Targeting Monocytic AML with NGM936: Preclinical Insights into a Novel T Cell Engager's Efficacy and Specificity

Acute myeloid leukemia (AML) with monocytic differentiation is a subtype that makes up 25-30% of AML cases and is associated with a poor prognosis, characterized by a low five-year survival rate and a higher risk of relapse. There is a challenge in treating this type due to the absence of highly specific target antigens for AML cells that do not affect healthy bone marrow cells. However, ILT3, a marker specific to monocytic AML, presents a potential target for treatment.

The study introduces NGM936, a T cell engager designed to target ILT3. This bispecific antibody is built on a modified human IgG1 backbone and features a unique design for assembly. It has shown high affinity for human ILT3 and does not react with related family members.

Through extensive testing with over 30 different ILT3 x CD3 engagers, NGM936 was selected for its effectiveness in inducing T cell-mediated cytotoxicity against AML cells with ILT3 expression while causing minimal cytokine release. It was found to be more effective than a vibecotamab biosimilar in terms of cytokine induction. NGM936 was capable of inducing cytotoxicity using both expanded and naive T cells and was effective against a wide range of ILT3 expression levels on tumor cells. Importantly, it did not affect CD34+ stem cells or non-monocytic immune cells, aligning with the absence of ILT3 on these cells.

In primary bone marrow cultures from M5 AML patients, NGM936 led to a reduction in AML cells and an increase in T cell proliferation and activation. Additionally, in a xenograft model involving NSG mice, NGM936 resulted in a dose-dependent reduction of circulating tumor cells.

NGM936 emerges as a promising therapeutic approach for monocytic AML, offering the possibility of targeting and eliminating leukemia cells while reducing the toxicity associated with affecting healthy bone marrow cells.