Antibody-Drug Conjugates (ADCs) have transformed cancer treatment by pairing antibody precision with the strength of cytotoxic drugs. Yet challenges like resistance, tumor diversity, and limited durability still limit their impact.
Dual Payload ADCs are emerging as a powerful next step. By carrying two different payloads on one antibody, they can shut down multiple resistance pathways, deliver additive or even synergistic tumor killing, and broaden options for hard-to-treat cancers.
The field is moving quickly-two dual-payload ADCs are already in clinical trials, with many more in development. Companies such as Callio Therapeutics, Chengdu Kanghong, and Sutro Biopharma are leading the charge with designs that combine TOP1 inhibitors with payload partners like tubulin inhibitors, RNA polymerase II inhibitors, or DDR-targeting agents. These strategies aim to outpace tumor escape mechanisms and deliver longer-lasting responses.
The growing momentum underscores that dual-payload ADCs are no longer theoretical-they are becoming a clinical reality.
Table adapted from Nature Reviews Drug Discovery, 2025.
BroadPharm's expertise in linker technology has already advanced the dual-drug ADC field. For example, MC-Val-Cit-PAB-Doxorubicin (BP-24434) and MC-Val-Cit-PAB-MMAE (BP-23969) (Figure 1) enabled the modular synthesis of single and dual-drug conjugates. Aldoxorubicin (BP-43220) and MC-VCP-Vinblastine (BP-43222) were also used (Nervig).
Figure 1. Chemical structures of the linker-drug conjugates applied in ADC construction, along with their abbreviations. The active payload released after lysosomal cleavage is highlighted in red for each molecule.
Key findings include:
Figure 2. Dual-drug ADCs T-DA2(MMAE)-Cys(VBL), T-DA2(vcDox)-Cys(DMAG), and TDA2(VBL)-Cys(DMAG) all showed enhanced toxicity towards tumor cells than their parent single-drug ADCs through synergistic payload effects (Nervig).
In a different study (Wilski), researchers developed a bispecific EGFR × cMET ADC equipped with two distinct payloads, MMAF (a tubulin inhibitor) and SN38 (a topoisomerase I inhibitor), connected through a tri-functional linker. Central to this innovation was BroadPharm's cleavable Azide-PEG8-Val-Cit-PABC-SN38 linker, which enabled precise conjugation of the SN38 payload to the bispecific EGFR×cMET antibody. Subsequently, dual-pay ADCs exhibited superior tumor growth inhibition at lower doses compared to their single-Pay ADC counterparts (Figure 3).
Figure 3: Dual-payload ADC 412a-MMAF+SN38 demonstrated superior tumor growth inhibition in BxPC-3 xenografts at low doses compared to single-payload ADCs, with optimal drug-antibody ratios yielding stable (>2 months at 4°C), high-purity conjugates that effectively overcome resistance mechanisms. Body weight remained stable across dosing groups, confirming tolerability.
The multi-target, dual-payload ADC demonstrated:
BroadPharm is at the forefront of linker technology for next-generation therapeutics, offering a wide selection of ADC linkers that feature:
To further empower pharmaceutical & biotech research, BroadPharm developed a series of proprietary dual payload linkers, which allow researchers to conjugate one single antibody with two distinct payloads in one step chemistry.
In addition to our ADC catalog offerings, BroadPharm provides bioconjugation services and custom synthesis tailored to your project's needs-delivering flexibility and precision from discovery through development.
Nervig, C. S., Rice, M., Marelli, M., Christie, R. J., & Owen, S. C. (2025). Modular synthesis of Anti-HER2 dual-drug antibody-drug conjugates demonstrating improved toxicity. Bioconjugate Chemistry, 36(2), 190-202.
Wilski, N. A., Haytko, P., Zha, Z., Wu, S., Jin, Y., Chen, P., ... & Chiu, M. L. (2025). A Dual-Payload Bispecific ADC Improved Potency and Efficacy over Single-Payload Bispecific ADCs. Pharmaceutics, 17(8), 967.