Biologics Research Laboratories, Tokyo Research Park, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
Anticancer Res. 2014 Jan;34(1):89-97.
Prostate-specific membrane antigen (PSMA) is an attractive target for treatment of prostate cancer. Using the PSMA-recognizing mouse monoclonal antibody 2C9 obtained in our previous study, the biological activities of PSMA antibody were evaluated. Mouse-human chimeric IgG1 of 2C9 (KM2777) showed antibody-dependent cellular cytotoxicity activity against PSMA-expressing prostate cancer cells in the presence of human peripheral blood mononuclear cells (PBMCs). To increase lymphocyte-mediated cytotoxicity of KM2777, C-terminus interleukin-2 (IL-2)-fused KM2777 (KM2812) was constructed. KM2812 retained binding activity to PSMA and exhibited growth-stimulating activity equivalent to IL-2 on the IL-2-dependent T-cell line CTLL-2. Moreover, KM2812 exhibited enhanced cytotoxic activity against PSMA-expressing prostate cancer cells in the presence of PBMCs compared with KM2777. In a xenograft tumor model using PSMA-expressing prostate cancer cells, KM2812 exhibited marked antitumor activity, accompanied by complete regression of tumor in some of the KM2812-treated mice. These results suggest that KM2812 has a therapeutic potential for prostate cancer by stimulating lymphocyte-mediated antitumor cytotoxicity.
前列腺特异性膜抗原（PSMA）是治疗前列腺癌的有吸引力的靶标。利用我们之前研究中获得的识别 PSMA 的鼠单克隆抗体 2C9，评估了 PSMA 抗体的生物学活性。2C9 的人鼠嵌合 IgG1（KM2777）在人外周血单核细胞（PBMC）存在的情况下对表达 PSMA 的前列腺癌细胞表现出抗体依赖性细胞毒性活性。为了增加 KM2777 的淋巴细胞介导的细胞毒性，构建了 C 末端白细胞介素 2（IL-2）融合的 KM2777（KM2812）。KM2812 保留了与 PSMA 的结合活性，并在依赖 IL-2 的 T 细胞系 CTLL-2 上表现出与 IL-2 相当的生长刺激活性。此外，与 KM2777 相比，KM2812 在 PBMC 存在的情况下对表达 PSMA 的前列腺癌细胞表现出增强的细胞毒性活性。在使用表达 PSMA 的前列腺癌细胞的异种移植肿瘤模型中，KM2812 表现出显著的抗肿瘤活性，一些接受 KM2812 治疗的小鼠的肿瘤完全消退。这些结果表明，KM2812 通过刺激淋巴细胞介导的抗肿瘤细胞毒性具有治疗前列腺癌的潜力。
