JPWO2021030488A5 - - Google Patents
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（ｉｉ）ヒトＯＸ４０抗原結合ドメインが、（ａ）配列番号２９を含むＶＨおよび配列番号２８を含むＶＬを含む抗体の、ヒトＯＸ４０への結合を競合的に阻害する、（ｂ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬを含む抗体として、ヒトＯＸ４０の同じエピトープに特異的に結合する、（ｃ）配列番号２９のＶＨおよび配列番号２８のＶＬにおいて６つのＣＤＲを含み、任意で、ＣＤＲが、ＩＭＧＴ定義ＣＤＲ、カバット定義ＣＤＲ、コチア定義ＣＤＲ、またはＡｂＭ定義ＣＤＲである、（ｄ）ＶＨおよびＶＬを含み、ＶＨが、配列番号２９のアミノ酸配列と少なくとも９５％同一であるアミノ酸配列を含む、（ｅ）ＶＨおよびＶＬを含み、ＶＨが、配列番号２９のアミノ酸配列を含む、（ｆ）ＶＨおよびＶＬを含み、ＶＬが、配列番号２８のアミノ酸配列と少なくとも９５％同一であるアミノ酸配列を含む、（ｇ）ＶＨおよびＶＬを含み、ＶＬが、配列番号２８のアミノ酸配列を含む、（ｈ）ＶＨおよびＶＬを含み、ＶＨが、配列番号３１のアミノ酸配列と少なくとも９５％同一であるアミノ酸配列を含む、（ｉ）ＶＨおよびＶＬを含み、ＶＨが、配列番号３１のアミノ酸配列を含む、（ｊ）ＶＨおよびＶＬを含み、ＶＬが、配列番号３０のアミノ酸配列と少なくとも９５％同一であるアミノ酸配列を含む、ならびに／もしくは（ｋ）ＶＨおよびＶＬを含み、ＶＬが、配列番号３０のアミノ酸配列を含む、
請求項１に記載の抗体。 (i) the human 4-1BB antigen-binding domain competitively inhibits the binding of an antibody comprising (a) a VH comprising SEQ ID NO: 17 and a VL comprising SEQ ID NO: 18 to human 4-1BB; (c) the VH of SEQ ID NO: 17 and SEQ ID NO: 18 that specifically binds to the same epitope of human 4-1BB as an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18; or 6 CDRs in the VH of SEQ ID NO: 19 and the VL of SEQ ID NO: 20 , wherein the CDRs are IMGT-defined CDRs, Kabat-defined CDRs, Chothia-defined CDRs, or AbM-defined CDRs (d) comprising VH and VL, wherein VH comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; (e) comprising VH and VL, wherein VH comprises the amino acid sequence of SEQ ID NO: 17; (f) comprising VH and VL, wherein VL comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18; and/ or (g) comprising VH and VL, wherein VL comprises SEQ ID NO: 18 and/or
(ii) the human OX40 antigen-binding domain competitively inhibits binding of an antibody comprising (a) a VH comprising SEQ ID NO:29 and a VL comprising SEQ ID NO:28 to human OX40; (c) 6 CDRs in VH of SEQ ID NO:29 and VL of SEQ ID NO:28 that specifically bind to the same epitope of human OX40 as an antibody comprising a VH comprising the amino acid sequence and a VL comprising the amino acid sequence of SEQ ID NO:28; optionally wherein the CDRs are IMGT defined CDRs, Kabat defined CDRs, Chothia defined CDRs or AbM defined CDRs; (e) comprising VH and VL, wherein VH comprises the amino acid sequence of SEQ ID NO:29, (f) comprising VH and VL, wherein VL comprises at least 95 amino acid sequences of SEQ ID NO:28 (g) comprising VH and VL, wherein VL comprises the amino acid sequence of SEQ ID NO: 28, (h) comprising VH and VL, wherein VH comprises at least the amino acid sequence of SEQ ID NO: 31 (i) comprising VH and VL, wherein VH comprises the amino acid sequence of SEQ ID NO: 31, comprising an amino acid sequence that is 95% identical, (j) comprising VH and VL, wherein VL comprises the amino acid sequence of SEQ ID NO: 30 comprising an amino acid sequence that is at least 95% identical, and/or (k) comprising VH and VL, wherein VL comprises the amino acid sequence of SEQ ID NO:30;
The antibody of claim 1.
