To improve the clinical potency of peptide-based antitumor vaccines, Mehta et al. developed a generalizable pharmacokinetic strategy to optimize immunogenicity. Viral and tumor peptides were fused to large carrier proteins, Transthyretin (TTR) and Albumin, with similar low systemic absorption, but different systemic half-lives [2d vs 21d, respectively]. Both showed efficient and prolonged Agn uptake in local dLNs and protection from proteolytic degradation, but TTR-peptide fusions had superior immunogenicity and a reduced risk of Agn tolerance in distal LNs. Overall, vaccine immunogenicity was increased by up to 90-fold compared to unfused peptide.
Contributed by Katherine Turner
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.
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Tech
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Harvard Graduate Program in Biophysics, Harvard University, Boston, MA, USA. (4) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (9) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Harvard-MIT Health Sciences and Technology Program, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Howard Hughes Medical Institute, Cambridge, MA, USA. (10) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. wittrup@mit.edu. (11) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu. The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. djirvine@mit.edu. Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu. Howard Hughes Medical Institute, Cambridge, MA, USA. djirvine@mit.edu.
