JPWO2021063201A5 - - Google Patents
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（ａ）配列番号３６に記載のＶＨに含有される、ＣＤＲ－Ｈ１若しくはその配列バリアント、ＣＤＲ－Ｈ２若しくはその配列バリアント及びＣＤＲ－Ｈ３若しくはその配列バリアント、並びに／又は
配列番号３７に記載のＶＬに含有される、ＣＤＲ－Ｌ１若しくはその配列バリアント、ＣＤＲ－Ｌ２若しくはその配列バリアント及びＣＤＲ－Ｌ３若しくはその配列バリアント、
（ｂ）配列番号１に記載の重鎖可変領域（ＶＨ）に含有される、ＣＤＲ－Ｈ１若しくはその配列バリアント、ＣＤＲ－Ｈ２若しくはその配列バリアント及びＣＤＲ－Ｈ３若しくはその配列バリアント、並びに／又は
配列番号２に記載の軽鎖可変領域（ＶＬ）に含有される、ＣＤＲ－Ｌ１若しくはその配列バリアント、ＣＤＲ－Ｌ２若しくはその配列バリアント及びＣＤＲ－Ｌ３若しくはその配列バリアント、
（ｃ）配列番号２０に記載のＶＨに含有される、ＣＤＲ－Ｈ１若しくはその配列バリアント、ＣＤＲ－Ｈ２若しくはその配列バリアント及びＣＤＲ－Ｈ３若しくはその配列バリアント、並びに／又は
配列番号２１に記載のＶＬに含有される、ＣＤＲ－Ｌ１若しくはその配列バリアント、ＣＤＲ－Ｌ２若しくはその配列バリアント及びＣＤＲ－Ｌ３若しくはその配列バリアント、
或いは
（ｄ）配列番号５４に記載のＶＨに含有される、ＣＤＲ－Ｈ１若しくはその配列バリアント、ＣＤＲ－Ｈ２若しくはその配列バリアント及びＣＤＲ－Ｈ３若しくはその配列バリアント、並びに／又は
配列番号５５に記載のＶＬに含有される、ＣＤＲ－Ｌ１若しくはその配列バリアント、ＣＤＲ－Ｌ２若しくはその配列バリアント及びＣＤＲ－Ｌ３若しくはその配列バリアント
を含み、
前記配列バリアントが、それが由来するＣＤＲと比較して、１個又は複数のアミノ酸の置換、欠失又は付加（例えば、１個、２個又は３個のアミノ酸の置換、欠失又は付加）を有するＣＤＲであり、好ましくは、前記置換が、保存的置換であり、
好ましくは、ＣＤＲが、Ｋａｂａｔ又はＩＭＧＴの番号付けシステムによって定義され、
好ましくは、前記抗体又はその抗原結合性断片の前記ＶＨ及び／又はＶＬが、ヒト又はマウスに由来する免疫グロブリンのフレームワーク領域（ＦＲ）を含み、
好ましくは、前記抗体又はその抗原結合性断片が、ヒトＰＤ－１に結合する、
抗体又はその抗原結合性断片。 An antibody or antigen-binding fragment thereof that specifically binds to PD-1, wherein the antibody or antigen-binding fragment thereof has the following complementarity determining regions (CDRs):
(a) CDR-H1 or a sequence variant thereof, CDR-H2 or a sequence variant thereof, and CDR-H3 or a sequence variant thereof contained in the VH set forth in SEQ ID NO: 36, and/or
CDR-L1 or a sequence variant thereof, CDR-L2 or a sequence variant thereof, and CDR-L3 or a sequence variant thereof, contained in the VL set forth in SEQ ID NO: 37;
( b ) CDR-H1 or a sequence variant thereof, CDR-H2 or a sequence variant thereof, and CDR-H3 or a sequence variant thereof contained in the heavy chain variable region (VH) set forth in SEQ ID NO: 1, and/or SEQ ID NO: CDR-L1 or a sequence variant thereof, CDR-L2 or a sequence variant thereof, and CDR-L3 or a sequence variant thereof, contained in the light chain variable region (VL) according to 2.
( c ) CDR-H1 or a sequence variant thereof, CDR-H2 or a sequence variant thereof, and CDR-H3 or a sequence variant thereof contained in the VH set forth in SEQ ID NO: 20, and/or the VL set forth in SEQ ID NO: 21. CDR-L1 or a sequence variant thereof, CDR-L2 or a sequence variant thereof, and CDR-L3 or a sequence variant thereof,
or (d) CDR-H1 or a sequence variant thereof, CDR-H2 or a sequence variant thereof, and CDR-H3 or a sequence variant thereof, and/or sequence contained in the VH set forth in SEQ ID NO: 54. Containing CDR-L1 or a sequence variant thereof, CDR-L2 or a sequence variant thereof, and CDR-L3 or a sequence variant thereof contained in the VL described in No. 55,
The sequence variant contains one or more amino acid substitutions, deletions or additions (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions) compared to the CDR from which it is derived. preferably the substitution is a conservative substitution,
Preferably, the CDRs are defined by the Kabat or IMGT numbering system;
Preferably, the VH and/or VL of the antibody or antigen-binding fragment thereof comprises an immunoglobulin framework region (FR) derived from human or mouse,
Preferably, the antibody or antigen-binding fragment thereof binds to human PD-1.
Antibodies or antigen-binding fragments thereof.
