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 . A humanized antibody that specifically binds to a C1q protein, wherein the antibody comprises a heavy chain variable region and a human heavy chain constant region, wherein the heavy chain variable region comprises an Fab region and the heavy chain constant region comprises an Fc region, wherein the Fab region specifically binds to the C1q protein, and wherein the Fc region is incapable of: (1) binding the C1q protein, (2) inducing complement activity, (3) and/or inducing antibody-dependent cellular cytotoxicity (ADCC). 
     
     
         2 . The antibody of  claim 1 , wherein the human heavy chain constant region is a human IgG4 heavy chain constant region. 
     
     
         3 . The antibody of  claim 2 , wherein the human IgG4 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 37, or an amino acid sequence with at least about 90% homology to the amino acid sequence of SEQ ID NO: 37. 
     
     
         4 . The antibody of  claim 2 , wherein the human IgG4 heavy chain constant region comprises an Fc region, and wherein the Fc region comprises one or more modifications. 
     
     
         5 . The antibody of  claim 4 , wherein the Fc region comprises one or more amino acid substitutions. 
     
     
         6 . The antibody of  claim 5 , wherein the Fc region comprises an amino acid substitution at position 248 according to Kabat numbering convention. 
     
     
         7 . The antibody of  claim 6 , wherein the Fc region comprises a leucine to glutamate amino acid substitution at position 248 according to Kabat numbering convention. 
     
     
         8 . The antibody of  claim 5 , wherein the amino acid substitution at position 248 inhibits the Fc region from interacting with an Fc receptor. 
     
     
         9 . The antibody of  claim 5 , wherein the Fc region comprises an amino acid substitution at position 241 according to Kabat numbering convention. 
     
     
         10 . The antibody of  claim 9 , wherein the Fc region comprises a serine to proline amino acid substitution at position 241 according to Kabat numbering convention. 
     
     
         11 . (canceled) 
     
     
         12 . The antibody of  claim 1 , wherein the antibody comprises 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 90% homology to the amino acid sequence selected from SEQ ID NOs: 1-4. 
     
     
         13 . The antibody of  claim 1 , wherein the antibody comprises 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 90% homology to the amino acid sequence selected from SEQ ID NOs: 5-8. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The antibody or antigen-binding fragment of  claim 1 , wherein the antigen-binding fragment is a Fab, F(ab′) 2  or Fab′ fragment. 
     
     
         17 - 22 . (canceled) 
     
     
         23 . An isolated polynucleotide comprising a nucleic acid sequence encoding the antibody of  claim 1 . 
     
     
         24 . An isolated host cell comprising the nucleic acid sequence of  claim 23 . 
     
     
         25 . A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         26 . A method of treating or preventing a disease associated with complement activation in an individual in need of such treatment, the method comprising the step of administering a therapeutically effective dose of the antibody of  claim 1 . 
     
     
         27 . A kit comprising an antibody of  claim 1 , and a package insert comprising instructions for using the antibody to treat or prevent a disease associated with complement activation in an individual in need of such treatment. 
     
     
         28 . A diagnostic kit comprising an antibody of  claim 1 . 
     
     
         29 . A method of detecting synapses in an individual, the method comprising
 a) administering an antibody of  claim 1  to the individual; and   b) detecting antibody bound to synapses, thereby detecting synapses in the individual.