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* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center,
Department of Neurology,
Program in Immunology, Harvard Medical School, Boston, MA 02115;
¶ Inflammation Discovery Research, Wyeth Research, Cambridge MA 02140;
|| Department of Infectious Diseases and Immunity, Hammersmith Hospital, Imperial College, London, United Kingdom;
# Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; and
** Department of Pathology and New York University Cancer Institute, New York University School of Medicine, New York, NY 10016
Rapid binding of peptides to MHC class II molecules is normally limited to a deep endosomal compartment where the coordinate action of low pH and HLA-DM displaces the invariant chain remnant CLIP or other peptides from the binding site. Exogenously added peptides are subject to proteolytic degradation for extended periods of time before they reach the relevant endosomal compartment, which limits the efficacy of peptide-based vaccines and therapeutics. In this study, we describe a family of small molecules that substantially accelerate the rate of peptide binding to HLA-DR molecules in the absence of HLA-DM. A structure-activity relationship study resulted in analogs with significantly higher potency and also defined key structural features required for activity. These compounds are active over a broad pH range and thus enable efficient peptide loading at the cell surface. The small molecules not only enhance peptide presentation by APC in vitro, but are also active in vivo where they substantially increase the fraction of APC on which displayed peptide is detectable. We propose that the small molecule quickly reaches draining lymph nodes along with the coadministered peptide and induces rapid loading of peptide before it is destroyed by proteases. Such compounds may be useful for enhancing the efficacy of peptide-based vaccines and other therapeutics that require binding to MHC class II molecules.
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 grants from the National Institutes of Health (R01NS044914, R01AI57493, and P01AI045757 to K.W.W.) and the Harvard NeuroDiscovery Center. M.J.C., X.X., G.D.C., and R.L.S. were supported by funds from the Harvard NeuroDiscovery Center.
2 Address correspondence and reprint requests to Dr. Kai Wucherpfennig, Dana-Farber Cancer Institute, Dona Building, Room 1410, 44 Binney Street, Boston, MA 02115. E-mail address: kai_wucherpfennig{at}dfci.harvard.edu
3 Abbreviations used in this paper: FP, fluorescence polarization; MBP, myelin basic protein; HA, hemagglutinin; pMBP, MBP peptide; SA, streptavidin; pHA, HA peptide; mP, millipolarization unit.
4 The online version of this article contains supplemental material.
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