title: Augmentation of SIV DNA vaccine-induced cellular immunity by targeting the 4-1BB costimulatory molecule.
abstract: DNA vaccines are effective at inducing antigen-specific cellular immune responses. Approaches to improve these responses, however, are needed. We examined the effect of stimulating 4-1BB, an activation-inducible T-cell costimulatory receptor, by intravenously co-administering anti-human 4-1BB monoclonal antibody (mAb) in DNA-immunized cynomolgus macaques. Three groups of six cynomolgus macaques were immunized intramuscularly with a DNA vaccine encoding SIV Gag antigen (pSIVgag) at weeks 0, 4 and 8. At days 12, 15, and 19, six macaques received anti-4-1BB 4E9 mAb and six macaques received anti-4-1BB 10C7 mAb. Treatment with 10C7 mAb led to a significant augmentation of SIV Gag-specific IFN-gamma, granzyme B and perforin responses. Treatment with humanized 4E9 mAb also resulted in an enhancement of SIV Gag-specific cellular responses but the magnitude was lower compared to animals receiving 10C7 mAb. These responses persisted up to week 40 and were mostly mediated by CD8(+) T cells. Treatment with anti-4-1BB mAb was more effective in driving the CD8(+) T cells toward a more differentiated CCR7(-)/CD45RA(+) effector state. This study demonstrates that targeting the 4-1BB molecule in vivo results in an enhanced and long-lasting cellular immune response. 4-1BB stimulation may be a promising approach to enhance the effectiveness of DNA vaccines.
authors.affiliation: Research Institute for Genetic and Human Therapy, Ploiclinico S. Matteo, 27100 Pavia, Italy.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Calarota
authors.forename: David A
authors.initials: DA
authors.lastname: Hokey
authors.forename: Anlan
authors.initials: A
authors.lastname: Dai
authors.forename: Maria N
authors.initials: MN
authors.lastname: Jure-Kunkel
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D053330:4-1BB Ligand / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D018449:SAIDS Vaccines; D019444:Vaccines, DNA