CHIMERIC ANTI-TNF-ALPHA MONOCLONAL-ANTIBODY CA2 BINDS RECOMBINANT TRANSMEMBRANE TNF-ALPHA AND ACTIVATES IMMUNE EFFECTOR FUNCTIONS
CHIMERIC ANTI-TNF-ALPHA MONOCLONAL-ANTIBODY CA2 BINDS RECOMBINANT TRANSMEMBRANE TNF-ALPHA AND ACTIVATES IMMUNE EFFECTOR FUNCTIONS
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DOI：
10.1006/cyto.1995.0029
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发表时间：
1995-04-01
期刊：
影响因子：
3.8
通讯作者：
GHRAYEB, J
中科院分区：
文献类型：
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作者：
SCALLON, BJ;MOORE, MA;GHRAYEB, J
临床试验结果表明，cA2，一种中和小鼠/人IgG1嵌合抗人tnf - α单克隆抗体，可能对类风湿关节炎患者有治疗作用。关节炎关节除了可溶性tnf - α水平升高外，还含有大量CD4(+) T细胞和巨噬细胞，这些细胞已知在激活时表达跨膜tnf - α，因此，我们试图确定cA2是否与跨膜TNF- α结合，以及这种结合对表达TNF- α的细胞有什么影响，为这些研究准备了一种表达细胞表面突变形式的跨膜TNF- α的细胞系，通过流式细胞术分析这些TNF+细胞，直接结合和竞争结合试验表明，cA2以高亲和力与跨膜形式的TNF- α结合，结合IgG1同型的cA2，但不结合IgG4版本的cA2。通过抗体依赖的细胞毒性和补体依赖的细胞毒性效应机制有效杀死TNF+细胞。这些发现表明，cA2除了阻断可溶性TNF- α活性外，还可以在体外结合跨膜TNF- α，并提示cA2结合可能导致体内表达TNF- α的细胞裂解。
Results of clinical trials have indicated that cA2, a neutralizing mouse/human IgG1 chimeric anti-human TNF-alpha monoclonal antibody, may have therapeutic benefit for rheumatoid arthritis patients, Arthritic joints contain, in addition to elevated levels of soluble TNF-alpha, high numbers of CD4(+) T cells and macrophages, cells known to express transmembrane TNF-alpha upon activation, For that reason, we sought to determine if cA2 binds to transmembrane TNF-alpha and what effects such binding may have on TNF-alpha-expressing cells, A cell line expressing a cell-surface, mutant form of transmembrane TNF-alpha was prepared for these studies, Analysis of these TNF+ cells by flow cytometry, direct binding, and competitive binding assays showed that cA2 binds to the transmembrane form of TNF-alpha with high avidity, Binding of the IgG1 isotype of cA2, but not an IgG4 version of cA2, resulted in efficient killing of the TNF+ cells by both antibody-dependent cellular toxicity and complement-dependent cytotoxicity effector mechanisms, These findings indicate that, in addition to blocking soluble TNF-alpha activity, cA2 can bind to transmembrane TNF-alpha in vitro and suggest that cA2 binding may lead to lysis of TNF-alpha-expressing cells in vivo.