Letter | Published:

Structure-based programming of lymph-node targeting in molecular vaccines

Nature volume 507, pages 519522 (27 March 2014) | Download Citation

Abstract

In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes1,2. Here we translate this ‘albumin hitchhiking’ approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.

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Acknowledgements

This work was supported in part by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the National Institutes of Health (grants AI091693, AI104715 and AI095109), the Department of Defense (W911NF-13-D-0001 and W911NF-07-D-0004, T.O. 8) and the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology and Harvard. D.J.I. is an investigator of the Howard Hughes Medical Institute. We thank T. C. Wu for kindly providing the TC-1 tumour cells. We thank the Koch Institute Swanson Biotechnology Center for technical support, specifically the applied therapeutics and whole animal imaging core facility, histology and flow cytometry core facility. The authors acknowledge the service to the MIT community of the late Sean Collier.

Author information

Affiliations

  1. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Haipeng Liu
    •  & Darrell J. Irvine
  2. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Haipeng Liu
    • , Kelly D. Moynihan
    • , Yiran Zheng
    • , Gregory L. Szeto
    • , Adrienne V. Li
    • , Bonnie Huang
    • , Clara Park
    •  & Darrell J. Irvine
  3. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Haipeng Liu
    • , Kelly D. Moynihan
    • , Yiran Zheng
    • , Gregory L. Szeto
    • , Adrienne V. Li
    • , Bonnie Huang
    •  & Darrell J. Irvine
  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Debra S. Van Egeren
  5. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02139, USA

    • Darrell J. Irvine
  6. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • Darrell J. Irvine

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Contributions

H.L. designed and performed most experiments and analysed the data, and wrote the manuscript; Y.Z. carried out tumour therapy experiments and analysed the data. K.D.M. carried out in vitro bioactivity studies of CpG, biolayer interforometry binding studies and in vivo immunizations of SIV Gag and analysed the data. A.V.L. and B.H. assisted in tetramer/in vivo cytotoxicity assays and contributed experimental suggestions. G.L.S. assisted with optimization of proinflamatory cytokine assays and helped in vitro bioactivity studies of CpG. G.L.S., C.P. and D.S.V.E. contributed to in vitro T-cell proliferation assays. D.J.I. supervised all experiments and wrote the manuscript.

Competing interests

A patent application for amphiphile vaccines has been filed, with D.J.I. and H.L. as inventors.

Corresponding author

Correspondence to Darrell J. Irvine.

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DOI

https://doi.org/10.1038/nature12978

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