Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti–human DEC205 monoclonal antibody

Abstract

Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-␥-and interleukin-2-producing CD4 ؉ T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of antihuman immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8 ؉ T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects. (Blood. 2010;116(19):3828-3838)

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

“…Due to the high efficiency of antigen delivery and presentation, DEC205 has been one of the major receptor targets for vaccination in dendritic-cell-based immune therapies (56,57), and it is typically done by fusing DEC205-specific antibody with a fragment or intact protein of the antigen as a surrogate ligand (58)(59)(60). The finding of keratins as the natural ligands of DEC205 may give opportunities to improve this protocol by using ligandfused antigens for better presentation.…”

Decisions About Dendritic Cells: Past, Present, and Future

“…The program is being directed by our clinical director, Sarah Schlesinger, with enormous help from Sarah Pollak and Lauren Sinnenberg. Our first proofof-concept study uses HIV gag p24 as the antigen targeted within human anti-human DEC-205 monoclonal antibody; the latter is manufactured through an active collaboration with Tibor Keler at Celldex Therapeutics (133). The first adjuvant being tested is poly IC.…”

ESAT-6–dependent cytosolic pattern recognition drives noncognate tuberculosis control in vivo

“…Therefore, determining which human APC subset in different tissues is the most efficient one for sensing ESAT-6 might enable the development of improved strategies aimed at the targeted delivery of TB vaccines to a particular APC subset (73,74) and lead to optimal and localized IL-18-mediated IFN-γ secretion. Another critical question arises from our study: how does ESAT-6 activate NLRP3 in vivo?…”