JP6476182B2 - 改変された高親和性ヒトt細胞受容体 - Google Patents
改変された高親和性ヒトt細胞受容体 Download PDFInfo
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- JP6476182B2 JP6476182B2 JP2016533150A JP2016533150A JP6476182B2 JP 6476182 B2 JP6476182 B2 JP 6476182B2 JP 2016533150 A JP2016533150 A JP 2016533150A JP 2016533150 A JP2016533150 A JP 2016533150A JP 6476182 B2 JP6476182 B2 JP 6476182B2
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Description
本出願は、米国特許法第119条(e)の規定の下、2013年11月22日に出願された米国仮特許出願第61/907,887号の利益を主張するものであり、この仮出願はその全体が参照により本明細書に援用される。
連邦政府資金による研究開発の記載
本出願に関連付けられる配列リストは、紙コピーの代わりにテキストフォーマットで提供され、これによって参照により本明細書に援用される。配列リストが含まれるテキストファイルの名称は、IMMU_003_01WO_ST25.txtである。本テキストファイルは、12KBであり、2014年11月21日に作成され、EFS−Webを介して電子的に提出されている。
スルビビンペプチド抗原は、国立癌研究所による上位75個の癌抗原の優先順位付けリストの第21位となっている(Cheever et al.(2009)Clin Cancer Res,15,5323−5337)。したがって、例えば、この癌抗原を特異的に標的とする治療剤などの薬剤を特定する必要が存在する。本発明は、例えば、インビボでの標的とされた送達のための可溶性形態で、または養子T細胞設定においてT細胞内へ導入される遺伝子として使用され得る、インビトロで改変された、より高い親和性のTCRを提供する。
例えば、本発明は、以下の項目を提供する。
(項目1)
野生型T細胞受容体に由来するVα及びVβを含む修飾されたT細胞受容体、またはその抗原結合断片であって、前記Vαまたは前記Vβ、またはその両方は、前記野生型T細胞受容体に関して1つ以上の相補性決定領域(CDR)内に突然変異を含み、前記修飾されたT細胞受容体は、ペプチドスルビビン及びHLA−A2分子の複合体にナノモルまたはより高い親和性(10 −6 M未満のK D 値)で結合する、前記修飾されたT細胞受容体。
(項目2)
前記修飾されたT細胞受容体は、配列番号1に記載されるVαアミノ酸配列を含む、項目1に記載の前記修飾されたT細胞受容体。
(項目3)
前記修飾されたT細胞受容体は、配列番号2に記載されるVαアミノ酸配列を含む、項目1に記載の前記修飾されたT細胞受容体。
(項目4)
前記修飾されたT細胞受容体は、配列番号3に記載されるアミノ酸配列を有する1本鎖T細胞受容体を含む、項目1に記載の前記修飾されたT細胞受容体。
(項目5)
前記修飾されたT細胞受容体は、配列番号4に記載されるアミノ酸配列を有する1本鎖T細胞受容体を含む、項目1に記載の前記修飾されたT細胞受容体。
(項目6)
配列番号1に記載されるVαアミノ酸配列に対して少なくとも80%の同一性を有するアミノ酸配列を含む修飾されたVαを含む、項目1に記載の前記修飾されたT細胞受容体。
(項目7)
配列番号2に記載されるVαアミノ酸配列に対して少なくとも80%の同一性を有するアミノ酸配列を含む修飾されたVαを含む、項目1に記載の前記修飾されたT細胞受容体。
(項目8)
前記修飾されたT細胞受容体は、CDR3α 92、CDR3α 100、CDR3α 101、CDR3α 102、及びCDR3α 103のうちの1つ以上において、アミノ酸置換を含む、項目2に記載の前記修飾されたT細胞受容体。
(項目9)
前記修飾されたT細胞受容体は、以下のアミノ酸突然変異:TCR Vα鎖突然変異N92S、N100K、A101G、R102Y、及びL103Kのうちの1つ以上を含む、項目2に記載の前記修飾されたT細胞受容体。
(項目10)
前記修飾されたT細胞受容体は、以下のアミノ酸突然変異:TCR Vα鎖突然変異N92H、N100G、A101W、R102Y、及びL103Tのうちの1つ以上を含む、項目3に記載の前記修飾されたT細胞受容体。
(項目11)
可溶性形態である、項目2に記載の前記修飾されたT細胞受容体。
(項目12)
前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、項目11に記載の前記修飾されたT細胞受容体を含む、前記治療剤。
(項目13)
前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、項目2に記載の前記修飾されたT細胞受容体を発現するヒトT細胞を含む、前記治療剤。
(項目14)
可溶性形態である、項目3に記載の前記修飾されたT細胞受容体。
(項目15)
前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、項目14に記載の前記修飾されたT細胞受容体を含む、前記治療剤。
(項目16)
前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、項目3に記載の前記修飾されたT細胞受容体を発現するヒトT細胞を含む、前記治療剤。
(項目17)
項目12、13、15、及び16のいずれか1項に記載の前記治療剤を投与することを含む、前記スルビビン抗原を発現する癌を有する対象を治療する方法。
配列番号1は、高親和性でスルビビン/HLA−A2に結合する、TCR(スルビビン−K2.4.1)の修飾されたVα領域のアミノ酸配列である。
T細胞受容体
指向性進化は、特異性pepMHCに関するより高い親和性を有するTCRを発生させるために使用されている。使用されてきた3つの異なるディスプレイ方法は、酵母ディスプレイ(Holler et al.(2003)Nat Immunol,4,55−62;Holler et al.(2000)Proc Natl Acad Sci U S A,97,5387−92)、ファージディスプレイ(Li et al.(2005)Nat Biotechnol,23,349−54)、及びT細胞ディスプレイ(Chervin et al.(2008)J Immunol Methods,339,175−84)である。3つのすべてのアプローチにおいて、プロセスは、野生型TCRの正常な低親和性を示すTCRの改変に関与し、その結果、TCRの突然変異体は、特異性pepMHCに対して(即ち、T細胞が特異的であった元の抗原に対して)改善された親和性を有した。したがって、野生型TCRは、CDRのうちの1つ以上における突然変異ライブラリを生成するためのテンプレートとして使用され、続いて、同族ペプチド−MHC抗原への結合によって、より高い親和性を有する突然変異体が選択された。かかるインビトロでの指向性進化は、野生型親和性の単に数倍のみではなくそれを超える親和性を改変するために必要であることは、当該技術分野において周知である。
