Design of a Novel Integration-deficient Lentivector Technology That Incorporates Genetic and Posttranslational Elements to Target Human Dendritic Cells

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....

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Published in:	Molecular therapy Vol. 22; no. 3; pp. 575 - 587
Main Authors:	Tareen, Semih U, Kelley-Clarke, Brenna, Nicolai, Christopher J, Cassiano, Linda A, Nelson, Lisa T, Slough, Megan M, Vin, Chintan D, Odegard, Jared M, Sloan, Derek D, Van Hoeven, Neal, Allen, James M, Dubensky, Thomas W, Robbins, Scott H
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-03-2014 Elsevier Limited Nature Publishing Group
Subjects:	Antigens Antigens, Viral - immunology CD8-Positive T-Lymphocytes - immunology Dendritic cells Dendritic Cells - immunology Genetic Vectors - administration & dosage Genomes Glycoproteins HEK293 Cells Heparan sulfate Humans Immune system Immunity, Cellular - immunology Immunotherapy Lentivirus - genetics Original Proteins Sindbis virus Sindbis Virus - genetics Tissue Distribution Viral Envelope Proteins - genetics United States > US
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1525-0016 1525-0024
DOI:	10.1038/mt.2013.278