A NEW ANTI-TUMOR IMMUNOTHERAPY TARGETING HUMAN PROTO-ONCOGENE PRODUCT

一种针对人类原癌基因的新型抗肿瘤免疫治疗产品

• 批准号: 04670752
• 负责人: TOKUDA Yutaka
• 金额: $ 1.34万
• 依托单位: TOKAI UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670752/
• 关键词: Adoptive immunotherapy; Proto-oncogene; C-erbB-2; CD4^+ T cell; Bispecific antibody; c-erbB-2; ヘルパーT細胞; 乳癌; Interleukin-2

To develop an efficient strategy for the targeting of anti-tumor effector cells, we prepared bispecific antibody(BSAb)containing anti-CD3 and an anti-c-erbB-2 proto-oncogene product. The prepared BSAb specifically reacts with both c-erbB-2-positive tumor cells and CD3^+CTL.Human CD4^+ helper/killer T cells, induced from peripheral-blood mononuclear cells by activation with immobilized anti-CD3 monoclonal antibody plus IL-2, showed no significant cytotoxicity against tumor cells. However, treatment of human CD4^+ helper/killer cells with the BSAb caused the induction of specific cytotoxicity against c-erbB-2-positive tumor cells. CD4^+ helper/killer cells also produced significant amounts of IL-2 during co-culture with c-erbB-2-positive tumor cells in the presence of the BSAb. Moreover, by combination with the BSAb, CD4^+ helper/killer cells showed a significant in vivo anti-tumor effect against c-erbB-2 positive human cancer cells in severe combined immunodeficiency mice. Our results strongly suggest that the c-erbB-2 proto-oncogene product on human tumor cells may be a good target for BSAb-directed adoptive tumor immunotherapy. Thus, we have established a large-scale culture system of these CD4^+ helper/killer T cells to provide enough number of the cells for future clinical trials.

为了开发一种有效的靶向抗肿瘤效应细胞的策略，我们制备了含有抗CD 3和抗c-erbB-2原癌基因产物的双特异性抗体（BSAb）。制备的BSAb可特异性地与c-erbB-2阳性肿瘤细胞和CD 3 ^+CTL反应，而用固定化抗CD 3单克隆抗体和IL-2激活外周血单个核细胞诱导的人CD 4 ^+辅助/杀伤T细胞对肿瘤细胞无明显的杀伤作用。然而，用BSAb处理人CD 4 ^+辅助/杀伤细胞可诱导针对c-erbB-2阳性肿瘤细胞的特异性细胞毒性。在与c-erbB-2阳性肿瘤细胞共培养的过程中，在BSAb存在的情况下，CD 4 ^+辅助/杀伤细胞也产生了大量的IL-2。此外，在严重联合免疫缺陷小鼠中，CD 4 ^+辅助/杀伤细胞与BSAb联合使用后，对c-erbB-2阳性人类癌细胞显示出显著的体内抗肿瘤作用。我们的研究结果有力地表明，c-erbB-2原癌基因产物的人肿瘤细胞可能是一个很好的靶点，为BSAb定向过继肿瘤免疫治疗。因此，我们建立了一个大规模的CD 4 ^+辅助/杀伤T细胞培养系统，为将来的临床试验提供足够数量的细胞。

项目成果

徳田 裕: "新しい癌免疫療法の開発を目的としたヒトCD4陽性細胞の選択的増殖培養系の確立" 東海大学総合研究機構報告. 16. 106-110 (1992)

Yutaka Tokuda：“建立人类 CD4 阳性细胞的选择性增殖培养系统，以开发新的癌症免疫疗法”东海大学研究组织报告，16. 106-110 (1992)。

Nishimura,Takashi: "Generation,propagation,and targeting of human CD4^+helper/killer T cells induced by anti-CD3 monoclonal antibody plus recombinant IL-2." J.Immunol.148. 285-291 (1992)

Nishimura, Takashi：“抗 CD3 单克隆抗体加重组 IL-2 诱导的人 CD4^ 辅助/杀伤 T 细胞的生成、增殖和靶向。”

Takashi Nishimura, et al.: "Generation, propagation, and targeting of human CD4^+ helper/killer T cells induced by anti-CD3 monoclonal antibody plus recombinant IL-2. An efficient strategy for adoptive tumor immunotherapy." J.Immunol. 148. 285-291 (1992)

Takashi Nishimura 等人：“抗 CD3 单克隆抗体加上重组 IL-2 诱导人 CD4+ 辅助/杀伤 T 细胞的生成、增殖和靶向。过继性肿瘤免疫治疗的有效策略。”

Nakamura,Yoshihiko: "Large-scale culture system of human CD4^+ helper/killer T cells for the application to adoptive tumour immunotherapy." Br.J.Cancer. 66. 20-26 (1992)

Nakamura, Yoshihiko：“用于过继性肿瘤免疫治疗的人类 CD4^ 辅助/杀伤 T 细胞的大规模培养系统。”

徳田 裕: "抗c-erbB-2×抗CD3 bispecific抗体とヒトCD4^+helper/killer細胞を用いた乳癌に対する免疫療法" 日本癌学会総会記事. 271- (1992)

Yutaka Tokuda：“使用抗 c-erbB-2 x 抗 CD3 双特异性抗体和人 CD4^+ 辅助/杀伤细胞进行乳腺癌免疫治疗”日本癌症协会大会文章 271- (1992)。