JP2021529557A - 抗腫瘍免疫チェックポイント調節因子アンタゴニスト - Google Patents
抗腫瘍免疫チェックポイント調節因子アンタゴニスト Download PDFInfo
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Abstract
Description
他の定義がされていない限り、本明細書中で使用される全ての技術的用語及び科学的用語は、本開示の方法及び組成物が属する分野の当業者によって一般に理解されている意味と同一の意味を有する。本明細書及び添付の請求項中で使用される場合、単数形「a」、「an」、及び「the」は、そうでないことが文脈によって明確に規定されない限り、複数の指示物を含むことに留意しなければならない。よって例えば、「あるペプチド(a peptide)」に関する言及は、「1つ以上の(one or more)」ペプチド、又は「複数(plurality)」のこのようなペプチドを含む。本出願の教示に関して、本出願に記載されているいずれの発行済みの特許又は特許出願公開は、参照により本出願に明示的に援用される。
一態様では、本出願は:(1)第1の免疫チェックポイント調節因子に特異的に結合する可変ドメイン領域を含有する、1対のアーム;及び(2)第2の免疫チェックポイント調節因子に特異的に結合する一本鎖(scFv)を有する免疫グロブリン足場を含む、抗腫瘍アンタゴニストを提供する。
別の態様では、本出願は、LAG‐3に特異的に結合する抗原結合部分を含む抗体を提供する。図19Aは、抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1Aに対応する重鎖CDR1、CD2、及びCDR3配列を示す。図19Bは、抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1Aに対応する軽鎖CDR1、CD2、及びCDR3配列を示す。図20は、抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1AのVH及びVL配列を示す。
いくつかの実施形態では、チェックポイント調節因子アンタゴニストは、抗TIGIT抗体、又はその1つ以上の抗原結合断片を含む。図1は、抗TIGIT mAbのCDR配列を示し、図2A〜2Bは、本出願で使用するための抗TIGIT抗体可変ドメイン配列の複数の実施形態を示す。
いくつかの実施形態では、チェックポイント調節因子アンタゴニストは、抗PD‐1抗体、又はその1つ以上の抗原結合断片を含む。図3は抗PD‐1 mAbのCDR配列を示し、図4A〜4Cは、本出願で使用するための抗PD‐1抗体可変ドメイン配列の複数の実施形態を示す。
いくつかの実施形態では、チェックポイント調節因子アンタゴニストは、抗PD‐L1抗体、又はその1つ以上の抗原結合断片を含む。図5は抗PD‐L1 mAbのCDR配列を示し、図6A〜6Cは、本出願で使用するための抗PD‐L1抗体可変ドメイン配列の複数の実施形態を示す。
本明細書に記載のHCVR及びLCVRは、免疫グロブリン足場に結合され得る。いくつかの実施形態では、免疫グロブリン足場は、IgG1、IgG2、又はIgG4として構成される。免疫グロブリン足場は、CH1‐CH2‐CH3領域を含んでよく、あるいは免疫グロブリン足場は、自然に発生するFc領域、又は自然に発生しない若しくは変異したFc領域、例えばエフェクタ機能を有しない若しくはほとんど有しないFc(例えばヒトIgG2若しくはIgG4)、若しくは腫瘍環境下でのTreg枯渇を強化するために1つ以上の活性化Fc受容体(FcγRI、FcγRIIa若しくはFcγRIIIa)への結合が強化されたFcを含んでよい。従って特定の実施形態では、本明細書に記載の抗TIGIT、抗PD‐1、抗PD‐L1、抗LAG‐3、 HCVR及びLCVRは、典型的には血清半減期、補体結合、Fc受容体結合、及び/又は抗原依存性細胞傷害性といった抗体の1つ以上の機能的特性を変化させるために、1つ以上の修飾を含むFcに結合され得る。
二重特異性抗体調製物を効率的に製造するための課題の1つは、結合特異性が異なる鎖が同時発現される際の、重鎖及び軽鎖の誤った対合に関する。表1は、結合特異性が異なる重鎖間の誤った対合を克服するための、複数のアミノ酸置換選択肢を示し、これは、所望の重鎖間での正しい会合を「強制する」、又は優先的に促進する。重鎖間の誤った対合を防止又は低減するためのいずれのアプローチを用いて、本開示による二重特異性抗腫瘍アンタゴニストを作製してよい。
