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

被引:184
作者
SIEGEL, SA
SHEALY, DJ
NAKADA, MT
LE, JM
WOLFE, DS
PROBERT, L
KOLLIAS, G
GHRAYEB, J
VILCEK, J
DADDONA, PE
机构
[1] CENTOCOR INC, DEPT IMMUNOL, MALVERN, PA 19355 USA
[2] CENTOCOR INC, DEPT MOLEC BIOL, MALVERN, PA 19355 USA
[3] NYU, MED CTR, DEPT MICROBIOL, NEW YORK, NY 10016 USA
[4] HELLEN INST PASTEUR, GENET MOLEC LAB, GR-11521 ATHENS, GREECE
关键词
TNF-ALPHA; CA2; RHEUMATOID ARTHRITIS;
D O I
10.1006/cyto.1995.1003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The pleiotropic cytokine tumour necrosis factor-alpha (TNF) is thought to play a central role in infectious, inflammatory and autoimmune diseases. Critical to the understanding and management of TNF-associated pathology is the development of highly specific agents capable of modifying 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-induced mitogenesis and IL-6 secretion by human fibroblasts, TNF-priming of human neutrophils, and the stimulation of human umbilical vein endothelial cells by TNF as measured by the expression of E-selectin, ICAM-1 and procoagulant activity. cA2 also specifically blocked TNF-induced adherence of human neutrophils to an endothelial cell monolayer. Receptor binding studies suggested that neutralization resulted from cA2 blocking of TNF binding to both p55 and p75 TNF receptors on the cells. in vivo, repeated administration of cA2 to transgenic mice that constitutively express human TNF reversed the cachectic phenotype and prevented subsequent mortality, These results demonstrated that cA2 effectively neutralized a broad range of TNF biological activities both in vitro and in vivo.
引用
收藏
页码:15 / 25
页数:11
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