Application of a Biocatalytic Strategy for the Preparation of Tiancimycin-Based Antibody–Drug Conjugates Revealing Key Insights into Structure–Activity Relationships

Antibody–drug
conjugates (ADCs) are cancer chemotherapeutics
that utilize a monoclonal antibody (mAb)-based delivery system, a
cytotoxic payload, and a chemical linker. ADC payloads must be strategically
functionalized to allow linker attachment without perturbing the potency
required for ADC efficacy. We previously developed a biocatalytic
system for the precise functionalization of tiancimycin (TNM)-based
payloads. The TNMs are anthraquinone-fused enediynes (AFEs) and have
yet to be translated into the clinic. Herein, we report the translation
of biocatalytically functionalized TNMs into ADCs in combination with
the dual-variable domain (DVD)-mAb platform. The DVD enables both
site-specific conjugation and a plug-and-play modularity for antigen-targeting
specificity. We evaluated three linker chemistries in terms of TNM-based
ADC potency and antigen selectivity, demonstrating a trade-off between
potency and selectivity. This represents the first application of
AFE-based payloads to DVDs for ADC development, a workflow that is
generalizable to further advance AFE-based ADCs for multiple cancer
types.