（１）重鎖可変領域（ＶＨ）及び／又は軽鎖可変領域（ＶＬ）であって、ＩＭＧＴの番号付けシステムによって定義して、
（１ａ）前記ＶＨが、配列番号３８に記載の配列を有するＣＤＲ－Ｈ１、配列番号３９に記載の配列を有するＣＤＲ－Ｈ２及び配列番号４０に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号４１に記載の配列を有するＣＤＲ－Ｌ１、配列番号４２に記載の配列を有するＣＤＲ－Ｌ２及び配列番号４３に記載の配列を有するＣＤＲ－Ｌ３を含むか、
（１ｂ）前記ＶＨが、配列番号３に記載の配列を有する相補性決定領域（ＣＤＲ）－Ｈ１、配列番号４に記載の配列を有するＣＤＲ－Ｈ２及び配列番号５に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号６に記載の配列を有するＣＤＲ－Ｌ１、配列番号７に記載の配列を有するＣＤＲ－Ｌ２及び配列番号８に記載の配列を有するＣＤＲ－Ｌ３を含むか、
（１ｃ）前記ＶＨが、配列番号２２に記載の配列を有するＣＤＲ－Ｈ１、配列番号２３に記載の配列を有するＣＤＲ－Ｈ２及び配列番号２４に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号２５に記載の配列を有するＣＤＲ－Ｌ１、配列番号２６に記載の配列を有するＣＤＲ－Ｌ２及び配列番号２７に記載の配列を有するＣＤＲ－Ｌ３を含むか、
又は
（１ｄ）前記ＶＨが、配列番号５６に記載の配列を有するＣＤＲ－Ｈ１、配列番号５７に記載の配列を有するＣＤＲ－Ｈ２及び配列番号５８に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号５９に記載の配列を有するＣＤＲ－Ｌ１、配列番号６０に記載の配列を有するＣＤＲ－Ｌ２及び配列番号６１に記載の配列を有するＣＤＲ－Ｌ３を含む、
ＶＨ及び／又はＶＬ、
或いは
（２）重鎖可変領域（ＶＨ）及び／又は軽鎖可変領域（ＶＬ）であって、Ｋａｂａｔの番号付けシステムによって定義して、
（２ａ）前記ＶＨが、配列番号４４に記載の配列を有するＣＤＲ－Ｈ１、配列番号４５に記載の配列を有するＣＤＲ－Ｈ２及び配列番号４７に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号４８に記載の配列を有するＣＤＲ－Ｌ１、配列番号４９に記載の配列を有するＣＤＲ－Ｌ２及び配列番号５０に記載の配列を有するＣＤＲ－Ｌ３を含むか、
（２ｂ）前記ＶＨが、配列番号９に記載の配列を有するＣＤＲ－Ｈ１、配列番号１０に記載の配列を有するＣＤＲ－Ｈ２及び配列番号１２に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号１３に記載の配列を有するＣＤＲ－Ｌ１、配列番号１４に記載の配列を有するＣＤＲ－Ｌ２及び配列番号１５に記載の配列を有するＣＤＲ－Ｌ３を含むか、
（２ｃ）前記ＶＨが、配列番号２８に記載の配列を有するＣＤＲ－Ｈ１、配列番号２９に記載の配列を有するＣＤＲ－Ｈ２及び配列番号３０に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号３１に記載の配列を有するＣＤＲ－Ｌ１、配列番号３２に記載の配列を有するＣＤＲ－Ｌ２及び配列番号３３に記載の配列を有するＣＤＲ－Ｌ３を含むか、
又は
（２ｄ）前記ＶＨが、配列番号６２に記載の配列を有するＣＤＲ－Ｈ１、配列番号６３に記載の配列を有するＣＤＲ－Ｈ２及び配列番号６４に記載の配列を有するＣＤＲ－Ｈ３を含み、並びに／若しくは
前記ＶＬが、配列番号６５に記載の配列を有するＣＤＲ－Ｌ１、配列番号６６に記載の配列を有するＣＤＲ－Ｌ２及び配列番号６７に記載の配列を有するＣＤＲ－Ｌ３を含む、
ＶＨ及び／又はＶＬ、
或いは
（３）重鎖可変領域（ＶＨ）及び／又は軽鎖可変領域（ＶＬ）であって、少なくとも１つのＣＤＲが、（１ａ）、（１ｂ）、（１ｃ）、（１ｄ）又は（２ａ）、（２ｂ）、（２ｃ）、（２ｄ）のうちのいずれか１つの前記ＶＨ及び／又はＶＬと比較して、１個若しくは複数のアミノ酸の置換、欠失若しくは付加、又はそれらの任意の組合せ（例えば、１個、２個若しくは３個のアミノ酸の置換、欠失若しくは付加、又はそれらの任意の組合せ）から選択される突然変異を含有し、好ましくは、前記置換が、保存的置換である、
ＶＨ及び／又はＶＬ
を含む、
請求項１に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof is
(1) a heavy chain variable region (VH) and/or a light chain variable region (VL), as defined by the IMGT numbering system;
(1a) the VH comprises CDR-H1 having the sequence set forth in SEQ ID NO: 38, CDR-H2 having the sequence set forth in SEQ ID NO: 39, and CDR-H3 having the sequence set forth in SEQ ID NO: 40, and/ Or
The VL includes CDR-L1 having the sequence set forth in SEQ ID NO: 41, CDR-L2 having the sequence set forth in SEQ ID NO: 42, and CDR-L3 having the sequence set forth in SEQ ID NO: 43,
(1 b ) The VH has a complementarity determining region (CDR)-H1 having the sequence set forth in SEQ ID NO: 3, a CDR-H2 having the sequence set forth in SEQ ID NO: 4, and a CDR having the sequence set forth in SEQ ID NO: 5. -H3 and/or the VL includes CDR-L1 having the sequence set forth in SEQ ID NO: 6, CDR-L2 having the sequence set forth in SEQ ID NO: 7, and CDR-L3 having the sequence set forth in SEQ ID NO: 8. contains or
(1 c ) the VH comprises CDR-H1 having the sequence set forth in SEQ ID NO: 22, CDR-H2 having the sequence set forth in SEQ ID NO: 23, and CDR-H3 having the sequence set forth in SEQ ID NO: 24, and /or the VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 25, CDR-L2 having the sequence set forth in SEQ ID NO: 26, and CDR-L3 having the sequence set forth in SEQ ID NO: 27;
or (1d) the VH is CDR-H1 having the sequence set forth in SEQ ID NO:56, CDR-H2 having the sequence set forth in SEQ ID NO:57, and CDR-H2 having the sequence set forth in SEQ ID NO:58. H3 and/or the VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 59, CDR-L2 having the sequence set forth in SEQ ID NO: 60, and CDR-L3 having the sequence set forth in SEQ ID NO: 61. include,
VH and/or VL,
or (2) a heavy chain variable region (VH) and/or a light chain variable region (VL), as defined by the Kabat numbering system,
(2a) the VH comprises CDR-H1 having the sequence set forth in SEQ ID NO: 44, CDR-H2 having the sequence set forth in SEQ ID NO: 45, and CDR-H3 having the sequence set forth in SEQ ID NO: 47, and/ Or
The VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 48, CDR-L2 having the sequence set forth in SEQ ID NO: 49, and CDR-L3 having the sequence set forth in SEQ ID NO: 50,
(2 b ) the VH includes CDR-H1 having the sequence set forth in SEQ ID NO: 9, CDR-H2 having the sequence set forth in SEQ ID NO: 10, and CDR-H3 having the sequence set forth in SEQ ID NO: 12, and /or the VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 13, CDR-L2 having the sequence set forth in SEQ ID NO: 14, and CDR-L3 having the sequence set forth in SEQ ID NO: 15;
(2 c ) the VH comprises CDR-H1 having the sequence set forth in SEQ ID NO: 28, CDR-H2 having the sequence set forth in SEQ ID NO: 29, and CDR-H3 having the sequence set forth in SEQ ID NO: 30, and /or the VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 31, CDR-L2 having the sequence set forth in SEQ ID NO: 32, and CDR-L3 having the sequence set forth in SEQ ID NO: 33 ;
or (2d) the VH is CDR-H1 having the sequence set forth in SEQ ID NO: 62, CDR-H2 having the sequence set forth in SEQ ID NO: 63, and CDR-H2 having the sequence set forth in SEQ ID NO: 64. H3 and/or the VL comprises CDR-L1 having the sequence set forth in SEQ ID NO: 65, CDR-L2 having the sequence set forth in SEQ ID NO: 66, and CDR-L3 having the sequence set forth in SEQ ID NO: 67. include,
VH and/or VL,
or (3) a heavy chain variable region (VH) and/or a light chain variable region (VL) in which at least one CDR is (1a), (1b), (1c), (1d) or (2a) , (2b), (2c), (2d), one or more amino acid substitutions, deletions or additions, or any combination thereof, compared to the VH and/or VL of any one of (2b), (2c), (2d). (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions, or any combination thereof), preferably said substitutions are conservative substitutions. ,
VH and/or VL
including,
The antibody or antigen-binding fragment thereof according to claim 1.
