ideasIdea
Alpha radioligands after ADC failure
When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.
Antigen often persists after ADC failure; resistance is at the payload level. A radioconjugate against the same antigen (TROP2, HER2, B7-H3, Nectin-4) would bypass efflux, TOP1 mutations, and SLFN11 loss.
Confidence
10%–30%likelyOnCo editors (initial estimate), 2026-09-07 · No radioconjugate against TROP2 or HER2 is in the clinic yet.
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.
What would test it
Run a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer with antigen PET selection and dosimetry.
Maturity
speculative