NZ752300A - Use of a long acting glp-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease - Google Patents
Use of a long acting glp-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease Download PDFInfo
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Abstract
The present invention relates to the use of a long-acting glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist conjugate in a method for the prevention or treatment of liver inflammation in non-alcoholic fatty liver disease.
Description
【DESCRIPTION】
【Invention Title】
USE OF A LONG ACTING GLP-1/GLUCAGON RECEPTOR DUAL AGONIST FOR
THE TREATMENT OF NON-ALCOHOLIC FATTY LIVER DISEASE
This application is a divisional of New Zealand patent application 730799, which is the
national phase entry in New Zealand of PCT international application
(published as ), filed 16 September 2015, all of which are incorporated herein
by reference.
【Technical Field】
The present disclosure relates to a pharmaceutical composition for the prevention or
treatment of non-alcoholic fatty liver disease, including a long-acting glucagon-like peptide-1
(GLP-1)/glucagon receptor dual agonist, and a method for preventing or treating non-alcoholic
fatty liver disease including administering the composition.
【Background Art】
Non-alcoholic fatty liver disease (NAFLD) is a type of a disease, showing histological
organization similar to those of alcoholic liver disease, although is not associated with alcohol
consumption, and is a kind of metabolic syndrome associated with non-alcoholic fatty liver
(NAFL), non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinomas.
The occurrence of non-alcoholic fatty liver diseases increases with an increase in population with
obesity and diabetes. In Korea, the annual incidence has reached approximately 16%.
Non-alcoholic fatty liver disease is known to be caused by various etiologies such as
insulin resistance, lipotoxicity and inflammatory responses. Among them, the most common
etiology is insulin resistance.
A lot of effort has been made to improve the insulin resistance to prevent/treat
non-alcoholic fatty liver disease. For example, currently clinical trials for thiazolidnedinones
(TZD) or metformin, a kind of insulin sensitizer, have been actively conducted (see, Hepatology
(2003) 38: 1008-17, J Clin Invest (2001) 108: 1167-74).
However, in the case of treatment with the TZD-based drugs, there are disadvantages of a
large weight gain and slow fluid flow, and thus the use of such treatment has been known to be
impossible for patients with a heart disease. In addition to the TZD-based drugs, clinical tests
using GLP-1 receptor agonists such as Victoza or Byetta for non-alcoholic fatty liver disease
have been actively conducted. However, in these cases, the in vivo half-life is extremely short,
and thus repeated administrations must be made once or at least twice per day, like other
polypeptide hormones. Therefore, there is a disadvantage due to inconvenience to patients. Such
frequent administrations cause great pain and discomfort to patients. That is, simply using
general therapeutic agents for diabetes as a therapeutic agent for non-alcoholic fatty liver disease,
through the mechanism of improving insulin resistance has disadvantages such as various
side-effects or patient's inconvenience. Due to these factors, when a drug known to be effective
in the treatment of diabetes, such as a drug for improving insulin resistance, is directly used as a
therapeutic agent for non-alcoholic fatty liver disease, various factors which may result in
problems such as side-effects have been known in the art. Hence, whether a drug known to be
effective in the treatment of diabetes, such as a drug for improving insulin resistance, can
definitely be used as a therapeutic agent for non-alcoholic fatty liver disease, is controversial.
Thus, there still remains a need to develop drugs capable of treating non-alcoholic fatty liver
disease while securing patient's convenience without side-effects.
【Disclosure】
【Technical Problem】
The present inventors have made many efforts to develop a drug for the prevention or
treatment of non-alcoholic fatty liver disease, which maximizes patient's compliance while
increasing the half life without side-effects such as body weight gain. As a result, the inventors
have discovered that the in vivo half life of a long-acting GLP-1/glucagon receptor dual agonist
linked to Fc fragment is greatly improved and also has an effective result of weight loss, and
further liver triglyceride and blood cholesterol are decreased. The present invention has been
completed on the basis of such discovery.
【Technical Solution】
An objective of the present invention is to provide a pharmaceutical composition for the
prevention or treatment of non-alcoholic fatty liver disease including a long-acting glucagon-like
peptide-1 (GLP-1)/glucagon receptor dual agonist; and/or to provide a method for preventing or
treating non-alcoholic fatty liver disease including administering the composition to a subject
suspected of or having the non-alcoholic liver disease; and/or to at least provide the public with a
useful choice.
【Summary of the Invention】
In a first aspect the present invention provides a use of a long-acting glucagon-like
peptide-1 (GLP-1)/glucagon receptor dual agonist conjugate in the preparation of a medicament
for the prevention or treatment of liver inflammation in non-alcoholic fatty liver disease, wherein
the conjugate comprises:
a GLP-1/glucagon receptor dual agonist comprising the amino acid sequence of any one of
SEQ ID NOs: 32, 33, 34, 2-23, or 27-31;
an immunoglobulin Fc region; and
a non-peptidyl polymer, wherein the non-peptidyl polymer covalently links the
GLP-1/glucagon receptor dual agonist and the immunoglobulin Fc region.
The long-acting GLP-1/glucagon receptor dual agonist described herein can widen the
choices of patients by expanding the category of drugs which had until new been applicable to
the non-alcoholic fatty liver disease, and increase patient's convenience by significantly
increasing the blood half life. Also described is a new alternative that can be applied without
danger to patients with diseases other than non-alcoholic fatty liver disease through reduction of
side-effects such as weight gain.
【Description of Drawings】
Fig. 1 is a graph showing changes in body weight and liver weight of the long-acting
GLP-1/glucagon receptor dual agonist in the high-fat, fructose and cholesterol containing high
trans-fat feed intake ob/ob mouse model.
Fig. 2 is a graph showing the results of measuring collagen-1a, TNF-α, SREBP-1c
mRNA of the long-acting GLP-1/glucagon receptor dual agonist in the high-fat, fructose and
cholesterol containing high trans-fat feed intake ob/ob mouse model.
Fig. 3 is a graph showing the reduction of the content of the liver triglyceride and serum
cholesterol of the long-acting GLP-1/glucagon receptor dual agonist in the high trans-fat feed
intake DI0 mouse model.
【Best Mode】
In order to accomplish the objectives, one aspect described herein is a pharmaceutical
composition for prevention or treatment of non-alcoholic fatty liver disease comprising a
long-acting glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist.
