AML / CD3 x CD33 x CD70 x CD123

Molecular Partners’ T-cell engager (TCE) programs leverage 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. Molecular Partners first TCE candidate is, being developed as a unique multi-specific treatment for acute myeloid leukemia (AML). Its component DARPin® modules are designed to deliver a deeper attack on a broader range of highly variable tumor cells while lowering the risk to healthy cells. This may allow Molecular Partners to significantly shift the therapeutic window for TCE use in AML, and avoid the trade-off between effective dosage and safety that other therapeutic developers have had to make.

Need

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 AML cells, particularly the population that initiate and sustain leukemia: leukemic stem cells (LSCs). CD3 represents a powerful tool in the fight against AML but development of CD3-based TCEs has consistently failed to deliver on its promise due to toxicities resulting from CRS, damage to healthy cells or an inability to overcome specific tumor defenses.

Rationale

The ability of multi-domain DARPin® candidates to integrate several capabilities has allowed Molecular Partners to deliver a finely controlled mechanism for CD3-based immune activation in AML. Through highly individualized binding specificity of each DARPin®, we can elicit a specific, and conditional immune activation. Our platform allows us to limit the ability of the CD3 DARPin® module to ‘activate’ until a minimum of two of the target proteins, CD70, CD123 and CD33, are bound. Because of this, our candidate can better target all of the sick cells, , and avoid healthy ones..

CD70 has been identified as a prominent target that is more strongly expressed on LSCs. CD123 and CD33 are mainly expressed on the cells that make up the ‘bulk’ of the cancer cell population. Their presence on healthy cell types has led to dose-limiting toxicities in other, non-DARPin®, candidates, but in combination with a CD70 binder on a DARPin® candidate, the primary intended effect of binding CD33 and CD123 is to further focus candidate binding on tumor cells and reduce damage to healthy cells.

Solution

Our candidate incorporates this three-target combination. Preclinical studies have strongly supported the intended mode of action, including an avidity ‘ramp up’ effect, whereby the overall binding to a target cell is much stronger when more than two target proteins are present. This further reduces the risk to healthy cells, which very rarely have even two of the antigens in question.