A pegylated derivative of α-galactosylceramide exhibits improved biological properties

The glycolipid a-galactosylceramide (alpha GalCer) has immunomodulatory properties, which have been exploited to combat cancer, chronic inflammatory diseases, and infections. However, its poor solubility makes aGalCer a suboptimal compound for in vivo applications. In this study, a pegylated derivative of aGalCer is characterized, which exhibits improved physical and biological properties. The new compound, alpha GalCerMPEG, is water-soluble and retains the specificity for the CDId receptor of aGalCer. 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 aGalCer. NK cells isolated from mice treated with aGalCerMPEG also had stronger cytotoxic activity on YAC-I cells than those obtained from animals receiving either aGalCer or CpG. Intranasal immunization studies performed in mice showed that aGalCerMPEG exerts stronger adjuvant activities than the parental compound aGalCer when tested at 0.35 vs 11.7 nM/dose. Coadministration of beta-galactosidase with alpha GaCerMPEG 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 aGalCerMPEG represents a promising tool for the development of immune interventions against infectious and noninfectious diseases.