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WO2024183622A1 - 一种抗her2抗体在制备治疗癌症的药物中的用途 - Google Patents

一种抗her2抗体在制备治疗癌症的药物中的用途 Download PDF

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Publication number
WO2024183622A1
WO2024183622A1 PCT/CN2024/079489 CN2024079489W WO2024183622A1 WO 2024183622 A1 WO2024183622 A1 WO 2024183622A1 CN 2024079489 W CN2024079489 W CN 2024079489W WO 2024183622 A1 WO2024183622 A1 WO 2024183622A1
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Prior art keywords
cancer
use according
her2 antibody
bile duct
antibody
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PCT/CN2024/079489
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English (en)
French (fr)
Inventor
徐铁
殷刘松
姜晓玲
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盛禾(中国)生物制药有限公司
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Publication of WO2024183622A1 publication Critical patent/WO2024183622A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to the use of an anti-HER2 antibody in preparing a medicine for treating biliary system cancer, gastric cancer or breast cancer.
  • HER2 is the abbreviation of human epidermal growth factor receptor 2, which is a proto-oncogene located in region 21 of the long arm of chromosome 17; it encodes a transmembrane protein with a molecular weight of 185KD, so it is also called p185HER2, a growth factor receptor with transmembrane tyrosine kinase activity.
  • the HER family has 4 members (HER1, HER2, HER3, HER4), all of which are transmembrane tyrosine kinase receptors with growth stimulating activity.
  • HER2 has no natural ligand, but can be activated by overexpression of homodimers or by heterodimers with other members of the HER family that can be activated by ligand binding, thereby activating receptor tyrosine kinases and triggering downstream signal cascades through multiple signal pathways such as mitogen-activated protein kinases, phosphatidylinositol-3-kinase-protein kinase B/Akt, phospholipase C-protein kinase C, and transcriptional signal transduction and activation proteins.
  • HER2 is expressed at low levels in very few tissues, but is overexpressed in more than 30% of human tumors. Overexpression of the HER2 gene is not only related to the occurrence and development of tumors, but is also an important clinical treatment detection and prognostic indicator, and an important target for the selection of tumor targeted therapy drugs.
  • HER2-positive breast cancer Currently, the most effective targeted drug for the treatment of HER2-positive breast cancer is Roche's anti-HER2 monoclonal antibody (trastuzumab, trade name Herceptin), which has become the first-line drug for the treatment of breast cancer both internationally and domestically.
  • trastuzumab trade name Herceptin
  • the currently published studies on the treatment of HER2-positive breast cancer with trastuzumab show that after an average of 4 years of treatment observation, nearly 90% of the treated female patients are still alive, and it shows good cardiac safety and tolerability.
  • CD16a The most important genetic polymorphism of IgG Fc receptor is CD16a, which can be divided into three genotypes: 158V/V, 158V/F, and 158F/F, depending on whether the amino acid at position 158 is phenylalanine (Phe, F) or valine (Val, V).
  • the patient's clinical response to trastuzumab is closely related to the patient's CD16a polymorphism.
  • the ORR ratios of patients with the three genotypes to trastuzumab were CD16a 158V/V (82%), 158V/F (42%), and 158F/F (35%), which were significantly different.
  • trastuzumab During trastuzumab treatment, the progression-free survival of patients with CD16a 158V/V, 158V/F, and 158F/F genotypes were 15.0 months, 11.1 months, and 12.9 months, respectively. Months. The genetic polymorphism of Fc receptors, their PBMC-mediated ADCC activity, and the patient's clinical response to trastuzumab are consistent. Trastuzumab cannot effectively mediate ADCC activity in patients with CD16a 158F/F type, which is also a reason for trastuzumab resistance in some patients.
  • the antibody of the present invention has been genetically engineered to knock out the FUT8 gene and completely eliminate the fucose at the Fc end of the antibody, thereby improving the ADCC effect of the monoclonal antibody drug.
  • the anti-HER2 antibody of the present invention is completely defucosylated, effectively improving the affinity of the antibody to the Fc receptor CD16a and the ADCC activity of the antibody, which is 20 times that of trastuzumab, and has excellent effects in the treatment of biliary system cancer, gastric cancer, and breast cancer, showing excellent anti-tumor activity and good safety and tolerability.
  • the present invention provides use of an anti-HER2 antibody in preparing a medicine for treating biliary system cancer, gastric cancer or breast cancer.
  • the present invention also provides an application of an anti-HER2 antibody in treating biliary system cancer, gastric cancer or breast cancer.
  • the biliary system cancer is bile duct cancer or gallbladder cancer.
  • the bile duct cancer is intrahepatic bile duct cancer, extrahepatic bile duct cancer, hilar bile duct cancer, perihilar bile duct cancer, or distal bile duct cancer.
  • the bile duct cancer is primary bile duct cancer, recurrent bile duct cancer, or metastatic bile duct cancer.
  • the gallbladder cancer is primary gallbladder cancer, recurrent gallbladder cancer, or metastatic gallbladder cancer.
  • the gastric cancer is gastric cardia-fundus cancer, gastric body cancer, or gastric antrum cancer.
  • the gastric cancer is primary gastric cancer, recurrent gastric cancer, or metastatic gastric cancer.
  • the breast cancer is invasive breast cancer, early invasive breast cancer, or invasive breast cancer of no special type.
  • the breast cancer is advanced breast cancer.
  • the anti-HER2 antibody is a defucosylated anti-HER2 antibody.
  • the light chain variable region of the anti-HER2 antibody comprises SEQ ID NO: 1. LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 2 and SEQ ID NO: 3; the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • the anti-HER2 antibody is a humanized antibody.
  • the light chain variable region sequence of the humanized antibody is the sequence shown in SEQ ID NO: 7
  • the heavy chain variable region sequence is the sequence shown in SEQ ID NO: 8.
  • the anti-HER2 antibody is used in the preparation of a medicament for treating biliary system cancer or in the treatment of biliary system cancer, wherein the anti-HER2 antibody dose is 10-20 mg/kg, preferably, the anti-HER2 antibody dose is 15 mg/kg.
  • the anti-HER2 antibody is used in the preparation of a medicament for treating gastric cancer or in the treatment of gastric cancer, wherein the anti-HER2 antibody dosage is 5-25 mg/kg, preferably, the anti-HER2 antibody dosage is 10 mg/kg or 20 mg/kg.
  • the anti-HER2 antibody is used in the preparation of a drug for treating breast cancer or in the treatment of breast cancer, wherein the anti-HER2 antibody dose is 5-25 mg/kg, preferably, the anti-HER2 antibody dose is 10 mg/kg or 20 mg/kg.
