Biomedical Engineering Reference
In-Depth Information
Amgen peptibody that selectively neutralizes Ang1 and
Ang2 interactions with their receptor Tie2 and therefore
inhibits endothelial cell proliferation and tumor growth.
Similar to AMG 531, AMG 386 uses the same peptibody
scaffold with two copies of active peptide fused at the
C-terminus of human IgG1 Fc. Flexible glycine linkers
are placed between Fc and the peptide as well as between
the two copies of peptide [44]. The active peptide was
derived by screening phage display peptide libraries against
human Ang2. The peptide-Fc-fusion protein was produced
in E. coli. AMG 386 was shown to neutralize both Ang2 and
Ang1 binding to their receptor Tie2 with IC50 values of
23 pM and 900 pM, respectively. The combination of Ang1
and Ang2 inhibition prevented vascular normalization with-
out affecting Ang2-mediated reduction in tumor vascularity
and led to greater tumor suppression than by inhibiting Ang1
or Ang2 individually. The total serum clearance was similar
in the dose range of 0.3-30 mg/kg suggesting that PK does
not vary with the serum concentration of the peptibody. The
mean value of terminal phase serum half-life ranged from
3.1 to 6.3 days. Pharmacokinetic profiling supported daily to
weekly subcutaneous administration.
In a randomized, double-blind, placebo-controlled Phase
II study, AMG 386 combined with weekly Paclitaxel in
patients with recurrent ovarian carcinoma extends survival
of heavily pretreated patients by almost two thirds (4.6-7.2
months), indicating potential as a first line treatment imme-
diately following surgery [45,46].
AMG 386 has been well tolerated in early clinical trials.
The toxicity profile of AMG 386 does not appear to overlap
with that of other anti-angiogenesis molecules, including
bevacizumab, sorafenib, and sunitinib, in relation to bleed-
ing or thromboembolic events. It is therefore possible that
future combinations of AMG 386 with other biologics such
as the VEGF inhibitors with or without chemotherapy will
allow for a multistrategy approach to the management of
advanced ovarian cancer.
trials were completed. Phase Ia was a randomized, placebo-
controlled single dose study in which lupus patients were
either intravenously dosed with 1, 3, or 6 mg/kg or sub-
cutaneously dosed with 0.1, 0.3, 1, or 3 mg/kg. Phase Ib was
a multidose study in which lupus patients were intravenously
dosed at 6 mg/kg or subcutaneously dosed at 0.3, 1, or
3mg/kg. A-623 was safe and well tolerated in both studies.
Phase Ib demonstrated a decrease in total B cells as early as
15 days of treatment, and selective but significant reduction
in total B cells among lupus patients were achieved. Encour-
aged by positive results from these clinical studies, Anthera
Pharmaceuticals initiated a Phase IIb study of A-623 for the
treatment of SLE.
8.5.1.4 Dulaglutide (LY2189265)
LY2189265, devel-
oped by Eli Lilly (Indianapolis, IN), is a GLP-1 receptor
agonist in which a modified GLP-1 peptide is fused to the
N-terminus of a modified immunoglobulin G (IgG4) Fc
fragment. Several mutations on the peptide are introduced
to improve the stability, solubility, and immunogenicity, and
these are discussed in more detail in later sections. A
relatively long, flexible linker consisting of three repeats
of GGGGS is inserted between the peptide and the
N-terminus of the IgG hinge to improve its in vitro activity.
To reduce potential complement-dependent and antibody-
dependent cell-mediated cytotoxicity (ADCC), the IgG4
isotype was used for the Fc. To further diminish the
ADCC activity by reducing the interactions of the Fc
with its high-affinity Fc receptors, both phenylalanine 234
and leucine 235 at the lower hinge region are mutated to
alanine. In addition, serine 228 at the core hinge region is
mutated to proline to eliminate the potential of forming an
intrachain disulfide bond in the core hinge region, which
would destabilize the homodimer structure of the Fc. To
reduce potential heterogeneity, the C-terminal lysine of the
IgG-Fc was deleted from the construct. LY2189265 demon-
strated similar in vitro and in vivo activities to native GLP-1
and significant reduction of weight gain in animal studies
[87].
In a Phase I, three-period, crossover, double-blind, pla-
cebo-controlled study, healthy volunteers received escalat-
ing subcutaneous doses of LY2189265 ranging from 0.1 to
12mg; the drug was generally well tolerated with some
increase in gastrointestinal symptoms with escalating doses.
The half-life of LY2189265 was
8.5.1.3 A-623 (AMG 623)
A-623 (previously called
AMG 623) is an antagonist peptibody designed to inhibit
the B-cell activating factor (BAFF) for the treatment for
lupus and other autoimmune diseases. It was originally
developed within Amgen Inc. and acquired by Anthera
Pharmaceuticals in 2008 for the treatment of lupus and
other autoimmune diseases. A-623 consisting of a BAFF-
binding peptide fused to the N-terminus of human IgG Fc
binds to BAFF and inhibits the interaction of BAFF with its
receptors. BAFF, a TNF family member, plays a critical role
in the development, maintenance, and survival of B cells.
Expressed primarily by macrophages, monocytes, and den-
dritic cells, BAFF interacts with three different receptors on
B cells: BAFF receptor (BAFF-R), B-cell maturation protein
(BCMA), and transmembrane activator and cyclophilin
ligand interactor (TACI) [85,86]. Phases Ia and Ib clinical
90 h, with C
max
occurring
between 24 and 48 h in most subjects. No antidrug anti-
bodies were observed [88].
In a Phase Ib study, type 2 diabetic patients received five
once-weekly doses of 0.05, 0.3, 1, 3, 5, or 8mg. Steady-state
concentration levels were obtained after the second weekly
dose with an average accumulation ratio (AUCweek 5:
AUCweek 1) estimated to be 1.44. The average peak-to-
trough concentration ratio (C
max
: C
min
) was between 2 to 3.
The time to maximal plasma drug concentration (t
max
)
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