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

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 mesothelin (MSLN). This glycoprotein is overexpressed across several cancers with high unmet need, including ovarian cancer (80%), and largely absent from healthy tissues. Molecular Partners have developed Radio-DARPins to selectively bind to MSLN while avoiding impact from high shedding, a challenge for previous development of therapeutics against MSLN.

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.

Problem

AML represents a highly resistant type of cancer with urgent need for effective therapies. Each year about 20,000 people in the U.S. are diagnosed with AML. Nearly half of these patients will die within two years of diagnosis due to the inability of current treatments to completely eradicate all AML cells, including blasts but also and particularly the population that initiate and sustain leukemia: leukemic stem cells (LSCs). Development of T cell engagers (TCEs) for AML has consistently failed to deliver on their promise due to severe toxicities resulting from cytokine release syndrome (CRS), damage to healthy cells or an inability to overcome specific tumor defenses.

Solution

MP0533 leverages the cell surface protein CD3 as a powerful immune activator, complemented by novel control mechanisms designed to help direct CD3-mediated cytotoxicity with heightened precision. In addition to CD3, MP0533 is designed to simultaneously target the antigens CD33, CD123 and CD70. AML cells commonly co-express at least two of the three target antigens whereas most healthy cells only express one or none. MP0533 binds with increasing avidity as the number of its target antigens present increases, thereby dramatically favoring binding to AML cells over healthy cells. This unique avidity-driven mode of action is designed to enable T cell-mediated killing of AML cells while preserving a therapeutic window that minimizes damage to healthy cells. Our preclinical studies strongly support the intended mode of action.

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.

T cell engagers (TCE) are a powerful class of immuno-oncology therapies but have faced a range of challenges such as high toxicity and limited specificity, particularly against solid tumors.

Solution

By employing a multi-specific Switch-DARPin approach, Molecular Partners aims to tackle current limitations of TCEs.

Masking of the CD3 binder prevents T cell activation in the absence of tumor antigens, potentially allowing for “silent” TCEs outside of tumors.

In addition, providing a co-stimulatory signal upon “switching on” of the DARPin candidate enables the safe use of potent co-stimulatory signals in TCEs for sustained and potent T cell responses.

The CD3 Switch-DARPin approach may enhance the efficacy of TCEs in a safe and targeted manner. It may also reduce the risk of a side effect associated with prior TCEs, a systemic inflammatory effect known as cytokine release syndrome (CRS).

Problem

First-generation immune agonist antibodies have been limited by severe systemic side effects in patients and therefore drug candidates have struggled to achieve a therapeutic window with an acceptable safety and favorable activity profile. Their potential for delivering anti-cancer immune attack thus remains underexploited.

Solution

MP0317 targets FAP – which is found at high density in the tumor stroma – and the immunostimulatory protein CD40 to enable tumor-localized immune activation. Through this proposed mechanism of action, MP0317 is designed to activate immune cells specifically within the tumor microenvironment, potentially delivering greater activity with fewer side effects compared to systemic CD40-targeting therapies. Our preclinical and initial clinical Phase 1 trial data confirm this mechanism of action.