JP2018527949A - 新規抗pd−l1抗体 - Google Patents
新規抗pd−l1抗体 Download PDFInfo
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- JP2018527949A JP2018527949A JP2018526289A JP2018526289A JP2018527949A JP 2018527949 A JP2018527949 A JP 2018527949A JP 2018526289 A JP2018526289 A JP 2018526289A JP 2018526289 A JP2018526289 A JP 2018526289A JP 2018527949 A JP2018527949 A JP 2018527949A
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Classifications
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- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- G—PHYSICS
- G01—MEASURING; TESTING
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
【選択図】図1
Description
a)配列番号1、配列番号3および/または配列番号5を含む重鎖可変領域、
b)配列番号13、配列番号15および/または配列番号17を含む重鎖可変領域、
c)配列番号25、配列番号27および/または配列番号29を含む重鎖可変領域、ならびに
d)配列番号37、配列番号39および/または配列番号41を含む重鎖可変領域
からなる群から選択される重鎖可変領域を含む。
a)配列番号7、配列番号9および/または配列番号11を含む軽鎖可変領域、
b)配列番号19、配列番号21および/または配列番号23を含む軽鎖可変領域、ならびに
c)配列番号31、配列番号33および/または配列番号35を含む軽鎖可変領域
からなる群から選択される軽鎖可変領域を含む。
a)配列番号1、配列番号3および/または配列番号5を含む重鎖可変領域ならびに配列番号7、配列番号9および/または配列番号11を含む軽鎖可変領域、
b)配列番号13、配列番号15および/もしくは配列番号17を含む重鎖可変領域ならびに配列番号19、配列番号21および/もしくは配列番号23を含む軽鎖可変領域、
c)配列番号25、配列番号27および/もしくは配列番号29を含む重鎖可変領域ならびに配列番号31、配列番号33および/もしくは配列番号35を含む軽鎖可変領域、または
d)配列番号37、配列番号39および/または配列番号41を含む重鎖可変領域ならびに配列番号19、配列番号21および/もしくは配列番号23を含む軽鎖可変領域
を含む。
a)配列番号43を含む重鎖可変領域および配列番号45を含む軽鎖可変領域、
b)配列番号47を含む重鎖可変領域および配列番号49を含む軽鎖可変領域、
c)配列番号51を含む重鎖可変領域および配列番号53を含む軽鎖可変領域、または
d)配列番号55を含む重鎖可変領域および配列番号49を含む軽鎖可変領域
を含む。
a)CD4+T細胞におけるIL−2の生成を誘導すること、
b)CD4+T細胞におけるIFNγの生成を誘導すること、
c)CD4+T細胞の増殖を誘導すること、および
d)Tregの抑制機能を逆転させること。
用語「抗体」は、本明細書において、特異的抗原と結合する任意の免疫グロブリン、モノクローナル抗体、ポリクローナル抗体、多重特異性抗体または二重特異性(二価)抗体を含む。天然の無傷の抗体は、2つの重鎖および2つの軽鎖を含む。各重鎖は、可変領域ならびに第1、第2および第3の定常領域からなり、各軽鎖は、可変領域および定常領域からなる。哺乳動物重鎖は、α、δ、ε、γおよびμとして分類され、哺乳動物軽鎖は、λまたはκとして分類される。抗体は、「Y」型を有し、Yのステムは、ジスルフィド結合を介して一緒に結合している2つの重鎖の第2および第3の定常領域からなる。Yの各アームは、単一軽鎖の可変および定常領域と結合している単一重鎖の可変領域および第1の定常領域を含む。軽鎖および重鎖の可変領域は、抗原結合に関与している。両鎖中の可変領域は、一般に、相補性決定領域(CDR)(LCDR1、LCDR2およびLCDR3を含む軽(L)鎖CDR、HCDR1、HCDR2、HCDR3を含む重(H)鎖CDR)と呼ばれる3つの高度可変ループを含有する。本明細書において開示される抗体および抗原結合断片のCDR境界は、Kabat、ChothiaまたはAl−Lazikaniの慣習(Al−Lazikani,B.、Chothia,C.、Lesk,A.M.、J.Mol.Biol.、第273巻(4号)、927頁(1997);Chothia,C.ら、J Mol Biol.12月5日;第186巻(3号):651〜63頁(1985年);Chothia,C.およびLesk,A.M.、J.Mol.Biol.、第196巻、901頁(1987年);Chothia,C.