Dual-payload antibody-drug conjugates (ADCs) have recently entered the first oncology clinical trials. This marks a major advancement in cancer therapeutics. Unlike traditional ADCs delivering a single cytotoxic agent, dual-payload ADCs carry two distinct drugs conjugated to the same antibody, enhancing efficacy and helping overcome tumor resistance.
By releasing two different cytotoxins that target separate cellular pathways, dual-payload ADCs offer a synergistic attack. This approach reduces resistance and improves outcomes compared to single-payload ADCs or combinations of individual agents. Their precision ensures both payloads reach the same tumor cells while minimizing systemic toxicity.
A milestone example is Chengdu Kanghong Biotech’s KH815, the first dual-payload ADC to enter clinical trials in 2025. KH815 targets Trop2, a protein highly expressed in aggressive solid tumors, and combines a topoisomerase I inhibitor with an RNA polymerase II inhibitor via a branched linker. With a drug-to-antibody ratio of ~7.5 and robust physicochemical stability, KH815 demonstrated superior tumor growth inhibition in preclinical models, including those resistant to Trodelvy. The ADCs maintained an acceptable toxicological profile, indicating a favorable safety margin.
At the 2025 AACR meeting, researchers disclosed more than a dozen dual-payload ADC candidates, reflecting growing global interest. While Asian companies currently lead clinical activity, Western biotech companies are also advancing novel antigen and payload strategies. However, challenges like manufacturing complexity and safely balancing dual-payload potency are being addressed through advanced conjugation chemistry and linker design.
In summary, dual-payload ADCs represent a fast-evolving frontier in targeted oncology, offering promise in boosting efficacy and overcoming resistance beyond current ADC therapies.
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