特定の実施形態では、本出願の抗腫瘍アンタゴニストは、1つ以上のペプチド及び/又は小分子薬剤に化学的にコンジュゲートされる。上記ペプチド又は小分子薬剤は、同一であっても異なっていてもよい。上記ペプチド又は小分子薬剤は例えば、還元されたSH基及び/又は炭水化物側鎖に付着させることができる。ペプチド又は小分子薬剤と抗体との共有又は非共有結合を作製する方法は当該技術分野において公知であり、いずれのこのような公知の方法を利用してよい。
本出願は更に、本出願のチェックポイント調節因子アンタゴニスト又は抗腫瘍アンタゴニストのうちのいずれの1つ以上を含むキットを提供する。いくつかの実施形態では、上記キットは更に、投与用のシリンジ及び針を含む追加の構成部品、並びに併用療法で共に使用するための検出用の二次抗体及び本明細書に記載の追加のヒト抗体を含む試薬を内包する。キットは典型的には、キットの内容物の用途を指示するラベル及び/又は説明書を含む。「ラベル(label)」又は「説明書(instruction)」は、キット上に若しくはキットと共に供給される、又は他の方法でキットに付属している、いずれの記述、又は記録された資料を含んでよい。
本出願の抗腫瘍アンタゴニストは、例えば免疫応答の強化、及び癌、感染症、又は自己免疫疾患の治療を含む、多数の試験管内及び生体内利用法を有する。
別の態様では、本出願は、被験者の体内での抗原特異的T細胞応答を強化するための併用療法を提供する。一実施形態では、上記方法は、T細胞を、抗TIGIT抗体、抗PD‐1抗体、抗PD‐L1抗体、抗LAG‐3抗体、これらの抗体断片、又は二重特異性抗腫瘍アンタゴニストと、第2の抗体、抗体断片、アンタゴニスト、又は薬剤との組み合わせと接触させることによって、抗原特異的T細胞応答又はアポトーシス経路を強化するステップを含む。例えばいくつかの実施形態では、第1の抗体又は抗体断片は、TIGITに特異的に結合し、第2の抗体又は抗体断片は、PD‐1、PD‐L1、又はLAG‐3に特異的に結合する。
別の態様では、本出願は、重鎖及び軽鎖を含む本出願の抗腫瘍アンタゴニストをコードする核酸、並びにこのような核酸を含む発現ベクターを提供する。特に、核酸は、本明細書に記載の抗体、アンタゴニスト、又は断片のうちのいずれに対応する1つ以上のHCDR、LCDR、HCVR及び/又はLCVRをコードする。
別の態様では、本出願は宿主細胞であって、本出願の単一特異性又は二重特異性抗腫瘍アンタゴニストをコードする核酸若しくは発現ベクター又は核酸/発現ベクターをコードする、抗TIGIT、抗PD‐1、抗PD‐L1及び/又は抗LAG‐3のHCVR及び/又はLCVRで形質転換された、宿主細胞を提供する。宿主細胞は、核酸若しくは発現ベクター、又は本明細書に記載の他の同時投与される抗体若しくはアンタゴニストのうちのいずれかをコードする、抗TIGIT、抗PD‐1、抗PD‐L1及び/又は抗LAG‐3のHCVR及び/又はLCVRを発現できるいずれの細菌又は真核細胞とすることができる。
本出願の別の態様は、癌、慢性感染症、又は易感染性疾患状態といった細胞増殖性障害を治療するための、医薬組成物及び方法に関する。一実施形態では、上記医薬組成物は、本出願の1つ以上の抗腫瘍アンタゴニストを含む。いくつかの実施形態では、1つ以上の上記抗腫瘍アンタゴニストは:1つ以上のチェックポイント調節因子アンタゴニスト、例えば抗T細胞Ig及びITIMドメイン(TIGIT)阻害剤、PD‐1阻害剤、PD‐L1阻害剤、並びにLAG‐3阻害剤を含む。1つ以上の上記アンタゴニストは、薬学的に許容可能な担体と共に処方される。本出願の医薬組成物は、本明細書に記載されるように、1つ以上の異なる抗体、1つ以上の多重特異性抗体、1つ以上の免疫複合体、又はこれらの組み合わせを含んでよい。
本出願のモノクローナル抗体(mAb)は、当該技術分野で公知の技法を用いて生成及びスクリーニングされる。例えばHarlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New Yorkを参照。抗原特異的ハイブリドーマmAbは、当該技術分野で公知の技法を用いてクローニング、配列決定、及び操作される。例えばLo. B.K.C Methods in Molecular Biology (Trademark). Volume 248 2004. Antibody Engineeringを参照。
図7A〜7Cは、3つの例示的な二重特異性抗腫瘍アンタゴニスト、Bi‐TPM‐93(図7A)、Bi‐TPM‐94A(図7B)、及びBi‐TPM‐94B(図7C)を示す。これらのアンタゴニストは、抗PD‐1(PD‐01)抗体バックボーン(図7A)、又は抗PD‐1(PD‐06/2P17)抗体バックボーン(図7A、7B)を、3xG4Sリンカー(図7A、7B)又は6xG4Sリンカー(図7C)で隔てられた抗TIGIT mAb T‐10/B21由来の重鎖及び軽鎖可変領域を有する抗TIGIT scFvと共に、含有する。
