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No Advantage of Cell-Penetrating Peptides over Receptor-Specific Antibodies in Targeting Antigen to Human Dendritic Cells for Cross-Presentation¹

Paul J. Tacken^*, Ben Joosten^*, Anita Reddy, Dayang Wu, Annemarie Eek, Peter Laverman, Anke Kretz-Rommel, Gosse J. Adema^*, Ruurd Torensma^* and Carl G. Figdor^2,*

^* Departments of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, and Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Alexion Pharmaceuticals, Cheshire, CT 06410; and Alexion Antibody Technologies, San Diego, CA 92121

Induction of CTL responses by dendritic cell (DC)-based vaccines requires efficient DC-loading strategies for class I Ags. Coupling Ags to cell-penetrating peptides (CPPs) or receptor-specific Abs improves Ag loading of DCs. In contrast to CPPs, receptor-specific Abs deliver conjugated Ags to DCs with high specificity, which is advantageous for in vivo strategies. It has, however, been speculated that CPPs facilitate uptake and endosomal escape of conjugated Ags, which would potently enhance cross-presentation. In this study, we directly compare the in vitro targeting efficiency of a humanized D1 Ab directed against the human DC surface receptor DC-SIGN hD1 to that of three CPPs. The three CPPs colocalized within endosomes when targeted to human monocyte-derived DCs simultaneously, whereas hD1 was present in a different set of endosomes. However, within 75 min after uptake CPPs and hD1 colocalized extensively within the lysosomal compartment. Ab-mediated targeting of class I-restricted peptides to DC-SIGN enhanced cross-presentation of the peptides, while only one of the CPPs enhanced peptide presentation. This CPP and hD1 enhanced cross-presentation with equal efficiencies. Thus, we found no evidence of CPP specifically favoring the delivery of conjugated Ag to the DC class I presentation pathway. Given the specificity with which Abs recognize their targets, this favors the use of DC receptor-specific Abs for in vivo vaccination strategies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research funding from Alexion Pharmaceuticals and European Commission contracts 512074 and 503037 to P.T. and C.F.

² Address correspondence and reprint requests to Dr. Carl G. Figdor, Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail address: c.figdor{at}ncmls.ru.nl

³ Abbreviations used in this paper: DC, dendritic cell; CPP, cell-penetrating peptide; DC-SIGN, DC-specific ICAM-grabbing nonintegrin; DTPA, diethylenetriamine pentaacetic acid; hD1, human D1 (Ab); iDC, immature DC; mDC, mature DC; PBLk, peripheral blood leukocyte; poly(I:C), polyinosinic-polycytidylic acid; polyR, polyarginine peptide; SA, streptavidin; SAMA, S-acetyl mercaptoacetic acid; scD1, single chain D1 (Ab).