  • antibody refers to a natural immunoglobulin or an immunoglobulin prepared by partial or complete synthesis. Antibodies can be isolated by reconstruction from natural resources such as plasma or serum in which the antibody naturally exists, or from the culture supernatant of hybridoma cells that produce antibodies, from animal immune serum, or from phage library screening. Alternatively, it can be partially or completely synthesized using techniques such as gene recombination.
  • antibody includes immunoglobulin molecules including four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and multimers thereof (e.g., IgM).
  • Each L chain is connected to the H chain by a covalent disulfide bond, and the two H chains are connected to each other by one or more disulfide bonds depending on the H chain isotype.
  • Each heavy chain has a variable region (abbreviated as VH in this article) at the N-terminus, followed by a constant region.
  • Each heavy chain includes a heavy chain variable region (abbreviated as HCVR or VH in this article) and a heavy chain constant region.
  • This heavy chain constant region includes three regions (domains), CH1, CH2, and CH3.
  • Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VH and VL) and light chain constant region.
  • the light chain constant region comprises a region (domain, CL1).
  • VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conservative regions, called framework regions (FRs, also known as skeleton regions or framework regions).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • Antibodies can be antibodies of different subclasses.
  • antibody includes, but is not limited to, monoclonal antibodies, fully human antibodies, humanized antibodies, camelid antibodies, chimeric antibodies, bispecific or multispecific antibodies, anti-idiotypic (anti-Id) antibodies (including, for example, anti-Id antibodies to antibodies of the present disclosure) or fusion proteins, etc.
  • the antibodies can be of any isotype/class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2).
  • humanized antibody refers to a chimeric antibody containing amino acid residues derived from human antibody sequences.
  • Humanized antibodies may contain some or all of the CDRs or HVRs from non-human animals or synthetic antibodies, while the framework and constant regions of the antibodies contain amino acid residues derived from human antibody sequences.
  • the heterologous reactions induced by chimeric antibodies due to carrying a large amount of heterologous protein components can be overcome.
  • Such framework sequences can be obtained from public DNA databases or published references including germline antibody gene sequences.
  • the human antibody variable region framework sequence can be subjected to minimal reverse mutations or back mutations to maintain activity.
  • variable region of an antibody refers to the variable region (VL) of an antibody light chain or the variable region (VH) of an antibody heavy chain, either alone or in combination.
  • VL variable region
  • VH variable region
  • the variable regions of the heavy and light chains are each composed of four framework regions (FRs) connected by three complementary determining regions (CDRs) (also referred to as hypervariable regions).
  • FRs framework regions
  • CDRs complementary determining regions
  • the CDRs in each chain are closely held together by the FRs and contribute to the formation of the antigen-binding site of the antibody together with the CDRs from the other chain.
  • variable refers to the fact that certain segments of the variable domain differ widely in sequence between antibodies.
  • the V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen.
  • variability is not evenly distributed across the entire variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) within the light and heavy chain variable domains.
  • HVRs hypervariable regions
  • FRs framework regions
  • the variable domains of natural heavy and light chains each contain four FR regions, most of which adopt a ⁇ -pleated configuration and are connected by three HVRs, which form loops connecting and, in some cases, forming part of the ⁇ -pleated structure.
  • the HVRs in each chain are held tightly together by the FR regions and, together with the HVRs of the other chains, contribute to the specificity of the antibody.
  • the constant domains are not directly involved in the binding of antibodies to antigens, but exhibit various effector functions, such as participation in antibody-dependent cellular toxicity of antibodies.
  • CDRs There are multiple methods/systems in the art to define and describe CDRs, and these systems and/or definitions have been developed and refined over the years, including Kabat, Chothia, IMGT, AbM, and Contact.
  • Kabat is the most commonly used, defining CDRs based on sequence variability
  • Chothia defines CDRs based on sequence variability based on the position of structural loop regions
  • the IMGT system defines CDRs based on sequence variability and position within the variable domain structure
  • AbM is defined based on Oxford Molecular's AbM antibody modeling software, which is a compromise between Kabat and Chothia
  • Contact defines CDRs based on analysis of complex crystal structures, which is similar to Chothia in many aspects.
  • the CDRs listed in the present invention are annotated using the Kabat numbering system.
  • defucosylation refers to the process of removing fucose from a glycoprotein.
  • chemotherapy generally refers to the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or by inhalation or in the form of a suppository.
  • treatment refers to a method of obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and/or a preventive benefit.
  • a therapeutic benefit generally refers to eradication or lessening of the severity of the underlying condition being treated.
  • a therapeutic benefit is achieved by eradicating, lessening the severity, or reducing the incidence of one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the subject (although the subject may still be afflicted with the underlying condition).
  • a composition may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.
  • administering refers to the act of delivering or causing delivery of a therapeutic or pharmaceutical composition to a subject's body by the methods described herein or known in the art.
  • Administering a therapeutic or pharmaceutical composition includes prescribing a therapeutic or pharmaceutical composition to be delivered to a patient.
  • Exemplary administration forms include oral dosage forms, such as tablets, capsules, syrups, suspensions; injectable dosage forms, such as intravenous (IV), intramuscular (IM) or intraperitoneal (IP); transdermal dosage forms, including creams, jellies, powders or patches; buccal dosage forms; inhalation powders, sprays, suspensions and rectal suppositories.
  • subject generally refers to a human or non-human animal, including but not limited to cats, dogs, horses, pigs, cows, sheep, goats, rabbits, mice, rats or monkeys. In the present invention, the subject refers to a human.
  • dose refers to the total amount of antibody administered to a subject in a course of treatment.
  • the dose can be a dose calculated on a weight basis, such as the amount administered to a subject calculated on the basis of the subject's body weight, Expressed in mg/kg.
  • the heavy chain of the anti-HER2 antibody is shown in SEQ ID NO: 9, and the light chain is shown in SEQ ID NO: 10.
  • a pair of sgRNAs are designed for the exon1 and exon7 regions of the FUT8 gene of CHO cells using CRISPR/Cas9 technology to construct FUT8 knockout vector plasmids 1 and 2; plasmids 1 and 2 are transfected into CHO cells to knock out the FUT8 gene in the CHO cells, thereby obtaining stable engineered cells with FUT8 gene silencing, and then obtaining the completely defucosylated anti-HER2 antibody of the present invention.
  • Each batch of antibodies produced for clinical purposes meets the requirements for virus safety and the sterility requirements of the Chinese Pharmacopoeia.
  • Each batch meets the requirements for identity, purity and effectiveness.
