What Are Dual Payload Linkers?

Dual-Payload ADC has emerged as a powerful strategy for oncology study, by attaching two distinct cytotoxic payloads to an antibody. Dual-payload ADCs can target two or more biological pathways or multiple nodes within the same pathway, maximizing treatment efficacy through synergistic effects and mitigating drug resistance (Beck).

Key scientific rationale:

• Overcome resistance and heterogeneity: two mechanisms of action can shut down parallel survival pathways and broaden tumor cell coverage (Mullard).
• Additive/synergistic efficacy at lower doses: multiple preclinical studies report stronger tumor growth inhibition and activity against hard-to-kill and even non-dividing tumor cells compared with single-payload ADCs (Mullard).
• Linker design is pivotal: cleavable dipeptide spacers such as Val-Cit with a self-immolative PABC unit are widely used to ensure stability in circulation and lysosomal release after cathepsin cleavage (Bargh).

Traditionally, dual-payload ADCs require multi-step conjugation, attaching different payloads step by step, adding complexity, time, and variability. In contrast, BroadPharm developed a class of dual-payload linkers, which enables true 1-step conjugation.

BroadPharm's Dual Payload Linkers are a class of proprietary linker molecules designed to carry two distinct therapeutic payloads in one molecule. This innovative design enables researchers to simultaneously conjugate two distinct payloads to antibodies in one, streamlined step, ensuring controlled, site-specific attachment, while dramatically simplifying manufacturing workflows and enhancing conjugation homogeneity.

Traditional dual-payload ADC development has long been hampered by complex, multi-step conjugation processes that sequentially attach different payloads, introducing significant variability, extended timelines, and complexity. BroadPharm has transformed this paradigm with our breakthrough class of dual-payload linkers that enable true single-step conjugation.

Examples of these new payload-linkers include:

• N-(Mal-C6-carbonyl)-N-bis(PEG8-Val-Cit-PAB-MMAE)

  

• N-(Mal)-N-(PEG8-Val-Cit-PAB-MMAE)-N-(PEG8-Val-Cit-PAB-Exatecan)

  

These linkers provide:

• Precise drug-to-antibody ratios for reproducibility.
• Plasma stability with efficient intracellular cleavage.
• Synergistic payload activity to enhance potency while minimizing off-target toxicity.

BroadPharm also offers conjugation-ready branched PEG linkers for attaching 2+ payloads simultaneously, giving researchers versatile, modular tools to design complex ADC architectures that optimize therapeutic index and broaden clinical possibilities.

BroadPharm: Your Trusted Partner in ADC

As a worldwide leading manufacturer and supplier of ADC linker and biochemical solutions, BroadPharm is dedicated to providing researchers with a wide variety of ADC linkers, ADC payloads, payload-linkers, dual-payload linkers, PEG linkers, and cleavable peptide linkers that drive innovation in ADC development. Our extensive portfolio ensures access to high-quality, ready-to-use payload linkers, backed by unmatched expertise and customer support.

In addition to our catalog offerings, BroadPharm provides bioconjugation services and custom synthesis tailored to your project's needs-delivering flexibility and precision from discovery through development.

References

Beck A, et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nature Reviews Drug Discovery (2017).

Bargh JD, et al. Cleavable linkers in antibody-drug conjugates. Chemical Society Reviews (2019).

Buecheler JW, et al. Development of antibody-drug conjugates: linker design and conjugation technology. mAbs (2020).

Mullard A. The ADC renaissance. Nature Reviews Drug Discovery (2023).

Recent dual-payload ADC overviews and preclinical datasets summarized in peer-reviewed literature and reviews above.