Colony Stimulating Factor 1 Receptor (CSF1R) and Its connection with Memory Retention

Colony Stimulating Factor 1 Receptor (CSF1R) is a cell-surface protein encoded, in humans, by the CSF1R gene. CSF1R is also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), and is encoded by CSF1R gene which controls the production, differentiation, and function of macrophages. This receptor mediates most- if not all- of the biological effects of this cytokine. Clinically, mutations in CSF1R are associated with various types of leukemia such as chronic myelomonocytic leukemia and type M4 acute myeloblastic leukemia. Also, increased levels of CSF1R1 are found in microglia in Alzheimer’s disease and after brain injuries. It is also believed to have a role in the process of mammary gland carcinogenesis. Mutations in the tyrosine kinase domain have been associated with hereditary diffuse leukoencephalopathy with spheroids.

A study conducted by Jian Luo et al. demonstrates that the systemic administration of human recombinant CSF1 ameliorates memory deficits in a transgenic mouse model of Alzheimer’s disease. Colony Stimulating Factors (CSF) has also a role in inflammatory responses. It helps in synergizing the attracting capabilities of chemokines and of inducing the accumulation and/or activation key components of inflammatory responses. Researchers are developing various therapeutic candidates in the form of a small molecule as well as monoclonal antibodies mainly for the treatment of cancers and inflammatory diseases. These drugs are being evaluated as monotherapy and/or combination therapy.

Major companies involved in the development of the CSF1R antagonists includes Eli Lilly and Company, Hoffmann-La Roche Novartis Pharmaceuticals, Pfizer, Daiichi Sankyo, Amgen and many other. Plexxikon (A member of the Daiichi Sankyo Group) has three products in its pipeline, including Pexidartinib in Phase III stage of development for the treatment of Tenosynovial Giant Cell Tumor (TGCT), Pigmented villonodular synovitis (PVNS), Giant cell tumors of the tendon sheath (GCT-TS), Glioblastoma and Melanoma. PLX7486 and PLX 73086 are currently in Phase I stage of development for the treatment of Pancreatic and Solid Tumors and Tenosynovial Giant Cell Tumor (TGCT), respectively. BCI Pharma has its two therapeutic candidates (Dual flt3-CSF1R kinase inhibitor and Selective CSF1R kinase inhibitor) in pipeline, currently in discovery stage of development.

Pexidartinib (Plexxikon), AB 1010 (AB Science SA), FPA-008 (Five Prime Therapeutics, Inc.) and SB1518 (CTI BioPharma) have been granted Orphan Drug Designation (ODD) by the US Food and Drug Administration (USFDA) and/or the European Medicines Agency (EMA) for different indications. More than 10 different types of collaboration agreement between different pharmaceutical and biotechnology companies and research institutes for the development of CSF1R antagonist makes it an interesting and promising target mainly for the Immuno-Oncology drugs, and has provided hope to meet the challenges of treating these diseases.

Insight by:
Mohammad Rizwan
Associate Analyst

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