# Dual-payload ADC

Source: https://onco.cc/technologies/dual-payload-adc/  
OnCo record `dual-payload-adc` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A dual-payload ADC is an ADC carrying two different poisons at once, so the tumour cannot escape by becoming resistant to one.

## Summary

Programs from Sutro, Mersana, Tavotek/Adcoris (ACR335, TOP1 inhibitor + non-TOP1/non-tubulin, DAR 4+4, phase 1 in 2026), and others place two payloads with distinct mechanisms on one antibody. Rationale: TOP1-payload cross-resistance after T-DXd, sacituzumab, or Dato-DXd. Also 'dual-mechanism' ADCs pairing a cytotoxic with an immune agonist.

## Fields

- Kind: Technology
- Status: phase-1
- Last checked: 2026-09-04
- Tags: frontier
- Principle: Orthogonal site-specific conjugation chemistries attach two payload classes at defined positions.
- Generation: 4th (next-gen)
- Strengths: Delays resistance; Combination therapy without additive antibody dose
- Limitations: Manufacturing; Two toxicity profiles in one molecule

## Sources

- Yamazaki et al., Antibody-drug conjugates with dual payloads for combating breast tumour heterogeneity and drug resistance (Nature Communications 2021): https://doi.org/10.1038/s41467-021-23793-7

## Connected records

- fronts: [Antibody-Drug Conjugates](https://onco.cc/fronts/adcs/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Site-specific conjugation & linker chemistry](https://onco.cc/technologies/site-specific-conjugation/)
- companies: [Callio Therapeutics](https://onco.cc/companies/callio-therapeutics/), [Debiopharm](https://onco.cc/companies/debiopharm/), [Sutro Biopharma](https://onco.cc/companies/sutro-biopharma/)
- key papers: [Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance](https://onco.cc/key-papers/paper-yamazaki-nat-commun/)
- cancers: [Metastatic triple-negative breast cancer](https://onco.cc/cancers/tnbc-metastatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- roadmaps: [ADC roadmap: from Mylotarg to bispecific and dual-payload ADCs](https://onco.cc/roadmaps/adc-generations/), [TNBC roadmap: from 'nothing to target' to ADC + immunotherapy first line](https://onco.cc/roadmaps/tnbc-history/), [TROP2 ADC roadmap: sacituzumab govitecan → Dato-DXd → sac-TMT → bispecifics and PET](https://onco.cc/roadmaps/trop2-adc-roadmap/)
- ideas: [Dual-payload ADCs in first line to prevent resistance](https://onco.cc/ideas/idea-dual-payload-first/), [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/)

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