Abstract 2380: The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor activity

Abstract

Abstract Checkpoint inhibitors (CPI) have transformed the treatment landscape for advanced solid tumors; however, a majority of cancers still do not respond to immune checkpoint therapy. In this study, we developed a bispecific antibody (BsAb) named KA-3004, targeting PD-L1 and human 4-1BB, with the aim of enhancing the functionality and survival of stimulated CD8+ T cells in the tumor microenvironment. This antibody was designed using our nanobody antibody discovery platform. KA-3004, in IgG1 format, incorporates mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It features two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PD-L1 with two Fabs at the N-terminal. KA-3004 binds to PD-L1 with high affinity, blocking the interaction of PD-1 and PD-L1. It 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 PD-L1 with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3004 effectively suppresses the growth of NCI-H292 tumors expressing PD-L1. Additionally, KA-3004 has 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, and KA-3004 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3004, developed with our nanobody antibody discovery platform, stands out as a promising pre-clinical candidate drug for the treatment of solid cancers. Citation Format: Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning, Guojin Wu. The bispecific antibody KA-3004, targeting PD-L1 and 4-1BB, is designed to enhance anti-tumor activity [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 2380.