TY - JOUR
T1 - Self-Adjuvanting Cancer Vaccines from Conjugation-Ready Lipid A Analogues and Synthetic Long Peptides
AU - Reintjens, Niels R.M.
AU - Tondini, Elena
AU - de Jong, Ana R.
AU - Meeuwenoord, Nico J.
AU - Chiodo, Fabrizio
AU - Peterse, Evert
AU - Overkleeft, Herman S.
AU - Filippov, Dmitri V.
AU - van der Marel, Gijsbert A.
AU - Ossendorp, Ferry
AU - Codée, Jeroen D.C.
PY - 2020/10/22
Y1 - 2020/10/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85094220154&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/acs.jmedchem.0c00851
DO - https://doi.org/10.1021/acs.jmedchem.0c00851
M3 - Article
C2 - 32960056
SN - 0022-2623
VL - 63
SP - 11691
EP - 11706
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -