JP7472183B2 - 活性化可能な抗ctla-4抗体およびその使用 - Google Patents
活性化可能な抗ctla-4抗体およびその使用 Download PDFInfo
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- JP7472183B2 JP7472183B2 JP2022036450A JP2022036450A JP7472183B2 JP 7472183 B2 JP7472183 B2 JP 7472183B2 JP 2022036450 A JP2022036450 A JP 2022036450A JP 2022036450 A JP2022036450 A JP 2022036450A JP 7472183 B2 JP7472183 B2 JP 7472183B2
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- CNHYKKNIIGEXAY-UHFFFAOYSA-N thiolan-2-imine Chemical compound N=C1CCCS1 CNHYKKNIIGEXAY-UHFFFAOYSA-N 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- 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
- C07K16/2818—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 CD28 or CD152
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Description
本出願は、2016年11月3日出願の米国仮特許出願第62/417,212号に基づく優先権の利益を主張し、その内容全体を引用により本明細書に包含させる。
電子的に提出された配列表(名称:3338_059PC02_SeqListing.txt;サイズ:527,968バイト;作成日:2017年10月27日)の内容は、その全体が引用により本明細書中に包含される。
免疫系は、腫瘍発生を制御し、腫瘍退縮に介在することができる。これには、腫瘍抗原特異的T細胞の産生と活性化が必要である。複数のT細胞共刺激受容体およびT細胞の負の調節因子、または共抑制性受容体が協調作用し、T細胞活性化、増殖およびエフェクター機能の獲得または喪失を制御する。最初に最もよく特徴付けられたT細胞共刺激性分子および共抑制性分子としては、CD28およびCTLA-4が挙げられる(Rudd et al. (2009) Immunol. Rev. 229: 12)。CD28は、抗原提示細胞上のB7-1およびB7-2リガンドに結合することによりT細胞受容体結合に共刺激性シグナルを提供する一方、CTLA-4は、T細胞増殖および機能を下方制御する負のシグナルを提供する。B7-1(CD80)およびB7-2(CD86)リガンドにも結合するが、CD28よりも高い親和性を有する、CTLA-4は、細胞自律的な(または内因性の)経路および非細胞自律的な(または外因性の)経路の両方を介してT細胞機能の負の調節因子として作用する。CD8およびCD4 Tエフェクター(Teff)機能の内因性調節には、T細胞活性化の結果としてのCTLA-4の誘導性表面発現、および対立する細胞でのB7リガンドの多価結合によるT細胞増殖およびサイトカイン増殖の阻害が介在する(Peggs et al. (2008) Immunol. Rev. 224:141)。
本発明は、重鎖可変(VH)ドメインを含む重鎖ならびにマスキング部分(MM)、切断可能部分(CM)および軽鎖可変(VL)ドメインを含む軽鎖を含む、活性化可能な抗ヒトCTLA-4抗体を提供する。かかる活性化可能な抗ヒトCTLA-4抗体は、腫瘍微小環境においてCTLA-4結合活性を有するが(ここで、マスキング部分は、腫瘍特異的プロテアーゼによる切断可能部分のタンパク質分解的切断によって除去される)、腫瘍外では顕著に低減したCTLA-4への結合を示す。このようにして、本発明の活性化可能な抗ヒトCTLA-4抗体は、抗腫瘍活性を保持しながら、腫瘍外の抗CTLA-4活性に関連する副作用を軽減する。
(i)CDRH1:SYTMH(配列番号557);CDRH2:FISYDGNNKYYADSVKG(配列番号558);および、CDRH3:TGWLGPFDY(配列番号559)を含む重鎖可変ドメイン(VH)を含む、重鎖;ならびに、
