Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs

Administration of adenovirus (Ad) vectors to immunologically naive experime ntal animals almost invariably results in the induction of systemic anti-Ad neutralizing antibodies. To determine if the human systemic humoral host r esponses to Ad vectors follow a similar pattern, we evaluated the systemic (serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after ad ministration of first generation (E1(-) E3(-)) Ad5-based gene transfer vect ors to different hosts. Ad(GV)CFTR.10 (carrying the normal human cystic fib rosis [CF] transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(1 0) particle units [PU]) repetitively (every 3 months or every 2 weeks) to t he airway epithelium of 15 individuals with CF. Ad(GV)CD.10 (carrying the E scherichia coli cytosine deaminase gene) was administered (8 x 10(8) to 8 x 10(9) PU; once a week, twice) directly to liver metastasis of five individ uals with colon cancer and by the intradermal route (8 x 107 to 8 x 10(9) P U, single administration) to six healthy individuals. Ad(GV)VEGF121.10 (car rying the human vascular endothelial growth factor 121 cDNA) was administer ed (4 x 10(8) to 4 x 10(9.5) PU, single administration) directly to the myo cardium of 11 individuals with ischemic heart disease. Ad vector administra tion to the airways of individuals with CF evoked no or minimal serum neutr alizing antibodies, even with repetitive administration. In contrast, intra tumor administration of an Ad vector to individuals with metastatic colon c ancer resulted in a robust antibody response, with anti-Ad neutralizing ant ibody titers of 10(2) to >10(4). Healthy individuals responded to single in tradermal Ad vector variably, from induction of no neutralizing anti-Ad ant ibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart d isease had a variable response to single intramyocardial vector administrat ion, ranging from minimal neutralizing antibody levels to titers of 10(4). Evaluation of the data from all trials showed no correlation between the pe ak serum neutralizing anti-Ad response and the dose of Ad vector administer ed (P > 0.1, all comparisons). In contrast, there was a striking correlatio n between the peak anti-Ad5 neutralizing antibody levels evoked by vector a dministration and the level of preexisting anti-Ad5 antibodies (P = 0.0001) . Thus, unlike the case for experimental animals, administration of Ad vect ors to humans does not invariably evoke a systemic anti-Ad neutralizing ant ibody response. In humans, the extent of the response is dictated by preexi sting antibody titers and modified by route of administration but is not do se dependent. Since the extent of anti-Ad neutralizing antibodies will like ly 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.