Anti-c1s antibodies and methods of use thereof

Abstract

The present disclosure provides antibodies that specifically bind complement pathway component C1s. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the anti-C1s antibodies; and host cells comprising the nucleic acids. The present disclosure provides compositions comprising the anti-C1s antibodies. The present disclosure provides methods of use of the anti-C1s antibodies.

What is claimed is: 
     
         1 . An antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) region and a heavy chain constant region, and the light chain comprises a light chain variable (VL) region;
 wherein the VL region comprises a VL complementary determining region (CDR) 1, a VL CDR2, and a VL CDR3, and wherein the VH region comprises a VH CDR1, a VH CDR2, and a VH CDR3;   wherein the VL CDR1 comprises SEQ ID NO: 1;   wherein the VL CDR2 comprises SEQ ID NO: 2;   wherein the VL CDR3 comprises SEQ ID NO: 3;   wherein the VH CDR1 comprises SEQ ID NO: 4;   wherein the VH CDR2 comprises SEQ ID NO: 5;   wherein the VH CDR3 comprises SEQ ID NO: 6;   wherein the heavy chain constant region comprises an IgG4 constant region, wherein amino acid residue 308 of the heavy chain constant region corresponding to SEQ ID NO: 28 is Leu, and amino acid residue 314 of the heavy chain constant region corresponding to SEQ ID NO: 28 is Ser;   and wherein the antibody specifically binds activated C1s.   
     
     
         2 . The antibody of  claim 1 , wherein amino acid residue 108 of the heavy chain constant region corresponding to SEQ ID NO: 28 is Pro. 
     
     
         3 . The antibody of  claim 1  or  2 , wherein amino acid residue 115 of the heavy chain constant region corresponding to SEQ ID NO: 28 is Glu. 
     
     
         4 . An antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable (VH) region and a heavy chain constant region, and the light chain comprises a light chain variable (VL) region;
 wherein the VL region comprises a VL complementary determining region (CDR) 1, a VL CDR2, and a VL CDR3, and wherein the VH region comprises a VH CDR1, a VH CDR2, and a VH CDR3;   wherein the VL CDR1 comprises SEQ ID NO: 1;   wherein the VL CDR2 comprises SEQ ID NO: 2;   wherein the VL CDR3 comprises SEQ ID NO: 3;   wherein the VH CDR1 comprises SEQ ID NO: 4;   wherein the VH CDR2 comprises SEQ ID NO: 5;   wherein the VH CDR3 comprises SEQ ID NO: 6;   wherein the heavy chain constant region comprises SEQ ID NO: 28;   and wherein the antibody specifically binds activated C1s.   
     
     
         5 . The antibody of any one of  claims 1  to  4 , wherein the VL region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 20, 22, and 24. 
     
     
         6 . The antibody of any one of  claims 1  to  5 , wherein the VH region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 12, 14, 16, and 18. 
     
     
         7 . The antibody of any one of  claims 1  to  6 , wherein:
 (a) the VH region comprises SEQ ID NO:10, and the VL region comprises SEQ ID NO:20; 
 (b) the VH region comprises SEQ ID NO:10, and the VL region comprises SEQ ID NO:22; 
 (c) the VH region comprises SEQ ID NO:10, and the VL region comprises SEQ ID NO:24; 
 (d) the VH region comprises SEQ ID NO:12, and the VL region comprises SEQ ID NO:20; 
 (e) the VH region comprises SEQ ID NO:12, and the VL region comprises SEQ ID NO:22; 
 (f) the VH region comprises SEQ ID NO:12, and the VL region comprises SEQ ID NO:24; 
 (g) the VH region comprises SEQ ID NO:14, and the VL region comprises SEQ ID NO:20; 
 (h) the VH region comprises SEQ ID NO:14, and the VL region comprises SEQ ID NO:22; 
 (i) the VH region comprises SEQ ID NO:14, and the VL region comprises SEQ ID NO:24; 
 (j) the VH region comprises SEQ ID NO:16, and the VL region comprises SEQ ID NO:20; 
 (j) the VH region comprises SEQ ID NO:16, and the VL region comprises SEQ ID NO:22; 
 (k) the VH region comprises SEQ ID NO:16, and the VL region comprises SEQ ID NO:24; 
 (l) the VH region comprises SEQ ID NO:18, and the VL region comprises SEQ ID NO:20; 
 (m) the VH region comprises SEQ ID NO:18, and the VL region comprises SEQ ID NO:22; or 
 (n) the VH region comprises SEQ ID NO:18, and the VL region comprises SEQ ID NO:24. 
 
     
     
         8 . The antibody of any one of  claims 1  to  7 , wherein the VH region comprises SEQ ID NO:14, and the VL region comprises SEQ ID NO:22. 
     
     
         9 . The antibody of any one of  claims 1  to  8 , wherein the light chain further comprises a light chain constant region. 
     
     
         10 . The antibody of  claim 9 , wherein the light chain constant region comprises SEQ ID NO: 45. 
     
     
         11 . The antibody of any one of  claims 1  to  10 , where the heavy chain comprises SEQ ID NO: 29. 
     
     
         12 . The antibody of any one of  claims 1  to  11 , wherein the light chain comprises SEQ ID NO: 30. 
     
     
         13 . The antibody of any one of  claims 1  to  12 , which is a bispecific antibody or a multispecific antibody. 
     
     
         14 . An immunoconjugate comprising the antibody of any one of  claims 1  to  13 . 
     
     
         15 . A nucleotide of a set of nucleotides encoding the antibody of any one of  claims 1  to  13 . 
     
     
         16 . A vector or a set of vectors comprising the nucleotide of the set of nucleotides of  claim 15 . 
     
     
         17 . A host cell comprising the nucleotide of the set of nucleotides of  claim 15  or the vector or the set of vectors of  claim 16 . 
     
     
         18 . A pharmaceutical composition comprising the antibody of any one of  claims 1  to  13 , the immunoconjugate of  claim 14 , the nucleotide or the set of nucleotides of  claim 15 , the vector or the set of vectors of  claim 16 , or the host cell of  claim 17 , and a pharmaceutically acceptable excipient. 
     
     
         19 . A method of inhibiting a complement pathway in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the antibody of any one of  claims 1  to  13 , the immunoconjugate of  claim 14 , the nucleotide or the set of nucleotides of  claim 15 , the vector or the set of vectors of  claim 16 , or the host cell of  claim 17 , or the pharmaceutical composition of  claim 18 . 
     
     
         20 . A method of treating a complement-mediated disease or disorder in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the antibody of any one of  claims 1  to  13 , the immunoconjugate of  claim 14 , the nucleotide or the set of nucleotides of  claim 15 , the vector or the set of vectors of  claim 16 , or the host cell of  claim 17 , or the pharmaceutical composition of  claim 18 .