Bi‐TPM‐93及びBi‐TPM‐94AのPD‐1遮断能力を評価するために、PD‐1 IC50アッセイを実施した。ここでは、二重特異性mAbの段階希釈物を、ヒトPD‐1トランスフェクト済みCHOK1細胞、及び7μg/mlのFITC標識ヒトPD‐L1‐Fcタンパク質を用いて、4℃で30分間インキュベーションした後、細胞を洗浄及び固定して、iQue intellicytシステムで分析した。図10のこのアッセイの結果は、PD‐01由来のVH及びVL配列を含有するBi‐TPM‐93(IC50=0.83nM)に比べて、PD‐06/2P17由来のVH及びVL配列を含有するBi‐TPM‐94(IC50=0.15nM)が、PD‐1とそのリガンドであるPD‐L1との間の相互作用を良好に遮断することを示す。
別の態様では、本出願は、ヒト免疫チェックポイント調節因子LAG‐3に特異的に結合するモノクローナル抗体又はその抗原結合部分のスクリーニング及び特性決定に関する。図19Aは、単離された抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1Aに対応する重鎖CDR1、CD2、及びCDR3配列を示す。図19Bは、抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1Aに対応する軽鎖CDR1、CD2及びCDR3配列を示す。図20は、抗LAG‐3 mAbである2L2A.1、2L2A.6、2L27B、及び3L1AのVH及びVL配列を示す。
実施例1に記載の二重特異性抗PD‐1/抗TIGIT scFvの設計及び特性決定に基づいて、この設計の製造性及び機能性に関する利益を、類似の二重特異性抗LAG‐3/抗TIGIT scFv設計に拡張できるかどうかを評価することを対象とした。図30A〜30Bは、2つの例示的な二重特異性抗腫瘍アンタゴニスト、延長されたscFvリンカー4xG4Sを有するBi‐LT‐1(図30A)、及び延長されたscFvリンカー6xG4Sを有するBi‐LT‐3(図30B)を示す。図31は、図30A〜30Bに示されている二重特異性アンタゴニストの機能性ドメインの配置をまとめたものである。図32は、図30A〜30Bに示されている二重特異性アンタゴニストに対応する重鎖(HC)及び軽鎖(LC)アミノ酸配列を示す。
Claims (30)
- PD‐1、PD‐L1、又はLAG‐3に特異的に結合する、第1の標的指向性ドメイン;及び
TIGITに特異的に結合するscFvを含む、第2の標的指向性ドメイン
を含む、抗腫瘍アンタゴニスト。 - 前記scFvは:
配列番号48、50、52、54、56、58、60、62、64、及び66からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリン重鎖可変領域(HCVR);並びに/又は
配列番号49、51、53、55、57、59、61、63、65、及び67からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリン軽鎖可変領域(LCVR);又は
前記HCVR及び前記LCVRの両方
を含む、請求項1に記載の抗腫瘍アンタゴニスト。 - 前記scFvは:
配列番号66のアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンHCVR;及び/又は
配列番号67のアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンLCVR
を含む、請求項1又は2に記載の抗腫瘍アンタゴニスト。 - 前記scFvは:
配列番号66のアミノ酸配列を有する免疫グロブリンHCVR;及び/又は
配列番号67のアミノ酸配列を有する免疫グロブリンLCVR
を含む、請求項1〜3のいずれか1項に記載の抗腫瘍アンタゴニスト。 - アミノ末端及びカルボキシ末端を有する免疫グロブリン足場を含む、請求項1〜4のいずれか1項に記載の抗腫瘍アンタゴニスト。
- ペプチドリンカーを介して、前記第1の標的指向性ドメインが、前記免疫グロブリン足場の前記アミノ末端に結合され、前記第2の標的指向性ドメインが、前記免疫グロブリン足場の前記カルボキシ末端に結合される、請求項5に記載の抗腫瘍アンタゴニスト。
- 前記ペプチドリンカーは、配列番号188〜191からなる群から選択されるアミノ酸配列を有する、請求項6に記載の抗腫瘍アンタゴニスト。
- 前記ペプチドリンカーは、配列番号191のアミノ酸配列を有する、請求項6又は7に記載の抗腫瘍アンタゴニスト。
- 前記第1の標的指向性ドメインは、PD‐1に特異的に結合する、請求項1〜8のいずれか1項に記載の抗腫瘍アンタゴニスト。
- 前記第1の標的指向性ドメインは:
(1)3つの相補性決定領域(HCDR):HCDR1、HCDR2、及びHCDR3を含む、免疫グロブリンHCVRであって、