(ii)(a)CDRL1:RASQSVGSSYLA(配列番号560);CDRL2:GAFSRAT(配列番号561);および、CDRL3:QQYGSSPWT(配列番号562)を含む軽鎖可変ドメイン(VL);(b)切断可能部分(CM);および、(c)マスキング部分(MM)を含む、軽鎖(ここで、軽鎖は、MM-CM-VLのようにN末端からC末端への構造的配置を有する)
を含む。
(i)CDRH1:SYTMH(配列番号557);CDRH2:FISYDGNNKYYADSVKG(配列番号558);および、CDRH3:TGWLGPFDY(配列番号559)を含む重鎖可変ドメイン(VH)を含む、重鎖;ならびに
(ii)N末端からC末端へ、(a)マスキング部分(MM);(b)切断可能部分(CM);および、(c)CDRL1:RASQSVGSSYLA(配列番号560);CDRL2:GAFSRAT(配列番号561);および、CDRL3:QQYGSSPWT(配列番号562)を含む軽鎖可変ドメイン(VL)を含む、軽鎖
を含む。
を含む、活性化可能な抗体を製造する方法を提供する。
本発明をより容易に理解することができるように、特定の用語を最初に定義する。さらなる定義を詳細な説明中に記載している。
本発明は、従来の抗CTLA-4抗体(例えば、イピリムマブ)と同程度に有効であるが、より大きい、すなわち改善された安全性プロファイルを有する、改善された抗CTLA-4抗体を提供する。具体的には、改善された抗CTLA-4抗体は、活性化されるとヒトCTLA-4に特異的に結合する活性化可能なモノクローナル抗体(mAb)である。本明細書において活性化可能な抗CTLA-4抗体またはCTLA-4活性化可能な抗体とも呼ばれるこれらの改善された抗CTLA-4抗体は、異常なCTLA-4の発現および/または活性に関連する疾患または障害を含むがこれらに限定されない疾患または障害の症状を処置、予防、その進行の遅延、緩和および/または軽減する方法において使用される。例えば、活性化可能な抗CTLA-4抗体は、癌または他の新生物状態の症状を処置、予防、その進行の遅延、緩和および/または軽減する方法において使用される。活性化可能な抗体は、例えば、米国特許第8,513,390号、同第8,518,404号;同第9,120,853号;同第9,127,053号、および国際公開WO2016/149201に記載されている。
ある態様において、抗体またはその抗原結合ドメイン(AB)は、米国特許第6,984,720号および同第7,605,238号(引用によりその内容全体を本明細書中に包含させる)にて10D1として識別される抗CTLA-4抗体 イピリムマブの相補性決定領域(CDR)を含む。イピリムマブ(以前は、MDX-010およびBMS-734016としても公知)は、YERVOY(登録商標)として市販されており、転移性黒色腫の治療用に承認され、他の癌で臨床治験中である。Hoos et al. (2010) Semin. Oncol. 37:533; Hodi et al. (2010) N. Engl. J. Med. 363:711; Pardoll (2012) Nat. Immunol. 13(12): 1129を参照のこと。
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (配列番号344)
イピリムマブ-VH鎖
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSS (配列番号345)
ヒトκ定常LC
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号346)
マウスκ定常軽鎖
RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKD眼RHNSYTCEATHKTSTSPIVKSFNRNEC (配列番号347)
イピリムマブ-ヒトκLC
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号348)
イピリムマブ-マウスκLC
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKD眼RHNSYTCEATHKTSTSPIVKSFNRNEC (配列番号349)
ヒトIgG1定常HC
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (配列番号350)
マウスIgG1定常HC
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (配列番号351)
マウスIgG2a定常HC
AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (配列番号352)