（ｉｉ）ヒト４－１ＢＢ結合ドメインが、配列番号１７、１９、２１、２３、３２、および１４３のいずれか１つのアミノ酸配列を含むＶＨを含む、ならびに／または
（ｉｉｉ）ヒト４－１ＢＢ結合ドメインが、配列番号１８、２０、２２、および２４からなる群より選択されるアミノ酸配列と少なくとも７５％、８０％、８５％、９０％、９５％、または９９％同一であるアミノ酸配列を含むＶＬを含む、ならびに／または
（ｉｖ）ヒト４－１ＢＢ結合ドメインが、配列番号１８、２０、２２、および２４のいずれか１つのアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖ）ヒト４－１ＢＢ結合ドメインが、（ａ）配列番号１７のアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列を含むＶＬ、（ｂ）配列番号１９のアミノ酸配列を含むＶＨおよび配列番号２０のアミノ酸配列を含むＶＬ、（ｃ）配列番号２１のアミノ酸配列を含むＶＨおよび配列番号２２のアミノ酸配列を含むＶＬ、（ｄ）配列番号２３のアミノ酸配列を含むＶＨおよび配列番号２４のアミノ酸配列を含むＶＬ、（ｅ）配列番号３２のアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列を含むＶＬ、または（ｆ）配列番号１４３のアミノ酸配列を含むＶＨおよび配列番号２０のアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖｉ）ヒト４－１ＢＢ結合ドメインが、配列番号１７のアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖｉｉ）ヒト４－１ＢＢ結合ドメインが、同じポリペプチド鎖にＶＨおよびＶＬを含む、もしくは
ヒト４－１ＢＢ結合ドメインが、同じポリペプチド鎖にＶＨおよびＶＬを含み、ヒト４－１ＢＢ結合ドメインのＶＨが、ヒト４－１ＢＢ結合ドメインのＶＬに対してＮ末端にある、もしくはヒト４－１ＢＢ結合ドメインのＶＨが、ヒト４－１ＢＢ結合ドメインのＶＬに対してＣ末端にある、もしくは
ヒト４－１ＢＢ結合ドメインが、同じポリペプチド鎖にＶＨおよびＶＬを含み、ヒト４－１ＢＢ結合ドメインが、ＶＨおよびＶＬの間のリンカーを含み、リンカーが、アミノ酸（Ｇｌｙ ４ Ｓｅｒ） ｎ を含んでもよく、ｎ＝１～５（配列番号１１７）であり、もしくはｎ＝３～５、もしくはｎ＝４～５、任意で、ｎ＝４である、
請求項１に記載の抗体。 (i) the human 4-1BB binding domain is at least 75%, 80%, 85%, 90%, 95% with an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 19, 21, 23, 32, and 143; , or a VH comprising an amino acid sequence that is 99% identical, or
(ii) the human 4-1BB binding domain comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs: 17, 19, 21, 23, 32, and 143, and/or
(iii) the human 4-1BB binding domain is at least 75%, 80%, 85%, 90%, 95%, or 99% with an amino acid sequence selected from the group consisting of SEQ ID NOS: 18, 20, 22, and 24; comprising a VL comprising identical amino acid sequences, and/or
(iv) the human 4-1BB binding domain comprises a VL comprising the amino acid sequence of any one of SEQ ID NOs: 18, 20, 22, and 24, and/or
(v) the human 4-1BB binding domain comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, (b) a VH comprising the amino acid sequence of SEQ ID NO: 19 and SEQ ID NO: 20 (c) VH comprising the amino acid sequence of SEQ ID NO: 21 and VL comprising the amino acid sequence of SEQ ID NO: 22; (d) VH comprising the amino acid sequence of SEQ ID NO: 23 and the amino acid sequence of SEQ ID NO: 24. (e) a VH comprising the amino acid sequence of SEQ ID NO:32 and a VL comprising the amino acid sequence of SEQ ID NO:18; or (f) a VH comprising the amino acid sequence of SEQ ID NO:143 and a VL comprising the amino acid sequence of SEQ ID NO:20. including and/or
(vi) the human 4-1BB binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, and/or
(vii) the human 4-1BB binding domain comprises VH and VL in the same polypeptide chain, or
the human 4-1BB binding domain comprises VH and VL in the same polypeptide chain, wherein the VH of the human 4-1BB binding domain is N-terminal to the VL of the human 4-1BB binding domain, or human 4-1BB the VH of the binding domain is C-terminal to the VL of the human 4-1BB binding domain, or
The human 4-1BB binding domain comprises VH and VL in the same polypeptide chain, the human 4-1BB binding domain comprises a linker between VH and VL, the linker comprising the amino acid (Gly 4 Ser ) n often n=1-5 (SEQ ID NO: 117), or n=3-5, or n=4-5, optionally n=4
The antibody of claim 1 .
ヒト４－１ＢＢ結合ドメインが、配列番号５８のアミノ酸配列を含むｓｃＦｖを含む、
請求項１、２、３（ｉ）から３（ｖｉ）のいずれか一項に記載の抗体。 the 4-1BB binding domain comprises an scFv comprising the amino acid sequence of any one of SEQ ID NOs: 42, 44, 58, 63, 77, and 145, or
the human 4-1BB binding domain comprises an scFv comprising the amino acid sequence of SEQ ID NO:58;
