PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver.
Systemic administration of adenoviral vectors leads to activation of innate and antigen-specific immunity. In an attempt to diminish T and B cell-specific immune responses to E1-deleted adenoviral vectors, capsid proteins were modified with various activated monomethoxypolyethylene glycols (MPEGs). The impact of this modification was studied in a murine model of liver-directed gene transfer in which an E1-deleted adenovirus expressing the lacZ gene was given intravenously. The efficiency of vector transduction of hepatocytes in vivo was not compromised by any of the polymer chemistries. PEGylation of the virus, however, diminished the activation of cytotoxic T lymphocytes and helper T cells of the type 1 subset (Th1 cells) against native viral antigens; neutralizing antibodies to native virus were also diminished. PEGylation prolonged transgene expression and allowed partial readministration with native virus or with a virus PEGylated with a heterologous chemical moiety. Apparently, modification of the capsid leads to a shift in antigenic epitopes because vector readministration was not possible when the immunizing vector had been modified by the same PEGylation chemistry used to modify the second vector. In light of these results, the concept of improving the performance of adenoviral vectors through modification of the capsid with PEG shows promise.
Croyle
Maria A
MA
Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia 19104, USA.
Chirmule
Narendra
N
Zhang
Yi
Y
Wilson
James M
JM
D017500:Adenovirus E1A Proteins / Q000172:deficiency / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D036022:Capsid Proteins / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D003673:Defective Viruses / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000502:physiology; D049452:Green Fluorescent Proteins; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D007275:Injections, Intravenous; D007763:Lac Operon; D008099:Liver / Q000378:metabolism / Q000821:virology*; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods*
D017500:Adenovirus E1A Proteins; D000914:Antibodies, Viral; D036022:Capsid Proteins; D016207:Cytokines; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D013450:Sulfones; C069114:2,2,2-trifluoroethane sulfonyl-monomethoxypolyethylene glycol; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols