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Journal of Virology, August 1999, p. 6729-6742, Vol. 73, No. 8
Division of Pulmonary and Critical Care
Medicine,1 Department of Cardiothoracic
Surgery,2 and Department of
Surgery,3 Weill Medical College of Cornell
University
Received 16 February 1999/Accepted 4 May 1999
Administration of adenovirus (Ad) vectors to immunologically naive
experimental animals almost invariably results in the induction of
systemic anti-Ad neutralizing antibodies. To determine if the human
systemic humoral host responses to Ad vectors follow a similar pattern,
we evaluated the systemic (serum) anti-Ad serotype 5 (Ad5) neutralizing
antibodies in humans after administration of first generation
(E1
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Variability of Human Systemic Humoral Immune
Responses to Adenovirus Gene Transfer Vectors Administered to
Different Organs
New York Presbyterian Hospital, New York, and
Division of Biostatistics, North Shore University Hospital,
Manhasset,4 New York
E3
) Ad5-based gene transfer vectors to
different hosts. AdGVCFTR.10 (carrying the normal human
cystic fibrosis [CF] transmembrane regulator cDNA) was sprayed
(8 × 107 to 2 × 1010 particle units
[PU]) repetitively (every 3 months or every 2 weeks) to the airway
epithelium of 15 individuals with CF. AdGVCD.10 (carrying
the Escherichia coli cytosine deaminase gene) was
administered (8 × 108 to 8 × 109
PU; once a week, twice) directly to liver metastasis of five individuals with colon cancer and by the intradermal route (8 × 107 to 8 × 109 PU, single administration)
to six healthy individuals. AdGVVEGF121.10 (carrying the
human vascular endothelial growth factor 121 cDNA) was administered
(4 × 108 to 4 × 109.5 PU, single
administration) directly to the myocardium of 11 individuals with
ischemic heart disease. Ad vector administration to the airways of
individuals with CF evoked no or minimal serum neutralizing antibodies,
even with repetitive administration. In contrast, intratumor
administration of an Ad vector to individuals with metastatic colon
cancer resulted in a robust antibody response, with anti-Ad
neutralizing antibody titers of 102 to >104.
Healthy individuals responded to single intradermal Ad vector variably,
from induction of no neutralizing anti-Ad antibodies to titers of
5 × 103. Likewise, individuals with ischemic heart
disease had a variable response to single intramyocardial vector
administration, ranging from minimal neutralizing antibody levels to
titers of 104. Evaluation of the data from all trials
showed no correlation between the peak serum neutralizing anti-Ad
response and the dose of Ad vector administered (P > 0.1, all comparisons). In contrast, there was a striking correlation
between the peak anti-Ad5 neutralizing antibody levels evoked by vector
administration and the level of preexisting anti-Ad5 antibodies
(P = 0.0001). Thus, unlike the case for experimental
animals, administration of Ad vectors to humans does not invariably
evoke a systemic anti-Ad neutralizing antibody response. In humans, the
extent of the response is dictated by preexisting antibody titers and
modified by route of administration but is not dose dependent. Since
the extent of anti-Ad neutralizing antibodies will likely modify the
efficacy of administration of Ad vectors, these observations are of
fundamental importance in designing human gene therapy trials and in
interpreting the efficacy of Ad vector-mediated gene transfer.
*
Corresponding author. Mailing address: Weill Medical
College of Cornell University
New York Presbyterian Hospital, 520 East 70th St., ST 505, New York, NY 10021. Phone: (212) 746-2258. Fax: (212)
746-8383. E-mail:
geneticmedicine{at}mail.med.cornell.edu.
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