イピリムマブ-VH-ヒトIgG1定常HC
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (配列番号353)
イピリムマブ-VH-マウスIgG1定常HC
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (配列番号354)
イピリムマブ-VH-マウスIgG2a定常HC
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (配列番号355)
ある態様において、CMはプロテアーゼに特異的であり、これは、処置および/または診断の部位における標的化された活性化可能な抗体の活性化のために腫瘍細胞における無調節なプロテアーゼ活性を活用するのに有用である。多数の研究が、固形腫瘍における異常なプロテアーゼレベル、例えばuPA、レグマイン、MT-SP1、マトリックスメタロプロテアーゼ(MMP)の相関を証明している(例えば、Murthy R V, et al. “Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer.” Clin Cancer Res. 11 (2005): 2293-2299; Nielsen B S, et al. “Urokinase plasminogen activator is localized in stromal cells in ductal breast cancer.” Lab Invest 81 (2001): 1485-1501; Look O R, et al. “In situ localization of gelatinolytic activity in the extracellular matrix of metastases of colon cancer in rat liver using quenched fluorogenic DQ-gelatin.” J Histochem Cytochem. 51 (2003): 821-829)。
本発明の活性化可能な抗CTLA-4抗体は、マスキング部分(MM)を含む。ある態様において、MMは、抗CTLA-4抗体にカップリングされるか、そうでなければ結合されるアミノ酸配列であって、MMが、抗CTLA-4抗体のCTLA-4への特異的結合能を低下させるように、活性化可能な抗CTLA-4抗体構築物内に位置する。ある態様において、MMは、抗原結合ドメインに特異的に結合する。好適なMMは、様々な既知の技術のいずれかを用いて同定される。例えば、ペプチドMMは、Daughertyらの米国特許出願公開第2009/0062142号およびDaughertyらの同第2012/0244154号(これらの内容は、その全体が引用により本明細書に包含される)に記載されている方法を用いて同定される。
本明細書に記載の特定の抗体は、表2から6に記載の、マスキング部分、切断可能部分、軽鎖可変ドメイン(VL)(または、対応するCDR)、および重鎖可変ドメイン(VH)(または、対応するCDR)の任意の組合せを含む活性化可能な抗CTLA-4抗体である。ある態様において、活性化可能な抗CTLA-4抗体は、マスキング部分としてYV01(配列番号1)、切断可能部分としてLSGRSDNH(配列番号313)、およびイピリムマブの軽鎖可変ドメイン(VL)(配列番号344)を含む軽鎖を含む。ある態様において、活性化可能な抗CTLA-4抗体は、マスキング部分としてYV01(配列番号1)、切断可能部分としてISSGLLSGRSDNH(2001)(配列番号297)、およびイピリムマブの軽鎖可変ドメイン(VL)のCDR(それぞれ、配列番号560、561および562)を含む軽鎖を含む。ある態様において、活性化可能な抗CTLA-4抗体は、イピリムマブの重鎖可変ドメイン(VH)(配列番号345)またはちょうど対応するCDR(配列番号557、558および559)を含む。
QGQSGSCRTQLYGYNLCPYGGGSSGGSGGSGGSGGGSGGGSGGSEIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号530) または
CRTQLYGYNLCPYGGGSSGGSGGSGGSGGGSGGGSGGSEIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号531)。
