The Therapeutic Index Dilemma
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…
To continue reading our latest highlights on oncology new product development including commentary and analysis BSB subscribers can log-in or you can click to access the content.
This content is restricted to subscribers
In a dramatic scientific plot twist, multiple companies are now racing to crack the code of the common Y220C mutation, with several novel approaches coming through. These range from non-covalent and covalent protein reactivators or stabilisers to heterobifunctional glues and even mRNA approaches.
At AACR 2025, an innovative US-based biotech revealed an elegant solution to one such notorious target: a molecular glue capable of hijacking natural cellular machinery to overcome what many considered impossible.
Last week when Summit Therapeutics announced the NMPA had approved their PD1xVEGF bispecific antibody ivonescimab, which showed “a clinically meaningful, positive trend” against pembrolizumab in a Chinese lung cancer trial, investors promptly responded by selling off the stock along with their German rival, BioNTech’s.
This regulatory sea change could dramatically compress timelines, reduce costs, and potentially improve predictive accuracy for human outcomes.
We highlight notable agents across different categories, track shifts in the competitive landscape, and consider what these selections might signal about the direction of oncology drug development.
