Camptothecin-, dolastatin- and duocarmycin-derived antibody-drug conjugates and their journey toward the clinic

Alkaloids, and more recently peptide-based natural products have long been compounds of great interest due to their wide range of biological properties. Exciting advancements in targeted therapies have allowed for enhanced specificity and pharmacokinetic profile improvement (ADMET). For example, antibody-drug conjugates (ADCs) have enhanced the safety profile such that previously excluded small molecules are now being reinvestigated as therapies. Herein, we showcase the development pipeline of small molecule natural products into ADCs, overcoming their inherent limitations and allowing for applications in clinical settings. The validity of this strategy is exemplified by three examples, camptothecin, dolastatins and duocarmycins. Collectively, these examples show that clinical translation not only depends on payload potency, but also on linker chemistry, drug-to-antibody ratio, payload permeability, bystander killing, and the resultant therapeutic window.