活性化可能な抗CTLA-4抗体を含む本発明の治療用製剤は、異常なCTLA-4発現および/または活性と関連する疾患または障害を含むが、これらに限定されない、疾患または障害の予防、処置またはそうでなければ緩和のために用いられる。例えば、活性化可能な抗CTLA-4抗体を含む本発明の治療法製剤は、癌免疫療法として、例えば癌に罹患している対象における内因性免疫応答を増強し、それによって対象を処置するために用いられ、その方法は、本明細書に記載の活性化可能な抗CTLA-4抗体のいずれかを治療的有効量で対象に投与することを含む。
当技術分野において知られている抗PD-1抗体は、本明細書に記載の方法において用いられ得る。特に、高い親和性でPD-1に特異的に結合する様々なヒトモノクローナル抗体は、米国特許第8,008,449号に記載されている。米国特許第8,008,449号に記載されている抗PD-1 ヒト化抗体はそれぞれ、以下の特徴のうちの1以上を示すことが実証されている:(a)Biacoreバイオセンサーシステムを用いた表面プラズモン共鳴によって決定するとき、1x10-7M未満のKDでヒトPD-1に結合する;(b)ヒトCD28、CTLA-4またはICOSに実質的に結合しない;(c)混合リンパ球反応(MLR)アッセイにおいてT細胞増殖を増加させる;(d)MLRアッセイにおいてインターフェロン-γを増加させる;(e)MLRアッセイにおいてIL-2分泌を増加させる;(f)ヒトPD-1およびカニクイザルPD-1に結合する;(g)PD-L1および/またはPD-L2のPD-1への結合を阻害する;(h)抗原特異的メモリー応答を刺激する;(i)抗体応答を刺激する;および、(j)インビボで腫瘍細胞増殖を阻害する。本発明において使用可能な抗PD-1抗体には、ヒトPD-1に特異的に結合し、そして少なくとも1つの、ある態様において、少なくとも5つの上記の特徴を示す、モノクローナル抗体が含まれる。
全ての抗PD-L1抗体を本明細書に記載の方法において用いることができる。本明細書に記載の方法において有用な抗PD-L1抗体の例としては、米国特許第9,580,507号に記載の抗体が挙げられる。米国特許第9,580,507号に記載の各抗PD-L1ヒトモノクローナル抗体は、以下の特徴の1以上を示すことが実証されている:(a)Biacoreバイオセンサーシステムを用いた表面プラズモン共鳴によって決定するとき、1x10-7M未満のKDでヒトPD-L1に結合する;(b)混合リンパ球反応(MLR)アッセイにおいてT細胞増殖を増加させる;(c)MLRアッセイにおいてインターフェロン-γ産生を増加させる;(d)MLRアッセイにおいてIL-2分泌を増加させる;(e)抗体応答を刺激する;および、(f)T細胞エフェクター細胞および/または樹状細胞に対する制御性T細胞(T regulatory cell)の効果を逆転させる。本発明において使用可能な抗PD-L1抗体には、ヒトPD-L1に特異的に結合し、そして少なくとも1つの、ある態様において、少なくとも5つの、上記の特徴を示す、モノクローナル抗体が含まれる。
本発明の活性化可能な抗CTLA-4抗体(本明細書中、“活性化合物”とも言う)、ならびにその誘導体、フラグメント、類縁体および相同体は、投与に適する医薬組成物に包含され得る。そのような組成物は、一般的に、活性化可能な抗体および薬学的に許容される担体を含む。本明細書で用いる用語“薬学的に許容される担体”は、医薬投与に適合する、あらゆる全ての溶媒、分散媒体、コーティング、抗菌剤および抗真菌剤、等張化剤および吸収遅延剤などを含むことを意図する。好適な担体は、この分野の標準的な参考書であるRemingtonのPharmaceutical Sciencesの最新版に記載されており、それは引用により本明細書中に包含される。そのような担体または希釈剤の好ましい例としては、水、生理食塩水、リンゲル溶液、デキストロース溶液および5%ヒト血清アルブミンが挙げられるが、これらに限定されない。リポソームおよび不揮発性油などの非水性ビークルも用いることができる。薬学的に活性な物質のためのそのような媒体および薬物の使用は、当技術分野においてよく知られている。任意の常套の媒体または薬物が活性化合物と適合しない場合を除き、組成物におけるそれらの使用が企図される。補助的活性化合物もまた、組成物に包含させ得る。
実施例1:
活性化可能な抗CTLA-4抗体についてのマスキング部分の同定
抗CTLA-4抗体のそれらの標的タンパク質への結合を減少させるマスキング部分(MM)を同定するために、PCT国際公開WO2009/025846、WO2010/081173およびWO2016/149201(それらの内容全体は引用により本明細書中に包含される)に記載の方法と同様の方法を用いて、抗CTLA-4抗体(すなわち、イピリムマブ)を用いて、ペプチドライブラリーをスクリーニングした。スクリーニングは、2回の磁気活性化細胞選別(MACS)精製と、その後の3回の蛍光活性化細胞選別(FACS)からなる。
