Modulating albumin-mediated transport of peptide-drug conjugates for antigen-specific Treg induction

Chun Yin Jerry Lau, Naomi Benne, Bo Lou, Olga Zharkova, Hui Jun Ting, Daniëlle Ter Braake, Nicky van Kronenburg, Marcel H Fens, Femke Broere, Wim E Hennink, Jiong-Wei Wang, Enrico Mastrobattista

Research output: Contribution to journalArticleAcademicpeer-review


The therapeutic potential of antigen-specific regulatory T cells (Treg) has been extensively explored, leading to the development of several tolerogenic vaccines. Dexamethasone-antigen conjugates represent a prominent class of tolerogenic vaccines that enable coordinated delivery of antigen and dexamethasone to target immune cells. The importance of nonspecific albumin association towards the biodistribution of antigen-adjuvant conjugates has gained increasing attention, by which hydrophobic and electrostatic interactions govern the association capacity. Using an ensemble of computational and experimental techniques, we evaluate the impact of charged residues adjacent to the drug conjugation site in dexamethasone-antigen conjugates (Dex-K/E4-OVA323, K: lysine, E: glutamate) towards their albumin association capacity and induction of antigen-specific Treg. We find that Dex-K4-OVA323 possesses a higher albumin association capacity than Dex-E4-OVA323, leading to enhanced liver distribution and antigen-presenting cell uptake. Furthermore, using an OVA323-specific adoptive-transfer mouse model, we show that Dex-K4-OVA323 selectively upregulated OVA323-specific Treg cells, whereas Dex-E4-OVA323 exerted no significant effect on Treg cells. Our findings serve as a guide to optimize the functionality of dexamethasone-antigen conjugate amid switching vaccine epitope sequences. Moreover, our study demonstrates that moderating the residues adjacent to the conjugation sites can serve as an engineering approach for future peptide-drug conjugate development.

Original languageEnglish
Pages (from-to)938-950
Number of pages13
JournalJournal of controlled release : official journal of the Controlled Release Society
Early online date19 Jun 2022
Publication statusPublished - Aug 2022


  • Peptide-drug conjugates
  • Albumin transport
  • Supramolecular medicine
  • Drug delivery
  • Antigen-specific tolerance


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