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.
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).
Dela Cruz
Jay Soriano
JS
Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA.
Trinh
Kamh Ryan
KR
Chen
Hsiao Wen
HW
Ribas
Antoni
A
Morrison
Sherie L
SL
Penichet
Manuel L
ML
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
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