LIGAND-RECEPTOR FUSION DIMERS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 224

FIGURE 15.6 (A) Pharmacokinetic profiles of hGH and GH-LRv0, intravenously injected into rat,
the LR-fusion shows a much reduced rate of clearance. (B) Pharmacokinetic profiles of hGH, GH-
LRv0, GH-LRv2, and GH-LRv3, subcutaneously injected into rats, all the LR-fusions show a much
reduced rate of clearance and delayed absorption—the peak concentration of the LR-fusions is
observed at 30 h, and the fusion molecules are still detectable at 8 days. (C) Pharmacokinetic
profiles of GH-LRv2 and GH-LRv3, subcutaneously injected into cynomolgous monkeys on days 0
and 14 (arrows)—the LR-fusions show a much reduced rate of clearance compared to hGH (inset).
Source: (C) This research was originally published in Clinical Science, Reference [14].

intravenous administration (precise determination was not
possible since the sampling protocol that was used was used
expected a longer half-life). Therefore, molecular weight
alone is not the cause of the exceptional pharmacokinetic
profiles of the LR-fusions.
The pharmacokinetics of GH-LRv2 and GH-LRv3 was
also evaluated in cynomolgous monkeys (Macaca fascicula-
ris) as part of the immunogenicity study [14] discussed later in
this chapter. Male 2- to 3-year-old cynomolgous monkeys
weighing

(n 3-4 per group) were treatedwith subcutaneous 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 rhGH (0.1mg/kg of body weight, daily
for 27 days). The animals were retained for a total of 6weeks
(42 days) after the initial injection and periodic blood samples
were taken. The serum levels of GH or LR-fusion were
measured using an ELISA against GH.
A greatly delayed clearance of the LR-fusions was
observed in the monkeys (Figure 15.6C; Table 15.1); the

¼

2.5 kg were used for this study; the monkeys

TABLE 15.1 Pharmacokinetic Parameters for hGH and the LR-Fusions for Rats and Monkeys

Rat Monkey

Molecule Clearance s.c. (mL/h/kg) t 1/2 s.c. (h) Clearance s.c. (mL/h/kg) t 1/2 s.c. (h)

hGH [12] 820 94 0.66 0.1 154 4.4 1.7 0.4

GH-LRv0 - 21 2 - -

GH-LRv2 2.8 0.2 25 6.4 1.7 0.2 54 6.8

GH-LRv3 2.7 0.2 26 6.8 0.96 0.2 76 4.9