Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses

Bioconjug Chem. 2016 Jan 20;27(1):110-20. doi: 10.1021/acs.bioconjchem.5b00528. Epub 2015 Dec 9.

Abstract

Generation of a CD8(+) response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8(+) T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8(+) T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an l-Rhamnose (Rha) epitope. We synthesized a 20-amino-acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated α-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper(I)-catalyzed azido-alkyne cycloaddition (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / immunology
  • Cell Proliferation
  • Chemistry Techniques, Synthetic
  • Cholesterol / chemistry
  • Epitopes / genetics
  • Epitopes / immunology
  • Female
  • Immunoconjugates / chemistry
  • Immunoconjugates / pharmacology*
  • Interferon-gamma / metabolism
  • Liposomes / chemistry
  • Mice, Inbred C57BL
  • Mucin-1 / chemistry*
  • Mucin-1 / immunology
  • Protein Engineering / methods
  • Rhamnose / immunology*
  • Vaccines / immunology*

Substances

  • Cancer Vaccines
  • Epitopes
  • Immunoconjugates
  • Liposomes
  • Mucin-1
  • Vaccines
  • Interferon-gamma
  • Cholesterol
  • Rhamnose