Abstract 6362: The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate tumors

Abstract

Abstract Cancer immunotherapy with 4-1BB agonists has faced limitations in further clinical development due to dose-limiting toxicity. PSMA, highly expressed in normal prostate tissue and prostate cancer, is a clinically validated target for prostate cancer treatment. In this study, we developed a bispecific antibody (BsAb), KA-3002, targeting PSMA and human 4-1BB, with the aim of restricting 4-1BB stimulation to the interior of tumors. KA-3002 was developed based on our nanobody antibody discovery platform. KA-3002, in IgG1 format, features mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It contains two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PSMA with two Fabs at the N-terminal. KA-3002 exhibits high avidity binding to prostate tumor cells expressing PSMA (EC50<1nM) and also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PSMA with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3002 effectively suppresses the growth of 22Rv1 tumors, which highly express PSMA. The antibody also demonstrates a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. KA-3002 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3002, developed with our nanobody antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity 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(6_Suppl):Abstract nr 6362.