The long-acting GLP-1/glucagon receptor dual agonist may be a long-acting
GLP-1/glucagon receptor dual agonist which is in a conjugated form, wherein a biocompatible
material or a carrier capable of increasing the duration of the activity of the dual agonist is linked
to the agonist by a covalent bond or a linker.
In the case of treatment with TZD-based drugs, which are drugs for improving insulin
response which is a mechanism for improving the insulin resistance, and conventional
therapeutic agents of non-alcoholic fatty liver disease, there are disadvantages in that it was not
possible for the treatment to apply to patients with heart diseases due to side-effects such as large
weight gain and slow fluid flow. In the case of protein drugs such as peptide hormone, there are
disadvantages in that the in vivo half life is short and thus repeated administration is necessary.
The present inventors have discovered that the long-acting GLP-1/glucagon receptor dual agonist
either has no side-effects of weight gain or reduces the side effect of weight gain in various
animal models of non-alcoholic liver disease and that the long-acting GLP-1/glucagon receptor
dual agonist can treat non-alcoholic fatty liver disease in a form in which sustainability in blood
is dramatically increased. Accordingly, described herein is the use of the long-acting
GLP-1/glucagon receptor dual agonist for the prevention or treatment of non-alcoholic fatty liver
disease.
The composition described herein is characterized by either having no side effect of
weight gain or reducing the side effect of weight gain.
Furthermore, the composition described herein can prevent or treat non-alcoholic fatty
liver disease by performing at least one of the following functions: (a) reducing the expression or
activity of collagen-1a, which is a fibrosis marker; (b) reducing the expression or activity of
tumor necrosis factor-α (TNF-α), which is a pro-inflammatory marker; (c) reducing the
expression or activity of sterol regulatory element binding protein-1c (SREBP-1c), which is a
lipogenesis marker; (d) reducing liver triglycerides; and (e) reducing blood cholesterol.
In one embodiment described herein, the long-acting GLP-1/glucagon receptor dual
agonist described herein was administered to various animal models of non-alcoholic fatty liver
disease. As a result, it was confirmed that the body weight and liver weight were significantly
decreased compared to those of a non-treated group (Fig. 1) and that there was no side-effect
such as weight gain as in the use of a conventional therapeutic agent. Furthermore, it was
confirmed that the expression of collagen-1a, TNF-α, SREBP-1c decreased remarkably
compared to that of the non-treated group, thus preventing fibrosis, i.e., hepatic fibrosis,
inhibiting inflammation, and inhibiting fat accumulation inhibition (Fig. 2). Therefore, it was
confirmed that the long-acting GLP-1/glucagon receptor dual agonist described herein can be
used as a drug for the prevention and treatment of various non-alcoholic liver diseases. In
addition, it was confirmed that liver triglycerides and blood cholesterol was significantly reduced
compared to those of the non-treated group and that they were significantly reduced to a normal
animal level (Fig. 3). Therefore, it was confirmed that the long-acting GLP-1/glucagon receptor
dual agonist described herein can be used as an excellent drug for the prevention and treatment
of various non-alcoholic liver diseases.
As used herein, the term "GLP-1/glucagon receptor dual agonist" may be used
interchangeably with a "GLP-1/glucagon dual agonist". The GLP-1/glucagon receptor dual
agonist includes all peptides, or fragments, precursors, derivatives or variants thereof which have
GLP-1/glucagon dual activity, like oxyntomodulin, a native GLP-1/glucagon receptor dual
agonist, and also materials that can activate the GLP-1 and glucagon receptor at the same time,
but is not limited thereto. In the present disclosure, the GLP-1/glucagon receptor agonist may be
a receptor dual-dual agonist applying the long-acting technique to overcome the short half-life,
and preferably a long-acting receptor dual agonist which can be administered once a week, but is
not limited thereto. Specific examples of the GLP-1/glucagon receptor dual agonist described
herein partially may include, for example, the GLP-1/glucagon receptor dual agonist, a
derivative thereof, and a long-acting type thereof as described in Korean Patent Application
Publication Nos. 100137271 and 100139579, whose entire contents are
incorporated herein by reference.
In one embodiment described herein, the long-acting GLP-1/glucagon receptor dual
agonist may be in a conjugate form, wherein a biocompatible material or a carrier is linked to the
agonist by a covalent bond or a linker. In another embodiment, such long-acting type may be in a
form, wherein a biocompatible material or a carrier can be linked directly to the GLP-1/glucagon
receptor dual agonist by a covalent bond by a known genetic recombination technique. The
long-acting type of the mentioned GLP-1/glucagon receptor dual agonist can improve the
half-life or bioavailability compared to a form in which the sequence of the GLP-1/glucagon
receptor dual agonist is not the long-acting type but is otherwise the same. In accordance with
one embodiment described herein, as one example of the long-acting GLP-1/glucagon receptor
dual agonist, a composition in which the immunoglobulin Fc region is linked to the 30th amino
acid of the GLP-1/glucagon receptor dual agonist by the non-peptide polymer linker, preferably
PEG, may be used, but is not limited thereto.
As used herein, the term "biocompatible material" or "carrier" refer to materials which
can increase the duration of the activity of the GLP-1/glucagon receptor dual agonist when the
biocompatible material and the carrier are covalently or non-covalently linked to the
GLP-1/glucagon receptor dual agonist described herein directly or indirectly to form a conjugate.
For example, when forming the conjugate, a material which can increase the in vivo half-life of
the GLP-1/glucagon receptor dual agonist may be a biocompatible material or carrier described
herein. The type of the biocompatible material or carrier that can be used to increase the
half-life varies, and examples thereof may include polyethylene glycol, fatty acid, cholesterol,
albumin and a fragment thereof, an albumin-binding substance, a polymer of repeating units of a
specific amino acid sequence, an antibody, an antibody fragment, an Fc neonatal receptor (FcRn)
binding material, an in vivo connective tissue, a nucleotide, fibronectin, transferrin, a saccharide,
a polymer, etc. Of course, the carriers or biocompatible materials may be used in combination of
at least two thereof. The biocompatible material or carrier includes a biocompatible material that
extends the in vivo half life through a covalent or non-covalent bond.
In the present disclosure, the methods in which the biocompatible material or the carrier
are linked to the GLP-1/glucagon receptor dual agonist include a genetic recombination method
and an in vitro linkage using polymers or low molecular chemicals, but are not limited thereto.
