Abstract 2381: The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors

Abstract Immunotherapy, which involves blocking PD-1 signaling, has revolutionized the treatment paradigm for advanced solid tumors. However, prostate cancer exhibits a low response ratio to anti-PD-1 therapy. In this study, we have developed a bispecific antibody (BsAb), KA-3001, targeting PSMA and human CD28, aiming to enhance T cell activation in the tumor microenvironment. KA-3001, in a regular IgG1 format, features an identical light chain and was designed using our common light chain bispecific antibody discovery platform with knob-into-hole technology. Mutations in the Fc domain were introduced to eliminate ADCC, ADCP, and CDC activity. KA-3001's two Fabs demonstrate high affinity for PSMA and relatively low affinity for CD28. In comparison to REGN5678, KA-3001 exhibits significantly stronger binding to PSMA-expressing prostate tumor cells, along with relatively lower CD28 activation, minimizing toxicity while maintaining anti-tumor efficacy. In PBMC humanized immunodeficient mouse tumor models, KA-3001 effectively suppresses the growth of 22Rv1 tumors with or without PD-1 antagonist antibody. Furthermore, KA-3001 has a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody through various treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. The BsAb demonstrates neither aggregation nor degradation. In conclusion, the BsAb KA-3001, developed using our common light chain antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Jiabei Liang, Chen Su, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3001, targeting PSMA and CD28, specifically enhances T cell activation within prostate tumors 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 2381.