Pipeline
Our DARPin platform has vast applicability across a range of diseases. Explore our pipeline:
MP0712 / DLL3-Radio-DARPin Therapy: SCLC and NETs
Molecular Partners has developed an in-house Radio-DARPin Therapy (RDT) platform that represents a unique and innovative delivery system for effective and selective delivery of radioactive payloads to solid tumors. Radioligand therapies have proven potential but have technological limitations that DARPins may address. DARPins have great intrinsic properties as vector – such as small size, high affinity and specificity – to enable robust, tumor-specific delivery of therapeutic radionuclides. The DARPin scaffold is highly stable and customizable allowing a range of additional features that can be tuned to an indication, a target, and radioisotope. Ultimately this may enable more effective treatment of small or hard-to-reach tumors.
In January 2024, Molecular Partners entered into a co-development agreement with Orano Med, a pioneer in targeted alpha therapy, to develop novel RDTs that use Orano Med’s 212Pb radioisotope as a payload to selectively kill cancer cells. Through the collaboration, the companies will share costs for preclinical and clinical development for four programs, the first of which is MP0712 (DLL3).
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.
Radio-DARPin Therapy: Solid Tumors (In-house Programs)
Molecular Partners has developed an in-house Radio-DARPin Therapy (RDT) Platform with a unique and innovative delivery system for radioactive payloads to solid tumors.
Need
Radiation therapies are a well-validated approach to treating cancer. However, the treatment often also affects healthy cells, resulting in harmful side effects. This limits the amount of radiation patients can receive, which can leave hard-to-reach tumor lesions untreated. This encourages relapse and ultimately limits therapeutic potential.
Rationale
The unique nature of DARPins as an engineered protein drug class may allow Molecular Partners to overcome the limitations of other radioligand therapies. Radio-DARPin Therapies are extremely targeted, specifically damaging tumor cells over healthy cells. The DARPin scaffold is highly customizable allowing a range of additional features tuned to an indication. Ultimately this may enable more effective treatment of small or hard-to-reach tumors.
Solution
Preclinical data shows that Molecular Partners’ proprietary Radio-DARPin Therapy Platform can deliver high amount of radioactivity to tumors without accumulating in other tissues. Further data shows that Molecular Partners has been able to engineer the surface of RDT candidates to dramatically reduce accumulation in the kidney which is a historical challenge for small protein-based delivery vectors. In preclinical models, this surface engineering did not affect tumor uptake or uptake in other healthy organs and combination with another kidney reduction strategy provided a cumulative benefit.
Radio-DARPin Therapy Platform: Solid Tumors (Partnered Programs)
Molecular Partners has developed an in-house Radio-DARPin Therapy (RDT) Platform with a unique and innovative delivery system for radioactive payloads to solid tumors. In 2021, the Company established a collaboration with Novartis in the form of a license agreement to develop, manufacture and commercialize Radio-DARPin Therapies for cancer.
Need
Radiation therapies are a well-validated approach to treating cancer. However, the treatment often also affects healthy cells, resulting in harmful side effects. This limits the amount of radiation patients can receive, which can leave hard-to-reach tumor lesions untreated. This encourages relapse and ultimately limits therapeutic potential.
Rationale
The unique nature of DARPins as an engineered protein drug class may allow Molecular Partners to overcome the limitations of other radioligand therapies. Radio-DARPin Therapies are extremely targeted, specifically damaging tumor cells over healthy cells. The DARPin scaffold is highly customizable allowing a range of additional features tuned to an indication. Ultimately this may enable more effective treatment of small or hard-to-reach tumors.
Solution
Preclinical data shows that Molecular Partners’ proprietary Radio-DARPin Therapy Platform can deliver high amount of radioactivity to tumors without accumulating in other tissues. Further data shows that Molecular Partners has been able to engineer the surface of RDT candidates to dramatically reduce accumulation in the kidney which is a historical challenge for small protein-based delivery vectors. In preclinical models, this surface engineering did not affect tumor uptake or uptake in other healthy organs and combination with another kidney reduction strategy provided a cumulative benefit.
