Treatment of autoimmune disorders with cd154 antibodies

Abstract

The present invention relates to a method of treating an autoimmune or inflammatory disease or a neurodegenerative disease with an antibody to CD154.

1 - 17 . (canceled) 
     
     
         18 . A method of treating an autoimmune, inflammatory, neurodegenerative or neuromuscular disorder in a mammalian subject comprising:
 a) administering an initial loading dose of about 20-60 mg/kg of antibody or antibody fragment binding specifically to CD154 to a subject in need of such treatment; and   b) about 2 weeks after the initial loading dose administering a further dose or doses of about half of the initial loading dose with a frequency of about once every other week of antibody or antibody fragment binding specifically to CD154 to the subject in need of such treatment.   
     
     
         19 . The method according to  claim 18 , wherein the initial loading dose is about 30 mg/kg and the further dose is about 15 mg/kg. 
     
     
         20 . The method according to  claim 18 , wherein the antibody or antibody fragment binding specifically to CD154 is administered to the patient in need thereof at least for 12 weeks. 
     
     
         21 . The method according to  claim 18 , wherein said antibody or antibody fragment binding specifically to CD154 is a neutralizing antibody or antibody fragment. 
     
     
         22 . The method according to  claim 18 , wherein said antibody or antibody fragment specifically binding to CD154 has a dissociation constant for monovalent binding to CD40 of KD≦4.55 pM as determined by surface plasmon resonance. 
     
     
         23 . The method according to  claim 18 , wherein said antibody or antibody fragment specifically binding to CD154 comprises a light chain variable region (LCVR) having a CDR1, a CDR2 and a CDR3 comprising the amino acid sequence of SEQ ID NOs:1, 2 and 3, respectively, and a heavy chain variable region (HCVR) having a CDR1, a CDR2 and a CDR3 comprising the amino acid sequence of SEQ ID NOs: 4, 5 and 6, respectively. 
     
     
         24 . The method according to  claim 23 , wherein said antibody or antibody fragment specifically binding to CD154 exhibits monovalent binding to CD40, and has only one binding site that binds specifically CD154. 
     
     
         25 . The method according to  claim 24 , wherein said antibody or antibody fragment specifically binding to CD154 contains the VL chain sequence shown in SEQ ID NO:7 and the VH chain sequence shown in SEQ ID NO:8. 
     
     
         26 . The method according to  claim 25 , wherein said antibody or antibody fragment specifically binding to CD154 has the light chain sequence shown in SEQ ID NO:9 and the heavy chain sequences shown in SEQ ID NO:10. 
     
     
         27 . The method according to  claim 26 , wherein said antibody or antibody fragment specifically binding to CD154 is a monovalent Fab′ having the light chain sequence shown in SEQ ID NO:9 and the heavy chain sequences shown in SEQ ID NO:10. 
     
     
         28 . The method according to  claim 27 , wherein said antibody or antibody fragment specifically binding to CD154 has
 a) a maleimide group covalently linked to a single thiol group in the modified hinge region; a lysine residue is covalently linked to the maleimide group; and   b) a methoxypoly(ethyleneglycol) polymer having a molecular weight of approximately 20 KDa is attached to each of the amine groups on the lysine residue.   
     
     
         29 . The method according to  claim 18 , wherein said autoimmune, inflammatory, neurodegenerative or neuromuscular disorder systemic lupus erythematosus (SLE), lupus nephritis, rheumatoid arthritis, seronegative spondyloarthropathies, psoriasis, psoriatic arthritis, scleroderma, Sjögren's syndrome, multiple sclerosis, type I diabetes, autoimmune uveitis and nephrotic syndrome or vasculitis. 
     
     
         30 . The method according to  claim 29 , wherein said antibody or antibody fragment specifically binding to CD154 is administered to a subject having systemic lupus erythematosus (SLE) wherein the subject treated achieves an improvement from baseline of one or more of the indices selected from SLEDAI, BILAG and Global Physician assessment. 
     
     
         31 . The method according to  claim 30 , wherein the subject treated achieves a SLEDAI Responder Index 4 (SRI-4). 
     
     
         32 . The method according to  claim 29 , wherein said subject has systemic lupus erythematosus (SLE) and wherein the subject treated achieves a 50% improvement from baseline of the SRI-50 index. 
     
     
         33 . The method according to  claim 29 , wherein said subject has systemic lupus erythematosus (SLE) and achieves an increase of 20%, 30%, 40%, 50%, 75% or 90% from baseline or normalization of complement C3 and C4 concentration, or a reduction of 20%, 30%, 40%, 50%, 75% or 90% of anti-double stranded DNA titre in serum. 
     
     
         34 . The method according to  claim 29 , wherein said subject has systemic lupus erythematosus (SLE) and wherein the subject reverts from seropositive to seronegative for anti-double stranded DNA antibodies.