Problem

Radiation therapies are a well-validated approach to treating cancer. However, the treatment often also affects healthy tissues, resulting in harmful side effects. This limits the amount of radiation patients can receive, which can leave hard-to-reach tumor lesions untreated. This leads to relapse and ultimately limits therapeutic potential. Various vector technologies have been investigated, with small protein-based vectors considered attractive but with certain challenges including significant accumulation in kidneys and resulting toxicity.

Solution

We have built on the DARPins’ innate advantages to engineer and advance our RDT platform. We have designed our RDT candidates to minimize kidney retention, one of the key challenges of the broader radiotherapy class, through our use of Stealth-DARPins — DARPins whose backbone is surface engineered to be excreted by kidneys in urine instead of being re-absorbed. Building on these results, we established a half-life engineering toolbox which leads to increased tumor uptake across multiple tumor targets.

Preclinical data shows that the RDT platform can deliver high amounts of radioactivity to tumors without accumulating in other tissues, and that RDT candidates can be engineered to dramatically reduce accumulation in the kidney.

Molecular Partners and Orano Med are co-developing a ²¹²Pb-based Radio-DARPin Therapy targeting the protein DLL3. Expression of DLL3 is low in healthy tissues but significantly increased in certain tumor types, providing an opportunity for selective targeting.

Problem

Activating the immune system to eliminate cancer cells is a highly investigated therapeutic approach with clinical validation. However, the full potential of such therapeutics is often limited by off-target and systemic side-effects. There is therefore a need for technologies that precisely engage immune cells and activate them in a focused setting, without harming healthy “bystander” cells.

Solution

As DARPin pioneers, we developed Switch-DARPins as a ‘logic-gated’ approach to enable targeted and conditional activation of immune cells. The precision of this approach has the potential to unlock previously challenging targets and enable safer use of powerful immune activators to treat cancer. This could have immediate applications in indications  where the lack of tumor-exclusive (or “clean”) targets and frequent T cell dysfunction limit the efficacy of approved T cell engagers. The potential of Switch-DARPins also extends to indications beyond cancer: e.g. for patients with autoimmune disease, Switch-DARPin-based approaches could provide a potent  alternative to CAR T cells for B and plasma cell elimination and immune system reset, with fewer side effects.