Abstract 3223: A highly selective and novel TCR-like antibody, IMB-202, targeting NK and T cell immune checkpoint for enhanced cancer immunotherapy

Abstract Human natural killer (NK) and T cells are essential cytotoxic effectors in tumor surveillance and elimination, with an increasingly important role in immune checkpoint inhibitor (ICI) therapies. While current ICIs have focused on inhibitory receptors on T cells, creating a paradigm shift in cancer treatment, challenges remain due to non-responders and treatment-associated adverse events. There is a growing need for alternatives that address these limitations and for strategies that enhance efficacy through combination with existing ICIs. In this study, we developed IMB-202, a therapeutic anti-cancer antibody designed to target the ligands (TOI, Target of Interest), which are overexpressed on tumor cells, of an immune checkpoint receptor on NK and T cells. This TOI plays a crucial role in tumor escape mechanisms by transmitting inhibitory signals to NK and T cells. While this target holds significant promise for ICIs, its development as a therapeutic antibody has been particularly challenging due to the high sequence homology among related family proteins, which complicates achieving the specificity. Through advanced phage display screening and affinity maturation, we successfully developed IMB-202 as a highly selective TCR-like antibody, capable of recognizing even a single amino acid difference in peptide sequences. IMB-202 binds with high affinity and specificity to TOI in various cancer cell lines and efficiently kills cancer cells by disrupting the immune evasion mechanisms, followed by activating NK and T cells, as well as through antibody-dependent cellular cytotoxicity (ADCC) in vitro. Additionally, IMB-202 demonstrated significant tumor growth inhibition in an in vivo xenograft mouse model. When applied to ePENDY technology, IMBiologics’ proprietary multivalent antibody platform, IMB-202-ePENDY demonstrated enhanced avidity and increased NK and T cell cytotoxicity against cancer cells. Furthermore, its rapid internalization of IMB-202 supports its potential as an antibody-drug conjugate (ADC) candidate, with robust internalization also observed in the ePENDY platform format. These findings highlight IMB-202 as a promising alternative to existing ICIs and as a first-in-class therapy, targeting a novel immune checkpoint ligand with exceptional selectivity. Additionally, IMB-202 demonstrates significant potential for superior anti-tumor efficacy, with the versatility to be applied across various therapeutic modalities. Citation Format: Inyoung Lee, Hyeonju Kang, Chaerin Yoo, Hong Jai Lee, Sungmuk Kang, Sunghyun Byun, Yongjun Kang, Chungmin Lee, Gyongsik Ha. A highly selective and novel TCR-like antibody, IMB-202, targeting NK and T cell immune checkpoint for enhanced cancer immunotherapy [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 3223.