An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers.
An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers.
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一种优化的基于 IgG 的 B7-H3xCD3 双特异性抗体，用于治疗胃肠道癌症。
DOI：
10.1016/j.ymthe.2023.02.010
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
H. Salih
中科院分区：
文献类型：
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作者：
L. Zekri;M. Lutz;N. Prakash;Timo Manz;Boris Klimovich;S. Mueller;Sebastian Hoerner;Ilona Hagelstein;Monika Engel;Anna V. Chashchina;Martin Pfluegler;J. Heitmann;G. Jung;H. Salih
基于T细胞的免疫疗法已经彻底改变了肿瘤治疗。然而，许多患者对治疗没有反应，长期缓解仍然很少见，特别是在胃肠道癌症如结肠直肠癌（CRC）中。B7-H3在包括CRC在内的多种癌症实体中在肿瘤细胞和肿瘤脉管系统上过表达，后者促进效应细胞在靶向治疗时涌入肿瘤部位。我们生成了一组T细胞招募B7-H3xCD3双特异性抗体（bsAbs），并表明靶向膜近端B7-H3表位可以使CD3亲和力降低100倍。在体外，我们的先导化合物CC-3表现出优异的肿瘤细胞杀伤、T细胞活化、增殖和记忆形成，同时减少了不需要的细胞因子释放。在体内，CC-3介导了三种独立模型的抗肿瘤活性，这些模型使用免疫功能低下的小鼠过继转移人效应细胞，以防止肺转移和侧腹肿瘤生长以及消除已建立的大肿瘤。因此，对靶标和CD3亲和力以及结合表位进行微调，可以产生具有良好治疗活性的B7-H3xCD3 bsab。CC-3目前正在进行良好生产规范（GMP）生产，以便在结直肠癌的临床“首次人体”研究中进行评估。
T cell-based immunotherapy has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions remain rare, particularly in gastrointestinal cancers like colorectal cancer (CRC). B7-H3 is overexpressed in multiple cancer entities including CRC on both tumor cells and tumor vasculature, the latter facilitating influx of effector cells into the tumor site upon therapeutic targeting. We generated a panel of T cell-recruiting B7-H3xCD3 bispecific antibodies (bsAbs) and show that targeting a membrane-proximal B7-H3 epitope allows for a 100-fold reduction of CD3 affinity.In vitro, our lead compound CC-3 showed superior tumor cell killing, T cell activation, proliferation, and memory formation, whereas undesired cytokine release was reduced.In vivo, CC-3 mediated potent antitumor activity in three independent models using immunocompromised mice adoptively transferred with human effector cells with regard to prevention of lung metastasis and flank tumor growth as well as elimination of large established tumors. Thus, fine-tuning of both target and CD3 affinities as well as binding epitopes allowed for the generation of a B7-H3xCD3 bsAbs with promising therapeutic activity. CC-3 is presently undergoing good manufacturing practice (GMP) production to enable evaluation in a clinical "first-in-human" study in CRC.