Hank J A, Robinson R R, Surfus J, Mueller B M, Reisfeld R A, Cheung N K, Sondel P M
Department of Human Oncology, University of Wisconsin, Madison 53792.
Cancer Res. 1990 Sep 1;50(17):5234-9.
Monoclonal antibodies (mAB) with tumor specificity are able to enhance the immunological specificity of interleukin 2 (IL-2)-activated lymphokine activated killer (LAK) cells. Antibodies may also be used to broaden the range of tumor types susceptible to immune mediated cytotoxicity by the activated LAK cells. In these studies, mAB with relative tumor specificity were used to target immunologically activated effector cells in an in vitro antibody dependent cell mediated cytotoxicity (ADCC) assay. The mAB included: 3F8 and 14.G2a, which are both specific for neuroblastoma and melanoma and recognize ganglioside GD2, and mAB ING-1, a mouse-human chimeric antibody with constant regions from human IgG1 and kappa chains and variable regions from a mouse mAB that binds to a broad range of human adenocarcinomas. Each of these mAB was able to mediate ADCC with fresh effector cells and antibody binding targets. When peripheral blood mononuclear cells were obtained from cancer patients prior to and following in vivo therapy with interleukin 2, a significant increase was noted in ADCC activity by peripheral blood mononuclear cells obtained following IL-2 therapy. Inclusion of IL-2 in the medium during the cytotoxic assay with mAB further boosted ADCC. The total activity seen was often greater than the sum of the independent LAK activity and standard ADCC activity. The cells responsible for this ADCC had the CD16+ Fc receptor. Combining IL-2 with mAB in clinical tumor therapy may lead to a wider range of tumor types being responsive to immunotherapy and may also enhance the efficacy of therapy by specifically targeting activated effector cells to tumor cells recognized by mAB. Our results provide strong support for the testing of these hypotheses in clinical trials by combining in vivo treatment with IL-2 and mAB able to mediate ADCC.
具有肿瘤特异性的单克隆抗体（mAB）能够增强白细胞介素2（IL-2）激活的淋巴因子激活的杀伤细胞（LAK）的免疫特异性。抗体还可用于扩大易受激活的LAK细胞免疫介导细胞毒性作用的肿瘤类型范围。在这些研究中，具有相对肿瘤特异性的mAB被用于在体外抗体依赖性细胞介导的细胞毒性（ADCC）试验中靶向免疫激活的效应细胞。这些mAB包括：3F8和14.G2a，它们对神经母细胞瘤和黑色素瘤均具有特异性，并识别神经节苷脂GD2；以及mAB ING-1，一种小鼠-人嵌合抗体，其恒定区来自人IgG1和κ链，可变区来自一种能结合多种人类腺癌的小鼠mAB。这些mAB中的每一种都能够与新鲜的效应细胞和抗体结合靶标介导ADCC。当在白细胞介素2进行体内治疗之前和之后从癌症患者获取外周血单核细胞时，发现白细胞介素2治疗后获取的外周血单核细胞的ADCC活性显著增加。在用mAB进行细胞毒性试验期间，培养基中加入白细胞介素2进一步增强了ADCC。观察到的总活性通常大于独立的LAK活性和标准ADCC活性之和。负责这种ADCC的细胞具有CD16 + Fc受体。在临床肿瘤治疗中将白细胞介素2与mAB联合使用可能会使更多类型的肿瘤对免疫治疗产生反应，还可能通过将激活的效应细胞特异性靶向mAB识别的肿瘤细胞来提高治疗效果。我们的结果为通过将体内治疗与能够介导ADCC的白细胞介素2和mAB联合使用在临床试验中检验这些假设提供了有力支持。
