Humanized anti-factor d antibodies and uses thereof

Abstract

The invention relates to anti-Factor D antibodies, their nucleic acid and amino acid sequences, the cells and vectors that harbor these antibodies and their production and their use in the preparation of compositions and medicaments for treatment of diseases and disorders associated with excessive or uncontrolled complement activation. These antibodies are useful for diagnostics, prophylaxis and treatment of disease.

1 . An anti-Factor D antibody comprising light chain HVRs of a reference antibody, wherein said anti-Factor D antibody further comprises a substitution at one or more positions of said reference antibody, wherein said reference antibody comprises light chain HVR-1 comprising ITSTDIDDDMN (SEQ ID NO: 30), light chain HVR-2 comprising GGNTLRP (SEQ ID NO: 35), and light chain HVR-3 comprising LQSDSLPYT (SEQ ID NO: 38), and wherein said substitution is one or more of the following:
 (a) amino acid at position 33 of the light chain is L or I;   (b) amino acid at position 34 of the light chain is A or Q;   (c) amino acid at position 52 of the light chain is S or A;   (d) amino acid at position 104 of the light chain is V;   (e) amino acid at position 1 of the heavy chain is E;   (f) amino acid at position 99 of the heavy chain is A or Q; or   (g) amino acid at position 100 of the heavy chain is A or Q.   
     
     
         2 . An anti-Factor D antibody comprising heavy chain HVRs of a reference antibody, wherein said anti-Factor D antibody further comprises a substitution at one or more positions of said reference antibody, wherein said reference antibody comprises heavy chain HVR-1 comprising GYTFTNYGMN (SEQ ID NO: 39), heavy chain HVR-2 comprising WINTYTGETTYADDFKG (SEQ ID NO: 40), and heavy chain HVR-3 comprising EGGVNN (SEQ ID NO: 41), and wherein said substitution is one or more of the following:
 (a) amino acid at position 33 of the light chain is L or I;   (b) amino acid at position 34 of the light chain is A or Q;   (c) amino acid at position 52 of the light chain is S or A;   (d) amino acid at position 104 of the light chain is V;   (e) amino acid at position 1 of the heavy chain is E;   (f) amino acid at position 99 of the heavy chain is A or Q; or   (g) amino acid at position 100 of the heavy chain is A or Q.   
     
     
         3 - 21 . (canceled) 
     
     
         22 . A polypeptide comprising the following amino acid sequence: X 1 VQLVQSGPELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYT GETTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCEREGGVX 2 X 3 WGQGTLVT VSS (SEQ ID NO: 74), wherein X 1  is Q or E; X 2  is N, A or Q; and X 3  is N, A or Q. 
     
     
         23 . A polypeptide comprising the following amino acid sequence: DIQVTQSPSSLSASVGDRVTITCITSTDIDDDX 4 X 5 WYQQKPGKVPKLLISGGX 6 TLRPGV PSRFSGSGSGTDFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKX 7 EIK (SEQ ID NO: 73), wherein X 4  is M, L or I; X 5  is N, A or Q; X 6  is N, S or A; and X 7  is L or V. 
     
     
         24 . A polypeptide comprising an amino acid sequence selected from the group comprising SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28 and SEQ ID NO: 29. 
     
     
         25 . A polypeptide comprising an amino acid sequence selected from the group comprising SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16 and SEQ ID NO: 17. 
     
     
         26 - 46 . (canceled) 
     
     
         47 . A polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 47 and 61. 
     
     
         48 . A polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO: 54 and 63. 
     
     
         49 - 51 . (canceled) 
     
     
         52 . A polynucleotide encoding an antibody of  claim 1  or  2 . 
     
     
         53 . A polynucleotide encoding a polypeptide of  claim 22 - 25  or  47 - 48 . 
     
     
         54 . A vector comprising the polynucleotide of  claim 52 . 
     
     
         55 . A host cell comprising the vector of  claim 54 . 
     
     
         56 . A host cell of  claim 55 , wherein the host cell is eukaryotic. 
     
     
         57 . A host cell of  claim 55 , wherein the host cell is a CHO cell. 
     
     
         58 . A method of making an anti-Factor D antibody, wherein the method comprises (a) culturing the host cell of  claim 55  under conditions suitable for expression of the polynucleotide encoding the antibody, and (b) isolating the antibody. 
     
     
         59 - 69 . (canceled) 
     
     
         70 . A method of treating a complement-associated disorder selected from the group comprising inflammatory disorders. 
     
     
         71 . A method of  claim 70 , wherein the inflammatory disorder is an autoimmune disease. 
     
     
         72 . A method of  claim 71 , wherein the autoimmune disease is selected from the group comprising systemic lupus erythematosus, myasthenia gravis, rheumatoid arthritis, Alzheimer's disease and multiple sclerosis. 
     
     
         73 . A method of treating a complement-associated disorder selected from the group comprising ocular diseases. 
     
     
         74 . A method of  claim 73 , wherein the ocular disease is selected from the group comprising age-related macular degeneration, diabetic retinopathy, choroidal neovascularization (CNV), uveitis, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, histoplasmosis of the eye, Central Retinal Vein Occlusion (CRVO), corneal neovascularization, and retinal neovascularization. 
     
     
         75 . A method of  claim 74 , wherein the age-related macular degeneration is selected from the group comprising intermediate dry AMD, and geographic atrophy. 
     
     
         76 . (canceled)