ら、Nature.12月21〜28日;第342巻(6252号):877〜83頁(1989年);Kabat E.A.ら、National Institutes of Health、Bethesda、Md.(1991年))によって定義または同定され得る。3つのCDRは、CDRよりもより高度に保存され、超可変ループを支持するスキャフォールドを形成するフレームワーク領域(FR)として知られる、両端に位置するストレッチの間に挿入されている。重鎖および軽鎖の定常領域は、抗原結合に関与しないが、種々のエフェクター機能を示す。抗体は、その重鎖の定常領域のアミノ酸配列に基づいてクラスに割り当てられる。抗体の5種の主要なクラスまたはアイソタイプとして、IgA、IgD、IgE、IgGおよびIgMがあり、これらは、α、δ、ε、γおよびμ重鎖それぞれの存在を特徴とする。主要な抗体クラスのうちいくつかは、IgG1(γ1重鎖)、IgG2(γ2重鎖)、IgG3(γ3重鎖)、IgG4(γ4重鎖)、IgA1(α1重鎖)またはIgA2(α2重鎖)などのサブクラスに分割される。
一態様では、本開示は、抗PD−L1抗体およびその抗原結合断片を提供する。CD279とも呼ばれるPD−1は、活性化されたT細胞によって発現される重要な免疫チェックポイント受容体としても知られており、免疫抑制を媒介する。PD−1リガンド1(PD−L1)は、種々の腫瘍細胞、間質細胞または両方で発現される40kDaの膜貫通タンパク質であり、PD−1と結合する。PD−1およびPD−L1間の相互作用の阻害は、T細胞反応を増強し、したがって、抗癌活性を媒介し得る。
Vセグメント:IGHV4−39*01
Dセグメント:IGHD1−26*01
Jセグメント:IGHJ4*02
Vセグメント:IGLV3−1*01
Jセグメント:IGLJ2*01
Vセグメント:IGHV3−23*01
Dセグメント:IGHD5−5*01
Jセグメント:IGHJ4*02
Vセグメント:IGLV3−21*02
Jセグメント:IGLJ2*01
Vセグメント:IGHV4−39*01
Dセグメント:決定されていない
Jセグメント:IGHJ4*02
Vセグメント:IGLV3−1*01
Jセグメント:IGLJ2*01
Vセグメント:IGHV3−23*01
Dセグメント:IGHD5−5*01
Jセグメント:IGHJ4*02
Vセグメント:IGLV3−21*02
Jセグメント:IGLJ2*01
本開示は、抗PD−L1抗体およびその抗原結合断片をコードする単離されたポリヌクレオチドを提供する。特定の実施形態では、単離されたポリヌクレオチドは、表1に提供されるCDR配列をコードする、表1に示されるような1種または複数のヌクレオチド配列を含む。
本開示は、抗PD−L1抗体またはその抗原結合断片を含むキットを提供する。いくつかの実施形態では、キットは、生体サンプルにおいてPD−L1の存在またはレベルを検出するために有用である。生体サンプルは、細胞または組織を含み得る。
本開示は、抗PD−L1抗体またはその抗原結合断片および1種または複数の医薬上許容される担体を含む医薬組成物をさらに提供する。
本開示は、抗PD−L1抗体またはその抗原結合断片を使用する方法をさらに提供する。
1.1 免疫処置:雌のOMTラット(Open Monoclonal Technology、Inc.、米国、パロアルトから入手、8〜10週齢)を、足蹠注射による、10μgのTiterMax中のヒトPD−L1 ECDタンパク質を用いて抗原刺激し、次いで、融合の準備が整うまで、3日毎に足蹠注射によるリン酸アルミニウムゲルアジュバント中のPD−L1 ECDタンパク質を用いてブーストした。抗PD−L1抗体血清力価を2週間毎にELISAまたはFACSによって調べた。
次いで、293F細胞培養上清中の抗体を、プロテインAアフィニティークロマトグラフィーを使用することによって精製した。
3.1 FACSによる競合アッセイ:完全ヒト抗体が、PD−L1のPD−1との結合を遮断できるか否かを調べるために、ヒトPD−L1を発現するCHO−K1細胞を、種々の濃度の完全ヒト抗体とともに4℃で1時間インキュベートした。結合していない抗体を洗浄除去し、次いで、細胞に、マウスFcタグが付けられたヒトPD−1を添加した。FITCがコンジュゲートしているヤギ抗マウスIgGを使用することによって、ヒトPD−1のPD−L1を発現する細胞との結合を検出し、続いて、BD Biosciences FACSCanto IIおよびFlowJoバージョンソフトウェアを使用する解析をした。
本明細書において提供される本発明の抗体1.14.4のエピトープを調べるために、1.14.4を使用してhPD−1でアラニンスキャニング実験および抗体結合に対する効果評価を実施した。
