Dual-payload ADCs are gaining importance as they offer a solution to overcome the tumor heterogeneity and treatment resistance faced by conventional ADCs.[1][2] These ADCs combine two different payloads, such as tubulin inhibitors such as MMAE and DM1, with GR50 values of 0.04 nM for both in some cell lines.[1] The new dual-payload ADC against HER2+ SK-BR-3 cells achieved a GR50 of 0.29 nM, versus 1967 nM for control trastuzumab, and against DLD-1 cells a GR50 of 3.36 nM versus 1971 nM.[1] The combination of Topo1i and PARPi in a dual-payload ADC showed higher activity compared to Topo1i ADC alone in in vitro and in vivo tests in MC38-hTF models at a dose of 5 mg/kg.[2] Using two payloads with a different mechanism can overcome resistance to payloads, as shown by clinical data from ASCO 2024, where changing the payload class maintained ADC efficacy regardless of antigen.[2] Advantages include simultaneous delivery of payloads, reduced toxicity, and simplified clinical development.[2] Ideal payloads have high cytotoxicity (0.001–1 nM), stability in blood, and low immunogenicity.[3] The DAR of approved ADCs ranges from 2 to 8, balancing efficacy, stability, and safety.[4]