11. The antibody of any one of claims 1 , 2, 3(i) to 3(vi) .
（ｉｉ）ヒト４－１ＢＢ結合ドメインが、ヒト化ＶＨ配列およびＶＬ配列を含む、ならびに／または
（ｉｉｉ）ヒトＯＸ４０結合ドメインが、配列番号２５、２７、２９、３１、および３３からなる群より選択されるアミノ酸配列と少なくとも７５％、８０％、８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＨを含む、ならびに／または
（ｉｖ）ヒトＯＸ４０結合ドメインが、配列番号２５、２７、２９、３１、および３３のいずれか１つのアミノ酸配列を含むＶＨを含む、
（ｖ）ヒトＯＸ４０結合ドメインが、配列番号２６、２８、３０、および３４～４１からなる群より選択されるアミノ酸配列と少なくとも７５％、８０％、８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＬを含む、および／または
（ｖｉ）ヒトＯＸ４０結合ドメインが、配列番号２６、２８、３０、および３４～４１のいずれか１つのアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖｉｉ）ヒトＯＸ４０結合ドメインが、（ａ）配列番号２５のアミノ酸配列を含むＶＨおよび配列番号２６のアミノ酸配列を含むＶＬ、（ｂ）配列番号２７のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｃ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号２６のアミノ酸配列含むＶＬ、（ｄ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列を含むＶＬ、（ｅ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｆ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列を含むＶＬ、（ｇ）配列番号３３のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｈ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３４のアミノ酸配列を含むＶＬ、（ｉ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３５のアミノ酸配列を含むＶＬ、（ｊ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３６のアミノ酸配列を含むＶＬ、（ｋ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３７のアミノ酸配列を含むＶＬ、（ｌ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３４のアミノ酸配列を含むＶＬ、（ｍ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３５のアミノ酸配列を含むＶＬ、（ｎ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３６のアミノ酸配列を含むＶＬ、（ｏ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３７のアミノ酸配列含むＶＬ、（ｐ）配列番号３１のアミノ酸配列含むＶＨおよび配列番号３８のアミノ酸配列含むＶＬ、（ｑ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３９のアミノ酸配列を含むＶＬ、（ｒ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号４０のアミノ酸配列を含むＶＬ、もしくは（ｓ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号４１のアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖｉｉｉ）ヒトＯＸ４０結合ドメインが、（ａ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｂ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列を含むＶＬ、または（ｃ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３５のアミノ酸配列を含むＶＬを含む、
請求項１から４のいずれか一項に記載の抗体。 (i) the human 4-1BB binding domain is capable of binding to cynomolgus monkey 4-1BB or the human 4-1BB binding domain is capable of stimulating human 4-1BB activity, and/or
(ii) the human 4-1BB binding domain comprises humanized VH and VL sequences, and/or
(iii) the human OX40 binding domain is at least 75%, 80%, 85%, 90%, 95%, or 99% with an amino acid sequence selected from the group consisting of SEQ ID NOS: 25, 27, 29, 31, and 33; comprising a VH comprising an identical amino acid sequence, and/or
(iv) the human OX40 binding domain comprises a VH comprising the amino acid sequence of any one of SEQ ID NOs: 25, 27, 29, 31, and 33;
(v) the human OX40 binding domain is at least 75%, 80%, 85%, 90%, 95%, or 99% with an amino acid sequence selected from the group consisting of SEQ ID NOS: 26, 28, 30, and 34-41; comprising a VL comprising identical amino acid sequences, and/or
(vi) the human OX40 binding domain comprises a VL comprising the amino acid sequence of any one of SEQ ID NOs: 26, 28, 30, and 34-41; and/or
(vii) the human OX40 binding domain comprises (a) a VH comprising the amino acid sequence of SEQ ID NO:25 and a VL comprising the amino acid sequence of SEQ ID NO:26, (b) a VH comprising the amino acid sequence of SEQ ID NO:27 and the amino acid sequence of SEQ ID NO:28 (c) VH comprising the amino acid sequence of SEQ ID NO:29 and VL comprising the amino acid sequence of SEQ ID NO:26; (d) VH comprising the amino acid sequence of SEQ ID NO:29 and VL comprising the amino acid sequence of SEQ ID NO:30; (e) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:28, (f) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:30, (g) sequence VH comprising the amino acid sequence of SEQ ID NO:33 and VL comprising the amino acid sequence of SEQ ID NO:28, (h) VH comprising the amino acid sequence of SEQ ID NO:29 and VL comprising the amino acid sequence of SEQ ID NO:34, (i) the amino acid sequence of SEQ ID NO:29 VH comprising the sequence and VL comprising the amino acid sequence of SEQ ID NO:35, (j) VH comprising the amino acid sequence of SEQ ID NO:29 and VL comprising the amino acid sequence of SEQ ID NO:36, (k) VH comprising the amino acid sequence of SEQ ID NO:29 and VL comprising the amino acid sequence of SEQ ID NO:37, (l) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:34, (m) VH comprising the amino acid sequence of SEQ ID NO:31 and SEQ ID NO:35 (n) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:36; (o) VH comprising the amino acid sequence of SEQ ID NO:31 and the amino acid sequence of SEQ ID NO:37 VL, (p) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:38, (q) VH comprising the amino acid sequence of SEQ ID NO:31 and VL comprising the amino acid sequence of SEQ ID NO:39, (r) sequence a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:40, or (s) a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:41, and/or
(viii) the human OX40 binding domain comprises (a) a VH comprising the amino acid sequence of SEQ ID NO:29 and a VL comprising the amino acid sequence of SEQ ID NO:28, (b) a VH comprising the amino acid sequence of SEQ ID NO:31 and the amino acid sequence of SEQ ID NO:30 or (c) a VH comprising the amino acid sequence of SEQ ID NO:29 and a VL comprising the amino acid sequence of SEQ ID NO:35,
5. The antibody of any one of claims 1-4 .
ヒトＯＸ４０結合ドメインが、同じポリペプチド鎖にＶＨおよびＶＬを含み、ヒトＯＸ４０結合ドメインのＶＨが、ヒトＯＸ４０結合ドメインのＶＬに対してＮ末端にある、もしくはヒトＯＸ４０結合ドメインのＶＨが、ヒトＯＸ４０結合ドメインのＶＬに対してＣ末端にある、もしくは
ヒトＯＸ４０結合ドメインが、ＶＨおよびＶＬの間のリンカーを含み、リンカーが、アミノ酸配列（Ｇｌｙ ４ Ｓｅｒ） ｎ を含んでもよく、ｎ＝１～５（配列番号１１７）であり、もしくはｎ＝３～５であり、任意で、ｎ＝４である、
請求項１から５のいずれか一項に記載の抗体。 the human OX40 binding domain comprises VH and VL in the same polypeptide chain, or
the human OX40 binding domain comprises VH and VL in the same polypeptide chain, wherein the VH of the human OX40 binding domain is N-terminal to the VL of the human OX40 binding domain, or the VH of the human OX40 binding domain is human OX40 C-terminal to the VL of the binding domain, or
The human OX40 binding domain comprises a linker between VH and VL, the linker optionally comprising the amino acid sequence (Gly 4 Ser) n , where n=1-5 (SEQ ID NO: 117), or n=3- 5, optionally n=4;