本発明は、周知の癌抗原スルビビン/HLA−A2に対する高親和性TCRを提供する。特定の実施形態では、改変されたTCRは、インビボでの標的とされた送達のための可溶性形態で、または養子移入方法もしくは治療においてT細胞によって組み換え発現されて使用され得る。具体的な実施形態では、TCRの1本鎖VαVβ形態(scTCR)骨格は、エフェクター分子をTCRが結合する場所(例えば、腫瘍)へ送達するために、サイトカイン、毒素、放射性同位体、化学療法剤、または(抗体−薬物結合体に類似した)薬物などのペイロードと共に調製及び使用され得る。TCRはまた、スルビビンを発現する癌細胞に対する応答を媒介するために、CD4+T細胞、CD8+T細胞、及び/またはナチュラルキラー(NK)細胞の養子移入などの細胞療法においても使用され得る。本明細書に提供されるscTCR骨格はまた、例えば、放射性同位体または蛍光部分などの検出可能な基への共有結合によって、例えば、TCRのアミン反応性またはスルフヒドリル反応性アミノ酸側鎖を通じて、腫瘍性またはウイルス会合細胞表面抗原の特定を通じて、例えば、悪性またはウイルス感染細胞の診断のためにも使用され得る。
生物学的に活性な基を含む本明細書に説明されるVβVα TCRタンパク質も、提供される。本明細書で使用するとき、「生物学的に活性な基」は、生物学的システムにおいて測定可能または検出可能な効果を引き起こす基である。一実施形態では、生物学的に活性な基は、以下から選択される:抗腫瘍剤、例えば、限定されるものではないが、血管形成阻害剤、酵素阻害剤、微小管阻害剤、DNA挿入剤もしくは架橋剤、DNA合成阻害剤など、サイトカイン、例えば、限定されるものではないが、IL−2、IL−15、GM−CSF、IL−12、TNF−α、IFN−γ、もしくはLT−α(Schrama et al.(2006)Nat Rev Drug Discov,5,147−59、Wong et al.(2011)Protein Eng Des Sel,24,373−83)、抗炎症基、例えば、限定されるものではないが、TGF−β、IL−37、IL−10(Nold et al.(2010)Nat Immunol,11,1014−22、Stone et al.(2012)Protein Engineering)、放射性同位体、例えば、限定されるものではないが、90Yもしくは131Iなど(Reichert and Valge−Archer(2007)Nat Rev Drug Discov,6,349−56)、毒素、例えば、限定されるものではないが、緑膿菌外毒素A、ジフテリア毒素、もしくはリシンのA鎖(Pastan et al.(2006)Nat Rev Cancer,6,559−65、Schrama et al.(2006)Nat Rev Drug Discov,5,147−59)、薬物、または例えば、1本鎖Fvなどの抗体。
本開示は、1本鎖T細胞受容体(scTCR)をコードする少なくとも1つのDNAセグメントを含むDNAベクターを企図する。
特定の標的リガンドに対して特異的なTCRは、特定の抗原に関連付けられる疾患、例えば、癌などの腫瘍性疾患または障害に罹患すると考えられる、ヒトを含む動物及び哺乳類の治療に有用である。本明細書に説明される方法に従って治療され得る癌の種類の例としては、限定されるものではないが、ウィルムス腫瘍、膀胱癌、乳癌、結腸癌、結腸直腸癌、食道癌、胃癌、肝細胞癌、腎臓癌、白血病、肝臓癌、肺癌、リンパ腫、黒色腫、神経芽細胞腫、非小細胞肺癌、口腔癌、骨肉腫、卵巣癌、膵臓癌、前立腺癌、腎性癌、皮膚癌、小細胞肺癌、及び精巣癌が挙げられる。
高親和性TCR及び高親和性TCRを含む薬学的組成物は、例えば、癌、腫瘍、悪性腫瘍、または腫瘍性疾患もしくは障害を有する患者を治療するために使用されてもよい。一実施形態では、癌を有する患者を治療する方法は、本明細書に説明される高親和性TCRを投与することを含む。別の実施形態では、高親和性TCRは、スルビビンに対して特異的である。一実施形態では、TCRは、配列番号1に記載されるアミノ酸配列を含むVαを含む。別の実施形態では、TCRは、配列番号2に記載されるアミノ酸配列を含むVαを含む。一実施形態では、高親和性TCRは、配列番号3に記載されるアミノ酸配列を含む1本鎖TCRである。別の実施形態では、高親和性TCRは、配列番号4に記載されるアミノ酸配列を含む1本鎖TCRである。別の実施形態では、高親和性TCRは、例えば、化学療法剤などの治療剤と組み合わせて投与される。また別の実施形態では、高親和性TCRは、生物学的に活性な基に結合される。
ペプチド/HLA−A2抗原に対するより高い親和性のためのTCRの改変
改善された親和性及び安定性のための1本鎖TCRの発見または発生のために使用される一般的な戦略が、図1に示される。このプロセスは、例証される通り6つのステップに関与する。
Tax:HLA.A2との複合体におけるVα2を使用するヒトTCR A6の分析
TCRはすべて、類似のIg折り畳み及び結合角度を採用し、pepMHCのTCR認識は、CDRループ上の特異性残基によって完全に媒介される(Garcia et al.(2009)Nat Immunol,10,143−7、Marrack et al.(2008)Annu Rev Immunol,26,171−203、Rudolph et al.(2006)Annu Rev Immunol,24,419−66))。スルビビンTCRの結晶構造は本開示の時点で利用可能ではないが、スルビビンTCRと同じVα2ドメインを使用したA6:Taxペプチド:HLA−A2複合体(PDB:1AO7)の構造(Garboczi et al.(1996)Nature,384,134−141)が示される。複合体の側面図は、6つのCDRを含有する可変ドメインの末端が、結合部位の中心領域がペプチドTax上に位置付けられた状態でTax:HLA.A2分子上に結合することを示した(図2A)。結晶構造は定常領域αを含まないが、但し、定常領域は全長構築物を安定化させるのに役立つ。上で説明されるステップ2において選択される安定化突然変異は、フレームワーク領域内で、例えば、Vα/Vβ相間、または全長TCR内でCα/VαもしくはCβ/Vβ相間の接合が生じる場所などで選択されることが多い。
スルビビンTCRの酵母ディスプレイ
改善された安定性(ステップ2)または改善された親和性(ステップ5)に関する選択を実施するために、TCR突然変異体のライブラリが立体構造エピトープまたはペプチド:MHCリガンドをそれぞれ認識する抗体に結合するためにスクリーニングされ得るディスプレイシステムを使用することが必要である。3つのディスプレイシステムが、より高い親和性に関してTCRを改変するために使用されており、また酵母ディスプレイ、ファージディスプレイ、及びT細胞(哺乳動物細胞)ディスプレイのプロセスのために使用することができた。リボソーム、RNA、DNA、及びCISディスプレイなどの代替的なディスプレイ方法も、このプロセスに好適であり得る。これらのすべての場合において、抗原に対して低い親和性を有する野生型TCRがシステム中にクローン化され、強化された安定性及びペプチド:MHCリガンドに対する親和性を有するTCRを改変するためのテンプレートとして使用された。これらのシステムのいずれも、単一のTCRがライブラリ及び強化された結合特性を有するTCRの選択のためのテンプレートとして使用される、本明細書に説明されるアプローチに適用することができた。
安定化させたスルビビンTCR、Surv−K2の変異性のライブラリの構築及び選択
テンプレートとしてスルビビン71と呼ばれるコラボレータから得られたスルビビン反応性TCRを利用して、スルビビン変異性のライブラリをこれまでに説明されている通りに発生させた(Richman et al.(2009)Methods Mol Biol,504,323−350)。線状pCT302ベクター、スルビビン変異性PCR生成物、及び免疫適格EBY 100酵母細胞を組み合わせることによって、ヒトスルビビン変異性のライブラリを、酵母ディスプレイベクター内へ導入した。結果として得られたライブラリを、電気穿孔法後の酵母の限界希釈アリコートをプレーティングすることによって判断し、約8.25×106個の独立クローンを含有した。ライブラリを、表4に従うFACSによって、ヒトVβ20、抗hVβ20 FITC IgG(Beckman Coulter)を認識する抗体に結合するために選択した。
