JP2020534840A - Glp−2誘導体の持続型結合体 - Google Patents
Glp−2誘導体の持続型結合体 Download PDFInfo
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- JP2020534840A JP2020534840A JP2020517828A JP2020517828A JP2020534840A JP 2020534840 A JP2020534840 A JP 2020534840A JP 2020517828 A JP2020517828 A JP 2020517828A JP 2020517828 A JP2020517828 A JP 2020517828A JP 2020534840 A JP2020534840 A JP 2020534840A
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- glp
- derivative
- conjugate
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- lysine
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001522 polyglycol ester Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 101150079601 recA gene Proteins 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000037432 silent mutation Effects 0.000 description 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
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- Biophysics (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
[一般式1]
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34(配列番号9)
[一般式1]
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34(配列番号9)
アラニン Ala,A
アルギニン Arg,R
アスパラギン Asn,N
アスパラギン酸 Asp,D
システイン Cys,C
グルタミン酸 Glu,E
グルタミン Gln,Q
グリシン Gly,G
ヒスチジン His,H
イソロイシン Ile,I
ロイシン Leu,L
リシン Lys,K
メチオニン Met,M
フェニルアラニン Phe,F
プロリン Pro,P
セリン Ser,S
トレオニン Thr,T
トリプトファン Trp,W
チロシン Tyr,Y
バリン Val,V
GLP−2(1−33)
HADGSFSDEMNTILDNLAARDFINWLIQTKITD(配列番号1)
[一般式1]
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34(配列番号9)
CA−GLP−2 KC−PEG(10K)−免疫グロブリンFc結合体又はCA−GLP−2 RC−PEG(10K)−免疫グロブリンFc結合体の製造
10kDaのMAL−ALD PEG(両末端の水素がそれぞれ3−[(3−N−マレイミジル)プロパノイル]アミノプロピル基とプロピルアルデヒド基で修飾された分子量10kDaのポリエチレングリコール,日本NOF社)をCA−GLP−2 KC又はCA−GLP−2 RC(CPC, Chinese Peptide Co, 中国)の34位のシステイン残基にペグ化させるために、CA−GLP−2 KC又はCA−GLP−2 RCとPEGのモル比を1:1〜2とし、ペプチドの濃度を1〜3mg/mlとして、1〜3時間反応させた。ここで、反応は、50mMトリス(Tris, pH7.5)とイソプロパノールの混合溶媒において行った。反応液は、クエン酸ナトリウム(pH2.0)、エタノールを含む緩衝液と塩化カリウムの濃度勾配によるSP Sepharose High Performance(GE, 米国)カラムを用いて精製し、モノペグ化された(mono-PEGylated)CA−GLP−2 KC又はモノペグ化されたCA−GLP−2 RCを得た。
CA−GLP−2 RK−PEG(3.4K又は10K)−免疫グロブリンFc結合体の製造
