Selective enhancement of the tumour necrotic activity of TNF alpha with monoclonal antibody.
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.
Rathjen
D A
DA
Peptide Technology Ltd., Sydney, NSW, Australia.
Furphy
L J
LJ
Aston
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000378:metabolism; D000939:Epitopes; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha