Second Generation Tiancimycin-Based Antibody-Drug Conjugates Enabled by Highly Efficient Semi-synthetic Approach...

Antibody-drug conjugates (ADCs) are advanced cancer therapeutics that combine an antibody-based delivery system with a cytotoxic payload through chemical linkers. Anthraquinone-fused enediyne (AFE) natural products, such as tiancimycins (TNMs), are emerging payload candidates with exceptional potency and a validated DNA-damaging mechanism of action. In this study, we describe the translation of semisynthetically functionalized TNMs, incorporating various linker chemistries, into ADCs featuring dual variable domain monoclonal immunoglobulin G1 antibodies (DVD IgG1s). DVD IgG1s enable site-specific conjugation and modular antigen-targeting specificity. As a proof-of-principle, keto-TNM A-anti-CD79b DVD IgG1-based ADCs were constructed on the basis of the significance of CD79b as a clinical target, with only one FDA-approved ADC available. Inspired by the structure-activity relationship data, a chemical strategy to synthesize keto-TNM A was developed, which exhibited the highest potency among the TNMs we have examined to date. Keto-TNM A was elaborated to a panel of anti-CD79b DVD IgG1-based ADCs featuring varying linker chemistries. The optimized ADC exhibited potent and selective activity across multiple CD79b-expressing cell lines and, most significantly, patient-derived primary chronic lymphocytic leukemia cells. This study provides an efficient approach to access functionalized AFEs at scale and speed and exploit their utility as payloads for ADCs targeting CD79b and beyond as the next generation immunotherapies.