title: 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-γ- 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 anti-human 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.
authors.affiliation: Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Laura
authors.initials: L
authors.lastname: Vitale
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: He
authors.forename: Christine
authors.initials: C
authors.lastname: Trumpfheller
authors.forename: Leonia
authors.initials: L
authors.lastname: Bozzacco
authors.forename: Yoonkyung
authors.initials: Y
authors.lastname: Do
authors.forename: Godwin
authors.initials: G
authors.lastname: Nchinda
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Park
authors.forename: Durga Bhavani
authors.initials: DB
authors.lastname: Dandamudi
authors.forename: Elina
authors.initials: E
authors.lastname: Shrestha
authors.forename: Maggi
authors.initials: M
authors.lastname: Pack
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
authors.forename: Tibor
authors.initials: T
authors.lastname: Keler
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.forename: Chae Gyu
authors.initials: CG
authors.lastname: Park
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001483:Base Sequence; D045142:Cross-Priming; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C093569:DEC-205 receptor; D017931:DNA Primers; D016655:HIV Core Protein p24; D037181:Lectins, C-Type; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D022223:Vaccines, Subunit; C514799:p24 protein, Human Immunodeficiency Virus Type 1