Evaluation\nof Double Self-Immolative Linker-Based\nAntibody–Drug Conjugate FDA022-BB05 with Enhanced Therapeutic\nPotential

Typical\nantibody–drug conjugates (ADCs) with valine–alanine\nlinkage, often conjugated with the amino group in payloads, face challenges\nwhen interacting with hydroxyl group-containing payloads. Herein,\nwe introduced a transformative Val–Ala-based double self-immolative\nlinker-payload platform, reshaping ADCs by optimizing hydroxyl group-containing\npayload integration. Utilizing this platform, <b>FDA022-BB05</b> was successfully conjugated with the hydroxyl group-containing payload\nDXd using trastuzumab (FDA022) as the monoclonal antibody (mAb). <b>FDA022-BB05</b> demonstrated enhanced stability, effective cathepsin\nB sensitivity, reduced cell proliferation, increased bystander killing,\nand targeted delivery. Notably, acute toxicity evaluations in diverse\npreclinical models indicated favorable safety profiles and tolerability,\nwith a broad therapeutic index in HER2-positive and -negative xenografts.\nOverall, these compelling findings support the promising therapeutic\npotential of <b>FDA022-BB05</b>, emphasizing the significance\nof diverse linker-payload platform strategies. This ADC is a valuable\naddition to targeted cancer therapy development, currently advancing\nthrough phase I clinical trials.