  • the defucosylated anti-HER2 antibody of the present invention is prepared into a preparation, which contains: 20 mg/mL of the defucosylated anti-HER2 antibody, 0.5 mg/mL of histidine hydrochloride monohydrate (pH 6.0), 0.3 mg/mL of histidine, 0.1 mg/mL of polysorbate 20 and 19 mg/mL of trehalose dihydrate ( ⁇ , ⁇ ).
  • Each borosilicate vial (10 mL) contains 100 mg of the defucosylated anti-HER2 antibody of the present invention, with a concentration of 20 mg/mL.
  • HER2-positive advanced solid tumors confirmed by histopathology and/or cytology who have failed standard treatment. Failure of standard treatment refers to: disease progression during treatment or after the last treatment, intolerance due to toxic side effects during treatment ( ⁇ grade 4 hematological toxicity or ⁇ grade 3 non-hematological toxicity after previous standard treatment), disease progression or recurrence during neoadjuvant/adjuvant treatment or within 6 months after the end of treatment.
  • HER2 positivity is defined as: IHC 3+, or IHC 2+ and positive/HER2 gene amplification by fluorescence in situ hybridization (FISH).
  • Physical condition score ECOG is 0 to 1 points.
  • Routine blood test hemoglobin (HGB) ⁇ 100 g/L, white blood cell count (WBC) ⁇ 3.0 ⁇ 10 9 /L, neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L, platelet count (PLT) ⁇ 75 ⁇ 10 9 /L;
  • Blood biochemistry total bilirubin (TBIL) ⁇ 1.5 ⁇ upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 3.0 ⁇ ULN, serum creatinine (Cr) ⁇ 1.5 ⁇ ULN or creatinine clearance calculated according to the Cockcroft-Gault formula ⁇ 50 mL/min.
  • ALT and AST 5.0 ⁇ ULN
  • TBIL 3.0 ⁇ ULN.
  • Subjects must agree to use at least one medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment period (female: such as intrauterine contraceptive device, birth control pills or condoms, etc.; male: such as condoms, abstinence, etc.), and female subjects must be non-breastfeeding.
  • the efficacy study of this study is an exploratory observation, with RECIST 1.1 as the evaluation standard, and tumor imaging evaluation is performed every 2 cycles ( ⁇ 7 days). After 6 months of the first medication, tumor imaging evaluation can be changed to every 4 cycles ( ⁇ 7 days) as appropriate.
  • Imaging includes computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain, neck, chest, abdomen, and pelvis, and bone scans and/or bone X-rays for patients with known or suspected bone metastases.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the same imaging techniques should be used for the same lesion types in subsequent tumor assessments as during the screening period. Antitumor activity will be assessed by radiographic imaging during the screening period and during treatment according to the trial flow chart; assessments should also be performed when disease progression is suspected (e.g., worsening of symptoms) and when subjects withdraw from treatment (if not assessed within the previous 28 days).
  • PR partial remission
  • DCR disease control rate
  • ORR objective response rate
  • the patient's previous tumor treatment history 1 Regimen/drug name: albumin-bound paclitaxel, capecitabine; 2 Treatment method: chemotherapy; 3 Best efficacy: PR (partial remission).
  • Dosage cycle Administer the drug every three weeks.
  • Efficacy The efficacy was evaluated in the second cycle and was SD; the efficacy was evaluated in the fourth and sixth cycles, both were PR, confirmed PR; the efficacy was evaluated in the eighth cycle as PD (disease progression), that is, DOR (duration of remission) for 4 cycles, 12 weeks.
  • CTCAE grade 1 adverse reactions such as anemia, hyperuricemia, diarrhea, constipation, and increased alanine aminotransferase.
  • HER2-positive advanced solid tumors confirmed by histopathology and/or cytology who have failed standard treatment. Failure of standard treatment refers to: disease progression during treatment or after the last treatment, intolerance due to toxic side effects during treatment ( ⁇ grade 4 hematological toxicity or ⁇ grade 3 non-hematological toxicity after previous standard treatment), disease progression or recurrence during neoadjuvant/adjuvant treatment or within 6 months after the end of treatment.
  • HER2 positivity is defined as: IHC 3+, or IHC 2+ and positive/HER2 gene amplification by fluorescence in situ hybridization (FISH).
  • Physical condition score ECOG is 0 to 1 points.
  • Routine blood test hemoglobin (HGB) ⁇ 100 g/L, white blood cell count (WBC) ⁇ 3.0 ⁇ 10 9 /L, neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L, platelet count (PLT) ⁇ 75 ⁇ 10 9 /L;
  • Blood biochemistry total bilirubin (TBIL) ⁇ 1.5 ⁇ upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 3.0 ⁇ ULN, serum creatinine (Cr) ⁇ 1.5 ⁇ ULN or creatinine clearance calculated according to the Cockcroft-Gault formula ⁇ 50 mL/min.
  • ALT and AST 5.0 ⁇ ULN
  • TBIL 3.0 ⁇ ULN.
  • Subjects must agree to use at least one medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment period (female: such as intrauterine contraceptive device, birth control pills or condoms, etc.; male: such as condoms, abstinence, etc.), and female subjects must be non-breastfeeding.
  • the efficacy study of this study is an exploratory observation, with RECIST 1.1 as the evaluation standard, and tumor imaging evaluation is performed every 2 cycles ( ⁇ 7 days). After 6 months of the first medication, tumor imaging evaluation can be changed to every 4 cycles ( ⁇ 7 days) as appropriate.
  • the patient's previous tumor treatment history 1
  • Regimen/drug name oxaliplatin, capecitabine, trastuzumab, irinotecan, apatinib, SHR-1701, albumin-bound paclitaxel; 2
  • Treatment methods chemotherapy, targeted therapy, immunotherapy; 3 Best efficacy: PR.
  • Dosage cycle Administer the drug every three weeks.
  • Adverse reactions hypocalcemia, hypoalbuminemia, hyperuricemia, anemia.
  • Anemia is a CTCAE grade 2 adverse reaction, and the others are CTCAE grade 1 adverse reactions.
  • the patient's previous tumor treatment history 1 Regimen/drug name: trastuzumab, oxaliplatin, capecitabine, S-1, albumin-paclitaxel; 2 Treatment method: targeted therapy, chemotherapy; 3 Best efficacy: PR.
  • Dosage cycle Administer the drug every three weeks.
  • CTCAE grade 1 adverse reactions such as hypoalbuminemia, phlebitis, and urinary tract infection.
  • HER2 positivity is defined as: IHC 3+, or IHC 2+ and positive/HER2 gene amplification by fluorescence in situ hybridization (FISH).
  • Physical condition score ECOG is 0 to 1 points.