コンセンサス1. C(L/M/V/T)Y(S/V/I)(F/L/M/A)(Y/F)N(V/I)CLDP (配列番号566)
コンセンサス2. CAQMYGYSMC(P/A)(H/R/A)T (配列番号567)
コンセンサス3. CX(M/I/Y/L/N/F)(Y/W/F/Q/T)(M/Y)YG(Y/V/F)(N/D)LCP(Y/F) (配列番号568)
コンセンサス4. (N/T)(S/T/M/A)CP(N/Y)HP(M/L)C(H/F/Y)D(Y/F/W) (配列番号569)。
活性化可能な抗muCTLA-4抗体の構築および特性化
活性化可能な抗CTLA-4抗体が腫瘍を処置するために用いられ得るという概念実証を示すために、6つの活性化可能な抗マウスCTLA-4抗体(クローン9D9に基づく)を、本明細書の実施例1および3に記載の方法と同様の技術を用いて構築した。これらの抗体は、マスキング部分としてのMY11またはMY03のいずれか、および切断可能部分としての、アミノ酸配列TSTSGRSANPRG(配列番号320)を有する“0003”、アミノ酸配列AVGLLAPP(配列番号323)を有する“1004”、またはアミノ酸配列ISSGLLSGRSDNH(配列番号297)を有する“2001”を含む。抗体は全てマウスIgG2aアイソタイプであった。対照として、抗マウスCTLA-4モノクローナル抗体(9D9)(“9D9 mg2a”)およびmIgG2aアイソタイプ(“mg2a”)を有するヒト抗ジフテリア毒素抗体を用いた。
活性化可能な抗ヒトCTLA-4抗体の構築
本明細書に記載の、抗CTLA4マスキング部分、切断可能部分および抗CTLA4抗体(例えば、イピリムマブ)を含む活性化可能な抗CTLA4抗体は、PCT公開公報WO2009/025846(同上)およびWO2010/081173(同上)、およびWO2016/118629(同上)に記載の方法と同様の方法により産生された。活性化可能な抗CTLA4抗体を、EXPI293(商標)細胞(Thermo Fisher Scientific)中で発現させ、そして製造業者のプロトコールに従ってプロテインAクロマトグラフィー(MabSelect SuRe、GE Healthcare)により精製した。得られた活性化可能な抗体の品質管理は、大部分が少なくとも95%のモノマーを含むことを示した。
活性化可能な抗ヒトCTLA-4抗体のインビトロ特性化
プロテアーゼ活性の不存在下における活性化可能な抗体のCTLA-4への結合能を評価するために、酵素結合免疫吸着アッセイ(ELISA)を用いて、結合親和性を測定した。簡単に説明すると、Nunc MaxiSorp(登録商標)プレートを、1μg/mLのヒトCTLA-4タンパク質(Sino Biological)のPBS溶液(pH 7.4)を100μL/ウェルで用いて、40℃にて一晩コーティングした。次いで、プレートをPBST(PBS、pH7.4、0.05% Tween-20)で3回洗浄し、ウェルを、室温で2時間、PBST中、10mg/mLのウシ血清アルブミン(BSA)を200μL/ウェル用いてブロッキングした。その後、プレートをPBSTでさらに3回洗浄した。その後、活性化可能な抗体を、下記の表8に示すように、段階希釈した。
活性化可能な抗ヒトCTLA-4抗体のインビボ特徴付け(characterization)
インビボで本明細書に記載の抗体を特徴付けするために、4つの活性化可能なヒト抗ヒトCTLA-4抗体(イピリムマブに基づく)を、マウスIgG2aを用いて調製した。該抗体は、マスキング部分としてYV04、YV23、YV24またはYV39、および切断可能部分として2001を含んだ(それぞれ、“Ipi YV04 2001”、“Ipi YV23 2001”、“Ipi YV24 2001”および“Ipi YV39 2001”)。対照として、イピリムマブ(“Ipi mg2a”)および非血縁のヒト抗ジフテリア毒素(“対照mg2a”)を用いた。これらの活性化可能な抗CTLA-4抗体の活性を、以下に記載のようにMC38腫瘍モデルを用いて評価した。
採取した腫瘍および脾臓を、gentleMACS Octo Dissociator(商標)(Miltenyi, San Diego, CA)で処理した。単一細胞懸濁液を以下のT細胞マーカーで染色した:CD4、CD8、CD19、ICOS、CD45、FoxP3、CTLA-4、CD3、Ki-67、PD-1、グランザイムBおよびLIVE/DEAD(登録商標)。
