecule, is, for example, 0.05 - 10 mg/kg (agent weight/subject weight), such as at least 0.1 mg/kg, 0.5 mg/kg kg, 1.0 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, 5.0 mg/kg, 5.5 mg/kg kg, 6.0 mg/kg, 6.5 mg/kg, 7.0 mg/kg, 7.5 mg/kg, 8.0 mg/kg, 8.5 mg/kg, 9.0 mg/kg; or 10 mg/kg, 9.5 mg/kg, 9.0 mg/kg, 8.5 mg/kg, 8.0 mg/kg, 7.5 mg/kg, 7.0 mg/kg, 6.5 mg/kg, 6.0 mg/kg, 5.5 mg/kg , in an amount less than or equal to 5.0 mg/kg, 4.5 mg/kg, 4.0 mg/kg, 3.5 mg/kg, 3.0 mg/kg, 2.5 mg/kg, 2.0 mg/kg, 1.5 mg/kg, 1.0 mg/kg, or Any combination of the upper and lower limits of these values is included. A therapeutically effective dose of a small molecule CD47 blocker as disclosed herein may also be, for example, from 0.01 mg/kg to 1,000 mg/kg and any subrange or value of mg/kg therein, such as from 0.01 mg/kg to 500 mg. /kg or 0.05 mg/kg to 500 mg/kg, or 0.5 mg/kg to 200 mg/kg, or 0.5 mg/kg to 150 mg/kg, or 1.0 mg/kg to 100 mg/kg, or 10 mg/kg kg to 50 mg/kg.
특정 측면에 따르면, 항-CD47 작용제는 SIRPα와 특이적으로 결합하고 하나의 세포 (예를 들어, 감염된 세포) 상의 CD47과 또 다른 세포 (예를 들어, 포식 세포) 상의 SIRPα 간의 상호작용을 감소시키는 가용성 CD47 폴리펩티드이다. 적합한 가용성 CD47 폴리펩티드는 SIRPα의 활성화가 식세포작용을 억제하기 때문에 SIRPα를 통한 신호전달을 활성화하거나 자극하지 않고 SIRPα와 결합할 수 있다. 대신, 적합한 가용성 CD47 폴리펩티드는 비-감염된 세포보다 감염된 세포의 우선적인 식세포작용을 용이하게 한다. 정상적인 비-표적 세포 (정상 세포)에 비해 더 높은 수준의 CD47을 발현하는 세포 (예를 들어, 감염된 세포)는 우선적으로 식세포작용될 것이다. 따라서, 적합한 가용성 CD47 폴리펩티드는 식세포작용을 억제하기에 충분한 신호전달 반응을 활성화/자극하지 않고서도 SIRPα와 특이적으로 결합한다. 일부 경우에, 적합한 가용성 CD47 폴리펩티드는 융합 단백질 (예를 들어, 미국 공개 번호 20100239579에 기재된 바와 같음)일 수 있다.According to certain aspects, an anti-CD47 agent specifically binds SIRPα and reduces the interaction between CD47 on one cell (eg, an infected cell) and SIRPα on another cell (eg, a phagocytic cell). It is a soluble CD47 polypeptide. Suitable soluble CD47 polypeptides can bind SIRPα without activating or stimulating signaling through SIRPα, since activation of SIRPα inhibits phagocytosis. Instead, suitable soluble CD47 polypeptides facilitate preferential phagocytosis of infected cells over non-infected cells. Cells that express higher levels of CD47 compared to normal non-target cells (normal cells) (eg, infected cells) will be preferentially phagocytosed. Thus, a suitable soluble CD47 polypeptide specifically binds to SIRPα without activating/stimulating a signaling response sufficient to inhibit phagocytosis. In some cases, a suitable soluble CD47 polypeptide may be a fusion protein (eg, as described in US Publication No. 20100239579).
유리하게, CD47 차단제는 방사성표지된 표적화제, 예컨대 방사성표지된 HER3 및/또는 HER2 표적화제의 세포독성 및 포식 증진 효과를 향상시킬 수 있으며, 표적화제의 용량 제한 방사선독성을 감소시킴으로써, 내약성을 개선시키고 표적화제의 더 높은 방사선 용량이 대상체의 치료에 사용/관용되도록 한다.Advantageously, CD47 blockers can enhance the cytotoxicity and phagocytosis enhancing effects of radiolabeled targeting agents, such as radiolabeled HER3 and/or HER2 targeting agents, and reduce dose limiting radiotoxicity of the targeting agent, thereby improving tolerability. and allow higher radiation doses of the targeting agent to be used/tolerated in the treatment of the subject.
실시예Example
실시예Example 1: One: 방사성표지된radiolabeled HER3HER3 표적화제의 생산 Production of targeting agent
HER3 표적화제, 예컨대 HER3에 대한 모노클로날 항체는 국제 공개 번호 WO 2017/155937 및 "부위-특이적 방사성접합체의 제조를 위한 조성물 및 방법"이라는 발명의 명칭으로 2019년 12월 9일에 출원된 미국 가출원 번호 63/042,651에 상세히 기재된 절차에 따라 인듐-111 (111In) 또는 악티늄-225 (225Ac)으로 표지될 수 있다HER3 targeting agents, such as monoclonal antibodies to HER3, are disclosed in International Publication No. WO 2017/155937 and filed on December 9, 2019 entitled "Compositions and Methods for the Preparation of Site-Specific Radioconjugates". It can be labeled with indium-111 ( 111 In) or actinium-225 ( 225 Ac) according to the procedures detailed in US Provisional Application No. 63/042,651.
방사성표지화 : 예를 들어, 항체는 예를 들어 본원 또는 선행 특허 출원에 기재된 바와 같이 킬레이트-보유 링커와 접합될 수 있다. 예시적인 링커는 적어도 도데칸 테트라아세트산 (DOTA)을 포함하며, 여기서 접합 반응의 목표는 3:1 내지 5:1의 DOTA-항체 비율을 달성하는 것이다. 그런 다음 방사성핵종 111In 또는 225Ac를 사용한 킬레이트화를 수행할 수 있으며, 그 결과로 생성된 111In- 또는 225Ac-표지된 항-HER3 항체의 효율성 및 순도를 HPLC 및 iTLC에 의해 결정할 수 있다. Radiolabeling : For example, the antibody may be conjugated with a chelate-bearing linker as described, for example, herein or in prior patent applications. Exemplary linkers include at least dodecane tetraacetic acid (DOTA), wherein the goal of the conjugation reaction is to achieve a DOTA-antibody ratio of 3:1 to 5:1. Chelation with the radionuclide 111 In or 225 Ac can then be performed, and the efficiency and purity of the resulting 111 In- or 225 Ac-labeled anti-HER3 antibody can be determined by HPLC and iTLC. .
225Ac에 대한 예시적인 표지화 반응은 하기와 같다: 15 μl 0.15 M NH4OAc 완충액, pH=6.5 및 2 μL (10 μg) DOTA-항-HER3 (5 mg/ml)을 포함하는 반응물을 에펜도르프 반응 튜브에서 혼합하고, 0.05 M HCl 중 4 μL 225Ac (10 μCi)를 연속적으로 부가할 수 있다. 튜브의 내용물을 피펫 팁으로 혼합하고 반응 혼합물을 100 rpm에서 진탕하면서 90분 동안 37℃에서 인큐베이션할 수 있다. 인큐베이션 기간이 끝나면, 3 μL의 1 mM DTPA 용액을 반응 혼합물에 부가하고 실온에서 20분 동안 인큐베이션하여 비반응 225Ac를 225Ac-DTPA 복합체와 결합시킬 수 있다. 10 cm 실리카겔 스트립과 10 mM EDTA/생리 식염수 이동 상을 사용한 순간 박층 크로마토그래피를 사용하여, 225Ac-표지된 항-HER3 (225Ac-DOTA-항-HER3)을 유리 225Ac (225Ac-DTPA)로부터 분리시키는 것을 통해 225Ac-DOTA-항-HER3의 방사화학적 순도를 결정할 수 있다. 이러한 시스템에서, 방사성표지된 항체는 적용 지점에 머물고 225Ac-DTPA는 용매 전면과 함께 이동한다. 스트립은 반으로 커팅하고 그의 도터를 제외하기 위해 225Ac에 대해 채널 72-110을 사용하는 다중 채널 분석기가 장착된 감마 계수기에서 계수할 수 있다.An exemplary labeling reaction for 225 Ac is as follows: A reaction containing 15 μl 0.15 M NH 4 OAc buffer, pH=6.5 and 2 μL (10 μg) DOTA-anti-HER3 (5 mg/ml) was prepared in Eppendorf Mix in a reaction tube and add 4 μL 225 Ac (10 μCi) in 0.05 M HCl sequentially. The contents of the tube can be mixed with a pipette tip and the reaction mixture can be incubated at 37° C. for 90 minutes while shaking at 100 rpm. At the end of the incubation period, 3 μL of a 1 mM DTPA solution can be added to the reaction mixture and incubated at room temperature for 20 minutes to bind unreacted 225 Ac to the 225 Ac-DTPA complex. 225 Ac-labeled anti-HER3 ( 225 Ac-DOTA-anti-HER3) was obtained as free 225 Ac ( 225 Ac-DTPA ), the radiochemical purity of 225 Ac-DOTA-anti-HER3 can be determined. In this system, the radiolabeled antibody stays at the point of application and the 225 Ac-DTPA migrates with the solvent front. The strip can be cut in half and counted in a gamma counter equipped with a multi-channel analyzer using channels 72-110 for 225 Ac to exclude its daughters.
정제 : 예시적인 방사성표지된 HER3 표적화제, 예컨대 225Ac-DOTA-항-HER3은 1% HSA로 사전 차단된 PD10 컬럼 상에서 또는 2 x 1.5 mL 세척, 스핀 당 3분으로 50 kDa MW 컷오프를 가지는 비바스핀(Vivaspin) 원심 농축기 상에서 정제될 수 있다. 정제 후 225Ac-DOTA-항-HER3의 HPLC 분석은 pH=7.4 및 1 ml/min의 유속에서 PBS로 용출된 TSK3000SW XL 컬럼을 사용하여, 플로우-스루 워터스 UV 및 바이오스캔 방사선 검출기가 장착된 워터스 HPLC 시스템을 사용하여 시행될 수 있다. Purification : An exemplary radiolabeled HER3 targeting agent, such as 225 Ac-DOTA-anti-HER3, was prepared on a PD10 column pre-blocked with 1% HSA or in a 2 x 1.5 mL wash, Viva with a 50 kDa MW cutoff of 3 minutes per spin. It can be purified on a Vivaspin centrifugal concentrator. HPLC analysis of 225 Ac-DOTA-anti-HER3 after purification was performed using a TSK3000SW XL column eluted with PBS at pH=7.4 and a flow rate of 1 ml/min, Waters equipped with a flow-through Waters UV and Bioscan radiation detector. This can be done using an HPLC system.
안정성 결정 : 예시적인 방사성표지된 HER3 표적화제, 예컨대 225Ac-DOTA-항-HER3이 안정성 결정에 사용될 수 있으며, 여기서 225Ac-DOTA-항-HER3은 원래의 용적으로 시험되거나 또는 작업 완충액 (0.15 M NH4OAc)으로 희석 (2-10배)되고, 실온 (rt)에서 48시간 또는 4℃에서 96시간 동안 인큐베이션되고 ITLC에 의해 시험될 수 있다. 안정성은 인큐베이션 전 및 후에 무손상 방사성표지된 항-HER3의 비교에 의해 결정된다. 225Ac로 표지된 다른 항체는 4℃에서 최대 96시간 동안 안정한 것으로 밝혀졌다. Stability Determination : An exemplary radiolabeled HER3 targeting agent, such as 225 Ac-DOTA-anti-HER3, can be used for stability determination, wherein 225 Ac-DOTA-anti-HER3 is tested in original volume or in a working buffer (0.15 M NH 4 OAc), incubated for 48 hours at room temperature (rt) or 96 hours at 4° C. and tested by ITLC. Stability is determined by comparison of intact radiolabeled anti-HER3 before and after incubation. Another antibody labeled with 225 Ac was found to be stable for up to 96 hours at 4°C.