CDR3αライブラリ構築、ならびにスルビビン:HLA.A2、Surv−K2.4.1、及びSurv−K2.4.6強化された結合を有する2つのスルビビンTCRの選択
重複伸長によるスプライシング(SOE)によって、変異性PCRライブラリの選択から単離した安定化Surv−K2クローンを、5個の残基にまたがるCDR3αライブラリの発生のためのテンプレートとして使用した。したがって、線状pCT302ベクター、Surv−K2 CDR3βライブラリPCR生成物、及び免疫適格EBY100酵母細胞を組み合わせることによって、ヒトSurv−K2 CDR3α scTCRライブラリを酵母ディスプレイベクター内へ導入した。結果として得られたライブラリを、電気穿孔法後の酵母の限界希釈アリコートをプレーティングすることによって判断し、2.98×107個の独立クローンを含有した。Surv−K2 CDR3αライブラリを、表5に従って、磁気カラムを使用して連続して3回、FACSを使用して1回ソートした。
高親和性スルビビンTCR、Surv−K2.4.1の結合分析
CDR3αライブラリの選択から単離したSurv−K2.4.1クローンの結合を評定するために、Surv−K2.4.1をディスプレイする酵母を、6.4nM、32nM、160nM、800nM、及び4μMでSurvT2M(LMLGEFLKL、配列番号5)/HLA−A2モノマーを用いて滴定し、フローサイトメトリーによって分析した(図6A)。非線形回帰分析を使用して値を正規化し、279±44.5nMのKD,appを判定した(図6B)。
スルビビン抗原に対する改善された親和性に関する単離されたTCRの配列分析
安定化scTCRクローンK2、ならびに親和性成熟ライブラリから単離されたスルビビン特異性(K2.4.1及びK2.4.6)高親和性1本鎖変異型の配列を判定した。図7に示されるように、酵母ディスプレイライブラリに由来する2つの高親和性クローンのCDR領域において突然変異が存在した。図7の下線付きの位置は、安定化突然変異のための変異性ライブラリ選択から生じた突然変異を示す。ボックス内の位置は、CDRライブラリから選択された親和性強化突然変異体を示す。
T細胞におけるK2.4.1 TCRのインビトロ活性
T細胞におけるK2.4.1 TCRの活性を評定するために、CD8T細胞を、AAD遺伝子組み換えマウスから単離した。次いで、これらのT細胞を、抗CD3/抗CD28ビーズで24時間活性化させた。T細胞は、マウス2C TCRのCα及びCβドメインに結合したK2.4.1 TCRのVα及びβドメインを含有するpMP71ベクターで、レトロウイルスによって形質導入された(図8A)。K2.4.1 TCRの発現を確認するために、T細胞を、形質導入の48時間後に、20nMの濃度のSurvT2M:HLA−A2テトラマーで染色した(図8B)。K2.4.1形質導入されたT細胞(黒色)は、模擬形質導入されたT細胞(灰色)よりもSurvT2M:HLA−A2の増加した結合を示し、高親和性TCRの表面発現を確認した。次いで、T細胞を、滴定濃度のスルビビンペプチドで外因的に負荷したT2細胞と共に1:1 E:Tで定温放置した。K2.4.1 TCRを発現するT細胞は、SurvT2Mペプチドの存在下で、かつWT1と呼ばれる対照ペプチド(RMFPNAPYL、配列番号14)と共に提示されないときに、活性化し、このTCRが、CD8T細胞において活性かつ特異的であることを示唆する。
スルビビン、Surv−K2.4.1、及びSurv−K2.4.6、TCRの治療的フォーマット
より高い親和性のTCRは、対応する抗原を発現する細胞を標的とするために種々のフォーマットにおいて使用され得ることは、現在よく知られている。したがって、上記に示される改変戦略から発生されるTCRは、図9に例証される通り、可溶性形態で、または養子T細胞療法のためのTCR遺伝子療法においてのいずれかで使用され得ることは、明らかである。
抗体、ペプチド:HLA−A2、MACS、及びフローサイトメトリー試薬
酵母表面発現を検出するために使用される抗体としては、抗HAエピトープタグ(クローン HA.11、Covance)、抗hVβ3 FITC抗体(Clone CH92、Beckman−Coulter)、抗hVβ3.1 FITC抗体(Clone 8F10、Thermo Scientific)、抗hVβ20抗体(Clone ELL1.4、Beckman−Coulter)、我々の実験室で発生された抗Vα2モノクローナル抗体(データは示されていない)、ヤギ抗マウスIgM APC(Life Technologies)、ヤギ抗マウスIgG F(ab’)2AlexaFluor(登録商標)647二次抗体(Invitrogen)、ストレプトアビジン−フィコエリトリン(SA:PE、BD Pharmingen)、及びMACSマイクロビーズ(Miltenyl Biotec)が挙げられる。
TCR可変領域断片(scTv)を、Trp培地中の増殖を可能にするガラクトース誘導性AGA2融合体を含有する酵母ディスプレイプラスミドpCT302(Vβ−L−Vα)中で発現させた(Boder and Wittrup(2000)Methods Enzymol,328,430−444)。scTv遺伝子の誘導は、形質転換されたEBY100酵母細胞の選択媒体中での定常期への増殖、続いてガラクトース含有培地への移入に関与する。テンプレートスルビビン1本鎖TCR遺伝子を、構築物のVα2ドメイン中にF49S突然変異を有する状態でGenscript(Piscataway,NJ,USA)によって合成した(Aggen et al.(2011)Protein Eng Des Sel,24,361−372)。
変異性のPCRを使用して、これまでに説明されている通りに無作為突然変異を発生させた(Richman et al.(2009)Mol Immunol,46,902−916)。同時に4〜5個の隣接するコドンにわたる重複伸長によるスプライシング(SOE)PCRによって、CDR1及び3ライブラリを発生させた(Horton et al.(1990)Biotechniques,8,528−535)。
選択の後、限界希釈物をプレーティングすることによってライブラリクローンを単離した。コロニーを増殖させ、ガラクトース含有培地(SG−CAA)内に48時間誘導し、1mLの1%PBS/BSAで洗浄し、種々の濃度のペプチド/HLA.A2 DimerX、ヤギ抗マウスIgG F(ab’)2AlexaFluor(登録商標)647二次抗体、または種々の濃度のUV交換ペプチド/HLA.A2、SA−PEを用いて染色した。細胞を洗浄し(1ml、1%PBS/BSA)、Accuri C6フローサイトメータで分析した。
参考文献
1. Addo M.M.,Draenert R.,Rathod A.,Verrill C.L.,Davis B.T.,Gandhi R.T.,Robbins G.K.,Basgoz N.O.,Stone D.R.,Cohen D.E.,Johnston M.N.,Flynn T.,Wurcel A.G.,Rosenberg E.S.,Altfeld M.and Walker B.D.(2007)Fully Differentiated HIV−1 Specific CD8+ T Effector Cells Are More Frequently Detectable in Controlled than in Progressive HIV−1 Infection.PLoS ONE 2,e321.
