JP2022500410A - 非マイクロサテライト高不安定性/ミスマッチ修復の良好な結腸直腸がんを処置するためのpd−1アンタゴニストおよびlag3アンタゴニストの組み合わせ - Google Patents
非マイクロサテライト高不安定性/ミスマッチ修復の良好な結腸直腸がんを処置するためのpd−1アンタゴニストおよびlag3アンタゴニストの組み合わせ Download PDFInfo
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Abstract
Description
BOR 最良総合効果
BID 1日2回の投薬
CBR 臨床的有用率
CDR 相補性決定領域
CHO チャイニーズハムスター卵巣
CR 完全奏功
DCR 病勢コントロール率
DFS 無病生存期間
DLT 用量制限毒性
DOR 奏功持続期間
DSDR 持続的病勢安定率
FFPE ホルマリン固定パラフィン包埋
FR フレームワーク領域
IgG 免疫グロブリンG
IHC 免疫組織化学または免疫組織化学的
irRC 免疫関連効果判定基準
IV 静脈内
MTD 最大耐量
NCBI 米国国立バイオテクノロジー情報センター
NCI 米国国立がん研究所
ORR 客観的奏効率
OS 全生存期間
PD 病勢進行
PD−1 プログラム死1
PD−L1 プログラム細胞死1リガンド1
PD−L2 プログラム細胞死1リガンド2
PFS 無増悪生存期間
PR 部分奏功
Q2W 2週に1回の投薬
Q3W 3週に1回の投薬
QD 1日に1回の投薬
RECIST 固形がんにおける効果判定基準
SD 病勢安定
VH 免疫グロブリン重鎖可変領域
VK 免疫グロブリンカッパ軽鎖可変領域
本発明がより容易に理解され得るように、ある種の技術用語および科学用語が下に具体的に定義される。本書類中のどこかで具体的に定義されないかぎり、本明細書中で用いられる全ての他の技術用語および科学用語は、本発明が属する技術分野の当業者により通例的に理解される意味を有す。
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET(配列番号32)。
MWEAQFLGLL FLQPLWVAPV KPLQPGAEVP VVWAQEGAPA QLPCSPTIPL QDLSLLRRAG
VTWQHQPDSG PPAAAPGHPL APGPHPAAPS SWGPRPRRYT VLSVGPGGLR SGRLPLQPRV
QLDERGRQRG DFSLWLRPAR RADAGEYRAA VHLRDRALSC RLRLRLGQAS MTASPPGSLR
ASDWVILNCS FSRPDRPASV HWFRNRGQGR VPVRESPHHH LAESFLFLPQ VSPMDSGPWG
CILTYRDGFN VSIMYNLTVL GLEPPTPLTV YAGAGSRVGL PCRLPAGVGT RSFLTAKWTP
PGGGPDLLVT GDNGDFTLRL EDVSQAQAGT YTCHIHLQEQ QLNATVTLAI ITVTPKSFGS
PGSLGKLLCE VTPVSGQERF VWSSLDTPSQ RSFSGPWLEA QEAQLLSQPW QCQLYQGERL
LGAAVYFTEL SSPGAQRSGR APGALPAGHL LLFLILGVLS LLLLVTGAFG FHLWRRQWRP
RRFSALEQGI HPPQAQSKIE ELEQEPEPEP EPEPEPEPEP EPEQL
(配列番号33);Uniprotアセッション番号P18627も参照されたい。
本発明の処置方法、医薬および使用において有用なPD−1アンタゴニストとしては、PD−1またはPD−L1に特異的に結合する、好ましくはヒトPD−1またはヒトPD−L1に特異的に結合するモノクローナル抗体(mAb)またはその抗原結合性断片を含む。mAbはヒト抗体、ヒト化抗体またはキメラ抗体であり得て、ヒト定常領域を包含し得る。いくつかの実施形態において、ヒト定常領域は、IgG1、IgG2、IgG3およびIgG4定常領域よりなる群から選択され、好ましい実施形態において、ヒト定常領域は、IgG1またはIgG4定常領域である。いくつかの実施形態において、抗原結合性断片は、Fab、Fab’−SH、F(ab’)2、scFvおよびFv断片よりなる群から選択される。
ペンブロリズマブ(MK−3475としても知られる)、WHO Drug Information,Vol.27,No.2,pages 161−162(2013)中に記載されている構造を有し、表3中に示される重鎖および軽鎖アミノ酸配列を含むヒト化IgG4 mAb;ニボルマブ(BMS−936558)、WHO Drug Information,Vol.27,No.1,pages 68−69(2013)中に記載されている構造を有し、表3中に示される重鎖および軽鎖アミノ酸配列を含むヒトIgG4 mAb;ヒト化抗体である、WO2008/156712中に記載されているh409A11、h409A16およびh409A17、ならびにMedImmuneにより開発中のAMP−514。
DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(配列番号22);および
以下のアミノ酸配列を含む重鎖免疫グロブリン:
QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
(配列番号23);または
以下のアミノ酸配列を含む軽鎖免疫グロブリン可変ドメイン:
DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK
(配列番号24(下線はCDR));および
以下のアミノ酸配列を含む重鎖免疫グロブリン可変ドメイン:
QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSS
(配列番号25(下線はCDR));または以下のCDRを含む:
CDR−L1:KASQSLDYEGDSDMN(配列番号26);
CDR−L2:GASNLES(配列番号27);
CDR−L3:QQSTEDPRT(配列番号28);
CDR−H1:DYNVD(配列番号29);
CDR−H2:DINPNDGGTIYAQKFQE(配列番号30);および
CDR−H3:NYRWFGAMDH(配列番号31)
本発明の1つの態様において、本発明は、個体にPD−1アンタゴニストおよびLAG3アンタゴニストを共投与することを含む、個体において非MSI−HまたはpMMRの結腸直腸がんを処置するための方法を提供する。本発明の別の態様において、本発明は、個体にPD−1アンタゴニストおよびLAG3アンタゴニストを含む組成物を投与することを含む、個体において非MSI−HまたはpMMRの結腸直腸がんを処置するための方法を提供する。
1. 非マイクロサテライト高不安定性(非MSI−H)のまたはミスマッチ修復良好(pMMR)な結腸直腸がんの処置における使用のためのLAG3アンタゴニストであって、前記使用がPD−1アンタゴニストとの組み合わせにおいてである、前記LAG3アンタゴニスト。
分子生物学における標準的方法は、Sambrook,Fritsch and Maniatis(1982&1989 2nd Edition,2001 3rd Edition) Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Sambrook and Russell(2001) Molecular Cloning,3rd ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY;Wu(1993) Recombinant DNA,Vol.217,Academic Press,San Diego,CA)に記載されている。標準的な方法はまた、Ausbelら、(2001) Current Protocols in Molecular Biology,Vols.1−4,John Wiley and Sons,Inc.New York,NY中にも出ており、これは細菌細胞におけるクローニングおよびDNA突然変異誘発(Vol.1)、哺乳動物細胞および酵母におけるクローニング(Vol.2)、複合糖質およびタンパク質の発現(Vol.3)およびバイオインフォマティクス(Vol.4)を記載している。
これは、組織学的または細胞学的に進行性固形腫瘍と確定診断された対象における、抗LAG3抗体Ab6単剤療法(パートA、アーム1)およびペンブロリズマブと組み合わせてのAb6(パートA、アーム2)の多施設共同の非盲検用量漸増試験であって、その後に、単剤療法としてのおよびペンブロリズマブと組み合わせてのAb6の有効性判定を伴う、ペンブロリズマブと組み合わせたAb6のランダム化および非ランダム化両方の用量確認(パートB)を行う試験である。
1. パートA − 臨床効果をもたらし得る治療が利用可能でない、組織学的または細胞学的に確認された転移性固形腫瘍を有する。
a. 局所療法によって不治とされるHNSCC。対象は、白金含有全身治療を受けた後に進行していた。局所進行性疾患に対する集学的治療の一部として与えられた全身治療は認められる。適格性のある原発腫瘍位置は、中咽頭、口腔、下咽頭および喉頭である。対象は、上咽頭(任意の組織型のもの)を原発腫瘍位置に有してはならない。PD−1処置のナイーブHNSCCコホートに組み入れられる対象は、先に抗PD−1/PD−L1治療で処置されていてはならない。
i. 少なくとも2回の抗PD−1/PD−L1 mAb投薬を受けている。
