A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16.
A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16.
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发表时间：
1993
期刊：
影响因子：
11.2
通讯作者：
L. Weiner;M. Holmes;G. Adams;F. LaCreta;P. Watts;I. Garcia de Palazzo
中科院分区：
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作者：
L. Weiner;M. Holmes;G. Adams;F. LaCreta;P. Watts;I. Garcia de Palazzo
临床上需要新的策略来利用单克隆抗体通过细胞效应机制靶向肿瘤以进行裂解的能力。在本报告中，我们研究了 2B1（一种双特异性单克隆抗体，对 c-erbB-2 癌基因产物和人 Fc gamma 受体 Fc gamma RIII (CD16) 的细胞外结构域具有特异性）的治疗效果，描述了该模型的特征和局限性，并检查了观察到的反应的机制。该模型在 scid 小鼠中使用 SK-OV-3 人卵巢癌异种移植物。这些细胞易于被人外周血淋巴细胞或淋巴因子激活的杀伤细胞进行 2B1 定向裂解，并在体内维持 c-erbB-2 表达。 125I标记的2B1选择性地在肿瘤中积聚，在静脉注射后24小时达到10.5%注射剂量/g肿瘤的峰值。注射。然而，这种结合的选择性会因 2B1 在肺部和其他正常器官中的积累以及在血液中的持续存在而降低。这是由于抗体与鼠肺、结肠、胃和皮肤结合而引起，这些鼠肺、结肠、胃和皮肤表达的表位被荷瘤小鼠中 2B1 的抗 c-erbB-2 成分所识别，但正常小鼠则不然。在使用抗体、人外周血淋巴细胞或淋巴因子激活的杀伤细胞和白细胞介素 2 的各种排列的治疗研究中，单独的细胞疗法对 SK-OV-3 异种移植物生长的影响很小，但在结合 2B1 治疗时显着改善。中位生存期从无治疗时的 80 +/- 3.5 天增加到用 100 微克 2B1、白细胞介素 2 和人外周血淋巴细胞治疗后的 131 +/- 7.3 天，其中 70% 的动物在第 150 天时没有表现出肿瘤的证据。当在人血清中施用细胞时，这些效果得以保留。相比之下，人血清消除了 520C9 的抗肿瘤作用，520C9 是 2B1 的亲本抗 c-erbB-2 抗体。因此，尽管该抗体靶向正常小鼠组织，但基于 2B1 的疗法具有治疗效果，且无明显毒性。由于2B1和白细胞介素2的组合可能具有抗肿瘤特性，因此可能涉及双特异性单克隆抗体促进表达c-erbB-2抗原的肿瘤与表达CD16的效应细胞缀合以外的机制。
New strategies are required to clinically exploit the ability of monoclonal antibodies to target tumor for lysis by cellular effector mechanisms. In this report we examine the therapeutic effects of 2B1, a bispecific monoclonal antibody with specificity for the extracellular domain of the c-erbB-2 oncogene product and the human Fc gamma receptor, Fc gamma RIII (CD16), describe the characteristics and limitations of this model, and examine the mechanisms underlying the observed responses. The model uses SK-OV-3 human ovarian carcinoma xenografts in scid mice. These cells are susceptible to 2B1-directed lysis by human peripheral blood lymphocytes or lymphokine-activated killer cells, and maintain c-erbB-2 expression in vivo. 125I-labeled 2B1 selectively accumulates in tumor, with a peak of 10.5% injected dose/g of tumor 24 h following its i.v. injection. However, the selectivity of this binding is lessened by 2B1 accumulation in the lungs and other normal organs and persistence in the blood. This is caused by antibody binding to murine lung, colon, stomach, and skin expressing the epitope recognized by the anti-c-erbB-2 component of 2B1 in tumor-bearing, but not normal mice. In treatment studies using various permutations of antibody, human peripheral blood lymphocytes or lymphokine-activated killer cells and interleukin 2, cellular therapy alone had minimal effects on SK-OV-3 xenograft growth, but significantly improved when 2B1 treatment was incorporated. Median survivals increased from 80 +/- 3.5 days with no therapy to 131 +/- 7.3 days following therapy with 100 micrograms 2B1, interleukin 2, and human peripheral blood lymphocytes, with 70% of animals exhibiting no evidence of tumor at day 150. These effects were preserved when the cells were administered in human serum. In contrast, human serum abolished the antitumor effects of 520C9, which is the parent anti-c-erbB-2 antibody of 2B1. Thus 2B1-based therapy has therapeutic effects, without obvious toxicity, despite the targeting of this antibody to normal murine tissues. Since combinations of 2B1 and interleukin 2 may have antitumor properties, mechanisms other than bispecific monoclonal antibody-promoted conjugation of c-erbB-2 antigen-expressing tumor to CD16-expressing effector cells may be involved.