（ａ）配列番号５２、５１、１６、１７及び３４のうちのいずれか１つに記載のＶＨ、並びに／又は配列番号５３、１８、１９及び３５のうちのいずれか１つに記載のＶＬ、
（ｂ）配列番号３６、１、２０及び５４のうちのいずれか１つに記載のＶＨ、並びに／又は配列番号３７、２、２１及び５５のうちのいずれか１つに記載のＶＬ、
（ｃ）（ａ）若しくは（ｂ）のいずれかの前記ＶＨと少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する重鎖可変領域（ＶＨ）；及び／又は（ａ）若しくは（ｂ）のいずれかの前記ＶＬと少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する軽鎖可変領域（ＶＬ）、或いは
（ｄ）（ａ）若しくは（ｂ）のいずれかの前記ＶＨと比較して、１個若しくは複数のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する重鎖可変領域（ＶＨ）；及び／又は（ａ）若しくは（ｂ）のいずれかの前記ＶＬと比較して、１個若しくは複数のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する軽鎖可変領域（ＶＬ）であって、好ましくは、前記置換が、保存的置換である、ＶＨ及び／又はＶＬ
を含む、請求項１又は２に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof is
(a) VH according to any one of SEQ ID NOs: 52, 51, 16, 17 and 34, and/or VL according to any one of SEQ ID NOs: 53, 18, 19 and 35;
( b ) VH as set forth in any one of SEQ ID NOs : 36, 1 , 20 and 54 and/or as set forth in any one of SEQ ID NOs : 37, 2 , 21 and 55 VL ,
( c) at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least a heavy chain variable region (VH) having 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; and/or at least with said VL of either (a) or (b); 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% or (d) one or more amino acid substitutions, deletions or additions compared to said VH of either (a) or (b); or any combination thereof (for example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or and/or one or more amino acid substitutions, deletions or additions compared to the VL of either (a) or (b); or any combination thereof (for example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or a light chain variable region (VL) having a VH and/or a VL (any combination of
The antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising:
（ａ）配列番号５２に記載の配列を有するＶＨ及び配列番号５３に記載の配列を有するＶＬ、
（ｂ）配列番号５１に記載の配列を有するＶＨ及び配列番号５３に記載の配列を有するＶＬ、
（ｃ）配列番号３６に記載の配列を有するＶＨ及び配列番号３７に記載の配列を有するＶＬ、
（ｄ）配列番号１に記載の配列を有するＶＨ及び配列番号２に記載の配列を有するＶＬ、
（ｅ）配列番号１６に記載の配列を有するＶＨ及び配列番号１８に記載の配列を有するＶＬ、
（ｆ）配列番号１７に記載の配列を有するＶＨ及び配列番号１９に記載の配列を有するＶＬ、
（ｇ）配列番号２０に記載の配列を有するＶＨ及び配列番号２１に記載の配列を有するＶＬ、
（ｈ）配列番号３４に記載の配列を有するＶＨ及び配列番号３５に記載の配列を有するＶＬ、
（ｉ）配列番号５４に記載の配列を有するＶＨ及び配列番号５５に記載の配列を有するＶＬ、
（ｊ）重鎖可変領域（ＶＨ）及び軽鎖可変領域（ＶＬ）であって、（ａ）～（ｉ）のうちのいずれかにおける前記ＶＨ及びＶＬと比較して、前記重鎖可変領域が、少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有し、及び／又は前記軽鎖可変領域（ＶＬ）が、少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有するか、或いは
（ｋ）重鎖可変領域（ＶＨ）及び軽鎖可変領域（ＶＬ）であって、（ａ）～（ｉ）のうちのいずれかにおける前記ＶＨ及びＶＬと比較して、前記重鎖可変領域（ＶＨ）が、１個若しくは複数のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有し、及び／又は前記軽鎖可変領域（ＶＬ）が、１個若しくは複数のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有し、好ましくは、前記置換が、保存的置換である
を含む、請求項１～３のいずれか一項に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof is
(a) VH having the sequence set forth in SEQ ID NO: 52 and VL having the sequence set forth in SEQ ID NO: 53;
(b) VH having the sequence set forth in SEQ ID NO: 51 and VL having the sequence set forth in SEQ ID NO: 53;
(c) VH having the sequence set forth in SEQ ID NO: 36 and VL having the sequence set forth in SEQ ID NO: 37;
( d ) VH having the sequence set forth in SEQ ID NO: 1 and VL having the sequence set forth in SEQ ID NO: 2,
( e ) VH having the sequence set forth in SEQ ID NO: 16 and VL having the sequence set forth in SEQ ID NO: 18,
( f ) VH having the sequence set forth in SEQ ID NO: 17 and VL having the sequence set forth in SEQ ID NO: 19,
( g ) VH having the sequence set forth in SEQ ID NO: 20 and VL having the sequence set forth in SEQ ID NO: 21,
( h ) VH having the sequence set forth in SEQ ID NO: 34 and VL having the sequence set forth in SEQ ID NO: 35 ,
( i) VH having the sequence set forth in SEQ ID NO: 54 and VL having the sequence set forth in SEQ ID NO: 55;
(j) a heavy chain variable region (VH) and a light chain variable region (VL), wherein compared to the VH and VL in any of (a) to (i), the heavy chain variable region , at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and/or said light chain variable region (VL) is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% have at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, or (k) a heavy chain variable region (VH) and a light chain variable region (VL ), wherein the heavy chain variable region (VH) has one or more amino acid substitutions, deletions, or additions compared to the VH and VL in any of (a) to (i). , or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or and/or the light chain variable region (VL) has one or more amino acid substitutions, deletions or additions, or any combination thereof (e.g. 1, 2 , 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions, or any combination thereof), preferably The antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, wherein the substitution is a conservative substitution.
（ａ）ヒト免疫グロブリン若しくはそのバリアントの重鎖定常領域（ＣＨ）、及び／又は
（ｂ）ヒト免疫グロブリン若しくはそのバリアントの軽鎖定常領域（ＣＬ）
を更に含み、
前記バリアントが、それが由来する野生型配列と少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有するか、又は前記バリアントが、それが由来する野生型配列と比較して、１個若しくは複数のアミノ酸の置換、欠失、付加、若しくはそれらの任意の組合せ（例えば、最大で５０個、最大で４５個、最大で４０個、最大で３５個、最大で３０個、最大で２５個、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の置換、欠失、付加、若しくはそれらの任意の組合せ；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失、付加、若しくはそれらの任意の組合せ）を有し、好ましくは、前記置換が、保存的置換であり、
好ましくは、前記重鎖定常領域が、ＩｇＧ重鎖定常領域、例えば、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３又はＩｇＧ４重鎖定常領域であり、
好ましくは、前記抗体又はその抗原結合性断片が、
（１）ヒトＩｇＧ１の重鎖定常領域、又は
（２）ヒトＩｇＧ４の重鎖定常領域
からなる群から選択される重鎖定常領域を含み、
好ましくは、前記軽鎖定常領域が、カッパ又はラムダ軽鎖定量領域であり、より好ましくは、前記抗体又はその抗原結合性断片が、ヒトカッパ軽鎖定常領域を含む、
請求項１～５のいずれか一項に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof is
(a) heavy chain constant region (CH) of a human immunoglobulin or variant thereof; and/or (b) light chain constant region (CL) of a human immunoglobulin or variant thereof.
further including;
The variant is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96% different from the wild type sequence from which it is derived. %, at least 97%, at least 98% or at least 99% sequence identity, or the variant has one or more amino acid substitutions, deletions, as compared to the wild-type sequence from which it is derived; addition, or any combination thereof (for example, up to 50, up to 45, up to 40, up to 35, up to 30, up to 25, up to 20, up to 15) , at most 10 or at most 5 amino acid substitutions, deletions, additions, or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions, additions, or any combination thereof), preferably said substitutions are conservative substitutions;
Preferably, the heavy chain constant region is an IgG heavy chain constant region, such as an IgG1, IgG2, IgG3 or IgG4 heavy chain constant region,
Preferably, the antibody or antigen-binding fragment thereof is
(1) a heavy chain constant region of human IgG1; or (2) a heavy chain constant region of human IgG4;
Preferably, the light chain constant region is a kappa or lambda light chain quantification region, more preferably, the antibody or antigen-binding fragment thereof comprises a human kappa light chain constant region.