e. 腎盂、輸尿管、膀胱または尿道の局所進行性または転移性の尿路上皮癌であって、移行上皮細胞型(または移行型が主体の場合は移行/非移行の混合型)であり、治癒目的の局所治療に適さないもの。
i. 少なくとも2回の抗PD−1/PD−L1 mAb投薬を受けている。
パートBの非MSI−H結腸直腸がん患者からの検体を処置の前に解析した。解析用の検体は、ホルマリン固定パラフィン包埋(FFPE)組織切片である。PD−L1発現についてのIHC染色は、US2017/0285037に従って(この文献は参照によりその全体が組み入れられる)、Dako Autostainer Link 48プラットフォーム(Dako AS480)およびPD−L1 IHC 22C3 pharmDxアッセイのために検証された自動化染色プロトコールを用いて実施した。ベースラインからの最良の標的病変変化を有する対象のウォーターフォールプロットを図2および3中に示す。
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Claims (27)
- 個体にPD−1アンタゴニストおよびLAG3アンタゴニストを投与することを含む、個体において非マイクロサテライト高不安定性(非MSI−H)のまたはミスマッチ修復の良好(pMMR)な結腸直腸がんを処置するための方法。
- PD−1アンタゴニストがモノクローナル抗体またはその抗原結合性断片である、請求項1の方法。
- 個体がヒトであり、PD−1アンタゴニストがヒトPD−1に特異的に結合してヒトPD−L1のヒトPD−1への結合をブロックするモノクローナル抗体またはその抗原結合性断片である、請求項1の方法。
- PD−1アンタゴニストがヒトPD−L2のヒトPD−1への結合もブロックする、請求項3の方法。
- PD−1アンタゴニストが、(a)配列番号1、2および3の軽鎖CDR、ならびに、(b)配列番号6、7および8の重鎖CDR、を含む抗体またはその抗原結合性断片である、請求項4の方法。
- PD−1アンタゴニストが重鎖および軽鎖を含む抗PD−1抗体であって、ここで、重鎖は配列番号9を含む重鎖可変領域を含み、そして、軽鎖は配列番号4を含む軽鎖可変領域を含む、請求項4の方法。
- PD−1アンタゴニストが重鎖および軽鎖を含む抗PD−1抗体であって、ここで、重鎖は配列番号10を含み、そして、軽鎖は配列番号5を含む、請求項4の方法。
- PD−1アンタゴニストがペンブロリズマブである、請求項4の方法。
- PD−1アンタゴニストがペンブロリズマブバリアントである、請求項4の方法。
- PD−1アンタゴニストがニボルマブである、請求項4の方法。
- LAG3アンタゴニストがLAG3のMHCクラスII分子への結合をブロックするモノクローナル抗体またはその抗原結合性断片である、請求項1から10のいずれか一項の方法。
- LAG3アンタゴニストが、(a)配列番号26、27および28の軽鎖CDR、ならびに、(b)配列番号29、30および31の重鎖CDR、を含む抗体またはその抗原結合性断片である、請求項1から10のいずれか一項の方法。
- LAG3アンタゴニストが重鎖および軽鎖を含む抗LAG3モノクローナル抗体であって、ここで、重鎖は配列番号25を含む重鎖可変領域を含み、そして、軽鎖は配列番号24を含む軽鎖可変領域を含む、請求項1から10のいずれか一項の方法。
- LAG3アンタゴニストが重鎖および軽鎖を含む抗LAG3抗体であって、ここで、重鎖は配列番号23を含み、そして、軽鎖は配列番号22を含む、請求項1から10のいずれか一項の方法。
- LAG3アンタゴニストがAb6バリアントである、請求項1から10のいずれか一項の方法。
- LAG3アンタゴニストがレラトリマブである、請求項1から10のいずれか一項の方法。
- PD−1アンタゴニストが重鎖および軽鎖を含むヒト化抗PD−1抗体であって、ここで、重鎖は配列番号6、7および8の重鎖CDRを含む重鎖可変領域を含み、そして、軽鎖は配列番号1、2および3の軽鎖CDRを含む軽鎖可変領域を含み;ならびに、LAG3アンタゴニストが重鎖および軽鎖を含むヒト化抗LAG3抗体であって、ここで、重鎖は配列番号29、30および31の重鎖CDRを含む重鎖可変領域を含み、そして、軽鎖は配列番号26、27および28の軽鎖CDRを含む軽鎖可変領域を含む、請求項1の方法。
- PD−1アンタゴニストが重鎖および軽鎖を含む抗PD−1抗体であって、ここで、重鎖は配列番号9を含む重鎖可変領域を含み、そして、軽鎖は配列番号4を含む軽鎖可変領域を含み;ならびに、LAG3アンタゴニストが重鎖および軽鎖を含む抗LAG3抗体であって、ここで、重鎖は配列番号25を含む重鎖可変領域を含み、そして、軽鎖は配列番号24を含む軽鎖可変領域を含む、請求項1の方法。
