ideasIdea
Two-target antibody drugs to close the antigen escape route
If a drug relies on one marker, the tumour can survive by dropping it. A drug that recognises two markers at once makes that escape harder.
Bispecific ADCs binding two tumour antigens can retain binding and internalisation when one antigen is lost, and may improve selectivity where either antigen alone is present on normal tissue. Several bispecific ADCs are in clinical development. The proposal is to test the antigen-escape hypothesis explicitly by comparing a bispecific ADC with its monospecific parent and measuring antigen status at progression.
Hypothesis
Patients treated with a bispecific ADC show a lower rate of antigen-loss-mediated resistance at progression than those treated with the matched monospecific ADC, with comparable toxicity.
Rationale
Dual-antigen targeting reduced escape in CAR-T experience with CD19 and CD22; the mechanism of escape is the same, and ADC engineering can now support two binding arms.
What would test it
Randomised phase 2 with mandatory progression biopsies comparing a bispecific ADC with its parent, with antigen-loss rate as a co-primary endpoint alongside progression-free survival.
Maturity
preclinical evidence
Who has to act
industry
Cost to try
Large (over $50M)
Years to first evidence
6
Bottlenecks it attacks
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
- Tumour heterogeneity and clonal evolution · A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.