Evaluation of Double Self-Immolative Linker-Based Antibody–Drug Conjugate FDA022-BB05 with Enhanced Therapeutic Potential

Typical antibody–drug conjugates (ADCs) with valine–alanine linkage, often conjugated with the amino group in payloads, face challenges when interacting with hydroxyl group-containing payloads. Herein, we introduced a transformative Val–Ala-based double self-immolative linker-payload platform, reshaping ADCs by optimizing hydroxyl group-containing payload integration. Utilizing this platform, FDA022-BB05 was successfully conjugated with the hydroxyl group-containing payload DXd using trastuzumab (FDA022) as the monoclonal antibody (mAb). FDA022-BB05 demonstrated enhanced stability, effective cathepsin B sensitivity, reduced cell proliferation, increased bystander killing, and targeted delivery. Notably, acute toxicity evaluations in diverse preclinical models indicated favorable safety profiles and tolerability, with a broad therapeutic index in HER2-positive and -negative xenografts. Overall, these compelling findings support the promising therapeutic potential of FDA022-BB05, emphasizing the significance of diverse linker-payload platform strategies. This ADC is a valuable addition to targeted cancer therapy development, currently advancing through phase I clinical trials.