腫瘍成長に対するhPD−L1抗体の阻害を評価するために、5×105個細胞/0.1mLのMC38−B7H1腫瘍細胞を、42匹の雄B−hPD−1ヒト化マウスの前側右肋骨の皮下に播種した。腫瘍の大きさが、約100mm3に達した時点で、マウスを群にし(5群、群あたり7匹)、以下のとおりに薬剤を投与した:群1:ビヒクル、群2:対照抗体BMK6(WO2011066389A1における詳細な記載を参照のこと)、群3:1.14.4、3mg/kg、群4:1.14.4、10mg/kgおよび群5:1.14.4、30mg/kg。すべての群に、2日に1回、6回の連続投与を用い、腹膜内注射によって投与した。動物を、投与の終了後さらに2週間連続的に観察した。腫瘍量および体重を、週に2回測定し、マウス体重の変化および投与期間の間の関係ならびに腫瘍量の変化および投与期間の間の関係を記録した。実験の最後に、治療群対ビヒクル群における腫瘍量の割合(T/C)および腫瘍成長阻害(TGI)を算出し、統計的に解析した。Graphpad Prism 5を用いてT検定を実施し、腫瘍量を統計的に解析した。P<0.05は、有意差を有すると考えた。
Claims (35)
- 配列番号1、3、5、13、15、17、25、27、29、37、39および41からなる群から選択される重鎖CDR配列を含む、単離された抗体または抗原結合断片。
- 7、9、11、19、21、23、31、33および35からなる群から選択される軽鎖CDR配列をさらに含む、請求項1に記載の抗体またはその抗原結合断片。
- a)配列番号1、配列番号3および/または配列番号5を含む重鎖可変領域、
b)配列番号13、配列番号15および/または配列番号17を含む重鎖可変領域、
c)配列番号25、配列番号27および/または配列番号29を含む重鎖可変領域、ならびに
d)配列番号37、配列番号39および/または配列番号41を含む重鎖可変領域
からなる群から選択される重鎖可変領域を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。 - a)配列番号7、配列番号9および/または配列番号11を含む軽鎖可変領域、
b)配列番号19、配列番号21および/または配列番号23を含む軽鎖可変領域、ならびに
c)配列番号31、配列番号33および/または配列番号35を含む軽鎖可変領域
からなる群から選択される軽鎖可変領域を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。 - a)配列番号1、配列番号3および/もしくは配列番号5を含む重鎖可変領域ならびに配列番号7、配列番号9および/もしくは配列番号11を含む軽鎖可変領域、
b)配列番号13、配列番号15および/もしくは配列番号17を含む重鎖可変領域ならびに配列番号19、配列番号21および/もしくは配列番号23を含む軽鎖可変領域、
c)配列番号25、配列番号27および/もしくは配列番号29を含む重鎖可変領域ならびに配列番号31、配列番号33および/もしくは配列番号35を含む軽鎖可変領域、または
d)配列番号37、配列番号39および/または配列番号41を含む重鎖可変領域ならびに配列番号19、配列番号21および/もしくは配列番号23を含む軽鎖可変領域
を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。 - 配列番号43、配列番号47、配列番号51および配列番号55からなる群から選択される重鎖可変領域を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 配列番号45、配列番号49および配列番号53からなる群から選択される軽鎖可変領域を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- a)配列番号43を含む重鎖可変領域および配列番号45を含む軽鎖可変領域、
b)配列番号47を含む重鎖可変領域および配列番号49を含む軽鎖可変領域、
c)配列番号51を含む重鎖可変領域および配列番号53を含む軽鎖可変領域、または
d)配列番号55を含む重鎖可変領域および配列番号49を含む軽鎖可変領域
を含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。 - プラズモン共鳴結合アッセイによって測定されるものとして、10-8M以下のKd値でヒトPD−L1と特異的に結合可能である、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 10nM以下または1nM以下のEC50でサルPD−L1と結合し、および/またはマウスPD−L1と結合しない、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 100nM以下のIC50で、ヒトまたはサルPD−L1の、その受容体との結合を阻害可能である、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- PD−L2と実質的に結合しない、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- ADCCまたはCDCまたはその両方を媒介しない、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 完全ヒトモノクローナル抗体である、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 完全ヒトモノクローナル抗体が、トランスジェニックラットによって生成される、請求項14に記載の抗体またはその抗原結合断片。