マウスを、体位、グルーミングおよび呼吸の変化、ならびに嗜眠について毎日チェックした。腫瘍および群の体重を、死亡、安楽死または試験期間の終了まで週2回記録した。処置に対する応答を腫瘍増殖阻害(TGI)の関数として測定し、これは以下のように計算された:% TGI={1-[(Tt-To)/(Ct-Co)]}×100、Tt=所定の日における処置群の腫瘍体積、To=初期の腫瘍体積、Ct=所定の日における対照群の腫瘍体積、Co=対照群の初期の腫瘍体積。腫瘍が約2500mm3を超える体積に達した場合、または潰瘍化したように見えた場合は、動物を安楽死させた。
マイクロソフトエクセルを用いて、腫瘍体積および体重の、平均値、標準偏差(SD)および中央値を計算した。試験動物の100%および少なくとも60%がそれぞれ各処置群に残ったときに、平均値および中央値を計算した。GraphPad Prism(登録商標)v.4ソフトウェアを用いてデータをプロットした。
修飾された切断可能部分を含む活性化可能な抗ヒトCTLA-4抗体のインビボ特徴付け
特定の切断可能部分配列における可能性のある脱アミド化部位を試験するために(実施例10参照)、ヒトIgG1および種々のCM配列を用いて活性化可能なヒト抗CTLA-4抗体を調製した。活性化可能な抗体は、マスキング部分としてYV39および切断可能部分として2001のいくつか変異体のうち1つ:WT(2001)、ANP(2012)、DNP(2011)またはQ(2008)を含む(それぞれ、“Ipi YV39 2001”、“Ipi YV39 2012”、“Ipi YV39 2011”および“Ipi YV39 2008”)。イピリムマブおよび非血縁のヒト抗ジフテリア毒素もまた対照として用いた。
活性化可能な抗ヒトCTLA-4抗体の非フコシル化バージョンのインビボ特徴付け
上記のように、コアフコース残基が存在しないことは、抗原結合またはCDCを変化させることなく、IgGの活性化FcγRIIIAへの改善された結合を介してADCCを強く増強することができる(Natsume et al. (2009) Drug Des. Devel. Ther. 3:7)。イピリムマブの非フコシル化形態(“Ipi NF”)およびipi YV39 2011の非フコシル化形態(“Ipi YV39 2011 NF”)を調製した。種々のマウス、ヒトおよびカニクイザルのFc受容体について、IpiおよびIpi NFの結合を決定した。結果を図19に示す。予期した通り、Ipi NFは、活性化受容体ヒトCD16a(FcγRIIIa)、カニクイザルCD16(FcγRIII)およびマウスFcγRIVに対して顕著に増強された親和性(すなわち、より低いKd)を示した。
カニクイザルにおける、活性化可能な抗ヒトCTLA-4抗体のインビボ特徴付け
霊長動物において抗CTLA-4抗体を評価するために、マスキング部分としてYV39を含み、切断可能部分として2001を含む活性化可能な抗体をカニクイザルに投与した。ビークルおよびイピリムマブを対照として用いた。各サルに10mgの抗体または抗CTLA-4活性化可能な抗体を投与し、抗体投与後0日目、4日目、8日目、15日目、22日目、36日目および43日目に採血した。図20に示すように、イピリムマブを投与されたサルにおいて、抗体投与後およそ8から15日目にKi67染色によって測定されるように、CD4+ T細胞増殖の急上昇があった。対照的に、活性化可能な抗CTLA-4抗体は、ビークル対照と同様に挙動し、そしてサルにおいてCD4+ T細胞増殖を誘導しなかった。これらのデータは、霊長動物においてさえも、活性化可能な抗CTLA-4抗体は、活性化を示したとしてもわずかしか示さず、特異的プロテアーゼが存在しないことを実証している。
活性化可能なCTLA-4抗体のKapp値およびME値
表9は、ヒトIgG1フォーマットにおける種々のマスキング部分および切断可能部分を含む、本明細書に記載の活性化可能な抗体についてのKapp値およびマスキング効率(ME)値を提供する。この表に提供された値は、図に示されたデータから計算された。Kappは、測定条件下での活性化可能な抗体の結合親和性を表し、この実施例ではELISAによる結合を表す。しかしながら、結合親和性は、初代細胞またはトランスフェクト細胞上で発現されるCTLA-4への結合によって、または限定されないが、表面プラズモン共鳴もしくは平衡透析などの他の物理的方法によっても測定できることを理解されたい。マスキング効率(ME)は、活性化可能な抗体のKappを、同じ条件下で測定したイピリムマブのKDで割ることによって計算される。
活性化型CTLA-4抗体の脱アミド化、異性化および安定化評価
実施例6に示唆されるように、特定の活性化可能なヒト抗CTLA-4抗体中の特定の切断可能部分(CM)配列における可能性のある脱アミド化部位を試験するために、そのような活性化可能な抗体を種々のCM配列を用いて調製した(すなわち、2001、2011、2012および2008)。切断可能部分2011、2012および2008において、2001切断可能部分に見られるDNH配列は、それぞれDNP、ANPおよびDQHに置き換えられた。
