Anti-complement factor C1q antibodies and uses thereof
The present invention provides anti-C1q antibodies and methods of using the same.
1. An anti-C1q antibody, comprising:
(a) a light chain hypervariable region (HVR) comprising HVR-L1 comprising the amino acid sequence of SEQ ID NO: 5, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 6, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 7; and
(b) a heavy chain HVR comprising HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 10, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 11.
2. The antibody of claim 1 , wherein the antibody comprises a light chain variable domain comprising at least about 85% homology to the amino acid sequence of SEQ ID NO: 4.
3. The antibody of claim 2 , wherein the antibody comprises a light chain variable domain comprising at least about 95% homology to the amino acid sequence of SEQ ID NO: 4.
4. The antibody of claim 3 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO:4.
5. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable domain comprising at least about 85% homology to the amino acid sequence of SEQ ID NO: 8.
6. The antibody of claim 5 , wherein the antibody comprises a heavy chain variable domain comprising at least about 95% homology to the amino acid sequence of SEQ ID NO: 8.
7. The antibody of claim 6 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:8.
8. The antibody of claim 1 , wherein the antibody binds specifically to human C1q, mouse C1q, and rat C1q, or both human C1q and mouse C1q.
9. The antibody of claim 1 , wherein the antibody has a dissociation constant (K D ) for human C1q and mouse C1q less than about 30 nM.
10. The antibody of claim 1 , wherein the antibody specifically binds to and inhibits a biological activity of C1q.
11. The antibody of claim 10 , wherein the biological activity is (a) C1q binding to an autoantibody, (b) C1q binding to C1r, (c) C1q binding to C1s, (d) C1q binding to phosphatidylserine, (e) C1q binding to pentraxin-3, (f) C1q binding to C-reactive protein (CRP), (g) C1q binding to globular C1q receptor (gC1qR), (h) C1q binding to complement receptor 1 (CR1), (i) C1q binding to beta-amyloid, or (j) C1q binding to calreticulin.
12. The antibody of claim 10 , wherein the biological activity is (a) activation of the classical complement activation pathway, (b) activation of antibody and complement dependent cytotoxicity, (c) CH50 hemolysis, (d) synapse loss, (e) B-cell antibody production, (f) dendritic cell maturation, (g) T-cell proliferation, (h) cytokine production, (i) microglia activation, (j) Arthus reaction, (k) phagocytosis of synapses or nerve endings, or (l) activation of complement receptor 3 (CR3/C3) expressing cells.
13. The antibody of claim 12 , wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis.
14. The antibody of claim 12 , wherein the antibody neutralizes at least 50%, at least 80%, or at least 90% of CH50 hemolysis.
15. The antibody of claim 12 , wherein the antibody neutralizes at least 50% of CH50 homolysis at a dose of less than 200 ng/ml, less than 100 ng/ml, less than 50 ng/ml, or less than 20 ng/ml.
16. The antibody of claim 1 , wherein the antibody is a murine, humanized, or chimeric antibody.
17. The antibody of claim 1 , wherein the antibody is of the IgG class.
18. The antibody of claim 17 , wherein the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.
19. The antibody of claim 1 , wherein the antibody is an antibody fragment.
20. The antibody of claim 19 , wherein the antibody fragment is a Fab, F(ab′)2 or Fab′ fragment.
21. A hybridoma cell with ATCC Accession Number PTA-120399.
22. A kit comprising the antibody of claim 1 and a package insert comprising instructions for using the antibody to treat a disease associated with complement activation in an individual.