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SIRPα-specific monoclonal antibody enables antibody-dependent phagocytosis of neuroblastoma cells

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Abstract

Immunotherapy with anti-GD2 monoclonal antibodies (mAbs) provides some benefits for patients with neuroblastoma (NB). However, the therapeutic efficacy remains limited, and treatment is associated with significant neuropathic pain. Targeting O-acetylated GD2 (OAcGD2) by 8B6 mAb has been proposed to avoid pain by more selective tumor cell targeting. Thorough understanding of its mode of action is necessary to optimize this treatment strategy. Here, we found that 8B6-mediated antibody-dependent cellular phagocytosis (ADCP) performed by macrophages is a key effector mechanism. But efficacy is limited by upregulation of CD47 expression on neuroblastoma cells in response to OAcGD2 mAb targeting, inhibiting 8B6-mediated ADCP. Antibody specific for the CD47 receptor SIRPα on macrophages restored 8B6-induced ADCP of CD47-expressing NB cells and improved the antitumor activity of 8B6 mAb therapy. These results identify ADCP as a critical mechanism for tumor cytolysis by anti-disialoganglioside mAb and support a combination with SIRPα blocking agents for effective neuroblastoma therapy.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank for their technical assistance the following facilities: plateau de cytométrie en flux et de tri cellulaire CYTOCELL, plateforme de Protéines Recombinantes P2R and Unité Thérapeutique Expérimentale UTE, and Wolfgang Hartmann, Gerhard-Domagk-Institute of Pathology, University Hospital Muenster.

Funding

This work was supported by La Ligue contre le Cancer (comités 44 et 56), the Fondation BMS pour la recherche en Immuno-oncologie, the Institut National du Cancer, and the Fondation de l’Université de Nantes.

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Authors and Affiliations

  1. CRCINA, Université de Nantes, 44000, Nantes, France

    Meriem Bahri, Sarah Vermeulen, Natacha Galopin, François Paris, Sophie Fougeray & Stéphane Birklé

  2. Pediatric Hematology and Oncology, University Children’s Hospital Muenster, 48149, Muenster, Germany

    Sareetha Kailayangiri & Claudia Rossig

  3. UFR Des Sciences Pharmaceutiques Et Biologiques, Université de Nantes, 44035-01, Nantes, France

    Sophie Fougeray & Stéphane Birklé

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  1. Meriem Bahri
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  2. Sareetha Kailayangiri
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Contributions

M.B. contributed to conceptualization, methodology, validation, formal analysis, investigation, and visualization. S.K. contributed to methodology, validation, formal analysis, and visualization. S.V. and N.G. contributed to methodology, validation, and formal analysis. C.R. contributed to conceptualization, resources, and writing—review and editing. F.P. acquired funding and contributed to writing—review and editing. S.F. contributed to conceptualization, methodology, investigation, and supervision and administrated the project. S.B. contributed to conceptualization, methodology, investigation, writing—original draft, visualization, and supervision, administrated the project, and acquired funding.

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Correspondence to Stéphane Birklé.

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MB, SV, SF, and SB are inventors of a granted patent covering the therapeutic uses of monoclonal antibodies targeting O-acetyl GD2 gangliosides.

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Bahri, M., Kailayangiri, S., Vermeulen, S. et al. SIRPα-specific monoclonal antibody enables antibody-dependent phagocytosis of neuroblastoma cells. Cancer Immunol Immunother 71, 71–83 (2022). https://doi.org/10.1007/s00262-021-02968-7

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