The FcRn binding material may be an immunoglobulin Fc region. For example, when
polyethylene glycol is used as the carrier, there may be included a Recode technique by Ambrx
Inc., which can attach position-specifically to polyethylene glycol. The methods may include a
glycopegylation technique by Neose company which can attach specifically to the glycosylated
moiety. Furthermore, the methods may include a releasable PEG technique in which
polyethylene glycol is removed, but is not limited thereto. The methods may include techniques
which can increase bioavailability using PEG. In addition, polymers such as polyethylene glycol,
polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol,
polyvinyl alcohol, polysaccharides, dextran, polyvinyl ethyl ether, biodegradable polymer, lipid
polymer, chitins, or hyaluronic acid may be included.
When albumin is used as a carrier, the methods may include a technology in which
albumins or albumin fragments can be directly covalently linked to peptides of the
GLP-1/glucagon receptor dual agonist to increase the in vivo stability. Even if albumin is not
directly linked, there may be included a technique in which the albumin binding materials, for
example, albumin-specific binding antibody or an antibody fragment are bound to the peptides to
bind to the albumin, and a technique in which a certain peptide/protein having a binding affinity
to albumin is bound to the peptides. In addition, the methods may include a technique in which a
fatty acid, etc., having a binding affinity to albumin is bound to the peptides, but is not limited
thereto. Any technique or binding method which can increase the in vivo stability using
albumin may be included herein.
The technique for binding to the peptide by using the antibody or antibody fragment as a
carrier in order to increase the in vivo half-life may also be included in the present disclosure.
The antibody or antibody fragment having a FcRn binding site can be used, and any antibody
fragment not containing FcRn binding site such as Fab can be used. CovX-body technique of
CovX company using a catalytic antibody may be included herein, and the technique which
increases the in vivo half-life using Fc fragments may be included in the present disclosure.
When using the Fc fragment, the linker binding to the Fc fragment and the peptide and its
binding method may include a peptide bond or a polyethylene glycol or the like, but is not
limited to thereto and any chemical binding method may be applicable. In addition, the binding
ratio of the GLP-1/glucagon receptor agonists dual agonist described herein may be 1:1 or 1:2,
but is not limited thereto, and any ratio which can increase the in vivo half-life may be included
without limitation.
Further, the carrier which is used to increase the in vivo half-life may be a non-peptidyl
material such as a polysaccharide or a fatty acid.
The linker binding to the carrier which is used to increase the in vivo half-life may
include peptides, polyethylene glycols, fatty acids, sugars, polymers, low molecular compounds,
nucleotides, and a combination thereof, and may be any chemical bond such as a non-covalent
chemical bond, a covalent chemical bond, etc., without limitation.
The formulation which can increase the bioavailability or continuously maintain the
activity may include a sustained release formulation by microparticles, nanoparticles and the like
using PLGA, hyaluronic acid, chitosan, etc.
Furthermore, the formulation of different aspects which can increase the bioavailability
or continuously maintain the activity may be a formulation such as implants, inhalants,
transnasal formulations or patches.
In one exemplary embodiment of the present disclosure, examples of the GLP-1/glucagon
receptor dual agonist can include a native GLP-1/glucagon receptor dual agonist such as
oxyntomodulin and the derivatives thereof, the long-acting formulation thereof, and the like can
also be included.
As used herein, the term "oxyntomodulin" means a peptide derived from a glucagon
precursor, pre-glucagon, and includes a native oxyntomodulin, precursors, derivatives, fragments
thereof, and variants thereof. Preferably, it can have the amino acid sequence of SEQ ID NO.
1(HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA).
The term, “oxyntomodulin variant” is a peptide having one or more amino acid sequences
different from those of native oxyntomodulin, and means a peptide that retains the function of
activating the GLP-1 and glucagon receptors, and it may be prepared by any one of substitution,
addition, deletion, and modification or by a combination thereof in a part of the amino acid
sequences of the native oxyntomodulin.
The term, "oxyntomodulin derivative" includes peptides, peptide derivatives or peptide
mimetics that are prepared by addition, deletion or substitution of amino acids of oxyntomodulin
so as to activate both of the GLP-1 receptor and the glucagon receptor at a high level, compared
to the native oxyntomodulin. Preferably, the oxyntomodulin derivative has an amino acid
th th
sequence of SEQ ID No. 25 and more preferably, its 16 and 20 amino acids form a ring.
The term, "oxyntomodulin fragment" means a fragment having one or more amino acids
added or deleted at the N-terminus or the C-terminus of the native oxyntomodulin, in which
non-naturally occurring amino acids (for example, D-type amino acid) can be added, and has a
function of activating both of the GLP-1 receptor and the glucagon receptor.
Each of the preparation methods for the variants, derivatives, and fragments of
oxyntomodulin can be used individually or in combination. For example, the present disclosure
includes a peptide that has one or more amino acids different from those of native peptide and
deamination of the N-terminal amino acid residue, and has a function of activating both of the
GLP-1 receptor and the glucagon receptor.
The C-terminal of the variants, derivatives, and fragments of oxyntomodulin described
herein may be amidated.
The carrier material which may be used in the present disclosure may be selected from
the group consisting of an antibody, an immunoglobulin Fc region, an albumin, a fatty acid, a
carbohydrate, a polymer having a repeating unit of a peptide, a transferrin, and a PEG, and
preferably an immunoglobulin Fc region. In one exemplary embodiment described herein, the
long-acting GLP-1/glucagon receptor dual agonist is linked to a carrier by the non-peptidyl
polymer as a linker. In one more exemplary embodiment, a carrier linked to a non-peptidyl
polymer is an immunoglobulin Fc fragment.
In the present disclosure, the long-acting GLP-1/glucagon receptor dual agonist is a form
in which the GLP-1/glucagon receptor dual agonist is each linked to an immunoglobulin Fc
region, and shows the sustainability and safety. Binding of the immunoglobulin Fc region and
the GLP-1/glucagon receptor dual agonist may be an inframe fusion without a linker or may be
linked using a non-peptide polymer linker. In the present disclosure, the immunoglobulin Fc may
be used interchangeably with immunoglobulin fragments.
As used herein, the term "non-peptidyl polymer" refers to a biocompatible polymer
including at least two repeating units linked to each other by any covalent bond excluding a
peptide bond. In the present disclosure, the non-peptidyl polymer may be interchangeably used
with the non-peptidyl linker.
