# Alpha radioligands after ADC failure

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

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-04
- 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.
- Proposed test: Run a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer with antigen PET selection and dosimetry.
- Maturity: speculative

## 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/), [Radio-antibody & radio-ADC](https://onco.cc/technologies/radioimmunotherapy/), [Targeted alpha therapy](https://onco.cc/technologies/targeted-alpha-therapy/), [TROP2 PET](https://onco.cc/technologies/trop2-pet/)
- targets: [B7-H3](https://onco.cc/targets/b7h3/), [HER2](https://onco.cc/targets/her2/), [TROP2](https://onco.cc/targets/trop2/)
- key papers: [Yarden and Sliwkowski 2001: untangling the ErbB signalling network](https://onco.cc/key-papers/paper-yarden-sliwkowski-erbb-network-nrmcb-2001/)

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