Camptothecins are increasingly preferred payloads for antibody-drug conjugates (ADCs). In this manuscript, Petersen, Brant, and colleagues present the design, selection, and characterization of ZD06519, a novel camptothecin tailored for ADCs, chosen from a library of ∼100 analogs. ZD06519 exhibits moderate free payload potency (∼1 nM) and, as an antibody conjugate, strong bystander activity, robust plasma stability, low hydrophobicity, and high-monomeric content. ZD06519 ADCs targeting diverse tumor-associated antigens display efficacy in a range of murine tumor models and are well tolerated in multiple preclinical toxicology species, supporting their future clinical development and highlighting the promise of this ADC platform.

Aberrant N-linked glycosylation is prevalent in many types of cancer. Small molecules targeting N-linked glycans are being actively investigated. Dang and colleagues identified penfluridol, an antipsychotic drug, which effectively decreased cell surface wheat germ agglutinin staining. Penfluridol appears to target MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation, thereby altering glycosylation...

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