Humanized anti-c1s antibodies and methods of use thereof

Abstract

The present disclosure provides humanized anti-C1s antibodies. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the humanized anti-C1s antibodies; and host cells comprising the nucleic acids. The present disclosure provides compositions comprising the humanized anti-C1s antibodies. The present disclosure provides methods of use of the humanized anti-C1s antibodies.

1 . A humanized antibody that specifically binds complement component C1s, wherein the antibody comprises:
 a) a VH region comprising the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 26) 
                 
                   (Q/E)VQL(V/Q)QSGAE(V/L)KKPGASVK(L/V)SC(T/A)ASGFNIK 
                 
                     
                 
                   DDYIHWV(K/R)QAPGQGLEWIGRIDPADGHTKYAPKFQVK(V/A)TITA 
                 
                     
                 
                   DTST(S/N)TAY(L/M)(E/Q)LSSL(R/T)SEDTAVYYCARYGYGREVF 
                 
                     
                 
                   DYWGQGTTVTVSS; 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       and
 b) a VL region comprising the amino acid sequence: 
 
       
         
           
                 
               
                   (SEQ ID NO: 27) 
                 
                   DIVLTQSPDSLAVSLGERATISCKASQSVDYDGDSYMNWYQQK(T/P)GQ 
                 
                     
                 
                   PPK(I/L)LIYDASNLESGIPARFSGSGSGTDFTLTISSLE(E/P)EDFA 
                 
                     
                 
                   (I/V)YYCQQSNEDPWTFGGGTKVEIK. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 .- 23 . (canceled) 
     
     
         24 . A method of reducing the level of a complement component cleavage product in an individual, the method comprising administering to the individual the antibody of  claim 1 , in an amount effective to inhibit C1s and to reduce the level of the cleavage product. 
     
     
         25 .- 35 . (canceled) 
     
     
         36 . A method of inhibiting C1s-mediated cleavage of a complement component in an individual, the method comprising administering to the individual the antibody of  claim 1 , in an amount effective to inhibit C1s-mediated cleavage of a complement component. 
     
     
         37 . A method of treating a complement-mediated disease or disorder in an individual, the method comprising administering to the individual a humanized antibody that specifically binds complement component C1s, wherein the antibody comprises:
 a) a VH region comprising the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 26) 
                 
                   
                     (Q/E)VQL(V/Q)QSGAE(V/L)KKPGASVK(L/V)SC(T/A)ASGFNIK 
                   
                 
                     
                 
                   
                     DDYIHWV(K/R)QAPGQGLEWIGRIDPADGHTKYAPKFQVK(V/A)TITA 
                   
                 
                     
                 
                   
                     DTST(S/N)TAY(L/M)(E/Q)LSSL(R/T)SEDTAVYYCARYGYGREVF 
                   
                 
                     
                 
                   
                     DYWGQGTTVTVSS; 
                   
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       and
 b) a VL region comprising the amino acid sequence: 
 
       
         
           
                 
               
                   (SEQ ID NO: 27) 
                 
                   
                     DIVLTQSPDSLAVSLGERATISCKASQSVDYDGDSYMNWYQQK(T/P)GQ 
                   
                 
                     
                 
                   
                     PPK(I/L)LIYDASNLESGIPARFSGSGSGTDFTLTISSLE(E/P)EDFA 
                   
                 
                     
                 
                     (I/V)YYCQQSNEDPWTFGGGTKVEIK , 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       in an amount effective to treat the complement-mediated disease or disorder. 
     
     
         38 . The method of  claim 37 , wherein the humanized antibody is selected from the group consisting of:
 a) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:14 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:22;   b) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:10 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:20;   c) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:10 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:22;   d) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:10 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:24;   e) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:12 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:20;   f) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:12 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:22;   g) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:12 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:24;   h) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:14 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:20;   i) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:14 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:24;   j) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:16 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:20;   k) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:16 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:22;   l) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:16 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:24;   m) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:18 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:20;   n) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:18 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:22; and   o) an antibody comprising a VH region comprising the amino acid sequence set forth in SEQ ID NO:18 and a VL region comprising the amino acid sequence set forth in SEQ ID NO:24.   
     
     
         39 . The method of  claim 37 , wherein the humanized antibody is a Fab fragment, a F(ab′)2 fragment, a scFv, or a Fv. 
     
     
         40 . The method of  claim 37 , wherein the humanized antibody comprises a heavy chain constant region of the isotype IgG1, IgG2, IgG3, or IgG4. 
     
     
         41 . The method of  claim 40 , wherein the humanized antibody comprises a heavy chain constant region of the isotype IgG4. 
     
     
         42 . The method of  claim 37 , wherein the administering is selected from the group consisting of intravenously administering, intramuscularly administering, intrathecally administering, and subcutaneously administering. 
     
