Anti-complement c1s antibodies and uses thereof

Abstract

The present disclosure provides antibodies that bind complement C1s protein; and nucleic acid molecules that encode such antibodies. In some embodiments, such anti-complement C1s antibodies inhibit proteolytic activity of C1s. The present disclosure also provides compositions comprising such antibodies, and methods to produce and use such antibodies, nucleic acid molecules, and compositions.

1 .- 89 . (canceled) 
     
     
         90 . A method comprising administering to a subject an antibody that binds to complement C1s protein, wherein the antibody comprises:
 a light chain complementarity-determining region-1 (CDR-L1) sequence, a light chain complementarity-determining region-2 (CDR-L2) sequence, and a light chain complementarity-determining region-3 (CDR-L3) sequence of an antibody light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 15; and   a heavy chain complementarity-determining region-1 (CDR-H1) sequence, a heavy chain complementarity-determining region-2 (CDR-H2) sequence, and a heavy chain complementarity-determining region-3 (CDR-H3) sequence of an antibody heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 16.   
     
     
         91 . The method of  claim 90 , wherein the antibody comprises:
 a light chain variable region that comprises a CDR-L1 amino acid sequence set forth in SEQ ID NO: 9, a CDR-L2 amino acid sequence set forth in SEQ ID NO: 10, and a CDR-L3 amino acid sequence set forth in SEQ ID NO: 11; and   a heavy chain variable region that comprises a CDR-H1 amino acid sequence set forth in SEQ ID NO: 12, a CDR-H2 amino acid sequence set forth in SEQ ID NO: 13, and a CDR-H3 amino acid sequence set forth in SEQ ID NO: 14.   
     
     
         92 . The method of  claim 90 , wherein the antibody comprises:
 an antibody light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 15; and   an antibody heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 16.   
     
     
         93 . The method of  claim 90 , wherein the antibody is administered subcutaneously, intravenously, or intramuscularly. 
     
     
         94 . (canceled) 
     
     
         95 . The method of  claim 90 , wherein the antibody is administered once a week, once every two weeks, or once a month. 
     
     
         96 . The method of  claim 90 , wherein the subject has a complement-mediated disorder. 
     
     
         97 . The method of  claim 96 , wherein the complement-mediated disorder is cold agglutinin disease. 
     
     
         98 . The method of  claim 96 , wherein the complement-mediated disorder is an autoimmune disease. 
     
     
         99 . The method of  claim 96 , wherein the complement-mediated disorder is bullous pemphigoid. 
     
     
         100 . The method of  claim 96 , wherein the complement-mediated disorder is antibody-mediated transplant rejection. 
     
     
         101 . The method of  claim 96 , wherein the complement-mediated disorder is immune thrombocytopenic purpura. 
     
     
         102 . The method of  claim 96 , wherein the complement-mediated disorder is multifocal motor neuropathy. 
     
     
         103 . The method of  claim 90 , wherein the subject is a human. 
     
     
         104 . The method of  claim 90 , wherein the antibody is a humanized antibody. 
     
     
         105 . The method of  claim 90 , wherein the antibody further comprises an IgG1 constant region, an IgG2 constant region, an IgG3 constant region, or an IgG4 constant region. 
     
     
         106 . The method of  claim 105 , wherein the humanized antibody further comprises an IgG4 constant region. 
     
     
         107 . The method of  claim 106 , wherein the IgG4 constant region comprises an S241P substitution (by Kabat numbering) and an L236E substitution (by EU numbering). 
     
     
         108 . The method of  claim 96 , wherein the humanized antibody is administered in an amount effective to treat the complement mediated disorder. 
     
     
         109 . A method of treating a complement-mediated disorder in subject, comprising administering to a subject having a complement-mediated disorder a therapeutically effective amount of a humanized antibody that binds complement C1s protein and comprises:
 a light chain complementarity-determining region-1 (CDR-L1) sequence, a light chain complementarity-determining region-2 (CDR-L2) sequence, and a light chain complementarity-determining region-3 (CDR-L3) sequence of an antibody light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 15; and   a heavy chain complementarity-determining region-1 (CDR-H1) sequence, a heavy chain complementarity-determining region-2 (CDR-H2) sequence, and a heavy chain complementarity-determining region-3 (CDR-H3) sequence of an antibody heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 16, thereby treating the complement-mediated disorder in the subject.   
     
     
         110 . The method of  claim 109 , wherein the complement-mediated disorder is immunothrombocytopenic purpura (ITP). 
     
     
         111 . The method of  claim 109 , wherein the complement-mediated disorder is bullous pemphigoid. 
     
     
         112 . The method of  claim 109 , wherein the complement-mediated disorder is multifocal motor neuropathy (MMN). 
     
     
         113 . The method of  claim 109 , wherein the complement-mediated disorder is antibody-mediated transplant rejection. 
     
     
         114 . A method of treating cold agglutinin disease in subject, comprising administering to a subject having cold agglutinin disease a therapeutically effective amount of a humanized antibody that binds complement C1s protein and comprises:
 a light chain complementarity-determining region-1 (CDR-L1) sequence, a light chain complementarity-determining region-2 (CDR-L2) sequence, and a light chain complementarity-determining region-3 (CDR-L3) sequence of an antibody light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 15; and   a heavy chain complementarity-determining region-1 (CDR-H1) sequence, a heavy chain complementarity-determining region-2 (CDR-H2) sequence, and a heavy chain complementarity-determining region-3 (CDR-H3) sequence of an antibody heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 16, thereby treating the cold agglutinin disease in the subject.   
     
     
         115 . A method of producing a humanized antibody that binds to a complement C1s protein, the method comprising culturing a cell comprising nucleic acids encoding the humanized antibody, wherein the humanized antibody comprises:
 a light chain complementarity-determining region-1 (CDR-L1) sequence, a light chain complementarity-determining region-2 (CDR-L2) sequence, and a light chain complementarity-determining region-3 (CDR-L3) sequence of an antibody light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 15; and   a heavy chain complementarity-determining region-1 (CDR-H1) sequence, a heavy chain complementarity-determining region-2 (CDR-H2) sequence, and a heavy chain complementarity-determining region-3 (CDR-H3) sequence of an antibody heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 16, wherein the nucleic acids are expressed in the cell and the humanized antibody is produced.