{"entity":{"id":"idea-dual-payload-first","kind":"idea","name":"Dual-payload ADCs in first line to prevent resistance","aka":[],"tldr":"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.","asOf":"2026-09-04","links":[{"label":"Yamazaki et al., Antibody-drug conjugates with dual payloads for combating breast tumour heterogeneity and drug resistance (Nature Communications 2021)","url":"https://doi.org/10.1038/s41467-021-23793-7"}],"tags":[],"related":["idea-payload-switching"],"cancers":["tnbc","breast-hr-positive"],"sections":[],"technologies":["dual-payload-adc","adc","site-specific-conjugation"],"targets":["trop2","her2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-yarden-sliwkowski-erbb-network-nrmcb-2001","paper-yamazaki-nat-commun"],"journals":[],"dependsOn":[],"notes":[],"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.","test":"Phase 1 dose-finding then randomised phase 2 vs single-payload ADC; monitor resistance biomarkers at progression.","maturity":"speculative"},"route":"/ideas/idea-dual-payload-first/","neighbours":{"idea":[{"id":"idea-payload-switching","kind":"idea","name":"Payload-class switching as the rule for ADC sequencing","route":"/ideas/idea-payload-switching/"}],"cancer":[{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"dual-payload-adc","kind":"technology","name":"Dual-payload ADC","route":"/technologies/dual-payload-adc/"},{"id":"site-specific-conjugation","kind":"technology","name":"Site-specific conjugation & linker chemistry","route":"/technologies/site-specific-conjugation/"}],"target":[{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"}],"paper":[{"id":"paper-yamazaki-nat-commun","kind":"paper","name":"Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance","route":"/key-papers/paper-yamazaki-nat-commun/"},{"id":"paper-yarden-sliwkowski-erbb-network-nrmcb-2001","kind":"paper","name":"Yarden and Sliwkowski 2001: untangling the ErbB signalling network","route":"/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"}]}}