Recombinant anti-cd4 antibodies for human therapy

Abstract

Chimeric antibodies specific to human CD4 antigen, DNA encoding, pharmaceutical compositions containing and use thereof as therapeutic agents are taught. These chimeric antibodies contain Old World monkey variable sequences and human constant domain sequences, preferably human gamma 1, gamma 4 or mutated forms thereof. These antibodies possess desirable therapeutic properties including low antigenicity, reduced (or absent) T cell depleting activity, good affinity to human CD4 and enhanced stability (in vivo half-life).

1 . A method for the treatment of an autoimmune or inflammatory disorder comprising administering the combination of
 (i) a non-T cell depleting chimeric anti-CD4 monoclonal antibody; and   (ii) an immunosuppressive agent effective for said autoimmune disorder.   
     
     
         2 . The method of  claim 1  wherein said autoimmune or inflammatory disorder is selected from the group consisting of Hashimoto's thyroiditis, primary myxoedema, thyrotoxicosis/Graves disease, pernicious anaemia, autoimmune atrophic gastritis, autoimmune carditis, Addison's disease, premature menopause, type 1-diabetes mellitus, Good pasture's syndrome, myasthenia gravis, multiple sclerosis, male infertility, pemphigus vulgaris, pemphigoid, sympathetic opthalmia, phacogenie uveitis, autoimmune haemolytic anaemia, idiopathic thromocytopenic purpura, idiopathic leucopenia, primary biliary cirrhosis, active chronic hepatitis (HBs Ag negative), cryptogenic cirrhosis, inflammatory bowel disease syndrome, Sjogren's syndrome, psoriasis, rheumatoid arthritis, dermatomyositis, scleroderma, mixed tissues connective disease, discoid lupus erythematosus, systemic vasculitis, and systemic lupus erythematosus (SLE). 
     
     
         3 . The method of  claim 1  wherein said disorder is rheumatoid arthritis. 
     
     
         4 . The method of  claim 1  wherein said antibody comprises human gamma 4 constant regions. 
     
     
         5 . The method of  claim 3  wherein the human heavy constant domain contains a mutation at position 236 comprising the substitution of a leucine to a glutamic acid and/or at position 229 by the substitution of serine to proline. 
     
     
         6 . The method of  claim 1  wherein said antibody is CE9γ4, CE9γ4λKm, CE9γ4E or CE9γ4PE. 
     
     
         7 . The method of  claim 1  wherein said immunosuppressive agent is selected from the group consisting of monoclonal antibodies to TNF-alpha, soluble receptor proteins specific to TNF-alpha, monoclonal antibodies or receptor proteins which antagonize the CD40/gp39 interaction CTLA-41 g and monoclonal antibodies which inhibit the B7/CD28 interaction. 
     
     
         8 . The method of  claim 3  wherein the immunosuppresive agent is selected from the group consisting of Rapamycin, Leflunomide, Tenidap, RS-61443 (Mycophenolate Mofetil), Surenyl (sodium Hyaluronate), anti-TCP (Vβ17) peptide vaccine, Anerva X (anti-MHC vaccine), and extracorpreal protein A immunoabsorbents and combinations thereof. 
     
     
         9 . The method of  claim 1  wherein the antibody is a chimeric antibody containing primate variable regions. 
     
     
         10 . The method of  claim 1  wherein the antibody is administered parenterally. 
     
     
         11 . The method of  claim 10  wherein parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal and intraperitoneal administration. 
     
     
         12 . The method of  claim 1  wherein the antibody is administered intravenously. 
     
     
         13 . The method of  claim 1  wherein the antibody dosage ranges from 0.05 to 100 mg/kg body weight per day. 
     
     
         14 . The method of  claim 13  wherein said dosage ranges from 0.5 to 10 mg/kg per day.