Synthesis and Evaluation of Liposomal Anti-GM3 Cancer Vaccine Candidates Covalently and Noncovalently Adjuvanted by αGalCer

J Med Chem. 2021 Feb 25;64(4):1951-1965. doi: 10.1021/acs.jmedchem.0c01186. Epub 2021 Feb 4.

Abstract

GM3, a typical tumor-associated carbohydrate antigen, is considered as an important target for cancer vaccine development, but its low immunogenicity limits its application. αGalCer, an iNKT cell agonist, has been employed as an adjuvant via a unique immune mode. Herein, we prepared and investigated two types of antitumor vaccine candidates: (a) self-adjuvanting vaccine GM3-αGalCer by conjugating GM3 with αGalCer and (b) noncovalent vaccine GM3-lipid/αGalCer, in which GM3 is linked with lipid anchor and coassembled with αGalCer. This demonstrated that βGalCer is an exceptionally optimized lipid anchor, which enables the noncovalent vaccine candidate GM3-βGalCer/αGalCer to evoke a comparable antibody level to GM3-αGalCer. However, the antibodies induced by GM3-αGalCer are better at recognition B16F10 cancer cells and more effectively activate the complement system. Our study highlights the importance of vaccine constructs utilizing covalent or noncovalent assembly between αGalCer with carbohydrate antigens and choosing an appropriate lipid anchor for use in noncovalent vaccine formulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Cancer Vaccines / chemical synthesis
  • Cancer Vaccines / immunology
  • Cancer Vaccines / pharmacology*
  • Carbohydrate Sequence
  • Female
  • G(M3) Ganglioside / analogs & derivatives
  • G(M3) Ganglioside / immunology
  • G(M3) Ganglioside / pharmacology*
  • Galactosylceramides / chemical synthesis
  • Galactosylceramides / immunology
  • Galactosylceramides / pharmacology*
  • Humans
  • Immunity, Humoral / drug effects
  • Immunoglobulin G / immunology
  • Liposomes / chemistry
  • Mice
  • Mice, Inbred BALB C
  • Natural Killer T-Cells / immunology
  • THP-1 Cells

Substances

  • Adjuvants, Immunologic
  • Cancer Vaccines
  • G(M3) Ganglioside
  • Galactosylceramides
  • Immunoglobulin G
  • Liposomes
  • alpha-galactosylceramide