The non-peptidyl polymer that may be used in the present disclosure may be selected
from the group consisting of a biodegradable polymer such as polyethylene glycol,
polypropylene glycol, ethylene glycol-propylene glycol copolymer, polyoxyethylated polyol,
polyvinyl alcohol, polysaccharide, dextran, polyvinyl ethyl ether, polylactic acid (PLA) or
polylactic-glycolic acid (PLGA), a lipid polymer, chitin, hyaluronic acid, and a combination
thereof, and preferably, the biodegradable polymer is polyethylene glycol. In addition,
derivatives thereof known in the art and derivatives easily prepared by a method known in the art
may be included in the scope described herein.
The peptide linker which is used in the fusion protein obtained by a conventional inframe
fusion method has a disadvantage in that it is easily cleaved in vivo by a protease, and thus a
sufficient effect of increasing the serum half-life of the active drug by a carrier cannot be
obtained as expected. However, in the present disclosure, the polymer having resistance to the
protease may be used to maintain the serum half-life of a peptide similarly as the carrier.
Therefore, any non-peptidyl polymer may be used without limitation, as long as it is a polymer
having the mentioned function, that is, a polymer having resistance to the in vivo protease. The
non-peptidyl polymer has a molecular weight in the range of 1 to 100 kDa, and preferably of 1 to
kDa. Further, the non-peptidyl polymer described herein, linked to the immunoglobulin Fc
region, may be one polymer or a combination of different types of polymers.
The non-peptidyl polymer used in the present disclosure has a reactive group capable of
binding to the immunoglobulin Fc region and protein drug. The reactive group at both ends of
the non-peptidyl polymeris preferably selected from the group consisting of a reactive aldehyde
group, a propionaldehyde, a butyraldehyde group, a maleimide group, and a succinimide
derivative. The succinimide derivative may be succinimidyl propionate, hydroxy succinimidyl,
succinimidyl carboxymethyl, or succinimidyl carbonate. In particular, when the non-peptidyl
polymer has a reactive group of the reactive aldehyde group at both ends thereof, it is effective to
minimize nonspecific reactions and link a physiologically active polypeptide and an
immunoglobulin at both ends of the non-peptidyl polymer. A final product produced by
reductive alkylation by an aldehyde bond is much more stable than that linked by an amide bond.
The aldehyde reactive group selectively binds to an N-terminus at a low pH, and binds to a lysine
residue to form a covalent bond at a high pH, such as pH 9.0. The reactive groups at both ends of
the non-peptidyl polymer may be the same or different from each other. For example, the
non-peptidyl polymer may possess a maleimide group at one end, and an aldehyde group, a
propionaldehyde group, or a butyraldehyde group at the other end. When a polyethylene glycol
having a reactive hydroxy group at both ends is used as the non-peptidyl polymer, the hydroxy
group may be activated to various reactive groups by known chemical reactions, or a
commercially available polyethylene glycol having a modified reactive group may be used to
prepare the long acting GLP-1/glucagon receptor dual agonist conjugate described herein.
In addition, the immunoglobulin Fc region is advantageous in terms of the preparation,
purification, and yield of the conjugate, because not only the molecular weight is relatively small
compared to the entire molecule, but the homogeneity of the materials is also greatly increased
and the potential of inducing antigenicity in blood is lowered, because the amino acid sequences
are different in each antibody, and thus the Fab portion showing a high non-homogeneity is
removed.
As used herein, the term "immunoglobulin Fc region" refers to the heavy-chain constant
region 2 (CH2) and the heavy-chain constant region 3 (CH3) of an immunoglobulin, excluding
the variable regions of the heavy and light chains, the heavy-chain constant region 1 (CH1), and
the light-chain constant region 1 (CL1) of the immunoglobulin. It may further include a hinge
region at the heavy-chain constant region. Also, the immunoglobulin Fc region described herein
may contain a part or all of the Fc region including the heavy-chain constant region 1 (CH1)
and/or the light-chain constant region 1 (CL1), except for the variable regions of the heavy and
light chains of the immunoglobulin, as long as it has an effect substantially equivalent to or
better than the native protein. Furthermore, the immunoglobulin Fc region may be a fragment
having a deletion of a relatively long portion of the amino acid sequence which corresponds to
CH2 and/or CH3. That is, the immunoglobulin Fc region described herein may comprise 1) a
CH1 domain, a CH2 domain, a CH3 domain, and a CH4 domain, 2) a CH1 domain and a CH2
domain, 3) a CH1 domain and a CH3 domain, 4) a CH2 domain and a CH3 domain, 5) a
combination of one or more domains and an immunoglobulin hinge region (or a portion of the
hinge region), and 6) a dimer of each domain of the heavy-chain constant regions and the
light-chain constant region.
Further, the immunoglobulin Fc region described herein includes a native amino acid
sequence as well as a sequence derivative (mutant) thereof. An amino acid sequence derivative
has a different sequence due to a deletion, an insertion, a non-conservative or conservative
substitution, or combinations thereof of one or more amino acid residues of the native amino acid
sequences. For example, in an IgG Fc, amino acid residues at positions 214 to 238, 297 to 299,
318 to 322, or 327 to 331, known to be important in binding , may be used as a suitable target for
modification.
Further, various kinds of derivatives are possible, including one in which a region
capable of forming a disulfide bond is deleted, certain amino acid residues are eliminated at the
N-terminal end of a native Fc, a methionine residue is added to the N-terminal end of a native Fc,
etc. Further, to remove effector functions, a complement-binding site, such as a Clq-binding site,
and an antibody dependent cell mediated cytotoxicity (ADCC) site may be deleted. Techniques
of preparing such sequence derivatives of the immunoglobulin Fc region are disclosed in
International Publication Nos: WO 97/34631, WO 96/32478, etc. Amino acid exchanges in
proteins and peptides, which do not entirely alter the activity of the molecules, are known in the
art (H. Neurath, R. L. Hill, The Proteins, Academic Press, New York, 1979). The most
commonly occurring exchanges are Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr,
Ser/Asn, Ala/Val, Ser/Gly, Thy/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, and
Asp/Gly, in both directions. In addition, the Fc region, if desired, may be modified by
phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, acetylation,
amidation, and the like.
The Fc derivatives are derivatives that have a biological activity identical to the Fc region
described herein, with improved structural stability of the Fc region, for example, against heat,
pH or the like.
