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Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy

Abstract

Tumour-targeted immunotherapy offers the unique advantage of specific tumouricidal effects with reduced immune-associated toxicity1,2. However, existing platforms suffer from low potency, inability to generate long-term immune memory and decreased activities against tumour-cell subpopulations with low targeting receptor levels3,4,5. Here we adopted a modular design approach that uses colloidal nanoparticles as substrates to create a multivalent bi-specific nanobioconjugate engager (mBiNE) to promote selective, immune-mediated eradication of cancer cells. By simultaneously targeting the human epidermal growth factor receptor 2 (HER2) expressed by cancer cells6 and pro-phagocytosis signalling mediated by calreticulin7, the mBiNE stimulated HER2-targeted phagocytosis and produced durable antitumour immune responses against HER2-expressing tumours. Interestingly, although the initial immune activation mediated by the mBiNE was receptor dependent, the subsequent antitumour immunity also generated protective effects against tumour-cell populations that lacked the HER2 receptor. Thus, the mBiNE represents a new targeted, nanomaterial-immunotherapy platform to stimulate innate and adaptive immunity and promote a universal antitumour response.

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Figure 1: The mBiNE enables bi-specific engagement of cancerous and professional APCs in a targeted manner.
Figure 2: The mBiNE promotes receptor-targeted phagocytosis of cancer cells by macrophages and enhances downstream immune activation mediated by professional APCs.
Figure 3: The mBiNE elicits antitumour immune responses in vivo in a receptor-targeted manner.
Figure 4: The mBiNE induces systemic, durable antitumour immunity.

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Acknowledgements

The authors thank P. Anastasiadis, L. Petrucelli, H. Crawford, J. Copland, D. Radisky, T. Gonwa and D. Page and his veterinary team for reagents and helpful discussions. We also thank L. Lewis-Tuffin for her help with flow cytometer and confocal experiments, J. A. Knight, R. Feathers, H.-J. Wen and E. E. Miller for their helpful discussions, and B. Edenfield for her assistance with immunohistological experiments. Finally, we thank C. Wogan from MD Anderson's Division of Radiation Oncology for editorial contributions and AXS Studio for preparing Fig. 4d. Research reported here was supported by the James C. and Sara K. Kennedy Award from Mayo Clinic (B.Y.S.K), Jorge and Leslie Bacardi Fund for the study of Regenerative Medicine, Mayo Clinic Center for Regenerative Medicine (B.Y.S.K.), Mayo Clinic Center for Individualized Medicine Gerstner Family Award (B.Y.S.K.), Helene Houle Mayo Clinic Career Development Award in Neurologic Surgery (B.Y.S.K.), Mayo Clinic Neuroregenerative Medicine Initiative for Neuro-Oncology Research (B.Y.S.K.), China Scholarships Council (No. 201406100114, H.Y.), DeMars Family Mayo Clinic Development Fund (B.Y.S.K.) and Strawn Family Mayo Clinic Development Fund (B.Y.S.K.).

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H.Y., W.J. and B.Y.S.K. conceived the study and designed the experiments. H.Y., C.A.V.R., Y.Q., X.L. and Y.C. performed the experiments and generated the data. H.Y., C.A.V. R., W.J., Y.W., R.E.W., K.Y., G.B., K.L.K. and B.Y.S.K. analysed the data and interpreted the results. All authors helped to write the paper.

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Correspondence to Wen Jiang or Betty Y. S. Kim.

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The Mayo Clinic has filed a patent application on the technology and intellectual property reported here.

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Yuan, H., Jiang, W., von Roemeling, C. et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nature Nanotech 12, 763–769 (2017). https://doi.org/10.1038/nnano.2017.69

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