前記HCDR1は、配列番号68、71、74、76、及び79からなる群から選択されるアミノ酸配列を有し、
前記HCDR2は、配列番号69、72、77、及び80からなる群から選択されるアミノ酸配列を有し、
前記HCDR3は、配列番号70、73、75、78、及び81からなる群から選択されるアミノ酸配列を有する、免疫グロブリンHCVR;並びに
(2)3つの相補性決定領域(LCDR):LCDR1、LCDR2、及びLCDR3を含む、免疫グロブリンLCVRであって、
前記LCDR1は、配列番号82、85、88、89、90、及び93からなる群から選択されるアミノ酸配列を有し、
前記LCDR2は、配列番号83、86、91、及び94からなる群から選択されるアミノ酸配列を有し、
前記LCDR3は、配列番号84、87、92、及び95からなる群から選択されるアミノ酸配列を有する、免疫グロブリンLCVR
を含む、請求項9に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号96、98、100、102、104、及び106からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンHCVR;並びに/又は
配列番号97、99、101、103、105、及び107からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンLCVR
を含む、請求項9又は10に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号106のアミノ酸配列を有する免疫グロブリンHCVR;及び/又は
配列番号107のアミノ酸配列を有する免疫グロブリンLCVR
を含む、請求項9〜11のいずれか1項に記載の抗腫瘍アンタゴニスト。 - 配列番号160若しくは配列番号162のアミノ酸配列を有する免疫グロブリン重鎖、及び/又は配列番号161のアミノ酸配列を有する免疫グロブリン軽鎖を含む、請求項9〜12のいずれか1項に記載の抗腫瘍アンタゴニスト。
- 前記第1の標的指向性ドメインは、PD‐L1に特異的に結合する、請求項1〜8のいずれか1項に記載の抗腫瘍アンタゴニスト。
- 前記第1の標的指向性ドメインは:
(1)3つの相補性決定領域(HCDR):HCDR1、HCDR2、及びHCDR3を含む、免疫グロブリンHCVRであって、
前記HCDR1は、配列番号108、111、117、及び120からなる群から選択されるアミノ酸配列を有し、
前記HCDR2は、配列番号109、112、114、116、118、121、及び125からなる群から選択されるアミノ酸配列を有し、
前記HCDR3は、配列番号110、113、115、119、及び122からなる群から選択されるアミノ酸配列を有する、免疫グロブリンHCVR;並びに
(2)3つの相補性決定領域(LCDR):LCDR1、LCDR2、及びLCDR3を含む、免疫グロブリンLCVRであって、
前記LCDR1は、配列番号123、126、130、133、及び136からなる群から選択されるアミノ酸配列を有し、
前記LCDR2は、配列番号126、127、131、134、及び137からなる群から選択されるアミノ酸配列を有し、
前記LCDR3は、配列番号125、128、129、132、135、及び138からなる群から選択されるアミノ酸配列を有する、免疫グロブリンLCVR
を含む、請求項14に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号139、141、143、145、147、149、151、及び153からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンHCVR;
配列番号140、142、144、146、148、150、152、及び154からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンLCVR;あるいは
前記免疫グロブリンHCVR及び前記免疫グロブリンLCVRの両方
を含む、請求項14又は15に記載の抗腫瘍アンタゴニスト。 - 配列番号153のアミノ酸配列を有する免疫グロブリンHCVR;
配列番号154のアミノ酸配列を有する免疫グロブリンLCVR;あるいは
前記免疫グロブリンHCVR及び前記免疫グロブリンLCVRの両方
を含む、請求項14〜16のいずれか1項に記載の抗腫瘍アンタゴニスト。 - 配列番号339〜341からなる群から選択されるアミノ酸配列を有する免疫グロブリン重鎖;及び/又は
配列番号338のアミノ酸配列を有する免疫グロブリン軽鎖
を含む、請求項14〜17のいずれか1項に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは、LAG‐3に特異的に結合する、請求項1〜8のいずれか1項に記載の抗腫瘍アンタゴニスト。