The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.
（１）ＥＵ番号付けシステムによる、２３４、２３５、２６５及び４３４位のうちの少なくとも１つに突然変異を有するヒトＩｇＧ１の重鎖定常領域、好ましくは、突然変異：Ｌ２３４Ａ、Ｌ２３５Ａ、Ｄ２６５Ａ及びＮ４３４Ａのうちの１、２、３又は４つを有するヒトＩｇＧ１の重鎖定常領域の変異体（例えば、配列番号８３に記載の重鎖定常領域）、
（２）配列番号８３に記載の重鎖定常領域（ＣＨ）又はそのバリアントであって、前記バリアントが、配列番号８３と比較して、最大で２０個のアミノ酸の保存的置換（例えば、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の保存的置換；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の保存的置換）を有するか、又は配列番号８３と少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する、重鎖定常領域（ＣＨ）又はそのバリアント
（３）ＥＵ番号付けシステムによるヒトＩｇＧ４の重鎖定常領域の変異体（Ｓ２２８Ｐ）、或いは
（４）配列番号８２に記載の重鎖定常領域（ＣＨ）又はそのバリアントであって、前記バリアントが、配列番号８２と比較して、最大で２０個のアミノ酸の保存的置換（例えば、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の保存的置換；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の保存的置換）を有するか、又は配列番号８２と少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する、重鎖定常領域（ＣＨ）又はそのバリアント、
を含み、
（２）又は（４）における前記突然変異又は置換が、前記突然変異又は置換なしの対応する抗体又は抗原結合性断片と比較して、前記抗体又は抗原結合性断片のＡＤＣＰ、ＡＤＣＣ及び／又はＣＤＣの活性をなくすか、又は低減し、
並びに／或いは
前記軽鎖定常領域又はそのバリアントが、
（５）カッパ軽鎖定常領域、又は
（６）配列番号８４に記載の軽鎖定常領域（ＣＬ）又はそのバリアントであって、前記バリアントが、配列番号８４と比較して、最大で２０個のアミノ酸の保存的置換（例えば、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の保存的置換；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の保存的置換）を有するか、又は配列番号８４と少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する、軽鎖定常領域（ＣＬ）又はそのバリアント
を含み、
好ましくは、前記抗体が、配列番号８２又は配列番号８３に記載の重鎖定常領域（ＣＨ）及び配列番号８４に記載の軽鎖定常領域（ＣＬ）を含む、
請求項６に記載の抗体又はその抗原結合性断片。 The heavy chain constant region or variant thereof is
(1) Heavy chain constant region of human IgG1 with a mutation in at least one of positions 234, 235, 265 and 434 according to the EU numbering system, preferably mutations: L234A, L235A, D265A and N434A. Variants of the heavy chain constant region of human IgG1 having one, two, three or four of them (e.g., the heavy chain constant region set forth in SEQ ID NO: 83),
(2) A heavy chain constant region (CH) set forth in SEQ ID NO: 83 or a variant thereof, wherein the variant comprises at most 20 conservative amino acid substitutions (e.g., at most Conservative substitutions of 20, at most 15, at most 10 or at most 5 amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8; 9 or 10 amino acid conservative substitutions) or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least Heavy chain constant region (CH) or variant thereof having 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity
( 3 ) Human IgG4 heavy chain constant region variant (S228P) according to the EU numbering system, or
(4 ) A heavy chain constant region (CH) set forth in SEQ ID NO: 82 or a variant thereof, wherein the variant comprises at most 20 conservative amino acid substitutions (e.g., at most Conservative substitutions of 20, at most 15, at most 10 or at most 5 amino acids; for example, 1, 2, 3, 4, 5, 6, 7, 8; 9 or 10 amino acid conservative substitutions) or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least a heavy chain constant region (CH) or variant thereof having 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity ;
including ;
The mutation or substitution in (2) or (4) improves ADCP, ADCC and/or CDC of the antibody or antigen-binding fragment compared to the corresponding antibody or antigen-binding fragment without the mutation or substitution. eliminate or reduce the activity of
and/or the light chain constant region or variant thereof,
(5) a kappa light chain constant region, or (6) a light chain constant region (CL) set forth in SEQ ID NO: 84, or a variant thereof, wherein the variant has at most 20 regions compared to SEQ ID NO: 84. Conservative substitutions of amino acids (e.g., conservative substitutions of at most 20, at most 15, at most 10 or at most 5 amino acids; for example, 1, 2, 3, 4, 5 , 6, 7, 8, 9 or 10 amino acid conservative substitutions) or at least 70%, at least 80%, at least 85%, at least 90%, at least 91% of SEQ ID NO: 84 a light chain constant region (CL) or variant thereof having at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity. including,
Preferably, the antibody comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 82 or SEQ ID NO: 83 and a light chain constant region (CL) as set forth in SEQ ID NO: 84.
The antibody or antigen-binding fragment thereof according to claim 6.
（ａ）配列番号５２に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号５３に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｂ）配列番号５１に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号５３に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｃ）配列番号３６に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号３７に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｄ）配列番号１に記載のＶＨ及び配列番号８３に記載の重鎖定常領域（ＣＨ）を含む重鎖、並びに配列番号２に記載のＶＬ及び配列番号８４に記載の軽鎖定常領域（ＣＬ）を含む軽鎖、
（ｅ）配列番号１６に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号１８に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｆ）配列番号１７に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号１９に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｇ）配列番号２０に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号２１に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｈ）配列番号３４に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号３５に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｉ）配列番号５４に記載のＶＨ及び配列番号８３に記載のＣＨを含む重鎖、並びに配列番号５５に記載のＶＬ及び配列番号８４に記載のＣＬを含む軽鎖、
（ｊ）重鎖及び軽鎖であって、（ａ）～（ｉ）のうちのいずれかにおける前記重鎖及び前記軽鎖と、前記重鎖が、少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有し、及び／又は前記軽鎖が、少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する、重鎖及び軽鎖
を含む、請求項１～７のいずれか一項に記載の抗体又はその抗原結合性断片。 The antibody is
(a) a heavy chain comprising a VH as set forth in SEQ ID NO: 52 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 53 and a CL as set forth in SEQ ID NO: 84;
(b) a heavy chain comprising a VH as set forth in SEQ ID NO: 51 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 53 and a CL as set forth in SEQ ID NO: 84;
(c) a heavy chain comprising a VH as set forth in SEQ ID NO: 36 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 37 and a CL as set forth in SEQ ID NO: 84;
( d ) A heavy chain comprising the VH set forth in SEQ ID NO: 1 and the heavy chain constant region (CH) set forth in SEQ ID NO: 83, and the VL set forth in SEQ ID NO: 2 and the light chain constant region (CL) set forth in SEQ ID NO: 84. ) containing light chains,
( e ) a heavy chain comprising a VH as set forth in SEQ ID NO: 16 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 18 and a CL as set forth in SEQ ID NO: 84;
( f ) a heavy chain comprising a VH as set forth in SEQ ID NO: 17 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 19 and a CL as set forth in SEQ ID NO: 84;
( g ) a heavy chain comprising a VH as set forth in SEQ ID NO: 20 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 21 and a CL as set forth in SEQ ID NO: 84;
( h ) a heavy chain comprising a VH as set forth in SEQ ID NO: 34 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 35 and a CL as set forth in SEQ ID NO: 84 ;
( i) a heavy chain comprising a VH as set forth in SEQ ID NO: 54 and a CH as set forth in SEQ ID NO: 83, and a light chain comprising a VL as set forth in SEQ ID NO: 55 and a CL as set forth in SEQ ID NO: 84;
(j) a heavy chain and a light chain, wherein the heavy chain and the light chain in any of (a) to (i) and the heavy chain are at least 70%, at least 80%, at least 85% , at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and/ or at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, 8. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, comprising a heavy chain and a light chain having at least 98% or at least 99% sequence identity.
（ａ）重鎖及び軽鎖であって、
前記重鎖が、
（ｉ）配列番号８６に記載の配列、
（ｉｉ）（ｉ）に記載の配列と比較して、１個若しくはいくつかのアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、最大で５０個、最大で４５個、最大で４０個、最大で３５個、最大で３０個、最大で２５個、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する配列、又は
（ｉｉｉ）（ｉ）に記載の配列と少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する配列
を含み、及び
前記軽鎖が、
（ｉｖ）配列番号８８に記載の配列、
（ｖ）（ｉｖ）に記載の配列と比較して、１個若しくはいくつかのアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、最大で５０個、最大で４５個、最大で４０個、最大で３５個、最大で３０個、最大で２５個、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する配列、又は
（ｖｉ）（ｉｖ）に記載の配列と少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する配列、
を含み、
好ましくは、（ｉｉ）又は（ｖ）における前記置換が、保存的置換である、重鎖及び軽鎖、
或いは
（ｂ）重鎖及び軽鎖であって、
前記重鎖が、
（ｉ）配列番号９０に記載の配列、
（ｉｉ）（ｉ）に記載の配列と比較して、１個若しくはいくつかのアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、最大で５０個、最大で４５個、最大で４０個、最大で３５個、最大で３０個、最大で２５個、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する配列、又は
（ｉｉｉ）（ｉ）に記載の配列と少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する配列
を含み、及び
前記軽鎖が、
（ｉｖ）配列番号１１に記載の配列、
（ｖ）（ｉｖ）に記載の配列と比較して、１個若しくはいくつかのアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ（例えば、最大で５０個、最大で４５個、最大で４０個、最大で３５個、最大で３０個、最大で２５個、最大で２０個、最大で１５個、最大で１０個若しくは最大で５個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ；例えば、１個、２個、３個、４個、５個、６個、７個、８個、９個若しくは１０個のアミノ酸の置換、欠失若しくは付加、若しくはそれらの任意の組合せ）を有する配列、又は
（ｖｉ）（ｉｖ）に記載の配列と少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％若しくは少なくとも９９％の配列同一性を有する配列（ｉｖ）
を含み、
好ましくは、（ｉｉ）又は（ｖ）における前記置換が、保存的置換である、重鎖及び軽鎖
を含む、請求項１～８のいずれか一項に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof is
(a) a heavy chain and a light chain,
The heavy chain is
(i) the sequence described in SEQ ID NO: 86,
(ii) substitution, deletion or addition of one or several amino acids, or any combination thereof (e.g. up to 50, up to 45, up to Substitution, deletion or addition of 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acids, or For example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or any combination thereof; (iii) at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% of the sequence according to (i) , comprising sequences having at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and said light chain comprises:
(iv) the sequence described in SEQ ID NO: 88,
(v) substitution, deletion or addition of one or several amino acids, or any combination thereof (e.g. up to 50, up to 45, up to Substitution, deletion or addition of 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acids, or For example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or any combination thereof; (vi) at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% of the sequence according to (iv) , sequences having at least 96%, at least 97%, at least 98% or at least 99% sequence identity;
including;
Preferably, said substitution in (ii) or (v) is a conservative substitution,
or (b) a heavy chain and a light chain,
The heavy chain is
(i) the sequence described in SEQ ID NO: 90,
(ii) substitution, deletion or addition of one or several amino acids, or any combination thereof (e.g. up to 50, up to 45, up to Substitution, deletion or addition of 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acids, or For example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or any combination thereof; (iii) at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% of the sequence according to (i) , comprising sequences having at least 96%, at least 97%, at least 98% or at least 99% sequence identity, and said light chain comprises:
(iv) the sequence described in SEQ ID NO: 11,
(v) substitution, deletion or addition of one or several amino acids, or any combination thereof (e.g. up to 50, up to 45, up to Substitution, deletion or addition of 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acids, or For example, substitution, deletion or addition of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids, or any combination thereof; (vi) at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% of the sequence according to (iv) , at least 96%, at least 97%, at least 98% or at least 99% sequence identity (iv)
including;
The antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, comprising a heavy chain and a light chain, wherein preferably the substitution in (ii) or (v) is a conservative substitution.
好ましくは、前記ｓｃＦｖが、
（ａ）配列番号５２に記載の配列を有するＶＨ及び配列番号５３に記載の配列を有するＶＬ、
（ｂ）配列番号５１に記載の配列を有するＶＨ及び配列番号５３に記載の配列を有するＶＬ、
（ｃ）配列番号３６に記載の配列を有するＶＨ及び配列番号３７に記載の配列を有するＶＬ、
（ｄ）配列番号１に記載の配列を有するＶＨ及び配列番号２に記載の配列を有するＶＬ、
（ｅ）配列番号１６に記載の配列を有するＶＨ及び配列番号１８に記載の配列を有するＶＬ、
（ｆ）配列番号１７に記載の配列を有するＶＨ及び配列番号１９に記載の配列を有するＶＬ、
（ｇ）配列番号２０に記載の配列を有するＶＨ及び配列番号２１に記載の配列を有するＶＬ、
（ｈ）配列番号３４に記載の配列を有するＶＨ及び配列番号３５に記載の配列を有するＶＬ、
又は
（ｉ）配列番号５４に記載の配列を有するＶＨ及び配列番号５５に記載の配列を有するＶＬ
を含む、請求項１～９のいずれか一項に記載の抗体又はその抗原結合性断片。 the antibody or antigen-binding fragment thereof is selected from the group consisting of scFv, Fab, Fab', F(ab') 2 , Fv fragment, disulfide-linked Fv (dsFv) and diabody;
Preferably, the scFv is
(a) VH having the sequence set forth in SEQ ID NO: 52 and VL having the sequence set forth in SEQ ID NO: 53;
(b) VH having the sequence set forth in SEQ ID NO: 51 and VL having the sequence set forth in SEQ ID NO: 53;
(c) VH having the sequence set forth in SEQ ID NO: 36 and VL having the sequence set forth in SEQ ID NO: 37;
( d ) VH having the sequence set forth in SEQ ID NO: 1 and VL having the sequence set forth in SEQ ID NO: 2,
( e ) VH having the sequence set forth in SEQ ID NO: 16 and VL having the sequence set forth in SEQ ID NO: 18,
( f ) VH having the sequence set forth in SEQ ID NO: 17 and VL having the sequence set forth in SEQ ID NO: 19,
( g ) VH having the sequence set forth in SEQ ID NO: 20 and VL having the sequence set forth in SEQ ID NO: 21,
( h ) VH having the sequence set forth in SEQ ID NO: 34 and VL having the sequence set forth in SEQ ID NO: 35 ,
or (i) VH having the sequence set forth in SEQ ID NO: 54 and VL having the sequence set forth in SEQ ID NO: 55.
The antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, comprising:
好ましくは、前記抗体又はその抗原結合性断片が、検出可能なマーカー、例えば、酵素（例えば、西洋ワサビペルオキシダーゼ）、放射性核種、蛍光色素、発光性物質（例えば、化学発光性物質）又はビオチンを有する、
請求項１～１０のいずれか一項に記載の抗体又はその抗原結合性断片。 the antibody or antigen-binding fragment thereof has a marker,
Preferably, the antibody or antigen-binding fragment thereof has a detectable marker, such as an enzyme (e.g. horseradish peroxidase), a radionuclide, a fluorescent dye, a luminescent substance (e.g. a chemiluminescent substance) or biotin. ,
The antibody or antigen-binding fragment thereof according to any one of claims 1 to 10.
（ａ）５０ｎＭ未満、例えば、２０ｎＭ、１０ｎＭ、１ｎＭ、０．１ｎＭ、０．０１ｎＭ、１ｐＭ、０．１ｐＭ未満又はそれよりも低いＫＤでＰＤ－１（例えば、ヒトＰＤ－１）に結合する、好ましくは、前記ＫＤが、バイオレイヤー干渉法（ＢＬＩ）又はＥＬＩＳＡによって測定される、
（ｂ）５０ｎＭ未満、例えば、２０ｎＭ、１０ｎＭ、１ｎＭ、０．９ｎＭ、０．８ｎＭ、０．７ｎＭ、０．６ｎＭ、０．５ｎＭ、０．４ｎＭ、０．３ｎＭ、０．２ｎＭ、０．１ｎＭ、０．０１ｎＭ、１ｐＭ、０．１ｐＭ未満又はそれよりも低いＥＣ５０でＰＤ－１（例えば、ヒトＰＤ－１）に結合する、好ましくは、前記ＥＣ５０が、フローサイトメトリー又は細胞競合ＥＬＩＳＡ技術によって測定される、
（ｃ）約０．１ｎｇ／ｍＬ～約１０００ｎｇ／ｍＬの範囲のＩＣ５０でＰＤ－１のＰＤ－Ｌ１又はＰＤ－Ｌ２への結合と競合する、好ましくは、前記ＩＣ５０が、ＥＬＩＳＡ技術によって測定される、
（ｄ）Ｔ細胞の活性化を増加させる、例えば、Ｔリンパ球におけるＩＦＮ－γ及び／又はＩＬ－２の発現を増加させる、
（ｅ）ＢＴＬＡ、ＰＤ－Ｌ１又はＩＣＯＳに結合しない、
（ｆ）腫瘍細胞を死滅させるか、又はその成長を阻害する、
（ｇ）良好な熱安定性を有する、或いは
（ｈ）ＡＤＣＰ、ＡＤＣＣ及びＣＤＣの活性のうちの少なくとも１つがないか、若しくは低減されている、例えば、ＡＤＣＣの活性がないか、若しくは低減されている；ＡＤＣＰの活性がないか、若しくは低減されている；ＡＤＣＰの活性がないか、若しくは低減されており、かつＡＤＣＣの活性がないか、若しくは低減されている；又は、ＡＤＣＰ、ＡＤＣＣ及びＣＤＣの活性がないか、若しくは低減されている
のうちの少なくとも１つを有する、請求項１～１１のいずれか一項に記載の抗体又はその抗原結合性断片。 The antibody or antigen-binding fragment thereof has the following properties:
(a) binds to PD-1 (e.g., human PD-1) with a K D of less than 50 nM, such as 20 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM, 1 pM, 0.1 pM or lower; , preferably said K D is measured by biolayer interferometry (BLI) or ELISA.
(b) less than 50 nM, such as 20 nM, 10 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM; Binds to PD-1 (e.g. human PD-1) with an EC 50 of less than 0.01 nM, 1 pM, 0.1 pM or lower, preferably when said EC 50 is determined by flow cytometry or cell competition ELISA techniques. to be measured,
(c) competes the binding of PD-1 to PD-L1 or PD-L2 with an IC 50 in the range of about 0.1 ng/mL to about 1000 ng/mL, preferably said IC 50 is determined by ELISA technique. be done,
(d) increasing T cell activation, e.g. increasing IFN-γ and/or IL-2 expression in T lymphocytes;
(e) does not bind to BTLA, PD-L1 or ICOS;
(f) killing tumor cells or inhibiting their growth;
(g) have good thermal stability; or (h) have at least one of the following activities: ADCP, ADCC and CDC, such as no or reduced activity of ADCC; ADCP activity is absent or reduced; ADCP activity is absent or reduced, and ADCC activity is absent or reduced; or ADCP, ADCC, and CDC activity is absent or reduced; The antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, which has at least one of no or reduced activity.
（ａ）前記抗体の前記重鎖をコードする前記核酸分子が、
（ｉ）配列番号８５に記載のヌクレオチド配列若しくはその縮重配列、
（ｉｉ）（ｉ）の前記ヌクレオチド配列と実質的に同一の配列（例えば、（ｉ）の前記ヌクレオチド配列と比較して、少なくとも約８５％、９０％、９５％、９９％以上の配列同一性を有する配列、又は１個若しくは複数のヌクレオチド置換を有する配列）、若しくは
（ｉｉｉ）３個、６個、１５個、３０個若しくは４５個以下のヌクレオチドにおいて、（ｉ）の前記ヌクレオチド配列と異なる配列
からなる群から選択される配列を有し、
並びに／又は、
前記抗体の前記軽鎖をコードする前記核酸分子が、
（ｉｖ）配列番号８７に記載のヌクレオチド配列若しくはその縮重配列、
（ｖ）（ｉｖ）の前記ヌクレオチド配列と実質的に同一の配列（例えば、（ｉｖ）の前記ヌクレオチド配列と比較して、少なくとも約８５％、９０％、９５％、９９％以上の配列同一性を有する配列、又は１個若しくは複数のヌクレオチド置換を有する配列）、若しくは
（ｖｉ）３個、６個、１５個、３０個若しくは４５個以下のヌクレオチドにおいて、（ｉｖ）の前記ヌクレオチド配列と異なる配列
からなる群から選択される配列を有するか、
或いは
（ｂ）前記抗体の前記重鎖をコードする前記核酸分子が、
（ｉ）配列番号８９に記載のヌクレオチド配列若しくはその縮重配列、
（ｉｉ）（ｉ）の前記ヌクレオチド配列と実質的に同一の配列（例えば、（ｉ）の前記ヌクレオチド配列と比較して、少なくとも約８５％、９０％、９５％、９９％以上の配列同一性を有する配列、又は１個若しくは複数のヌクレオチド置換を有する配列）、若しくは
（ｉｉｉ）３個、６個、１５個、３０個若しくは４５個以下のヌクレオチドにおいて、（ｉ）の前記ヌクレオチド配列と異なる配列
からなる群から選択される配列を有し、
並びに／又は、
前記抗体の前記軽鎖をコードする前記核酸分子が、
（ｉｖ）配列番号４６に記載のヌクレオチド配列若しくはその縮重配列、
（ｖ）（ｉｖ）の前記ヌクレオチド配列と実質的に同一の配列（例えば、（ｉｖ）の前記ヌクレオチド配列と比較して、少なくとも約８５％、９０％、９５％、９９％以上の配列同一性を有する配列、又は１個若しくは複数のヌクレオチド置換を有する配列）、若しくは
（ｖｉ）３個、６個、１５個、３０個若しくは４５個以下のヌクレオチドにおいて、（ｉｖ）の前記ヌクレオチド配列と異なる配列
からなる群から選択される配列を有し、
好ましくは、前記抗体の前記重鎖をコードする前記核酸分子が、配列番号８５に記載のヌクレオチド配列若しくはその縮重配列を有し、及び／又は前記抗体の前記軽鎖をコードする前記核酸分子が、配列番号８７に記載のヌクレオチド配列若しくはその縮重配列を有し、
好ましくは、前記抗体の前記重鎖をコードする前記核酸分子が、配列番号８９に記載のヌクレオチド配列若しくはその縮重配列を有し、及び／又は前記抗体の前記軽鎖をコードする前記核酸分子が、配列番号４６に記載のヌクレオチド配列若しくはその縮重配列を有する、
請求項１３に記載の単離された核酸分子。 comprising a nucleic acid molecule encoding the heavy chain of the antibody and/or a nucleic acid molecule encoding the light chain of the antibody,
(a) the nucleic acid molecule encoding the heavy chain of the antibody,
(i) the nucleotide sequence set forth in SEQ ID NO: 85 or a degenerate sequence thereof;
(ii) a sequence substantially identical to said nucleotide sequence of (i) (e.g., at least about 85%, 90%, 95%, 99% or more sequence identity as compared to said nucleotide sequence of (i)); or (iii) a sequence that differs from the nucleotide sequence of (i) in not more than 3, 6, 15, 30 or 45 nucleotides. having an array selected from the group consisting of;
and/or
