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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Sep 22

PMID 32960056

Citations 15

Authors

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 Codee

Affiliations

Soon will be listed here.

Abstract

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 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 . Synthetic TLR4 ligands thus show great promise in potentiating the conjugate vaccine platform for application in cancer vaccination.

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