An oral TLR7 agonist is a potent adjuvant of DNA vaccination in transgenic mouse tumor models.
In vivo electroporation of plasmid DNA (DNA-EP) is an efficient and safe method for vaccines resulting in increased DNA uptake, enhanced protein expression and increased immune responses to the target antigen in a variety of species. To further enhance the efficacy of DNA-EP, we have evaluated the toll-like receptor7 (TLR7) agonist-2, 9, substituted 8-hydroxyadenosine derivative or SM360320--as an adjuvant to vaccines against HER2/neu and CEA in BALB-neuT and CEA transgenic mice (CEA.Tg), respectively. SM360320 induced in vivo secretion of interferon alpha (IFNalpha) and exerted a significant antitumor effect in CEA.Tg mice challenged with a syngenic tumor cell line expressing CEA and an additive effect with a CEA vaccine. Additionally, combination of SM360320 with plasmid encoding the extracellular and transmembrane domain of ratHER2/neu affected the spontaneous tumor progression in BALB-neuT mice treated in an advanced disease setting. The antitumor effect in mice treated with DNA-EP and SM360320 was associated with an anti-CEA and anti-p185(neu) antibody isotype switch from IgG1 to IgG2a. These data demonstrate that SM360320 exerts significant antitumor effects and can act in association with DNA-EP for CEA-positive colon cancer and HER2-positive mammary carcinoma. These observations therefore emphasize the potential of SM360320 as immunological adjuvant for therapeutic DNA vaccines.
Dharmapuri
S
S
Department of Oncology and Pharmacology, IRBM P Angeletti, Pomezia, Italy.
Aurisicchio
L
L
Neuner
P
P
Verdirame
M
M
Ciliberto
G
G
La Monica
N
N
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; C508876:SM360320; D051199:Toll-Like Receptor 7; D019444:Vaccines, DNA; D000225:Adenine