  • Routine blood test hemoglobin (HGB) ⁇ 100 g/L, white blood cell count (WBC) ⁇ 3.0 ⁇ 10 9 /L, neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L, platelet count (PLT) ⁇ 75 ⁇ 10 9 /L;
  • Blood biochemistry total bilirubin (TBIL) ⁇ 1.5 ⁇ upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 3.0 ⁇ ULN, serum creatinine (Cr) ⁇ 1.5 ⁇ ULN or creatinine clearance calculated according to the Cockcroft-Gault formula ⁇ 50 mL/min.
  • ALT and AST 5.0 ⁇ ULN
  • TBIL 3.0 ⁇ ULN.
  • Subjects must agree to use at least one medically approved contraceptive method during the study treatment period and within 6 months after the end of the study treatment period (female: such as intrauterine contraceptive device, birth control pills or condoms, etc.; male: such as condoms, abstinence, etc.), and female subjects must be non-breastfeeding.
  • the efficacy study of this study is an exploratory observation, with RECIST 1.1 as the evaluation standard, and tumor imaging evaluation is performed every 2 cycles ( ⁇ 7 days). After 6 months of the first medication, tumor imaging evaluation can be changed to every 4 cycles ( ⁇ 7 days) as appropriate.
  • Imaging includes computed tomography (CT) or magnetic resonance imaging (MRI) scans of the brain, neck, chest, abdomen, and pelvis, bone scans and/or bone X-rays for patients with known or suspected bone metastases.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • the same imaging techniques should be used for the same lesion types in subsequent tumor assessments as during the screening period. Antitumor activity will be assessed by radiographic imaging during the screening period and during treatment according to the trial flow chart; assessments should also be performed when disease progression is suspected (e.g., worsening of symptoms) and when subjects withdraw from treatment (if not assessed within the previous 28 days).
  • the patient's previous tumor treatment history 1 Regimen/drug name: docetaxel, trastuzumab, pertuzumab; 2 Treatment method: chemotherapy, targeted therapy; 3 Best efficacy: PR.
  • Dosage cycle Administer the drug every three weeks.
  • the patient's previous tumor treatment history 1 Regimen/drug name: Pyrotinib tablets/placebo, trastuzumab, docetaxel; 2 Treatment method: targeted therapy, chemotherapy; 3 Best efficacy: PR.
  • Dosage cycle Administer the drug every three weeks.
  • CTCAE grade 1 adverse reactions such as hypoalbuminemia, hypocalcemia, and increased alanine aminotransferase.

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Abstract

一种抗HER2抗体在制备治疗胆道系统癌症或胃癌或乳腺癌的药物中的用途。该抗HER2抗体完全去岩藻糖基化，有效地提高抗体与Fc受体CD16a的亲和力，提高抗体的ADCC活性，表现出优异的抗肿瘤活性以及良好的安全性和耐受性。

Description

一种抗HER2抗体在制备治疗癌症的药物中的用途 技术领域
本发明属于生物医药领域，具体涉及一种抗HER2抗体在制备治疗胆道系统癌症或胃癌或乳腺癌的药物中的用途。
背景技术
HER2是人类表皮生长因子受体2的简称，是一种原癌基因，位于17号染色体长臂的21区；编码分子量185KD的跨膜蛋白，因此又被称为p185HER2，具有跨膜酪氨酸激酶活性的生长因子受体。HER家族有4个成员(HER1，HER2，HER3，HER4)，均为跨膜酪氨酸激酶受体，具有刺激生长的活性。HER2没有天然配体，但可通过过表达同源二聚体或者通过与可被配体结合而活化的其他HER家族的成员的异源二聚体而激活，进而激活受体酪氨酸激酶，通过分裂原活化蛋白激酶、磷脂酰肌醇-3-激酶-蛋白激酶B/Akt、磷脂酶C-蛋白激酶C及转录信号转导和活化蛋白等多条信号通路触发下游信号的级联反应。HER2在极少数组织内低水平表达，而在30％以上的人类肿瘤中过表达。HER2基因的过表达不仅与肿瘤的发生发展相关，还是一个重要的临床治疗检测与预后指标，并且是肿瘤靶向治疗药物选择的一个重要靶点。
目前用于HER2阳性乳腺癌治疗效果最好的靶向药物为罗氏公司的抗HER2单克隆抗体(曲妥珠单抗，商品名赫赛汀)，该药物已经成为国际和国内治疗乳腺癌的一线药物。目前公布的HER2阳性乳腺癌曲妥珠单抗治疗研究表明，经过平均4年的治疗观察，近90％的接受治疗的女性患者仍然生存，而且显示了良好心脏安全性和耐受性。
IgG Fc受体最重要的基因多态性为CD16a，根据其158位上氨基酸是苯丙氨酸(Phe，F)或颉氨酸(Val，V)，可以分为158V/V、158V/F、158F/F三种基因型。患者对于曲妥珠单抗的临床反应与患者CD16a的多态性密切相关。三种基因型患者对曲妥珠单抗的ORR比例分别为CD16a 158V/V(82％)、158V/F(42％)、158F/F(35％)，具有显著差异。曲妥珠单抗治疗中，CD16a 158V/V、158V/F与158F/F基因型患者的无进展生存期分别为15.0个月、11.1个月、12.9 个月。Fc受体的基因多态性，其PBMC介导的ADCC活性，以及患者对于曲妥珠单抗的临床反应具有一致性。曲妥珠单抗不能在CD16a 158F/F类型患者体内有效地介导ADCC活性，也成为曲妥珠单抗对某些患者无效的耐药的一个原因。
本发明的抗体经过基因工程改造，敲除FUT8基因，完全消除抗体Fc端的岩藻糖，从而提高单抗药物的ADCC作用。此外，本发明的抗HER2抗体完全去岩藻糖基化，有效地提高抗体与Fc受体CD16a的亲和力，提高抗体的ADCC活性，其ADCC活性为曲妥珠单抗的20倍，在胆道系统癌症、胃癌、乳腺癌的治疗中效果优异，表现出优异的抗肿瘤活性以及良好的安全性和耐受性。
发明内容
本发明提供了一种抗HER2抗体在制备治疗胆道系统癌症或胃癌或乳腺癌的药物中的用途。
本发明还提供了一种抗HER2抗体在治疗胆道系统癌症或胃癌或乳腺癌中的应用。
在一些实施方案中，所述胆道系统癌症是胆管癌或胆囊癌。
在一些实施方案中，所述胆管癌是肝内胆管癌、肝外胆管癌、肝门部胆管癌、肝门周胆管癌或远端胆管癌。
在一些实施方案中，所述胆管癌是原发性胆管癌、复发性胆管癌或转移性胆管癌。
在一些实施方案中，所述胆囊癌是乳头状癌、粘液癌、鳞状细胞癌、腺鳞癌或未分化癌。
在一些实施方案中，所述胆囊癌是原发性胆囊癌、复发性胆囊癌或转移性胆囊癌。
在一些实施方案中，所述胃癌是胃底贲门癌、胃体癌或胃窦癌。
在一些实施方案中，所述胃癌是原发性胃癌、复发性胃癌或转移性胃癌。
在一些实施方案中，所述乳腺癌是浸润性乳腺癌、早期浸润性乳腺癌或浸润性非特殊型乳腺癌。
在一些实施方案中，所述乳腺癌是晚期乳腺癌。
在一些实施方案中，所述抗HER2抗体是去岩藻糖基化的抗HER2抗体。
在一些实施方案中，所述抗HER2抗体的轻链可变区包含分别如SEQ ID NO： 1、SEQ ID NO：2和SEQ ID NO：3所示的LCDR1、LCDR2和LCDR3；重链可变区包含分别如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的HCDR1、HCDR2和HCDR3。
在一些实施方案中，所述抗HER2抗体为人源化抗体。
在一些实施方案中，所述人源化抗体的轻链可变区序列为如SEQ ID NO：7所示的序列，重链可变区序列为如SEQ ID NO：8所示的序列。
在一些实施方案中，所述抗HER2抗体在制备治疗胆道系统癌症的药物的用途或在治疗胆道系统癌症中的应用，其中所述抗HER2抗体剂量为10-20mg/kg，优选地，所述抗HER2抗体剂量为15mg/kg。
在一些实施方案中，所述抗HER2抗体在制备治疗胃癌的药物的用途或在治疗胃癌中的应用，其中所述抗HER2抗体剂量为5-25mg/kg，优选地，所述抗HER2抗体剂量为10mg/kg或20mg/kg。
在一些实施方案中，所述抗HER2抗体在制备治疗乳腺癌的药物的用途或在治疗乳腺癌中的应用，其中所述抗HER2抗体剂量为5-25mg/kg，优选地，所述抗HER2抗体剂量为10mg/kg或20mg/kg。
术语的详细说明
为了更容易理解本发明，以下具体定义了某些技术和科学术语。除非在本文中另有明确定义，本文使用的所有其它技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
术语“抗体”是指天然的免疫球蛋白或者通过部分或完全合成而制备的免疫球蛋白。抗体可从天然存在该抗体的血浆或血清等的天然资源、或者产生抗体的杂交瘤细胞的培养上清中、动物免疫血清中、噬菌体文库筛选进行重建得到分离。备选地，可通过使用基因重组等的技术部分或完全地合成。术语“抗体”包含包括通过双硫键相互连接的四条多肽链，二条重(H)链和二条轻(L)链的免疫球蛋白分子以及其多聚体(例如IgM)。每个L链通过一个共价二硫键连接于H链，而两个H链视H链同种型而定通过一个或多个二硫键彼此连接。每个重链在N末端具有可变区(在本文中缩写为VH)，继之以恒定区。各重链包含重链可变区(文中缩写为HCVR或VH)和重链恒定区。这一重链恒定区包含三个区(结构域)，CH1、CH2和CH3。各轻链包含轻链可变区(文中缩写为LCVR或 VL)和轻链恒定区。轻链恒定区包含一个区(结构域，CL1)。VH和VL区可进一步细分为高变区，称为互补决定区(CDR)，其间散布着较保守性区域，称为框架区(framework region，FR，也称骨架区、构架区)。各VH和VL是由三个CDR和四个FR所组成，以下列顺序由氨基端排列到羧基端：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。抗体可以是不同亚类(subclass)的抗体。术语“抗体”包括但不限于单克隆抗体、全人抗体、人源化抗体、骆驼抗体、嵌合抗体、双特异性或多特异性抗体、抗独特型(抗Id)抗体(包括，例如，针对本披露的抗体的抗Id抗体)或融合蛋白等。这些抗体可以属于任何同种型/类型(例如，IgG、IgE、IgM、IgD、IgA和IgY)或亚类(例如，IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。
