Discovery and Preclinical Evaluation of PBX-7016, a Methylenedioxy-Camptothecin Payload for Antibody-Drug Conjugates with Enhanced Therapeutic Potential

Camptothecin derivatives have become cornerstone payloads
in antibody–drug
conjugates (ADCs), with recent clinical success driving continued
optimization to improve therapeutic efficacy and safety. Herein, we
present the development of PBX-7016 (14), a novel methylenedioxy-camptothecin
analog. Hybrid molecules combining FL118 and Exatecan pharmacophores
were synthesized and tested in vitro, yielding three
lead compounds characterized by dual Topo1 inhibition and antiapoptotic
protein suppression. Functional evaluation of ADC constructs incorporating
these payloads validated physicochemical compatibility with antibody
conjugation, target-dependent cytotoxicity, and antibody-like pharmacokinetics.
When benchmarked against Enhertu, these ADCs showed superior bystander
killing and in vivo efficacy across multiple xenograft
models. Furthermore, PBX-7016–based ADCs maintained strong
efficacy against various tumor-associated antigens, demonstrating
therapeutic versatility. Notably, in vitro ADME profiling
and rodent toxicology studies confirmed a favorable safety profile
and good tolerability. PBX-7016 represents a differentiated
camptothecin payload with strong translational promise, and its ADCs
are currently advancing through Phase I trials.