Targeting Leukemia Stem Cells: The Efficacy and Safety of MP0533 in AML and MDS Treatment

Acute myeloid leukemia (AML) is a disease where cancer stem cells are resistant to standard treatments, leading to frequent relapses. Innovative treatments like CAR T cells and T cell engagers (TCEs) are being developed to target tumor-associated antigens (TAAs) that are overexpressed on these cancer cells. The idea is to create a TCE that can target multiple TAAs at once, which could lead to a more efficient and precise destruction of AML stem cells and blast cells, with minimal impact on healthy cells. This approach could also tackle the diversity of AML cells by targeting different patterns of TAA expression.

The researchers used a vast library of DARPin molecules to create multi-specific binders capable of targeting multiple TAAs. They developed MP0533, a CD3-engaging DARPin that can simultaneously target CD33, CD123, and CD70. This molecule was designed to have an extended half-life and was tested for its efficacy and safety both in the lab and in animal models.

Tests showed that MP0533 was significantly more potent in killing cancer cells that expressed at least two of the three targeted TAAs compared to cells expressing just one. The molecule was also able to activate and kill AML cells in samples from patients with varying levels of TAA expression.

In addition, MP0533 was able to selectively target leukemia stem cells without significantly affecting healthy stem cells. It also showed a reduced release of cytokines, suggesting a safer profile compared to TCEs that target a single TAA. There was no observed toxicity in cells that express CD123, and no T cell fratricide was seen due to CD70 expression on activated T cells.

In animal models, MP0533 induced T cell infiltration into tumors and showed anti-tumor activity without causing systemic toxicities. The molecule's efficacy and safety were confirmed, and it is suggested that it could offer a more convenient once-weekly intravenous therapy.

The study concludes that MP0533 is a promising multi-specific DARPin molecule with high efficacy and the potential for improved selectivity and safety. A Phase I clinical trial to evaluate its safety and dosage in humans is planned.