CSF1R Gene Editing    

Colony stimulating factor 1 receptor (CSF1R) is a single-pass transmembrane receptor with an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain with tyrosine kinase activity. Ligand binding of CSF1 or the interleukin 34 ligand to CSF1R results in receptor dimerization, upregulation of CSF1R tyrosine kinase activity, phosphorylation of CSF1R tyrosine residues, and downstream signaling events. Many tumor cells have been found to secrete CSF1, which activates monocyte/macrophage cells by CSF1R. The level of CSF1 in tumors has been demonstrated to correlate with the level of tumor-associated macrophages (TAMs) in the tumor. Higher levels of TAMs have been shown to correlate with poorer patient prognoses. Besides, CSF1 has been found to promote tumor growth and progression to metastasis in, such as, human breast cancer xenografts in mice. CSF1 and its receptor have also been found to be involved in diverse inflammatory and autoimmune diseases. For instance, synovial endothelial cells from joints afflicted with rheumatoid arthritis have been found to produce CSF1, indicating a role for CSF1 and its receptor in the disease.

Figure 1. The transition from M2 macrophages to M1 macrophages in a TAM population induced by blockade of the CSF1/CSF-1R signal pathway. (Jian-Yang Ao, et al. 2017)

CSF1R-blocking Antibodies in Multiple Myeloma

Multiple myeloma (MM), a plasma cell malignancy, is characterized by the proliferation of monoclonal plasma cells in the bone marrow (BM) and destructive lytic bone disease. In recent years, chemotherapy combined with novel agents, such as bortezomib and lenalidomide, has greatly improved the therapeutic efficacy for patients with MM; however, MM remains mostly incurable. Recent studies have indicated that targeting macrophages by CSF1R blocking antibodies can inhibit tumor growth in vivo. Mechanistic studies showed that macrophages in the BM of patients with MM were largely the M2-like phenotype, which promotes tumor progression; and blocking CSF1R partially depleted macrophages and myeloma-associated macrophages (MAMs) and effectively skewed the macrophages phenotype from M2 to M1-like phenotype, thereby inhibiting tumor progression. Consistent with the therapeutic effects of CSF1R blockade in solid tumors, researchers found that CSF1R-blocking monoclonal antibodies (mAbs) inhibited MM growth in vivo, and the combination of CSF1R-blocking mAbs and chemotherapy further improved the therapeutic efficacy against established MM.

Clinical Application with CSF1R Inhibitor

Many small molecules and mAbs directed at CSF1R or its ligand CSF1 are in clinical development both as monotherapy and in combination with standard treatment modalities such as chemotherapy as well as other cancer-immunotherapy methods. Among the class of small molecules, pexidartinib (PLX3397), an oral tyrosine kinase inhibitor of CSF1R, cKIT, mutant FLT3, and PDGFR-β, is the subject of the broadest clinical development program in monotherapy, with completed or ongoing studies in c-kit-mutated melanoma, glioblastoma (GBM), classical Hodgkin lymphoma (cHL), prostate cancer, neurofibroma, sarcoma, and leukemias. Additional CSF1R-targeting small molecules, including ARRY-382, BLZ945, PLX7486, and JNJ-40346527, are currently being investigated in solid tumors and cHL. mAbs in clinical development include AMG820, emactuzumab, IMC-CS4, cabiralizumab, MCS110, and PD-0360324, with the latter two being the only compounds targeting the ligand CSF1.

CSF1R Gene Editing Service

The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. Thus, the CSF1/CSF1R axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively CSF1R gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• CSF1R Gene Knockout: We offer CSF1R gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service that covers from sgRNA design and construct, pronuclear microinjection to Founders genotyping and breeding.

• CSF1R Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop CSF1R knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of CSF1R knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

Related Products at CRISPR/Cas9 Platform^CB