Document Type
Article
Publication Date
11-24-2025
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 found that all ISAC designs exhibited evidence of antidrug-antibody (ADA) induction. We found that the combination of a cleavable linker, a highly permeable TLR7 agonist payload, and ablation of FcγR binding results in ISACs that exhibit particularly favorable properties for continued development.
Publisher Attribution
© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY-NC-ND 4.0 .
Recommended Citation
Fang, Siteng; Benjamin, Samantha R.; Wu, Lina; Rahman, Mohammad Asikur; Elder, Kayla K.; Ojo, Victor T.; Zhang, Tao; Brooks, Tracy A.; and Tumey, L. Nathan, "Dissecting the Efficacy and Immunogenicity of TLR7 Agonist–Antibody Conjugates through the Lens of Fc Effector Function, Conjugation Strategies, and Linker Cleavability" (2025). Pharmacy Faculty Scholarship. 93.
https://orb.binghamton.edu/pharmacy_fac/93
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Comments
https://doi.org/10.1021/acs.jmedchem.5c01908