Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant

Abstract

The glycolipid α-galactosylceramide (α-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, α-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to α-GalCer, we performed step-wise screening assays on a focused library of 25 α-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than α-GalCer on HIV and malaria vaccines in mice.

Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

“…1). Among them, 17 glycolipids studied by Li et al suggested that the 7DW8-5 had the greatest capacity for induction of IFN-γ production in human NKT cells and binding to CD1d (24). In this study, five glycolipids (C34, C30, C35, C36, and C37) were also evaluated and compared to 17 previously reported phenyl glycolipids.…”

Lipid and Carbohydrate Modifications of α-Galactosylceramide Differently Influence Mouse and Human Type I Natural Killer T Cell Activation

“…Like EF77, 7DW8-5 also has a modification in the acyl group. The length of the chain has been shortened to 11 carbons and a parafluor-phenyl group has been added (19,20). The rationale behind those different modifications is that changes in the lipid moiety would be expected to mainly influence the lipid interaction with CD1d, whereas changes in the galactose moiety and linkage can affect interaction with CD1d; the TCR and they could confer resistance to endoglycosidases upon injection into mice and thus could increase the half-life in serum.…”

Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl α-GalCer Analogues

“…16 α-GalCer derivatives with different aryl moieties at the acyl chain terminus have exhibited remarkable activity. 19,20 These analogues exhibited strong iNKT stimulation with Th1 bias. 20,21 According to Wu et al, their docking models revealed additional hydrogen bonding between the phenyl/aryl ring of the fatty acyl chain and the aromatic amino acid residues present on the wall of the A′ pocket in the CD1d hydrophobic groove.…”

“…19,20 These analogues exhibited strong iNKT stimulation with Th1 bias. 20,21 According to Wu et al, their docking models revealed additional hydrogen bonding between the phenyl/aryl ring of the fatty acyl chain and the aromatic amino acid residues present on the wall of the A′ pocket in the CD1d hydrophobic groove. 22 One such analogue (7DW8−5) from the same structural class exhibited superior adjuvant activity compared to that of α-GalCer in HIV and malaria vaccines in mice.…”

“…22 One such analogue (7DW8−5) from the same structural class exhibited superior adjuvant activity compared to that of α-GalCer in HIV and malaria vaccines in mice. 20,23 To achieve a better stimulatory effect with an enhanced Th1 and Th2 response, we have designed novel α-GalCer analogues that combine both the previously discussed properties. A benzyl group is utilized to serve as an aryl terminus of the alkyl chain, which was attached to the azido-galactosylceramide moiety through a triazole linker.…”