LIGAND-RECEPTOR FUSION DIMERS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 225

clearance was even more delayed than that observed in rats,
the clearance rates for GH-LRv2 and GH-LRv3 were,
respectively, 91 and 160 times less than that of GH [12].
Both of the LR-fusions evaluated in this pharmacokinetic
study did not show any appreciable accumulation or reduc-
tion in systemic exposure (AUC 0- t ) over the dosing period,
and the average of systemic exposure of GH-LRv3 was

isoflurane anesthesia. The effects of the LR-fusions on the
rats were studied over a 10-day period. The rats were
injected with vehicle, hGH or GH-LRv0. Dosing of hGH
was daily (10 doses), every 2 days (five doses), every 5 days
(two doses), or only on day 1 (one dose). The LR-fusions and
vehicle were injected every 2 days (five doses), every 5 days
(two doses), or only on day 1 (one dose). The injection
solutions of vehicle, hGH or LR-fusion never exceeded
2mL/kg and an equimolar total dose, of

1.7

times greater than that of GH-LRv2.
Previous studies of allometric scaling have shown that the
clearance of human GH (hGH) is fourfold less in monkeys
compared to rats and twofold less in humans compared to
monkeys [23]. A similar ratio was observed for the clearance
rates of the LR-fusions between rat and monkey, there was a
1.6- to 2.8-fold reduction in the clearance rate in monkeys
compared to rats. If the difference in clearance rats observed
for hGH can be extrapolated to the LR-fusions in humans
then the fusion proteins could provide a 2-3 weekly GH
replacement therapy [14].

10 nmol, of
hGH and LR-fusion was given over the 10-day period of
the study. The rats were weighed daily. Terminal bleeds were
collected and assayed using an ELISA against GH and an
ELISA against IGF-1 (insulin-like growth factor 1) (Octeia
Rat/Mouse IGF-1 Assay Kit, iDS).
The daily dose of hGH induced a body weight increase of
15-20 g over the 10-day period of the study, reduction in the
frequency of treatment caused a reduction in the increase
in body weight over the 10-day period of the study
(Figure 1.7A). GH-LRv0 produced a similar increase in
body weight in all the treatment regimens studied, this
increase was comparable to that produced by the daily
dose of hGH (Figure 1.7B). Closer investigation of the
growth profiles shows that hGH produced a weight gain
on the day it was injected but did not have an effect after

15.4.4 Pharmacodynamics

The pharmacodynamic effects of the LR-fusions were stud-
ied using Sprague-Dawley rats, which had been hypophy-
sectomized (made GH deficient) at 4 weeks of age under

FIGURE 15.7 (A) The effects of hGH on hypophysectomised rats over a 10-day period using
different dose regimens; daily ( 10), every 2 days ( 5), every 5 days ( 2) and once on day 1 ( 1).
The increase in body weight decreases as the frequency of injections decreases. (B) The effects of
GH-LRv0 on hypophysectomized rats over a 10-day period using different dose regimens. There is
little difference in the weight gain after 10 days for all the dosing regimens; the increase in weight
is comparable to the daily dose of GH. (C) A comparison of the pharmacodynamics of all the
LR-fusions. (D) Blood serum IGF-1 levels in the terminal bleeds of the rats that underwent the
pharmacodynamic study. The graph shows the measurements for vehicle, rats given a daily
dose ( 10) of hGH, and the rats given a single dose ( 1) of the LR-fusions.