Faron-supported research in Theranostics identifies secreted Clever-1 (sClever-1) as an independent driver of immune evasion in cancer, deepening the understanding of bexmarilimab’s mode of action

Study details how bexmarilimab treatment reduces circulating sClever-1 in patients with cancer, a key factor in T-cell suppression and PD-1 therapy resistance

TURKU, FINLAND – Faron Pharmaceuticals Ltd. (AIM: FARN, First North: FARON), a clinical-stage biopharmaceutical company focused on tackling cancers through novel immunotherapies, announced the publication of a new study in the peer-reviewed journal Theranostics. The research identified a secreted, truncated form of the Clever-1 receptor (sClever-1) as a key immunosuppressive mediator in cancer that impaired T-cell responses and was associated with resistance to anti-programmed cell death protein -1 (PD-1) immunotherapies.

The study, supported by Faron Pharmaceuticals and grants from leading international funding bodies, including Cancer Research UK (CRUK), the NIHR Birmingham Biomedical Research Centre, the Research Council of Finland, and the Sigrid Jusélius Foundation, provided significant new insights into the biology of Clever-1, the target of Faron’s wholly owned, first-in-class immunotherapy asset, bexmarilimab. Clever-1 is an immunosuppressive receptor found on macrophages leading to tumor growth and metastases (i.e. helps cancer evade the immune system).

In this study, researchers analyzed plasma samples from breast cancer patients (n=139) and bexmarilimab-treated clinical trial participants (n=193) as well as healthy donors and discovered that a secreted form of Clever-1 or sClever-1 was significantly enriched in the plasma of cancer patients compared to healthy individuals.

“Our research unveils a previously unrecognized mechanism of immune suppression in cancer, where a secreted form of Clever-1 actively hinders T-cell responses,” said Maija Hollmén, senior author of the study, MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland. “We have shown that sClever-1 operates independently of the cellular receptor and contributes to an immunosuppressive environment. This discovery not only deepens our understanding of cancer immunology but also strongly validates Clever-1 as a critical therapeutic target to overcome immune evasion.”

sClever-1, released by macrophages and endothelial cells, was found to bind to activated T cells, impairing their signaling and promoting the differentiation of suppressive T cells, contributing to tumor immune evasion. Moreover, high sClever-1 levels were associated with resistance to anti-PD-1 therapy.

Importantly, the study demonstrated that bexmarilimab treatment significantly reduced the release of sClever-1 in cancer patients. This reduction in circulating sClever-1 correlated with decreased engagement on T cells, providing a direct mechanistic link to the peripheral T-cell activation previously observed in bexmarilimab-treated patients.

The findings also suggest that high levels of sClever-1 are associated with resistance to anti-PD-1 checkpoint inhibitors, identifying sClever-1 as a potential biomarker to guide immunotherapy strategies. In patient-derived tumor explants, the addition of a recombinant sClever-1 protein led to a significant increase in the secretion of TGF-β, a key immunosuppressive cytokine.

“These unique findings further solidify our conviction in bexmarilimab's unique mechanism of action,” said Petri Bono, Faron’s Chief Medical Officer. “The ability of bexmarilimab to reduce systemic levels of the immunosuppressive sClever-1 provides a clear rationale for its potential to overcome immunotherapy resistance. This adds to the growing body of evidence supporting bexmarilimab’s development as a potential cornerstone of immunotherapy for patients with aggressive cancers. This provides also a very intriguing basis of using soluble Clever-1 to inactivate T-cells in conditions where they are attacking our own body, i.e. in a wide range of auto-immune and inflammatory conditions”

Link to the original article.

About bexmarilimab