Furthermore, these Fc regions may be obtained from native forms isolated from humans
and other animals including cows, goats, pigs, mice, rabbits, hamsters, rats, guinea pigs, etc., or
may be recombinants or derivatives thereof, obtained from transformed animal cells or
microorganisms. Herein, they may be obtained from a native form by isolating whole
immunoglobulins from human or animal organisms and then treating them with a protease.
When papain is treated, papain digests the native immunoglobulin into Fab and Fc regions, and
when pepsin is treated, the native immunoglobulin is cut into pF'c and F(ab)2. Fc or pF'c may be
isolated by size exclusion chromatography, etc. Preferably, a human-derived Fc region is a
recombinant immunoglobulin Fc region that is obtained from a microorganism.
In addition, the immunoglobulin Fc region may be in the form of having native sugar
chains, or increased or decreased sugar chains compared to a native form, or may be in a
deglycosylated form. The increase, decrease, or removal of the immunoglobulin Fc sugar chains
may be achieved by methods common in the art, such as a chemical method, an enzymatic
method and a genetic engineering method using a microorganism. The removal of sugar chains
from an Fc region results in a remarkable decrease in binding affinity to the C1q part and a
decrease or loss in antibody-dependent cell-mediated cytotoxicity or complement-dependent
cytotoxicity, thereby not inducing unnecessary immune responses in-vivo. In this regard, an
immunoglobulin Fc region in a deglycosylated or aglycosylated form may be more suitable for
the objective described herein as a drug carrier.
As used herein, the term "deglycosylation" refers to enzymatically removing sugar
moieties from an Fc region, and the term "aglycosylation" refers to an Fc region which is
produced in a prokaryote, preferably E. coli, and is not glycosylated.
Meanwhile, the immunoglobulin Fc region may be derived from humans or other animals
including cows, goats, pigs, mice, rabbits, hamsters, rats, guinea pigs, etc., and preferably from
humans.
Also, the immunoglobulin Fc region may be an Fc region that is derived from IgG, IgA,
IgD, IgE and IgM, a combination thereof, or hybrids thereof. Preferably, it is derived from IgG
or IgM which are the most abundant in human blood, and most preferably from IgG, which is
known to enhance the half-lives of ligand-binding proteins, but is not limited thereto.
As used herein, the term "combination" refers to that polypeptides encoding single-chain
immunoglobulin Fc regions of the same origin are linked to a single-chain polypeptide of a
different origin to form a dimer or multimer. That is, a dimer or multimer may be formed from
two or more fragments selected from the group consisting of IgG Fc, IgA Fc, IgM Fc, IgD Fc,
and IgE Fc fragments.
As used herein, the term "hybrid" refers to that a sequence corresponding to at least two
Fc fragments of a different origin is present in a single-chain immunoglobulin Fc region. In the
present disclosure, various types of hybrid are possible. That is, the hybrid consisting of 1 to 4
domains selected from the group consisting of CH1, CH2, CH3 and CH4 of IgG Fc, IgM Fc, IgA
Fc, IgE Fc and IgD Fc is possible, and may include a hinge.
On the other hand, IgG may also be classified into IgG1, IgG2, IgG3, and IgG4
sub-classes, and in the present disclosure, a combination or hybridization thereof is possible. It is
preferably IgG2 and IgG4 sub-classes, and most preferably is a Fc region of IgG4 that
substantially does not have an effector function such as a complement dependent cytotoxicity
(CDC).
That is, the immunoglobulin Fc region for the carrier of the drug described herein may be,
for example, human IgG4-derived aglycosylated Fc region, but is not limited thereto. The
human-derived Fc region is preferred over nonhuman-derived Fc region which can cause
undesirable immune responses, for example, which can act as an antigen in the human body to
produce a new antibody.
The method for preparing a long-acting GLP-1/glucagon receptor dual agonist described
herein is not particularly limited. For example, details of the preparation method and its effects
are described, for example, in Korean Patent Application Publication No. 100139579.
Using the long-acting GLP-1/glucagon receptor dual agonist has huge advantages of that
the number of administration to a chronic patient who needs daily administration can be
dramatically reduced due to an increase in the blood half-life and in vivo sustainability, thereby
improving the quality of life of the patient. Therefore, this is very helpful in the treatment of
non-alcoholic fatty liver disease.
As used herein, the term "non-alcoholic fatty liver disease" refers to fatty liver cases in
which there is no history of alcohol consumption or in which alcohol consumption is not related
to the occurrence. The fatty liver refers to a phenomenon in which there is abnormal
accumulation of triglyceride in liver cells, compared to normal levels of triglyceride. About 5%
of normal liver consists of fat tissue and the main components of the fat are triglycerides, fatty
acids, phospholipids, cholesterols, and cholesterol esters. However, once the fatty liver occurs,
most of the components are replaced with triglyceride. If the amount of triglycerides is more than
% of the liver weight, it is diagnosed as fatty liver. The fatty liver is caused by a lipid
metabolism disorder or a defect in the process of carrying excessive fat in the liver cells, and is
mainly caused by disorders of lipid metabolism in the liver. Most of the fat accumulated in the
fatty liver may be a triglyceride. The non-alcoholic fatty liver disease includes non-alcoholic
fatty liver, nonalcoholic steatohepatitis, cirrhosis, liver cancer, and the like, but the fatty liver
disease to be prevented or treated with the composition described herein is included without
limitation.
As used herein, the term "prevention" refers to all of the actions by which the
non-alcoholic fatty liver disease is prevented or delayed by administration of the composition
described herein. The "treatment" refers to all of the actions by which the symptoms of the
non-alcoholic fatty liver disease are alleviated, or positively changed. The treatment of the
non-alcoholic fatty liver disease is applicable to any mammal that may experience the
non-alcoholic fatty liver disease, and examples thereof include not only humans and primates,
but also cattle such as cow, pig, sheep, horse, dog and cat, without limitation, but is preferably a
human.
As used herein, the term "administration" refers to introduction of an amount of a
predetermined substance to a patient by a suitable method. The composition described herein
may be administered via any of the common routes, as long as it is able to reach a desired tissue.
For example, it may be intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal,
oral, topical, intranasal, intrapulmonary, or intrarectal administration, but is not limited thereto.
However, since peptides are digested upon oral administration, active ingredients of a
composition for oral administration should be coated or formulated for protection against
degradation in the stomach. Preferably, the composition may be administered in the form of
injections. In addition, the long-acting formulation may be administered by any apparatus in
which an active material can be transported into a target cell.
The administration dose and frequency of the pharmaceutical composition described
herein are determined by the type of active ingredient, together with various factors such as the
disease to be treated, administration route, patient's age, gender, and body weight, and disease
severity.
The pharmaceutical composition described herein may further include a pharmaceutically
acceptable carrier, excipient, or diluent. As used herein, the term "pharmaceutically acceptable
carrier" refers to a carrier or a diluent that does not stimulate the organism and inhibit biological
activity or characteristics of an administered compound. For oral administration, the carrier may
include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersing agent, a
stabilizer, a suspending agent, a colorant, and a flavoring agent. For injectable preparations, the
carrier may include a buffering agent, a preserving agent, an analgesic, a solubilizer, an isotonic
agent, a stabilizer, etc. For preparations for topical administration, the carrier may include a base,
an excipient, a lubricant, a preserving agent, etc.
The composition described herein may be formulated into a variety of dosage forms in
combination with the aforementioned pharmaceutically acceptable carriers. For example, for oral
administration, the pharmaceutical composition may be formulated into tablets, troches, capsules,
elixirs, suspensions, syrups or wafers. For injectable preparations, the pharmaceutical
composition may be formulated into an ampule as a single dosage form or a multidose container.
The pharmaceutical composition may also be formulated into solutions, suspensions, tablets,
pills, capsules and long-acting preparations.
On the other hand, examples of the carrier, the excipient, and the diluent suitable for the
pharmaceutical formulations include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol,
erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calciumphosphate, calcium silicate,
cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water,
methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils. In
addition, the pharmaceutical formulations may further include fillers, anti-coagulating agents,
lubricants, humectants, flavorants, and antiseptics.
Also described is a method for preventing or treating a non-alcoholic liver disease,
comprising a step of administering the composition comprising the long-acting GLP-1/glucagon
receptor dual agonist to a subject, exclusive of humans, at high risk of or having the
non-alcoholic liver disease.
The description of the composition and non-alcoholic fatty liver disease is the same as
above.
【Mode for Invention】
Hereinafter, the present invention will be described in more detail by way of examples.
These examples are only intended to illustrate the present invention, and the scope of the present
invention is not construed as being limited to these examples.
Example 1 : Synthesis of oxyntomodulin derivatives
In the examples, oxyntomodulin derivatives having the following amino acid sequences
were synthesized (Table 1).
【Table 1】
SEQ ID NO Sequence Note
SEQ ID NO: 1 HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRN
RNNIA
SEQ ID NO: 2 CA-SQGTFTSDYSKYLDEEAVRLFIEWLMNTKR
NRNNIA
SEQ ID NO: 3 CA-SQGTFTSDYSKYLDERRAQDFVAWLKNTGP
SSGAPPPS
SEQ ID NO: 4 CA-GQGTFTSDYSRYLEEEAVRLFIEWLKNGGPS
SGAPPPS
SEQ ID NO: 5 CA-GQGTFTSDYSRQMEEEAVRLFIEWLKNGGPS
SGAPPPS
SEQ ID NO: 6 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGT
FTSDYSKYLD
SEQ ID NO: 7 CA-SQGTFTSDYSRYLDEEAVRLFIEWLMNTK
SEQ ID NO: 8 CA-SQGTFTSDLSRQLEEEAVRLFIEWLMNK
SEQ ID NO: 9 CA-GQGTFTSDYSRYLDEEAVXLFIEWLMNTKR
NRNNIA
SEQ ID NO: 10 CA-SQGTFTSDYSRQMEEEAVRLFIEWLMNGGP
SSGAPPPSK
SEQ ID NO: 11 CA-GEGTFTSDLSRQMEEEAVRLFIEWAAHSQGT
FTSDYSRYLDK
SEQ ID NO: 12 CA-SQGTFTSDYSRYLDGGGHGEGTFTSDLSKQ
MEEEAVK
SEQ ID NO: 13 CA-SQGTFTSDYSRYLDXEAVXLFIEWLMNTK
SEQ ID NO: 14 CA-GQGTFTSDYSRYLDEEAVXLFIXWLMNTKR
NRNNIA
SEQ ID NO: 15 CA-GQGTFTSDYSRYLDEEAVRLFIXWLMNTKR
NRNNIA
SEQ ID NO: 16 CA-SQGTFTSDLSRQLEGGGHSQGTFTSDLSRQL
SEQ ID NO: 17 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNTKRN
RNNIA
SEQ ID NO: 18 CA-SQGTFTSDYSRYLDEEAVRLFIEWIRNGGPSS
GAPPPSK
SEQ ID NO: 19 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNTKRN Ring Formation
RNNIA
SEQ ID NO: 20 CA-SQGTFTSDYSRYLDEEAVKLFIEWIRNGGPS Ring Formation
SGAPPPSK
SEQ ID NO: 21 CA-SQGTFTSDYSRQLEEEAVRLFIEWVRNTKRN
RNNIA
SEQ ID NO: 22 DA-SQGTFTSDYSKYLDEKRAKEFVQWLMNTK Ring Formation
SEQ ID NO: 23 HAibQGTFTSDYSKYLDEKRAKEFVCWLMNT
SEQ ID NO: 24 HAibQGTFTSDY SKYLDEKRAK EFVQWLMNTC
SEQ ID NO: 25 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC Ring Formation
SEQ ID NO: 26 HAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC Ring Formation
SEQ ID NO: 27 HAibQGTFTSDYSKYLDEQAAKEFICWLMNT Ring Formation
SEQ ID NO: 28 HAibQGTFTSDY SKYLDEKRAK EFVQWLMNT
SEQ ID NO: 29 H(d)SQGTFTSDYSKYLDSRRAQDFVQWLMNTK
RNRNNIA
SEQ ID NO: 30 CA-SQGTFTSDYSKYLDSRRAQDFVQWLMNTKR
NRNNIA
SEQ ID NO: 31 CA-(d)SQGTFTSDYSKYLDSRRAQDFVQWLMNT
KRNRNNIA
SEQ ID NO: 32 CA-AibQGTFTSDYSKYLDEKRAKEFVQWLMNT Ring Formation
SEQ ID NO: 33 HAibQGTFTSDYAKYLDEKRAKEFVQWLMNTC Ring Formation
SEQ ID NO: 34 YAibQGTFTSDYSKYLDEKRAKEFVQWLMNTC Ring Formation
In Table 1, amino acids in bold and underlined in each of SEQ ID NOS: 19, 20, 22, 25,
26, 27, 32, 33 and 34, taken together form a ring, and amino acids represented by X mean a
non-native amino acid, alpha-methyl-glutamic acid. In addition, CA represents 4-imidazoacetyl,
and DA represents desamino-histidyl.