MP0533 / CD33 x CD123 x CD70 x CD3: r/r AML and AML/MDS
MP0533 is a novel tetra-specific DARPin therapy in clinical development for patients with acute myeloid leukemia (AML). It uses avidity-driven targeting to preferentially bind to AML cells and kills them through activation of T cells.
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.
Mechanism of Action
MP0621 / cKIT x CD16a x CD47 Switch-DARPin
The multispecific cKIT x CD16a x CD47 Switch-DARPin is the first program of the company’s Switch-DARPin platform for targeted and conditional immune cell activation, designed as a next-generation conditioning regimen for hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML) and beyond.
- cKIT is a highly attractive target to eliminate hematopoietic stem cells (HSCs) – and leukemia stem cells (LSCs) – as it is critical for stem cell maintenance and renewal.
- The CD16a DARPin allows engaging NK cells and macrophages to selectively kill HSCs.
- Conditional blocking of the “don’t eat me” signal (CD47) only on HSCs via a Switch-DARPin allows leveraging the power of CD47 inhibition without its associated toxicity.
Switch-DARPin Platform: Next-Gen Immune Cell Engagers
Molecular Partners’ Switch-DARPin platform provides a logic-gated “on/off” function (the “Switch”) to multispecific DARPin candidates, leading to immune activation only in the presence of defined antigens. This novel and highly precise approach enables targeted and conditional activation of T cells at the right time and place.
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).
Mechanism of Action
MP0317 / FAP x CD40: Advanced Solid Tumors
MP0317 is a CD40 agonist designed to activate immune cells specifically within the tumor microenvironment by anchoring to fibroblast activation protein (FAP). This mechanism of action is proposed to enable immune activation directly in the tumor with fewer systemic side effects in patients.
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.
Mechanism of Action
Ensovibep / Sars-Cov-2: COVID
Ensovibep is a COVID-19 antiviral therapeutic candidate designed specifically to inactivate SARS-CoV-2 – the virus that causes COVID-19 – with extremely high potency that is preserved against novel variants. In January 2022, we announced positive topline results from our Phase 2 global clinical study of ensovibep in acute COVID-19 ambulatory patients showing approximately 80 percent reduction of the of combined risk of hospitalization, emergency room visits, or death compared to placebo, regardless of vaccination status. It was shown to be safe and well-tolerated. Comprehensive in vitro studies of ensovibep demonstrate its high inhibitory potency against all COVID-19 variants of concern, including Omicron, as of December 2021. Novartis has informed Molecular Partners of its intent to in-license ensovibep and is expected to lead late-stage development and commercialization.
Ensovibep offers a differentiated approach to treating COVID-19 through a single molecule that can target up to three parts of the SARS-CoV-2 virus simultaneously to neutralize the virus through cooperative binding. This offers potentially broader efficacy and reduced potential for the development of viral drug resistance. All DARPins are produced through a rapid, high-yield microbial fermentation process.
MP0420
Need
COVID-19 represents the biggest disease burden in the world today through its impact on healthcare, society and economies. A multi-solution strategy is needed to combat the pandemic and the need for antiviral treatments to complement global vaccination efforts has never been greater. As disease transmission continues through pockets of unvaccinated populations, in patients with compromised immune systems and co-morbidities, and as variants continue to emerge, millions of patients around the world are in need of differentiated therapies that are specifically designed to combat COVID-19 in all its forms.
Rationale
The DARPin platform is designed to be used to rapidly generate diverse, multifunctional drug candidates, capable of binding to multiple targets at once. As a tri-specific candidate with cooperative binding, ensovibep’s unique pan-variant design has allowed it to retain full potency against all known variants of concern including the Omicron variant in comprehensive preclinical studies conducted to-date.
Solution
Ensovibep is a unique tri-specific candidate designed to preserve potency against viral variance. It exhibits among the most potent viral inhibition against all variants of concern reported to date. In the EMPATHY Phase 2 global clinical trial, ensovibep demonstrated approximately an 80 percent reduction of combined risk of hospitalization, emergency room visits or death in non-hospitalized patients compared to placebo regardless of vaccination status. It was shown to be safe and well-tolerated. If approved or authorized, ensovibep will be the first multi-specific antiviral molecule for the treatment of COVID-19.
Mechanism of Action
*The co-development agreement with Orano Med includes four programs, including MP0712 (DLL3).