면역반응성 (IR) 결정 : 예시적인 방사성표지된 HER3 표적화제, 예컨대 225Ac-DOTA-항-HER3이 면역반응성 실험에 사용될 수 있다. HER3 양성 세포 및 대조군 HER3 음성 세포는 결합량을 조사하기 위해 샘플당 100만개 내지 750만개 세포의 양으로 사용될 수 있다 (몇 번의 세척 후 세포에 대한 방사능 결합 퍼센트; 또는 면역반응성 분획 (IRF) 비드 검정을 사용하여 문헌 [Sharma, 2019]에 기재된 바와 같이 개시된 방법에 따라 수행될 수 있음). 111In 또는 225Ac로 방사성표지된 다른 항체에 대한 이전 검정은 약 50-60% 면역반응성을 입증하였다. Immunoreactivity (IR) Determination : Exemplary radiolabeled HER3 targeting agents such as 225 Ac-DOTA-anti-HER3 can be used in immunoreactivity experiments. HER3 positive cells and control HER3 negative cells can be used in amounts of 1 million to 7.5 million cells per sample to examine the amount of binding (percent radioactive binding to cells after several washes; or immunoreactive fraction (IRF) bead assay). It can be carried out according to the disclosed method as described in the literature [Sharma, 2019] using Previous assays for other antibodies radiolabeled with 111 In or 225 Ac demonstrated about 50-60% immunoreactivity.
실시예Example 2 - 예시적인 2 - Exemplary PARPiPARPi 투여 및 투여 요법 Dosage and dosing regimen
(A) (A) 올라파립olaparib ( ( 린파르자Linparza ®) - 정상적인 및 ®) - normal and 감소된reduced 투여 요법 dosing regimen
올라파립은 린파르자®라는 상표명으로 아스트라제네카에서 판매된다. 린파르자®는 100 mg 및 150 mg의 정제 형태로 판매된다. 투여량은 1일 총 600 mg에 대해 1일 2회 경구 복용되는 300 mg이다. 투여는 질환이 진행되거나 허용할 수 없는 독성이 나타날 때까지 계속된다. 이러한 투여 요법은 치료되는 장애에 관계없이 린파르자®에 대한 "정상적인" 인간 투여 요법으로서 본원에 지칭된다. 더 짧은 투여 기간 (예를 들어, 21일)을 갖거나 더 적은 린파르자® (예를 들어, 300 mg/일)의 투여를 포함하는 임의의 투여 요법은 "감소된" 인간 투여 요법으로서 본원에 지칭된다. 감소된 인간 투여 요법의 예는 하기를 포함한다: (i) 550 mg/일; (ii) 500 mg/일; (iii) 450 mg/일; (iv) 400 mg/일; (v) 350 mg/일; (vi) 300 mg/일; (vii) 250 mg/일; (viii) 200 mg/일; (ix) 150 mg/일; (x) 100 mg/일; 또는 (xi) 50 mg/일.Olaparib is marketed by AstraZeneca under the brand name Lynparza®. Lynparza® is sold in tablet form of 100 mg and 150 mg. The dosage is 300 mg taken orally twice daily for a total of 600 mg per day. Administration is continued until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the “normal” human dosing regimen for Lynparza® regardless of the disorder being treated. Any dosing regimen that has a shorter dosing period (e.g., 21 days) or involves less administration of Lynparza® (e.g., 300 mg/day) is described herein as a "reduced" human dosing regimen. is referred to Examples of reduced human dosing regimens include: (i) 550 mg/day; (ii) 500 mg/day; (iii) 450 mg/day; (iv) 400 mg/day; (v) 350 mg/day; (vi) 300 mg/day; (vii) 250 mg/day; (viii) 200 mg/day; (ix) 150 mg/day; (x) 100 mg/day; or (xi) 50 mg/day.
(B) (B) 니라파립niraparib ( ( 제줄라Zejula ®) - 정상적인 및 ®) - normal and 감소된reduced 투여 요법 dosing regimen
니라파립은 제줄라®라는 상표명으로 테사로(Tesaro)에서 판매된다. 제줄라®는 100 mg의 캡슐 형태로 판매된다. 투여량은 1일 1회 경구 복용되는 300 mg이다. 투여는 질환이 진행되거나 허용할 수 없는 부작용이 나타날 때까지 계속된다. 이러한 투여 요법은 치료되는 장애에 관계없이 제줄라®에 대한 "정상적인" 인간 투여 요법으로서 본원에 지칭된다. 더 짧은 투여 기간 (예를 들어, 21일)을 갖거나 더 적은 제줄라® (예를 들어, 150 mg/일)의 투여를 포함하는 임의의 투여 요법은 "감소된" 인간 투여 요법으로서 본원에 지칭된다. 감소된 인간 투여 요법의 예는 하기를 포함한다: (i) 250 mg/일; (ii) 200 mg/일; (iii) 150 mg/일; (iv) 100 mg/일; 또는 (v) 50 mg/일.Niraparib is marketed by Tesaro under the brand name Zejula®. Zejula® is sold in capsule form of 100 mg. The dosage is 300 mg taken orally once daily. Administration is continued until disease progression or unacceptable side effects occur. This dosing regimen is referred to herein as the “normal” human dosing regimen for Zejula® regardless of the disorder being treated. Any dosing regimen that has a shorter dosing period (eg, 21 days) or involves less administration of Zejula® (eg, 150 mg/day) is herein described as a "reduced" human dosing regimen. is referred to Examples of reduced human dosing regimens include: (i) 250 mg/day; (ii) 200 mg/day; (iii) 150 mg/day; (iv) 100 mg/day; or (v) 50 mg/day.
(C) (C) 루카파립Lucaparib ( ( 루브라카Rubraca ®) - 정상적인 및 ®) - normal and 감소된reduced 투여 요법 dosing regimen
루카파립은 루브라카™라는 상표명으로 클로비스 온콜로지, 인크.(Clovis Oncology, Inc.)에서 판매된다. 루브라카™는 200 mg 및 300 mg의 정제 형태로 판매된다. 투여량은 1일 총 1,200 mg에 대해 1일 2회 경구 복용되는 600 mg이다. 투여는 질환이 진행되거나 허용할 수 없는 독성이 나타날 때까지 계속된다. 이러한 투여 요법은 치료되는 장애에 관계없이 루브라카™에 대한 "정상적인" 인간 투여 요법으로서 본원에 지칭된다. 더 짧은 투여 기간 (예를 들어, 21일)을 갖거나 더 적은 루브라카™ (예를 들어, 600 mg/일)의 투여를 포함하는 임의의 투여 요법은 "감소된" 인간 투여 요법으로서 본원에 지칭된다. 감소된 인간 투여 요법의 예는 하기를 포함한다: (i) 1,150 mg/일; (ii) 1,100 mg/일; (iii) 1,050 mg/일; (iv) 1,000 mg/일; (v) 950 mg/일; (vi) 900 mg/일; (vii) 850 mg/일; (viii) 800 mg/일; (ix) 750 mg/일; (x) 700 mg/일; (xi) 650 mg/일; (xii) 600 mg/일; (xiii) 550 mg/일; (xiv) 500 mg/일; (xv) 450 mg/일; (xvi) 400 mg/일; (xvii) 350 mg/일; (xviii) 300 mg/일; (xix) 250 mg/일; (xx) 200 mg/일; (xxi) 150 mg/일; 또는 (xxii) 100 mg/일.Lucaparib is marketed by Clovis Oncology, Inc. under the trade name Lubraca™. Rubraca™ is sold in tablet form of 200 mg and 300 mg. The dosage is 600 mg taken orally twice daily for a total of 1,200 mg per day. Administration is continued until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the “normal” human dosing regimen for Rubraca™ regardless of the disorder being treated. Any dosing regimen having a shorter dosing period (e.g., 21 days) or involving less administration of Rubraca™ (e.g., 600 mg/day) is herein referred to as a "reduced" human dosing regimen. is referred to Examples of reduced human dosing regimens include: (i) 1,150 mg/day; (ii) 1,100 mg/day; (iii) 1,050 mg/day; (iv) 1,000 mg/day; (v) 950 mg/day; (vi) 900 mg/day; (vii) 850 mg/day; (viii) 800 mg/day; (ix) 750 mg/day; (x) 700 mg/day; (xi) 650 mg/day; (xii) 600 mg/day; (xiii) 550 mg/day; (xiv) 500 mg/day; (xv) 450 mg/day; (xvi) 400 mg/day; (xvii) 350 mg/day; (xviii) 300 mg/day; (xix) 250 mg/day; (xx) 200 mg/day; (xxi) 150 mg/day; or (xxii) 100 mg/day.
(D) - (D)- 탈라조파립Thalazoparib ( ( 탈젠나Talgenna ™) - 정상적인 및 ™) - normal and 감소된reduced 투여 요법 dosing regimen
탈라조파립은 탈젠나™라는 상표명으로 화이자 랩스(Pfizer Labs)에서 판매된다. 탈젠나™는 1 mg의 캡슐 형태로 판매된다. 투여량은 경구 복용되는 1 mg이다. 투여는 질환이 진행되거나 허용할 수 없는 독성이 나타날 때까지 계속된다. 이러한 투여 요법은 치료되는 장애에 관계없이 탈젠나™에 대한 "정상적인" 인간 투여 요법으로서 본원에 지칭된다. 더 짧은 투여 기간 (예를 들어, 21일)을 갖거나 더 적은 탈젠나™ (예를 들어, 0.5 mg/일)의 투여를 포함하는 임의의 투여 요법은 "감소된" 인간 투여 요법으로서 본원에 지칭된다. 감소된 인간 투여 요법의 예는 하기를 포함한다: (i) 0.9 mg/일; (ii) 0.8 mg/일; (iii) 0.7 mg/일; (iv) 0.6 mg/일; (v) 0.5 mg/일; (vi) 0.4 mg/일; (vii) 0.3 mg/일; (viii) 0.2 mg/일; 또는 (ix) 0.1 mg/일.Talazoparib is marketed by Pfizer Labs under the trade name Talgenna™. Talgenna™ is sold in 1 mg capsule form. The dosage is 1 mg taken orally. Administration is continued until disease progression or unacceptable toxicity. This dosing regimen is referred to herein as the "normal" human dosing regimen for Talgenna™ regardless of the disorder being treated. Any dosing regimen having a shorter dosing period (eg, 21 days) or involving less administration of Taljenna™ (eg, 0.5 mg/day) is herein described as a "reduced" human dosing regimen. is referred to Examples of reduced human dosing regimens include: (i) 0.9 mg/day; (ii) 0.8 mg/day; (iii) 0.7 mg/day; (iv) 0.6 mg/day; (v) 0.5 mg/day; (vi) 0.4 mg/day; (vii) 0.3 mg/day; (viii) 0.2 mg/day; or (ix) 0.1 mg/day.
실시예Example 3: 3: HER3HER3 표적화제 및 targeting agent and PARPi에to PARPi 대한 투여 요법 Dosing regimen for
인간 환자는 하기 요법에 따라 치료될 수 있다. 올라파립, 니라파립, 루카파립 또는 탈라조파립 (PARPi) 중 하나는 실시예 2에 열거된 투여 요법 중 하나에 따라 경구 투여되며, 단일 또는 분할 투여로 본원에 상세히 기재된 바와 같이 방사성표지된 HER3 표적화제의 정맥내 투여가 수반된다. 예를 들어, 투여 요법은 예를 들어: (a) PARPi 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) 각각은 동일한 날에 시작하여 투여되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) PARPi는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것; 또는 (b) PARPi 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) PARPi 투여는 HER3 표적화제 투여에 적어도 1주 선행되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) PARPi는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것을 포함한다.Human patients can be treated according to the following regimen. One of olaparib, niraparib, rucaparib, or thalazoparib (PARPi) is administered orally according to one of the dosing regimens listed in Example 2, either as single or divided doses, to a radiolabeled HER3 target as described in detail herein. Intravenous administration of topical is involved. For example, a dosing regimen may include, for example: (a) PARPi and the HER3 targeting agent are administered concurrently, wherein (i) each is administered starting on the same day, and (ii) the HER3 targeting agent is administered for at least 1 week. (iii) PARPi is administered daily or twice daily (as appropriate) for a period equal to or greater than the period of administration of the HER3-targeting agent; or (b) the PARPi and the HER3 targeting agent are administered concurrently, wherein (i) the PARPi administration precedes the HER3 targeting agent by at least 1 week, and (ii) the HER3 targeting agent is administered in a single dose or divided by at least 1 week intervals. (iii) PARPi is administered daily or twice daily (if appropriate) for a period of time equal to or greater than the period of administration of the HER3 targeting agent.