Hereafter, a representative long-acting GLP-1/glucagon receptor dual agonist, i.e., the
long-acting GLP-1/glucagon receptor dual agonist in which Fc is linked to the 30th amino acid
of the GLP-1/glucagon receptor dual agonist by the non-peptidyl polymer, PEG (polyethylene
glycol), was prepared and used in Examples 2 to 3 below.
Example 2: Confirmation of the effects of the long-acting GLP-1/glucagon receptor dual
agonist on non-alcoholic fatty liver disease in the high-fat, fructose and cholesterol containing
high trans-fat feed intake ob/ob mouse model
In order to confirm the effects of the long-acting GLP-1/glucagon receptor dual agonist
on non-alcoholic fatty liver disease, a high-fat (40% kcal), fructose(22%) and cholesterol
(2%)-containing high trans-fat diet (HTF diet) was taken to administrated to ob/ob mouse model
for 8 weeks to prepare an animal model for non-alcoholic fatty liver disease. Then, the
long-acting GLP-1/glucagon receptor dual agonist was subcutaneously administered to the
mouse once every two days (Q2D) with 0.7 and 1.4 nmol/kg and the administration was repeated
for 4 weeks. The weight of the animals was compared to that of the vehicle-treated group during
the 4-week test. After completion of the 4 week-test, the liver weights were measured and
compared. Further, after completion of the 4 week-test, mRNAs of, collagen-1a which is a
fibrosis marker; TNF-α which is a pro-inflammatory marker; and SREBP-1c which is a
lipogenesis marker were confirmed.
As a result, the measurement of the body weight and the liver weight after administration
for 4 weeks has shown that, in the long-acting GLP-1/glucagon receptor dual agonist, the weight
was significantly reduced as compared to that of vehicle-treated group (Fig. 1). Such results
suggest that the long-acting GLP-1/glucagon receptor dual agonist of the present invention can
suppress the weight gain which occurs in the animal model for non-alcoholic fatty liver disease
and that it can reduce the side-effects of conventional drugs for improving insulin resistance.
Further, the comparison of mRNA of collagen-1a, TNF-α, SREBP-1c has shown that in
the long-acting GLP-1/glucagon receptor dual agonist-treated group, these mRNA were
significantly reduced (Fig. 2). Such results suggest that the long-acting GLP-1/glucagon receptor
dual agonist of the present invention reduces fibrosis, pro-inflammation and the like in the
animal model for the non-alcoholic fatty liver disease and inhibit fat production, thus being
effective for the prevention and treatment of non-alcoholic fatty liver disease.
Example 3: Confirmation of the effects of the long-acting GLP-1/glucagon receptor
dual agonist on non-alcoholic fatty liver disease in the high trans-fat feed intake DI0 mouse
model
In order to confirm the effects of the long-acting GLP-1/glucagon receptor dual agonist
on the non-alcoholic fatty liver disease, a 60% high trans-fat diet was administered to normal
mouse model(C57BL/6) for 12 weeks to prepare an animal model for non-alcoholic fatty liver
disease. Then, 3nmol/kg of the long-acting GLP-1/glucagon receptor dual agonist was
subcutaneously administered to the mouse once every week (QW) and the administration was
repeated for 4 weeks. After completion of the 4 week-test, hepatic triglyceride (hepatic TG) and
serum cholesterol were measured.
As a result, the measurement of the hepatic triglycerides and serum cholesterol after
administration for 4 weeks has shown that, in the case of administration of the long-acting
GLP-1/glucagon receptor dual agonist, they were significantly reduced as compared to those of
the vehicle-treated group and also that they were significantly reduced to the level of a normal
animal which has undergone a chow diet (Fig. 3). Such results suggest that the long-acting
GLP-1/glucagon receptor dual agonist described herein can reduce the hepatic triglyceride and
serum cholesterol to normal animal levels in the animal model for the non-alcoholic fatty liver
disease, thus being effective for the prevention and treatment of non-alcoholic fatty liver disease.
From the above description, a person skilled in the art will appreciate that the invention
may be embodied in other specific forms without changing the technical spirit or essential
characteristics. In this regard, the embodiments described above should be understood to be
illustrative rather than restrictive in every respect. The scope of the invention should be
construed that the meaning and scope of the appended claims rather than the detailed description
and all changes or variations derived from the equivalent concepts fall within the scope of the
present invention.
The term “comprising” as used in this specification and claims means “consisting at least
in part of”. When interpreting statements in this specification, and claims which include the
term “comprising”, it is to be understood that other features that are additional to the features
prefaced by this term in each statement or claim may also be present. Related terms such as
“comprise” and “comprised” are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
In the description in this specification reference may be made to subject matter that is not
within the scope of the claims of the current application. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention as
defined in the claims of this application.
The following numbered paragraphs define particular aspects of the present invention:
【Paragraph 1】
A pharmaceutical composition for the prevention or treatment of non-alcoholic fatty
liver disease comprising a long-acting glucagon-like peptide-1 (GLP-1)/glucagon receptor dual
agonist.
【Paragraph 2】
The pharmaceutical composition according to paragraph 1, wherein the composition is
characterized by either having no side effect of weight gain or reducing the side effect of weight
gain.
【Paragraph 3】
The pharmaceutical composition according to paragraph 1, wherein the composition
performs at least one of the following features:
a) reducing the expression or activity of collagen-1a, which is a fibrosis marker;
b) reducing the expression or activity of tumor necrosis factor-α (TNF-α), which is a
pro-inflammatory marker;
c) reducing the expression or activity of sterol regulatory element binding protein-1c
(SREBP-1c), which is a lipogenesis marker;
d) reducing liver triglycerides; and
e) reducing blood cholesterol.
【Paragraph 4】
The pharmaceutical composition according to paragraph 1, wherein the non-alcoholic
fatty liver disease is at least one disease selected from the group consisting of non-alcoholic fatty
liver, non-alcoholic steatohepatitis, cirrhosis, and liver cancer.
