Abstract 5295: Tumor targeted-CD28 bispecific antibody with optimized potency, robust anti-tumoral activity and stringent CD3-dependence

Abstract CD28 is an essential co-stimulatory signal (Signal 2) for optimal T cell function upon TCR/CD3 activation (signal 1). However, clinical development of CD28 agonist antibodies has been confounded by toxicities presumably from CD3-independent and/or tumor non-specific activation. Here we report a rationally screened CD28 agonist antibody with optimized potency, from which a PSMAxCD28 bispecific was made. The bispecific antibody had several unique features: (1) minimal activity in the absence of CD3, even under stringent conditions, (2) superior tumor killing in vivo alone and in combination with anti-PD1 antibody, (3) requirement of abundant level of PSMA for activation, sparing PSMAlow cells, and (4) extended half-life in human-CD28 KI mice. To summarize, our anti-CD28 bispecific antibody enhances dependence on TCR/CD3 (Signal 1), induces selective killing of PSMA high expressing cancer cells, and elicits robust tumor eradiation in-vivo with extended PK. These features may translate to further improvements in efficacy and safety for tumor-targeted CD28 bispecific antibodies. Citation Format: Xiguang Zhang, Shiqi Cao, Li, Shuaixiang Zhou, Yao Xiong, Dian Kang, Feifei Wang, Jie Ren, Keke Fei, Jianglu Wang, Jinchang Lu, Huizhong Xiong. Tumor targeted-CD28 bispecific antibody with optimized potency, robust anti-tumoral activity and stringent CD3-dependence abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5295.