실시예Example 4: 4: HER3HER3 표적화제 및 CD47 Targeting agents and CD47 차단제에 대한 투여 요법Dosage regimen for blockers
본 발명의 특정 측면에 따르면, CD47 차단제는 예를 들어, CD47이 SIRPα와 결합하는 것을 방지하는 모노클로날 항체일 수 있다. 예시적인 단백질 CD47 차단제는 마그롤리맙, 렘조파를리맙, AO-176, TTI-621, TTI-622, 또는 그의 조합을 포함한다. CD47 차단제는 대안적으로, 또는 부가적으로, CD47 및/또는 SIRPα의 발현을 조정하는 작용제, 예컨대 CD47의 번역을 차단하는 포스포로디아미데이트 모르폴리노 올리고머 (PMO), 예컨대 MBT-001 (PMO, 모르폴리노, 서열: 5'-CGTCACAGGCAGGACCCACTGCCCA-3' [서열식별번호: 114]) 또는 미국 특허 번호 8,557,788, 미국 특허 번호 8,236,313, 미국 특허 번호 10,370,439 및 국제 공개 번호 WO2008060785 중 임의의 것에 개시된 PMO 올리고머 CD47 억제제 중 임의의 것을 포함할 수 있다. 항-CD47 항체의 치료상 유효 용량은 적어도 0.05 - 10 mg/kg을 포함한다. 따라서, 본 발명의 방법은 단일 또는 분할 투여로 본원에 상세히 기재된 바와 같은 방사성표지된 HER3 표적화제의 정맥내 투여와 수반하여, 항-CD47 항체 또는 다른 작용제 중 하나 이상을 투여하는 것을 포함할 수 있다. 예를 들어, 투여 요법은 예를 들어: (a) 항-CD47 항체 또는 작용제 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) 각각은 동일한 날에 시작하여 투여되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) 항-CD47 항체 또는 작용제는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것; 또는 (b) 항-CD47 항체 또는 작용제 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) 항-CD47 항체 또는 작용제 투여는 HER3 표적화제 투여에 적어도 1주 선행되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) 항-CD47 항체 또는 작용제는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것을 포함한다.According to certain aspects of the invention, the CD47 blocking agent can be, for example, a monoclonal antibody that prevents CD47 from binding to SIRPα. Exemplary protein CD47 blockers include magnolimab, remzoparlimab, AO-176, TTI-621, TTI-622, or combinations thereof. A CD47 blocker may alternatively, or additionally, be an agent that modulates the expression of CD47 and/or SIRPα, such as a phosphorodiamidate morpholino oligomer (PMO) that blocks translation of CD47, such as MBT-001 (PMO) , morpholino, sequence: 5'-CGTCACAGGCAGGACCCACTGCCCA-3' [SEQ ID NO: 114]) or the PMO oligomer CD47 disclosed in any of U.S. Pat. No. 8,557,788, U.S. Pat. No. 8,236,313, U.S. Pat. No. 10,370,439 and International Publication No. WO2008060785. any of the inhibitors. A therapeutically effective dose of an anti-CD47 antibody includes at least 0.05 - 10 mg/kg. Thus, the methods of the present invention may comprise administering one or more of an anti-CD47 antibody or other agent concomitantly with intravenous administration of a radiolabeled HER3 targeting agent as described in detail herein in single or divided doses. . For example, a dosing regimen may include, for example: (a) an anti-CD47 antibody or agent and a HER3 targeting agent are administered concurrently, wherein (i) each is administered starting on the same day, and (ii) the HER3 targeting agent is administered concurrently. wherein the agent is administered in single or divided doses at intervals of at least one week, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (as appropriate) for a period equal to or longer than the period of administration of the HER3 targeting agent. thing; or (b) the anti-CD47 antibody or agent and the HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody or agent administration precedes the HER3 targeting agent by at least one week, and (ii) the HER3 targeting agent is administered as a single dose or divided dose at intervals of at least 1 week, and (iii) the anti-CD47 antibody or agent is administered daily or twice daily (if appropriate) for a period equal to or longer than the period of administration of the HER3 targeting agent. include
실시예Example 5: 5: HER3HER3 표적화제 및 targeting agent and ICI에to ICI 대한 투여 요법 Dosing regimen for
본 발명의 특정 측면에 따르면, 면역 체크포인트 억제제 (ICI)는 PD-1, PD-L1, PD-L2, CTLA-4, CD137 중 임의의 것에 대한 모노클로날 항체일 수 있다. 이들 항체의 치료상 유효 용량은 적어도 0.05 - 10 mg/kg을 포함한다. 따라서, 본 발명의 방법은 단일 또는 분할 투여로 본원에 상세히 기재된 바와 같은 방사성표지된 HER3 표적화제의 정맥내 투여를 수반하여, 하나 이상의 ICI를 투여하는 것을 포함한다. 예를 들어, 투여 요법은 예를 들어: (a) ICI 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) 각각은 동일한 날에 시작하여 투여되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) ICI는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것; 또는 (b) ICI 및 HER3 표적화제가 공동으로 투여되는 것, 여기서 (i) 항-CD47 항체 투여는 HER3 표적화제 투여에 적어도 1주 선행되고, (ii) HER3 표적화제는 1주 이상의 간격으로 단일 용량 또는 분할 용량으로 투여되며, (iii) ICI는 HER3 표적화제 투여 기간과 동일하거나 초과하는 기간 동안 매일 또는 1일 2회 (적절한 경우) 투여되는 것을 포함한다.According to certain aspects of the invention, the immune checkpoint inhibitor (ICI) may be a monoclonal antibody to any of PD-1, PD-L1, PD-L2, CTLA-4, CD137. Therapeutically effective doses of these antibodies include at least 0.05 - 10 mg/kg. Accordingly, the methods of the present invention include administering one or more ICIs accompanied by intravenous administration of a radiolabeled HER3 targeting agent as described in detail herein, in single or divided doses. For example, a dosing regimen may include, for example: (a) the ICI and the HER3-targeting agent are administered concurrently, wherein (i) each is administered starting on the same day, and (ii) the HER3-targeting agent is administered for at least 1 week. (iii) the ICI is administered daily or twice daily (as appropriate) for a period equal to or greater than the period of administration of the HER3-targeting agent; or (b) the ICI and the HER3 targeting agent are administered concurrently, wherein (i) the anti-CD47 antibody administration precedes the HER3 targeting agent by at least 1 week, and (ii) the HER3 targeting agent is administered as a single administration at least 1 week apart. (iii) the ICI is administered daily or twice daily (as appropriate) for a period equal to or greater than the period of administration of the HER3 targeting agent.
제한 없이, 하기 측면이 또한 본 개시내용에 의해 제공된다:Without limitation, the following aspects are also provided by the present disclosure:
측면 1. 포유동물 대상체에게 방사성표지된 HER3 표적화제의 치료 유효량을 투여하는 단계를 포함하는, 상기 포유동물 대상체, 예컨대 인간 환자에서 고형 암을 치료하는 방법.
측면 2. 임의의 앞선 측면에 있어서, 고형 암이 유방암, 위암, 방광암, 자궁경부암, 자궁내막암, 피부암, 위암, 고환암, 식도암, 세기관지폐포암, 전립선암, 결장직장암, 난소암, 자궁경부 유표피암, 췌장암, 폐암, 신장암, 두경부암, 또는 그의 임의의 조합인 방법.
측면 3. 임의의 앞선 측면에 있어서, 고형 암이 결장직장암, 위암, 난소암, 비-소세포 폐 암종, 두경부 편평 세포암, 췌장암, 신장암, 또는 그의 임의의 조합인 방법.
측면 4. 임의의 앞선 측면에 있어서, 고형 암이 HER3-양성 암, 예컨대 HER3-양성 고형 종양인 방법.
측면 5. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 131I, 125I, 123I, 90Y, 177Lu, 186Re, 188Re, 89Sr, 153Sm, 32P, 225Ac, 213Bi, 213Po, 211At, 212Bi, 213Bi, 223Ra, 227Th, 149Tb, 137Cs, 212Pb, 103Pd, 또는 본원에 개시된 것 중 임의의 것, 또는 그의 임의의 조합으로부터 선택된 방사성표지를 포함하는 것인 방법.
측면 6. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 131I, 90Y, 177Lu, 225Ac, 213Bi, 211At, 213Bi, 227Th, 212Pb, 또는 그의 임의의 조합으로부터 선택된 방사성표지를 포함하는 것인 방법.
측면 7. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 HER3에 대한 항체를 포함하는 것인 방법.
측면 8. 임의의 앞선 측면에 있어서, HER3 표적화제가 항-HER3 모노클로날 항체, 예컨대 본원에 개시된 것 중 임의의 것, 예컨대 파트리투맙, 세리반투맙 (MM-121), 룸레투주맙, 엘젬투맙, GSK2849330 및 AV-203, 및 그의 임의의 조합으로부터 선택된 HER3 항체를 포함하는 것인 방법.
측면 9. 임의의 앞선 측면에 있어서, HER3 표적화제가 (i) 서열식별번호: 77을 포함하는 중쇄 서열 및/또는 서열식별번호: 78을 포함하는 경쇄 서열을 갖거나; (ii) 서열식별번호: 15를 포함하는 CDR-H1, 서열식별번호: 16을 포함하는 CDR-H2 및/또는 서열식별번호: 17을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역, 및/또는 서열식별번호: 18을 포함하는 CDR-L1, 서열식별번호: 19를 포함하는 CDR-L2, 및/또는 서열식별번호: 20을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역을 갖거나; (iii) 서열식별번호: 21을 포함하는 이뮤노글로불린 중쇄 가변 영역 및/또는 서열식별번호: 22를 포함하는 이뮤노글로불린 경쇄 가변 영역을 갖거나; 또는 (iv) 서열식별번호: 23의 이뮤노글로불린 중쇄 아미노산 서열 및/또는 서열식별번호: 24의 이뮤노글로불린 경쇄 아미노산 서열을 갖는 모노클로날 항체를 포함하는 것인 방법.Aspect 9. The HER3 targeting agent of any preceding aspect, wherein the HER3 targeting agent (i) has a heavy chain sequence comprising SEQ ID NO:77 and/or a light chain sequence comprising SEQ ID NO:78; (ii) an immunoglobulin heavy chain variable region comprising CDR-H1 comprising SEQ ID NO: 15, CDR-H2 comprising SEQ ID NO: 16 and/or CDR-H3 comprising SEQ ID NO: 17; and/or an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 18, CDR-L2 comprising SEQ ID NO: 19, and/or CDR-L3 comprising SEQ ID NO: 20. have; (iii) has an immunoglobulin heavy chain variable region comprising SEQ ID NO: 21 and/or an immunoglobulin light chain variable region comprising SEQ ID NO: 22; or (iv) a monoclonal antibody having the immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 23 and/or the immunoglobulin light chain amino acid sequence of SEQ ID NO: 24.
측면 10. 임의의 앞선 측면에 있어서, HER3 표적화제가 서열식별번호: 7에 제시된 바와 같은 아미노산 서열을 갖는 중쇄 가변 영역 및/또는 서열식별번호: 8에 제시된 바와 같은 아미노산 서열을 갖는 경쇄 가변 영역을 포함하는 모노클로날 항체를 포함하는 것인 방법.
측면 11. 임의의 앞선 측면에 있어서, HER3 표적화제가 각각 서열식별번호: 13 및/또는 1-3에 제시된 바와 같은 아미노산 서열을 갖는 중쇄 N-말단 영역 및 상보성 결정 영역 (CDR) 중 하나 이상을 포함하고/하거나 각각 서열식별번호: 14 및/또는 4-6에 제시된 바와 같은 아미노산 서열을 갖는 경쇄 N-말단 영역 및 CDR 중 하나 이상을 포함하는 모노클로날 항체를 포함하는 것인 방법.
