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

Naveen K Mehta; Roma V Pradhan; Ava P Soleimany; Kelly D Moynihan; Adrienne M Rothschilds; Noor Momin; Kavya Rakhra; Jordi Mata-Fink; Sangeeta N Bhatia; K Dane Wittrup; Darrell J Irvine

doi:10.1038/s41551-020-0563-4

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

Nat Biomed Eng. 2020 Jun;4(6):636-648. doi: 10.1038/s41551-020-0563-4. Epub 2020 Jun 1.

Authors

Naveen K Mehta^{1

2}, Roma V Pradhan², Ava P Soleimany^{1

3}, Kelly D Moynihan^{1

2

4}, Adrienne M Rothschilds^{1

2}, Noor Momin^{1

2}, Kavya Rakhra¹, Jordi Mata-Fink^{4

5}, Sangeeta N Bhatia^{1

2

6

7

8

9

10}, K Dane Wittrup^{11

12

13}, Darrell J Irvine^{14

15

16

17

18}

Affiliations

¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Harvard Graduate Program in Biophysics, Harvard University, Boston, MA, USA.
⁴ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
⁵ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Harvard-MIT Health Sciences and Technology Program, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁰ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹¹ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu.
¹² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu.
¹³ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu.
¹⁴ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
¹⁵ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
¹⁶ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. djirvine@mit.edu.
¹⁷ Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
¹⁸ Howard Hughes Medical Institute, Cambridge, MA, USA. djirvine@mit.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Albumins / immunology
Animals
Antigens, Neoplasm
Basic-Leucine Zipper Transcription Factors
CD8-Positive T-Lymphocytes
Cancer Vaccines / immunology*
Cancer Vaccines / pharmacology*
Cell Line, Tumor
Epitopes
Immunity, Cellular
Immunogenicity, Vaccine / immunology*
Immunotherapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Repressor Proteins / genetics
T-Lymphocytes / immunology*
Vaccines, Subunit / immunology*
Vaccines, Subunit / pharmacokinetics*

Substances

Albumins
Antigens, Neoplasm
Basic-Leucine Zipper Transcription Factors
Cancer Vaccines
Epitopes
Repressor Proteins
SNFT protein, mouse
Vaccines, Subunit
oncofetal antigens

Abstract

Publication types

MeSH terms

Substances

Grants and funding