Primus F J, Pendurthi T K, Hutzell P, Kashmiri S, Slavin D C, Callahan R, Schlom J
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892.
Cancer Immunol Immunother. 1990;31(6):349-57. doi: 10.1007/BF01741406.
Chimeric mouse/human B72.3 (cB72.3) antibodies having a human IgG1 (gamma 1) or IgG4 (gamma 4) constant region were compared to the native murine IgG1 B72.3 (nB72.3) monoclonal antibody (mAb) for their ability to participate with human effector cells in antibody-dependent cellular cytotoxicity (ADCC). Because the TAG-72 antigen recognized by B72.3 is poorly expressed on tissue-cultured tumor cell lines, the xenografted OVCAR-3 human ovarian carcinoma ascites was used as a cytotoxicity target. The lytic activity of the cB72.3(gamma 1) mAb with peripheral blood lymphocytes was 1.5- to 50-fold greater than that of the nB72.3 mAb and usually the cB72.3(gamma 4) mAb. However, lymphocytes from some donors had similar ADCC activity with either the cB72.3(gamma 1) or cB72.3(gamma 4) mAb. The cB72.3(gamma 1) and the murine anti-colon carcinoma CO17-1A mAb had comparable activity in mediating ADCC against the OVCAR-3 tumor. Exposure of lymphoid cells to interleukin-2 (IL-2) (100-500 U/ml) for 24 h to generate lymphokine-activated killer (LAK) cells augmented ADCC mediated by the cB72.3(gamma 1) mAb 2- to 22-fold. By contrast, LAK cells from most donors expressed weak non-specific cytotoxicity against OVCAR-3 ascites tumor cells. The cB72.3(gamma 1), and to a lesser extent, the cB72.3(gamma 4) chimera also participated with monocytes in mediating ADCC, but the antibody-dependent lytic potency of monocytic effectors was much weaker than that of IL-2-activated lymphoid cells. These studies show that the cB72.3(gamma 1) mAb has appreciable ADCC-mediating properties, suggesting a potential role for its incorporation into treatment strategies utilizing adoptive killer cell and/or lymphokine therapy.
将具有人IgG1（γ1）或IgG4（γ4）恒定区的嵌合小鼠/人B72.3（cB72.3）抗体与天然鼠IgG1 B72.3（nB72.3）单克隆抗体（mAb）在与人类效应细胞参与抗体依赖性细胞毒性（ADCC）方面的能力进行了比较。由于B72.3识别的TAG-72抗原在组织培养的肿瘤细胞系上表达较差，因此将异种移植的OVCAR-3人卵巢癌腹水用作细胞毒性靶标。cB72.3（γ1）mAb对外周血淋巴细胞的裂解活性比nB72.3 mAb以及通常的cB72.3（γ4）mAb高1.5至50倍。然而，来自一些供体的淋巴细胞对cB72.3（γ1）或cB72.3（γ4）mAb具有相似的ADCC活性。cB72.3（γ1）和鼠抗结肠癌CO17-1A mAb在介导针对OVCAR-3肿瘤的ADCC方面具有相当的活性。将淋巴细胞暴露于白细胞介素-2（IL-2）（100 - 500 U/ml）24小时以产生淋巴因子激活的杀伤（LAK）细胞，可使cB72.3（γ1）mAb介导的ADCC增强2至22倍。相比之下，大多数供体的LAK细胞对OVCAR-3腹水肿瘤细胞表现出较弱的非特异性细胞毒性。cB72.3（γ1）以及在较小程度上cB72.3（γ4）嵌合体也与单核细胞一起参与介导ADCC，但单核细胞效应器的抗体依赖性裂解效力比IL-2激活的淋巴细胞弱得多。这些研究表明，cB72.3（γ1）mAb具有明显的介导ADCC的特性，这表明将其纳入利用过继性杀伤细胞和/或淋巴因子疗法的治疗策略中具有潜在作用。