- 前記第1の標的指向性ドメインは:
(1)3つの相補性決定領域(HCDR):HCDR1、HCDR2、及びHCDR3を含む、免疫グロブリンHCVRであって、
前記HCDR1は、配列番号163、166、及び169からなる群から選択されるアミノ酸配列を有し、
前記HCDR2は、配列番号164、167、及び170からなる群から選択されるアミノ酸配列を有し、
前記HCDR3は、配列番号165、168、及び171からなる群から選択されるアミノ酸配列を有する、免疫グロブリンHCVR;並びに
(2)3つの相補性決定領域(LCDR):LCDR1、LCDR2、及びLCDR3を含む、免疫グロブリンLCVRであって、
前記LCDR1は、配列番号172、175、及び177からなる群から選択されるアミノ酸配列を有し、
前記LCDR2は、配列番号173、及び178からなる群から選択されるアミノ酸配列を有し、
前記LCDR3は、配列番号174、176、及び179からなる群から選択されるアミノ酸配列を有する、免疫グロブリンLCVR
を含む、請求項19に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号180、182、184、及び186からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンHCVR;並びに/又は
配列番号181、183、185、及び187からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンLCVR
を含む、請求項19又は20に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号180のアミノ酸配列を有する免疫グロブリンHCVR;及び/又は
配列番号181のアミノ酸配列を有する免疫グロブリンLCVR
を含む、請求項19〜21のいずれか1項に記載の抗腫瘍アンタゴニスト。 - 前記第1の標的指向性ドメインは:
配列番号192若しくは配列番号193のアミノ酸配列を有する免疫グロブリン重鎖;及び/又は
配列番号194のアミノ酸配列を有する免疫グロブリン軽鎖
を含む、請求項19〜22のいずれか1項に記載の抗腫瘍アンタゴニスト。 - (1)3つの相補性決定領域(HCDR):HCDR1、HCDR2、及びHCDR3を含む、免疫グロブリンHCVRであって、
前記HCDR1は、配列番号163、166、及び169からなる群から選択されるアミノ酸配列を有し、
前記HCDR2は、配列番号164、167、及び170からなる群から選択されるアミノ酸配列を有し、
前記HCDR3は、配列番号165、168、及び171からなる群から選択されるアミノ酸配列を有する、免疫グロブリンHCVR;
(2)3つの相補性決定領域(LCDR):LCDR1、LCDR2、及びLCDR3を含む、免疫グロブリンLCVRであって、
前記LCDR1は、配列番号172、175、及び177からなる群から選択されるアミノ酸配列を有し、
前記LCDR2は、配列番号173、及び178からなる群から選択されるアミノ酸配列を有し、
前記LCDR3は、配列番号174、176、及び179からなる群から選択されるアミノ酸配列を有する、免疫グロブリンLCVR
を含む、抗体又は前記抗体の抗原結合部分であって、
前記抗体又は前記抗体の前記抗原結合部分は、ヒトLAG‐3に特異的に結合する、抗体又は前記抗体の抗原結合部分。 - 配列番号180、182、184、及び186からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンHCVR;並びに/又は
配列番号181、183、185、及び187からなる群から選択されるアミノ酸配列と少なくとも90%の同一性を有する、免疫グロブリンLCVR
を含む、請求項24に記載の抗体又は前記抗体の抗原結合部分。 - 配列番号180のアミノ酸配列を有する免疫グロブリンHCVR;及び/又は
配列番号181のアミノ酸配列を有する免疫グロブリンLCVR
を含む、請求項24又は25に記載の抗体又は前記抗体の抗原結合部分。 - 請求項1〜26のいずれか1項に記載の抗腫瘍アンタゴニスト、抗体、又は前記抗体の抗原結合部分をコードする、1つ以上の核酸。
- 請求項27に記載の1つ以上の核酸を含む、1つ以上の発現ベクター。
- 請求項28に記載の1つ以上の発現ベクターで形質転換された、宿主細胞。
- 被験者の体内の細胞増殖性障害の治療方法であって:
それを必要とする被験者に、有効量の請求項1〜26のいずれか1項に記載の抗腫瘍アンタゴニストを投与するステップ
を含む、方法。
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