术语“人源化抗体”是指含有源于人抗体序列的氨基酸残基的嵌合抗体。人源化抗体可含有来自非人动物或合成抗体的CDR或HVR中的一些或全部，而抗体的框架区和恒定区含有源于人抗体序列的氨基酸残基。可以克服嵌合抗体由于携带大量异源蛋白成分，从而诱导的异源性反应。此类构架序列可以从包括种系抗体基因序列的公共DNA数据库或公开的参考文献获得。为避免免疫原性下降的同时，引起的活性下降，可对所述的人抗体可变区框架序列进行最少的反向突变或回复突变，以保持活性。
术语抗体的“可变区”是指单独的或组合的抗体轻链的可变区(VL)或抗体重链的可变区(VH)。如在本领域中已知的，重链和轻链的可变区各自由通过3个互补决定区(CDR)(也称为高变区)连接的4个框架区(FR)组成。每一条链中的CDR通过FR紧密地保持在一起并且与来自另一条链的CDR一起促成抗体的抗原结合部位的形成。
术语“可变”是指以下事实：可变域的某些区段在抗体之间在序列上广泛不同。V结构域介导抗原结合并限定特定抗体对于其特定抗原的特异性。然而，可变性在整个可变域范围上并非均匀分布的。相反，它集中于轻链与重链可变域内三个称为高变区(HVR)的区段中。可变域的更高度保守部分被称作框架区(FR)。天然重链与轻链的可变域各自包含四个FR区，大部分采用β-折叠构型，由三个HVR连接，其形成环连接，并且在一些情况下形成β-折叠结构的一部分。每条链中的HVR通过FR区紧密保持在一起，并且与其它链的HVR一起促成抗体的 抗原结合位点的形成。恒定域不直接牵涉于抗体与抗原的结合中，但展现出各种效应功能，例如参与抗体的抗体依赖性细胞毒性。
本领域中有多种方法/系统来定义和描述CDR，这些系统和/或定义已经开发和精制多年，包括Kabat、Chothia、IMGT、AbM和Contact。Kabat是最常用的，基于序列变异性定义CDR；Chothia基于结构循环区域的位置基于序列变异性定义CDR；IMGT系统基于可变域结构内的序列变异性和位置定义CDR；AbM是基于牛津分子公司的AbM抗体建模软件进行定义，是Kabat和Chothia之间的折衷；Contact基于对复杂晶体结构的分析定义CDR，在多个方面与Chothia类似。本发明中列举的CDR使用Kabat编号系统标注。
术语“去岩藻糖基化”是指从糖蛋白去除岩藻糖的过程。
术语“化疗”通常是指通过各种方法向癌症患者施用一种或多种化疗药物和/或其它试剂，所述方法包括静脉内、口服、肌内、腹膜内、膀胱内、皮下、经皮、口腔或吸入或以栓剂的形式。
术语“治疗”是指获得有益或所需的结果(包括但不限于治疗益处和/或预防益处)的方法。治疗益处通常是指根除或减轻所治疗的潜在病症的严重性。此外，通过根除、减轻严重性或减少与潜在病症相关的一种或多种生理症状的发生率，以使得在受试者中观察到改善(尽管受试者仍然可能受到潜在病症折磨)来实现治疗益处。对于预防益处，可向处于发展特定疾病的风险中的受试者，或报告疾病的一种或多种生理症状的受试者施用组合物，即使可能尚未进行该疾病的诊断。
术语“施用”是指通过本文描述的方法将治疗或药物组合物递送或导致递送至受试者身体的行为或本领域中已知的。施用治疗或药物组合物包括开具将被递送到患者体内的治疗或药物组合物的处方。示例性的给药形式包括口服剂型，例如片剂、胶囊剂、糖浆剂、混悬剂；可注射剂型，例如静脉内(IV)、肌内(IM)或腹膜内(IP)；透皮剂型，包括霜剂、果冻剂、粉剂或贴剂；口腔剂型；吸入粉剂、喷雾剂、混悬剂和直肠栓剂。
术语“受试者”通常是指人或非人动物，包括但不限于猫、狗、马、猪、牛、绵羊、山羊、兔、小鼠、大鼠或猴。本发明中受试者是指人。
术语“剂量”是指一个疗程内向受试者施用的抗体的总量。剂量可以是以重量为基础计算的剂量，例如以受试者体重为基础计算的向受试者施用的量，以 mg/kg表示。
具体实施方式
实施例一受试药物的制备
抗HER2抗体的重链如SEQ ID NO：9所示，轻链如SEQ ID NO：10所示。根据专利CN114457110A公开的敲除FUT8基因的方法，利用CRISPR/Cas9技术，针对CHO细胞FUT8基因的exon1和exon7区域各设计一对sgRNA，构建FUT8敲除载体质粒1和质粒2；将质粒1和质粒2转染进CHO细胞，敲除CHO细胞中的FUT8基因，得到FUT8基因沉默的稳定工程化细胞，进而得到本发明的完全去岩藻糖基化的抗HER2抗体。
针对临床目的生产的每批抗体均满足病毒安全性要求以及中国药典对无菌性的要求。每批均满足对于特性、纯度、有效性的规定。
将本发明的去岩藻糖基化的抗HER2抗体制成制剂，该制剂中包含：20mg/mL的去岩藻糖基化的抗HER2抗体，0.5mg/mL的一水合盐酸组氨酸(pH6.0)，0.3mg/mL的组氨酸，0.1mg/mL的聚山梨酯20以及19mg/mL的二水合海藻糖(α，α)。每个硼硅西林瓶(10mL)中含有100mg的本发明的去岩藻糖基化的抗HER2抗体，浓度为20mg/mL。
实施例二抗HER2抗体在胆道系统癌症患者中的I期临床研究
1.入组标准
受试者必须符合以下标准才能参加本研究：
1)年龄为18～75周岁(包含上下限)，国人男女均可。
2)I期研究：经病理组织学和/或细胞学确诊的经标准治疗失败的HER2阳性晚期实体瘤受试者。标准治疗失败是指：治疗过程中或末次治疗后出现疾病进展、治疗过程中因毒副作用而不能耐受(既往接受标准治疗后出现≥4级的血液学毒性或≥3级的非血液学毒性)、新辅助/辅助治疗期间或治疗结束后6个月内出现疾病进展或复发。HER2阳性定义为：IHC 3+，或IHC 2+且经荧光原位杂交法(Fluorescence in situ hybridization，FISH)检测呈阳性/HER2基因扩增。
3)根据RECIST 1.1标准，至少有一个可测量病灶，可测量病灶未接受过局 部治疗(包括局部放疗、消融及介入治疗等)。
4)体力状况评分ECOG为0～1分。
5)具有良好的器官功能(正常值上限以各研究中心正常值范围为准)，若检查前接受了升白药、促血小板生成素、集落刺激因子，应至少清洗1周。实验室检查应满足：①血常规：血红蛋白(HGB)≥100g/L、白细胞计数(WBC)≥3.0×109/L、中性粒细胞计数(ANC)≥1.5×109/L、血小板计数(PLT)≥75×109/L；②血生化：总胆红素(TBIL)≤1.5×正常值上限(ULN)、谷丙转氨酶(ALT)和谷草转氨酶(AST)≤3.0×ULN、血清肌酐(Cr)≤1.5×ULN或根据Cockcroft-Gault公式法计算肌酐清除率≥50mL/min。对于肝癌或肝转移受试者，ALT和AST≤5.0×ULN，TBIL≤3.0×ULN。
