Extensive Biotransformation Profiling of AZD8205, an Anti-B7-H4 Antibody-Drug Conjugate, Elucidates Pathways Underlying its Stability In Vivo

Le résumé fourni par la source

What happens to macromolecules in vivo? What drives structure-activity relationship and in vivo stability for antibody-drug conjugates (ADCs)? These interrelated questions are increasingly relevant due to the re-emerging importance of ADCs as an impactful therapeutic modality and the gaps that exist in our understanding of ADC structural determinants that underlie ADC in vivo stability. Complex macromolecules, such as ADCs may undergo changes in vivo due to their intricate structure as biotransformations may occur on the linker, the payload and/or at the modified conjugation site. Furthermore, dissection of ADC metabolism presents a substantial analytical challenge due to the difficulty in identification or quantification of minor changes on a large macromolecule. We employed immunocapture-LCMS methods to evaluate in vivo changes in drug-antibody ratio (DAR) profile in four different lead ADCs. This comprehensive characterization revealed that a critical structural determinant contributing to ADC design was the selection of the linker as the competition between the retro-Michael deconjugation and thio-succinimide hydrolysis reactions resulted in superb conjugation stability in vivo. These data, in conjunction with additional factors, informed the selection of AZD8205, a B7-H4-directed cysteine-conjugated ADC bearing a novel topoisomerase I inhibitor payload, with durable DAR, currently being studied in the clinic for the potential treatment of solid malignancies (NCT05123482). These results highlight the relevance of studying macromolecule biotransformation and elucidating the ADC structure-in vivo stability relationship. The comprehensive nature of this work increases confidence in our understanding of these processes. We hope this analytical approach can inform future development of bioconjugate drug candidates.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.