New immuno Adoptive tangeting thesapy using bispecific Amtibody

使用双特异性 Amtibody 的新型免疫过继治疗疗法

• 批准号: 07807120
• 负责人: SUZUKI Masanori
• 金额: $ 1.34万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07807120/
• 关键词: Bileduct Canungwy; MOC-1; bispecific antibody; Adoptive immunotherapy; MUC-1; bispecific抗体; 胆嚢癌; バイスペシフィック抗体; 癌免疫療法

For the purpose of establishing a new adoptive immunotherapy for bile duct carcinoma (BDC), we synthesized two bispecific antibodies (BsAbs), MUC1*CD3 BsAb constructed with MUSE11 (anti-MUC1 tumor antigen) and OKT-3 (anti-CD3), and MUC1*CD28 BsAb constructed with MSUE11 and 15E8 (anti-CD28) antibodies. These two BsAbs reacted well with both MUC1-positive target tumor cells and effector lymphokine-activated killer (LAK) cells. Investigation of in vitro cytotoxicity [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide assay] revealed that the MCU1*CD3 BsAb could antigen-specifically enhance the cytotoxicity of LAK cells. Addition of the two BsAbS (MUC1*CD3 BsAb plus MUC1*CD28 BsAb) in vitro resulted in a 60% cytotoxicity, similar to that obtained with BsAb (MUC1*CD3) alone. Interleukin 12-induced LAK cells demonstrated far greater cytotoxicity (50%) than their interleukin 2-induced counterparts (LAK cells), and this was also enhanced by the BsAbs. When 2*10^7 LAK cells sensitized with both kinds of BsAbs were administered four times i.v.to BDC-grafted severe combined immunodeficient mice (tumor size 5 mm in diameter), inhibition of tumor growth was observed. Thus, BsAb-LAK therapy for control of BDC warrants clinical trials.

为了建立一种新的胆管癌（BDC）过继免疫疗法，我们合成了两种双特异性抗体（BsAb），即由MUSE11（抗MUC1肿瘤抗原）和OKT-3（抗CD3）构建的MUC1*CD3 BsAb，和用 MSUE11 和 15E8（抗 CD28）抗体构建的 MUC1*CD28 BsAb。这两种 BsAb 与 MUC1 阳性靶肿瘤细胞和效应淋巴因子激活杀伤 (LAK) 细胞反应良好。体外细胞毒性研究[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物测定]表明，MCU1*CD3 BsAb 可以抗原特异性增强 LAK 细胞的细胞毒性。体外添加两种 BsAb（MUC1*CD3 BsAb 加 MUC1*CD28 BsAb）可产生 60% 的细胞毒性，与单独使用 BsAb (MUC1*CD3) 获得的细胞毒性相似。白细胞介素 12 诱导的 LAK 细胞表现出比白细胞介素 2 诱导的对应细胞（LAK 细胞）更大的细胞毒性 (50%)，并且双特异性抗体也增强了这种细胞毒性。当用两种 BsAb 致敏的 2*10^7 LAK 细胞静脉注射四次给 BDC 移植的严重联合免疫缺陷小鼠（肿瘤直径 5 mm）时，观察到肿瘤生长的抑制。因此，用于控制 BDC 的 BsAb-LAK 疗法值得进行临床试验。

项目成果

鈴木正徳: "MUC-1-specific Targeting Immunitherapy with bispeufic Antibedies Inhibition of Xenografted Puiness lile duct Ca." Cancer reserch. 56. 4205-4212 (1996)

Masanori Suzuki：“MUC-1 特异性靶向免疫治疗与双特异性抗体抑制异种移植的胆汁管癌症研究。”56. 4205-4212 (1996)

鈴木正徳: "MUC-1-specific targeting Immuuotherspy with bispeafic Antibodies・Inlibition of xenografted luman luile bet Ca.groweh" Cancer resfearh. 56. 4205-4212 (1996)

Masanori Suzuki：“使用双特异性抗体的 MUC-1 特异性靶向免疫治疗·异种移植 luile bet Ca.groweh 的抑制” Cancer resfearh 56. 4205-4212 (1996)