6)左心室射血分数(LVEF)≥50％。
7)预计生存期≥3个月。
8)受试者需同意在研究治疗期间和研究治疗期结束后6个月内至少采用一种经医学认可的避孕措施(女性：如宫内节育器，避孕药或避孕套等；男性：如避孕套、禁欲等)，女性受试者需为非哺乳期。
9)对研究内容、过程及可能出现的风险和受益充分知情并签署知情同意书。依从性良好，能够配合完成研究与随访。
2.疗效评价标准
本研究的有效性研究为探索性观察，以RECIST 1.1为评价标准，每2个周期(±7天)进行一次肿瘤影像学评价。在第一次用药6个月后，酌情改为每4个周期(±7天)进行一次肿瘤影像学评价。
对肿瘤缓解的评估将包括所有已知或可疑的发病部位。成像包括脑部、颈部、胸部、腹部和盆腔的计算机断层扫描(CT)或磁共振成像(MRI)扫描，骨扫描和/或骨X射线用于患者已知或可疑的骨转移。
在后续肿瘤评估中对相同类型的病灶应采用与在筛选期相同的成像技术。抗肿瘤活性的评估将根据试验流程图通过放射影像学在筛选期和治疗过程中进行；当怀疑疾病发生进展(例如，症状恶化)和受试者退出治疗时(如果没有在之前的28天内做过评估)，也应进行评估。
3.治疗概况
共入组2例受试者，观察到的安全性事件符合胆道系统癌症患者人群特征，未观察新的安全性信号。其中1例患者进行过至少一次治疗后肿瘤评估，1例患者病情部分缓解(PR)，疾病控制率(DCR)为100％，客观缓解率(ORR)为100％。临床试验结果表明，去岩藻糖基化的抗HER2抗体显示出良好的抑瘤效果。
4.典型病例
该病例既往肿瘤治疗史：①方案/药物名称：白蛋白结合型紫杉醇、卡培他滨；②治疗方式：化疗；③最佳疗效：PR(部分缓解)。
剂量：15mg/kg。
给药周期：每三周为一个周期，进行给药。
疗效：第2周期进行评效，为SD；第4周期和第6周期进行评效，均为PR，确证PR；第8周期评效为PD(疾病进展)，即DOR(缓解持续时间)4个周期，12周。
不良反应：贫血、高尿酸血症、腹泻、便秘、丙氨酸氨基转移酶升高等CTCAE1级不良反应。
结果显示，本发明的去岩藻糖基化的抗HER2抗体表现出优异的抗肿瘤活性以及良好的安全性和耐受性。
实施例三抗HER2抗体在胃癌患者中的I期临床研究
1.入组标准
受试者必须符合以下标准才能参加本研究：
1)年龄为18～75周岁(包含上下限)，国人男女均可。
2)I期研究：经病理组织学和/或细胞学确诊的经标准治疗失败的HER2阳性晚期实体瘤受试者。标准治疗失败是指：治疗过程中或末次治疗后出现疾病进展、治疗过程中因毒副作用而不能耐受(既往接受标准治疗后出现≥4级的血液学毒性或≥3级的非血液学毒性)、新辅助/辅助治疗期间或治疗结束后6个月内出现疾病进展或复发。HER2阳性定义为：IHC 3+，或IHC 2+且经荧光原位杂交法(Fluorescence in situ hybridization，FISH)检测呈阳性/HER2基因扩增。
3)根据RECIST 1.1标准，至少有一个可测量病灶，可测量病灶未接受过局 部治疗(包括局部放疗、消融及介入治疗等)。
4)体力状况评分ECOG为0～1分。
5)具有良好的器官功能(正常值上限以各研究中心正常值范围为准)，若检查前接受了升白药、促血小板生成素、集落刺激因子，应至少清洗1周。实验室检查应满足：①血常规：血红蛋白(HGB)≥100g/L、白细胞计数(WBC)≥3.0×109/L、中性粒细胞计数(ANC)≥1.5×109/L、血小板计数(PLT)≥75×109/L；②血生化：总胆红素(TBIL)≤1.5×正常值上限(ULN)、谷丙转氨酶(ALT)和谷草转氨酶(AST)≤3.0×ULN、血清肌酐(Cr)≤1.5×ULN或根据Cockcroft-Gault公式法计算肌酐清除率≥50mL/min。对于肝癌或肝转移受试者，ALT和AST≤5.0×ULN，TBIL≤3.0×ULN。
6)左心室射血分数(LVEF)≥50％。
7)预计生存期≥3个月。
8)受试者需同意在研究治疗期间和研究治疗期结束后6个月内至少采用一种经医学认可的避孕措施(女性：如宫内节育器，避孕药或避孕套等；男性：如避孕套、禁欲等)，女性受试者需为非哺乳期。
9)对研究内容、过程及可能出现的风险和受益充分知情并签署知情同意书。依从性良好，能够配合完成研究与随访。
2.疗效评价标准
本研究的有效性研究为探索性观察，以RECIST 1.1为评价标准，每2个周期(±7天)进行一次肿瘤影像学评价。在第一次用药6个月后，酌情改为每4个周期(±7天)进行一次肿瘤影像学评价。
对肿瘤缓解的评估将包括所有已知或可疑的发病部位。成像包括脑部、颈部、胸部、腹部和盆腔的计算机断层扫描(CT)或磁共振成像(MRI)扫描，骨扫描和/或骨X射线用于患者已知或可疑的骨转移。
在后续肿瘤评估中对相同类型的病灶应采用与在筛选期相同的成像技术。抗肿瘤活性的评估将根据试验流程图通过放射影像学在筛选期和治疗过程中进行；当怀疑疾病发生进展(例如，症状恶化)和受试者退出治疗时(如果没有在之前的28天内做过评估)，也应进行评估。
3.治疗概况
共入组2例受试者，观察到的安全性事件符合胃癌患者人群特征，未观察新的安全性信号。其中2例患者进行过至少一次治疗后肿瘤评估，2例患者病情稳定(SD)，疾病控制率(DCR)为100％。临床试验结果表明，去岩藻糖基化的抗HER2抗体显示出良好的抑瘤效果。
4.典型病例
病例1
该病例既往肿瘤治疗史：①方案/药物名称：奥沙利铂、卡培他滨、曲妥珠单抗、伊立替康、阿帕替尼、SHR-1701、白蛋白结合紫杉醇；②治疗方式：化疗、靶向治疗、免疫治疗；③最佳疗效：PR。
剂量：10mg/kg。
给药周期：每三周为一个周期，进行给药。
疗效：第2、4、6、8周期进行评效，均为SD(疾病稳定)。
不良反应：低钙血症、低白蛋白血症、高尿酸血症、贫血，其中，贫血为CTCAE2级不良反应，其它均为CTCAE 1级不良反应。
病例2
该病例既往肿瘤治疗史：①方案/药物名称：曲妥珠单抗、奥沙利铂、卡培他滨、替吉奥、白蛋白紫杉醇；②治疗方式：靶向治疗、化疗；③最佳疗效：PR。
剂量：20mg/kg。
给药周期：每三周为一个周期，进行给药。
疗效：第2、4周期进行评效，均为SD。
不良反应：低白蛋白血症、静脉炎、尿路感染等CTCAE 1级不良反应。
结果显示，本发明的去岩藻糖基化的抗HER2抗体表现出优异的抗肿瘤活性以及良好的安全性和耐受性。
实施例四抗HER2抗体在乳腺癌患者中的I期临床研究
1.入组标准
受试者必须符合以下标准才能参加本研究：
1)年龄为18～75周岁(包含上下限)，国人男女均可。