측면 12. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제의 유효량이 최대 허용 용량인 방법.
측면 13. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 225Ac-, 177Lu-, 또는 131I-표지된 것인 방법.
측면 14. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제의 치료 유효량이 2 Gy 미만, 또는 8 Gy 미만, 예컨대 2 Gy 내지 8 Gy의 용량을 대상체에게 전달하는 단일 용량을 포함하는 것인 방법.
측면 15. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 225Ac-표지되고, 225Ac-표지된 HER3 표적화제의 유효량이 0.1 내지 50 uCi/kg (대상체의 체중), 또는 0.2 내지 20 uCi/kg (대상체의 체중), 또는 0.5 내지 10 uCi/kg (대상체의 체중)의 용량을 포함하는 것인 방법.Aspect 15. The method of any preceding aspect, wherein the radiolabeled HER3 targeting agent is 225 Ac-labeled, and the effective amount of the 225 Ac-labeled HER3 targeting agent is from 0.1 to 50 uCi/kg (body weight of the subject), or from 0.2 to 20 uCi/kg (body weight of the subject), or a dose of 0.5 to 10 uCi/kg (body weight of the subject).
측면 16. 임의의 앞선 측면에 있어서, 방사성표지된 HER3 표적화제가 225Ac-표지되는 HER3에 대한 완전한 길이의 항체이고, 225Ac-표지된 HER3 표적화제의 유효량이 5 uCi/kg (대상체의 체중) 미만, 예컨대 0.1 내지 5 uCi/kg (대상체의 체중)을 포함하는 것인 방법.
측면 17. 측면 1 내지 6 중 어느 한 측면에 있어서, 방사성표지된 HER3 표적화제가 225Ac-표지되는 HER3에 대한 항체 단편, 예컨대 미니바디 또는 나노바디이고, 225Ac-표지된 HER3 표적화제의 유효량이 5 uCi/kg (대상체의 체중) 초과, 예컨대 5 내지 20 uCi/kg (대상체의 체중)을 포함하는 것인 방법.Aspect 17. The method of any one of
측면 18. 측면 1 내지 14 중 어느 한 측면에 있어서, 방사성표지된 HER3 표적화제가 225Ac-표지되고, 225Ac-표지된 HER3 표적화제의 유효량이 2 μCi 내지 2 mCi, 또는 2 μCi 내지 250 μCi, 또는 75 μCi 내지 400 μCi를 포함하는 것인 방법.
측면 19. 측면 1 내지 14 중 어느 한 측면에 있어서, 방사성동위원소 표지된 HER3 표적화제가 177Lu-표지되고, HER3 표적화제의 유효량이 1000 uCi/kg (대상체의 체중) 미만의 용량, 예컨대 1 내지 900 uCi/kg (대상체의 체중), 또는 5 내지 250 uCi/kg (대상체의 체중) 또는 50 내지 450 uCi/kg (체중)의 용량을 포함하는 것인 방법.Aspect 19. The method of any one of
측면 20. 측면 1 내지 14 중 어느 한 측면에 있어서, 방사성동위원소 표지된 HER3 표적화제가 177Lu-표지되고, 177Lu-표지된 HER3 표적화제의 유효량이 10 mCi 내지 30 mCi 이하, 또는 적어도 100 μCi 내지 3 mCi 이하, 또는 3 mCi 내지 30 mCi 이하의 용량을 포함하는 것인 방법.
측면 21. 측면 1 내지 14 중 어느 한 측면에 있어서, 방사성표지된 HER3 표적화제가 131I-표지되고, 131I-표지된 HER3 표적화제의 유효량이 1200 mCi 미만의 용량, 예컨대 25 내지 1200 mCi, 또는 100 내지 400 mCi, 또는 300 내지 600 mCi, 또는 500 내지 1000 mCi의 용량을 포함하는 것인 방법.Aspect 21. The method of any one of
측면 22. 측면 1 내지 14 중 어느 한 측면에 있어서, 방사성표지된 HER3 표적화제가 131I-표지되고, 131I-표지된 HER3 표적화제의 유효량이 200 mCi 미만의 용량, 예컨대 1 내지 200 mCi, 또는 25 내지 175 mCi, 또는 50 내지 150 mCi의 용량을 포함하는 것인 방법.
측면 23. 임의의 앞선 측면에 있어서, HER3 표적화제의 유효량이 3 mg/kg (대상체의 체중) 미만, 예컨대 0.001 mg/kg (환자 체중) 내지 3.0 mg/kg (환자 체중), 또는 0.005 mg/kg (환자 체중) 내지 2.0 mg/kg (환자 체중), 또는 0.01 mg/kg (환자 체중) 내지 1 mg/kg (환자 체중), 또는 0.1 mg/kg (환자 체중) 내지 0.6 mg/kg (환자 체중), 또는 0.3 mg/kg (환자 체중), 또는 0.4 mg/kg (환자 체중), 또는 0.5 mg/kg (환자 체중), 또는 0.6 mg/kg (환자 체중)의 단백질 용량을 포함하는 것인 방법.Aspect 23. The method of any preceding aspect, wherein the effective amount of the HER3 targeting agent is less than 3 mg/kg (subject's body weight), such as 0.001 mg/kg (patient's body weight) to 3.0 mg/kg (patient's body weight), or 0.005 mg/kg (patient's body weight). kg (patient body weight) to 2.0 mg/kg (patient body weight), or 0.01 mg/kg (patient body weight) to 1 mg/kg (patient body weight), or 0.1 mg/kg (patient body weight) to 0.6 mg/kg (patient body weight) body weight), or 0.3 mg/kg (patient body weight), or 0.4 mg/kg (patient body weight), or 0.5 mg/kg (patient body weight), or 0.6 mg/kg (patient body weight) method.
측면 24. 임의의 앞선 측면에 있어서, HER3 표적화제가 치료 기간 전체에 걸쳐 7일, 10일, 12일, 14일, 20일, 24일, 28일, 36일 및 42일마다 1회로 이루어진 군으로부터 선택된 투여 스케줄에 따라 투여되며, 여기서 치료 기간은 적어도 2회 투여를 포함하는 것인 방법.
측면 25. 측면 1 내지 6 중 어느 한 측면에 있어서, HER3 표적화제가 펩티드 또는 소분자인 방법.Aspect 25. The method of any one of aspects 1-6, wherein the HER3 targeting agent is a peptide or small molecule.
측면 26. 임의의 앞선 측면에 있어서, 치료 유효량의 면역 체크포인트 요법, 화학요법제, DNA 손상 반응 억제제 (DDRi), CD47 차단제, 또는 그의 조합을 대상체에게 투여하는 단계를 추가로 포함하는 방법.
측면 27. 측면 26에 있어서, 면역 체크포인트 요법이 CTLA-4, PD-1, TIM-3, VISTA, BTLA, LAG-3, TIGIT, CD28, OX40, GITR, CD137, CD40, CD40L, CD27, HVEM, PD-L1, PD-L2, PD-L3, PD-L4, CD80, CD86, CD137-L, GITR-L, CD226, B7-H3, B7-H4, BTLA, TIGIT, GALS, KIR, 2B4, CD160, 또는 CGEN-15049에 대한 항체 또는 기타 차단제, 또는 이러한 항체 및 차단제의 임의의 조합을 포함하는 것인 방법.Aspect 27. The method of
측면 28. 측면 27에 있어서, 면역 체크포인트 요법이 PD-1, PD-L1, PD-L2, CTLA-4, CD137에 대한 항체, 또는 그의 조합을 포함하는 것인 방법.
측면 29. 측면 26에 있어서, DDRi가 폴리(ADP-리보스) 폴리머라제 억제제 (PARPi), 모세혈관확장성 운동실조증 돌연변이된 억제제 (ATMi), 모세혈관확장성 운동실조증 돌연변이된 및 Rad-3 관련된 억제제 (ATRi), 또는 Wee1 억제제를 포함하는 것인 방법.Aspect 29. The method of
측면 30. 측면 29에 있어서, PARPi가 올라파립, 니라파립, 루카파립 및 탈라조파립 중 하나 이상을 포함하는 것인 방법.
측면 31. 측면 29에 있어서, ATMi가 KU-55933, KU-59403, 워트만닌, CP466722, 또는 KU-60019 중 하나 이상을 포함하는 것인 방법.Aspect 31. The method of aspect 29, wherein the ATMi comprises one or more of KU-55933, KU-59403, wortmannin, CP466722, or KU-60019.
측면 32. 측면 29에 있어서, ATRi가 쉬잔드린 B, NU6027, NVP-BEA235, VE-821, VE-822, AZ20, 또는 AZD6738 중 하나 이상을 포함하는 것인 방법.
측면 33. 측면 29에 있어서, Wee1 억제제가 AZD-1775 (즉, 아다보세르팁)를 포함하는 것인 방법.Aspect 33. The method of aspect 29, wherein the Weel inhibitor comprises AZD-1775 (ie, Adavosertip).
측면 34. 측면 26에 있어서, CD47 차단제가 CD47이 SIRPα와 결합하는 것을 방지하는 작용제, 예컨대 모노클로날 항체 및/또는 CD47 발현을 조정하는 작용제를 포함하는 것인 방법.
측면 35. 측면 34에 있어서, CD47 차단제가 마그롤리맙, 렘조파를리맙, AO-176, TTI-621, TTI-622, 또는 그의 조합 중 하나 이상을 포함하고/하거나; CD47 발현을 조정하는 작용제가 CD47의 발현을 감소시키는 포스포로디아미데이트 모르폴리노 올리고머 (PMO) (예를 들어, MBT-001)를 포함하는 것인 방법.Aspect 35. The method of
측면 36. 측면 34에 있어서, CD47 차단제의 치료 유효량이 0.05 내지 5 mg/kg (환자 체중)을 포함하는 것인 방법.
측면 37. 측면 26에 있어서, HER3 표적화제가 면역 체크포인트 요법 및/또는 DDRi 및/또는 CD47 차단제의 투여 전 적어도 1주에 투여되거나; 또는 면역 체크포인트 요법 및/또는 DDRi 및/또는 CD47 차단제가 HER3 표적화제의 투여 전 적어도 1주에 투여되는 것인 방법.Aspect 37. The method of
측면 38. 측면 26에 있어서, HER3 표적화제가 면역 체크포인트 요법 또는 DDRi 또는 CD47 차단제 중 하나와 함께 투여되고, 면역 체크포인트 요법 또는 DDRi 또는 CD47 차단제 중 다른 것은 HER3 표적화제의 투여 전 또는 후에 투여되는 것인 방법.
측면 39. 측면 26에 있어서, HER3 표적화제가 면역 체크포인트 요법 및/또는 DDRi 및/또는 CD47 차단제와 동시에 투여되는 것인 방법.Aspect 39. The method of
측면 40. 임의의 앞선 측면에 있어서, HER3 표적화제가 다중특이적 항체이며, 여기서 다중특이적 항체는 HER3의 에피토프와 특이적으로 결합하는 제1 표적 인식 성분, 및 제1 표적 인식 성분과 상이한 HER3의 에피토프, 또는 상이한 항원의 에피토프와 특이적으로 결합하는 제2 표적 인식 성분을 포함하는 것인 방법.
측면 41. 측면 40에 있어서, HER3 표적화제가 HER3/HER2에 대한 이중특이적 항체, 예컨대 MM-111 또는 MCLA0-128, 또는 IGF-1R/HER3에 대한 이중특이적 항체, 예컨대 MM-141 (즉, 이스티라투맙), 및/또는 HER1/HER3에 대한 이중특이적 항체, 예컨대 MEHD7945A (즉, 둘리고투맙)를 포함하는 것인 방법.Aspect 41. The method of
측면 42. 대상체를 HER3-양성 세포로 진단하는 단계; 및 대상체가 HER3-양성 세포를 갖는 경우, 측면 1 내지 41의 방법 중 임의의 것에 따라 치료 유효량의 HER3 표적화제를 대상체에게 투여하는 단계를 포함하는, 증식성 질환 또는 장애를 치료하는 방법.Aspect 42. diagnosing the subject as having HER3-positive cells; and if the subject has HER3-positive cells, a method of treating a proliferative disease or disorder comprising administering to the subject a therapeutically effective amount of a HER3 targeting agent according to any of the methods of aspects 1-41.
