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

Johnson, T. S., Mahnke, K., Storn, V., Schoenfeld, K., Ring, S., Nettelbeck, D. M., Haisma, H. J., Le Gall, F., Kontermann, R. E. & Enk, A. H., 15-Dec-2008, In : Clinical Cancer Research. 14, 24, p. 8169-8177 9 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Theron S. Johnson
  • Karsten Mahnke
  • Volker Storn
  • Kurt Schoenfeld
  • Sabine Ring
  • Dirk M. Nettelbeck
  • Hidde J. Haisma
  • Fabrice Le Gall
  • Roland E. Kontermann
  • Alexander H. Enk

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: C57BI/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.

Original languageEnglish
Pages (from-to)8169-8177
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number24
Publication statusPublished - 15-Dec-2008

    Keywords

  • IN-VIVO, RECEPTOR, EFFICACY, DEC-205, PROTEIN, STATE, DNA, IMMUNOTHERAPY, THERAPY, VACCINE

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