Abstract 1790: Enhancing ADC efficacy through Fc-binding peptide engineered with ECM binding moiety: A versatile platform targeting various tumors and other malignancies

Abstract Antibody-drug conjugates (ADCs) are an emerging class of immunotherapeutics permitting the delivery of therapeutics with sufficient potency and specificity by doing so systemic toxicity typical of conventional chemotherapy is minimized. However, the challenges in controlling their internalization have posed a hurdle in maximizing the therapeutic potential of ADCs. Here we present a novel FcBP-based modality called FcBC17, an FcBP coupled with an extracellular matrix (ECM)-binding moiety, which plays an ADC enhancer by improving the cell binding and internalization of ADCs through a biologically active mechanism. FcBC17 comprises an FcBP, a linker, and an ECM-binding peptide and tightly associates with IgG antibodies. The efficacy of FcBC17 was demonstrated using PAb001, a humanized IgG1 antibody targeting MUC1-C developed by Peptron. Due to its reversible binding to the Fc-region of PAb001, the structural and functional integrity of PAb001 remains and also additional effort to modify PAb001 is unnecessary, representing a simple, broadly applicable strategy to enable antibody delivery into cells. We show that FcBC17 improved cell binding of PAb001 in diverse cancer cells with different levels of MUC1. In addition, PAb001-FcBC17 conjugate showed a better internalization in cancer cells and intriguingly, a biologically active mechanism such as endocytosis seemed to mediate the internalization, suggesting that FcBC17 might enhance the cytotoxicity of PAb001-ADC (PAb001-MMAE or PAb001-DXd) through enhancing its cell binding and internalization actively. Indeed, the cytotoxicity of PAb001-ADC was greatly improved with the conjugation of FcBC17 against cancer cells that otherwise showed a poor IC50 with the treatment of PAb001-ADC, and no cytotoxicity was observed with the treatment of FcBC17 alone, indicating that the ADC enhancement was likely due to the improved internalization of PAb001-ADC through the conjugation of FcBC17. Moreover, due to the nature of FcBP whose binding is separated on acidic pH conditions, PAb001-FcBC17 conjugate remains stable under normal physiological conditions, ensuring that the efficacy of PAb001-ADC is not compromised upon clinical treatment. In conclusion, the binding and internalization of PAb001-ADC on cancer cells could be greatly enhanced with the conjugation of FcBC17 which in turn has resulted in the dramatic improvement of the cytotoxicity mediated with PAb001-ADC, implying that the critical limitation of conventional ADCs in controlling cellular internalization may be ameliorated through our FcBP-based approach. The versatility of our approach as an ADC enhancer will be further demonstrated across various applications, not only in targeting MUC1-expressing tumors but also in treating other types of cancers and malignancies through diverse therapeutic antibody formats. Citation Format: Dae Young Kim, Yujin Park, Dahye Sim, Hana Kang, Sung Min Kim, Yejin Bang, Hee Young Kang, Hoil Choi. Enhancing ADC efficacy through Fc-binding peptide engineered with ECM binding moiety: A versatile platform targeting various tumors and other malignancies [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 1790.