3.4kDa又は10kDaのALD(2)PEG(両末端の水素がプロピルアルデヒド基で修飾された分子量3.4kDaのポリエチレングリコール,日本NOF社)をCA−GLP−2 RK(CPC, Chinese Peptide Co., 中国)の34位のリシン残基にペグ化させるために、CA−GLP−2 RKとPEGのモル比を1:5〜1:20とし、ペプチドの濃度を5〜10mg/mlとして、2〜8℃で4〜16時間反応させた。ここで、反応は、20mMヘペス(HEPES, pH7.5)とエタノールにおいて行い、還元剤として20mMシアノ水素化ホウ素ナトリウムを添加して反応させた。反応液は、クエン酸ナトリウム(pH2.0)、エタノールを含む緩衝液と塩化カリウムの濃度勾配を用いたSource 15S(GE, 米国)カラムを用いて精製し、モノペグ化されたCA−GLP−2 RKを得た。
CA−GLP−2 KK−PEG(10K)−免疫グロブリンFc結合体及びCA−GLP−2 KAZK−PEG(10K)−免疫グロブリンFc結合体の製造
実施例2の方法により、CA−GLP−2 KK及びCA−GLP−2 KAZKを用いて、免疫グロブリンFcにCA−GLP−2 KK又はCA−GLP−2 KAZKがPEGにより共有結合で連結された結合体であるCA GLP−2 KK(10K PEG)誘導体の持続型結合体CA−GLP−2 KK−PEG(10K)−免疫グロブリンFcとCA GLP−2 KAZK(10K PEG)誘導体の持続型結合体CA−GLP−2 KAZK−PEG(10K)−免疫グロブリンFcを製造及び精製した。
GLP−2誘導体及びその持続型結合体のin vitro活性確認
前記実施例で得たGLP−2誘導体及びGLP−2誘導体持続型結合体の活性を測定するために、GLP−2受容体が形質転換された細胞株を用いて、in vitroで細胞活性を測定する方法を行った。前記細胞株は、CHO(Chinese hamster ovary)−K1がヒトGLP−2受容体を発現するように形質転換したものであり、GLP−2の活性を測定するのに適している(DiscoverX, USA)。
GLP−2誘導体の持続型結合体のSDラットにおける薬物動態確認
GLP−2誘導体の持続型結合体の薬物動態を正常ラットにおいて比較した。8週齢の正常ラットをCA GLP−2 KC(10K PEG)誘導体、CA GLP−2 RC(10K PEG)誘導体、CA GLP−2 RK(10K PEG)誘導体及びCA GLP−2 RK(3.4K PEG)誘導体の持続型結合体投与群(2.52mg/kg)に分けた。正常ラットに前記試験物質を1群当たり3匹ずつ単回皮下投与し、CA GLP−2 KC(10K PEG)誘導体の持続型結合体においては1、4、8、24、48、72、96、120、144及び168時間後に尾静脈採血により全血を収集し、それ以外のCA GLP−2誘導体の持続型結合体においては1、4、8、24、48、72、96、120、144、168、192、216、240、264、288、312及び336時間後に尾静脈採血により全血を収集した。全血を1.5mL容量のマイクロチューブに入れ、5,000rpmにて常温で10分間遠心分離して血清を分離し、その後−20℃で保管した。保管した各群の血清は、ELISA分析法により血清中の濃度を定量化した。CA GLP−2誘導体持続型結合体においては、ビオチン標識されたGLP−2モノクローナル抗体(Phoenix Pharmaceuticals, #B-028-14)をストレプトアビジン(Streptadivin)がコーティングされたプレート(Roche, #11645692001)に結合させ、その後血清と1時間反応させた。洗浄後に抗ヒトIgG4−HPR(Alpha Diagonosis, #10124)を入れ、常温で1時間反応させ、その後TMB試薬で発色反応させ、450nmの波長で吸光度を測定した。血清中の濃度を用いて薬物動態パラメータを算出した。
GLP−2誘導体の持続型結合体とtedulglutideのSDラットにおける薬物動態比較
Teduglutide及びGLP−2誘導体の持続型結合体の薬物動態を比較した。8週齢の正常ラットをTeduglutide投与群(2.5mg/kg)とCA GLP−2 RK(3.4K PEG)誘導体の持続型結合体投与群(0.705mg/kg)に分けた。正常ラットに前記試験物質を1群当たり3匹ずつ単回皮下投与し、Teduglutide投与群においては0.25、0.5、1、1.5、2、3、4、6、8及び24時間後に尾静脈採血により全血を収集し、CA GLP−2 RK誘導体の持続型結合体投与群においては4、8、24、48、72、96、120、144、168、192、216、240、264、288、312及び336時間後に尾静脈採血により全血を収集した。全血を1.5mL容量のマイクロチューブに入れ、5,000rpmにて常温で10分間遠心分離して血清を分離し、その後−20℃で保管した。保管した各群の血清は、ELISA分析法により血清中の濃度を定量化した。Teduglutideにおいては、GLP−2 ELISA Kit(Alpco, #48-GP2HU-E01.1)を用いた。CA GLP−2 RK誘導体の持続型結合体においては、ビオチン標識されたGLP−2ポリクローナル抗体(Phoenix Pharmaceuticals, #B-028-14)をストレプトアビジン(Streptavidin)がコーティングされたプレート(Roche, #11645692001)に結合させ、その後血清と1時間反応させた。洗浄後に抗ヒトIgG4−HPR(Alpha Diagonosis, #10124)を入れ、常温で1時間反応させ、その後TMB試薬で発色反応させ、450nmの波長で吸光度を測定した。血清中の濃度を用いて薬物動態パラメータを算出した。
