control animal administered glycerol containing buffer had no rise in serum 
neutralizing titer at any time. One of the animals receiving AvlCFl had an 
increase in titer (<1:10 to 1:10) after 7 days which remained elevated 
(1:40) for at least 83 days. This animal had a minimally elevated titer 
(1:10) pretreatment which may indicate unknown prior exposure to human 
adenovirus, or cross -reacting virus. 
In rhesus study 5C, AvlCFl (n=2) was delivered to the right mains tem bron- 
chus at day zero, followed by Ad 5 (10* pfu/kg) delivered to the mainstem 
bronchus at day 7. An additional 2 animals received only Ad 5 (same dose) 
at day 7. Serum neutralization titers did not rise in either animal admin- 
istered only Ad5 . However, similar to the response seen in one animal in 
group 2C administered a second dose of AdRSV./3gal, both animals in group 4C 
who received AvlCFl followed by Ad5 did not have an increase in serum 
neutralization titer until after Ad5 was administered. Titers in these 
animals rose to 1:20 to 1:40 and remained elevated for at least 56 days, 
but fell to <1:10 at 83 days. 
In summary, airway administration of a recombinant, replication deficient 
adenovirus vector results in increase in serum antibodies in cotton rats 
against adenovirus for at least 4 months. In rhesus, serum neutralization 
antibodies to Ad5 are observed after 10 days with a fall in titer after 50 
days. Repeat administration of vector within one month prolongs the period 
of elevation of the neutralization titer. From these data, and from the 
accumulated data of respiratory tract administration of adenovirus in 
humans, it is reasonable to assume that administration of AdCFTR to the 
nasal and bronchial epithelium of individuals with CF will elicit 
antibodies in blood against adenovirus components of AdCFTR. Until the 
studies are carried out in individuals with CF, it is not possible to 
predict the local anti -AdCFTR response, if any. This is particularly true 
because the epithelial milieu in the CF lung is very hostile to proteins 
such as immunoglobulins (see Section 4.4 and references Fick et al . , 1984). 
If such humoral immunity is induced in the individuals receiving AdCFTR it 
may (or may not) have consequences for future therapy with AdCFTR. This is 
discussed in Section 4.6, 5.2 and 5.6. 
4.6 Does Repeat Administration of the Vector Pose a Risk? 
The protocol is specifically designed to evaluate a one time administration 
of the vector (once to the nasal epithelium, and once to the bronchial 
epithelium one day later), not repetitive dosing. There are several reasons 
for this (see Section 5.2 constraints that dictate design of the protocol). 
Most importantly, there is no way of estimating the dose and intervals 
between dosing without determining the "pharmacokinetics" of the biologic 
and clinical efficacy parameters following a one time administration. Fur- 
ther, it is conceivable that the efficacy will be long lasting and that 
chronic therapy will only need very infrequent intervals . 
Despite this, looking toward the future, it is relevant to ask whether 
repeat administration of the vector poses a risk to the individual should 
this study demonstrate it will be required in the future. 
Recombinant DNA Research, Volume 16 
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