ideasIdea
Use antibodies to deliver protein-destroying drugs into the right cells
Drugs that destroy proteins can hit healthy cells too. Attaching them to an antibody that only docks onto tumour cells would keep them where they are needed.
Degrader-antibody conjugates replace cytotoxic payloads with a targeted protein degrader, so the payload is only released inside antigen-positive cells. Early programmes target BRD4 and other essential proteins that are too toxic to degrade systemically. This is a route to attack undruggable but essential nuclear proteins that would otherwise be intolerable.
Hypothesis
A degrader-antibody conjugate produces antigen-dependent degradation of an essential nuclear target in vivo with a therapeutic window at least five-fold wider than the free degrader.
Rationale
ADC linker and payload technology is mature; the constraint on degrading essential proteins is normal-tissue exposure, exactly the problem conjugation solves. Bystander effects may also address antigen heterogeneity.
What would test it
Compare matched free degrader and conjugate in an antigen-positive versus antigen-negative xenograft pair, with tumour and normal-tissue degradation pharmacodynamics and marrow toxicity as endpoints.
Maturity
preclinical evidence
Who has to act
industry
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- Toxicity and quality of life are undervalued · Trials measure how long people live, not how they live. Side-effects are under-reported and under-treated.