Monoclonal antibodies to soluble human TNF receptor (TNF binding protein) enhance its ability to block TNF toxicity.
A soluble extracellular fragment of the human 55-60 kDa tumor necrosis factor receptor (sTNF-R I), originally isolated from urine, binds both TNF-alpha and TNF-beta and blocks the activity of these cytokines in biological assays. Three monoclonal antibodies (mAbs) raised against sTNF-R I (TBP-1, -2 and -6) as well as a mAb developed by immunization with the intact receptor (H398) were analysed for their epitope specificities in ELISAs and for biological activity in cytotoxicity assays on murine L-M cells. TBP-2 and H398 bind to related epitopes on sTNF-R I; they compete with TNF-alpha for binding and block the protective effect of sTNF-R I in the bioassay. MAbs TBP-1 and TBP-6 recognize two further, independent epitopes; both bind sTNF-R I in the presence of an excess of TNF-alpha. Both TBP-1 and TBP-6 markedly enhance the ability of sTNF-R I to protect cells against the cytotoxic activities of TNF-alpha and TNF-beta, but have no activity in the absence of sTNF-R I. Fab fragments show much lower activity. We propose that the ability of certain mAbs to enhance the protective activity of sTNF-R is due to a steric hindrance phenomenon.
Adolf
G R
GR
Department of Cell Biology, Ernst Boehringer-Institut für Arzneimittelforschung, Bender + Co Ges mbH, Vienna, Austria.
Frühbeis
B
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000276:immunology* / Q000494:pharmacology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D011956:Receptors, Cell Surface / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1