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

摘要

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.

主权项

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.