Uncialamycin-based antibody–drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

Abstract

Antibody–drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin γ1I, have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

Anthraquinone-fused enediynes: discovery, biosynthesis and development

“…Natural Product Reports characterization of the nine metabolites, including sungeidines A (6), B-H (34)(35)(36)(37)(38)(39)(40) and anthramycin (41). Compounds 6 and 34 feature a pyrrolidine ring and a tetracyclic backbone fused to an anthrathiophenone moiety.…”

“…18). 34 These linker-drugs were then conjugated to different antibodies (the anti-T1 antibody and anti-CD46 antibody) to afford two sets of targeting ADCs and a non-targeting control antibody (nTAb). The targeting ADCs exhibited impressive in vitro cytotoxicity and selectivity profiles against an engineered HEK293T cell line that expresses high levels of T1 and CD46 compared to the nontargeting ones.…”

“…32,33 These synthetic compounds allow the structure-activity relationships (SARs) of AFEs to be studied and provide various payload candidates for the development of AFEbased antibody-drug conjugates (ADCs). 34 Considerable knowledge has been accumulated on the discovery, biosynthesis, resistance, total synthesis and preclinical development of AFEs in the past ve years. However, no systematic review has yet been published on AFEs, a relatively small subfamily of natural products.…”

“…32,33 These synthetic compounds allow the structure–activity relationships (SARs) of AFEs to be studied and provide various payload candidates for the development of AFE-based antibody–drug conjugates (ADCs). 34…”

Antibody-Antineoplastic Conjugates in Gynecological Malignancies: Current Status and Future Perspectives

“…Finally, it is worth mentioning that some ADCs show a bystander killing effect that occurs when the antineoplastic agents not only act in the targeted cells but also in the surrounding or bystander cells, that can express or not the target antigen [ 70 ]. This is especially interesting as the anticancer effect is potentiated.…”