Abstract 6089: The bispecific antibody KA-3458, targeting CD38 and CD28, specifically enhances T cell activation within the tumor microenvironment

Abstract KA-3458 is a bispecific antibody (BsAb) designed to target CD38 and human CD28, aiming to enhance T cell activation within the tumor microenvironment, particularly in blood cancers like multiple myeloma and lymphoma, where CD38 is highly expressed. While bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown clinical promise, the addition of CD28 co-stimulatory signals may further boost T cell responses against tumors. KA-3458, engineered in an IgG4 format with an identical light chain, was created using our common light chain bispecific antibody discovery platform and knob-into-hole technology. The antibody’s two Fabs show high affinity for CD38 and relatively lower affinity for CD28. In in vitro combination assays, KA-3458 significantly enhances T cell activation and cytotoxic activity of CD3 T cell engagers targeting CD20 or GPRC5D, which are critical for the treatment of lymphoma or multiple myeloma, respectively. Cytokine release assays performed with human PBMCs co-cultured with lymphoma cells revealed that KA-3458 enhances the release of INF-γ but not IL-6, in the presence of a CD20 T cell engager, suggesting a favorable safety profile. In PBMC-humanized immunodeficient mouse models, KA-3458 further improves the cytotoxicity of CD3 T cell engagers against CD20 or GPRC5D, targeting tumors in lymphoma or multiple myeloma models, respectively, which strongly express CD38. Additionally, KA-3458 has a normal half-life in Balb/c mice and demonstrates excellent developability. Toxicity studies are currently underway. In conclusion, KA-3458, developed using our common light chain bispecific antibody discovery platform, shows great potential as a preclinical candidate for the treatment of relapsed/refractory B-cell lymphoma and multiple myeloma. Citation Format: Guojin Wu, Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Jinying Ning. The bispecific antibody KA-3458, targeting CD38 and CD28, specifically enhances T cell activation within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6089.