ANTIBODY DIRECTED CELLULAR IMMUNOTHERAPY OF COLON CANCER

结肠癌的抗体定向细胞免疫治疗

• 批准号: 3813409
• 负责人: F J PRIMUS
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3813409
• 关键词: CD3 molecule; T lymphocyte; antibody dependent killer cell; antibody specificity; antileukocyte isoantibody; antireceptor antibody; antitumor antibody; carcinoma; cell mediated cytotoxicity; cellular oncology; colon neoplasms; cytotoxic T lymphocyte; human subject; hybrid antibody; immunoconjugates; interleukin 2; leukocyte activation /transformation; lymphocyte; macrophage; metastasis; monoclonal antibody; natural killer cells; neoplasm /cancer immunotherapy; passive immunization; tissue /cell culture; tumor antigens; xenotransplantation

This project is examining the role that monoclonal antibodies (MAb) against human colonic tumor antigens have in directing and augmenting the cytotoxic activity of NK/LAK cells and T cells. A MAb designated D612 (IgG2a) has been generated that uniformly reacted with the cell surface of approximately 80% of primary or metastatic colorectal carcinomas. Normal tissue reactivity of D612 was confined mainly to the small and large intestine, while non-gastrointestinal normal tissues were routinely negative. D612 mediated antibody-dependent cellular cytotoxicity in conjunction with normal human peripheral blood mononuclear cells was increased by effector cell activation with interleukin 2 (IL-2). For retargeting of T cells, heteroantibody conjugates between the anticolon tumor MAb, B38.1, and anti-CD3 (OKT-3) were chemically prepared, and these were tested along with effectors obtained from PBMNC stimulated with anti-CD3 and IL-2. The heteroantibody-mediated cellular cytotoxicity activity was similar on a per cell basis among effector populations prepared by stimulation with IL-2, anti-CD3, or a combination of these reagents. However, the total lytic activity of anti-CD3 + IL-2-stimulated cultures was much higher due to the greater expansion in cell number achieved by the combination treatment. These studies suggest that MAbs with restricted normal tissue reactivity and ability to direct the cellular cytotoxicity of a broader spectrum of killer lymphocytes activated by lymphokines and other agents might augment the efficacy of colon cancer immunotherapy.

该项目正在研究单克隆抗体（MAb）对 人结肠肿瘤抗原在引导和增强细胞毒性 NK/LAK细胞和T细胞的活性。命名为D 612（IgG 2a）的MAb具有 与细胞表面均匀反应， 约80%的原发性或转移性结直肠癌。正常 D 612的组织反应性主要局限于小细胞和大细胞， 肠，而非胃肠道正常组织常规 阴性D 612介导的抗体依赖性细胞毒性 与正常人外周血单个核细胞的结合， 通过用白细胞介素2（IL-2）激活效应细胞而增加。为 重靶向T细胞，抗结肠之间的异源抗体缀合物 化学制备肿瘤单克隆抗体、B38.1和抗CD 3（OKT-3）， 与从用刺激的PBMNC获得的效应器一起沿着进行测试 抗CD 3和IL-2。异源抗体介导的细胞毒作用 在每个细胞的基础上，效应群体之间的活性相似 通过用IL-2、抗CD 3或这些的组合刺激制备 试剂然而，抗CD 3 + IL-2刺激的总裂解活性低于抗CD 3 + IL-2刺激的总裂解活性。 由于细胞数量的更大扩增， 这是通过联合治疗实现的。这些研究表明， 限制正常组织的反应性和引导细胞 激活的广谱杀伤淋巴细胞的细胞毒性 淋巴因子和其他药物可能会增强结肠癌的疗效 免疫疗法。