Inhibition of Melanoma Growth by Targeting of Antigen to Dendritic Cells via an Anti-DEC-205 Single-Chain Fragment Variable Molecule

• Published in: Clinical cancer research Vol. 14; no. 24; pp. 8169 - 8177
• Main Authors: Johnson, Theron S, Mahnke, Karsten, Storn, Volker, Schönfeld, Kurt, Ring, Sabine, Nettelbeck, Dirk M, Haisma, Hidde J, Le Gall, Fabrice, Kontermann, Roland E, Enk, Alexander H
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15.12.2008
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; antigen targeting; Antigens, CD - immunology; Antigens, Neoplasm - immunology; DEC-205; Dendritic Cells - immunology; gp100 Melanoma Antigen; Immunoglobulin Fragments - therapeutic use; Lectins, C-Type - immunology; melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Minor Histocompatibility Antigens; Receptors, Cell Surface - immunology; scFv; tumor suppression
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1474

Purpose: Our goal was to target melanoma antigens to the dendritic cell-specific receptor DEC-205. DEC-205 is an antigen receptor expressed on dendritic cells and has been shown to guide antigens to MHC class I and II compartments for processing and presentation to T cells. Experimental Design: The melanoma tumor-associated antigen (TAA), gp100, was fused to the single-chain fragment variable (scFv) specific for DEC-205. The binding capacity of the scFv was tested on lymph node-isolated CD11c + cells. Mixed lymphocyte reactions were carried out to show an increased proliferative capacity of gp100 antigen-specific CD4 and CD8 T cells. Furthermore the scFv-TAA was used in a therapeutic setting using two different melanoma mouse models. Results: C57Bl/6 mice were injected with scFv-DEC-205-gp100, monoclonal antibody anti-DEC-205, or PBS. Using fluorescence-activated cell sorting, we showed that lymph node CD11c + dendritic cells stained positive for the binding of the scFv-mDEC-205-gp100 and the anti-DEC-205 monoclonal antibody, whereas the PBS-injected animals were negative. In mixed lymphocyte reactions, bone marrow-derived dendritic cells pulsed with scFv-mDEC-205-gp100 significantly increased proliferation of gp100-specific CD8 + and CD4 + T cells beyond gp100 peptide-pulsed or nonpulsed bone marrow-derived dendritic cells. Finally, in B16/F10 and RET models, a concentration-dependent suppression of tumor growth using scFv-mDEC-205-gp100 (66% reduction of tumor volume), in comparison with gp100 peptide vaccination, was observed. Conclusions: Our results indicate that the scFv-mDEC-205-gp100 targets TAA to dendritic cells in vivo for presentation on both MHC class I and II molecules. In vivo , this leads to an improved immune response and a decrease in tumor growth rate.