2. Aggen D.H.,Chervin A.S.,Insaidoo F.K.,Piepenbrink K.,H.,Baker B.M.and Kranz D.M.(2011)Identification and engineering of human variable regions that allow expression of stable single−chain T cell receptors.Protein Engineering,Design,& Selection 24,361−72.
3. Anikeeva N.,Mareeva T.,Liu W.and Sykulev Y.(2009)Can oligomeric T−cell receptor be used as a tool to detect viral peptide epitopes on infected cells?Clin Immunol 130,98−109.
4. Armstrong K.M.,Piepenbrink K.H.and Baker B.M.(2008)Conformational changes and flexibility in T−cell receptor recognition of peptide−MHC complexes.Biochem J 415,183−96.
5. Ashfield R.and Jakobsen B.K.(2006)Making high−affinity T−cell receptors:a new class of targeted therapeutics.IDrugs 9,554−9.
6. Bargou R.,Leo E.,Zugmaier G.,Klinger M.,Goebeler M.,Knop S.,Noppeney R.,Viardot A.,Hess G.,Schuler M.,Einsele H.,Brandl C.,Wolf A.,Kirchinger P.,Klappers P.,Schmidt M.,Riethmuller G.,Reinhardt C.,Baeuerle P.A.and Kufer P.(2008)Tumor regression in cancer patients by very low doses of a T cell−engaging antibody.Science 321,974−7.
7. Benatuil L.,Perez J.M.,Belk J.and Hsieh C.M.(2010)An improved yeast transformation method for the generation of very large human antibody libraries.Protein Eng Des Sel 23,155−9.
8. Bird R.E.,Hardman K.D.,Jacobson J.W.,Johnson S.,Kaufman B.M.,Lee S.M.,Lee T.,Pope S.H.,Riordan G.S.and Whitlow M.(1988)Single−chain antigen−binding proteins.Science 242,423−426.
9. Boder E.T.and Wittrup K.D.(1997)Yeast surface display for screening combinatorial polypeptide libraries.Nat.Biotech.15,553−557.
10. Boder E.T.and Wittrup K.D.(2000)Yeast surface display for directed evolution of protein expression,affinity,and stability.Methods Enzymol 328,430−44.
11. Boon T.and Old L.J.(1997)Cancer tumor antigens.Curr Opin Immunol 9,681−3.
12. Borbulevych O.Y.,Santhanagopolan S.M.,Hossain M.and Baker B.M.(2011)TCRs used in cancer gene therapy cross−react with MART−1/Melan−A tumor antigens via distinct mechanisms.J Immunol 187,2453−63.
13. Brower V.(1997)Enbrel’s phase III reinforces prospects in RA[news].Nat Biotechnol 15,1240.
14. Bulek A.M.,Cole D.K.,Skowera A.,Dolton G.,Gras S.,Madura F.,Fuller A.,Miles J.J.,Gostick E.,Price D.A.,Drijfhout J.W.,Knight R.R.,Huang G.C.,Lissin N.,Molloy P.E.,Wooldridge L.,Jakobsen B.K.,Rossjohn J.,Peakman M.,Rizkallah P.J.and Sewell A.K.(2012)Structural basis for the killing of human beta cells by CD8(+)T cells in type 1 diabetes.Nat Immunol 13,283−9.
15. Cheever M.A.,Allison J.P.,Ferris A.S.,Finn O.J.,Hastings B.M.,Hecht T.T.,Mellman I.,Prindiville S.A.,Viner J.L.,Weiner L.M.and Matrisian L.M.(2009)The prioritization of cancer antigens:a national cancer institute pilot project for the acceleration of translational research.Clin Cancer Res 15,5323−37.
16. Chervin A.S.,Aggen D.H.,Raseman J.M.and Kranz D.M.(2008)Engineering higher affinity T cell receptors using a T cell display system.J Immunol Methods 339,175−84.
17. Chervin AS,Stone JD,Soto CM,Engels B,Schreiber H,Roy EJ,and Kranz DM.(2013)Design of T−cell receptor libraries with diverse binding properties to examine adoptive T−cell responses.Gene Ther.
18. Colby D.W.,Kellogg B.A.,Graff C.P.,Yeung Y.A.,Swers J.S.and Wittrup K.D.(2004)Engineering antibody affinity by yeast surface display.Methods Enzymol 388,348−58.
19. Davis M.M.and Bjorkman P.J.(1988)T−cell antigen receptor genes and T−cell recognition.Nature 334,395−402.
20. Davis M.M.,Boniface J.J.,Reich Z.,Lyons D.,Hampl J.,Arden B.and Chien Y.(1998)Ligand recognition by alpha beta T cell receptors.Annu Rev Immunol 16,523−544.
21. Ding Y.H.,Baker B.M.,Garboczi D.N.,Biddison W.E.and Wiley D.C.(1999)Four A6−TCR/peptide/HLA−A2 structures that generate very different T cell signals are nearly identical.Immunity 11,45−56.
22. Foote J.and Eisen H.N.(2000)Breaking the affinity ceiling for antibodies and T cell receptors.Proc Natl Acad Sci U S A 97,10679−81.
23. Garboczi D.N.,Ghosh P.,Utz U.,Fan Q.R.,Biddison W.E.and Wiley D.C.(1996)Structure of the complex between human T−cell receptor,viral peptide and HLA−A2.Nature 384,134−141.
24. Garcia K.C.,Adams J.J.,Feng D.and Ely L.K.(2009)The molecular basis of TCR germline bias for MHC is surprisingly simple.Nat Immunol 10,143−7.
25. Haidar J.N.,Pierce B.,Yu Y.,Tong W.,Li M.and Weng Z.(2009)Structure−based design of a T−cell receptor leads to nearly 100−fold improvement in binding affinity for pepMHC.Proteins 74,948−60.
26. Harkiolaki M.,Holmes S.L.,Svendsen P.,Gregersen J.W.,Jensen L.T.,McMahon R.,Friese M.A.,van Boxel G.,Etzensperger R.,Tzartos J.S.,Kranc K.,Sainsbury S.,Harlos K.,Mellins E.D.,Palace J.,Esiri M.M.,van der Merwe P.A.,Jones E.Y.and Fugger L.(2009)T cell−mediated autoimmune disease due to low−affinity crossreactivity to common microbial peptides.Immunity 30,348−57.
27. Hawse W.F.,Champion M.M.,Joyce M.V.,Hellman L.M.,Hossain M.,Ryan V.,Pierce B.G.,Weng Z.and Baker B.M.(2012)Cutting edge:evidence for a dynamically driven T cell signaling mechanism.J Immunol 188,5819−23.
28. Holler P.D.,Chlewicki L.K.and Kranz D.M.(2003)TCRs with high affinity for foreign pMHC show self−reactivity.Nat Immunol 4,55−62.
