Biomedical Engineering Reference
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this; while the GH-LRv0 maintained its effect for 10 days
postinjection. GH-LRv2 and GH-LRv3 had similar effects to
GH-LRv0 (Figure 15.7C).
Analysis of the 10-day terminal bleeds from the rats for
the GH-dependent biomarker IGF-1 showed elevated levels
of IGF-1 in the animals given the LR-fusions; the IGF-1
levels were similar to that of the IGF-1 levels in the animals
treated with daily doses of hGH (Figure 1.7D).
(0.1mg/kg of body weight, daily for 27 days). The animals
were retained for a total of 6 weeks (42 days) after the initial
injection and periodic blood samples were taken.
An ELISA-based assay was used to analyze the blood
serum samples for the presence of antibodies against the
respective injected molecule. The cutoff for a positive result
was the absorbance measured spectrophotometrically at
450 nm for the negative control plus 3 standard deviations
(SD). Serum samples giving a positive reading were further
analyzed using an inhibition assay to determine if the result
was a false positive or a true positive.
None of the animals in the study showed anti-test
molecule antibodies (Table 15.2) with the exception of
anti-GH-LRv2 antibodies detected in one animal on day
44. One animal treated with GH-LRv3 had a positive
reading before drug administration and this remained
positive throughout the study, this animal was excluded
from the study.
15.4.5 Immunogenicity
The immunogenicity of the LR-fusions was evaluated in
cynomolgous monkeys, male 2- to 3-year-old cynomolgous
monkeys weighing
2.5 kg were used for this study; the
monkeys (n
3-4 per group) were treated with sub-
cutaneous injections of vehicle (on days 0 and 14), GH-
LRv2 (1mg/kg of body weight on days 0 and 14), GH-LRv3
(1mg/kg of body weight on days 0 and 14), and hGH
ΒΌ
TABLE 15.2
Immunogenicity of hGH and the LR-Fusions in Cynomolgous Monkeys
Vehicle
1mg/kg per Dose GH-LRv2
Animal No.
101
103
105
201
203
205
207
Time
Day 0 (predose)
0.060
0.066
0.052
0.067
0.053
0.046
0.132
Day 6 (144 h)
0.047
0.064
0.068
0.071
0.072
0.051
0.119
Day 14 (predose)
0.060
0.046
0.050
0.064
0.077
0.080
0.106
Day 20 (144 h)
0.058
0.077
0.065
0.059
0.050
0.077
0.129
Day 26 (288 h)
0.067
0.054
0.055
0.049
0.078
0.068
0.118
Day 43 (696 h)
0.068
0.071
0.055
0.071
0.134
0.210
0.078
Vehicle
1mg/kg per Dose GH-LRv3
Animal No.
101
103
105
301
303
305
307
Time
Day 0 (predose)
0.060
0.066
0.052
0.056
(0.371)
0.069
0.085
Day 6 (144 h)
0.047
0.064
0.068
0.060
(0.196)
0.064
0.082
Day 14 (predose)
0.060
0.046
0.050
0.065
(0.305)
0.064
0.086
Day 20 (144 h)
0.058
0.077
0.065
0.073
(0.403)
0.068
0.083
Day 26 (288 h)
0.067
0.054
0.055
0.056
(0.371)
0.069
0.085
Day 43 (696 h)
0.068
0.071
0.055
0.060
(0.196)
0.064
0.082
Vehicle
0.1mg/kg per Dose hGH
Animal No.
101
103
105
401
403
405
407
Time
Day 0 (predose)
0.062
0.071
0.079
0.059
0.066
0.049
0.060
Day 6 (144 h)
0.063
0.074
0.070
0.070
0.067
0.059
0.058
Day 14 (predose)
0.062
0.075
0.069
0.066
0.180
0.064
0.083
Day 20 (144 h)
0.064
0.069
0.081
0.132
0.185
0.081
0.109
Day 26 (288 h)
0.063
0.083
0.062
0.167
0.060
0.109
0.085
Day 43 (696 h)
0.062
0.096
0.065
0.147
0.136
0.076
0.074
Table shows the absorbencies at 450 nm for the sera from cynomolgous monkeys given hGH, GH-LRv2 or GH-LRv3. Positive immunogenic results are shown
in bold and false positives are shown in brackets. The cutoffs for positive reactions were
0.157 for GH-LRv2,
0.156 for GH-LRv3, and
0.210 for hGH,
these cutoff values were determined during the qualification of the respective assays.
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