Claims (20)
- 重鎖および軽鎖を含む活性化可能な抗ヒトCTLA-4抗体であって:
(i)重鎖がCDRH1:SYTMH(配列番号557);CDRH2:FISYDGNNKYYADSVKG(配列番号558);およびCDRH3:TGWLGPFDY(配列番号559)を含む重鎖可変ドメイン(VH)を含み;および
(ii)軽鎖が以下を含み:
(a)CDRL1:RASQSVGSSYLA(配列番号560);CDRL2:GAFSRAT(配列番号561);およびCDRL3:QQYGSSPWT(配列番号562)を含む軽鎖可変ドメイン(VL);
(b)切断可能部分(CM)、ここでCMは2001(配列番号297)、2011(配列番号304)、および2012(配列番号305)からなる群から選択される;および
(c)マスキング部分(MM)、
ここで、軽鎖がN末端からC末端へMM-CM-VLの構造的配置を有し;かつ
活性化可能な抗ヒトCTLA-4抗体が非フコシル化されている、活性化可能な抗ヒトCTLA-4抗体。 - MMが、YV01(配列番号1)、YV02(配列番号2)、YV03(配列番号3)、YV04(配列番号4)、YV05(配列番号5)、YV06(配列番号6)、YV07(配列番号7)、YV08(配列番号8)、YV09(配列番号9)、YV10(配列番号10)、YV11(配列番号11)、YV12(配列番号12)、YV13(配列番号13)、YV14(配列番号14)、YV15(配列番号15)、YV16(配列番号16)、YV17(配列番号17)、YV18(配列番号18)、YV19(配列番号19)、YV20(配列番号20)、YV21(配列番号21)、YV22(配列番号22)、YV23(配列番号23)、YV24(配列番号24)、YV25(配列番号25)、YV26(配列番号26)、YV27(配列番号27)、YV28(配列番号28)、YV29(配列番号29)、YV30(配列番号30)、YV31(配列番号31)、YV32(配列番号32)、YV33(配列番号33)、YV34(配列番号34)、YV35(配列番号35)、YV36(配列番号36)、YV37(配列番号37)、YV38(配列番号38)、YV39(配列番号39)、YV40(配列番号40)、YV41(配列番号41)、YV42(配列番号42)、YV43(配列番号43)、YV44(配列番号44)、YV45(配列番号45)、YV46(配列番号46)、YV47(配列番号47)、YV48(配列番号48)、YV49(配列番号49)、YV50(配列番号50)、YV51(配列番号51)、YV52(配列番号52)、YV53(配列番号53)、YV54(配列番号54)、YV55(配列番号55)、YV56(配列番号56)、YV57(配列番号57)、YV58(配列番号58)、YV60(配列番号59)、YV61(配列番号60)、YV62(配列番号61)、YV63(配列番号62)、YV64(配列番号63)、YV65(配列番号64)、およびYV66(配列番号65)からなる群より選択される、請求項1に記載の活性化可能な抗ヒトCTLA-4抗体。
- MMが、YV04、YV23、YV24、YV39、YV61、YV62、YV63、またはYV64である、請求項2に記載の活性化可能な抗ヒトCTLA-4抗体。
- MMがYV39である、請求項3に記載の活性化可能な抗ヒトCTLA-4抗体。
- CMが、配列番号304に記載のアミノ酸配列を含む、請求項1-4のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体。
- 請求項1-5のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体であって:
(i)重鎖が、ヒトIgG1定常ドメインをさらに含み;かつ
(ii)軽鎖が、ヒト軽鎖カッパ定常ドメインをさらに含む、活性化可能な抗ヒトCTLA-4抗体。 - 第一のリンカーペプチド(LP1)および第二のリンカーペプチド(LP2)をさらに含む、請求項1-6のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体であって、ここで軽鎖がN末端からC末端へMM-LP1-CM-LP2-VLまたはMM-LP2-CM-LP1-VLの構造的配置を有する、活性化可能な抗ヒトCTLA-4抗体。
- スペーサーをさらに含む請求項1-7のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体であって、ここで軽鎖がN末端からC末端へスペーサー-MM-CM-VLの構造的配置を有する、活性化可能な抗ヒトCTLA-4抗体。