29. Holler P.D.,Holman P.O.,Shusta E.V.,O’Herrin S.,Wittrup K.D.and Kranz D.M.(2000)In vitro evolution of a T cell receptor with high affinity for peptide/MHC.Proc Natl Acad Sci U S A 97,5387−92.
30. Holliger P.,Prospero T.and Winter G.(1993)”Diabodies”:small bivalent and bispecific antibody fragments.Proc Natl Acad Sci U S A 90,6444−8.
31. Hoogenboom H.R.(2005)Selecting and screening recombinant antibody libraries.Nat Biotechnol 23,1105−16.
32. JJarvis L.M.(2012)Rethinking Antibody−Drug Conjugates.Chemical and Engineering News 90,12−18.
33. Kessels H.W.,van Den Boom M.D.,Spits H.,Hooijberg E.and Schumacher T.N.(2000)Changing T cell specificity by retroviral T cell receptor display.Proc Natl Acad Sci U S A 97,14578−83.
34. Kieke M.C.,Shusta E.V.,Boder E.T.,Teyton L.,Wittrup K.D.and Kranz D.M.(1999)Selection of functional T cell receptor mutants from a yeast surface− display library.Proc Natl Acad Sci U S A 96,5651−6.
35. Lauck F.,Smith C.A.,Friedland G.F.,Humphris E.L.and Kortemme T.(2010)RosettaBackrub−−a web server for flexible backbone protein structure modeling and design.Nucleic Acids Res 38,W569−75.
36. Li Y.,Moysey R.,Molloy P.E.,Vuidepot A.L.,Mahon T.,Baston E.,Dunn S.,Liddy N.,Jacob J.,Jakobsen B.K.and Boulter J.M.(2005)Directed evolution of human T−cell receptors with picomolar affinities by phage display.Nat Biotechnol 23,349−54.
37. Liddy N.,Bossi G.,Adams K.J.,Lissina A.,Mahon T.M.,Hassan N.J.,Gavarret J.,Bianchi F.C.,Pumphrey N.J.,Ladell K.,Gostick E.,Sewell A.K.,Lissin N.M.,Harwood N.E.,Molloy P.E.,Li Y.,Cameron B.J.,Sami M.,Baston E.E.,Todorov P.T.,Paston S.J.,Dennis R.E.,Harper J.V.,Dunn S.M.,Ashfield R.,Johnson A.,McGrath Y.,Plesa G.,June C.H.,Kalos M.,Price D.A.,Vuidepot A.,Williams D.D.,Sutton D.H.and Jakobsen B.K.(2012)Monoclonal TCR−redirected tumor cell killing.Nat Med.
38. Litvak−Greenfeld D.and Benhar I.(2012)Risks and untoward toxicities of antibody−based immunoconjugates.Adv Drug Deliv Rev.
39. Manning T.C.and Kranz D.M.(1999)Binding energetics of T−cell receptors:correlation with immunological consequences.Immunology Today 20,417−422.
40. Marrack P.,Scott−Browne J.P.,Dai S.,Gapin L.and Kappler J.W.(2008)Evolutionarily conserved amino acids that control TCR−MHC interaction.Annu Rev Immunol 26,171−203.
41. Marsh S.G.E.,Parham P.and Barber L.D.(2000)The HLA Facts Book.Academic Press,London.
42. Mason D.(1998)A very high level of crossreactivity is an essential feature of the T− cell receptor.Immunol Today 19,395−404.
43. Miller B.R.,Demarest S.J.,Lugovskoy A.,Huang F.,Wu X.,Snyder W.B.,Croner L.J.,Wang N.,Amatucci A.,Michaelson J.S.and Glaser S.M.(2010)Stability engineering of scFvs for the development of bispecific and multivalent antibodies.Protein Eng Des Sel 23,549−57.
44. Molloy P.E.,Sewell A.K.and Jakobsen B.K.(2005)Soluble T cell receptors:novel immunotherapies.Curr Opin Pharmacol 5,438−43.
45. Murphy K.(2012)Janeway’s immunobiology.Garland Science,New York.
46. Nold M.F.,Nold−Petry C.A.,Zepp J.A.,Palmer B.E.,Bufler P.and Dinarello C.A.(2010)IL−37 is a fundamental inhibitor of innate immunity.Nat Immunol 11,1014−22.
47. Pastan I.,Hassan R.,Fitzgerald D.J.and Kreitman R.J.(2006)Immunotoxin therapy of cancer.Nat Rev Cancer 6,559−65.
48. Pierce B.G.,Haidar J.N.,Yu Y.and Weng Z.(2010)Combinations of affinity−enhancing mutations in a T cell receptor reveal highly nonadditive effects within and between complementarity determining regions and chains.Biochemistry 49,7050−9.
49. Porter D.L.,Levine B.L.,Kalos M.,Bagg A.and June C.H.(2011)Chimeric antigen receptor−modified T cells in chronic lymphoid leukemia.N Engl J Med 365,725−33.
50. Reichert J.M.and Valge−Archer V.E.(2007)Development trends for monoclonal antibody cancer therapeutics.Nat Rev Drug Discov 6,349−56.
51. Ricart A.D.and Tolcher A.W.(2007)Technology insight:cytotoxic drug immunoconjugates for cancer therapy.Nat Clin Pract Oncol 4,245−55.
52. Richman S.A.,Aggen D.H.,Dossett M.L.,Donermeyer D.L.,Allen P.M.,Greenberg P.D.and Kranz D.M.(2009)Structural features of T cell receptor variable regions that enhance domain stability and enable expression as single−chain ValphaVbeta fragments.Mol Immunol 46,902−16.
53. Richman S.A.and Kranz D.M.(2007)Display,engineering,and applications of antigen−specific T cell receptors.Biomol Eng 24,361−73.
54. Rock K.L.and Goldberg A.L.(1999)Degradation of cell proteins and the generation of MHC class I− presented peptides.Annu Rev Immunol 17,739−79.
55. Rudolph M.G.,Stanfield R.L.and Wilson I.A.(2006)How TCRs bind MHCs,peptides,and coreceptors.Annu Rev Immunol 24,419−66.
56. Sadelain M.,Brentjens R.and Riviere I.(2009)The promise and potential pitfalls of chimeric antigen receptors.Curr Opin Immunol 21,215−23.
57. Sami M.,Rizkallah P.J.,Dunn S.,Molloy P.,Moysey R.,Vuidepot A.,Baston E.,Todorov P.,Li Y.,Gao F.,Boulter J.M.and Jakobsen B.K.(2007)Crystal structures of high affinity human T−cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry.Protein Eng Des Sel 20,397−403.
58. Schrama D.,Reisfeld R.A.and Becker J.C.(2006)Antibody targeted drugs as cancer therapeutics.Nat Rev Drug Discov 5,147−59.
59. Scott J.K.and Smith G.P.(1990)Searching for peptide ligands with an epitope library.Science 249,386−90.
60. Skowera A.,Ellis R.J.,Varela−Calvino R.,Arif S.,Huang G.C.,Van−Krinks C.,Zaremba A.,Rackham C.,Allen J.S.,Tree T.I.,Zhao M.,Dayan C.M.,Sewell A.K.,Unger W.W.,Drijfhout J.W.,Ossendorp F.,Roep B.O.and Peakman M.(2008)CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose−regulated preproinsulin epitope.J Clin Invest 118,3390−402.
