THE MOUSE-HUMAN CHIMERIC MONOCLONAL-ANTIBODY CA2 NEUTRALIZES TNF IN-VITRO AND PROTECTS TRANSGENIC MICE FROM CACHEXIA AND TNF LETHALITY IN-VIVO
THE MOUSE-HUMAN CHIMERIC MONOCLONAL-ANTIBODY CA2 NEUTRALIZES TNF IN-VITRO AND PROTECTS TRANSGENIC MICE FROM CACHEXIA AND TNF LETHALITY IN-VIVO
复制标题
DOI：
10.1006/cyto.1995.1003
复制
发表时间：
1995-01-01
期刊：
影响因子：
3.8
通讯作者：
DADDONA, PE
中科院分区：
文献类型：
--
作者：
SIEGEL, SA;SHEALY, DJ;DADDONA, PE
多效性细胞因子肿瘤坏死因子-α（TNF）被认为在感染性、炎症性和自身免疫性疾病中发挥核心作用。关键的理解和管理的TNF相关的病理是高度特异性的药物能够修改TNF活性的发展，我们评估了高亲和力的小鼠/人嵌合抗TNF单克隆抗体（cA 2）的能力，中和在体外和体内的TNF的生物学效应。cA 2抑制TNF诱导的人成纤维细胞的有丝分裂和IL-6分泌、TNF引发的人中性粒细胞以及TNF刺激的人脐静脉内皮细胞，如通过E-选择素、ICAM-1和促凝血活性的表达所测量的。cA 2还特异性阻断TNF诱导的人中性粒细胞与内皮细胞单层的粘附。受体结合研究表明，中和作用是由于cA 2阻断了TNF与细胞上p55和p75 TNF受体的结合。在体内，向组成型表达人TNF的转基因小鼠重复施用cA 2逆转恶病质表型并防止随后的死亡。这些结果证明cA 2在体外和体内均有效地中和广泛的TNF生物活性。
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.