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* Celldex Therapeutics, Bloomsbury, NJ 08804;
Department of Medicine and Microbiology, Columbia University, New York, NY 10032;
Medarex, Milpitas, CA 95035; and
Medarex, Bloomsbury, NJ 08804
Pattern recognition receptors are preferentially expressed on APCs allowing selective uptake of pathogens for the initiation of antimicrobial immunity. In particular, C-type lectin receptors, including the mannose receptor (MR), facilitate APC-mediated adsorptive endocytosis of microbial glyconjugates. We have investigated the potential of antigenic targeting to the MR as a means to induce Ag-specific humoral and cellular immunity. hMR transgenic (hMR Tg) mice were generated to allow specific targeting with the anti-hMR Ab, B11. We show that hMR targeting induced both humoral and cellular antigenic specific immunity. Immunization of hMR Tg mice with B11 mAbs induced potent humoral responses independent of adjuvant. Injection of hMR Tg mice with mouse anti-hMR Ab clone 19.2 elicited anti-Id-specific humoral immunity while non-Tg mice were unresponsive. B11-OVA fusion proteins (B11-OVA) were efficiently presented to OVA-specific CD4 and CD8 T cells in MR Tg, but not in non-Tg, mice. Effector differentiation of responding T cells in MR Tg mice was significantly enhanced with concomitant immunization with the TLR agonist, CpG. Administration of both CpG and B11-OVA to hMR Tg mice induced OVA-specific tumor immunity while WT mice remained unprotected. These studies support the clinical development of immunotherapeutic approaches in cancer using pattern recognition receptor targeting systems for the selective delivery of tumor Ags to APCs.
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 National Institutes of Health Grant R01 NCI CA94037 (to R.C.).
2 L.-Z.H., A.C., and J.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Raphael Clynes, Department of Medicine and Microbiology, Columbia University, New York, NY 10032; E-mail address: rc645{at}columbia.edu or Dr. Tibor Keler, Celldex Therapeutics, Bloomsbury, NJ 08804; E-mail address: tkeler{at}celldextherapeutics.com
4 Abbreviations used in this paper: MR, mannose receptor; CLR, calcium-dependent lectin receptor; M
, macrophage; DC, dendritic cell; hMR, human MR; BAC, bacterial artificial chromosome; muMR, mouse MR; BM, bone marrow; PEC, peritoneal exudate cell; DT, diphtheria toxin; WT, wild type.
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