- 請求項6に記載の活性化可能な抗ヒトCTLA-4抗体であって:
(i)重鎖が、配列番号345に記載のアミノ酸配列を含み;かつ
(ii)軽鎖が、配列番号563、配列番号564、または配列番号565に記載のアミノ酸配列を含む、活性化可能な抗ヒトCTLA-4抗体。 - 軽鎖が、配列番号564に記載のアミノ酸配列を含む、請求項9に記載の活性化可能な抗ヒトCTLA-4抗体。
- 重鎖および軽鎖を含む活性化可能な抗ヒトCTLA-4抗体であって、ここで重鎖が配列番号353のアミノ酸配列を含み、かつ軽鎖が配列番号448のアミノ酸配列を含み、かつ、ここで活性化可能な抗ヒトCTLA-4抗体が非フコシル化されている、活性化可能な抗ヒトCTLA-4抗体。
- 毒性剤をさらに含む、請求項1-11のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体。
- 検出可能部分をさらに含む、請求項1-11のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体。
- 請求項1-11のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体および担体を含む、医薬組成物。
- さらなる治療剤を含む、請求項14に記載の医薬組成物。
- 請求項1-11のいずれか一項に記載の活性化可能な抗ヒトCTLA-4抗体の重鎖および軽鎖をコードする、単離された核酸分子。
- (i)請求項16に記載の単離された核酸分子を含む細胞を、非フコシル化された活性化可能な抗ヒトCTLA-4抗体の発現をもたらす条件下で培養すること;および
(ii)生産された非フコシル化された活性化可能な抗ヒトCTLA-4抗体を回収すること、を含む、非フコシル化された活性化可能な抗ヒトCTLA-4抗体を製造する方法。 - 請求項14または15に記載の医薬組成物の、それを必要とする対象においてCTLA-4活性を低下させるための医薬の製造における使用。
- 請求項14または15に記載の医薬組成物の、それを必要とする対象において癌を処置する、癌の症状を軽減する、または癌の進行を遅延させるための医薬の製造における使用。
- 癌が、膀胱癌、骨の癌、乳癌、カルチノイド、子宮頸癌、結腸癌、子宮内膜癌、神経膠腫、頭頸部癌、肝臓癌、肺癌、リンパ腫、黒色腫、卵巣癌、膵臓癌、前立腺癌、腎癌、肉腫、皮膚癌、胃癌、精巣癌、甲状腺癌、泌尿生殖器癌または尿路上皮癌である、請求項19に記載の使用。
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AU2017355446A1 (en) | 2019-05-02 |
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KR102584340B1 (ko) | 2023-10-10 |
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BR112019008223A2 (pt) | 2019-07-16 |
PE20191131A1 (es) | 2019-09-02 |
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SG11201902857SA (en) | 2019-05-30 |
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US11117968B2 (en) | 2021-09-14 |
JP2022091800A (ja) | 2022-06-21 |
EA201990875A1 (ru) | 2019-09-30 |
KR20190072626A (ko) | 2019-06-25 |
EP3535300A1 (en) | 2019-09-11 |
US20220089734A1 (en) | 2022-03-24 |
CN110072890B (zh) | 2022-11-29 |
KR20230141941A (ko) | 2023-10-10 |
WO2018085555A8 (en) | 2018-05-31 |
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TWI784983B (zh) | 2022-12-01 |
IL265625A (en) | 2019-05-30 |
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