Document Detail


Target-mediated disposition model describing the dynamics of IL12 and IFNγ after administration of a mifepristone-inducible adenoviral vector for IL-12 expression in mice.
MedLine Citation:
PMID:  23135926     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Interleukin-12 (IL12) is a cytokine with potential applications in the treatment of cancer given the potent immune response that it triggers, in part due to its ability to stimulate expression of interferon-γ (IFNγ). To avoid the toxicity associated with systemic exposure to IL12, a high-capacity adenoviral vector carrying a liver-specific, mifepristone-inducible IL12 expression system (HC-Ad/RUmIL12) has been developed. However, the maintenance of IL12 expression at therapeutic levels is compromised by the inhibitory effect of IFNγ on inducible systems. The aim of this work is to develop a semi-mechanistic model to characterize the relationship between IL12 and IFNγ in wild-type and knock-out mice for the IFNγ receptor treated with HC-Ad/RUmIL12 under different dosing regimens in order to better understand the key mechanisms controlling the system. Rapid binding was considered to account for target-mediated disposition exhibited by both cytokines (equilibrium dissociation constant were 18 and 2.28 pM for IL12 and IFNγ, respectively). The final model included: (1) IFNγ receptor turnover, (2) irreversible free cytokine elimination from the serum compartment, (3) internalization of the IL12 receptor complex, (4) IL12 expression upregulated by the co-administration of the adenoviral vector and mifepristone and downregulated by the IFNγ receptor, and (5) synthesis of IFNγ controlled by the relative increments in the bound IL12. In conclusion, a model simultaneously describing the kinetics of IL12 and IFNγ in the context of gene therapy was developed and validated with additional data. The model was applied to design an experimental dosing protocol intended to maintain sustained therapeutic IL12 levels.
Authors:
Zinnia Patricia Parra-Guillen; Alvaro Janda; Pilar Alzuguren; Pedro Berraondo; Ruben Hernandez-Alcoceba; Iñaki F Troconiz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-08
Journal Detail:
Title:  The AAPS journal     Volume:  15     ISSN:  1550-7416     ISO Abbreviation:  AAPS J     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-08-02     Revised Date:  2013-11-14    
Medline Journal Info:
Nlm Unique ID:  101223209     Medline TA:  AAPS J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  183-94     Citation Subset:  IM    
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, C/ Irunlarrea 1, 31008, Pamplona, Navarra, Spain.
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics
Animals
Female
Genetic Therapy
Genetic Vectors
Interferon-gamma / genetics*
Interleukin-12 / genetics*
Mice
Mice, Inbred C57BL
Mifepristone / pharmacology*
Models, Biological
Receptors, Interferon / metabolism
Chemical
Reg. No./Substance:
0/Receptors, Interferon; 0/interferon gamma receptor; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma; 84371-65-3/Mifepristone
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