6. The antibody of any one of claims 1-5 .
ヒトＯＸ４０結合ドメインが、配列番号５９、６２、または６６のいずれか１つのアミノ酸配列を含むｓｃＦｖを含む、
請求項１から５のいずれか一項に記載の抗体。 the OX40 binding domain comprises an scFv comprising the amino acid sequence of any one of SEQ ID NOs: 46, 47, 52, 54, 56, 59-62, 64-76, and 146; or
the human OX40 binding domain comprises an scFv comprising the amino acid sequence of any one of SEQ ID NOs: 59, 62, or 66;
6. The antibody of any one of claims 1-5 .
（ｉｉ）ヒトＯＸ４０結合ドメインが、ヒトＯＸ４０活性を刺激することができる、ならびに／または
（ｉｉｉ）ＯＸ４０結合ドメインが、マウスもしくはラットのＶＨ配列およびＶＬ配列を含む、ならびに／または
（ｉｖ）ヒト４－１ＢＢ結合ドメインが、配列番号１７のアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列を含むＶＬを含み、ＯＸ４０結合ドメインが、（ａ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｂ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列を含むＶＬ、または（ｃ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３５のアミノ酸配列を含むＶＬを含む、ならびに／または
（ｖ）ヒト４－ＢＢ結合ドメインおよびヒトＯＸ４０結合ドメインを含む抗体であって、ヒト４－１ＢＢ結合ドメインが、配列番号５８のアミノ酸配列と少なくとも８５％、９０％、９５％、または９９％同一であるアミノ酸配列を含むｓｃＦｖを含み、ヒトＯＸ４０結合ドメインが、配列番号５９、６２、または６６のいずれか１つのアミノ酸配列と少なくとも８５％、９０％、９５％、または９９％同一であるアミノ酸配列を含むｓｃＦｖを含む、もしくは
ヒト４－１ＢＢ結合ドメインが、配列番号５８のアミノ酸配列を含むｓｃＦｖを含み、ヒトＯＸ４０結合ドメインが、配列番号５９、６２、または６６のいずれか１つのアミノ酸配列を含むｓｃＦｖを含む、ならびに／または
（ｖｉ）ヒト４－１ＢＢ結合ドメインおよびヒトＯＸ４０結合ドメインが、同じポリペプチド上にある、または
（ｖｉｉ）ヒト４－１ＢＢ結合ドメインが、ヒトＯＸ４０結合ドメインに対してＮ末端にある、もしくはヒト４－１ＢＢ結合ドメインが、ヒトＯＸ４０結合ドメインに対してＣ末端にある、
請求項１から７のいずれか一項に記載の抗体。 (i) the OX40 binding domain is capable of binding to cynomolgus monkey OX40, and/or
(ii) the human OX40 binding domain is capable of stimulating human OX40 activity, and/or
(iii) the OX40 binding domain comprises mouse or rat VH and VL sequences, and/or
(iv) the human 4-1BB binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and the VL comprising the amino acid sequence of SEQ ID NO: 18, and the OX40 binding domain comprises (a) a VH comprising the amino acid sequence of SEQ ID NO: 29; and a VL comprising the amino acid sequence of SEQ ID NO: 28, (b) a VH comprising the amino acid sequence of SEQ ID NO: 31 and a VL comprising the amino acid sequence of SEQ ID NO: 30, or (c) a VH comprising the amino acid sequence of SEQ ID NO: 29 and SEQ ID NO: comprising a VL comprising a sequence of 35 amino acids, and/or
(v) an antibody comprising a human 4-BB binding domain and a human OX40 binding domain, wherein the human 4-1BB binding domain is at least 85%, 90%, 95%, or 99% identical to the amino acid sequence of SEQ ID NO:58; wherein the human OX40 binding domain is at least 85%, 90%, 95% or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 59, 62 or 66 comprising a scFv comprising, or
the human 4-1BB binding domain comprises a scFv comprising the amino acid sequence of SEQ ID NO:58 and the human OX40 binding domain comprises an scFv comprising the amino acid sequence of any one of SEQ ID NO:59, 62, or 66; and/or
(vi) the human 4-1BB binding domain and the human OX40 binding domain are on the same polypeptide, or
(vii) the human 4-1BB binding domain is N-terminal to the human OX40 binding domain, or the human 4-1BB binding domain is C-terminal to the human OX40 binding domain;