- PD−1アンタゴニストが重鎖および軽鎖を含む抗PD−1抗体であって、ここで、重鎖は配列番号10を含み、そして、軽鎖は配列番号5を含み;ならびに、LAG3アンタゴニストが重鎖および軽鎖を含む抗LAG3抗体であって、ここで、重鎖は配列番号23を含み、そして、軽鎖は配列番号22を含む、請求項1の方法。
- PD−1アンタゴニストおよびLAG3アンタゴニストが共−製剤化される、請求項1から19のいずれか一項の方法。
- PD−1アンタゴニストおよびLAG3アンタゴニストが共投与される、請求項1から19のいずれか一項の方法。
- 個体が、先行して抗PD−1もしくは抗PD−L1治療で処置されていない、または先に抗PD−1治療を受けた際に進行性と確認されている、請求項1から21のいずれか一項の方法。
- 個体の腫瘍細胞がPD−L1発現陽性である、請求項1から22のいずれか一項の方法。
- 個体が、PD−L1発現についての単核炎症密度スコア≧2を有する、請求項1から22のいずれか一項の方法。
- 個体が、PD−L1発現についての組み合わせ陽性スコア≧1%を有する、請求項1から22のいずれか一項の方法。
- PD−L1発現が、PD−L1 IHC 22C3 pharmDxアッセイによって測定される、請求項24または25の方法。
- さらに、mFOLFOX7(オキサリプラチン、ロイコボリンおよび5−FU)またはFOLFIRI(イリノテカン、ロイコボリンおよび5−FU)を投与することを含む、請求項1〜26のいずれか一項の方法。
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US201862730772P | 2018-09-13 | 2018-09-13 | |
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US62/755,844 | 2018-11-05 | ||
PCT/US2019/050122 WO2020055702A1 (en) | 2018-09-13 | 2019-09-09 | Combination of pd-1 antagonist and lag3 antagonist for treating non-microsatellite instablity-high/proficient mismatch repair colorectal cancer |
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KR20240047338A (ko) | 2021-05-14 | 2024-04-12 | 신닥스 파마슈티컬스, 인크. | 메닌-mll 상호작용의 억제제 |
WO2023164638A1 (en) * | 2022-02-25 | 2023-08-31 | Bristol-Myers Squibb Company | Combination therapy for colorectal carcinoma |
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WO2016011357A1 (en) * | 2014-07-18 | 2016-01-21 | Advaxis, Inc. | Combination of a pd-1 antagonist and a listeria-based vaccine for treating prostate cancer |
JO3663B1 (ar) * | 2014-08-19 | 2020-08-27 | Merck Sharp & Dohme | الأجسام المضادة لمضاد lag3 وأجزاء ربط الأنتيجين |
US20170097333A1 (en) * | 2015-09-28 | 2017-04-06 | Merck Sharp & Dohme Corp. | Cell based assay to measure the t-cell stimulating capacity of anti-lag3 antibodies and other agents |
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US10613092B2 (en) * | 2016-04-01 | 2020-04-07 | Agilent Technologies, Inc. | Scoring methods for anti-PD therapy eligibility and compositions for performing same |
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