Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy.
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.
Department of Bioengineering and Center for Intracellular Delivery of Biologics, University of Washington, Seattle Washington 98195, USA.
Suzanne
S
Foster
Craig L
CL
Duvall
Emily F
EF
Crownover
Allan S
AS
Hoffman
Patrick S
PS
Stayton
D000179:Acrylates / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D018572:Disease-Free Survival; D016503:Drug Delivery Systems / Q000379:methods*; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000032:analysis / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008689:Methacrylates / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009757:Nylons / Q000737:chemistry / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D013945:Thymoma / Q000401:mortality / Q000628:therapy; D013953:Thymus Neoplasms / Q000401:mortality / Q000628:therapy; D016896:Treatment Outcome
D000179:Acrylates; D000941:Antigens; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D008689:Methacrylates; D009757:Nylons; D011108:Polymers; C109846:poly(2-(diethylamino)ethyl methacrylate); D010047:Ovalbumin; C036658:acrylic acid