Abstract
The binding and biological activity of human TNF alpha on endothelial and tumour cells has been studied in the presence of monoclonal antibodies (MAbs). In particular, one monoclonal antibody to TNF alpha (MAb 32) has been identified which failed to inhibit binding and cytotoxicity of TNF alpha on WEHI-164 tumour cells but which was a potent inhibitor of TNF alpha-induced endothelial cell procoagulant activity on bovine aortic endothelial cells. The ability of MAb 32 to inhibit selectively the actions of TNF alpha on endothelial cells but not on tumour cells suggests a mechanism for enhancement of the anti-tumour action of TNF alpha in vivo when in complex with this antibody. Treatment of tumour bearing mice (WEHI-164 and Meth A fibrosarcoma) with TNF alpha-MAb 32 complex resulted in a 5- to 10-fold enhancement in the potency of the cytokine in comparison to free TNF alpha. Complexes between this cytokine and other MAbs generally resulted in either no effect or inhibition of TNF alpha activity in vivo and in vitro. Neither intact MAb 32 nor FAb' fragments of MAb 32 showed any tumour regressive activity in the absence of TNF alpha. The FAb' fragments were equipotent to the bivalent form of the antibody in enhancing TNF alpha activity. These data provide evidence that it is possible to segregate the individual biological activities of TNF alpha with concomitant enhancement of the tumour regressive activity of the cytokine in vivo.
Highlights
Only inhibited '25I-TNF, binding to endothelial cells. This correlated with the corresponding effects of monoclonal antibodies (MAbs) 32 and MAb 47 on the cytotoxic effects of TNF
Since the toxicity of TNFa may manifest as a direct result of its interaction with a variety of receptors on different tissues following systemic administration, we have examined the possibility of 'restricting' the specificity of this cytokine to particular receptor subsets with monoclonal antibodies (MAb)
By employing this approach it is shown that the binding of TNF¢ to different receptors can be selectively modulated by a particular MAb (MAb 32)
Summary
Animals and tumour cell lines All experiments were performed using female BALB/c mice aged 10-12 weeks obtained from the CSIRO Division of Biomolecular Engineering animal facility. The WEHI-164 fibrosarcoma line was obtained from Dr Geeta Chauhdri Received 23 September 1991; and in revised form 21 February 1992. The Meth A sarcoma lines were obtained from Dr Elizabeth Richards (Sloan Kettering Cancer Centre)
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