Abstract 6013: Bi-specific complement engagers (BiCEs) - A novel platform for the potentiation of therapeutic antibodies based on effective complement engagement through C1q

Abstract The complement system is a crucial component of the innate immune response, enhancing the body's ability to clear pathogens and damaged cells. It facilitates immune defense mechanisms by promoting inflammation, opsonization, and direct lysis of target cells through the formation of membrane attack complexes (MACs). However, therapeutic antibodies designed to exploit complement-mediated cytotoxicity have faced limitations, including dependence on antigen density, structural constraints related to antibody binding orientation, and the inhibition of complement activation by regulatory molecules expressed on target cells. To address these challenges, we developed a modular IgG-based bispecific antibody platform that engages the complement-initiating protein C1q by fusing anti-C1q variable heavy chain domains (VHHs) to either the heavy or light chains of IgGs. In this study, we present data demonstrating the broad applicability of our platform by enhancing existing complement-deficient antibodies that target a diverse range of clinically relevant tumor antigens with C1q engagers. The resulting bispecific complement engagers (BiCEs) effectively engage C1q and induce robust complement-dependent cytotoxicity (CDC) against cancer cell lines expressing varying levels of target antigens with superior efficacy compared to competing technologies. Moreover, the BiCE molecules retain binding to the neonatal Fc receptor (FcRn) and Fc gamma receptors (FcγRs), resulting in an extended half-life and preservation of secondary effector functions such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Our findings suggest that effective activation of the complement system through complement engagers offers a promising alternative to antibody-drug conjugates (ADCs) and T-cell therapies, providing an opportunity to target antigens with lower tumor specificity and potentially expanding therapeutic options for patients with cancer. Citation Format: Mikael Winkler, Dennis Pedersen, Heidi Gytz, Troels Kjær, Nina Dybdal, Alex Ferapontov, Sara Dam, Laust Bavnhøj, Sofia Mølgaard, Pascal Merchiers, Mikkel Wandahl Pedersen, Nick Laursen. Bi-specific complement engagers (BiCEs) - A novel platform for the potentiation of therapeutic antibodies based on effective complement engagement through C1q [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 6013.