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

 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 Ig-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high affinity binding to hDEC205. Also CD11c promoter hDEC205 transgenic mice were generated, and 3G9 selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced IFN-gamma and IL-2 producing CD4(+) T cells in hDEC205 transgenic mice if poly IC was coadministered as adjuvant. The T cell response was broad recognizing at least 3 Gag peptides and high titers of anti-human IgG antibody were made. Anti-hDEC205 also improved 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, published online. [Epub ahead of print]