8. The antibody of any one of claims 1-7 .
免疫グロブリン定常領域を含み、免疫グロブリン定常領域が、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、ＩｇＧ４、ＩｇＡ１、ＩｇＡ２もしくはＩｇＤの免疫グロブリンＣＨ２ドメインおよびＣＨ３ドメインを含み、もしくは免疫グロブリン定常領域が、ＩｇＧ１の免疫グロブリンＣＨ２ドメインおよびＣＨ３ドメインを含む、ならびに／または
（ｉｉ）ＣＨ１ドメインを含まない、ならびに／または
（ｉｉｉ）免疫グロブリン定常領域が、ＦｃγＲ１、ＦｃγＲＩＩａ、ＦｃγＲＩＩｂ、ＦｃγＲＩＩａ、およびＦｃγＲＩＩＩｂへの結合を防止するために、野生型免疫グロブリン定常領域と比較して、１つ、２つ、３つ、４つ、５つもしくはそれ以上のアミノ酸の置換および／もしくは欠失を含む、ならびに／または
（ｉｖ）免疫グロブリン定常領域が、Ｆｃ媒介Ｔ細胞活性化を防止もしくは低減するために、野生型免疫グロブリン定常領域と比較して、１つ、２つ、３つ、４つ、５つもしくはそれ以上のアミノ酸の置換および／もしくは欠失を含む、ならびに／または
（ｖ）免疫グロブリン定常領域が、ＣＤＣ活性化を防止もしくは低減するために、野生型免疫グロブリン定常領域と比較して、１つ、２つ、３つ、４つ、５つもしくはそれ以上のアミノ酸の置換および／もしくは欠失を含む、ならびに／または
（ｖｉ）免疫グロブリン定常領域が、ＡＤＣＣ活性化を防止もしくは低減するために、野生型免疫グロブリン定常領域と比較して、１つ、２つ、３つ、４つ、５つもしくはそれ以上のアミノ酸の置換および／もしくは欠失を含む、ならびに／または
（ｖｉｉ）免疫グロブリン定常領域が、ＥＵナンバリングシステムにしたがって置換Ｅ２３３Ｐ、Ｌ２３４Ａ、Ｌ２３５Ａ、Ｇ２３７Ａ、およびＫ３２２ＡならびにＧ２３６の欠失を含むＩｇＧ１ ＣＨ２ドメインを含む、もしくは
免疫グロブリン定常領域およびヒト４－１ＢＢ結合ドメインの間ならびに／もしくは免疫グロブリン定常領域およびヒトＯＸ４０結合ドメインの間のリンカーを含む、もしくは
免疫グロブリン定常領域およびヒト４－１ＢＢ結合ドメインの間ならびに／もしくは免疫グロブリン定常領域およびヒトＯＸ４０結合ドメインの間のリンカーを含み、免疫グロブリン定常領域およびヒト４－１ＢＢ結合ドメインの間ならびに／もしくは免疫グロブリン定常領域およびヒトＯＸ４０結合ドメインの間のリンカーが、１０～３０個のアミノ酸、１５～３０個のアミノ酸、もしくは２０～３０個のアミノ酸を含む、もしくは
免疫グロブリン定常領域およびヒト４－１ＢＢ結合ドメインの間もしくは免疫グロブリン定常領域およびヒトＯＸ４０結合ドメインの間のリンカーが、アミノ酸配列（Ｇｌｙ ４ Ｓｅｒ） ｎ を含み、ｎ＝１～５（配列番号１１７）であり、任意で、ｎ＝１である、ならびに／または
（ｖｉｉｉ）２つのポリペプチドの二量体もしくはホモ二量体を含み、各ポリペプチドが、順にアミノ末端からカルボキシル末端に、第１ｓｃＦｖ、ヒンジ領域、免疫グロブリン定常領域、および第２ｓｃＦｖを含み、
（ａ）第１ｓｃＦｖが、ヒト４－１ＢＢ抗原結合ドメインを含み、第２ｓｃＦｖが、ヒトＯＸ４０抗原結合ドメインを含む、もしくは
（ｂ）第１ｓｃＦｖが、ヒトＯＸ４０抗原結合ドメインを含み、第２ｓｃＦｖが、ヒト４－１ＢＢ抗原結合ドメインを含む、ならびに／または
（ｉｘ）第１ｓｃＦｖが、ヒト４－１ＢＢ結合ドメインを含み、第２ｓｃＦｖが、ヒトＯＸ４０抗原結合ドメインを含む、ならびに／または
（ｘ）ヒンジが、ＩｇＧ １ ヒンジであり、もしくはヒンジが、配列番号１１５のアミノ酸１～１５を含む、ならびに／または
（ｘｉ）ヒンジおよび免疫グロブリン定常領域が、配列番号１１５のアミノ酸配列を含む、ならびに／または
（ｘｉｉ）免疫グロブリン定常領域およびヒトＯＸ４０結合ドメインの間にあるリンカーを含み、リンカーが、アミノ酸配列（Ｇｌｙ ４ Ｓｅｒ） ｎ を含み、ｎ＝１～５（配列番号１～１７）であり、任意で、ｎ＝１である、もしくは
ヒト４－１ＢＢ結合ドメインが、配列番号１７のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＬを含み、ヒトＯＸ４０結合ドメインが、（ａ）配列番号２９のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＬ、（ｂ）配列番号３１のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＬ、もしくは（ｃ）配列番号２９のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸を含むＶＨおよび配列番号３５のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含むＶＬを含む、ならびに／または
（ｘｉｉｉ）ヒト４－１ＢＢ結合ドメインが、配列番号１７のアミノ酸配列を含むＶＨおよび配列番号１８のアミノ酸配列を含むＶＬを含み、ヒトＯＸ４０結合ドメインが、（ａ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号２８のアミノ酸配列を含むＶＬ、（ｂ）配列番号３１のアミノ酸配列を含むＶＨおよび配列番号３０のアミノ酸配列を含むＶＬ、もしくは（ｃ）配列番号２９のアミノ酸配列を含むＶＨおよび配列番号３５のアミノ酸配列を含むＶＬを含む、ならびに／または
（ｘｉｖ）ヒト４－１ＢＢ結合ドメインが、配列番号５８のアミノ酸配列と少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含み、ヒトＯＸ４０結合ドメインが、配列番号５９、６２、もしくは６６のアミノ酸配列のいずれか１つと少なくとも８５％、９０％、９５％、もしくは９９％同一であるアミノ酸配列を含む、ならびに／または
（ｘｖ）ヒト４－１ＢＢ結合ドメインが、配列番号５８のアミノ酸配列を含み、ヒトＯＸ４０結合ドメインが、配列番号５９、６２、または６６のいずれか１つのアミノ酸配列を含む、ならびに／または
（ｘｖｉ）ヒト４－１ＢＢ結合ドメインおよびヒトＯＸ４０結合ドメインが、別個のペプチド上にある、ならびに／または
（ｘｖｉｉ）ヒト４－１ＢＢ結合ドメインが、別個のポリペプチド上にＶＨおよびＶＬを含む、ならびに／または
（ｘｖｉｉｉ）ヒトＯＸ４０結合ドメインが、別個のポリペプチド上にＶＨおよびＶＬを含む、ならびに／または
（ｘｉｘ）ノブ－イン－ホール（ｋｎｏｂ－ｉｎ－ｈｏｌｅ）（ＫＩＨ）抗体、ＣＨ３ドメインにおいて一致した突然変異を含むＩｇＧ１抗体、交換されたＶＨを有する２つの改変Ｆｖフラグメント、ダイアボディ、ｓｃＦｖ×ｓｃＦｖ、ｓｃＦｖ－Ｆｃ－ｓｃＦｖ、クアドローマ、ＣｒｏｓｓＭａｂ Ｆａｂ、ＣｒｏｓｓＭａｂ ＶＨ－ＶＬ、もしくはストランド－エクスチェンジ・エンジニアード・ドメイン・ボディ（ＳＥＥＤｂｏｄｙ）である、ならびに／または
（ｘｘ）ヒト４－１ＢＢおよびヒトＯＸ４０に同時に結合することができる、ならびに／または
（ｘｘｉ）ＣＤ８ ＋ Ｔ細胞、ＣＤ４ ＋ Ｔ細胞、および／もしくはＮＫ細胞の用量依存的拡大を促進することができる、もしくは、
ＣＤ８＋Ｔ細胞、ＣＤ４＋Ｔ細胞、およびＮＫ細胞の用量依存的拡大を促進することができる、ならびに／または
（ｘｘｉｉ）ＣＤ８＋Ｔ細胞、ＣＤ４＋Ｔ細胞、および／もしくはＮＫ細胞を活性化することができる、もしくは
ＣＤ８＋Ｔ細胞、ＣＤ４＋Ｔ細胞、およびＮＫ細胞を活性化することができる、もしくは
ＣＤ８＋Ｔ細胞、ＣＤ４＋Ｔ細胞、および／もしくはＮＫ細胞におけるグランザイム発現を誘発することができる、もしくは
腫瘍細胞を溶解する、もしくは
理論的ｐＩが７．５未満、７．６未満、７．７未満、７．８未満、７．９未満もしくは８未満である、もしくは
約６４～６９、６４～６８、６４～６７、もしくは６５～６８のＴｍを示す、もしくは
刺激されたＰＢＭＣからのＩＦＮ－γ、ＩＬ－２、および／もしくはＴＮＦ－αの分泌を増加させることができる、ならびに／または
（ｘｘｉｉｉ）ヒト４－１ＢＢに対してアゴニスティックであり、ヒトＯＸ４０に対してアゴニスティックである、ならびに／または
（ｘｘｉｖ）単離されている、ならびに／または
（ｘｘｖ）モノクローナル抗体である、ならびに／または
（ｘｘｖｉ）検出可能な標識をさらに含む、
請求項１から８のいずれか一項に記載の抗体。 (i) comprises an immunoglobulin constant region, or