2)I期研究：经病理组织学和/或细胞学确诊的经标准治疗失败的HER2阳 性晚期实体瘤受试者。标准治疗失败是指：治疗过程中或末次治疗后出现疾病进展、治疗过程中因毒副作用而不能耐受(既往接受标准治疗后出现≥4级的血液学毒性或≥3级的非血液学毒性)、新辅助/辅助治疗期间或治疗结束后6个月内出现疾病进展或复发。HER2阳性定义为：IHC 3+，或IHC 2+且经荧光原位杂交法(Fluorescence in situ hybridization，FISH)检测呈阳性/HER2基因扩增。
3)根据RECIST 1.1标准，至少有一个可测量病灶，可测量病灶未接受过局部治疗(包括局部放疗、消融及介入治疗等)。
4)体力状况评分ECOG为0～1分。
5)具有良好的器官功能(正常值上限以各研究中心正常值范围为准)，若检查前接受了升白药、促血小板生成素、集落刺激因子，应至少清洗1周。实验室检查应满足：①血常规：血红蛋白(HGB)≥100g/L、白细胞计数(WBC)≥3.0×109/L、中性粒细胞计数(ANC)≥1.5×109/L、血小板计数(PLT)≥75×109/L；②血生化：总胆红素(TBIL)≤1.5×正常值上限(ULN)、谷丙转氨酶(ALT)和谷草转氨酶(AST)≤3.0×ULN、血清肌酐(Cr)≤1.5×ULN或根据Cockcroft-Gault公式法计算肌酐清除率≥50mL/min。对于肝癌或肝转移受试者，ALT和AST≤5.0×ULN，TBIL≤3.0×ULN。
6)左心室射血分数(LVEF)≥50％。
7)预计生存期≥3个月。
8)受试者需同意在研究治疗期间和研究治疗期结束后6个月内至少采用一种经医学认可的避孕措施(女性：如宫内节育器，避孕药或避孕套等；男性：如避孕套、禁欲等)，女性受试者需为非哺乳期。
9)对研究内容、过程及可能出现的风险和受益充分知情并签署知情同意书。依从性良好，能够配合完成研究与随访。
2.疗效评价标准
本研究的有效性研究为探索性观察，以RECIST 1.1为评价标准，每2个周期(±7天)进行一次肿瘤影像学评价。在第一次用药6个月后，酌情改为每4个周期(±7天)进行一次肿瘤影像学评价。
对肿瘤缓解的评估将包括所有已知或可疑的发病部位。成像包括脑部、颈部、胸部、腹部和盆腔的计算机断层扫描(CT)或磁共振成像(MRI)扫描，骨扫描 和/或骨X射线用于患者已知或可疑的骨转移。
在后续肿瘤评估中对相同类型的病灶应采用与在筛选期相同的成像技术。抗肿瘤活性的评估将根据试验流程图通过放射影像学在筛选期和治疗过程中进行；当怀疑疾病发生进展(例如，症状恶化)和受试者退出治疗时(如果没有在之前的28天内做过评估)，也应进行评估。
3.治疗概况
共入组8例受试者，观察到的安全性事件符合乳腺癌患者人群特征，未观察新的安全性信号。其中7例患者进行过至少一次治疗后肿瘤评估，2例患者病情稳定(SD)，疾病控制率(DCR)为28.6％。临床试验结果表明，去岩藻糖基化的抗HER2抗体显示出良好的抑瘤效果。
4.典型病例
病例1
该病例既往肿瘤治疗史：①方案/药物名称：多西他赛、曲妥珠单抗、帕妥珠单抗；②治疗方式：化疗、靶向治疗；③最佳疗效：PR。
剂量：10mg/kg。
给药周期：每三周为一个周期，进行给药。
疗效：第2、4、6、8、10、12、14、16周期进行评效，均为SD(疾病稳定)。
不良反应：低白蛋白血症、高血糖症、白细胞减少、中性粒细胞减少等CTCAE1级不良反应。
病例2
该病例既往肿瘤治疗史：①方案/药物名称：吡咯替尼片/安慰剂、曲妥珠单抗、多西他赛；②治疗方式：靶向治疗、化疗；③最佳疗效：PR。
剂量：20mg/kg。
给药周期：每三周为一个周期，进行给药。
疗效：第2周期进行评效，为SD。
不良反应：低白蛋白血症、低钙血症、丙氨酸氨基转移酶升高等CTCAE 1级不良反应。
结果显示，本发明的去岩藻糖基化的抗HER2抗体表现出优异的抗肿瘤活性以及良好的安全性和耐受性。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求为保护范围。

Claims (17)

  1. 一种抗HER2抗体在制备治疗胆道系统癌症或胃癌或乳腺癌的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述胆道系统癌症是胆管癌或胆囊癌。
  3. 根据权利要求2所述的用途，其特征在于，所述胆管癌是肝内胆管癌、肝外胆管癌、肝门部胆管癌、肝门周胆管癌或远端胆管癌。
  4. 根据权利要求2或3所述的用途，其特征在于，所述胆管癌是原发性胆管癌、复发性胆管癌或转移性胆管癌。
  5. 根据权利要求2所述的用途，其特征在于，所述胆囊癌是乳头状癌、粘液癌、鳞状细胞癌、腺鳞癌或未分化癌。
  6. 根据权利要求2或5所述的用途，其特征在于，所述胆囊癌是原发性胆囊癌、复发性胆囊癌或转移性胆囊癌。
  7. 根据权利要求1所述的用途，其特征在于，所述胃癌是胃底贲门癌、胃体癌或胃窦癌。
  8. 根据权利要求1或7所述的用途，其特征在于，所述胃癌是原发性胃癌、复发性胃癌或转移性胃癌。
  9. 根据权利要求1所述的用途，其特征在于，所述乳腺癌是浸润性乳腺癌、早期浸润性乳腺癌或浸润性非特殊型乳腺癌。
  10. 根据权利要求9所述的用途，其特征在于，所述乳腺癌是晚期乳腺癌。
  11. 根据权利要求1-10任一项所述的用途，其特征在于，所述抗HER2抗体是去岩藻糖基化的抗HER2抗体。
  12. 根据权利要求11所述的用途，其特征在于，所述抗HER2抗体的轻链可变区包含分别如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的LCDR1、LCDR2和LCDR3；重链可变区包含分别如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的HCDR1、HCDR2和HCDR3。
  13. 根据权利要求12所述的用途，其特征在于，所述抗HER2抗体为人源化抗体。
  14. 根据权利要求13所述的用途，其特征在于，所述人源化抗体的轻链可变区序列为如SEQ ID NO：7所示的序列，重链可变区序列为如SEQ ID NO：8所示的序列。
  15. 根据权利要求2-6任一项所述的用途，其特征在于，所述抗HER2抗体剂量为10-20mg/kg，优选地，所述抗HER2抗体剂量为15mg/kg。
  16. 根据权利要求7或8所述的用途，其特征在于，所述抗HER2抗体剂量为5-25mg/kg，优选地，所述抗HER2抗体剂量为10mg/kg或20mg/kg。
  17. 根据权利要求9或10所述的用途，其特征在于，所述抗HER2抗体剂量为5-25mg/kg，优选地，所述抗HER2抗体剂量为10mg/kg或20mg/kg。
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