This is a story about how smart engineering and protocol innovation are reshaping T cell engager (TCE) – and potentially also antibody-drug conjugate (ADC) development.

To mask or not?

TCEs promised to bring the power of immunotherapy to solid tumours, but the story hasn’t been straightforward so far.

Despite compelling biology and mechanistic rationale, many promising agents have repeatedly stumbled over the same obstacle: a painfully narrow therapeutic window.

The culprit?

On-target/off-tumour effects triggering severe cytokine release and limiting dosing before efficacy can be fully realised. What if the solution wasn’t abandoning these targets altogether, but instead rethinking how we approach them?

Recent innovations in the HER2 space reveal three distinct strategies – clever sequencing protocols, avidity-driven engineering, and sophisticated masking approaches – which may finally crack this stubborn problem. The implications extend far beyond HER2 and could reshape development across multiple modalities, including ADCs.

For biotech strategists, the lessons here also challenge conventional portfolio wisdom about ‘over crowded targets’ and offer a roadmap for rescuing programs once deemed too toxic to pursue…

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