Compositions for selective reduction of circulating bioactive soluble tnf and methods for treating tnf-mediated disease

Abstract

An isolated or synthetic antibody or ligand is provided that specifically binds to an epitope of a dissociated monomer of human TNF. Such binding disrupts assembly of the monomer into bioactive trimeric human sTNF. A pharmaceutical composition contains one or more antibodies or ligands: (a) an antibody or ligand that specifically binds the TNF monomer-specific epitope having the sequence PSDKPVAH or PSDKPVAHV, amino acids 8-15 or 8-16 of SEQ ID NO: 1; and (b) an antibody or ligand that specifically binds the TNF monomer-specific epitope having the sequence EPIYLGGVF, amino acids 116 to 124 of SEQ ID NO: 1. A combination of antibodies or ligands that bind or are reactive with (a) and/or (b) are useful in methods for treating a subject having a disease (e.g., rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, atherosclerosis, metabolic syndrome, Alzheimer's Disease, HIV, Type II diabetes) mediated by human TNF. These methods and compositions disrupt or reduce the in vivo assembly or reassembly of dissociated monomers of TNF into bioactive trimeric human sTNF.

What is claimed is: 
     
         1 . A monoclonal antibody or a fragment of the antibody that specifically binds to an epitope on a dissociated monomer of human TNF, the epitope having the amino acid sequence EPIYLGGVF, amino acids 116 to 124 of SEQ ID NO: 1, said specific binding disrupting assembly of the monomer into bioactive trimeric human soluble TNF, without binding to intact bioactive trimeric human soluble TNF or trimeric transmembrane TNF. 
     
     
         2 . The antibody or fragment according to  claim 2 , which is a single chain of an antibody, a recombinant antibody, a chimeric antibody, a humanized antibody, a human antibody, or a bi-specific antibody. 
     
     
         3 . The antibody or ligand according to  claim 2 , which is a bi-specific antibody reactive with the TNF monomer-specific epitope having the sequence EPIYLGGVF, amino acids 116 to 124 of SEQ ID NO: 1 and with a TNF monomer-specific epitope having the sequence PSDKPVAH or PSDKPVAHV, amino acids 8-15 or 8-16 of SEQ ID NO: 1. 
     
     
         4 . The antibody or fragment according to  claim 2 , wherein said antibody fragment is an sc-Fv construct, a Fab construct, a Fab 2  construct, or a construct containing a light chain or heavy chain variable or complementarity determining region (CDR) sequence. 
     
     
         5 . A pharmaceutical composition comprising a monoclonal antibody or fragment thereof that specifically binds to an epitope on a dissociated monomer of human TNF, the epitope having the amino acid sequence EPIYLGGVF, amino acids 116 to 124 of SEQ ID NO: 1, said specific binding disrupting assembly of the monomer into bioactive trimeric human soluble TNF, without binding to intact bioactive trimeric human soluble TNF or trimeric transmembrane TNF, and a pharmaceutically acceptable carrier or diluent. 
     
     
         6 . A pharmaceutical composition consisting essentially of a monoclonal antibody or antigen-binding fragment thereof that specifically binds to an epitope on a dissociated monomer of human TNF, the epitope having the amino acid sequence EPIYLGGVF, amino acids 116 to 124, said specific binding disrupting assembly of the monomer into bioactive trimeric human soluble TNF, without binding to intact bioactive trimeric human soluble TNF or trimeric transmembrane TNF, and a pharmaceutically acceptable carrier or diluent. 
     
     
         7 . A pharmaceutical composition comprising an antibody or fragment of  claim 2 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         8 . A pharmaceutical composition comprising an antibody or fragment of  claim 3 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         9 . A pharmaceutical composition comprising an antibody or fragment of  claim 4 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         10 . A method for treating a subject having a disease mediated by human TNF comprising reducing the amount or concentration of bioactive trimeric sTNF in the blood of a subject having the disease without affecting the amount, concentration or bioactivity of tmTNF by disrupting or reducing the in vivo assembly or reassembly of dissociated monomers of sTNF into bioactive trimeric human sTNF by administering to a subject in need thereof the monoclonal antibody or fragment of  claim 1 . 
     
     
         11 . The method according to  claim 10 , wherein said disease is rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, obesity, metabolic syndrome, atherosclerosis, associated cardiovascular disease, Alzheimer's disease, a neurodegenerative disease, a pathogenic effect of bioactive, trimeric sTNF produced during inflammation or during the course of an inflammatory disorder, HIV-1, or type II diabetes. 
     
     
         12 . A method for treating a subject having a disease mediated by human TNF comprising reducing the amount or concentration of bioactive trimeric sTNF in the blood of a subject having the disease without affecting the amount, concentration or bioactivity of tmTNF by disrupting or reducing the in vivo assembly or reassembly of dissociated monomers of sTNF into bioactive trimeric human sTNF by administering to a subject in need thereof the composition of  claim 5 . 
     
     
         13 . The method according to  claim 12 , wherein said disease is rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, obesity, metabolic syndrome, atherosclerosis, associated cardiovascular disease, Alzheimer's disease, a neurodegenerative disease, a pathogenic effect of bioactive, trimeric sTNF produced during inflammation or during the course of an inflammatory disorder, HIV-1, or type II diabetes.