Methods of treatment for alzheimer's disease and huntington's disease

Abstract

This invention relates generally to methods of treatment for neurodegenerative diseases such as Alzheimer's disease, Alzheimer's-related diseases, and Huntington's disease, and more specifically to methods involving the inhibition of the classical pathway of complement activation.

1 . A method of treating or preventing Alzheimer's disease or Huntington's disease comprising administering an anti-C1q antibody. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the anti-C1q antibody is:
 a) an anti-C1q antibody comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody M1 produced by a hybridoma cell line with ATCC Accession Number PTA-120399 or progeny thereof; and/or wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 of the monoclonal antibody M1 produced by a hybridoma cell line with ATCC Accession Number PTA-120399 or progeny thereof;   b) an isolated anti-C1q antibody which binds essentially the same C1q epitope as the antibody M1 produced by the hybridoma cell line with ATCC Accession Number PTA-120399 or anti-C1q binding fragments thereof; or   c) an murine anti-human C1q monoclonal antibody M1 produced by a hybridoma cell line with ATCC Accession Number PTA-120399, or progeny thereof.   
     
     
         4 . The method of  claim 1 , wherein the anti-C1q antibody binds to a C1q protein and binds to one or more amino acids of the C1q protein within amino acid residues selected from:
 a) amino acid residues 196-226 of SEQ ID NO:1 (SEQ ID NO:6), or amino acid residues of a C1q protein chain A (C1qA) corresponding to amino acid residues 196-226 (GLFQVVSGGMVLQLQQGDQVWVEKDPKKGHI) of SEQ ID NO:1 (SEQ ID NO:6);   b) amino acid residues 196-221 of SEQ ID NO:1 (SEQ ID NO:7), or amino acid residues of a C1qA corresponding to amino acid residues 196-221 (GLFQVVSGGMVLQLQQGDQVWVEKDP) of SEQ ID. NO:1 (SEQ ID NO:7);   c) amino acid residues 202-221 of SEQ ID NO:1 (SEQ ID NO:8), or amino acid residues of a C1qA corresponding to amino acid residues 202-221 (SGGMVLQLQQGDQVWVEKDP) of SEQ ID NO:1 (SEQ ID NO:8);   d) amino acid residues 202-219 of SEQ ID NO:1 (SEQ ID NO:9), or amino acid residues of a C1qA corresponding to amino acid residues 202-219 (SGGMVLQLQQGDQVWVEK) of SEQ ID NO:1 (SEQ ID NO:9); and   e) amino acid residues Lys 219 and/or Ser 202 of SEQ ID NO:1, or amino acid residues of a C1qA corresponding Lys 219 and/or Ser 202 of SEQ ID NO:1.   
     
     
         5 . The method of  claim 1 , wherein the anti-C1q antibody binds to one or more amino acids of the C1q protein within amino acid residues selected from:
 a) amino acid residues 218-240 of SEQ ID NO:3 (SEQ ID NO:10) or amino acid residues of a C1q protein chain C (C1qC) corresponding to amino acid residues 218-240 (WLAVNDYYDMVGI QGSDSVFSGF) of SEQ ID NO:3 (SEQ ID NO:10);   b) amino acid residues 225-240 of SEQ ID NO:3 (SEQ ID NO:11) or amino acid residues of a C1qC corresponding to amino acid residues 225-240 (YDMVGI QGSDSVFSGF) of SEQ ID NO:3 (SEQ ID NO:11);   c) amino acid residues 225-232 of SEQ ID NO:3 (SEQ ID NO:12) or amino acid residues of a C1qC corresponding to amino acid residues 225-232 (YDMVGIQG) of SEQ ID NO:3 (SEQ ID NO:12);   d) amino acid residue Tyr 225 of SEQ ID NO:3 or an amino acid residue of a C1qC corresponding to amino acid residue Tyr 225 of SEQ ID NO:3;   e) amino acid residues 174-196 of SEQ ID NO:3 (SEQ ID NO:13) or amino acid residues of a C1qC corresponding to amino acid residues 174-196 (HTANLCVLLYRSGVKVVTFCGHT) of SEQ ID NO:3 (SEQ ID NO:13);   f) amino acid residues 184-192 of SEQ ID NO:3 (SEQ ID NO:14) or amino acid residues of a C1qC corresponding to amino acid residues 184-192 (RSGVKVVTF) of SEQ ID NO:3 (SEQ ID NO:14);   g) amino acid residues 185-187 of SEQ ID NO:3 or amino acid residues of a C1qC corresponding to amino acid residues 185-187 (SGV) of SEQ ID NO:3; and   h) amino acid residue Ser 185 of SEQ ID NO:3 or an amino acid residue of a C1qC corresponding to amino acid residue Ser 185 of SEQ ID NO:3.   
     