측면 43. 측면 42에 있어서, 진단 단계가 대상체로부터 혈액 또는 조직 샘플을 수득하는 것; 그 샘플을 기판 위에 고정시키는 것; 및 진단 항체를 사용하여 HER3 항원의 존재 또는 부재를 검출하는 것을 포함하며, 여기서 진단 항체는 방사성표지, 예컨대 3H, 14C, 32P, 35S, 및 125I; 형광 또는 화학발광 화합물, 예컨대 플루오레세인 이소티오시아네이트, 로다민 또는 루시페린; 또는 효소, 예컨대 알칼리성 포스파타제, β-갈락토시다제 또는 서양고추냉이 퍼옥시다제로 표지된 HER3에 대한 항체를 포함하는 것인 방법.Aspect 43. The method of aspect 42, wherein the diagnosing step comprises obtaining a blood or tissue sample from the subject; immobilizing the sample on a substrate; and detecting the presence or absence of the HER3 antigen using a diagnostic antibody, wherein the diagnostic antibody is a radiolabel, such as 3 H, 14 C, 32 P, 35 S, and 125 I; fluorescent or chemiluminescent compounds such as fluorescein isothiocyanate, rhodamine or luciferin; or an antibody to HER3 labeled with an enzyme such as alkaline phosphatase, β-galactosidase or horseradish peroxidase.
측면 44. 측면 42에 있어서, 진단 단계가 대상체에게 HER3 표적화제를 투여하는 것, 여기서 HER3 표적화제는 18F, 11C, 68Ga, 64Cu, 89Zr, 124I, 99mTc, 또는 111In을 포함하는 군으로부터 선택된 방사성표지를 포함하는 것; HER3 표적화제가 조직 부위에 축적되기에 충분한 시간을 기다리는 것; 및 HER3-양성 세포의 존재 또는 부재를 검출하기 위해 비-침습적 영상화 기술로 조직을 영상화하는 것을 포함하는 것인 방법.
측면 45. 측면 44에 있어서, 비-침습적 영상화 기술이 18F, 11C, 68Ga, 64Cu, 89Zr, 또는 124I 표지된 HER3 표적화제의 경우에는 양전자 방출 단층촬영 (PET 영상화)을 포함하거나, 또는 99mTc 또는 111In 표지된 HER3 표적화제의 경우에는 단일 광자 방출 컴퓨터 단층촬영 (SPECT 영상화)을 포함하는 것인 방법.Aspect 45. The method of
본원에는 다양한 구체적 실시양태가 예시 및 기재되었지만, 본 발명(들)의 요지 및 범위를 벗어나지 않고서도 다양한 변화가 이루어질 수 있는 것으로 인지될 것이다. 더욱이, 본 발명의 한 측면과 연계해서 기재된 특색은 본원에서 조합하여 명시적으로 예시되지 않더라도 본 발명의 다른 측면과 연계해서 사용될 수 있다.While various specific embodiments have been illustrated and described herein, it will be appreciated that various changes may be made without departing from the spirit and scope of the invention(s). Moreover, features described in connection with one aspect of the invention may be used in connection with other aspects of the invention even if not explicitly illustrated in combination herein.
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SEQUENCE LISTING <110> ACTINIUM PHARMACEUTICALS, INC. <120> HER3 RADIOIMMUNOTHERAPY FOR THE TREATMENT OF SOLID CANCERS <130> ATNM-010PCT <140> <141> <150> PCT/US21/56259 <151> 2021-10-22 <150> US 63/250,725 <151> 2021-09-30 <150> US 63/226,699 <151> 2021-07-28 <150> US 63/118,181 <151> 2020-11-25 <150> US 63/116,225 <151> 2020-11-20 <160> 118 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> Mus musculus <400> 1 Ser His Trp Leu His 1 5 <210> 2 <211> 17 <212> PRT <213> Mus musculus <400> 2 Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe Lys 1 5 10 15 Gly <210> 3 <211> 11 <212> PRT <213> mus musculus <400> 3 Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 1 5 10 <210> 4 <211> 16 <212> PRT <213> mus musculus <400> 4 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 5 <211> 7 <212> PRT <213> mus musculus <400> 5 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 6 <211> 9 <212> PRT <213> mus musculus <400> 6 Phe Gln Gly Ser Tyr Val Pro Trp Thr 1 5 <210> 7 <211> 120 <212> PRT <213> mus musculus <400> 7 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Ala 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 8 <211> 112 <212> PRT <213> mus musculus <400> 8 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 9 <211> 463 <212> PRT <213> mus musculus <400> 9 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Ser His Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn 65 70 75 80 Gln Asn Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 145 150 155 160 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala 210 215 220 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 225 230 235 240 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 275 280 285 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 290 295 300 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 305 310 315 320 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 325 330 335 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 370 375 380 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 385 390 395 400 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 405 410 415 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 420 425 430 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 435 440 445 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 10 <211> 238 <212> PRT <213> mus musculus <400> 10 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 11 <211> 444 <212> PRT <213> mus musculus <400> 11 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val 115 120 125 Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr 130 135 140 Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr 145 150 155 160 Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser 180 185 190 Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala 195 200 205 Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys 210 215 220 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 245 250 255 Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe 260 265 270 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 290 295 300 Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val 305 310 315 320 Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 325 330 335 Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys 340 345 350 Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp 355 360 365 Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro 370 375 380 Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser 385 390 395 400 Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala 405 410 415 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 420 425 430 His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <210> 12 <211> 219 <212> PRT <213> mus musculus <400> 12 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 13 <211> 10 <212> PRT <213> mus musculus <400> 13 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu 1 5 10 <210> 14 <211> 10 <212> PRT <213> mus musculus <400> 14 Asp Val Leu Met Thr Gln Ile Pro Leu Ser 1 5 10 <210> 15 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 15 Asp Tyr Ala Met Ser 1 5 <210> 16 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 16 Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 17 Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr 1 5 10 <210> 18 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 18 Arg Ala Ser Gln Glu Ile Ser Gly Tyr Leu Ser 1 5 10 <210> 19 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 19 Ala Ala Ser Thr Leu Asp Ser 1 5 <210> 20 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 20 Leu Gln Tyr Asp Ser Tyr Pro Tyr Thr 1 5 <210> 21 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 22 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 23 <211> 471 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 23 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 24 <211> 236 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 25 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 25 Ser His Trp Leu His 1 5 <210> 26 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 26 Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe Lys 1 5 10 15 Gly <210> 27 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 27 Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 1 5 10 <210> 28 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 28 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 29 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 29 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 30 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 30 Phe Gln Gly Ser Tyr Val Pro Trp Thr 1 5 <210> 31 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 32 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 33 <211> 463 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Ser His Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn 65 70 75 80 Gln Asn Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 145 150 155 160 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala 210 215 220 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 225 230 235 240 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 275 280 285 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 290 295 300 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 305 310 315 320 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 325 330 335 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 370 375 380 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 385 390 395 400 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 405 410 415 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 420 425 430 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 435 440 445 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 34 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 34 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 35 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 35 Thr Phe Gly Leu Ser Val Gly 1 5 <210> 36 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 36 His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala Leu Lys Ser 1 5 10 15 <210> 37 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 37 Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr 1 5 10 <210> 38 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 38 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr 1 5 10 15 <210> 39 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 39 Arg Met Ser Asn Leu Ala Ser 1 5 <210> 40 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 40 Met Gln His Leu Glu Tyr Pro Phe Thr 1 5 <210> 41 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 41 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe 20 25 30 Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 42 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 42 Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 43 <211> 475 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 43 Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr 1 5 10 15 Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Phe Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys 50 55 60 Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr 65 70 75 80 Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys 85 90 95 Asn Gln Val Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser 145 150 155 160 Ser Val Thr Ser Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe 180 185 190 Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala 210 215 220 His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly 225 230 235 240 Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys 245 250 255 Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro 260 265 270 Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 290 295 300 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 305 310 315 320 Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile 325 330 335 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 340 345 350 Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys 355 360 365 Gly Leu Val Arg Ala Pro Gln Val Tyr Thr Leu Pro Pro Pro Ala Glu 370 375 380 Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe 385 390 395 400 Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu 405 410 415 Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr 420 425 430 Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr 435 440 445 Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr 450 455 460 Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys 465 470 475 <210> 44 <211> 239 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 44 Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro 1 5 10 15 Gly Ala Ile Gly Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro 20 25 30 Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser 35 40 45 Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe 85 90 95 Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 100 105 110 Cys Met Gln His Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140 Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp 165 170 175 Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys 195 200 205 Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys 210 215 220 Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 45 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 45 Asp His Ile Ile His 1 5 <210> 46 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 46 Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 47 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 47 Gly Tyr Tyr Tyr Ala Met Asp Tyr 1 5 <210> 48 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 48 Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 49 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 49 Phe Gln Gly Ser His Val Pro Phe Thr 1 5 <210> 50 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 50 Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His 20 25 30 Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 <210> 51 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 51 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 52 <211> 460 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 52 Met Glu Trp Ser Trp Val Ser Leu Phe Phe Leu Ser Val Thr Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe 35 40 45 Thr Asp His Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn 65 70 75 80 Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln 115 120 125 Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val 130 135 140 Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr 145 150 155 160 Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr 165 170 175 Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 180 185 190 Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser 195 200 205 Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala 210 215 220 Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys 225 230 235 240 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe 245 250 255 Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 260 265 270 Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe 275 280 285 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 305 310 315 320 Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val 325 330 335 Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys 355 360 365 Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp 370 375 380 Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro 385 390 395 400 Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser 405 410 415 Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala 420 425 430 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 435 440 445 His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 53 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Arg Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 54 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 54 Ser Tyr Trp Met His 1 5 <210> 55 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 55 Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 56 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 56 Asn Tyr Ser Gly Asp Tyr 1 5 <210> 57 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 57 Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 58 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 58 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 59 <211> 458 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 59 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Cys 1 5 10 15 Val His Ser Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe 35 40 45 Ser Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn 65 70 75 80 Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly 145 150 155 160 Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn 165 170 175 Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser 210 215 220 Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro 225 230 235 240 Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro 245 250 255 Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys 260 265 270 Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp 275 280 285 Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu 290 295 300 Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met 305 310 315 320 His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser 325 330 335 Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly 340 345 350 Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln 355 360 365 Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe 370 375 380 Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu 385 390 395 400 Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe 405 410 415 Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn 420 425 430 Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr 435 440 445 Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <210> 60 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 60 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 61 Thr Tyr Gly Met Ser 1 5 <210> 62 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 62 Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe Lys 1 5 10 15 Gly <210> 63 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 63 Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr 1 5 10 <210> 64 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 64 Ile Thr Ser Thr Asp Ile Asp Asp Asp Met Asn 1 5 10 <210> 65 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 65 Glu Gly Asn Thr Leu Arg Pro 1 5 <210> 66 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 66 Leu Gln Ser Asp Asn Leu Pro Tyr Thr 1 5 <210> 67 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 67 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 68 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 68 Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly 1 5 10 15 Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu Asn Met Leu Ser 65 70 75 80 Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 69 <211> 464 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 69 Met Gly Trp Leu Trp Asn Leu Leu Phe Leu Met Ala Ala Ala Gln Ser 1 5 10 15 Ala Gln Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys 20 25 30 Pro Gly Glu Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe 35 40 45 Thr Thr Tyr Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu 50 55 60 Lys Trp Met Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala 65 70 75 80 Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser 85 90 95 Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr 100 105 110 Tyr Phe Cys Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr 130 135 140 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 145 150 155 160 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 195 200 205 Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val 210 215 220 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 225 230 235 240 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 245 250 255 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 260 265 270 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 275 280 285 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 290 295 300 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 305 310 315 320 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 325 330 335 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 340 345 350 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 355 360 365 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 370 375 380 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 385 390 395 400 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 405 410 415 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 420 425 430 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 435 440 445 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 70 <211> 234 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 70 Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys Val Ser 1 5 10 15 Asp Ser Arg Ala Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser 20 25 30 Met Ala Ile Gly Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp 35 40 45 Ile Asp Asp Asp Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro 50 55 60 Lys Leu Leu Ile Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu 85 90 95 Asn Met Leu Ser Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp 100 105 110 Asn Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 115 120 125 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 130 135 140 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 165 170 175 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 195 200 205 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 210 215 220 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 <210> 71 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 71 Asn Tyr Trp Met His 1 5 <210> 72 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 72 Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 73 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 73 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 74 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 74 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 75 <211> 458 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 75 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asn Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn 65 70 75 80 Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly 145 150 155 160 Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn 165 170 175 Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser 210 215 220 Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro 225 230 235 240 Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro 245 250 255 Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys 260 265 270 Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp 275 280 285 Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu 290 295 300 Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met 305 310 315 320 His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser 325 330 335 Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly 340 345 350 Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln 355 360 365 Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe 370 375 380 Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu 385 390 395 400 Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe 405 410 415 Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn 420 425 430 Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr 435 440 445 Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <210> 76 <211> 238 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 76 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 77 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 77 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 78 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 78 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 79 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 79 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 80 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 80 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 81 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 81 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 82 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 82 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 83 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 83 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 84 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 84 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 85 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 85 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 86 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 86 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 87 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 87 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 88 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 88 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 89 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 89 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 90 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 90 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 91 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 91 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Gln Lys Pro Gly Gly Ala Ile Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 92 <211> 468 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 92 Met Asn Phe Gly Leu Ser Leu Met Phe Leu Val Leu Val Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 65 70 75 80 Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Asn Leu Tyr Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 245 250 255 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 260 265 270 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 275 280 285 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 290 295 300 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 305 310 315 320 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 325 330 335 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 340 345 350 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Gly Lys 465 <210> 93 <211> 236 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 93 Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Leu Gly Glu Arg Val Ser Leu Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Leu Gln Gln Lys Pro Asp Gly 50 55 60 Thr Ile Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Lys Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr 85 90 95 Ile Gly Ser Leu Glu Ser Glu Asp Leu Ala Asp Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 94 <211> 471 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 94 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 95 <211> 467 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 95 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 145 150 155 160 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys 210 215 220 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 225 230 235 240 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile 340 345 350 Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Pro Gly Lys 465 <210> 96 <211> 236 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 96 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 97 <211> 236 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 97 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 98 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain no leader sequence <400> 98 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 99 <211> 445 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain no leader sequence <400> 99 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 100 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain no leader sequence <400> 100 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 101 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain no leader sequence <400> 101 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 102 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 102 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 103 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 103 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 104 <211> 448 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 104 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 105 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 105 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 106 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 106 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Glu Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 107 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 107 Asp Ile Glu Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Asn Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 108 <211> 445 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 108 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 109 <211> 217 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 109 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn Val Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Glu Val Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val 145 150 155 160 Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Ala Glu Cys Ser 210 215 <210> 110 <211> 449 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 110 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Ser Ser 20 25 30 Tyr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Ala Gly Thr Gly Ser Pro Ser Tyr Asn Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Arg Asp Tyr Tyr Ser Asn Ser Leu Thr Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly <210> 111 <211> 220 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 111 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 112 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Antibody heavy chain <400> 112 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Ser Gln Gly Lys Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Asp Glu Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 113 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> Antibody light chain <400> 113 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Thr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 114 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> Morpholino <400> 114 cgtcacaggc aggacccact gccca 25 <210> 115 <211> 1342 <212> PRT <213> Homo sapiens <400> 115 Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu 1 5 10 15 Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr 20 25 30 Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr 35 40 45 Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu 50 55 60 Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile 65 70 75 80 Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr 85 90 95 Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp 100 105 110 Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser 115 120 125 His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser 130 135 140 Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr 145 150 155 160 Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val 165 170 175 Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly 180 185 190 Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr 195 200 205 Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn 210 215 220 Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp 225 230 235 240 Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val 245 250 255 Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu 260 265 270 Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala 275 280 285 Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala 290 295 300 Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys 305 310 315 320 Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser 325 330 335 Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val 340 345 350 Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu 355 360 365 Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu 370 375 380 Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln 385 390 395 400 Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr 405 410 415 Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile 420 425 430 Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu 435 440 445 Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr 450 455 460 His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu 465 470 475 480 Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu 485 490 495 Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro 500 505 510 Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val 515 520 525 Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala 530 535 540 His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu 545 550 555 560 Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys 565 570 575 Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly 580 585 590 Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn 595 600 605 Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro 610 615 620 Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr 625 630 635 640 His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe 645 650 655 Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln 660 665 670 Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu 675 680 685 Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe 690 695 700 Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe 705 710 715 720 Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys 725 730 735 Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser 740 745 750 Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His 755 760 765 Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln 770 775 780 Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg 785 790 795 800 Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val 805 810 815 Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His 820 825 830 Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val 835 840 845 Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys 850 855 860 Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu 865 870 875 880 Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser 885 890 895 Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr 900 905 910 Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu 915 920 925 Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met 930 935 940 Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu 945 950 955 960 Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu 965 970 975 Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro 980 985 990 His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu 995 1000 1005 Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala 1010 1015 1020 Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu 1025 1030 1035 Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly 1040 1045 1050 Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu 1055 1060 1065 Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser 1070 1075 1080 Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu 1085 1090 1095 Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser 1100 1105 1110 Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly 1115 1120 1125 Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu Leu Thr Pro Val 1130 1135 1140 Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly 1145 1150 1155 Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg 1160 1165 1170 Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr 1175 1180 1185 Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg 1190 1195 1200 Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu 1205 1210 1215 Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala 1220 1225 1230 Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile 1235 1240 1245 Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met 1250 1255 1260 Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala 1265 1270 1275 Met Gly Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg 1280 1285 1290 Ala Phe Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala 1295 1300 1305 Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe 1310 1315 1320 Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn 1325 1330 1335 Ala Gln Arg Thr 1340 <210> 116 <211> 345 <212> PRT <213> Artificial Sequence <220> <223> Fusion protein <400> 116 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> 117 <211> 345 <212> PRT <213> Artificial Sequence <220> <223> Fusion protein <400> 117 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> 118 <211> 347 <212> PRT <213> Artificial Sequence <220> <223> Fusion protein <400> 118 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 115 120 125 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 130 135 140 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 145 150 155 160 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 165 170 175 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 180 185 190 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 195 200 205 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 210 215 220 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 225 230 235 240 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 245 250 255 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 260 265 270 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 275 280 285 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 290 295 300 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 305 310 315 320 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 325 330 335 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 340 345 SEQUENCE LISTING <110> ACTINIUM PHARMACEUTICALS, INC. <120> HER3 RADIOIMMUNOTHERAPY FOR THE TREATMENT OF SOLID CANCERS <130> ATNM-010PCT <140> <141> <150> PCT/US21/56259 <151> 2021-10-22 <150> US 63/250,725 <151> 2021-09-30 <150> US 63/226,699 <151> 2021-07-28 <150> US 63/118,181 <151> 2020-11-25 <150> US 63/116,225 <151> 2020-11-20 <160> 118 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT 213 <213> <400> 1 Ser His Trp Leu His 1 5 <210> 2 <211> 17 <212> PRT 213 <213> <400> 2 Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe Lys 1 5 10 15 Gly <210> 3 <211> 11 <212> PRT 213 <213> <400> 3 Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 1 5 10 <210> 4 <211> 16 <212> PRT 213 <213> <400> 4 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 5 <211> 7 <212> PRT 213 <213> <400> 5 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 6 <211> 9 <212> PRT 213 <213> <400> 6 Phe Gln Gly Ser Tyr Val Pro Trp Thr 1 5 <210> 7 <211> 120 <212> PRT 213 <213> <400> 7 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Ala 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 8 <211> 112 <212> PRT 213 <213> <400> 8 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 9 <211> 463 <212> PRT 213 <213> <400> 9 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Ser His Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn 65 70 75 80 Gln Asn Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 145 150 155 160 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala 210 215 220 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 225 230 235 240 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 275 280 285 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 290 295 300 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 305 310 315 320 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 325 330 335 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 370 375 380 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 385 390 395 400 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 405 410 415 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 420 425 430 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 435 440 445 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 10 <211> 238 <212> PRT 213 <213> <400> 10 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 11 <211> 444 <212> PRT 213 <213> <400> 11 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val 115 120 125 Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr 130 135 140 Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr 145 150 155 160 Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser 180 185 190 Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala 195 200 205 Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys 210 215 220 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 245 250 255 Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe 260 265 270 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 290 295 300 Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val 305 310 315 320 Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 325 330 335 Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys 340 345 350 Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp 355 360 365 Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro 370 375 380 Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser 385 390 395 400 Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala 405 410 415 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 420 425 430 His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <210> 12 <211> 219 <212> PRT 213 <213> <400> 12 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 13 <211> 10 <212> PRT 213 <213> <400> 13 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu 1 5 10 <210> 14 <211> 10 <212> PRT 213 <213> <400> 14 Asp Val Leu Met Thr Gln Ile Pro Leu Ser 1 5 10 <210> 15 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 15 Asp Tyr Ala Met Ser 1 5 <210> 16 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 16 Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys 1 5 10 15 Gly <210> 17 <211> 10 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 17 Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr 1 5 10 <210> 18 <211> 11 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 18 Arg Ala Ser Gln Glu Ile Ser Gly Tyr Leu Ser 1 5 10 <210> 19 <211> 7 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 19 Ala Ala Ser Thr Leu Asp Ser 1 5 <210> 20 <211> 9 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 20 Leu Gln Tyr Asp Ser Tyr Pro Tyr Thr 1 5 <210> 21 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 22 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 23 <211> 471 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 23 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 24 <211> 236 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 25 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 25 Ser His Trp Leu His 1 5 <210> 26 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 26 Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe Lys 1 5 10 15 Gly <210> 27 <211> 11 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 27 Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 1 5 10 <210> 28 <211> 16 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 28 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 29 <211> 7 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 29 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 30 <211> 9 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 30 Phe Gln Gly Ser Tyr Val Pro Trp Thr 1 5 <210> 31 <211> 120 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 31 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 32 <211> 112 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 32 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 33 <211> 463 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 33 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Ser His Trp Leu His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Val Leu Asp Pro Ser Asp Phe Tyr Ser Asn Tyr Asn 65 70 75 80 Gln Asn Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Leu Ser Gly Asp Tyr Ala Met Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser 145 150 155 160 Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe 180 185 190 Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala 210 215 220 His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp 225 230 235 240 Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val 245 250 255 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 260 265 270 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 275 280 285 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 290 295 300 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 305 310 315 320 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 325 330 335 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 355 360 365 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met 370 375 380 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 385 390 395 400 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 405 410 415 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 420 425 430 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 435 440 445 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 34 <211> 238 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 34 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Ser Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 35 <211> 7 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 35 Thr Phe Gly Leu Ser Val Gly 1 5 <210> 36 <211> 16 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 36 His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala Leu Lys Ser 1 5 10 15 <210> 37 <211> 10 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 37 Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr 1 5 10 <210> 38 <211> 16 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 38 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr 1 5 10 15 <210> 39 <211> 7 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 39 Arg Met Ser Asn Leu Ala Ser 1 5 <210> 40 <211> 9 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 40 Met Gln His Leu Glu Tyr Pro Phe Thr 1 5 <210> 41 <211> 120 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 41 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Phe 20 25 30 Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ala 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Thr Leu Thr Val Ser Ser 115 120 <210> 42 <211> 112 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 42 Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 43 <211> 475 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 43 Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr 1 5 10 15 Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Arg 20 25 30 Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu 35 40 45 Ser Thr Phe Gly Leu Ser Val Gly Trp Ile Arg Gln Pro Ser Gly Lys 50 55 60 Gly Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr 65 70 75 80 Asn Pro Ala Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys 85 90 95 Asn Gln Val Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala 100 105 110 Thr Tyr Tyr Cys Ala Arg Ile Gly Ala Asp Ala Leu Pro Phe Asp Tyr 115 120 125 Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro 130 135 140 Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser 145 150 155 160 Ser Val Thr Ser Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val 165 170 175 Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe 180 185 190 Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr 195 200 205 Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala 210 215 220 His Pro Ala Ser Ser Thr Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly 225 230 235 240 Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys 245 250 255 Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro 260 265 270 Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr 275 280 285 Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser 290 295 300 Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His 305 310 315 320 Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile 325 330 335 Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn 340 345 350 Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys 355 360 365 Gly Leu Val Arg Ala Pro Gln Val Tyr Thr Leu Pro Pro Pro Ala Glu 370 375 380 Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe 385 390 395 400 Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu 405 410 415 Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr 420 425 430 Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr 435 440 445 Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr 450 455 460 Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys 465 470 475 <210> 44 <211> 239 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 44 Met Arg Cys Leu Ala Glu Phe Leu Gly Leu Leu Val Leu Trp Ile Pro 1 5 10 15 Gly Ala Ile Gly Asp Ile Val Leu Thr Gln Thr Ala Pro Ser Val Pro 20 25 30 Val Thr Pro Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser 35 40 45 Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg 50 55 60 Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala 65 70 75 80 Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe 85 90 95 Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr 100 105 110 Cys Met Gln His Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125 Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140 Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe 145 150 155 160 Leu Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp 165 170 175 Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp 180 185 190 Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys 195 200 205 Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys 210 215 220 Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 45 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 45 Asp His Ile Ile His 1 5 <210> 46 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 46 Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe Lys 1 5 10 15 Gly <210> 47 <211> 8 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 47 Gly Tyr Tyr Tyr Ala Met Asp Tyr 1 5 <210> 48 <211> 16 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 48 Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 49 <211> 9 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 49 Phe Gln Gly Ser His Val Pro Phe Thr 1 5 <210> 50 <211> 117 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 50 Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His 20 25 30 Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn Glu Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 <210> 51 <211> 112 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 51 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 52 <211> 460 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 52 Met Glu Trp Ser Trp Val Ser Leu Phe Phe Leu Ser Val Thr Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys 20 25 30 Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Val Ser Gly Tyr Thr Phe 35 40 45 Thr Asp His Ile Ile His Trp Met Lys Gln Arg Pro Glu Gln Gly Leu 50 55 60 Glu Trp Ile Gly Tyr Ile Tyr Pro Arg Asp Gly Tyr Ile Lys Tyr Asn 65 70 75 80 Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Phe Cys Ala Arg Gly Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln 115 120 125 Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val 130 135 140 Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr 145 150 155 160 Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr 165 170 175 Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val 180 185 190 Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser 195 200 205 Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala 210 215 220 Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys 225 230 235 240 Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe 245 250 255 Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val 260 265 270 Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe 275 280 285 Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro 305 310 315 320 Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val 325 330 335 Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys 355 360 365 Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp 370 375 380 Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro 385 390 395 400 Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser 405 410 415 Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala 420 425 430 Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His 435 440 445 His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 53 <211> 238 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 53 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Arg Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Ile Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Glu Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 54 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 54 Ser Tyr Trp Met His 1 5 <210> 55 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 55 Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 56 <211> 6 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 56 Asn Tyr Ser Gly Asp Tyr 1 5 <210> 57 <211> 115 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 57 Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn Pro Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 58 <211> 112 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 58 Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 59 <211> 458 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 59 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Cys 1 5 10 15 Val His Ser Gln Val Gln Leu Leu Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe 35 40 45 Ser Ser Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Val Tyr Thr Asn Tyr Asn 65 70 75 80 Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly 145 150 155 160 Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn 165 170 175 Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser 210 215 220 Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro 225 230 235 240 Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro 245 250 255 Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys 260 265 270 Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp 275 280 285 Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu 290 295 300 Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met 305 310 315 320 His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser 325 330 335 Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly 340 345 350 Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln 355 360 365 Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe 370 375 380 Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu 385 390 395 400 Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe 405 410 415 Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn 420 425 430 Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr 435 440 445 Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <210> 60 <211> 238 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 60 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Ile Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 61 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 61 Thr Tyr Gly Met Ser 1 5 <210> 62 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 62 Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe Lys 1 5 10 15 Gly <210> 63 <211> 12 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 63 Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr 1 5 10 <210> 64 <211> 11 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 64 Ile Thr Ser Thr Asp Ile Asp Asp Asp Met Asn 1 5 10 <210> 65 <211> 7 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 65 Glu Gly Asn Thr Leu Arg Pro 1 5 <210> 66 <211> 9 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 66 Leu Gln Ser Asp Asn Leu Pro Tyr Thr 1 5 <210> 67 <211> 121 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 67 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe Thr Thr Tyr 20 25 30 Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 68 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 68 Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly 1 5 10 15 Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp 20 25 30 Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile 35 40 45 Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu Asn Met Leu Ser 65 70 75 80 Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 69 <211> 464 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 69 Met Gly Trp Leu Trp Asn Leu Leu Phe Leu Met Ala Ala Ala Gln Ser 1 5 10 15 Ala Gln Ala Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys 20 25 30 Pro Gly Glu Ala Val Lys Ile Ser Cys Lys Ser Ser Gly Tyr Thr Phe 35 40 45 Thr Thr Tyr Gly Met Ser Trp Val Lys Gln Ala Pro Gly Arg Ala Leu 50 55 60 Lys Trp Met Gly Trp Ile Asn Thr Tyr Ser Gly Val Pro Thr Tyr Ala 65 70 75 80 Asp Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Ser Ser Ala Ser 85 90 95 Thr Ala Tyr Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr 100 105 110 Tyr Phe Cys Ala Arg Gly Arg Asp Gly Tyr Gln Val Ala Trp Phe Ala 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr 130 135 140 Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn 145 150 155 160 Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val 195 200 205 Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Asn Val 210 215 220 Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg 225 230 235 240 Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser 245 250 255 Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu 260 265 270 Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro 275 280 285 Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala 290 295 300 Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val 305 310 315 320 Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe 325 330 335 Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr 340 345 350 Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile 355 360 365 Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys 370 375 380 Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp 385 390 395 400 Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp 405 410 415 Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser 420 425 430 Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly 435 440 445 Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 460 <210> 70 <211> 234 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 70 Met Phe Ser Leu Ala Leu Leu Leu Ser Leu Leu Leu Leu Cys Val Ser 1 5 10 15 Asp Ser Arg Ala Glu Thr Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser 20 25 30 Met Ala Ile Gly Asp Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp 35 40 45 Ile Asp Asp Asp Met Asn Trp Phe Gln Gln Lys Pro Gly Glu Pro Pro 50 55 60 Lys Leu Leu Ile Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Tyr Gly Thr Asp Phe Ile Phe Thr Ile Glu 85 90 95 Asn Met Leu Ser Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp 100 105 110 Asn Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 115 120 125 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 130 135 140 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 165 170 175 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 195 200 205 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 210 215 220 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 <210> 71 <211> 5 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 71 Asn Tyr Trp Met His 1 5 <210> 72 <211> 17 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 72 Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe Lys 1 5 10 15 Gly <210> 73 <211> 115 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 73 Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Pro Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110 Val Ser Ser 115 <210> 74 <211> 112 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 74 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 75 <211> 458 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 75 Met Gly Trp Ser Cys Ile Ile Val Leu Leu Val Ser Thr Ala Thr Gly 1 5 10 15 Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg 20 25 30 Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Asn Tyr Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60 Glu Trp Ile Gly Met Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn 65 70 75 80 Pro Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser 85 90 95 Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asn Tyr Ser Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140 Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly 145 150 155 160 Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn 165 170 175 Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Asp Leu Tyr Thr Leu Ser Ser Ser Ser Val Thr Val Pro Ser Ser Thr 195 200 205 Trp Pro Ser Gln Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser 210 215 220 Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro 225 230 235 240 Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro 245 250 255 Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys 260 265 270 Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp 275 280 285 Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu 290 295 300 Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met 305 310 315 320 His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser 325 330 335 Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly 340 345 350 Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln 355 360 365 Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe 370 375 380 Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu 385 390 395 400 Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe 405 410 415 Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn 420 425 430 Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr 435 440 445 Glu Lys Ser Leu Ser His Ser Pro Gly Lys 450 455 <210> 76 <211> 238 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 76 Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala 1 5 10 15 Ser Ser Ser Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30 Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile 35 40 45 Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro 50 55 60 Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser 65 70 75 80 Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95 Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys 100 105 110 Phe Gln Gly Ser Tyr Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125 Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140 Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu 145 150 155 160 Asn Asn Phe Tyr Pro Arg Asp Ile Asn Val Lys Trp Lys Ile Asp Gly 165 170 175 Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser 180 185 190 Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp 195 200 205 Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr 210 215 220 Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 225 230 235 <210> 77 <211> 449 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 77 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 78 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 78 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 79 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 79 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 80 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 80 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 81 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 81 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 82 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 82 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 83 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 83 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 84 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 84 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 85 <211> 119 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 85 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Asn Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 86 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 86 Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 87 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 87 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 88 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 88 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 89 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 89 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 90 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 90 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 91 <211> 107 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 91 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Leu Gln Gln Lys Pro Gly Gly Ala Ile Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 92 <211> 468 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 92 Met Asn Phe Gly Leu Ser Leu Met Phe Leu Val Leu Val Leu Lys Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu 50 55 60 Glu Trp Val Ala Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro 65 70 75 80 Asp Asn Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Asn Leu Tyr Leu Gln Met Ser His Leu Lys Ser Glu Asp Thr Ala Met 100 105 110 Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 225 230 235 240 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 245 250 255 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 260 265 270 