Combination of bispecific fusion protein and anti-Her2 antibody for tumor treatment
The present disclosure provides a use of an immune checkpoint inhibitor in combination with a Her2 inhibitor in the preparation of a medicament for treating tumor in a subject in need thereof, and also provides a pharmaceutical composition comprising an effective amount of said immune checkpoint inhibitor and an effective amount of said Her2 inhibitor, and optionally a pharmaceutically acceptable excipient, as well as a use of the pharmaceutical composition in the preparation of a medicament for treating tumor in a subject in need thereof.
1 . A method for treating tumor in a subject in need thereof, comprising administering to said subject an immune checkpoint inhibitor in combination with a Her2 inhibitor,
wherein said immune checkpoint inhibitor is capable of specifically binding to PD-L1 (programmed death-ligand 1) and CTLA4 (cytotoxic T-lymphocyte associated protein 4), wherein said immune checkpoint inhibitor is a dimer, and said dimer formed by two polypeptide chains, with each of said two polypeptide chains comprising an antibody Fc subunit, wherein said dimer comprises two or more immunoglobulin single variable domains (ISVDs), at least one of said ISVDs is specific for PD-L1, and at least one of said ISVDs is specific for CTLA4,
wherein said ISVD specific for PD-L1 comprises heavy chain CDR1-3 (complementarity determining region), said CDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 5, said CDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 4, and said CDR1 comprises an amino acid sequence as set forth in SEQ ID NO: 3,
wherein said ISVD specific for CTLA4 comprises heavy chain CDR1-3, said CDR3 comprises an amino acid sequence as set forth in SEQ ID NO: 19, said CDR2 comprises an amino acid sequence as set forth in SEQ ID NO: 18, and said CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 17, and
wherein said Her2 inhibitor is a bispecific antibody, and said bispecific antibody has a common light chain and two heavy chains, wherein the variable region of the common light chain comprises the sequence as set forth in amino acid positions 1 to 107 of SEQ ID NO: 65; and wherein the heavy chain variable regions comprise sequences as set forth in SEQ ID NO: 87 and SEQ ID NO: 88, respectively.
2 . The method according to claim 1 , wherein for one or both of said two polypeptide chains, said ISVD specific for PD-L1 is fused to said ISVD specific for CTLA4, optionally via a linker.
3 . The method according to claim 1 , wherein said ISVD specific for PD-L1 is capable of binding to N-terminal IgV (immunoglobulin variable) domain of human PD-L1.
4 . The method according to claim 1 , wherein said ISVD specific for PD-L1 is capable of binding to a conformational epitope of human PD-L1 N-terminal IgV domain, wherein said conformational epitope comprises residues I54, Y56, E58, Q66, R113, D61, N63, V68, M115, S117, Y123 and R125 of said human PD-L1 N-terminal IgV domain, and wherein said human PD-L1 N-terminal IgV domain comprises an amino acid sequence as set forth in SEQ ID NO: 64.
5 . The method according to claim 1 , wherein said ISVD specific for PD-L1 comprises a heavy chain variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO: 6, 10, 12, 13, 14 and 15.
6 . The method according to claim 1 , wherein said ISVD specific for CTLA4 comprises a heavy chain variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NO: 20, 22, and 24-32.
7 . The method according to claim 1 , wherein one or both of said two polypeptide chains comprises an amino acid sequence as set forth in any one of SEQ ID NO: 40-43, 46, 48 and 50.
8 . The method according to claim 1 , wherein said Her2 inhibitor is administrated at dose of 0.01 mg/kg to 100 mg/kg, and/or said immune checkpoint inhibitor is administrated at dose of 0.01 mg/kg to 100 mg/kg.
9 . The method according to claim 1 , wherein said Her2 inhibitor is administrated at a dosing frequency of four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks or once every twelve weeks, and/or said immune checkpoint inhibitor is administrated at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, or once every twelve weeks.
10 . The method according to claim 1 , wherein said tumor is selected from a group consisting of a solid tumor and a hematologic tumor.
11 . A pharmaceutical composition comprising an effective amount of said immune checkpoint inhibitor and an effective amount of said Her2 inhibitor according to claim 1 , and optionally a pharmaceutically acceptable excipient.
12 . A method for treating tumor in a subject in need thereof, comprising administering to said subject the pharmaceutical composition according to claim 11 .