Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy.

Abstract

Protein-based vaccines have significant potential as infectious disease and anticancer therapeutics, but clinical impact has been limited in some applications by their inability to generate a coordinated cellular immune response. Here, a pH-responsive carrier incorporating poly(propylacrylic acid) (PPAA) was evaluated to test whether improved cytosolic delivery of a protein antigen could enhance CD8+ cytotoxic lymphocyte generation and prophylactic tumor vaccine responses. PPAA was directly conjugated to the model ovalbumin antigen via reducible disulfide linkages and was also tested in a particulate formulation after condensation with cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA). Intracellular trafficking studies revealed that both PPAA-containing formulations were stably internalized and evaded exocytotic pathways, leading to increased intracellular accumulation and potential access to the cytosolic MHC-1 antigen presentation pathway. In an EG.7-OVA mouse tumor protection model, both PPAA-containing carriers robustly inhibited tumor growth and led to an approximately 3.5-fold increase in the longevity of tumor-free survival relative to controls. Mechanistically, this response was attributed to the 8-fold increase in production of ovalbumin-specific CD8+ T-lymphocytes and an 11-fold increase in production of antiovalbumin IgG. Significantly, this is one of the first demonstrated examples of in vivo immunotherapeutic efficacy using soluble protein-polymer conjugates. These results suggest that carriers enhancing cytosolic delivery of protein antigens could lead to more robust CD8+ T-cell response and demonstrate the potential of pH-responsive PPAA-based carriers for therapeutic vaccine applications.

• Authors: Suzanne Foster, Craig L Duvall, Emily F Crownover, Allan S Hoffman, Patrick S Stayton
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 21 Issue 12 Pg. 2205-12 (Dec 15 2010) ISSN: 1520-4812 [Electronic] United States
• PMID: 21043513 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Acrylates
• Antigens
• Cancer Vaccines
• Immunoglobulin G
• Methacrylates
• Nylons
• Polymers
• poly(2-(diethylamino)ethyl methacrylate)
• Ovalbumin
• acrylic acid

Topics

• Acrylates (chemistry, metabolism)
• Animals
• Antigen Presentation (immunology)
• Antigens (administration & dosage, immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cancer Vaccines (immunology, metabolism)
• Cell Proliferation
• Disease-Free Survival
• Drug Delivery Systems (methods)
• Endosomes (immunology, metabolism)
• Female
• Hydrogen-Ion Concentration
• Immunoglobulin G (analysis, biosynthesis)
• Lymphocyte Activation (immunology)
• Methacrylates (chemistry, metabolism)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Nylons (chemistry, metabolism)
• Ovalbumin (administration & dosage, immunology, metabolism)
• Polymers (chemistry, metabolism)
• Thymoma (mortality, therapy)
• Thymus Neoplasms (mortality, therapy)
• Treatment Outcome