Dissecting the Efficacy and Immunogenicity of TLR7 Agonist-Antibody Conjugates through the Lens of Fc Effector Function, Conjugation Strategies, and Linker Cleavability.

ABSTRACT: The advent of immuno-oncology therapeutics has given rise to antibody-drug conjugates (ADC) designed to selectively activate pattern recognition receptors such as Toll-Like Receptors (TLRs). In contrast to classical ADC technology, these Immune Stimulating Antibody Conjugates (ISACs) are widely reported to rely on Fcγ-mediated uptake and noncleavable linkers. Herein, we systematically study the impact of Fc effector function, linker cleavability, and conjugation strategy on the efficacy and immunogenicity of a series of TLR7 agonist-based ISACs. We demonstrate that the combination of FcγR-ablation and incorporation of a cleavable linker results in increased stimulation of myeloid cells, enhanced efficacy, and improved tolerability as compared to traditional ISAC designs. Interestingly, we

SUBMITTER: Fang S 

PROVIDER: S-EPMC12703737 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature