# Dual-payload ADCs in first line to prevent resistance

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

## TL;DR

Rather than waiting for resistance to one payload and then switching, give two mechanisms from day one, as HIV therapy does.

## Summary

Rather than waiting for resistance to one payload and then switching, this idea gives two payload mechanisms from day one, as HIV therapy does. A TOP1 plus tubulin or TOP1 plus DNA-crosslinker dual-payload TROP2 or HER2 ADC is expected to outperform a single-payload ADC in first-line metastatic breast cancer at equivalent toxicity, because combination therapy prevents selection of resistant clones and dual-payload ADCs achieve this without doubling antibody dose. ACR335 and the Sutro and Mersana programmes show manufacturability. The test is phase 1 dose-finding then a randomised phase 2 against a single-payload ADC. Speculative in maturity, it addresses the bottlenecks Acquired resistance to every therapy and Too many combinations to test.

## Fields

- Kind: Idea
- Last checked: 2026-09-04
- Hypothesis: A TOP1 + tubulin (or TOP1 + DNA-crosslinker) dual-payload TROP2 or HER2 ADC produces longer PFS in first-line metastatic breast cancer than a single-payload ADC at equivalent toxicity.
- Rationale: Orthogonal resistance mechanisms; ACR335 and Sutro/Mersana programmes demonstrate manufacturability.
- Proposed test: Phase 1 dose-finding then randomised phase 2 vs single-payload ADC; monitor resistance biomarkers at progression.
- Maturity: speculative

## 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

- ideas: [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/)
- cancers: [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Dual-payload ADC](https://onco.cc/technologies/dual-payload-adc/), [Site-specific conjugation & linker chemistry](https://onco.cc/technologies/site-specific-conjugation/)
- targets: [HER2](https://onco.cc/targets/her2/), [TROP2](https://onco.cc/targets/trop2/)
- 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/), [Yarden and Sliwkowski 2001: untangling the ErbB signalling network](https://onco.cc/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/)
- 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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