comprising an immunoglobulin constant region, wherein the immunoglobulin constant region comprises the immunoglobulin CH2 and CH3 domains of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgD, or wherein the immunoglobulin constant region is the immunoglobulin CH2 domain of IgG1 and a CH3 domain, and/or
(ii) does not contain a CH1 domain, and/or
(iii) the immunoglobulin constant region is 1, 2, 3, 4 compared to the wild-type immunoglobulin constant region to prevent binding to FcγR1, FcγRIIa, FcγRIIb, FcγRIIa, and FcγRIIIb , contains substitutions and/or deletions of 5 or more amino acids, and/or
(iv) the immunoglobulin constant region has 1, 2, 3, 4, 5 or more relative to the wild-type immunoglobulin constant region to prevent or reduce Fc-mediated T cell activation; contains substitutions and/or deletions of the above amino acids, and/or
(v) the immunoglobulin constant region has 1, 2, 3, 4, 5 or more amino acids compared to the wild-type immunoglobulin constant region to prevent or reduce CDC activation and/or
(vi) the immunoglobulin constant region has 1, 2, 3, 4, 5 or more amino acids compared to the wild-type immunoglobulin constant region to prevent or reduce ADCC activation and/or
(vii) the immunoglobulin constant region comprises an IgG1 CH2 domain comprising substitutions E233P, L234A, L235A, G237A, and K322A and deletion of G236 according to the EU numbering system, or
comprising a linker between the immunoglobulin constant region and the human 4-1BB binding domain and/or between the immunoglobulin constant region and the human OX40 binding domain, or
a linker between the immunoglobulin constant region and the human 4-1BB binding domain and/or between the immunoglobulin constant region and the human OX40 binding domain, comprising a linker between the immunoglobulin constant region and the human 4-1BB binding domain and/or the immunoglobulin the linker between the constant region and the human OX40 binding domain comprises 10-30 amino acids, 15-30 amino acids, or 20-30 amino acids, or
The linker between the immunoglobulin constant region and the human 4-1BB binding domain or between the immunoglobulin constant region and the human OX40 binding domain comprises the amino acid sequence (Gly 4 Ser) n , where n=1-5 (SEQ ID NO: 117) and optionally n=1 and/or
(viii) comprising a dimer or homodimer of two polypeptides, each polypeptide comprising, in order from amino-terminus to carboxyl-terminus, a first scFv, a hinge region, an immunoglobulin constant region, and a second scFv;
(a) the first scFv comprises a human 4-1BB antigen binding domain and the second scFv comprises a human OX40 antigen binding domain, or
(b) the first scFv comprises a human OX40 antigen binding domain and the second scFv comprises a human 4-1BB antigen binding domain, and/or
(ix) the first scFv comprises a human 4-1BB binding domain and the second scFv comprises a human OX40 antigen binding domain, and/or
(x) the hinge is an IgG 1 hinge or the hinge comprises amino acids 1-15 of SEQ ID NO: 115; and/or
(xi) the hinge and immunoglobulin constant region comprise the amino acid sequence of SEQ ID NO: 115; and/or
(xii) comprising a linker between the immunoglobulin constant region and the human OX40 binding domain, the linker comprising the amino acid sequence (Gly 4 Ser) n , where n=1-5 (SEQ ID NOs: 1-17); and n=1, or