     
         6 . The method of  claim 1 , wherein the anti-C1q antibody binds to a C1q protein and binds to one or more amino acids of the C1q protein chain A (C1qA) within amino acid residues selected from:
 a) amino acid residues 196-226 of SEQ ID NO:1 (SEQ ID NO:6), or amino acid residues of a C1q protein chain A (C1qA) corresponding to amino acid residues 196-226 (GLFQVVSGGMVLQLQQGDQVWVEKDPKKGHI) of SEQ ID NO:1 (SEQ ID NO:6);   b) amino acid residues 196-221 of SEQ ID NO:1 (SEQ ID NO:7), or amino acid residues of a C1qA corresponding to amino acid residues 196-221 (GLFQVVSGGMVLQLQQGDQVWVEKDP) of SEQ ID. NO:1 (SEQ ID NO:7);   c) amino acid residues 202-221 of SEQ ID NO:1 (SEQ ID NO:8), or amino acid residues of a C1qA corresponding to amino acid residues 202-221 (SGGMVLQLQQGDQVWVEKDP) of SEQ ID NO:1 (SEQ ID NO:8);   d) amino acid residues 202-219 of SEQ ID NO:1 (SEQ ID NO:9), or amino acid residues of a C1qA corresponding to amino acid residues 202-219 (SGGMVLQLQQGDQVWVEK) of SEQ ID NO:1 (SEQ ID NO:9); and   e) amino acid residue Lys 219 of SEQ ID NO:1, or an amino acid residue of a C1qA corresponding Lys 219 of SEQ ID NO:1; and   wherein the anti-C1q antibody binds to one or more amino acids of the C1q protein chain C (C1qC) within amino acid residues selected from:   a) amino acid residues 174-196 of SEQ ID NO:3 (SEQ ID NO:13) or amino acid residues of a C1qC corresponding to amino acid residues 174-196 (HTANLCVLLYRSGVKVVTFCGHT) of SEQ ID NO:3 (SEQ ID NO:13);   b) amino acid residues 184-192 of SEQ ID NO:3 (SEQ ID NO:14) or amino acid residues of a C1qC corresponding to amino acid residues 184-192 (RSGVKVVTF) of SEQ ID NO:3 (SEQ ID NO:14);   c) amino acid residues 185-187 of SEQ ID NO:3 or amino acid residues of a C1qC corresponding to amino acid residues 185-187 (SGV) of SEQ ID NO:3; and   d) amino acid residue Ser 185 of SEQ ID NO:3 or an amino acid residue of a C1qC corresponding to amino acid residue Ser 185 of SEQ ID NO:3.   
     
     
         7 . The method of  claim 1 , wherein the anti-C1q antibody binds specifically to rat C1q, both human C1q and mouse C1q, or human C1q, mouse C1q, and rat C1q. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the anti-C1q antibody has a dissociation constant (K D ) for human C1q and mouse C1q less than about 30 nM. 
     
     
         11 - 16 . (canceled) 
     
     
         17 . The method  claim 1 , wherein the anti-C1q antibody specifically binds to and inhibits a biological activity of C1q. 
     
