Humanized anti-complement factor c1q antibodies and uses thereof

Abstract

The present disclosure is directed to humanized anti-C1q antibodies and methods of using them.

1 - 29 . (canceled) 
     
     
         30 . An anti-C1q antibody Fab fragment, wherein the antibody Fab fragment comprises:
 a) a heavy chain variable domain, and the heavy chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 1-4, or an amino acid sequence with at least about 95% homology to the amino acid sequence selected from SEQ ID NOs: 1-4 and wherein the heavy chain variable domain comprises an HVR-H1 having the amino acid sequence of SEQ ID NO: 23, an HVR-H2 having the amino acid sequence of SEQ ID NO: 24, and an HVR-H3 having the amino acid sequence of SEQ ID NO: 25; and/or   b) a light chain variable domain, and the light chain variable domain comprises an amino acid sequence selected from SEQ ID NOs: 5-8, or an amino acid sequence with at least about 95% homology to the amino acid sequence selected from SEQ ID NOs: 5-8 and wherein the light chain variable domain comprises an HVR-L1 having the amino acid sequence of SEQ ID NO: 30, an HVR-L2 having the amino acid sequence of SEQ ID NO: 31, and an HVR-L3 having the amino acid sequence of SEQ ID NO: 32.   
     
     
         31 . The antibody Fab fragment of  claim 30 , wherein the antibody comprises a human heavy chain constant region, wherein the human heavy chain constant region is a human IgG4 heavy chain constant region. 
     
     
         32 . The antibody Fab fragment of  claim 30 , wherein the antibody binds specifically to rat C1q, to both human C1q and mouse C1q, or to human C1q, mouse C1q, and rat C1q. 
     
     
         33 . The antibody Fab fragment of  claim 30 , wherein the antibody has a dissociation constant (K D ) for human C1q that ranges from less than about 10 μM to less than about 5 μM; wherein the antibody has dissociation constant (K D ) for mouse C1q that ranges from less than about 125 nM to less than about 5 μM. 
     
     
         34 . The antibody Fab fragment of  claim 30 , wherein the antibody specifically binds to and inhibits a biological activity of C1q. 
     
     
         35 . The antibody Fab fragment of  claim 34 , wherein the biological activity is (1) C1q binding to an autoantibody, (2) C1q binding to C1r, (3) C1q binding to C1s, (4) C1q binding to phosphatidylserine, (5) C1q binding to pentraxin-3, (6) C1q binding to C-reactive protein (CRP), (7) C1q binding to globular C1q receptor (gC1qR), (8) C1q binding to complement receptor 1 (CR1), (9) C1q binding to beta-amyloid, or (10) C1q binding to calreticulin. 
     
     
         36 . The antibody Fab fragment of  claim 34 , wherein the biological activity is (1) activation of the classical complement activation pathway, (2) activation of antibody and complement dependent cytotoxicity, (3) CH50 hemolysis, (4) synapse loss, (5) B-cell antibody production, (6) dendritic cell maturation, (7) T-cell proliferation, (8) cytokine production (9) microglia activation, (10) Arthus reaction, (11) phagocytosis of synapses or nerve endings, or (12) activation of complement receptor 3 (CR3/C3) expressing cells. 
     
     
         37 . The antibody Fab fragment of  claim 36 , wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis. 
     
     
         38 . The antibody Fab fragment of  claim 37 , wherein the antibody is capable of neutralizing from at least about 50%, to at least about 90% of CH50 hemolysis. 
     
     
         39 . A pharmaceutical composition comprising the antibody Fab fragment of  claim 30  and a pharmaceutically acceptable carrier. 
     
     
         40 . A kit comprising an antibody Fab fragment of  claim 30 , and a package insert comprising instructions for using the antibody Fab fragment to treat a disease associated with complement activation in an individual in need of such treatment. 
     
     
         41 . A anti-C1q antibody Fab fragment, the antibody Fab fragment comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence of SEQ ID NO: 3, and wherein the light chain variable domain comprises an amino acid sequence of SEQ ID NO: 7. 
     
     
         42 . The antibody Fab fragment of  claim 41 , wherein the antibody comprises a human heavy chain constant region, wherein the human heavy chain constant region is a human IgG4 heavy chain constant region. 
     
     
         43 . The antibody Fab fragment of  claim 41 , wherein the antibody binds specifically to rat C1q, to both human C1q and mouse C1q, or to human C1q, mouse C1q, and rat C1q. 
     
     
         44 . The antibody Fab fragment of  claim 41 , wherein the antibody has a dissociation constant (K D ) for human C1q that ranges from less than about 10 μM to less than about 5 μM; wherein the antibody has dissociation constant (K D ) for mouse C1q that ranges from less than about 125 nM to less than about 5 μM. 
     
     
         45 . The antibody Fab fragment of  claim 41 , wherein the antibody specifically binds to and inhibits a biological activity of C1q. 
     
     
         46 . The antibody Fab fragment of  claim 45 , wherein the biological activity is (1) C1q binding to an autoantibody, (2) C1q binding to C1r, (3) C1q binding to C1s, (4) C1q binding to phosphatidylserine, (5) C1q binding to pentraxin-3, (6) C1q binding to C-reactive protein (CRP), (7) C1q binding to globular C1q receptor (gC1qR), (8) C1q binding to complement receptor 1 (CR1), (9) C1q binding to beta-amyloid, or (10) C1q binding to calreticulin. 
     
     
         47 . The antibody Fab fragment of  claim 45 , wherein the biological activity is (1) activation of the classical complement activation pathway, (2) activation of antibody and complement dependent cytotoxicity, (3) CH50 hemolysis, (4) synapse loss, (5) B-cell antibody production, (6) dendritic cell maturation, (7) T-cell proliferation, (8) cytokine production (9) microglia activation, (10) Arthus reaction, (11) phagocytosis of synapses or nerve endings, or (12) activation of complement receptor 3 (CR3/C3) expressing cells. 
     
     
         48 . The antibody Fab fragment of  claim 47 , wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis. 
     
     
         49 . The antibody Fab fragment of  claim 48 , wherein the antibody is capable of neutralizing from at least about 50%, to at least about 90% of CH50 hemolysis. 
     
     
         50 . A pharmaceutical composition comprising the antibody Fab fragment of  claim 41  and a pharmaceutically acceptable carrier. 
     
     
         51 . A kit comprising an antibody Fab fragment of  claim 41 , and a package insert comprising instructions for using the antibody Fab fragment to treat a disease associated with complement activation in an individual in need of such treatment.