METHODS OF TREATING AUTOIMMUNE AND ALLOIMMUNE DISORDERS
The present disclosure provides methods of treating an alloimmune or autoimmune disorder in an individual; the methods involve administering to the individual an effective amount of an antibody specific for complement component C1s. The present disclosure provides a method of monitoring the efficacy of a subject treatment method; the method involves detecting the level of autoantibody or alloantibody in a biological sample obtained from the individual.
1 . A method of reducing the level of autoantibody or alloantibody titers in an individual afflicted with an autoimmune or alloimmune disorder, the method comprising
administering to the individual an antibody that specifically binds complement component 1s (C1s) in an amount and for a period effective to reduce the level of autoantibody or alloantibody titers.
2 - 9 . (canceled)
10 . A method of reducing B-cell proliferation and/or B-cell activation in an individual afflicted with an autoimmune or alloimmune disorder, the method comprising
administering to the individual an antibody that specifically binds complement component 1s (C1s) in an amount and for a period effective to reduce B-cell proliferation.
11 - 35 . (canceled)
36 . A method of monitoring efficacy of treatment with an antibody that specifically binds complement component 1s (C1s) in an individual afflicted with an autoimmune or alloimmune disorder, the method comprising:
detecting a first level of at least one marker of B-cell activation in a first sample obtained from the individual at a first time point; and
detecting a second level of the at least one marker of B-cell activation in a second sample obtained from the individual at a second time point that is later than the first time point,
wherein a decrease in the second level compared to the first level of the at least one marker of B-cell activation indicates that treatment of the individual with the antibody is efficacious for treating the autoimmune or alloimmune disorder.
37 . The method of claim 36 , wherein the first time point is prior to treatment of the individual with the antibody, and the second time point is after treatment of the individual with the antibody.
38 . The method of claim 36 , wherein the first time point is after treatment of the individual with the antibody, and the second time point is from 2 days to 6 months after the first time point.
39 . The method of claim 36 , wherein the at least one marker of B-cell activation comprises at least one cytokine produced or modulated by a B-cell.
40 . The method of claim 39 , wherein the at least one cytokine comprises at least one pro-inflammatory cytokine and/or at least one immunosuppressive cytokine.
41 . The method of claim 39 , wherein the at least one cytokine is selected from the group consisting of IL-2, IL-4, IL-6, IL-12, IFN-7, TNF-α, IL-10, and TGF-β.
42 . The method of claim 36 , wherein the at least one marker of B-cell activation comprises at least one cell surface marker of a B-cell.
43 . The method of claim 42 , wherein the at least one cell surface marker is selected from the group consisting of CD23, CD25, CD27, CD30, CD38, CD69, CD80, CD86, CD135, IgM, and CD10.
44 . The method of claim 36 , wherein the first and second samples are biological samples selected from the group consisting of blood samples, serum samples, plasma samples, bone marrow samples, and tissue biopsy samples.
45 . The method of claim 36 , wherein the antibody is humanized.
46 . The method of claim 45 , wherein the antibody comprises a humanized VL framework region.
47 . The method of claim 45 , wherein the antibody comprises a humanized VH framework region.
48 . The method of claim 45 , wherein the antibody comprises a humanized VL framework region and a humanized VH framework region.
49 . The method of claim 36 , wherein the antibody comprises:
a heavy chain variable region comprising: a complementarity determining region (CDR)-H1 comprising amino acid sequence GFNIKDDYIHWV (SEQ ID NO: 9), a CDR-H2 comprising amino acid sequence IDPADGHTKY (SEQ ID NO: 10), and a CDR-H3 comprising amino acid sequence ARYGYGREVFDY (SEQ ID NO: 11); and
a light chain variable region comprising: a CDR-L1 comprising amino acid sequence QSVDYDGDSYMN (SEQ ID NO: 12), a CDR-L2 comprising amino acid sequence DASNLESGIP (SEQ ID NO: 13), and a CDR-L3 comprising amino acid sequence QQSNEDPWT (SEQ ID NO: 14).
50 . The method of claim 36 , wherein the antibody comprises:
a heavy chain variable region comprising: a CDR-H1 comprising amino acid sequence NYAMS (SEQ ID NO: 95), a CDR-H2 comprising amino acid sequence TISSGGSHTYYLDSVKG (SEQ ID NO: 96), and a CDR-H3 comprising amino acid sequence LFTGYAMDY (SEQ ID NO: 97); and
a light chain variable region comprising: a CDR-L1 comprising amino acid sequence TASSSVSSSYLH (SEQ ID NO: 98), a CDR-L2 comprising amino acid sequence STSNLAS (SEQ ID NO: 99), and a CDR-L3 comprising amino acid sequence HQYYRLPPIT (SEQ ID NO: 92).