title: Design of a novel integration-deficient lentivector technology that incorporates genetic and posttranslational elements to target human dendritic cells.
abstract: As sentinels of the immune system, dendritic cells (DCs) play an essential role in regulating cellular immune responses. One of the main challenges of developing DC-targeted therapies includes the delivery of antigen to DCs in order to promote the activation of antigen-specific effector CD8 T cells. With the goal of creating antigen-directed immunotherapeutics that can be safely administered directly to patients, Immune Design has developed a platform of novel integration-deficient lentiviral vectors that target and deliver antigen-encoding nucleic acids to human DCs. This platform, termed ID-VP02, utilizes a novel genetic variant of a Sindbis virus envelope glycoprotein with posttranslational carbohydrate modifications in combination with Vpx, a SIVmac viral accessory protein, to achieve efficient targeting and transduction of human DCs. In addition, ID-VP02 incorporates safety features in its design that include two redundant mechanisms to render ID-VP02 integration-deficient. Here, we describe the characteristics that allow ID-VP02 to specifically transduce human DCs, and the advances that ID-VP02 brings to conventional third-generation lentiviral vector design as well as demonstrate upstream production yields that will enable manufacturing feasibility studies to be conducted.
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Semih U
authors.initials: SU
authors.lastname: Tareen
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Brenna
authors.initials: B
authors.lastname: Kelley-Clarke
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nicolai
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Cassiano
authors.affiliation: TRIA Bioscience Corp., Seattle, Washington, USA.
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Nelson
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Slough
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Chintan D
authors.initials: CD
authors.lastname: Vin
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Odegard
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Van Hoeven
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Allen
authors.affiliation: Immune Design Corp., Seattle, Washington, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.affiliation: Immune Design Corp., Seattle, Washington, USA; TRIA Bioscience Corp., Seattle, Washington, USA. Electronic address: scott.robbins@immunedesign.com.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Robbins
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors / Q000008:administration & dosage; D057809:HEK293 Cells; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D016086:Lentivirus / Q000235:genetics*; D012845:Sindbis Virus / Q000235:genetics*; D014018:Tissue Distribution; D014759:Viral Envelope Proteins / Q000235:genetics*
chemical_list: D000956:Antigens, Viral; D014759:Viral Envelope Proteins