     
         43 . The method of  claim 37 , wherein the complement-mediated disease or disorder is Alzheimer's disease, amyotrophic lateral sclerosis, anaphylaxis, argyrophilic grain dementia, arthritis asthma, atherosclerosis, atypical hemolytic uremic syndrome, autoimmune diseases Barraquer-Simons syndrome, Behcet's disease, British type amyloid angiopathy, bullous pemphigoid, Buerger's disease, C1q nephropathy, cancer, catastrophic antiphospholipid syndrome, cerebral amyloid angiopathy, cold agglutinin disease, corticobasal degeneration, Creutzfeldt-Jakob disease, Crohn's disease, cryoglobulinemic vasculitis, dementia pugilistica, dementia with Lewy Bodies (DLB), diffuse neurofibrillary tangles with calcification, Discoid lupus erythematosus, Down's syndrome, Evan's syndrome, focal segmental glomerulosclerosis, formal thought disorder, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration, Gerstmann-Straussler-Scheinker disease, Guillain-Barre syndrome, Hallervorden-Spatz disease, hemolytic-uremic syndrome, hereditary angioedema, hypophosphastasis, idiopathic pneumonia syndrome, immune complex diseases, inclusion body myositis, infectious disease, inflammatory disease, ischemia/reperfusion injury, mild cognitive impairment, immunothrombocytopenic purpura (ITP), molybdenum cofactor deficiency (MoCD) type A, membranoproliferative glomerulonephritis (MPGN) I, membranoproliferative glomerulonephritis (MPGN) II (dense deposit disease), membranous nephritis, multi-infarct dementia, lupus, glomerulonephritis, Kawasaki disease, multifocal motor neuropathy, multiple sclerosis, multiple system atrophy, myasthenia gravis, myocardial infarction, myotonic dystrophy, neuromyelitis optica, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, Parkinson's disease, Parkinson's disease with dementia, paroxysmal nocturnal hemoglobinuria, Pemphigus vulgaris, Pick's disease, postencephalitic parkinsonism, polymyositis, prion protein cerebral amyloid angiopathy, progressive, subcortical gliosis, progressive supranuclear palsy, psoriasis, sepsis, Shiga-toxin  E. coli  (STEC)-HuS, spinal muscular atrophy, stroke, subacute sclerosing panencephalitis, Tangle only dementia, transplant rejection, vasculitis, Wegner's granulomatosis, sickle cell disease, cryoglobulinemia, mixed cryoglobulinemia, essential mixed cryoglobulinemia, Type II mixed cryoglobulinemia, Type III mixed cryoglobulinemia, nephritis, drug-induced thrombocytopenia, lupus nephritis, Epidermolysis bullosa acquisita, delayed hemolytic transfusion reaction, hypocomplementemic urticarial vasculitis syndrome, pseudophakic bullous keratopathy or platelet refractoriness. 
     
     
         44 . The method of  claim 37 , wherein the complement-mediated disease or disorder is cold agglutinin disease, immunothrombocytopenic purpura (ITP), bullous pemphigoid, multifocal motor neuropathy, antibody-mediated transplant rejection, or rheumatoid arthritis. 
     
     
         45 . The method of  claim 37 , wherein the complement-mediated disease or disorder is autoimmune disease. 
     
     
         46 . The method of  claim 37 , wherein the complement-mediated disease or disorder is antibody-mediated transplant rejection. 
     
     
         47 . A method of treating a complement-mediated disease or disorder in an individual, the method comprising administering to the individual a humanized antibody that specifically binds complement component C1s, wherein the antibody comprises a VH region comprising the amino acid sequence set forth in SEQ ID NO:14, a VL region comprising the amino acid sequence set forth in SEQ ID NO:22. 
     
     
         48 . The method of  claim 47 , wherein the antibody further comprises a heavy chain constant region of the isotype IgG4. 
     
     
         49 . The method of  claim 47 , wherein the humanized antibody is a Fab fragment, a F(ab′)2 fragment, a scFv, or a Fv. 
     
     
         50 . The method of  claim 47 , wherein the administering is selected from the group consisting of intravenously administering, intramuscularly administering, intrathecally administering, and subcutaneously administering. 
     
     
         51 . The method of  claim 47 , wherein the complement-mediated disease or disorder is cold agglutinin disease, immunothrombocytopenic purpura (ITP), bullous pemphigoid, multifocal motor neuropathy, antibody-mediated transplant rejection, or rheumatoid arthritis. 
     
     
         52 . The method of  claim 47 , wherein the complement-mediated disease or disorder is autoimmune disease. 
     
     
         53 . A container comprising a composition the humanized antibody of  claim 1  and a pharmaceutically acceptable excipient.