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 275 280 285 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 290 295 300 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 305 310 315 320 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 325 330 335 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 340 345 350 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 355 360 365 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val 370 375 380 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 385 390 395 400 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 405 410 415 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 420 425 430 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 435 440 445 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 450 455 460 Ser Pro Gly Lys 465 <210> 93 <211> 236 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 93 Met Asp Met Arg Val Pro Ala His Val Phe Gly Phe Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Leu Gly Glu Arg Val Ser Leu Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Leu Gln Gln Lys Pro Asp Gly 50 55 60 Thr Ile Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Lys Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr 85 90 95 Ile Gly Ser Leu Glu Ser Glu Asp Leu Ala Asp Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 94 <211> 471 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 94 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 145 150 155 160 Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys 210 215 220 Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 225 230 235 240 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 245 250 255 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 260 265 270 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 275 280 285 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 290 295 300 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 305 310 315 320 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 325 330 335 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 340 345 350 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 355 360 365 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 370 375 380 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 385 390 395 400 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 405 410 415 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 420 425 430 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 435 440 445 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 450 455 460 Leu Ser Leu Ser Pro Gly Lys 465 470 <210> 95 <211> 467 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 95 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly 20 25 30 Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly 35 40 45 Phe Thr Phe Ser Asp Tyr Ala Met Ser Trp Ile Arg Gln Ala Pro Gly 50 55 60 Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr 65 70 75 80 Tyr Tyr Pro Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn 85 90 95 Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp 100 105 110 Thr Ala Val Tyr Tyr Cys Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe 115 120 125 Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr 130 135 140 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 145 150 155 160 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 165 170 175 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 180 185 190 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 195 200 205 Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys 210 215 220 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu 225 230 235 240 Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 245 250 255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe 305 310 315 320 Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile 340 345 350 Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Pro Gly Lys 465 <210> 96 <211> 236 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 96 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Ser Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 97 <211> 236 <212> PRT <213> artificial sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 97 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln Glu Ile Ser Gly Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Arg Leu Ile Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 100 105 110 Tyr Asp Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> 98 <211> 449 <212> PRT <213> artificial sequence <220> <223> Antibody heavy chain no leader sequence <400> 98 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <210> 99 <211> 445 <212> PRT <213> artificial sequence <220> <223> Antibody heavy chain no leader sequence <400> 99 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Asp Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Trp Gly Asp Tyr Asp Gly Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 100 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain no leader sequence <400> 100 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 101 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain no leader sequence <400> 101 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asp Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 102 <211> 450 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 102 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 103 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 103 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 104 <211> 448 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 104 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr 20 25 30 Thr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asp Val Asn Pro Asn Ser Gly Gly Ser Ile Tyr Asn Gln Arg Phe 50 55 60 Lys Gly Arg Phe Thr Leu Ser Val Asp Arg Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asn Leu Gly Pro Ser Phe Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 105 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 105 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Gly 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ile Tyr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 106 <211> 447 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 106 Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Val Thr Ile Ser Val Glu Thr Ser Lys Asn Gln Phe Ser Leu 65 70 75 80 Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Lys Trp Thr Trp Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 107 <211> 220 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 107 Asp Ile Glu Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Ser Asn Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Asn Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 108 <211> 445 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 108 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Val Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Ser Ser Gly Gly Trp Thr Leu Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Gly Leu Lys Met Ala Thr Ile Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 210 215 220 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln 260 265 270 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 290 295 300 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 305 310 315 320 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415 Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 109 <211> 217 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 109 Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn Val Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile Ile Tyr Glu Val Ser Gln Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser 85 90 95 Ser Ile Phe Val Ile Phe Gly Gly Gly Thr Lys Val Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Val Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro Val 145 150 155 160 Lys Val Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Arg Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Ala Glu Cys Ser 210 215 <210> 110 <211> 449 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 110 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Arg Ser Ser 20 25 30 Tyr Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Tyr Ala Gly Thr Gly Ser Pro Ser Tyr Asn Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Arg Asp Tyr Tyr Ser Asn Ser Leu Thr Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly <210> 111 <211> 220 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 111 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Ser 85 90 95 Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110 Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 145 150 155 160 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 220 <210> 112 <211> 446 <212> PRT <213> artificial sequence <220> 223 <#223> <400> 112 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Ser Gln Gly Lys Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Trp Gly Asp Glu Gly Phe Asp Ile Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 <210> 113 <211> 214 <212> PRT <213> artificial sequence <220> <223> Antibody light chain <400> 113 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Phe Pro Thr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 114 <211> 25 <212> DNA <213> artificial sequence <220> <223> <400> 114 cgtcacaggc aggacccact gccca 25 <210> 115 <211> 1342 <212> PRT <213> Homo sapiens <400> 115 Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu Leu Phe Ser Leu 1 5 10 15 Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr 20 25 30 Leu Asn Gly Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr 35 40 45 Leu Tyr Lys Leu Tyr Glu Arg Cys Glu Val Val Met Gly Asn Leu Glu 50 55 60 Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu Gln Trp Ile 65 70 75 80 Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr 85 90 95 Leu Pro Leu Pro Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp 100 105 110 Gly Lys Phe Ala Ile Phe Val Met Leu Asn Tyr Asn Thr Asn Ser Ser 115 120 125 His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile Leu Ser 130 135 140 Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr 145 150 155 160 Ile Asp Trp Arg Asp Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val 165 170 175 Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys His Glu Val Cys Lys Gly 180 185 190 Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys Thr 195 200 205 Ile Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn 210 215 220 Gln Cys Cys His Asp Glu Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp 225 230 235 240 Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp Ser Gly Ala Cys Val 245 250 255 Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu 260 265 270 Glu Pro Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala 275 280 285 Ser Cys Pro His Asn Phe Val Val Asp Gln Thr Ser Cys Val Arg Ala 290 295 300 Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly Leu Lys Met Cys 305 310 315 320 Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser 325 330 335 Gly Ser Arg Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val 340 345 350 Asn Cys Thr Lys Ile Leu Gly Asn Leu Asp Phe Leu Ile Thr Gly Leu 355 360 365 Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro Glu Lys Leu 370 375 380 Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln 385 390 395 400 Ser Trp Pro Pro His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr 405 410 415 Thr Ile Gly Gly Arg Ser Leu Tyr Asn Arg Gly Phe Ser Leu Leu Ile 420 425 430 Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu Lys Glu 435 440 445 Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr 450 455 460 His His Ser Leu Asn Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu 465 470 475 480 Arg Leu Asp Ile Lys His Asn Arg Pro Arg Arg Asp Cys Val Ala Glu 485 490 495 Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly Pro 500 505 510 Gly Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val 515 520 525 Cys Val Thr His Cys Asn Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala 530 535 540 His Glu Ala Glu Cys Phe Ser Cys His Pro Glu Cys Gln Pro Met Glu 545 550 555 560 Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys 565 570 575 Ala His Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly 580 585 590 Val Leu Gly Ala Lys Gly Pro Ile Tyr Lys Tyr Pro Asp Val Gln Asn 595 600 605 Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly Cys Lys Gly Pro 610 615 620 Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr 625 630 635 640 His Leu Thr Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe 645 650 655 Met Met Leu Gly Gly Thr Phe Leu Tyr Trp Arg Gly Arg Arg Ile Gln 660 665 670 Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu Ser Ile Glu 675 680 685 Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe 690 695 700 Lys Glu Thr Glu Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe 705 710 715 720 Gly Thr Val His Lys Gly Val Trp Ile Pro Glu Gly Glu Ser Ile Lys 725 730 735 Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg Gln Ser 740 745 750 Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His 755 760 765 Ala His Ile Val Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln 770 775 780 Leu Val Thr Gln Tyr Leu Pro Leu Gly Ser Leu Leu Asp His Val Arg 785 790 795 800 Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu Asn Trp Gly Val 805 810 815 Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His 820 825 830 Arg Asn Leu Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val 835 840 845 Gln Val Ala Asp Phe Gly Val Ala Asp Leu Leu Pro Pro Asp Asp Lys 850 855 860 Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp Met Ala Leu 865 870 875 880 Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser 885 890 895 Tyr Gly Val Thr Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr 900 905 910 Ala Gly Leu Arg Leu Ala Glu Val Pro Asp Leu Leu Glu Lys Gly Glu 915 920 925 Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met Val Met 930 935 940 Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu 945 950 955 960 Leu Ala Asn Glu Phe Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu 965 970 975 Val Ile Lys Arg Glu Ser Gly Pro Gly Ile Ala Pro Gly Pro Glu Pro 980 985 990 His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu Pro Glu 995 1000 1005 Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala 1010 1015 1020 Thr Thr Thr Leu Gly Ser Ala Leu Ser Leu Pro Val Gly Thr Leu 1025 1030 1035 Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu Ser Pro Ser Ser Gly 1040 1045 1050 Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu 1055 1060 1065 Ser Ala Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser 1070 1075 1080 Leu His Pro Met Pro Arg Gly Cys Leu Ala Ser Glu Ser Ser Glu 1085 1090 1095 Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu Lys Val Ser 1100 1105 1110 Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly 1115 1120 1125 Asp Ser Ala Tyr His Ser Gln Arg His Ser Leu Leu Thr Pro Val 1130 1135 1140 Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu Glu Asp Val Asn Gly 1145 1150 1155 Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg 1160 1165 1170 Glu Gly Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr 1175 1180 1185 Glu Glu Glu Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg Arg 1190 1195 1200 Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser Ser Leu Glu 1205 1210 1215 Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala 1220 1225 1230 Ser Leu Gly Ser Thr Gln Ser Cys Pro Leu His Pro Val Pro Ile 1235 1240 1245 Met Pro Thr Ala Gly Thr Thr Pro Asp Glu Asp Tyr Glu Tyr Met 1250 1255 1260 Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala 1265 1270 1275 Met Gly Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg 1280 1285 1290 Ala Phe Gln Gly Pro Gly His Gln Ala Pro His Val His Tyr Ala 1295 1300 1305 Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp Ser Ala Phe 1310 1315 1320 Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn 1325 1330 1335 Ala Gln Arg Thr 1340 <210> 116 <211> 345 <212> PRT <213> artificial sequence <220> <223> fusion proteins <400> 116 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> 117 <211> 345 <212> PRT <213> artificial sequence <220> <223> fusion protein <400> 117 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 115 120 125 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 130 135 140 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 145 150 155 160 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 165 170 175 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 180 185 190 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 195 200 205 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 210 215 220 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 225 230 235 240 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 245 250 255 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 260 265 270 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 275 280 285 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 290 295 300 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 305 310 315 320 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 325 330 335 Lys Ser Leu Ser Leu Ser Pro Gly Lys 340 345 <210> 118 <211> 347 <212> PRT <213> artificial sequence <220> <223> fusion proteins <400> 118 Glu Glu Glu Leu Gln Val Ile Gln Pro Asp Lys Ser Val Ser Val Ala 1 5 10 15 Ala Gly Glu Ser Ala Ile Leu His Cys Thr Val Thr Ser Leu Ile Pro 20 25 30 Val Gly Pro Ile Gln Trp Phe Arg Gly Ala Gly Pro Ala Arg Glu Leu 35 40 45 Ile Tyr Asn Gln Lys Glu Gly His Phe Pro Arg Val Thr Thr Val Ser 50 55 60 Glu Ser Thr Lys Arg Glu Asn Met Asp Phe Ser Ile Ser Ile Ser Asn 65 70 75 80 Ile Thr Pro Ala Asp Ala Gly Thr Tyr Tyr Cys Val Lys Phe Arg Lys 85 90 95 Gly Ser Pro Asp Thr Glu Phe Lys Ser Gly Ala Gly Thr Glu Leu Ser 100 105 110 Val Arg Ala Lys Pro Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro 115 120 125 Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 130 135 140 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 145 150 155 160 Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn 165 170 175 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 180 185 190 Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 195 200 205 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 210 215 220 Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys 225 230 235 240 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu 245 250 255 Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 260 265 270 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 275 280 285 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 290 295 300 Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly 305 310 315 320 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 325 330 335 Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 340 345
Claims (31)
를 포함하는, 포유동물 대상체에서 고형 암을 치료하는 방법.Administering to a mammalian subject a therapeutically effective amount of a radionuclide-labeled HER3 targeting agent.
A method of treating solid cancer in a mammalian subject, comprising:
(i) (a) 서열식별번호: 15를 포함하는 CDR-H1, 서열식별번호: 16을 포함하는 CDR-H2, 및/또는 서열식별번호: 17을 포함하는 CDR-H3을 포함하는 이뮤노글로불린 중쇄 가변 영역, 및
(b) 서열식별번호: 18을 포함하는 CDR-L1, 서열식별번호: 19를 포함하는 CDR-L2, 및/또는 서열식별번호: 20을 포함하는 CDR-L3을 포함하는 이뮤노글로불린 경쇄 가변 영역
중 하나 또는 둘 다;
(ii) 서열식별번호: 21을 포함하는 이뮤노글로불린 중쇄 가변 영역 및 서열식별번호: 22를 포함하는 이뮤노글로불린 경쇄 가변 영역 중 하나 또는 둘 다; 또는
(iii) 서열식별번호: 23의 이뮤노글로불린 중쇄 아미노산 서열 및 서열식별번호: 24의 이뮤노글로불린 경쇄 아미노산 서열 중 하나 또는 둘 다
를 포함하는 모노클로날 항체를 포함하는 것인 방법.The method of claim 1, wherein the radionuclide-labeled HER3 targeting agent is:
(i) (a) an immunoglobulin comprising CDR-H1 comprising SEQ ID NO: 15, CDR-H2 comprising SEQ ID NO: 16, and/or CDR-H3 comprising SEQ ID NO: 17 heavy chain variable region, and
(b) an immunoglobulin light chain variable region comprising CDR-L1 comprising SEQ ID NO: 18, CDR-L2 comprising SEQ ID NO: 19, and/or CDR-L3 comprising SEQ ID NO: 20
either or both;
(ii) one or both of an immunoglobulin heavy chain variable region comprising SEQ ID NO: 21 and an immunoglobulin light chain variable region comprising SEQ ID NO: 22; or
(iii) one or both of the immunoglobulin heavy chain amino acid sequence of SEQ ID NO: 23 and the immunoglobulin light chain amino acid sequence of SEQ ID NO: 24
A method comprising a monoclonal antibody comprising a.
HER3 표적화제의 방사성표지된 분획 및 HER3 표적화제의 비-방사성표지된 분획을 포함하는 치료 조성물의 치료 유효량을 대상체에게 투여하는 것
을 포함하는 것인 방법.26. The method of any one of claims 1 to 25, wherein the administering step is:
Administering to a subject a therapeutically effective amount of a therapeutic composition comprising a radiolabeled fraction of a HER3 targeting agent and a non-radiolabeled fraction of a HER3 targeting agent.
A method comprising a.
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US202063116225P | 2020-11-20 | 2020-11-20 | |
US63/116,225 | 2020-11-20 | ||
US202063118181P | 2020-11-25 | 2020-11-25 | |
US63/118,181 | 2020-11-25 | ||
US202163226699P | 2021-07-28 | 2021-07-28 | |
US63/226,699 | 2021-07-28 | ||
US202163250725P | 2021-09-30 | 2021-09-30 | |
US63/250,725 | 2021-09-30 | ||
USPCT/US2021/056259 | 2021-10-22 | ||
PCT/US2021/056259 WO2022087416A1 (en) | 2020-10-22 | 2021-10-22 | Combination radioimmunotherapy and cd47 blockade in the treatment of cancer |
PCT/US2021/060370 WO2022109404A1 (en) | 2020-11-20 | 2021-11-22 | Her3 radioimmunotherapy for the treatment of solid cancers |
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AU (1) | AU2021382717A1 (en) |
CA (1) | CA3199259A1 (en) |
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