Yang Chen, Wang Ping, Yang Mingjun, Lu Qizhong, Zhu Zhixiong, Lu Huaqing, Li Hexian, Zhang Zongliang, Li Meng, Zhao Lizhou, Li Jia, Ling Bo, Fu Xuemei, Tong Aiping
State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Blood Research Laboratory, Chengdu Blood Center, Gongtong Street, Jinjiang District, Chengdu 610041, China.
Int Immunopharmacol. 2025 Aug 28;161:115032. doi: 10.1016/j.intimp.2025.115032. Epub 2025 Jun 13.
B7-H3, an immune-checkpoint molecule that is overexpressed in several cancer types, has been identified as a promising immunotherapy target. However, most immunotherapy approaches against B7-H3 tumor cells focus on manipulating the T cells. Natural killer (NK) cells, another important part of the cellular immune system, also exhibit anti-tumor properties and play complementary roles in tumor eradication with T cells. In this study, natural killer group 2D (NKG2D), an activating receptor in most cytotoxic immune cells, was selected for engaging NK cells. We obtained specific anti-NKG2D nanobodies via phage display and developed a series of B7-H3 × NKG2D bispecific antibodies (bsAb) with different formats to fight against the B7-H3 tumor cells. Through functional comparison of candidate antibodies in vitro, B1-C53 was selected and further modified with the optimized Fc fragment (known as FC-C53) to enhance anti-tumor immunity by antibody-dependent cell-mediated cytotoxicity (ADCC). Stronger tumor lysis mediated by FC-C53 was demonstrated both in vitro and in vivo when simultaneously directed at both NK cells and CD8 T cells, particularly after the additional administration of a B7-H3 × CD3 bispecific T cell engager that targets B7-H3 with another epitope. Overall, we provided a strategy based on the B7-H3 × NKG2D antibody to improve the anti-B7-H3 immunotherapy approaches by orchestrating cytotoxic lymphocytes.
B7-H3是一种在多种癌症类型中过表达的免疫检查点分子，已被确定为一个有前景的免疫治疗靶点。然而，大多数针对B7-H3肿瘤细胞的免疫治疗方法都集中在操纵T细胞上。自然杀伤（NK）细胞是细胞免疫系统的另一个重要组成部分，也具有抗肿瘤特性，并在与T细胞协同根除肿瘤中发挥互补作用。在本研究中，选择了大多数细胞毒性免疫细胞中的一种激活受体——自然杀伤细胞2D（NKG2D）来激活NK细胞。我们通过噬菌体展示获得了特异性抗NKG2D纳米抗体，并开发了一系列不同形式的B7-H3×NKG2D双特异性抗体（bsAb）来对抗B7-H3肿瘤细胞。通过体外对候选抗体的功能比较，选择了B1-C53并用优化的Fc片段（称为FC-C53）进行进一步修饰，以通过抗体依赖性细胞介导的细胞毒性（ADCC）增强抗肿瘤免疫力。当同时作用于NK细胞和CD8 T细胞时，特别是在额外施用靶向B7-H3另一个表位的B7-H3×CD3双特异性T细胞衔接器后，FC-C53在体外和体内均表现出更强的肿瘤细胞裂解作用。总体而言，我们提供了一种基于B7-H3×NKG2D抗体的策略，通过协调细胞毒性淋巴细胞来改进抗B7-H3免疫治疗方法。
