Oncology – novel mechanisms

Need

CD3-targeted T-cell engagement has been shown to be a very potent anti-tumor approach but after initial success, other types of therapies have struggled with toxicity, sub-optimal specificity and other challenges. These candidates typically target a single type of tumor-associated antigen (TAA). Most TAAs are also present on many healthy cells, but at a lower concentration, and as such it is difficult to select any single target to differentiate between cancer cells and healthy cells.

This approach needs substantial refinement to unlock the full potential of CD3-targeted T-cell attack.

Rationale

We have made significant progress to integrate the CD3-targeting approach to T-cell engagement to overcome these challenges and have developed several different DARPins that target CD3, which we are evaluating for prioritization.

Solution

To overcome the limitations of other candidates and increase specificity, our multi-domain T-cell engager therapeutic candidates target two or three different TAAs, with optimized affinity for their targets. We believe this will deliver better specificity for the tumor, reducing off-tumor effects, allowing for higher dose levels and enhanced efficacy.

We have also developed two further capabilities for added control over T-cell engagement: time-controlled activation of the CD3 effector function to further minimize the risk of side effects and provide sustained activity; and spatial control to ensure activation only around a tumor through use of a CD3 Prodrug DARPin. This blocker prevents T-cell recruitment in its non-cleaved state, but is designed to allow activation of the CD3 binder in the tumor microenvironment upon linker cleavage by tumor-associated proteases.