61. Smith C.A.and Kortemme T.(2008)Backrub−like backbone simulation recapitulates natural protein conformational variability and improves mutant side−chain prediction.J Mol Biol 380,742−56.
62. Soo Hoo W.F.,Lacy M.J.,Denzin L.K.,Voss E.W.J.,Hardman K.D.and Kranz D.M.(1992)Characterization of a single−chain T cell receptor expressed in E.Coli.Proc.Natl.Acad.Sci.89,4759−4763.
63. Starr T.K.,Jameson S.C.and Hogquist K.A.(2003)Positive and negative selection of T cells.Annu Rev Immunol 21,139−76.
64. Starwalt S.E.,Masteller E.L.,Bluestone J.A.and Kranz D.M.(2003)Directed evolution of a single−chain class II MHC product by yeast display.Protein Eng 16,147−56.
65. Stone J.D.,Chervin A.S.,Aggen D.H.and Kranz D.M.(2012)T cell receptor engineering.Methods Enzymol 503,189−222.
66. Stone J.D.,Yin Y.,Mo M.,Weber K.S.,Donermeyer D.L.,Allen P.M.,Mariuzza R.A.and Kranz D.M.(2012)Engineering High−Affinity T Cell Receptor/ Cytokine Fusions for Therapeutic Targeting.In Protein Engineering(Edited by Kaumaya P.).InTech.
67. Stroncek D.F.,Berger C.,Cheever M.A.,Childs R.W.,Dudley M.E.,Flynn P.,Gattinoni L.,Heath J.R.,Kalos M.,Marincola F.M.,Miller J.S.,Mostoslavsky G.,Powell D.J.,Jr.,Rao M.,Restifo N.P.,Rosenberg S.A.,O’Shea J.and Melief C.J.(2012)New directions in cellular therapy of cancer:a summary of the summit on cellular therapy for cancer.J Transl Med 10,48.
68. Swers J.S.,Kellogg B.A.and Wittrup K.D.(2004)Shuffled antibody libraries created by in vivo homologous recombination and yeast surface display.Nucleic Acids Res 32,e36.
69. Tayal V.and Kalra B.S.(2008)Cytokines and anti−cytokines as therapeutics−−an update.Eur J Pharmacol 579,1−12.
70. Thakur A.and Lum L.G.(2010)Cancer therapy with bispecific antibodies:Clinical experience.Curr Opin Mol Ther 12,340−9.
71. Tonegawa S.(1988)Nobel lecture in physiology or medicine−−1987.Somatic generation of immune diversity.In Vitro Cell Dev Biol 24,253−65.
72. Tsomides T.J.,Aldovini A.,Johnson R.P.,Walker B.D.,Young R.A.and Eisen H.N.(1994)Naturally processed viral peptides recognized by cytotoxic T lymphocytes on cells chronically infected by human immunodeficiency virus type 1.J Exp Med 180,1283−93.
73. Turner D.J.,Ritter M.A.and George A.J.(1997)Importance of the linker in expression of single−chain Fv antibody fragments:optimisation of peptide sequence using phage display technology.J Immunol Methods 205,43−54.
74. Utz U.,Banks D.,Jacobson S.and Biddison W.E.(1996)Analysis of the T−cell receptor repertoire of human T−cell leukemia virus type 1(HTLV−1)Tax−specific CD8+ cytotoxic T lymphocytes from patients with HTLV−1−associated disease:evidence for oligoclonal expansion.J Virol 70,843−51.
75. Varela−Rohena A.,Molloy P.E.,Dunn S.M.,Li Y.,Suhoski M.M.,Carroll R.G.,Milicic A.,Mahon T.,Sutton D.H.,Laugel B.,Moysey R.,Cameron B.J.,Vuidepot A.,Purbhoo M.A.,Cole D.K.,Phillips R.E.,June C.H.,Jakobsen B.K.,Sewell A.K.and Riley J.L.(2008)Control of HIV−1 immune escape by CD8 T cells expressing enhanced T−cell receptor.Nat Med 14,1390−5.
76. Weber K.S.,Donermeyer D.L.,Allen P.M.and Kranz D.M.(2005)Class II−restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function.Proc Natl Acad Sci U S A 102,19033−8.
77. Wong R.L.,Liu B.,Zhu X.,You L.,Kong L.,Han K.P.,Lee H.I.,Chavaillaz P.A.,Jin M.,Wang Y.,Rhode P.R.and Wong H.C.(2011)Interleukin−15:Interleukin−15 receptor alpha scaffold for creation of multivalent targeted immune molecules.Protein Eng Des Sel 24,373−83.
米国特許
第7,569,357号、2004年2月20日出願、2009年8月4日発行、Board of Trustees University of Illinois.High affinity TCR proteins and methods.
第7,465,787号、2003年12月16日出願、2008年12月16日発行、Board of Trustees University of Illinois.Yeast cell surface display of proteins and uses therof.
第6,759,243号、2000年12月6日出願、20047月6日発行、Board of Trustees University of Illinois.High affinity TCR proteins and methods.
第6,699,658号、1998年1月20日出願、2004年3月2日発行、Board of Trustees University of Illinois.Yeast cell surface display of proteins and uses therof.
第6,696,251号、2000年11月28日出願、2004年2月24日発行、Board of Trustees University of Illinois.Yeast cell surface display of proteins and uses therof.
第6,423,538号、2000年11月28日出願、2002年7月23日発行、Board of Trustees University of Illinois.Yeast cell surface display of proteins and uses therof.
第6,300,065号、1998年8月26日出願、2001年10月9日発行、Board of Trustees University of Illinois.Yeast cell surface display of proteins and uses therof.
第8,143,376号、2005年5月18日出願、2012年3月27日発行、Immunocore Limited;High affinity NY−ESO T cell receptor.
第8,088,379号、2007年9月26日出願、2012年1月3日発行、Immunocore Limited;Modified T cell receptors and related materials and methods.
第8,017,730号、2006年5月19日出願、2011年9月13日発行、Immunocore Limited;T cell receptors which bind to VYGFVRACL−HLA−A24.
第7,763,718号、2007年10月29日出願、2010年7月27日発行、Immunocore Limited;Soluble T cell receptors.
第7,666,604号、2003年7月9日出願、2010年2月23日発行、Immunocore Limited;Modified soluble T cell receptor.
第7,608,410号、2008年10月7日出願、2009年10月27日発行、Immunocore Limited;Method of improving T cell receptors.uble T cell receptors.
第7,569,664号、2003年10月3日出願、2009年8月4日発行、Immunocore Limited;Single chain recombinant T cell receptors.
第8,105,830号、2002年11月5日出願、2012年1月31日発行、Altor Bioscience Corporation;Polyspecific binding molecules and uses therof.
第6,534,633号、1999年10月21日出願、2003年3月18日、Altor Bioscience Corporation;Polyspecific binding molecules and uses therof.
