ANTI-COMPLEMENT C1S ANTIBODIES AND USES THEREOF
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.