Abstract 6011: Neoantigen peptide-loaded anti-CD40-spycatcher antibody as a novel cancer vaccine platform

Abstract Precision cancer therapy opened up an attractive strategy by therapeutic vaccines targeting neoantigens. Neoantigens are immunogenic and HLA-bound epitopes capable of activating helper and cytotoxic T lymphocytes and not subject to immunological tolerance. However, personalized peptide-based cancer vaccines still have the limitations to formulate and deliver. For example, most vaccine technology was initially based on the use of adjuvants (e.g., alum), which only provides moderate therapeutic effects. To address these issues, we utilize the engineered anti-CD40 agonistic antibody expressing Spy-Catcher003 (αCD40-SC) as a novel antigen presenting cells (APCs)-targeted peptide vaccine delivery platform for effective cancer immunotherapy. Since targeting and activating the CD40 receptor on APCs via anti-CD40 agonistic antibody has been shown to elicit superior T cells priming and boost antigen-specific CD8+ T. Besides, the use of SpyCatcher003, which is a 113-residue protein with reactive Lys31, could trigger spontaneous and irreversible amidation reaction with SpyTag003. SpyTag003/SpyCatcher003 is a protein coupling approach, which can form an intermolecular isopeptide bond between Lys31 and Asp117. Moreover, the protein pair can react with a rate of 5.5 x 105 M-1 s-1, which is helpful for potential therapeutic application.Therefore, we hypothesize the efficient and specific delivery, accomplished via SpyCatcher003-expressed anti-mouse CD40 agonistic antibody and SpyTag003-conjugated neoantigen peptide, will ensure the present of neoantigens to T cells and elicit robust and durable specific CD8+ T cell response. Our goal is to directly deliver neoantigen peptide-loaded αCD40-SC to APCs in draining lymph nodes (dLN) as a therapeutic vaccine. Citation Format: Xiaoying Cai, Dahee Jung, Seung-Oe Lim, Steve Seung-Young Lee. Neoantigen peptide-loaded anti-CD40-spycatcher antibody as a novel cancer vaccine platform [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 6011.