THE MOUSE-HUMAN CHIMERIC MONOCLONAL-ANTIBODY CA2 NEUTRALIZES TNF IN-VITRO AND PROTECTS TRANSGENIC MICE FROM CACHEXIA AND TNF LETHALITY IN-VIVO

The pleiotropic cytokine tumour necrosis factor-alpha (TNF) is thought to play a central role in infectious, inflammatory and autoimmune dis eases. Critical to the understanding and management of TNF-associated pathology is the development of highly specific agents capable of modi fying TNF activity, We evaluated the ability of a high affinity mouse/ human chimeric anti-TNF monoclonal antibody (cA2) to neutralize the in vitro and in vivo biological effects of TNF. cA2 inhibited TNF-induce d mitogenesis and IL-6 secretion by human fibroblasts, TNF-priming of human neutrophils, and the stimulation of human umbilical vein endothe lial cells by TNF as measured by the expression of E-selectin, ICAM-1 and procoagulant activity. cA2 also specifically blocked TNF-induced a dherence of human neutrophils to an endothelial cell monolayer. Recept or binding studies suggested that neutralization resulted from cA2 blo cking of TNF binding to both p55 and p75 TNF receptors on the cells. i n vivo, repeated administration of cA2 to transgenic mice that constit utively express human TNF reversed the cachectic phenotype and prevent ed subsequent mortality, These results demonstrated that cA2 effective ly neutralized a broad range of TNF biological activities both in vitr o and in vivo.