title: Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys.
abstract: Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8(+) lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.
authors.affiliation: Transgene, 11 rue de Molsheim, Strasbourg Cedex, France.
authors.forename: H
authors.initials: H
authors.lastname: Haegel-Kronenberger
authors.forename: K
authors.initials: K
authors.lastname: Haanstra
authors.forename: C
authors.initials: C
authors.lastname: Ziller-Remy
authors.forename: A P
authors.initials: AP
authors.lastname: Ortiz Buijsse
authors.forename: J
authors.initials: J
authors.lastname: Vermeiren
authors.forename: F
authors.initials: F
authors.lastname: Stoeckel
authors.forename: S W
authors.initials: SW
authors.lastname: Van Gool
authors.forename: J L
authors.initials: JL
authors.lastname: Ceuppens
authors.forename: M
authors.initials: M
authors.lastname: Mehtali
authors.forename: M
authors.initials: M
authors.lastname: De Boer
authors.forename: M
authors.initials: M
authors.lastname: Jonker
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000096:biosynthesis; D015703:Antigens, CD / Q000276:immunology; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D019076:Transgenes
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D008562:Membrane Glycoproteins