Claims (17)
- 野生型T細胞受容体に由来するVα及びVβを含む修飾されたT細胞受容体、またはその抗原結合断片であって、前記Vαまたは前記Vβ、またはその両方は、前記野生型T細胞受容体に関して1つ以上の相補性決定領域(CDR)内に突然変異を含み、前記Vαは、配列番号1の残基92〜96、または、配列番号2の残基92〜96を含むアミノ酸配列を含み、前記修飾されたT細胞受容体は、ペプチドスルビビン及びHLA−A2分子の複合体にナノモルまたはより高い親和性(10−6M未満のKD値)で結合する、前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、配列番号1に記載されるVαアミノ酸配列を含む、請求項1に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、配列番号2に記載されるVαアミノ酸配列を含む、請求項1に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、配列番号3に記載されるアミノ酸配列を有する1本鎖T細胞受容体を含む、請求項1に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、配列番号4に記載されるアミノ酸配列を有する1本鎖T細胞受容体を含む、請求項1に記載の前記修飾されたT細胞受容体。
- 配列番号1に記載されるVαアミノ酸配列に対して少なくとも90%の同一性を有するアミノ酸配列を含む修飾されたVαを含む、請求項1に記載の前記修飾されたT細胞受容体。
- 配列番号2に記載されるVαアミノ酸配列に対して少なくとも90%の同一性を有するアミノ酸配列を含む修飾されたVαを含む、請求項1に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、CDR3α 92、CDR3α 100、CDR3α 101、CDR3α 102、及びCDR3α 103のうちの1つ以上において、アミノ酸置換を含む、請求項2に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、以下のアミノ酸突然変異:TCR Vα鎖突然変異N92S、N100K、A101G、R102Y、及びL103Kのうちの1つ以上を含む、請求項2に記載の前記修飾されたT細胞受容体。
- 前記修飾されたT細胞受容体は、以下のアミノ酸突然変異:TCR Vα鎖突然変異N92H、N100G、A101W、R102Y、及びL103Tのうちの1つ以上を含む、請求項3に記載の前記修飾されたT細胞受容体。
- 可溶性形態である、請求項2に記載の前記修飾されたT細胞受容体。
- 前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、請求項11に記載の前記修飾されたT細胞受容体を含む、前記治療剤。
- 前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、請求項2に記載の前記修飾されたT細胞受容体を発現するヒトT細胞を含む、前記治療剤。
- 可溶性形態である、請求項3に記載の前記修飾されたT細胞受容体。
- 前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、請求項14に記載の前記修飾されたT細胞受容体を含む、前記治療剤。
- 前記スルビビン抗原を発現する癌細胞を標的とする治療剤であって、請求項3に記載の前記修飾されたT細胞受容体を発現するヒトT細胞を含む、前記治療剤。
- 請求項12、13、15、及び16のいずれか1項に記載の前記治療剤を含む、前記スルビビン抗原を発現する癌を有する対象を治療するための組成物。
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Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007047764A2 (en) | 2005-10-17 | 2007-04-26 | Sloan Kettering Institute For Cancer Research | Wt1 hla class ii-binding peptides and compositions and methods comprising same |
US9265816B2 (en) | 2006-04-10 | 2016-02-23 | Sloan Kettering Institute For Cancer Research | Immunogenic WT-1 peptides and methods of use thereof |
CN104684577B (zh) | 2012-01-13 | 2018-05-08 | 纪念斯隆凯特林癌症中心 | 免疫原性wt-1肽及其使用方法 |
US10815273B2 (en) | 2013-01-15 | 2020-10-27 | Memorial Sloan Kettering Cancer Center | Immunogenic WT-1 peptides and methods of use thereof |
EP3769782A1 (en) | 2013-01-15 | 2021-01-27 | Memorial Sloan Kettering Cancer Center | Immunogenic wt-1 peptides and methods of use thereof |
JP6476182B2 (ja) | 2013-11-22 | 2019-02-27 | ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ | 改変された高親和性ヒトt細胞受容体 |
AU2016325384B2 (en) * | 2015-09-22 | 2021-07-22 | Julius-Maximilians-Universitat Wurzburg | A method for high level and stable gene transfer in lymphocytes |
CA2998270A1 (en) * | 2015-10-01 | 2017-04-06 | Ospedale San Raffaele S.R.L. | Tcr and uses thereof |
GB201520570D0 (en) * | 2015-11-23 | 2016-01-06 | Immunocore Ltd & Adaptimmune Ltd | Peptides |
EP3394092A1 (en) | 2015-12-23 | 2018-10-31 | Fred Hutchinson Cancer Research Center | High affinity t cell receptors and uses thereof |
MA45491A (fr) * | 2016-06-27 | 2019-05-01 | Juno Therapeutics Inc | Épitopes à restriction cmh-e, molécules de liaison et procédés et utilisations associés |
WO2018090057A1 (en) * | 2016-11-14 | 2018-05-17 | Fred Hutchinson Cancer Research Center | High affinity merkel cell polyomavirus t antigen-specific tcrs and uses thereof |
CN110582299A (zh) * | 2017-03-15 | 2019-12-17 | 弗雷德哈钦森癌症研究中心 | 高亲和力mage-a1特异性tcr及其用途 |
TWI835730B (zh) * | 2017-04-24 | 2024-03-21 | 義大利聖拉斐爾醫院 | Tcr及肽 |
JP7181517B2 (ja) * | 2018-01-23 | 2022-12-01 | 国立大学法人三重大学 | T細胞レセプター |
WO2020023556A1 (en) * | 2018-07-23 | 2020-01-30 | Magenta Therapeutics, Inc. | Use of anti-cd137 antibody drug conjugate (adc) in allogeneic cell therapy |
GB201911066D0 (en) | 2019-08-02 | 2019-09-18 | Achilles Therapeutics Ltd | T cell therapy |
CA3147717A1 (en) * | 2019-08-20 | 2021-02-25 | Fred Hutchinson Cancer Research Center | T-cell immunotherapy specific for wt-1 |
JP2023513706A (ja) * | 2020-02-12 | 2023-04-03 | アッヴィ・インコーポレイテッド | 二特異性結合分子 |
JP2023524435A (ja) | 2020-04-28 | 2023-06-12 | アキレス セラピューティクス ユーケー リミテッド | T細胞療法 |
WO2022214835A1 (en) | 2021-04-09 | 2022-10-13 | Achilles Therapeutics Uk Limited | Batch release assay for pharmaceutical products relating to t cell therapies |
GB202109886D0 (en) | 2021-07-08 | 2021-08-25 | Achilles Therapeutics Uk Ltd | Assay |
EP4359511A1 (en) | 2021-06-22 | 2024-05-01 | Achilles Therapeutics UK Limited | A method for producing antigen-specific t cells |
MX2024000941A (es) * | 2021-07-19 | 2024-04-18 | Univ Texas | Péptidos y receptores manipulados de linfocitos t dirigidos a antígenos fanci, rad51 y pbk y métodos de uso. |
Family Cites Families (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL154598B (nl) | 1970-11-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van laagmoleculire verbindingen en van eiwitten die deze verbindingen specifiek kunnen binden, alsmede testverpakking. |
US3817837A (en) | 1971-05-14 | 1974-06-18 | Syva Corp | Enzyme amplification assay |
US3927193A (en) | 1973-05-18 | 1975-12-16 | Hoffmann La Roche | Localization of tumors by radiolabelled antibodies |
US3939350A (en) | 1974-04-29 | 1976-02-17 | Board Of Trustees Of The Leland Stanford Junior University | Fluorescent immunoassay employing total reflection for activation |
US3996345A (en) | 1974-08-12 | 1976-12-07 | Syva Company | Fluorescence quenching with immunological pairs in immunoassays |
