Clever-1

In recent years, increasing attention has been paid to the contribution of scavenger receptors in regulating macrophage responses to different stimuli. Clever-1 (also known as Stabilin-1) is a multifunctional molecule conferring scavenging ability on a subset of anti-inflammatory macrophages. In these cells, it is involved in receptor-mediated endocytosis and recycling, intracellular sorting, and transcytosis of altered and normal self-components. More recently, we have found that the progression of melanoma tumor growth and metastasis is attenuated in Stab1-/- (Clever-1 knock out) mice, and in mice treated with anti-Clever-1 therapy. Clever-1–positive macrophages are found in human cancers and high number of Clever-1–positive macrophages is associated with shorter disease-free survival in colorectal cancers of advanced stage and overall survival in bladder cancer. Clever-1 expression is increased on circulating monocytes and tissue macrophages in situations where immunosuppressive events prevail, such as pregnancy and cancer. Also, it has been demonstrated that the expression of Clever-1 on human monocytes suppresses the activation of Th1 lymphocytes indicating a possible role of Clever-1 in regulating monocyte/macrophage responses to inflammatory stimulus.

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Figure. Effect of Clever-1 targeted treatment on cancer growth. Clever-1 positive M2 macrophages (pictured green) maintain cancer growth by expressing growth factors as well as immune-suppressing molecules. By blocking the action of Clever-1 with CLEVEGEN, macrophages are converted into M1 type cells (red in the picture), expressing T-cell activating receptors and producing TNF-α (tumor necrosis factor). As a result, the tumor is targeted by a common attack of macrophages and lymphocytes and cancer cells are eliminated (tumor rejection).

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By modulating Clever-1 functions we hope to help the majority of patients lacking response to immune checkpoint blockage by converting cold tumours hot. We work together with Faron Pharmaceuticals Ltd to support the development of their lead compound CLEVEGEN into clinical trials. CLEVEGEN is a humanized IgG4 that targets a functional epitope on Clever-1.

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The MATINS (Macrophage Antibody to FP-1305 To INhibit immune Suppression) study is a first-in-human open label Phase I/II adaptive clinical trial (sponsored by Faron Pharmaceuticals) in selected metastatic or inoperable solid tumors to investigate the safety and efficacy of CLEVEGEN (FP-1305), the humanized monoclonal antibody against Clever-1. The selected tumors are cutaneous melanoma, hepatobiliary, pancreatic, ovarian or colorectal cancer, which are all known to contain high amounts of Clever-1 positive TAMs. The trial is to be run in three parts. Part I will be conducted to determine the safe and tolerable dose of CLEVEGEN, which will then be used in Part II to expand the cohorts of individual tumor types. Part III of the trial aims to confirm the efficacy of CLEVEGEN with the cohorts selected based on Part II.

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The possibility of probing the molecular landscape of solid tumors via a blood draw (liquid biopsy) has attracted remarkable interest among the oncology community. Our group aims at identifying patients under immunosuppression who could benefit from immunoswitching therapies. To date we have detected increased expression of Clever-1 on peripheral monocytes (the precursors of TAMs) in cancer patients. This provides the benefit of patient selection during the MATINS trial as an indicator of prevailing immunosuppressive inflammation. We find this highly important since patient selection is central to the success of targeted therapies and identification of tumor specific molecular landscapes is pivotal to guiding treatment choices. Longitudinal surveillance of anti-tumor immune responses is essential for precision medicine but cannot be effectively achieved using tissue biopsy specimens. The MATINS trial offers our group a unique possibility to investigate the inflammatory responses related to the release of immunosuppression in tumors before, during and after CLEVEGEN therapy and identify markers of response for future drug development. Future cancer treatments will involve combination therapies, and we think that CLEVEGEN could bring a synergistic benefit for example to anti-PD-1/PD-L1 and increase the success rate of these cancer treatments.