【Paragraph 5】
The pharmaceutical composition according to paragraph 1, wherein the long-acting
glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist simultaneously activates GLP-1
receptor and the glucagon receptor.
【Paragraph 6】
The pharmaceutical composition according to paragraph 1, wherein the long-acting
glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist is in a conjugate form, wherein
a biocompatible material or a carrier capable of increasing the duration of the activity of the dual
agonist is linked to the agonist by a covalent bond or a linker.
【Paragraph 7】
The pharmaceutical composition according to paragraph 1, wherein the long-acting
glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist has the amino acid sequence of
SEQ ID NO.25 and the amino acid at position 16 and 20 forms a ring.
【Paragraph 8】
The pharmaceutical composition according to paragraph 1, wherein the long-acting
glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist is linked to an immunoglobulin
Fc region via a non-peptidyl polymer, wherein the non-peptidyl polymer is selected from the
group consisting of polyethylene glycol, polypropylene glycol, ethylene glycol-propylene glycol
copolymers, polyoxyethylated polyols, polyvinyl alcohol, polysaccharides, dextran, polyvinyl
ethyl ether, biodegradable polymers, lipid polymers, chitins, hyaluronic acid, and combinations
thereof.
【Paragraph 9】
The pharmaceutical composition according to paragraph 8, wherein the immunoglobulin
Fc region is aglycosylated.
【Paragraph 10】
The pharmaceutical composition according to paragraph 9, wherein the immunoglobulin
Fc region comprises one to four domains selected from the group consisting of CH1, CH2, CH3,
and CH4 domains.
【Paragraph 11】
The pharmaceutical composition according to paragraph 10, wherein the immunoglobulin
Fc region further comprises a hinge region.
【Paragraph 12】
The pharmaceutical composition according to paragraph 8, wherein the immunoglobulin
Fc region is an Fc region derived from an immunoglobulin selected from the group consisting of
IgG, IgA, IgD, IgE, and IgM.
【Paragraph 13】
The pharmaceutical composition according to paragraph 12, wherein each domain on the
immunoglobulin Fc region is a hybrid of domains having different origins selected from the
group consisting of IgG, IgA, IgD, IgE, and IgM.
【Paragraph 14】
The pharmaceutical composition according to paragraph 12, wherein the
immunoglobulin Fc region is a dimer or polymer consisting of a single-chain immunoglobulins
consisting of domains having the same origin.
【Paragraph 15】
The pharmaceutical composition according to paragraph 1, wherein the composition
further comprises a pharmaceutically acceptable carrier.
【Paragraph 16】
The pharmaceutical composition according to paragraph 1, wherein the long-acting
glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist is a conjugate in which a
GLP-1/glucagon dual agonist represented by SEQ ID NO: 25 and an immunoglobulin Fc region
are linked by a non-peptidyl polymer linker.
【Paragraph 17】
th th
The pharmaceutical composition according to paragraph 16, wherein the 16 and 20
amino acid of long-acting glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist
represented by SEQ ID NO: 25 form a ring.
【Paragraph 18】
The pharmaceutical composition according to paragraph 16, wherein the non-peptidyl
polymer linker is PEG.
【Paragraph 19】
A method for preventing or treating a non-alcoholic liver disease, comprising
administering the pharmaceutical composition of any one of paragraphs 1 to 18 to a subject,
exclusive of humans, at high risk of or having the non-alcoholic liver disease.
Claims (16)
1. Use of a long-acting glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist conjugate in the preparation of a medicament for the prevention or treatment of liver inflammation in non-alcoholic fatty liver disease, wherein the conjugate comprises: a GLP-1/glucagon receptor dual agonist comprising the amino acid sequence of any one of SEQ ID NOs: 32, 33, 34, 2-23, or 27-31; an immunoglobulin Fc region; and a non-peptidyl polymer, wherein the non-peptidyl polymer covalently links the GLP-1/glucagon receptor dual agonist and the immunoglobulin Fc region.
2. The use according to claim 1, wherein the medicament is characterized by either having no side effect of weight gain or reducing the side effect of weight gain.
3. The use according to claim 1 or 2, wherein the medicament reduces the expression or activity of tumor necrosis factor-α (TNF- α), which is a pro-inflammatory marker.
4. The use according to any one of the previous claims, wherein the non-alcoholic fatty liver disease is at least one disease selected from the group consisting of non-alcoholic fatty liver, non-alcoholic steatohepatitis, cirrhosis, and liver cancer.
5. The use according to any one of the previous claims, wherein the long-acting GLP-1/glucagon receptor dual agonist conjugate simultaneously activates GLP-1 receptor and the glucagon receptor.
6. The use according to any one of claims 1-5, wherein the amino acids at positions 12 and 16 or 16 and 20 of the GLP-1/glucagon receptor dual agonist form a ring.
7. The use according to any one of the previous claims, wherein the non-peptidyl polymer comprises polyethylene glycol, polypropylene glycol, an ethylene glycol-propylene glycol copolymer, a polyoxyethylated polyol, polyvinyl alcohol, a polysaccharide, polyvinyl ethyl ether, a biodegradable polymer, a lipid polymer, hyaluronic acid, or a combination thereof.
8. The use according to claim 7, wherein the non-peptidyl polymer is polyethylene glycol.
9. The use according to claim 7, wherein the polysaccharide is dextran, a chitin, or a combination thereof.
10. The use according to any one of the previous claims, wherein the immunoglobulin Fc region is aglycosylated.
11. The use according to claim 10, wherein the immunoglobulin Fc region comprises one to four domains selected from CH1, CH2, CH3, or CH4 domains.
12. The use according to claim 11, wherein the immunoglobulin Fc region further comprises a hinge region.
13. The use according to any one of the previous claims, wherein the immunoglobulin Fc region is an Fc region derived from an IgG, IgA, IgD, IgE, or IgM.
14. The use according to claim 13, wherein each domain of the immunoglobulin Fc region is a hybrid of domains having different origins from IgG, IgA, IgD, IgE, or IgM.
15. The use according to claim 13, wherein the immunoglobulin Fc region is a dimer or polymer consisting of single chain immunoglobulins consisting of domains having the same origin.
16. The use according to any one of claims 1-15, substantially as herein described and exemplified.
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NZ730799A NZ730799A (en) | 2014-09-16 | 2015-09-16 | Use of a long acting glp-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease |
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