{"entity":{"id":"idea-alpha-after-adc","kind":"idea","name":"Alpha radioligands after ADC failure","aka":[],"tldr":"When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.","summary":"When ADCs against a surface protein stop working because the payload no longer kills, this idea uses the same protein to deliver radiation instead. Antigen often persists after ADC failure with resistance at the payload level, so a 225Ac- or 177Lu-labelled anti-TROP2 or anti-HER2 antibody would bypass efflux, TOP1 mutations and SLFN11 loss, and crossfire would cover antigen-heterogeneous neighbours. The test is a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer, with antigen PET selection and dosimetry. Speculative in maturity, it complements Payload-class switching as the rule for ADC sequencing and draws on radio-antibody and radio-ADC, targeted alpha therapy and TROP2 PET.","asOf":"2026-09-04","links":[],"tags":[],"related":["idea-payload-switching"],"cancers":["tnbc","breast-hr-positive"],"sections":[],"technologies":["radioimmunotherapy","targeted-alpha-therapy","adc","trop2-pet"],"targets":["trop2","her2","b7h3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-yarden-sliwkowski-erbb-network-nrmcb-2001"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"225Ac- or 177Lu-labelled anti-TROP2 or anti-HER2 antibodies produce responses in patients progressing on TROP2 or HER2 ADCs with retained antigen expression on PET.","rationale":"Radiation cytotoxicity is independent of drug efflux and payload-specific resistance; crossfire covers antigen-heterogeneous neighbours.","test":"Run a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer with antigen PET selection and dosimetry.","maturity":"speculative"},"route":"/ideas/idea-alpha-after-adc/","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":"radioimmunotherapy","kind":"technology","name":"Radio-antibody & radio-ADC","route":"/technologies/radioimmunotherapy/"},{"id":"targeted-alpha-therapy","kind":"technology","name":"Targeted alpha therapy","route":"/technologies/targeted-alpha-therapy/"},{"id":"trop2-pet","kind":"technology","name":"TROP2 PET","route":"/technologies/trop2-pet/"}],"target":[{"id":"b7h3","kind":"target","name":"B7-H3","route":"/targets/b7h3/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"trop2","kind":"target","name":"TROP2","route":"/targets/trop2/"}],"paper":[{"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/"}]}}