Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII
Human neutrophil interactions of a bispecific monoclonal antibody targeting tumor and human Fcγ RIII
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DOI：
10.1007/s002620050264
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发表时间：
1996-03
期刊：
影响因子：
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通讯作者：
L. Weiner;R. Alpaugh;A. R. Amoroso;G. Adams;D. Ring;M. W. Barth
中科院分区：
文献类型：
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作者：
L. Weiner;R. Alpaugh;A. R. Amoroso;G. Adams;D. Ring;M. W. Barth
2B1是一种针对c-erb B-2和CD16(FcγRIII)抗原的双特异性鼠单抗。C-erb B-2在多种腺癌中高表达，CD16是聚集免疫球蛋白的低亲和力Fcγ受体，由多形核白细胞、自然杀伤细胞和分化的单核巨噬细胞表达。2B1可增强NK细胞和巨噬细胞对c-erbB-2高表达肿瘤的体外杀伤作用。在这篇报道中，我们研究了2B1和PMN之间的相互作用，以评估这些相互作用对2B1促进的人NK细胞体外肿瘤细胞毒作用的影响。在浓度为10μg/ml2B1时，2B1与中性粒细胞的结合力最强。然而，在37℃的非平衡条件下，2B1在体外迅速从PMN解离。这种解离不是由CD16脱落引起的。用~(125)I-2B1标记中性粒细胞，37℃孵育后，分离的2B1的Fab区不与脱落的CD16胞外区形成络合物。虽然2B1与PMN的大部分结合仅归因于FAB与FcγRIII的结合，但Pmn相关的2B1也通过Fcγ结构域/FcγRII相互作用结合。2B1对表达c-erbB-2的SK-OV-3肿瘤细胞的体外杀伤作用不明显。当PMN与外周血淋巴细胞、SK-OV-3肿瘤和2B1共同孵育时，肿瘤最大溶解所需的2B1浓度降低。尽管PMN可能是体内系统给药2B1的重要竞争结合池，但这种bsmAb的靶向细胞毒性特性的治疗潜力不应受到影响。
2B1 is a bispecific murine monoclonal antibody (bsmAb) targeting the c-erbB-2 and CD16 (FcγRIII) antigens. c-erbB-2 is over-expressed by a variety of adenocarcinomas, and CD16, the low-affinity Fcγ receptor for aggregated immunoglobulins, is expressed by polymorphonuclear leukocytes (PMN), natural killer (NK) cells and differentiated mononuclear phagocytes. 2B1 potentiates the in vitro lysis of c-erbB-2 over-expressing tumors by NK cells and macrophages. In this report, the interactions between 2B1 and PMN were investigated to assess the impact of these associations on in vitro 2B1-promoted tumor cytotoxicity by human NK cells. The peak binding of 2B1 to PMN was observed at a concentration of 10 μg/ml 2B1. However, 2B1 rapidly dissociated from PMN in vitro at 37°C in non-equilibrium conditions. This dissociation was not caused by CD16 shedding. When PMN were labeled with125I-2B1 and incubated at 37°C and the supernatants examined by HPLC analysis, the Fab regions of dissociated 2B1 were not complexed with shed CD16 extracellular domain. While most of the binding of 2B1 to PMN was solely attributable to Fab-directed binding to FcγRIII, PMN-associated 2B1 also bound through Fcγ-domain/FcγRII interactions. 2B1 did not promote in vitro PMN cytotoxicity against c-erbB-2-expressing SK-OV-3 tumor cells. When PMN were coincubated with peripheral blood lymphocytes, SK-OV-3 tumor and 2B1, the concentration of 2B1 required for maximal tumor lysis was lowered. Although PMN may serve as a significant competitive binding pool of systemically administered 2B1 in vivo, the therapeutic potential of the targeted cytotoxicity properties of this bsmAb should not be compromised.