     
         18 . The method of  claim 17 , 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, (10) C1q binding to calreticulin, (11) activation of the classical complement activation pathway, (12) activation of antibody and complement dependent cytotoxicity, (13) CH50 hemolysis, (14) synapse loss, (15) B-cell antibody production, (16) dendritic cell maturation, (17) T-cell proliferation, (18) cytokine production (19) microglia activation, (20) Arthus reaction, (21) phagocytosis of synapses or nerve endings, or (22) activation of complement receptor 3 (CR3/C3) expressing cells. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18 , wherein CH50 hemolysis comprises human, mouse, and/or rat CH50 hemolysis. 
     
     
         21 . The method of  18 , wherein the anti-C1q antibody is capable of neutralizing at least 50%, at least 80%, or at least 90% of CH50 hemolysis. 
     
     
         22 . The method of  claim 18 , wherein the anti-C1q antibody is capable of neutralizing at least 50% of CH50 hemolysis 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. 
     
     
         23 . The method of  claim 1 , wherein the anti-C1q antibody is a murine, a humanized, a chimeric, or a human antibody. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 23 , wherein the anti-C1q antibody binds to amino acid residue Lys 219 and Ser 202 of the human C1qA as shown in SEQ ID NO:1 or amino acids of a human C1qA corresponding to Lys 219 and Ser 202 as shown in SEQ ID NO:1, and amino acid residue Tyr 225 of the human C1qC as shown in SEQ ID NO:3 or an amino acid residue of a human C1qC corresponding to Tyr 225 as shown in SEQ ID NO:3. 
     
     
         26 . The method of  claim 23 , wherein the anti-C1q antibody binds to amino acid residue Lys 219 of the human C1qA as shown in SEQ ID NO:1 or an amino acid residue of a human C1qA corresponding to Lys 219 as shown in SEQ ID NO:1, and amino acid residue Ser 185 of the human C1qC as shown in SEQ ID NO:3 or an amino acid residue of a human C1qC corresponding to Ser 185 as shown in SEQ ID NO:3. 
     
     
         27 . The method of  claim 1 , wherein the anti-C1q antibody is a multivalent antibody or a bispecific antibody. 
     
     
         28 - 34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein the anti-C1q antibody is an antibody fragment, wherein the fragment is a Fab, F(ab′) 2  or Fab ′ fragment. 
     
     
         36 - 38 . (canceled) 
     
     
         39 . The method of  claim 35 , wherein the antibody fragment has a shorter half-life as compared to its corresponding full-length antibody. 
     
     
         40 - 41 . (canceled) 
     
     
         42 . The method of  claim 1 , wherein the anti-C1q antibody inhibits complement-dependent cell-mediated cytotoxicity (CDCC) activation pathway by an amount from at least 30% to at least 99.9%. 
     
     
         43 . The method of  claim 1 , wherein the anti-C1q antibody does not inhibit the lectin complement activation pathway. 
     
     
         44 . The method of  claim 1 , wherein the anti-C1q antibody having a dissociation constant (K D ) for its corresponding antigen from 100 nM to 0.005 nM or less than 0.005 nM. 
     
     
         45 . The method of  claim 1 , wherein the anti-C1q antibody inhibits autoantibody-dependent and complement-dependent cytotoxicity (CDC). 
     
     
         46 . The method of  claim 1 , wherein the anti-C1q antibody prevents amplification of the alternative complement activation pathway initiated by C1q binding. 
     
     
         47 . (canceled) 
     
     
         48 . The method of  claim 1 , wherein the anti-C1q antibody does not inhibit autoantibody-dependent cellular cytotoxicity (ADCC). 
     
     
         49 . The method of  claim 1 , comprising administering a therapeutically effective amount of two antibodies, wherein the two antibodies are selected from an anti-C1q antibody, an anti-C1r antibody, and an anti-C1s antibody. 
     
     
         50 - 54 . (canceled)