Multispecific antibodies for immuno-oncology

Abstract

Multispecific antibody having a binding site for ICOS and a binding site for a second antigen, e.g., an immune checkpoint molecule such as PD-L1. Use of the multispecific antibody in immuno-oncology, including for treatment of solid tumours.

What is claimed is: 
     
         1 - 32 . (canceled) 
     
     
         33 . A multispecific antibody comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, the second polypeptide, and the third polypeptide form a Fab-scFv-Fc multispecific antibody,
 wherein the first polypeptide comprises, from N- to C-terminus, a light chain variable region A, a light chain constant region (CL),   wherein the second polypeptide comprises, from N- to C-terminus, a heavy chain variable region A, a CH1 heavy chain constant region, and heavy chain constant regions CH2 and CH3,   wherein the third polypeptide comprises, from N- to C-terminus, a single chain fragment variable region B, and heavy chain constant regions CH2 and CH3,   wherein the light chain variable region A and the heavy chain variable region A bind an immune activator, and   wherein the single chain fragment variable region B binds an immune check point inhibitor.   
     
     
         34 . A composition comprising the multispecific antibody according to  claim 33  and a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         35 . The composition according to  claim 34 , further comprising a therapeutic agent selected from the group consisting of:
 a) immune checkpoint inhibitors;   b) immune stimulators;   c) chemokine receptor antagonists;   d) targeted kinase inhibitors;   e) angiogenesis inhibitors;   f) cytokines;   g) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3;   h) bi-specific molecules;   i) oncolytic viruses;   j) vaccination with tumour associated antigens;   k) cell-based therapies; and   1) adoptive transfer of tumour specific T-cells or LAK cells.   
     
     
         36 . The method of treating a solid tumor in a human, wherein the immune activator is an agonistic anti-ICOS antibody and the immune check point inhibitor is an anti-PD-1 antibody. 
     
     
         37 . The method of treating a solid tumor in a human, comprising administering to the human a therapeutically effective amount of a multispecific antibody according to  claim 33 . 
     
     
         38 . The method according to  claim 37 , further comprising administering to the human a further therapy, optionally a further therapeutic agent, optionally wherein the further therapeutic agent is selected from the group consisting of:
 a) immune checkpoint inhibitors   b) immune stimulators;   c) chemokine receptor antagonists;   d) targeted kinase inhibitors;   e) angiogenesis inhibitors;   f) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3;   g) other bi-specific molecules;   h) oncolytic viruses   i) vaccination with tumour associated antigens;   j) cell-based therapies; and   k) adoptive transfer of tumour specific T-cells or LAK cells, 
 or optionally wherein the further therapy is chemotherapy, radiotherapy, and/or surgical removal of tumour. 
     
     
         39 . The method of  claim 37 , wherein the immune stimulator is an immune stimulating peptide, a chemokine, or a cytokine. 
     
     
         40 . A nucleic acid that encodes the first polypeptide, the second polypeptide, or the third polypeptide of the multispecific antibody according to  claim 33 . 
     
     
         41 . A vector comprising the nucleic acid according to  claim 40 ; optionally wherein the vector is a CHO or HEK293 vector. 
     
     
         42 . An isolated host cell comprising the vector according to  claim 41 . 
     
     
         43 . A multispecific antibody comprising a first polypeptide, a second polypeptide, and a third polypeptide, wherein the first polypeptide, the second polypeptide, and the third polypeptide form a Fab-scFv-Fc multispecific antibody,
 wherein the first polypeptide comprises, from N- to C-terminus, a light chain variable region A, a light chain constant region (CL),   wherein the second polypeptide comprises, from N- to C-terminus, a heavy chain variable region A, a CH1 heavy chain constant region, and heavy chain constant regions CH2 and CH3,   wherein the third polypeptide comprises, from N- to C-terminus, a single chain fragment variable region B, and heavy chain constant regions CH2 and CH3,   wherein the light chain variable region A and the heavy chain variable region A binds immune check point inhibitor, and   wherein the single chain fragment variable region B binds immune activator.   
     
     
         44 . A composition comprising the multispecific antibody according to  claim 43  and a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         45 . The composition according to  claim 43 , further comprising a therapeutic agent selected from the group consisting of:
 a) immune checkpoint inhibitors;   b) immune stimulators;   c) chemokine receptor antagonists;   d) targeted kinase inhibitors;   e) angiogenesis inhibitors;   f) cytokines;   g) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3;   h) bi-specific molecules;   i) oncolytic viruses;   j) vaccination with tumour associated antigens;   k) cell-based therapies; and   1) adoptive transfer of tumour specific T-cells or LAK cells.   
     
     
         46 . The method of treating a solid tumor in a human, comprising administering to the human a therapeutically effective amount of a multispecific antibody according to  claim 43 . 
     
     
         47 . The method according to  claim 45 , further comprising administering to the human a further therapy, optionally a further therapeutic agent, optionally wherein the further therapeutic agent is selected from the group consisting of:
 a) immune checkpoint inhibitors   b) immune stimulators;   c) chemokine receptor antagonists;   d) targeted kinase inhibitors;   e) angiogenesis inhibitors;   f) bispecific T-cell engagers (BiTEs) having at least one specificity against CD3;   g) other bi-specific molecules;   h) oncolytic viruses   i) vaccination with tumour associated antigens;   j) cell-based therapies; and   k) adoptive transfer of tumour specific T-cells or LAK cells, 
 or optionally wherein the further therapy is chemotherapy, radiotherapy, and/or surgical removal of tumour. 
     
     
         48 . The method of  claim 47 , wherein the immune stimulator is an immune stimulating peptide, a chemokine, or a cytokine. 
     
     
         49 . The method of treating a solid tumor in a human, wherein the immune activator is an agonistic anti-ICOS antibody and the immune check point inhibitor is an anti-PD-1 antibody. 
     
     
         50 . A nucleic acid that encodes the first polypeptide, the second polypeptide, or the third polypeptide of the multispecific antibody according to  claim 43 . 
     
     
         51 . A vector comprising the nucleic acid according to  claim 50 ; optionally wherein the vector is a CHO or HEK293 vector. 
     
     
         52 . An isolated host cell comprising the vector according to  claim 51 .