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

Cheolho Cheong, Jae Hoon Choi, Laura Vitale, Li Zhen He, Christine Trumpfheller, Leonia Bozzacco, Yoonkyung Do, Godwin Nchinda, Sung Ho Park, Durga Bhavani Dandamudi, Elina Shrestha, Maggi Pack, Han Woong Lee, Tibor Keler, Ralph M. Steinman, Chae Gyu Park

Research output: Contribution to journalArticle

80 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)3828-3838
Number of pages11
JournalBlood
Volume116
Issue number19
DOIs
Publication statusPublished - 2010 Nov 11

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T-cells
Humoral Immunity
Cellular Immunity
Dendritic Cells
Monoclonal Antibodies
HIV
Proteins
Vaccines
Immunization
Poly C
T-Lymphocytes
Interferons
Interleukin-2
Immunoglobulins
Transgenic Mice
Animals
Fusion reactions
Immunoglobulin G
Immunity
HIV Core Protein p24

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Cheong, Cheolho ; Choi, Jae Hoon ; Vitale, Laura ; He, Li Zhen ; Trumpfheller, Christine ; Bozzacco, Leonia ; Do, Yoonkyung ; Nchinda, Godwin ; Park, Sung Ho ; Dandamudi, Durga Bhavani ; Shrestha, Elina ; Pack, Maggi ; Lee, Han Woong ; Keler, Tibor ; Steinman, Ralph M. ; Park, Chae Gyu. / Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody. In: Blood. 2010 ; Vol. 116, No. 19. pp. 3828-3838.
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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 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.",
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Cheong, C, Choi, JH, Vitale, L, He, LZ, Trumpfheller, C, Bozzacco, L, Do, Y, Nchinda, G, Park, SH, Dandamudi, DB, Shrestha, E, Pack, M, Lee, HW, Keler, T, Steinman, RM & Park, CG 2010, 'Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody', Blood, vol. 116, no. 19, pp. 3828-3838. https://doi.org/10.1182/blood-2010-06-288068

Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody. / Cheong, Cheolho; Choi, Jae Hoon; Vitale, Laura; He, Li Zhen; Trumpfheller, Christine; Bozzacco, Leonia; Do, Yoonkyung; Nchinda, Godwin; Park, Sung Ho; Dandamudi, Durga Bhavani; Shrestha, Elina; Pack, Maggi; Lee, Han Woong; Keler, Tibor; Steinman, Ralph M.; Park, Chae Gyu.

In: Blood, Vol. 116, No. 19, 11.11.2010, p. 3828-3838.

Research output: Contribution to journalArticle

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AU - He, Li Zhen

AU - Trumpfheller, Christine

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AU - Park, Sung Ho

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AU - Shrestha, Elina

AU - Pack, Maggi

AU - Lee, Han Woong

AU - Keler, Tibor

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AU - Park, Chae Gyu

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