Pharmacokinetic tuning of protein–antigen fusions enhances the immunogenicity of T-cell vaccines

Abstract

The formulations of peptide-based antitumour vaccines being tested in clinical studies are generally associated with weak potency. Here, we show that pharmacokinetically tuning the responses of peptide vaccines by fusing the peptide epitopes to carrier proteins optimizes vaccine immunogenicity in mice. In particular, we show in immunized mice that the carrier protein transthyretin simultaneously optimizes three factors: efficient antigen uptake in draining lymphatics from the site of injection, protection of antigen payloads from proteolytic degradation and reduction of antigen presentation in uninflamed distal lymphoid organs. Optimizing these factors increases vaccine immunogenicity by up to 90-fold and maximizes the responses to viral antigens, tumour-associated antigens, oncofetal antigens and shared neoantigens. Protein–peptide epitope fusions represent a facile and generalizable strategy for enhancing the T-cell responses elicited by subunit vaccines.

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Fig. 1: Albumin fusion enhances the bioavailability of antigen in the dLN.
Fig. 2: Albumin delivery of epitopes is a generalizable immunogenicity enhancement strategy.
Fig. 3: The systemic distribution of albumin fusions induces tolerance.
Fig. 4: TTR fusions outperform MSA fusions due to a faster clearance rate.
Fig. 5: TTR–antigen fusion vaccines.
Fig. 6: TTR-antigen fusions in cancer immunotherapy.

Data availability

The main data supporting the findings of this study are available within the paper and its Supplementary information. The associated raw data are too numerous to be readily shared publicly but can be made available from the corresponding author on reasonable request.

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Acknowledgements

We thank the Koch Institute Swanson Biotechnology Center, particularly the Flow Cytometry and Animal Imaging and Preclinical Testing Core Facilities, as well as the Biophysical Instrumentation Facility for technical support. This work was supported, in part, by the National Institutes of Health (grant no. CA174795 and the National Institute of General Medical Sciences-NIH Interdepartmental Biotechnology Training Program). D.J.I. is an investigator of the Howard Hughes Medical Institute.

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N.K.M., K.D.W. and D.J.I. designed the studies and wrote the manuscript. N.K.M., R.V.P. and A.P.S. carried out experiments. K.D.M., A.M.R., N.M. and K.R. assisted with experiments. J.M.-F. provided the DEC-205 binders. S.N.B. lent expertise to the tolerization studies.

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Correspondence to K. Dane Wittrup or Darrell J. Irvine.

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D.J.I., K.D.W., N.K.M. and K.R. are inventors on a related patent that covers the primary technology outlined in the manuscript. Massachusetts Institute of Technology is the assignee for this patent application. Application number: US15/452,266. D.J.I. has ownership interest in and is a consultant/advisory board member for Elicio Therapeutics. The remaining authors report no competing interests.

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Mehta, N.K., Pradhan, R.V., Soleimany, A.P. et al. Pharmacokinetic tuning of protein–antigen fusions enhances the immunogenicity of T-cell vaccines. Nat Biomed Eng 4, 636–648 (2020). https://doi.org/10.1038/s41551-020-0563-4

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