A VH comprising an amino acid sequence whose human 4-1BB binding domain is at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO: 17 and at least 85%, 90% of the amino acid sequence of SEQ ID NO: 18 , 95% or 99% identical, wherein the human OX40 binding domain is (a) at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO:29 a VH comprising an amino acid sequence and a VL comprising an amino acid sequence that is at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO:28; (b) at least 85%, 90% to the amino acid sequence of SEQ ID NO:31; a VH comprising an amino acid sequence that is %, 95% or 99% identical and a VL comprising an amino acid sequence that is at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO:30, or (c) VH comprising amino acids that are at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO:29 and at least 85%, 90%, 95% or 99% identical to the amino acid sequence of SEQ ID NO:35 comprising a VL comprising an amino acid sequence, and/or
(xiii) the human 4-1BB binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO: 17 and a VL comprising the amino acid sequence of SEQ ID NO: 18, and the human OX40 binding domain comprises (a) the amino acid sequence of SEQ ID NO: 29; (b) a VH comprising the amino acid sequence of SEQ ID NO:31 and a VL comprising the amino acid sequence of SEQ ID NO:30; or (c) a VH comprising the amino acid sequence of SEQ ID NO:29 and the sequence comprising a VL comprising the amino acid sequence of number 35, and/or
(xiv) the human 4-1BB binding domain comprises an amino acid sequence that is at least 85%, 90%, 95%, or 99% identical to the amino acid sequence of SEQ ID NO:58, and the human OX40 binding domain comprises SEQ ID NOS:59, 62; or an amino acid sequence that is at least 85%, 90%, 95%, or 99% identical to any one of the 66 amino acid sequences, and/or
(xv) the human 4-1BB binding domain comprises the amino acid sequence of SEQ ID NO:58 and the human OX40 binding domain comprises the amino acid sequence of any one of SEQ ID NOs:59, 62, or 66; and/or
(xvi) the human 4-1BB binding domain and the human OX40 binding domain are on separate peptides, and/or
(xvii) the human 4-1BB binding domain comprises VH and VL on separate polypeptides, and/or
(xviii) the human OX40 binding domain comprises VH and VL on separate polypeptides, and/or
(xix) knob-in-hole (KIH) antibody, IgG1 antibody containing concordant mutations in the CH3 domain, two modified Fv fragments with swapped VHs, diabodies, scFv×scFv , scFv-Fc-scFv, quadroma, CrossMab Fab, CrossMab VH-VL, or a strand-exchange engineered domain body (SEEDbody), and/or
(xx) capable of binding simultaneously to human 4-1BB and human OX40, and/or
(xxi) capable of promoting dose-dependent expansion of CD8 + T cells, CD4 + T cells, and/or NK cells, or
capable of promoting dose-dependent expansion of CD8+ T cells, CD4+ T cells, and NK cells, and/or
(xxii) can activate CD8+ T cells, CD4+ T cells, and/or NK cells, or
capable of activating CD8+ T cells, CD4+ T cells, and NK cells, or
capable of inducing granzyme expression in CD8+ T cells, CD4+ T cells, and/or NK cells, or
lyse tumor cells, or
The theoretical pI is less than 7.5, less than 7.6, less than 7.7, less than 7.8, less than 7.9 or less than 8, or
exhibits a Tm of about 64-69, 64-68, 64-67, or 65-68, or
can increase secretion of IFN-γ, IL-2, and/or TNF-α from stimulated PBMCs, and/or
(xxiii) is agonistic to human 4-1BB and is agonistic to human OX40, and/or
(xxiv) isolated and/or
(xxv) is a monoclonal antibody, and/or
(xxvi) further comprising a detectable label;
9. The antibody of any one of claims 1-8 .
（ｉｉ）請求項１から９のいずれか一項に記載の抗体をコードするポリヌクレオチドの組み合わせ、もしくは
ポリヌクレオチドが、１つのベクターにコードされているもしくは複数のベクターにコードされている、請求項１から９のいずれか一項に記載の抗体をコードするポリヌクレオチドの組み合わせ、
を含み、
任意で、ＣＨＯ、ＨＥＫ２９３、またはＣＯＳ細胞からなる群より選択される、
宿主細胞。 (i) the polynucleotide of claim 10 or the vector of claim 11 , or
(ii) a combination of polynucleotides encoding the antibody of any one of claims 1-9, or
10. A combination of polynucleotides encoding the antibody of any one of claims 1 to 9, wherein the polynucleotides are encoded in one vector or encoded in multiple vectors;
including
optionally selected from the group consisting of CHO, HEK293, or COS cells;
host cell.
