Emactuzumab (RG-7155) is a

humanized monoclonal antibody Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal ant ...

directed against

colony stimulating factor 1 receptor Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). CS ...

(CSF-1R) expressed on macrophages and has demonstrated a profound antitumor effect through interference with the CSF-1/CSF-1R axis, along with a manageable safety profile in patients with diffuse-type tenosynovial giant cell tumors (d-TGCT).

History

This drug was originally developed by

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX S ...

Genentech Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...

. In August 2020, Celleron Therapeutics signed a deal to acquire an exclusive worldwide license for the asset. In November 2020, Celleron Therapeutics incorporated a subsidiary, SynOx Therapeutics, to focus on the development, registration, and commercialisation of emactuzumab

Mechanism of Action

Emactuzumab is a humanized monoclonal antibody directed against the

tyrosine kinase receptor Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...

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 macrophage Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived bl ...

s (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.

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 CD68 ( Cluster of Differentiation 68) is a protein highly expressed by cells in the monocyte lineage (e.g., monocytic phagocytes, osteoclasts), by circulating macrophages, and by tissue macrophages (e.g., Kupffer cells, microglia). Structure a ...

CD163 CD163 (Cluster of Differentiation 163) is a protein that in humans is encoded by the CD163 gene. CD163 is the high affinity scavenger receptor for the hemoglobin-haptoglobin complex and in the absence of haptoglobin - with lower affinity - for hem ...

(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 2% 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.

References

Monoclonal antibodies {{monoclonal-antibody-stub