The nucleic acid molecule encoding the light chain of the antibody,
(iv) the nucleotide sequence set forth in SEQ ID NO: 87 or a degenerate sequence thereof;
(v) a sequence substantially identical to said nucleotide sequence of (iv) (e.g., at least about 85%, 90%, 95%, 99% or more sequence identity as compared to said nucleotide sequence of (iv)); or (vi) differs from the nucleotide sequence of (iv) in no more than 3, 6, 15, 30 or 45 nucleotides. has a sequence selected from the group consisting of;
or (b) the nucleic acid molecule encoding the heavy chain of the antibody is
(i) the nucleotide sequence set forth in SEQ ID NO: 89 or a degenerate sequence thereof;
(ii) a sequence substantially identical to said nucleotide sequence of (i) (e.g., at least about 85%, 90%, 95%, 99% or more sequence identity as compared to said nucleotide sequence of (i)); or (iii) a sequence that differs from the nucleotide sequence of (i) in not more than 3, 6, 15, 30 or 45 nucleotides. having an array selected from the group consisting of;
and/or
The nucleic acid molecule encoding the light chain of the antibody,
(iv) the nucleotide sequence set forth in SEQ ID NO: 46 or a degenerate sequence thereof;
(v) a sequence substantially identical to said nucleotide sequence of (iv) (e.g., at least about 85%, 90%, 95%, 99% or more sequence identity as compared to said nucleotide sequence of (iv)); or (vi) differs from the nucleotide sequence of (iv) in no more than 3, 6, 15, 30 or 45 nucleotides. having an array selected from the group consisting of;
Preferably, the nucleic acid molecule encoding the heavy chain of the antibody has the nucleotide sequence set forth in SEQ ID NO: 85 or a degenerate sequence thereof, and/or the nucleic acid molecule encoding the light chain of the antibody has the nucleotide sequence set forth in SEQ ID NO: 85 or a degenerate sequence thereof. , having the nucleotide sequence set forth in SEQ ID NO: 87 or a degenerate sequence thereof,
Preferably, the nucleic acid molecule encoding the heavy chain of the antibody has the nucleotide sequence set forth in SEQ ID NO: 89 or a degenerate sequence thereof, and/or the nucleic acid molecule encoding the light chain of the antibody has the nucleotide sequence set forth in SEQ ID NO: 89 or a degenerate sequence thereof. , having the nucleotide sequence set forth in SEQ ID NO: 46 or a degenerate sequence thereof,
14. The isolated nucleic acid molecule of claim 13.
好ましくは、前記多特異性抗体が、二特異性抗体、又は三特異性抗体、又は四特異性抗体である、多特異性抗体。 A multispecific antibody comprising a first antibody or fragment thereof and an additional antibody or fragment thereof or an antibody mimetic, wherein said first antibody or fragment thereof is according to any one of claims 1 to 12. An antibody or antigen-binding fragment thereof that specifically binds to PD-1 as described above,
Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody.
任意選択で、前記医薬組成物が、追加の薬学的活性薬剤、例えば、抗腫瘍剤、放射性医薬品、免疫調節効果と関連する薬剤又は自己免疫疾患と関連する薬剤を更に含み、より好ましくは、前記抗腫瘍剤が、免疫調節効果と関連する抗体、例えば、抗ＬＡＧ－３抗体（例えば、ＡＢ１２Ｔ８）又はＴＩＭ－３抗体（例えば、ＡＢ１２Ｓ３）から選択される、
医薬組成物。 The antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, the nucleic acid molecule according to claim 13 or 14, the vector according to claim 15, the host cell according to claim 16, A multispecific antibody according to claim 18, a conjugate according to claim 19, a CAR cell according to claim 20, an oncolytic virus according to claim 21 and/or a fusion protein according to claim 22, and a pharmaceutically acceptable carrier and/or excipient, the composition comprising:
Optionally, said pharmaceutical composition further comprises an additional pharmaceutically active agent, such as an antineoplastic agent, a radiopharmaceutical, an agent associated with immunomodulatory effects or an agent associated with autoimmune diseases, more preferably said the anti-tumor agent is selected from antibodies associated with immunomodulatory effects, such as anti-LAG-3 antibodies (e.g. AB12T8) or TIM-3 antibodies (e.g. AB12S3);
Pharmaceutical composition.
（１）ＰＤ－１のＰＤ－Ｌ１又はＰＤ－Ｌ２への結合を阻害するか、又はブロックする、
（２）ＰＤ－１の活性を下方調節するか、又は排除する、
（３）ＰＤ－１又はＰＤ－Ｌ１又はＰＤ－Ｌ２によって誘導される免疫抑制を低減するか、又は軽減する、
（４）Ｔリンパ球におけるＩＦＮγ又はＩＬ－２の産生を増加させる、
（５）腫瘍細胞を死滅させるＴリンパ球の能力を増強する
のうちの少なくとも１つを誘発するのに十分な有効用量の前記抗体又はその抗原結合性断片を含む、請求項２３に記載の医薬組成物。 The pharmaceutical composition has the following biological activity in a subject:
(1) inhibiting or blocking the binding of PD-1 to PD-L1 or PD-L2;
(2) downregulating or eliminating the activity of PD-1;
(3) reduce or alleviate immunosuppression induced by PD-1 or PD-L1 or PD-L2;
(4) increasing the production of IFNγ or IL-2 in T lymphocytes;
24. The medicament of claim 23, comprising an effective dose of said antibody or antigen-binding fragment thereof sufficient to induce at least one of: (5) enhancing the ability of T lymphocytes to kill tumor cells. Composition.
