Vaccination with novel combinations of anti-HER2/neu cytokines fusion proteins and soluble protein antigen elicits a protective immune response against HER2/neu expressing tumors.
We have previously demonstrated that anti-HER2/neu IgG3-(IL-2), (IL-12)-IgG3, or IgG3-(GM-CSF) antibody fusion proteins (mono-AbFPs) elicit anti-tumor activity against murine tumors expressing HER2/neu when used as adjuvants of extracellular domain of HER2/neu (ECD(HER2)) protein vaccination. We have now studied the effect of combinations of IL-2 and IL-12 or IL-12 and GM-CSF mono-AbFPs during vaccination with ECD(HER2). In addition, we developed two novel anti-HER2/neu IgG3-cytokine fusion proteins in which IL-2 and IL-12 or IL-12 and GM-CSF were fused to the same IgG3 molecule (bi-AbFPs). (IL-12)-IgG3-(IL-2) and (IL-12)-IgG3-(GM-CSF) were properly assembled and retained both cytokine activity and the ability to bind antigen. Vaccination of mice with ECD(HER2) and a combination of cytokines as either bi-AbFPs or two mono-AbFPs activated both Thl and Th2 immune responses and resulted in significant protection against challenge with a HER2/neu expressing tumor. Our results suggest that this approach will be effective in the prevention and/or treatment of HER2/neu expressing tumors.
Helguera
Gustavo
G
Department of Microbiology, Immunology and Molecular Genetics and the Molecular Biology Institute, University of California, 405 Hilgard Avenue, Box 148906, Los Angeles, CA 90095-1489, USA.
Dela Cruz
Jay S
JS
Lowe
Christine
C
Ng
Patrick P
PP
Trinh
Ryan
R
Morrison
Sherie L
SL
Penichet
Manuel L
ML
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism; D018734:Genes, erbB-2 / Q000235:genetics* / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000276:immunology*; D014162:Transfection; D014611:Vaccination
D000276:Adjuvants, Immunologic; D000906:Antibodies; D019496:Cancer Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor