A unique anti-CD115 monoclonal antibody which inhibits osteolysis and skews human monocyte differentiation from M2-polarized macrophages toward dendritic cells.
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.
Transgene; Illkirch-Graffenstaden, France.
Hélène
H
Haegel
Christine
C
Thioudellet
Rémy
R
Hallet
Michel
M
Geist
Thierry
T
Menguy
Fabrice
F
Le Pogam
Jean-Baptiste
JB
Marchand
Myew-Ling
ML
Toh
Vanessa
V
Duong
Alexandre
A
Calcei
Nathalie
N
Settelen
Xavier
X
Preville
Marie
M
Hennequi
Benoit
B
Grellier
Philippe
P
Ancian
Jukka
J
Rissanen
Pascal
P
Clayette
Christine
C
Guillen
Ronald
R
Rooke
Jean-Yves
JY
Bonnefoy
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D041681:NIH 3T3 Cells; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010014:Osteolysis / Q000276:immunology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D015850:Interleukin-6; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
CD115; CSF-1R; FcγR; M-CSFR; M2-macrophages; cancer immunotherapy; dendritic cells; immunomodulation; osteolysis; tumor microenvironment