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.