Biomedical Engineering Reference
In-Depth Information
ranged from 12 to 72 h and was similar between the first and
the fifth dose. The mean plasma half-life determined after
the last dose was 95.4 h. The mean steady-state apparent
clearance and volume of distribution were 0.157 L/h and
21.5 L, respectively [89]. A flat profile with no burst effect
allows once-weekly dosing.
The efficacy and safety of LY2189265 was further eval-
uated in a placebo-controlled double-blinded study. Two
hundred sixty two obese type 2 diabetic patients were
randomized to once-weekly subcutaneous injections of
either placebo, or 1 of 2 titrated doses of LY2189265
(0.5mg for 4 weeks followed by 1.0mg for 12 weeks; or
1.0mg for 4 weeks followed by 2.0mg for 12 weeks), or
1.0mg for 16 weeks [47].
At week 16, glycosylated hemoglobin A1c (HbA1c) (all
hemoglobin to at least 1 g/dL above baseline was achieved
9 to 10 days after administration, with a maximum effect
between 19 and 26 days [91].
CNTO 530 is the second generation of the erythropoietin
MIMETIBODY protein generated after intensive protein
engineering efforts to improve both the biological and
biophysical properties of CNTO 528. It addresses heteroge-
neity and aggregation issues and exhibits a better circulating
half-life and significantly better pharmacodynamic activities
in animal studies. Single subcutaneous doses of
1mg/kg in
mice caused a long-lived reticulocytosis and an increase in
RBC and Hgb that was maintained for at least 29 days [92].
<
8.5.2.2 CNTO736
CNTO736, another example of MIM-
ETIBODY technology, is a GLP-1 receptor agonist. It
incorporates a GLP-1 peptide analog, which has an amino
acid substitution rendering it more resistant to dipeptidyl
peptidase IV digestion. CNTO736 dose dependently
increases cAMP and insulin secretion from islets in a
glucose-dependent manner. Studies in rodent models of
type 2 diabetes demonstrated that acute dosing with
CNTO736 lowers fasting and postprandial blood glucose
with a significantly longer duration of action than native
GLP-1, and chronic dosing with CNTO736 decreases body
weight [93].
p
0.001) and both fasting (p
0.001) and postprandial
<
<
(p
0.05) blood glucose decreased significantly compared
to placebo at all LY2189265 doses. Weight loss was dose-
dependent and ranged from
<
1.34
0.39 kg to
2.55
0.05 vs. placebo). At the
highest LY2189265 dosage, the most common adverse
events were nausea (13.8%), diarrhea (13.8%), and abdom-
inal distension (13.8%). Hypoglycemia was uncommon
overall (
0.40 kg at 16 weeks (all p
<
0.8 episodes/patient/30 days) but more common
with LY2189265 than placebo through the initial 4 weeks
(p
0.05). No differences in cardiovascular events or
blood pressure were demonstrated between treatments
[47]. The positive data from the Phase II study summarized
here convinced Lilly to move the Fc-fusion protein to
Phase III clinical trials.
<
8.6 CONSIDERATIONS AND CHALLENGES
FOR ENGINEERING PEPTIDE-Fc-FUSION
THERAPEUTICS
As a class of biological therapeutics, peptide-Fc-fusion
protein therapeutics have some distinct advantages. They
have a good circulating half-life (e.g., more than a week for
CNTO 528), although in many cases their serum half-lives
are shorter than the half-lives of antibodies, probably due to
lower serum stability. They can be engineered as both potent
antagonists and agonists. Preclinical and clinical studies
have reported that Fc therapeutics, in general, are safe,
well tolerated, and have low toxicity. In addition, thanks
to the Fc-domain, the Fc-fusion proteins share many physi-
cal and chemical properties with mAbs. As a result, many
advanced technologies developed for mAb drugs can be
used for Fc-fusion therapeutics as well, such as engineering,
optimization, expression, purification,
8.5.2 MIMETIBODY
TM
Technology
Centocor's MIMETIBODY
TM
platform was developed to
extend the half-life of different peptides while keeping
intrinsic activities similar to that of their parent peptides.
Figure 8.1D illustrates a typical MIMETIBODY construct,
in which a bioactive peptide sequence is genetically linked
to an Fc domain. A variety of bioactive peptides have been
successfully engineered into the platform, demonstrating the
utility and versatility of the MIMETIBODY technology.
8.5.2.1 CNTO 528/CNTO 530
CNTO 528 is the first
successful example using our MIMETIBODY technology. It
comprises a human IgG1 Fc and a 20 amino acid eryth-
ropoietin mimetic peptide 1 (EMP1), identified through the
panning of combinatorial phage peptide libraries; EMP1 can
bind and activate the EPO receptor in a variety of cell-based
and animal assays [90]. In a first-in-human Phase I clinical
study, CNTO 528 was well tolerated and exhibited a dose-
dependent half-life, mean t
1/2
ranging from 1.55 days (with
0.03mg/kg dose) to 7.60 days (with 0.9 mg/kg dose).
The maximum effect on the reticulocyte response occurred
formulation, and
production.
However, unlike antibodies, the physical, chemical, and
pharmacological properties of Fc-fusion proteins, such as
solubility, stability, and pharmacokinetic properties, are
significantly different from one drug to the other. Many
of those differences are largely determined by the properties
of the region other than Fc domain. Since each individual
Fc-fusion partner has its own properties, careful design,
engineering, and optimization work on an Fc-fusion protein
8-9 days after administration. A median increase in
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