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Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

Bottom Line: As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity.This resulted in the inhibition of cancer-induced weight loss.CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

ABSTRACT
Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

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Therapeutic effects of anti-mouse CD115 mAb alone or combined with Paclitaxel in the PyMT mouse model.At 16 weeks of age, transgenic PyMT mice were administered 50 mg/kg of mAb AFS98 or isotype control or PBS, IP, 3 times per week for 4 weeks, alone (A, B) or combined (C, D) with Paclitaxel at 5 mg/kg, IP, once a week for 3 weeks. A. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for AFS98- compared to PBS-treated mice. At week 20, * p<0.05 for AFS98- and Rat IgG- vs PBS-treated mice. B. The percentage of surviving mice was significantly increased in the AFS98-treated group. * Log-rank test p<0.05 between AFS98- and Rat IgG-treated groups and ** p<0.005 between AFS98- and PBS-treated mice (n = 10). C. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for the combination Paclitaxel+AFS98 compared with Paclitaxel+PBS, and p<0.01 compared with Paclitaxel+Rat IgG. **p<0.01 and ***p<0.001 for Paclitaxel+AFS98 compared with Paclitaxel+Rat IgG or PBS (n = 10). D. The percentage of surviving mice was significantly increased by AFS98 combined with Paclitaxel. ** Log-rank test p<0.01 for mice treated with Paclitaxel+AFS98 compared to Paclitaxel+Rat IgG or PBS.
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pone-0073310-g006: Therapeutic effects of anti-mouse CD115 mAb alone or combined with Paclitaxel in the PyMT mouse model.At 16 weeks of age, transgenic PyMT mice were administered 50 mg/kg of mAb AFS98 or isotype control or PBS, IP, 3 times per week for 4 weeks, alone (A, B) or combined (C, D) with Paclitaxel at 5 mg/kg, IP, once a week for 3 weeks. A. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for AFS98- compared to PBS-treated mice. At week 20, * p<0.05 for AFS98- and Rat IgG- vs PBS-treated mice. B. The percentage of surviving mice was significantly increased in the AFS98-treated group. * Log-rank test p<0.05 between AFS98- and Rat IgG-treated groups and ** p<0.005 between AFS98- and PBS-treated mice (n = 10). C. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for the combination Paclitaxel+AFS98 compared with Paclitaxel+PBS, and p<0.01 compared with Paclitaxel+Rat IgG. **p<0.01 and ***p<0.001 for Paclitaxel+AFS98 compared with Paclitaxel+Rat IgG or PBS (n = 10). D. The percentage of surviving mice was significantly increased by AFS98 combined with Paclitaxel. ** Log-rank test p<0.01 for mice treated with Paclitaxel+AFS98 compared to Paclitaxel+Rat IgG or PBS.

Mentions: We then studied the effect of anti-CD115 mAb treatment administered later during tumor progression. AFS98 was dosed (50 mg/kg, IP 3 times per week, for 3 weeks) starting from week 16, when all tumors were palpable, mostly at the EC stage without yet reaching the LC stage (Figure 3). One week after termination of the treatment (week 20), the sizes of primary tumors were significantly reduced in the AFS98-treated group compared to the PBS- (p = 0.0101, n = 10) but not to the IgG-treated mice (p = 0.1457, n = 10) (Figure 6A). Survival was significantly prolonged by AFS98 compared to either PBS (p = 0.0031) or IgG (p = 0.0474) (Figure 6B). As seen when treatment was initiated earlier (Figure 5), depletion of CD163+ macrophages was observed in tumors from mice treated with AFS98 (Figure S4).


Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

Therapeutic effects of anti-mouse CD115 mAb alone or combined with Paclitaxel in the PyMT mouse model.At 16 weeks of age, transgenic PyMT mice were administered 50 mg/kg of mAb AFS98 or isotype control or PBS, IP, 3 times per week for 4 weeks, alone (A, B) or combined (C, D) with Paclitaxel at 5 mg/kg, IP, once a week for 3 weeks. A. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for AFS98- compared to PBS-treated mice. At week 20, * p<0.05 for AFS98- and Rat IgG- vs PBS-treated mice. B. The percentage of surviving mice was significantly increased in the AFS98-treated group. * Log-rank test p<0.05 between AFS98- and Rat IgG-treated groups and ** p<0.005 between AFS98- and PBS-treated mice (n = 10). C. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for the combination Paclitaxel+AFS98 compared with Paclitaxel+PBS, and p<0.01 compared with Paclitaxel+Rat IgG. **p<0.01 and ***p<0.001 for Paclitaxel+AFS98 compared with Paclitaxel+Rat IgG or PBS (n = 10). D. The percentage of surviving mice was significantly increased by AFS98 combined with Paclitaxel. ** Log-rank test p<0.01 for mice treated with Paclitaxel+AFS98 compared to Paclitaxel+Rat IgG or PBS.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g006: Therapeutic effects of anti-mouse CD115 mAb alone or combined with Paclitaxel in the PyMT mouse model.At 16 weeks of age, transgenic PyMT mice were administered 50 mg/kg of mAb AFS98 or isotype control or PBS, IP, 3 times per week for 4 weeks, alone (A, B) or combined (C, D) with Paclitaxel at 5 mg/kg, IP, once a week for 3 weeks. A. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for AFS98- compared to PBS-treated mice. At week 20, * p<0.05 for AFS98- and Rat IgG- vs PBS-treated mice. B. The percentage of surviving mice was significantly increased in the AFS98-treated group. * Log-rank test p<0.05 between AFS98- and Rat IgG-treated groups and ** p<0.005 between AFS98- and PBS-treated mice (n = 10). C. Tumor volumes are represented as means ± SEM. * Mann-Whitney’s test p<0.05 for the combination Paclitaxel+AFS98 compared with Paclitaxel+PBS, and p<0.01 compared with Paclitaxel+Rat IgG. **p<0.01 and ***p<0.001 for Paclitaxel+AFS98 compared with Paclitaxel+Rat IgG or PBS (n = 10). D. The percentage of surviving mice was significantly increased by AFS98 combined with Paclitaxel. ** Log-rank test p<0.01 for mice treated with Paclitaxel+AFS98 compared to Paclitaxel+Rat IgG or PBS.
Mentions: We then studied the effect of anti-CD115 mAb treatment administered later during tumor progression. AFS98 was dosed (50 mg/kg, IP 3 times per week, for 3 weeks) starting from week 16, when all tumors were palpable, mostly at the EC stage without yet reaching the LC stage (Figure 3). One week after termination of the treatment (week 20), the sizes of primary tumors were significantly reduced in the AFS98-treated group compared to the PBS- (p = 0.0101, n = 10) but not to the IgG-treated mice (p = 0.1457, n = 10) (Figure 6A). Survival was significantly prolonged by AFS98 compared to either PBS (p = 0.0031) or IgG (p = 0.0474) (Figure 6B). As seen when treatment was initiated earlier (Figure 5), depletion of CD163+ macrophages was observed in tumors from mice treated with AFS98 (Figure S4).

Bottom Line: As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity.This resulted in the inhibition of cancer-induced weight loss.CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

ABSTRACT
Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

Show MeSH
Related in: MedlinePlus