US4277437A (en) | 1978-04-05 | 1981-07-07 | Syva Company | Kit for carrying out chemically induced fluorescence immunoassay |
US4275149A (en) | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4361544A (en) | 1980-03-03 | 1982-11-30 | Goldenberg Milton David | Tumor localization and therapy with labeled antibodies specific to intracellular tumor-associated markers |
US4444744A (en) | 1980-03-03 | 1984-04-24 | Goldenberg Milton David | Tumor localization and therapy with labeled antibodies to cell surface antigens |
US4348376A (en) | 1980-03-03 | 1982-09-07 | Goldenberg Milton David | Tumor localization and therapy with labeled anti-CEA antibody |
US4331647A (en) | 1980-03-03 | 1982-05-25 | Goldenberg Milton David | Tumor localization and therapy with labeled antibody fragments specific to tumor-associated markers |
US4366241A (en) | 1980-08-07 | 1982-12-28 | Syva Company | Concentrating zone method in heterogeneous immunoassays |
US4468457A (en) | 1981-06-01 | 1984-08-28 | David M. Goldenberg | Method for producing a CSAp tryptic peptide and anti-CSAp antibodies |
US5101827A (en) | 1985-07-05 | 1992-04-07 | Immunomedics, Inc. | Lymphographic and organ imaging method and kit |
US4640561A (en) | 1985-11-15 | 1987-02-03 | Ford Motor Company | Flexible printed circuit connector |
US5059413A (en) | 1988-04-18 | 1991-10-22 | Xoma Corporation | Scintigraphic monitoring of immunotoxins using radionuclides and heterobifunctional chelators |
DK0486622T3 (da) | 1989-08-09 | 1999-07-19 | Rhomed Inc | Direkte radiomærkning af antistoffer og andre proteiner med technetium eller rhenium |
US5299253A (en) | 1992-04-10 | 1994-03-29 | Akzo N.V. | Alignment system to overlay abdominal computer aided tomography and magnetic resonance anatomy with single photon emission tomography |
US6696251B1 (en) | 1996-05-31 | 2004-02-24 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
US6699658B1 (en) | 1996-05-31 | 2004-03-02 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
US6300065B1 (en) | 1996-05-31 | 2001-10-09 | Board Of Trustees Of The University Of Illinois | Yeast cell surface display of proteins and uses thereof |
US6759243B2 (en) | 1998-01-20 | 2004-07-06 | Board Of Trustees Of The University Of Illinois | High affinity TCR proteins and methods |
NZ507887A (en) | 1998-05-19 | 2002-12-20 | Avidex Ltd | Soluble T cell receptor |
AU1218000A (en) | 1998-10-21 | 2000-05-08 | Sunol Molecular Corporation | Polyspecific binding molecules and uses thereof |
WO2003020763A2 (en) | 2001-08-31 | 2003-03-13 | Avidex Limited | Soluble t cell receptor |
US7892559B2 (en) | 2002-01-30 | 2011-02-22 | Survac Aps | Survivin-derived peptides and use thereof |
EP1549748B1 (en) | 2002-10-09 | 2014-10-01 | Immunocore Ltd. | Single chain recombinant t cell receptors |
GB0304068D0 (en) | 2003-02-22 | 2003-03-26 | Avidex Ltd | Substances |
GB0328363D0 (en) * | 2003-12-06 | 2004-01-14 | Imp College Innovations Ltd | Therapeutically useful molecules |
JP4972549B2 (ja) | 2004-05-19 | 2012-07-11 | イムノコア リミテッド | T細胞レセプターを改善する方法 |
US8143376B2 (en) | 2004-05-19 | 2012-03-27 | Immunocore Limited | High affinity NY-ESO T cell receptor |
GB0524477D0 (en) | 2005-11-30 | 2006-01-11 | Avidex Ltd | Isolated T cell receptors which specifically bind to vygfvracl-hla-24 |
GB0511124D0 (en) | 2005-06-01 | 2005-07-06 | Avidex Ltd | High affinity melan-a t cell receptors |
AT503861B1 (de) | 2006-07-05 | 2008-06-15 | F Star Biotech Forsch & Entw | Verfahren zur manipulation von t-zell-rezeptoren |
US8088379B2 (en) | 2006-09-26 | 2012-01-03 | The United States Of America As Represented By The Department Of Health And Human Services | Modified T cell receptors and related materials and methods |
US9281917B2 (en) | 2007-01-03 | 2016-03-08 | Nokia Technologies Oy | Shared control channel structure |
CA2743669C (en) * | 2008-11-24 | 2018-10-16 | Helmholtz Zentrum Muenchen Deutsches Forschungszentrum Fuer Gesundheit Und Umwelt (Gmbh) | High affinity t cell receptor and use thereof |
WO2010075417A1 (en) | 2008-12-23 | 2010-07-01 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Survivin specific t cell receptor for treating cancer |
US9409969B2 (en) | 2009-02-09 | 2016-08-09 | Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) | Repertoire of allo-restricted peptide-specific T cell receptor sequences and use thereof |
GB0911566D0 (en) | 2009-07-03 | 2009-08-12 | Immunocore Ltd | T cell receptors |
US10464987B2 (en) * | 2009-10-06 | 2019-11-05 | Abbvie Inc. | Human single-chain T cell receptors |
BR112013003647A2 (pt) | 2010-07-28 | 2017-11-07 | Immunocore Ltd | receptores de células t. |
PL2618835T3 (pl) * | 2010-09-20 | 2017-12-29 | Biontech Cell & Gene Therapies Gmbh | Swoiste względem antygenu receptory komórek T i epitopy dla komórek T |
EP2844743B1 (en) | 2012-05-03 | 2021-01-13 | Fred Hutchinson Cancer Research Center | Enhanced affinity t cell receptors and methods for making the same |
WO2014191465A1 (en) * | 2013-05-28 | 2014-12-04 | Møller Niels Iversen | Peptides derived from lawsonia intracellularis and their use in vaccination |
PL228457B1 (pl) | 2013-08-30 | 2018-03-30 | Univ Jagiellonski | Tomograf hybrydowy TOF-PET/CT |
JP6476182B2 (ja) | 2013-11-22 | 2019-02-27 | ザ ボード オブ トラスティーズ オブ ザ ユニバーシティ オブ イリノイ | 改変された高親和性ヒトt細胞受容体 |
CN107074970B (zh) | 2014-08-04 | 2021-07-30 | 弗雷德哈钦森癌症研究中心 | 特异性针对wt-1的t细胞免疫疗法 |
CN113105562B (zh) * | 2018-09-26 | 2023-12-01 | 安源医药科技(上海)有限公司 | 突变型单链人凝血因子viii在制备融合蛋白中的应用 |
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