Results of a recent study “validate the therapeutic potential” of bexmarilimab, a Clever-1 targeting antibody currently under evaluation in clinical trials as a part of a combination treatment for myeloid malignancies.
Arno Ylitalo, a doctoral student at the University of Turku in Finland, and senior author Mika Kontro, MD, PhD, of the University of Helsinki, presented the study’s results during the American Association of Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome.
Clever-1—also known as stabilin-1—is expressed by monocytes and immunosuppression macrophages. Bexmarilimab “demonstrates many immunomodulatory effects, along with promising anti-tumor activity against solid tumors in patients with multiple lines of previous treatment,” according to the study’s authors.
The researchers profiled Clever-1 expression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). They also tested the potential of bexmarilimab—alone and in combination with azacitidine and venetoclax—as a growth inhibitor and immunomodulator.
The study’s investigators used AML cell lines (n=11) and frozen mononuclear cells extracted from bone marrow aspirates of patients with AML (n=42) and very high-risk MDS (n=4). They treated the samples with bexmarilimab alone or in combination with azacitidine and venetoclax for 48 hours. The researchers used flow cytometry to detect different cell populations and T-cell activation markers.
They confirmed Clever-1 protein was expressed in AML cell lines and showed bexmarilimab treatment induced metabolic and growth inhibition of KG1 blasts, which have high Clever-1 levels.
In patients with AML, those with French, American, and British (FAB) classification subtype M4/M5 had the highest levels of Clever-1, along with patients classified as FAB subtype M2 “with consequent rapid release,” according to the study’s authors.
Clever-1 expression was negatively correlated with the expression of the human leukocyte antigen (HLA)-DR isotype. Clever-1 expression was also negatively correlated with bone marrow T-cell frequency, which is “in line with the immunosuppressed state associated with high Clever-1,” the study’s authors wrote.
Ex vivo treatment with bexmarilimab in primary AML bone marrow cells led to a “notable increase” of fivefold to tenfold in monocyte HLA-DR in samples with low basal HLA-DR and high Clever-1. Adding azacitidine to bexmarilimab augmented HLA-DR induction by 20% to 110%, with a mean of 44%. FAB subtype M1/M2 showed an increase in activation markers after ex vivo treatment with bexmarilimab in CD8-positive T-cells.
“This project is the first comprehensive investigation of Clever-1 expression in AML and MDS patient [bone marrow] blasts and monocytes,” the study’s authors concluded. “Ex vivo treatment with bexmarilimab, alone or in combination with azacitidine or venetoclax, indicate enhanced antigen presentation capability and immunological activation. “These results validate the therapeutic potential of bexmarilimab in myeloid malignancies. The safety, tolerability, and preliminary efficacy of bexmarilimab is now further investigated in combination with venetoclax and/or azacitidine in a phase I/II clinical trial, BEXMAB.”
Ylitalo A, Aakko S, Kuusanmäki H, et al. Ex vivo immune activation with the macrophage-targeting immunotherapy, anti-Clever-1 antibody bexmarilimab, in acute myeloid leukemia and myelodysplastic syndrome. Abstract #14.Presented at the American Association of Cancer Research Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; January 23-25, 2023; Austin, Texas.