- 先行する請求項のいずれかに記載の抗体またはその抗原結合断片と同一のエピトープについて競合する、抗体またはその抗原結合断片。
- ヒトPD−L1のその受容体との結合を遮断可能であり、それによって、以下の活性:
a)CD4+T細胞におけるIL−2の生成を誘導すること、
b)CD4+T細胞におけるIFNγの生成を誘導すること、
c)CD4+T細胞の増殖を誘導すること、および
d)Tregの抑制機能を逆転させること
のうち少なくとも1つを提供する、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。 - ラクダ化単一ドメイン抗体、ダイアボディー、scFv、scFv二量体、BsFv、dsFv、(dsFv)2、dsFv−dsFv’、Fv断片、Fab、Fab’、F(ab’)2、dsダイアボディー、ナノボディー、ドメイン抗体または二価ドメイン抗体である、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 免疫グロブリン定常領域をさらに含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- コンジュゲートをさらに含む、先行する請求項のいずれかに記載の抗体またはその抗原結合断片。
- 請求項1から19に記載の抗体またはその抗原結合断片をコードする単離されたポリヌクレオチド。
- 請求項21に記載の単離されたポリヌクレオチドを含むベクター。
- 請求項22に記載のベクターを含む宿主細胞。
- 請求項1から19のいずれかに記載の抗体またはその抗原結合断片を発現させる方法であって、請求項23に記載の宿主細胞を、請求項21に記載のポリヌクレオチドが発現される条件下で培養することを含む、方法。
- 請求項1から20のいずれかに記載の抗体またはその抗原結合断片を含むキット。
- 生体サンプルにおいてヒトまたはサルPD−L1の存在またはレベルを検出する方法であって、生体サンプルを、請求項1から20のいずれかに記載の抗体またはその抗原結合断片に対して曝露すること、およびサンプルにおいてヒトまたはサルPD−L1の存在またはレベルを調べることを含む、方法。
- PD−L1アンタゴニストに対して応答する可能性が高い障害または状態を有する個体を同定する方法であって、請求項1から20のいずれかに記載の抗体またはその抗原結合断片を用いて、個体から得られた試験生体サンプルにおいてPD−L1の存在またはレベルを調べることを含み、試験生体サンプルにおけるPD−L1の存在または上方制御されたレベルが、応答性の見込みを示す、方法。
- 個体に、治療上有効な量の、請求項1から20のいずれかに記載の抗体またはその抗原結合断片を投与することをさらに含む、請求項27に記載の方法。
- PD−L1アンタゴニストで処置された対象における、治療的応答または疾患の進行をモニタリングする方法であって、請求項1から20のいずれかに記載の抗PD−L1抗体またはその抗原結合断片を用いて、個体から得られた試験生体サンプルにおいてPD−L1の存在またはレベルを調べることを含む方法。
- 請求項1から20のいずれかに記載の抗体またはその抗原結合断片および1種または複数の医薬上許容される担体を含む医薬組成物。
- 免疫応答の上方制御から恩恵を受けるであろう対象における状態を処置する方法であって、対象に、治療上有効な量の、請求項1から20のいずれかに記載の抗体またはその抗原結合断片を投与することを含む、方法。
- 対象が、PD−L1の上方制御された発現を有する、請求項31に記載の方法。
- 免疫応答の上方制御から恩恵を受けるであろう状態を処置するための医薬の製造における、請求項1から20のいずれかに記載の抗体またはその抗原結合断片の使用。
- 状態が、癌または慢性ウイルス感染である、請求項33に記載の使用。
- エピトープが、PD−L1の以下のアミノ酸残基:E58、E60、D61、K62、N63およびR113のうち少なくとも1個を含む、請求項16に記載の抗体またはその抗原結合断片。
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BR112018002428A2 (pt) | 2018-09-18 |
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PT3332006T (pt) | 2024-01-09 |
KR20180037222A (ko) | 2018-04-11 |
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EP3332006B1 (en) | 2023-10-11 |
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IL256803B (en) | 2022-11-01 |
SI3332006T1 (sl) | 2024-02-29 |
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JP2022115897A (ja) | 2022-08-09 |
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