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 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.
Cheong
Cheolho
C
Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10065, USA.
Choi
Jae-Hoon
JH
Vitale
Laura
L
He
Li-Zhen
LZ
Trumpfheller
Christine
C
Bozzacco
Leonia
L
Do
Yoonkyung
Y
Nchinda
Godwin
G
Park
Sung Ho
SH
Dandamudi
Durga Bhavani
DB
Shrestha
Elina
E
Pack
Maggi
M
Lee
Han-Woong
HW
Keler
Tibor
T
Steinman
Ralph M
RM
Park
Chae Gyu
CG
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
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