What Are Dual-Payload ADC Linkers?

Dual-payload ADC linkers are a class of advanced payload-linker molecules with two payloads—either identical or distinct—attached via a single linker. By conjugating an antibody with a linker carrying two distinct payloads, this strategy can enhance therapeutic efficacy, reduce drug resistance, and improve tumor targeting in antibody-drug conjugates (ADCs).

Instead of conjugating two distinct payloads step by step, dual-payload linkers enable the synthesis of dual-payload ADCs through a streamlined one-step conjugation process.

Key Scientific Rationale:

• Overcome resistance and tumor heterogeneity: dual mechanisms of action can simultaneously disrupt parallel survival pathways, improving coverage across diverse tumor cell populations.^1-3
• Enhanced efficacy at lower doses: preclinical studies demonstrate stronger tumor growth inhibition and activity against difficult-to-treat—even non-dividing—cell compared to single-payload ADCs.^1-3
• Linker design is pivotal: integration of cleavable dipeptides (e.g., Val-Cit) with self-immolative PABC spacers in dual-payload linkers enables high stability in circulation and efficient payload release upon lysosomal enzyme cleavage.^1,2

The development of dual-payload ADCs typically involves a multi-step conjugation process in which each payload is attached sequentially. This approach increases manufacturing complexity, extends processing time, and introduces greater product variability. To address these challenges, BroadPharm has developed proprietary dual-payload linkers that enable true one-step conjugation, allowing two distinct payloads to be simultaneously conjugated to an antibody in a single streamlined process.

This innovative approach supports controlled, site-specific conjugation, enhances product homogeneity, and simplifies manufacturing workflows, enabling more efficient, reproducible, and scalable ADC development.^2,4

Examples of these dual-payload linkers include:

• Dual-payload ADC linkers with two distinct payloads
• N-(Azido-PEG4)-N-(PEG4-Val-Cit-PAB-MMAE)-N-(PEG4-Val-Cit-PAB-Exatecan)

  

• N-(Azido-PEG4)-N-(PEG4-Val-Cit-PAB-MMAE)-N-(PEG4-GGFG-Dxd)

  

• Dual-payload ADC linkers with two identical payloads
• N-(Azido-PEG4)-N-bis(PEG4-Val-Cit-PAB-MMAE)

  

These linkers provide:

• Precise and controlled drug-to-antibody ratios (DAR) for improved reproducibility and consistency.^2,4
• Excellent plasma stability combined with efficient intracellular payload release.^1,2
• Synergistic dual-payload activity designed to enhance therapeutic potency while minimizing off-target toxicity.^1,3

BroadPharm also offers conjugation-ready branched PEG linkers designed for the simultaneous attachment of two or more payloads, providing researchers with versatile and modular tools for constructing complex ADC architectures. These advanced linker solutions help optimize therapeutic index while expanding the possibilities for next-generation ADC development.

BroadPharm: Your Trusted Partner in ADC Innovation

As a worldwide leading manufacturer and supplier of ADC linkers and biochemical solutions, BroadPharm is committed to supporting innovation in antibody-drug conjugate research and development. Our extensive portfolio includes high-quality ADC linkers, ADC payloads, dual-payload linkers, PEG linkers, and cleavable peptide linkers designed to accelerate discovery and streamline development workflows.

Beyond our catalog products, BroadPharm also provides comprehensive bioconjugation services and custom synthesis solutions tailored to your project’s specific requirements. We deliver the flexibility, precision, and technical expertise you need from early discovery through advanced development stages.

References

1. Su, Z.; Xiao, D.; Xie, F.; Liu, L.; Wang, Y.; Fan, S.; Zhou, X.; Li, S. Antibody–Drug Conjugates: Recent Advances in Linker Chemistry. Acta Pharm. Sin. B 2021, 11 (12), 3889–3907. https://doi.org/10.1016/j.apsb.2021.03.042
2. McCombs, J. R.; Owen, S. C. Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry. AAPS J. 2015, 17 (2), 339–351. https://doi.org/10.1208/s12248-014-9710-8
3. Wang, R.; Zhao, R.; Gao, Y.; Li, Y. Antibody–Drug Conjugates (ADCs): Current and Future Perspectives. J. Hematol. Oncol. 2025, 18, 41. https://doi.org/10.1186/s13045-025-01704-3
4. Wu, G.; Zhang, Y.; Chen, L.; Xu, H. Antibody–Drug Conjugates (ADCs): A Review of Structural Design and Emerging Technologies. Molecules 2026, 31 (7), 1180. https://doi.org/10.3390/molecules31071180