（ｂ）Ｔ細胞、もしくはＣＤ４＋Ｔ細胞もしくはＣＤ８＋Ｔ細胞であるＴ細胞、または
（ｃ）ＮＫ細胞およびＴ細胞、もしくはＮＫ細胞およびＣＤ４＋Ｔ細胞もしくはＣＤ８＋Ｔ細胞であるＴ細胞、または
（ｄ）Ｔ細胞、もしくはＣＤ４＋Ｔ細胞もしくはＣＤ８＋Ｔ細胞であるＴ細胞
を、請求項１から９のいずれか一項に記載の抗体または請求項１５に記載の医薬組成物と接触させることを含む、
（ａ）ＮＫ細胞増殖を高めるための、または
（ｂ）Ｔ細胞増殖を高めるための、または
（ｃ）ＮＫ細胞増殖およびＴ細胞増殖を高めるための、または
（ｄ）Ｔ細胞同時刺激経路を刺激するための、
インビトロの方法。 (a) NK cells , or
(b) T cells, or T cells that are CD4+ T cells or CD8+ T cells, or
(c) NK cells and T cells, or T cells that are NK cells and CD4+ T cells or CD8+ T cells, or
(d) T cells, or T cells that are CD4+ T cells or CD8+ T cells
with the antibody of any one of claims 1 to 9 or the pharmaceutical composition of claim 15 ,
(a) for enhancing NK cell proliferation , or
(b) for enhancing T cell proliferation, or
(c) to increase NK cell proliferation and T cell proliferation, or
(d) to stimulate the T cell co-stimulatory pathway,
in vitro method.
（ｂ）対象における腫瘍浸潤リンパ球の数を増加させるための、または
（ｃ）対象におけるエフェクタ細胞によりグランザイムの発現を増強させるための、または
（ｄ）対象における腫瘍細胞の数を低減させるための、または
（ｅ）対象における癌を処置するための、
方法における使用のための請求項１から９のいずれか一項に記載の抗体または請求項１５に記載の医薬組成物であって、前記方法が、請求項１から９のいずれか一項に記載の抗体または請求項１５に記載の医薬組成物の有効量を対象に投与することを含む、抗体または医薬組成物。 (a) for enhancing an immune response in a subject , or
(b) to increase the number of tumor-infiltrating lymphocytes in a subject, or
(c) for enhancing granzyme expression by effector cells in a subject, or
(d) to reduce the number of tumor cells in a subject, or
(e) to treat cancer in a subject;
16. An antibody according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 15 for use in a method, wherein said method comprises or the pharmaceutical composition of claim 15 to a subject .
（ｉｉ）癌が、肉腫、癌腫、もしくはリンパ腫である、ならびに／または
（ｉｉｉ）癌が、メラノーマ、腎癌、膵癌、肺癌、胃癌、結腸癌／腸癌、前立腺癌、卵巣癌、乳癌、肝癌、脳癌、もしくは血液癌からなる群より選択される、ならびに／または
（ｉｖ）対象が、ヒトであり、もしくは対象が、ヒトであり腫瘍浸潤リンパ球に対して４－１ＢＢおよびＯＸ４０を発現する、
請求項１７（ｅ）に記載の使用のための抗体または医薬組成物。 (i) the cancer is a solid tumor cancer and/or
(ii) the cancer is sarcoma, carcinoma, or lymphoma, and/or
(iii) the cancer is selected from the group consisting of melanoma, renal cancer, pancreatic cancer, lung cancer, gastric cancer, colon/bowel cancer, prostate cancer, ovarian cancer, breast cancer, liver cancer, brain cancer, or blood cancer; and/or
(iv) the subject is human, or the subject is human and expresses 4-1BB and OX40 to tumor-infiltrating lymphocytes;
Antibody or pharmaceutical composition for use according to claim 17(e) .
16. An antibody according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 15 for use in therapy.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
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| US201962885751P | 2019-08-12 | 2019-08-12 | |
| US62/885,751 | 2019-08-12 | ||
| US201962902318P | 2019-09-18 | 2019-09-18 | |
| US62/902,318 | 2019-09-18 | ||
| US201962911010P | 2019-10-04 | 2019-10-04 | |
| US62/911,010 | 2019-10-04 | ||
| US202063056115P | 2020-07-24 | 2020-07-24 | |
| US63/056,115 | 2020-07-24 | ||
| PCT/US2020/046005 WO2021030488A1 (en) | 2019-08-12 | 2020-08-12 | 4-1bb and ox40 binding proteins and related compositions and methods, antibodies against 4-1bb, antibodies against ox40 |
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| JP2022545368A JP2022545368A (en) | 2022-10-27 |
| JPWO2021030488A5 true JPWO2021030488A5 (en) | 2023-08-22 |
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| US (1) | US20220242962A1 (en) |
| EP (1) | EP4013506A1 (en) |
| JP (1) | JP2022545368A (en) |
| CN (1) | CN114867751A (en) |
| AU (1) | AU2020329217A1 (en) |
| BR (1) | BR112022002761A2 (en) |
| CA (1) | CA3150762A1 (en) |
| IL (1) | IL290498A (en) |
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