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: Jay Soriano Dela Cruz, Kamh Ryan Trinh, Hsiao Wen Chen, Antoni Ribas, Sherie L Morrison, Manuel L Penichet
• Journal: Molecular immunology (Mol Immunol) Vol. 43 Issue 6 Pg. 667-76 (Feb 2006) ISSN: 0161-5890 [Print] England
• PMID: 15908002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• Immunoglobulin G
• Interleukin-2
• Recombinant Fusion Proteins
• Granulocyte-Macrophage Colony-Stimulating Factor
• Ovalbumin
• Receptor, ErbB-2

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antigen Presentation
• Antigens, Neoplasm (immunology)
• Dendritic Cells (immunology)
• Endosomes
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor
• Immunity
• Immunoglobulin G
• Immunotherapy
• Interleukin-2
• Mice
• Mice, Inbred BALB C
• Ovalbumin
• Receptor, ErbB-2 (immunology)
• Recombinant Fusion Proteins (immunology)
• Vaccination