CSF-1R, a receptor protein-tyrosine kinase belonging to the PDGFR family, serves as a cell surface receptor for IL-34 and CSF1. It plays pivotal roles in haematopoiesis, proliferation regulation, cell survival, and microglia and monocyte maturation, influencing overall immune responses.

Tenosynovial giant cell tumor (TGCT), an uncommon and locally aggressive benign tumor originating from joint synovium, bursae, and tendon sheaths, poses challenges in achieving a definitive cure due to high recurrence rates even after primary surgical resection.

Consequently, systemic therapies targeting the CSF1-CSF1R axis have emerged as promising treatment avenues. Moreover, utilizing CSF1R tyrosine kinase inhibitors (TKIs) and anti-CSF1R antibodies has shown encouraging results in managing TGCT.

Emactuzumab (RG7155), a specific humanized monoclonal antibody, hinders CSF1R activation, primarily on macrophages and monocytes. By selectively inhibiting tumor-associated macrophages (M2 polarized) that fuel tumor growth, Emactuzumab spares granulocyte-macrophage colony-stimulating factor-dependent M1 macrophages essential for anti-tumor activities.

Emactuzumab is a CSF-1R inhibitory mAb for TGCT research.

In vitro, Emactuzumab (RG 7155) demonstrates a high binding affinity to human and cynomolgus CSF-1R (Kd = 0.2 nM), and effectively blocking CSF-1R dimerization. Furthermore, at 0-10 μg/mL over 7 days, Emactuzumab significantly suppresses the viability of CSF-1-differentiated macrophages (IC50: 0.3 nM). Notably, when administered at 30 μg/mL for 6 days, Emactuzumab triggers cell death in in vitro-differentiated human M2-like macrophages.

Emactuzumab (RG 7155)(i.v., 0.1-100 mg/kg), Emactuzumab (RG 7155) elevates CSF-1 levels in the peripheral blood of nonhuman primates. Additionally, Emactuzumab (i.v., 0, 30-100 mg/kg, once weekly for two weeks) effectively eliminates CSF-1R+CD163+ macrophages in vivo. Besides, Emactuzumab increases CSF-1 concentration in serum and efficiently reduces CSF-1R and CD68+163+ macrophages in the liver (Kupffer cells) and colon of cynomologus monkeys.

In summary, Emactuzumab is a humanized monoclonal antibody that blocks CSF1R activation, and shows antitumor effect against tenosynovial giant cell tumor.

References:

[1] Carola H Ries, et al. Cancer Cell. 2014 Jun 16;25(6):846-59.

[2] Antonia Stamatiou, et al. Future Pharmacol. 2023, 3(4), 926-937.

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