Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

Theruvath, J.; Menard, M.; Smith, B. A.; Linde, M. H.; Coles, G.; Wu, W.; Kiru, L.; Delaidelli, A.; Silberstein, J. L.; Banuelos, A.; Dhingra, S.; Sotillo, E.; Heitzeneder, S.; Tousley, A.; Lattin, J.; Xu, P.; Huang, J.; Nasholm, N.; Dalton, G. N.; He, A.; Kuo, T. C.; Sangalang, E. R. B.; Pons, J.; Barkal, A.; Brewer, R.; Marjon, K. D.; Marshall, P. L.; Fernandes, R.; Cochran, J.; Sorensen, P.; Daldrup-Link, H. E.; Weissman, I. L.; Sage, J.; Majeti, R.; Bertozzi, C. R.; Weiss, W. A.; Mackall, C. L.; Majzner, R. G.

doi:10.1101/2021.03.19.436221

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bioRxiv · 10.1101/2021.03.19.436221

Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

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Abstract

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.

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Theruvath, J., Menard, M., Smith, B. A., Linde, M. H., Coles, G., Wu, W., Kiru, L., Delaidelli, A., Silberstein, J. L., Banuelos, A., Dhingra, S., Sotillo, E., Heitzeneder, S., Tousley, A., Lattin, J., Xu, P., Huang, J., Nasholm, N., Dalton, G. N., He, A., Kuo, T. C., Sangalang, E. R. B., Pons, J., Barkal, A., Brewer, R., Marjon, K. D., Marshall, P. L., Fernandes, R., Cochran, J., Sorensen, P., Daldrup-Link, H. E., Weissman, I. L., Sage, J., Majeti, R., Bertozzi, C. R., Weiss, W. A., Mackall, C. L., Majzner, R. G.. 2021-03-21. Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication. https://doi.org/10.1101/2021.03.19.436221

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