任意選択で、前記腫瘍が、以下の組織：皮膚、骨髄、血液、リンパ液、頭頸部、脳、肺、乳房、胃、胆嚢、肝臓、膵臓、腸、卵巣、前立腺、副腎、腎臓、膀胱、子宮、子宮頸部、精巣、陰茎及び軟組織のうちの１つ又は複数に由来し、
任意選択で、前記感染症が、細菌感染症、病原体感染症、真菌感染症及びウイルス感染症からなる群から選択され、
任意選択で、前記感染症が、ウイルス感染症、例えば、ＨＩＶ、Ｂ型肝炎又はＣ型肝炎であり、任意選択で、前記感染症が、結核であり、
任意選択で、前記自己免疫疾患が、糖尿病、重症筋無力症、胃炎、天疱瘡、原発性胆汁性肝硬変、多発性硬化症、狼瘡、大腸炎、リウマチ性疾患及び甲状腺疾患からなる群から選択され、
好ましくは、前記腫瘍が、肺がん、肝臓がん、卵巣がん、子宮頸がん、皮膚がん、結腸がん、直腸がん、神経膠腫、膀胱がん、乳がん、腎臓がん、食道がん、胃がん、口腔扁平上皮がん、尿道上皮細胞がん及び膵臓がん、並びに頭頸部腫瘍からなる群から選択され、
好ましくは、前記抗腫瘍剤が、免疫調節効果と関連する抗体、例えば、抗ＬＡＧ－３抗体（例えば、ＡＢ１２Ｔ８）又はＴＩＭ－３抗体（例えば、ＡＢ１２Ｓ３）であり、
任意選択で、請求項２３又は２４に記載の医薬組成物及び追加の薬学的活性薬剤が、組み合わせて又は別々に、同時又は連続して投与される、
使用。 The antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, or according to claims 13 or 14, in the preparation of a medicament for preventing and/or treating tumors, infectious diseases or autoimmune diseases. A nucleic acid molecule according to claim 15, or a host cell according to claim 16, or a multispecific antibody according to claim 18, or a conjugate according to claim 19, or claim 20. or an oncolytic virus according to claim 21, or a fusion protein according to claim 22, or a pharmaceutical composition according to claim 23 or 24, or the use of a pharmaceutical composition according to claim 23 or 24 and an additional pharmaceutically active agent (e.g. an antineoplastic agent, a radiopharmaceutical, an agent associated with immunomodulatory effects or an agent associated with autoimmune diseases), ,
Optionally, the tumor is in the following tissues: skin, bone marrow, blood, lymph, head and neck, brain, lungs, breast, stomach, gallbladder, liver, pancreas, intestines, ovaries, prostate, adrenal glands, kidneys, bladder, uterus. , from one or more of the following: cervix, testis, penis and soft tissue;
Optionally, said infectious disease is selected from the group consisting of a bacterial infection, a pathogenic infection, a fungal infection and a viral infection;
Optionally, the infectious disease is a viral infection, such as HIV, hepatitis B or hepatitis C; optionally, the infectious disease is tuberculosis;
Optionally, said autoimmune disease is selected from the group consisting of diabetes, myasthenia gravis, gastritis, pemphigus, primary biliary cirrhosis, multiple sclerosis, lupus, colitis, rheumatic diseases and thyroid diseases. ,
Preferably, the tumor is lung cancer, liver cancer, ovarian cancer, cervical cancer, skin cancer, colon cancer, rectal cancer, glioma, bladder cancer, breast cancer, kidney cancer, or esophagus cancer. selected from the group consisting of: gastric cancer, oral squamous cell carcinoma, urothelial cell carcinoma and pancreatic cancer, and head and neck tumors;
Preferably, the anti-tumor agent is an antibody associated with immunomodulatory effects, such as an anti-LAG-3 antibody (e.g. AB12T8) or a TIM-3 antibody (e.g. AB12S3),
Optionally, a pharmaceutical composition according to claim 23 or 24 and an additional pharmaceutically active agent are administered in combination or separately, simultaneously or sequentially.
use.
（１）ＰＤ－１のＰＤ－Ｌ１又はＰＤ－Ｌ２への結合を阻害するか、又はブロックする、
（２）ＰＤ－１の活性を下方調節するか、又は排除する、
（３）ＰＤ－１又はＰＤ－Ｌ１又はＰＤ－Ｌ２によって誘導される免疫抑制を低減するか、又は軽減する、
（４）Ｔリンパ球におけるＩＦＮγ又はＩＬ－２の産生を増加させる、
（５）腫瘍細胞を死滅させるＴリンパ球の能力を増強する
のうちの少なくとも１つのためである、請求項２６に記載の使用。 The medicine is
(1) inhibiting or blocking the binding of PD-1 to PD-L1 or PD-L2;
(2) downregulating or eliminating the activity of PD-1;
(3) reduce or alleviate immunosuppression induced by PD-1 or PD-L1 or PD-L2;
(4) increasing the production of IFNγ or IL-2 in T lymphocytes;
27. The use according to claim 26, wherein the use is for at least one of: (5) enhancing the ability of T lymphocytes to kill tumor cells.
有効量の、請求項１～１２のいずれか一項に記載の抗体若しくはその抗原結合性断片、又は請求項１３若しくは１４に記載の核酸分子、又は請求項１５に記載のベクター、又は請求項１６に記載の宿主細胞、又は請求項１８に記載の多特異性抗体、又は請求項１９に記載のコンジュゲート、又は請求項２０に記載のキメラ抗原受容体（ＣＡＲ）を発現する細胞、又は請求項２１に記載の腫瘍溶解性ウイルス、又は請求項２２に記載の融合タンパク質、又は請求項２３若しくは２４に記載の医薬組成物を投与するステップ、
任意選択で、抗腫瘍剤、放射性医薬品、免疫調節効果と関連する薬剤又は自己免疫疾患と関連する薬剤のうちの１つ若しくは複数を、前記抗体若しくはその抗原結合性断片、前記核酸分子、前記ベクター、前記宿主細胞、前記多特性抗体、前記コンジュゲート又は前記医薬組成物の投与と同時、その前又はその後に投与するステップ
を含む方法。 in vivo or in vitro: (1) inhibiting or blocking the binding of PD-1 to PD-L1 or PD-L2; (2) downregulating or eliminating the activity of PD-1; , (3) reduce or relieve immunosuppression of PD-1 or PD-L1 or PD-L2, (4) increase the production of IFNγ or IL-2 in T lymphocytes, and (5) tumors. A method for at least one of enhancing the ability of T lymphocytes to kill cells, the method comprising:
an effective amount of an antibody according to any one of claims 1 to 12 or an antigen-binding fragment thereof, or a nucleic acid molecule according to claim 13 or 14, or a vector according to claim 15, or claim 16. or a multispecific antibody according to claim 18, or a conjugate according to claim 19, or a cell expressing a chimeric antigen receptor (CAR) according to claim 20, or a cell expressing a chimeric antigen receptor (CAR) according to claim 20. administering an oncolytic virus according to claim 21, or a fusion protein according to claim 22, or a pharmaceutical composition according to claim 23 or 24;
Optionally, one or more of an anti-tumor agent, a radiopharmaceutical, an agent associated with immunomodulatory effects or an agent associated with autoimmune disease is administered to said antibody or antigen-binding fragment thereof, said nucleic acid molecule, said vector. , the host cell, the multispecific antibody, the conjugate, or the pharmaceutical composition.
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