Emactuzumab was originally developed by Roche/Genentech. In August 2020, Celleron Therapeutics signed a deal to acquire an exclusive worldwide license for the asset.[5] In November 2020, Celleron Therapeutics incorporated a subsidiary, SynOx Therapeutics, to focus on the development, registration, and commercialisation of emactuzumab.[6]
Mechanism of action
Emactuzumab is a humanized monoclonal antibody directed against the tyrosine kinase receptor colony stimulating factor 1 receptor (CSF1R; CSF-1R; CD115), also known as macrophage colony-stimulating factor receptor (M-CSFR), with potential antineoplastic and immunomodulating activities. Upon administration, emactuzumab binds to CSF1R expressed on macrophages and inhibits the binding of colony-stimulating factor-1 (CSF-1) to CSF1R. This prevents CSF1R activation and CSF1R-mediated signaling in these cells, which blocks the production of inflammatory mediators by macrophages and reduces inflammation. By blocking both the activity of CSF1R-dependent tumor-associated macrophages (TAMs) and the recruitment of TAMs to the tumor microenvironment, emactuzumab enhances T-cell infiltration and antitumor T-cell immune responses, which inhibits the proliferation of tumor cells. TAMs play key roles in immune suppression and promoting inflammation, tumor cell proliferation and survival.[7]
Clinical efficacy
In a Phase Ib clinical study, biopsies were taken from TGCT subjects before and on emactuzumab treatment, and immunohistochemistry was performed with antibodies against CD68/CD163 (biomarkers for TAMs) and CSF-1R. Altogether, 36 patients (57%) had evaluable paired tumour biopsy samples (taken at baseline and on treatment at four weeks, after two cycles of emactuzumab at doses of 900 – 2000 mg). A significant reduction of >50% of CD68/CD163-positive macrophages and CSF1R-positive macrophages was seen in 22 patients (61%), showing that the neutralisation of CSF-1R by emactuzumab resulted in the concomitant depletion of TAMs. In the efficacy cohort, 45 of 63 patients (71%) had a best overall response of complete response or partial response (PR) and the disease control rate was 98% (62 of 63 patients). None of the patients were assessed with progressive disease at the time of treatment discontinuation, although the majority of patients (39 patients [62%]) only received a limited number of four or five treatment cycles. After one- and two-year follow-up MRI, 19/27 patients (70%) and 9/14 patients (64%), respectively, were still in response at these time points.[8]
^Ries CH, Hoves S, Cannarile MA, Rüttinger D (August 2015). "CSF-1/CSF-1R targeting agents in clinical development for cancer therapy". Current Opinion in Pharmacology. 23: 45–51. doi:10.1016/j.coph.2015.05.008. PMID26051995.
^Cassier PA, Italiano A, Gomez-Roca CA, Le Tourneau C, Toulmonde M, Cannarile MA, et al. (August 2015). "CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study". The Lancet. Oncology. 16 (8): 949–956. doi:10.1016/S1470-2045(15)00132-1. PMID26179200.
^"NCI Drug Dictionary: Emactuzumab". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute (NCI). 2011-02-02.