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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.

SUBMITTER: Haegel H

PROVIDER: S-EPMC3851226 | biostudies-literature | 2013 Sep-Oct

REPOSITORIES: biostudies-literature

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

Haegel Hélène H Thioudellet Christine C Hallet Rémy R Geist Michel M Menguy Thierry T Le Pogam Fabrice F Marchand Jean-Baptiste JB Toh Myew-Ling ML Duong Vanessa V Calcei Alexandre A Settelen Nathalie N Preville Xavier X Hennequi Marie M Grellier Benoit B Ancian Philippe P Rissanen Jukka J Clayette Pascal P Guillen Christine C Rooke Ronald R Bonnefoy Jean-Yves JY

mAbs 20130715 5

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 i ...[more]

PMID: 23924795

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Project description:Respiratory macrophage subpopulations exhibit unique phenotypes depending on their location within the respiratory tract, posing a challenge to in vitro macrophage model systems. Soluble mediator secretion, surface marker expression, gene signatures, and phagocytosis are among the characteristics that are typically independently measured to phenotype these cells. Bioenergetics is emerging as a key central regulator of macrophage function and phenotype but is often not included in the characterization of human monocyte-derived macrophage (hMDM) models. The objective of this study was to expand the phenotype characterization of naïve hMDMs, and their M1 and M2 subsets by measuring cellular bioenergetic outcomes and including an expanded cytokine profile. Known markers of M0, M1 and M2 phenotypes were also measured and integrated into the phenotype characterization. Peripheral blood monocytes from healthy volunteers were differentiated into hMDM and polarized with either IFN-γ + LPS (M1) or IL-4 (M2). As expected, our M0, M1, and M2 hMDMs exhibited cell surface marker, phagocytosis, and gene expression profiles indicative of their different phenotypes. M2 hMDMs however were uniquely characterized and different from M1 hMDMs by being preferentially dependent on oxidativte phosphorylation for their ATP generation and by secreting a distinct cluster of soluble mediators (MCP4, MDC, and TARC). In contrast, M1 hMDMs secreted prototypic pro-inflammatory cytokines (MCP1, eotaxin, eotaxin-3, IL12p70, IL-1α, IL15, TNF-β, IL-6, TNF-α, IL12p40, IL-13, and IL-2), but demonstrated a relatively constitutively heightened bioenergetic state, and relied on glycolysis for ATP generation. These data are similar to the bioenergetic profiles we previously observed in vivo in sputum (M1) and BAL (M2)-derived macrophages in healthy volunteers, supporting the notion that polarized hMDMs can provide an acceptable in vitro model to study specific human respiratory macrophage subtypes.

Dataset Information

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

Publications

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

Similar Datasets

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