Immunity 
Constraints 
(1) Almost all adults have evidence of anti -adenovirus antibodies in blood 
(Strauss, 1984) and studies in cotton rats have shown that a one time 
administration of AdCFTR to the respiratory tract induces anti-AdCFTR 
antibodies in blood within 1 week (Section 4.5). Vaccine-related 
trials in non-human primates and humans suggest that administration of 
adenovirus vectors containing an exogenous gene to the respiratory 
tract does not elicit significant humoral immunity to the exogenous 
gene product, but there is anti -adenovirus humoral immunity. Thus, it 
is prudent to assume that the initial respiratory administration of 
AdCFTR (nasal or bronchial) may elicit anti-AdCFTR antibodies in blood 
and/or lung. If so, there are three possible consequences: (a) the 
antibodies are irrelevant and there will be no consequences; (b) the 
antibodies will modulate an inflammatory process in the airways upon 
re -challenge with AdCFTR; and (3) the antibodies will be neutralizing, 
thus preventing the vector from reaching the target cells upon re- 
challenge . 
Conclusions Regarding Design of the Protocol 
(1) First administer the vector to the nasal epithelium. If after 24 hr, 
there is no sign of acute toxicity, administer the vector to the large 
bronchi of the same individual. The span of 24 hr will permit 
assessment of acute toxicity, but will not be sufficient for the 
development of an initial or anamnestic response to the adenovirus 
vector . 
(2) This design will permit evaluation of the anti-vector humoral 
immunity in blood and lung as a function of time, permitting 
rational design of future protocols. 
Dose 
Constraints 
(1) Because AdCFTR is a new "drug", it will be necessary to evaluate 
possible toxicity with ascending doses. There are limitations, 
however, in how this can be achieved. Because of the constraint of 
possible immune reactions, the toxicity evaluation cannot be achieved 
by ascending dosages in the same individual. Further, to offer a 
possibility of benefit to the individual the starting dose cannot be 
too low. 
(2) There is a limitation in volume that can be administered to the 
nostril compared to the bronchi, but the volume will spread out over 
the respective epithelial sheets. Thus, if the same titer is 
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Recombinant DNA Research, Volume 16 
