The effect of bexmarilimab on acute myeloid leukemia cells

Abstract

Acute myeloid leukemia (AML) is a hematological disease, caused by uncontrollable differentiation of immature hematopoietic cells. AML is treated with intensive chemotherapy or with targeted treatments, but despite the advantages of the treatment options, the relapse rate in AML remains high. Common lymphatic endothelial and vascular endothelial receptor 1 (Clever-1) is a multifunctional protein found in immunosuppressive macrophages, for example, and interestingly also in the cells of myeloid malignancies. Clever-1 is an important regulator of tumor growth and therefore, anti-Clever-1-antibody bexmarilimab is studied in a phase I/II clinical trial for AML treatment (BEXMAB; NCT05428969). In this project, we studied the direct anti-leukemic effect of bexmarilimab on AML cells with a set of commercial AML cell lines, MOLM-13, MV4-11, HL-60, and Kasumi-1. We studied the Clever-1 expression of these cell lines with flow cytometry and found that these cell lines express Clever-1, but the protein is mainly intracellular. In flow cytometry-based proliferation assay bexmarilimab did not impair the proliferation of any of the cell lines tested even when combined with azacitidine. However, bulk RNA sequencing revealed that bexmarilimab regulates genes important for mitochondrial respiration. Thus, we performed Seahorse assays and showed that bexmarilimab decreases the spare respiratory capacity in MOLM-13 and HL-60 cells, indicating impairment in oxidative phosphorylation. These results provide important information about bexmarilimab’s mode of action, which is related to mitochondrial metabolism. This is encouraging because AML cells are known to be dependent on oxidative phosphorylation for their energy supply.