Feng Yan, Xie Kun, Yin Yanxin, Li Bingyu, Pi Chenyu, Xu Xiaoqing, Huang Tao, Zhang Jingming, Wang Bo, Gu Hua, Fang Jianmin
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
Biomedical Research Center, Suzhou 230031, China.
Life (Basel). 2022 Jan 21;12(2):157. doi: 10.3390/life12020157.
B7-H3 plays an important role in tumor apoptosis, proliferation, adhesion, angiogenesis, invasion, migration, and evasion of immune surveillance. It is overexpressed in various human solid tumor tissues. In patients, B7-H3 overexpression correlates with advanced stages, poor clinical outcomes, and resistance to therapy. The roles of B7-H3 in tumor progression make it a potential candidate for targeted therapy. Here, we generated a mouse anti-human B7-H3 antibody and demonstrated its binding activity via Tongji University Suzhou Instituteprotein-based and cell-based assays. We then developed a novel format anti-B7-H3 × anti-CD3 bispecific antibody based on the antibody-binding fragment of the anti-B7-H3 antibody and single-chain variable fragment structure of anti-CD3 antibody (OKT3) and demonstrated that this bispecific antibody mediated potent cytotoxic activities against various B7-H3-positive tumor cell lines in vitro by improving T cell activation and proliferation. This bispecific antibody also demonstrated potent antitumor activity in humanized mice xenograft models. These results revealed that the novel anti-B7-H3 × anti-CD3 bispecific antibody has the potential to be employed in treatment of B7-H3-positive solid tumors.
B7-H3在肿瘤细胞凋亡、增殖、黏附、血管生成、侵袭、迁移以及免疫逃逸等过程中发挥着重要作用。它在多种人类实体瘤组织中呈过表达状态。在患者体内，B7-H3的过表达与肿瘤晚期、临床预后不良以及治疗耐药相关。B7-H3在肿瘤进展中的作用使其成为靶向治疗的潜在候选靶点。在此，我们制备了一种小鼠抗人B7-H3抗体，并通过同济大学苏州研究院基于蛋白质和细胞的实验证实了其结合活性。随后，我们基于抗B7-H3抗体的抗体结合片段和抗CD3抗体（OKT3）的单链可变片段结构，开发了一种新型抗B7-H3×抗CD3双特异性抗体，并证明该双特异性抗体通过增强T细胞活化和增殖，在体外对多种B7-H3阳性肿瘤细胞系介导了强大的细胞毒活性。这种双特异性抗体在人源化小鼠异种移植模型中也表现出强大的抗肿瘤活性。这些结果表明，新型抗B7-H3×抗CD3双特异性抗体具有用于治疗B7-H3阳性实体瘤的潜力。
