Siegel S A, Shealy D J, Nakada M T, Le J, Woulfe D S, Probert L, Kollias G, Ghrayeb J, Vilcek J, Daddona P E
Department of Immunology, Centocor, Inc., Malvern PA 19355, USA.
Cytokine. 1995 Jan;7(1):15-25. doi: 10.1006/cyto.1995.1003.
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.
多效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起核心作用。对于理解和处理与TNF相关的病理状况而言，开发能够调节TNF活性的高特异性药物至关重要。我们评估了一种高亲和力的小鼠/人嵌合抗TNF单克隆抗体（cA2）中和TNF体外和体内生物学效应的能力。cA2抑制了TNF诱导的人成纤维细胞的有丝分裂和IL-6分泌、TNF对人中性粒细胞的启动作用，以及通过E-选择素、细胞间黏附分子-1（ICAM-1）的表达和促凝血活性所测定的TNF对人脐静脉内皮细胞的刺激作用。cA2还特异性地阻断了TNF诱导的人中性粒细胞与内皮细胞单层的黏附。受体结合研究表明，中和作用是由于cA2阻断了TNF与细胞上p55和p75 TNF受体的结合。在体内，对组成性表达人TNF的转基因小鼠重复给予cA2可逆转恶病质表型并防止随后的死亡。这些结果表明，cA2在体外和体内均能有效中和广泛的TNF生物学活性。
