32A9，一种新型人抗体，用于设计针对肝细胞癌中glypican-3的免

StephenW

32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma

    Xiaoyu Liu, Fang Gao, Longwei Jiang, Meng Jia, Lei Ao, Ming Lu, Liming Gou, Mitchell Ho, Shaochang Jia, Fei Chen & Wei Gao

Journal of Translational Medicine volume 18, Article number: 295 (2020) Cite this article

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Abstract
Background

Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC.
Methods

We isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo.
Results

32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CAR-T cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CAR-T cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo.
Conclusions

Our study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.

StephenW

32A9，一种新型人抗体，用于设计针对肝细胞癌中glypican-3的免疫毒素和CAR-T细胞

    刘晓宇，高芳，江龙威，孟佳，敖雷，吕明，郭黎明，何敏哲，贾绍昌，陈飞＆高伟

Journal of转化医学杂志第18卷，文章编号：295（2020）引用本文

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抽象
背景

使用基于抗体的靶向疗法（例如抗体偶联物和嵌合抗原受体T（CAR-T）细胞疗法）治疗肝细胞癌（HCC）显示出有效的抗肿瘤功效。 Glypican-3（GPC3）是新兴的HCC治疗靶标；因此，针对GPC3的抗体将成为开发HCC免疫疗法的有用工具。
方法

我们通过噬菌体展示技术分离了一种新型人类单克隆抗体32A9。我们确定了32A9的特异性，亲和力，表位和抗肿瘤活性，并开发了基于32A9的免疫疗法技术来评估HCC在体外或体内的治疗效力。
结果

32A9以有效的亲和力和特异性识别人GPC3。 32A9的表位位于GPC3蛋白核心的区域中，靠近HS链的修饰位点，并且位于GPC3的Wnt结合位点之外。 32A9抗体在体内显着抑制HCC异种移植肿瘤的生长。然后，我们通过构建免疫毒素和CAR-T细胞追求两种基于32A9的免疫治疗策略。 32A9免疫毒素对GPC3阳性癌细胞表现出特定的细胞毒性，而32A9 CAR-T细胞在体外有效消除GPC3阳性HCC细胞并在体内引起HCC异种移植肿瘤消退。
结论

我们的研究为32A9作为HCC免疫疗法的有希望的GPC3特异性抗体候选物提供了理论依据。

StephenW

https://translational-medicine.b ... /s12967-020-02462-1