HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ramakrishna, V. Articles by Endres, M. J. Search for Related Content PubMed PubMed Citation Articles by Ramakrishna, V. Articles by Endres, M. J.

Mannose Receptor Targeting of Tumor Antigen pmel17 to Human Dendritic Cells Directs Anti-Melanoma T Cell Responses via Multiple HLA Molecules

Venky Ramakrishna^1,*, John F. Treml^1,*, Laura Vitale^*, John E. Connolly^2,, Thomas O’Neill^*, Patricia A. Smith^*, Charles L. Jones^*, Li-Zhen He^*, Joel Goldstein^*, Paul K. Wallace, Tibor Keler^* and Michael J. Endres^3,*

^* Medarex, Inc., Bloomsbury, NJ 08804; Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756; and Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 14263

Targeting recycling endocytic receptors with specific Abs provides a means for introducing a variety of tumor-associated Ags into human dendritic cells (DCs), culminating in their efficient presentation to T cells. We have generated a human mAb (B11) against the mannose receptor that is rapidly internalized by DCs through receptor-mediated endocytosis. By genetically linking the melanoma Ag, pmel17, to Ab B11, we obtained the fully human fusion protein, B11-pmel17. Treatment of DCs with B11-pmel17 resulted in the presentation of pmel17 in the context of HLA class I and class II molecules. Thus, potent pmel17-specific T cells were cytotoxic toward gp100⁺ HLA-matched melanoma targets, but not HLA-mismatched melanoma or gp100^- nonmelanoma tumor lines. Importantly, competitive inhibition of lysis of an otherwise susceptible melanoma cell line by cold targets pulsed with known gp100 CD8 T cell epitopes as well as a dose-dependent proliferative response to Th epitopes demonstrates that DCs can process targeted Ag for activation of cytotoxic as well as helper arms of the immune response. Thus, the specific targeting of soluble exogenous tumor Ag to the DC mannose receptor directly contributes to the generation of multiple HLA-restricted Ag-specific T cell responses.

This article has been cited by other articles:

				H. Wei, S. Wang, D. Zhang, S. Hou, W. Qian, B. Li, H. Guo, G. Kou, J. He, H. Wang, et al. Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice Clin. Cancer Res., July 15, 2009; 15(14): 4612 - 4621. [Abstract] [Full Text] [PDF]

				S.-i. Fujii, A. Goto, and K. Shimizu Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity Blood, April 30, 2009; 113(18): 4262 - 4272. [Abstract] [Full Text] [PDF]

				P. J. Tacken, B. Joosten, A. Reddy, D. Wu, A. Eek, P. Laverman, A. Kretz-Rommel, G. J. Adema, R. Torensma, and C. G. Figdor No Advantage of Cell-Penetrating Peptides over Receptor-Specific Antibodies in Targeting Antigen to Human Dendritic Cells for Cross-Presentation J. Immunol., June 1, 2008; 180(11): 7687 - 7696. [Abstract] [Full Text] [PDF]

				J. Idoyaga, C. Cheong, K. Suda, N. Suda, J. Y. Kim, H. Lee, C. G. Park, and R. M. Steinman Cutting Edge: Langerin/CD207 Receptor on Dendritic Cells Mediates Efficient Antigen Presentation on MHC I and II Products In Vivo J. Immunol., March 15, 2008; 180(6): 3647 - 3650. [Abstract] [Full Text] [PDF]

				L.-Z. He, A. Crocker, J. Lee, J. Mendoza-Ramirez, X.-T. Wang, L. A. Vitale, T. O'Neill, C. Petromilli, H.-F. Zhang, J. Lopez, et al. Antigenic Targeting of the Human Mannose Receptor Induces Tumor Immunity J. Immunol., May 15, 2007; 178(10): 6259 - 6267. [Abstract] [Full Text] [PDF]

				E. J. McKenzie, P. R. Taylor, R. J. Stillion, A. D. Lucas, J. Harris, S. Gordon, and L. Martinez-Pomares Mannose Receptor Expression and Function Define a New Population of Murine Dendritic Cells J. Immunol., April 15, 2007; 178(8): 4975 - 4983. [Abstract] [Full Text] [PDF]

				R. W. Carter, C. Thompson, D. M. Reid, S. Y. C. Wong, and D. F. Tough Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1 J. Immunol., August 15, 2006; 177(4): 2276 - 2284. [Abstract] [Full Text] [PDF]

				J. C. Valencia, H. Watabe, A. Chi, F. Rouzaud, K. G. Chen, W. D. Vieira, K. Takahashi, Y. Yamaguchi, W. Berens, K. Nagashima, et al. Sorting of Pmel17 to melanosomes through the plasma membrane by AP1 and AP2: evidence for the polarized nature of melanocytes J. Cell Sci., March 15, 2006; 119(6): 1080 - 1091. [Abstract] [Full Text] [PDF]

				J. S. Lam, M. K. Mansour, C. A. Specht, and S. M. Levitz A Model Vaccine Exploiting Fungal Mannosylation to Increase Antigen Immunogenicity J. Immunol., December 1, 2005; 175(11): 7496 - 7503. [Abstract] [Full Text] [PDF]

				Y. Su, T. Bakker, J. Harris, C. Tsang, G. D. Brown, M. R. Wormald, S. Gordon, R. A. Dwek, P. M. Rudd, and L. Martinez-Pomares Glycosylation Influences the Lectin Activities of the Macrophage Mannose Receptor J. Biol. Chem., September 23, 2005; 280(38): 32811 - 32820. [Abstract] [Full Text] [PDF]

				P. J. Tacken, I. J. M. de Vries, K. Gijzen, B. Joosten, D. Wu, R. P. Rother, S. J. Faas, C. J. A. Punt, R. Torensma, G. J. Adema, et al. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody Blood, August 15, 2005; 106(4): 1278 - 1285. [Abstract] [Full Text] [PDF]