Self-Adjuvanting Cancer Vaccines from Conjugation-Ready Lipid A Analogues and Synthetic Long Peptides

Niels R.M. Reintjens, Elena Tondini, Ana R. de Jong, Nico J. Meeuwenoord, Fabrizio Chiodo, Evert Peterse, Herman S. Overkleeft, Dmitri V. Filippov, Gijsbert A. van der Marel, Ferry Ossendorp, Jeroen D.C. Codée

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27 Citations (Scopus)


Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to an immunostimulating agent, have been shown to be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants for covalent linking to peptides or proteins. We here introduce a conjugation-ready TLR4 ligand, CRX-527, a potent powerful lipid A analogue, in the generation of novel conjugate-vaccine modalities. Effective chemistry has been developed for the synthesis of the conjugation-ready ligand as well as the connection of it to the peptide antigen. Different linker systems and connection modes to a model peptide were explored, and in vitro evaluation of the conjugates showed them to be powerful immune-activating agents, significantly more effective than the separate components. Mounting the CRX-527 ligand at the N-terminus of the model peptide antigen delivered a vaccine modality that proved to be potent in activation of dendritic cells, in facilitating antigen presentation, and in initiating specific CD8+ T-cell-mediated killing of antigen-loaded target cells in vivo. Synthetic TLR4 ligands thus show great promise in potentiating the conjugate vaccine platform for application in cancer vaccination.

Original languageEnglish
Pages (from-to)11691-11706
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number20
Publication statusPublished - 22 Oct 2020

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