A Pegylated Derivative of α-Galactosylceramide Exhibits Improved Biological Properties

Abstract

The glycolipid α-galactosylceramide (αGalCer) has immunomodulatory properties, which have been exploited to combat cancer, chronic inflammatory diseases, and infections. However, its poor solubility makes αGalCer a suboptimal compound for in vivo applications. In this study, a pegylated derivative of αGalCer is characterized, which exhibits improved physical and biological properties. The new compound, αGalCerMPEG, is water-soluble and retains the specificity for the CD1d receptor of αGalCer. The in vitro stimulatory properties on immune cells (e.g., dendritic cells and splenocytes) are maintained intact, even when tested at a 33-fold lower concentration of the active moiety than αGalCer. NK cells isolated from mice treated with αGalCerMPEG also had stronger cytotoxic activity on YAC-1 cells than those obtained from animals receiving either αGalCer or CpG. Intranasal immunization studies performed in mice showed that αGalCerMPEG exerts stronger adjuvant activities than the parental compound αGalCer when tested at 0.35 vs 11.7 nM/dose. Coadministration of β-galactosidase with αGalCerMPEG resulted not only in high titers of Ag-specific Abs in serum (i.e., 1:512,000), but also in the stimulation of stronger Th2 and secretory IgA responses, both at local and remote mucosal effector sites (i.e., nose, lung, and vagina). The new synthetic derivative αGalCerMPEG represents a promising tool for the development of immune interventions against infectious and noninfectious diseases.

Activated NKT cells imprint NK‐cell differentiation, functionality and education

“…Thus, in the present study the potential of activated NKT cells to modulate fundamental NK-cell properties was investigated using a pegylated derivative of αGalCer (αGalCerMPEG). This compound has been shown to exhibit superior physicochemical and immune modulatory properties as compared to the parental compound [25]. We addressed the influence of αGalCerMPEG-activated NKT cells on the differentiation status of NK cells, as well as their implications in the process of NK-cell education and the subsequent functional properties.…”

“…To produce water soluble αGalCer, a pegylated derivative was generated as described in Ebensen et al [25]. Briefly, the parental compound αGalCer was mixed with methyl-PEG-COOH.…”

Aminocyclitol‐Substituted Phytoceramides and their Effects on iNKT Cell Stimulation

“…All cyclitols obtained contain an hydroxy group in place of the galactose hydroxymethyl substituent, a group not involved in a-GalCer-CD1d binding and TCR recognition and not essential for iNKT activity. [20,42] Interestingly, the aminocyclitols better match the gluco configuration over the galacto configuration because of the equatorial orientation of the 4'OH, a change that would not influence ligand binding as a-GalCer 4'OH does not interact with any CD1d residues, but is relevant for TCR recognition through a hydrogen bond to Ser 26. The observed biological activity of HS44 (and also for 3 a,b) is in accordance with the iNKT activity of the structurally related a-glucosylphytoceramide, [6] which is a weaker agonist than a-GalCer.…”

Selective quantitation of the incorporation of the immunomodulator α-galactosylceramide in liposomes using LC–MS/MS

“…The lipophilic nature of α-GalCer ( Figure 1) results in poor solubility in most pharmaceutical solvents [5]. Consequently, α-GalCer is an ideal candidate for formulation into liposomes.…”