title: Anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) promote HER2/neu processing and presentation by dendritic cells: implications in immunotherapy and vaccination strategies.
abstract: HER2/neu, a transmembrane glycoprotein overexpressed in several types of human cancers, is a potential target for active immunotherapy. However, this protein and especially its extracellular domain (ECD(HER2)), is weakly immunogenic and is poorly processed by dendritic cells (DCs). Previously, we showed that anti-HER2/neu IgG3-(IL-2) and anti-HER2/neu IgG3-(GM-CSF) fusion proteins can enhance the immunogenicity of ECD(HER2) in mice, and that the non-covalent physical association between each antibody fusion proteins and ECD(HER2) was critical to elicit optimal protective immunity against HER2/neu expressing tumors. We now use the professional antigen-presenting DCs to investigate the effect of the antibody fusion protein binding to ECD(HER2) on its trafficking and presentation. We found that when the extracellular domain of HER2/neu fused to ovalbumin (OVA-ECD(HER2)) is bound by HER2/neu-specific antibody-(IL-2) or antibody-(GM-CSF) fusion proteins, the bound antigen is more efficiently processed by murine bone-marrow-derived dendritic cells (BMDCs) and presented to OVA-specific T-cells than the unbound OVA-ECD(HER2). We also found that ECD(HER2) bound by anti-HER2/neu IgG3-(IL-2) is very efficiently internalized and that the internalized ECD(HER2) is not retained in the early endosomal compartments but traffics to the antigen-processing compartments. These results are consistent with our earlier in vivo studies and suggest that both antibody-(IL-2) and antibody-(GM-CSF) fusion proteins can be used to enhance the immune response to poorly immunogenic antigens including tumor-associated antigens (TAAs).
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Jay Soriano
authors.initials: JS
authors.lastname: Dela Cruz
authors.forename: Kamh Ryan
authors.initials: KR
authors.lastname: Trinh
authors.forename: Hsiao Wen
authors.initials: HW
authors.lastname: Chen
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Sherie L
authors.initials: SL
authors.lastname: Morrison
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Penichet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007109:Immunity; D007074:Immunoglobulin G; D007167:Immunotherapy; D007376:Interleukin-2; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014611:Vaccination
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007074:Immunoglobulin G; D007376:Interleukin-2; D010047:Ovalbumin; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins