A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells

Abstract

Cancer progression has been associated with the presence of tumor-associated M2-macrophages (M2-TAMs) able to inhibit anti-tumor immune responses. It is also often associated with metastasis-induced bone destruction mediated by osteoclasts. Both cell types are controlled by the CD115 (CSF-1R)/colony-stimulating factor-1 (CSF-1, M-CSF) pathway, making CD115 a promising target for cancer therapy. Anti-human CD115 monoclonal antibodies (mAbs) that inhibit the receptor function have been generated in a number of laboratories. These mAbs compete with CSF-1 binding to CD115, dramatically affecting monocyte survival and preventing osteoclast and macrophage differentiation, but they also block CD115/CSF-1 internalization and degradation, which could lead to potent rebound CSF-1 effects in patients after mAb treatment has ended. We thus generated and selected a non-ligand competitive anti-CD115 mAb that exerts only partial inhibitory effects on CD115 signaling without blocking the internalization or the degradation of the CD115/CSF-1 complex. This mAb, H27K15, affects monocyte survival only minimally, but downregulates osteoclast differentiation and activity. Importantly, it inhibits monocyte differentiation to CD163⁺CD64⁺ M2-polarized suppressor macrophages, skewing their differentiation toward CD14^-CD1a⁺ dendritic cells (DCs). In line with this observation, H27K15 also drastically inhibits monocyte chemotactic protein-1 secretion and reduces interleukin-6 production; these two molecules are known to be involved in M2-macrophage recruitment. Thus, the non-depleting mAb H27K15 is a promising anti-tumor candidate, able to inhibit osteoclast differentiation, likely decreasing metastasis-induced osteolysis, and able to prevent M2 polarization of TAMs while inducing DCs, hence contributing to the creation of more efficient anti-tumor immune responses.

Keywords: :

• CD115
• CSF-1R
• FcγR
• M-CSFR
• M2-macrophages
• cancer immunotherapy
• dendritic cells
• immunomodulation
• osteolysis
• tumor microenvironment

Disclosure of Potential Conflicts of Interest

Most authors are employees of Transgene, the company that patented mAb H27K15.

Acknowledgments

We thank Guillaume Fichet and Christine Kreuz for their contribution in the macrophage differentiation experiments, Pascal Mercier from Roche for the gift of rituximab, and Pascale Jeannin, Jean-Pierre Abastado, Bruce Acres and Jean-Luc Teillaud for critical reading of the manuscript.

Supplemental Materials

All supplemental materials can be found here: www.landesbioscience.com/journals/mabs/article/25743.