Enhanced major histocompatibility complex class I-dependent presentation
of antigens modified with cationic and fusogenic peptides
Reiner Laus, Thomas J. Graddis, Itzhak Hakim
& Damir Vidovic
Dendreon Corporation, Seattle,
WA 98121.
Correspondence should be addressed to Damir Vidovic dvidovic@dendreon.comcytotoxic T cellsantigen presentationdendritic cells
Soluble extracellular protein antigens are notoriously poor stimulators
of CD8+ cytotoxic T-lymphocyte (CTL) responses, largely because
these antigens have inefficient access to an endogenous cytosolic pathway
of the major histocompatibility complex (MHC) class I−dependent antigen
presentation. Here, we present a strategy that facilitates antigen penetration
into the cytosol of antigen-presenting cells (APC) by addition to the antigen
of charge-modifying peptide sequences. As a result of this intervention, the
charge modification enhances antigen uptake into APC by counteracting the
repulsive cell surface charge, and then endosomal membranes are disrupted
with a subsequent release of antigen into the cytosol. This technology significantly
improves MHC class I−dependent antigen presentation to CTL, enabling
a more efficient generation of specific CTL immunity in vivo. The strategy
described here has potential for use in developing efficient vaccines for
antigen-specific immunotherapy of human malignancies.