GLP−2誘導体の持続型結合体の正常マウスにおけるin vivo腸重量増加効果の確認
Teduglutide及びGLP−2誘導体の持続型結合体のin vivo腸重量増加効果を正常マウスにおいて確認した。
Claims (23)
- グルカゴン様ペプチド−2(GLP−2)誘導体と免疫グロブリンFc領域が非ペプチド性重合体を介して前記非ペプチド性重合体の両末端にそれぞれ共有結合で連結されたGLP−2結合体であって、
前記非ペプチド性重合体は、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール−プロピレングリコール共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、ポリサッカライド、デキストラン、ポリビニルエチルエーテル、脂質重合体、キチン類、ヒアルロン酸及びそれらの組み合わせからなる群から選択されるGLP−2結合体。 - 前記GLP−2誘導体は、下記一般式1のアミノ酸配列を含む、請求項1に記載のGLP−2結合体。
[一般式1]
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34(配列番号9)
(ここで、X1はヒスチジン、イミダゾアセチルデスヒスチジン、デスアミノヒスチジン、β−ヒドロキシイミダゾプロピオニルデスヒスチジン、N−ジメチルヒスチジン又はβ−カルボキシイミダゾプロピオニルデスヒスチジンであり、
X2はアラニン、グリシン又はAib(2-aminoisobutyric acid)であり、
X30はリシン又はアルギニンであり、
X34は不在であるか、リシン、アルギニン、グルタミン、ヒスチジン、6−アジドリシン又はシステインであるが、
一般式1のアミノ酸配列のうち配列番号1と同じ配列は除く。) - 前記GLP−2誘導体は、(1)X2がグリシンであるか、(2)X30がアルギニンであるか、又は(3)X2がグリシンであり、X30がアルギニンである、請求項2に記載のGLP−2結合体。
- 前記GLP−2誘導体は、
(1)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34がシステインであるか、
(2)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34がリシンであるか、
(3)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がアルギニンであり、X34がリシンであるか、
(4)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34が6−アジドリシンであるか、
(5)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がアルギニンであり、X34がシステインであるか、
(6)X1がイミダゾアセチルデスヒスチジンであり、X2がAibであり、X30がリシンであり、X34がシステインであるか、又は
(7)X1がヒスチジンであり、X2がAibであり、X30がリシンであり、X34がシステインである、請求項2又は3に記載のGLP−2結合体。 - 前記GLP−2誘導体は、少なくとも1つの残基がシステイン、リシン、アルギニン、グルタミン、ヒスチジン又は6−アジドリシンである、請求項1〜4のいずれか一項に記載のGLP−2結合体。
- 前記GLP−2誘導体は、配列番号2〜8からなる群から選択されるアミノ酸配列である、請求項1〜5のいずれか一項に記載のGLP−2結合体。
- 前記非ペプチド性重合体の両末端がそれぞれ免疫グロブリンFc領域とGLP−2誘導体のヒドロキシ基、チオール基、アミノ基又はアジド基に結合された、請求項1〜6のいずれか一項に記載のGLP−2結合体。
- 前記免疫グロブリンFc領域は非グリコシル化されたことを特徴とする、請求項1〜7のいずれか一項に記載のGLP−2結合体。
- 前記免疫グロブリンFc領域はヒンジ領域を含む、請求項1〜8のいずれか一項に記載のGLP−2結合体。
- 前記免疫グロブリンFc領域はIgG4 Fc領域である、請求項1〜9のいずれか一項に記載のGLP−2結合体。
- 下記一般式1のアミノ酸配列を含むGLP−2誘導体。
[一般式1]
X1X2DGSFSDEMNTILDNLAARDFINWLIQTX30ITDX34(配列番号9)
(ここで、X1はヒスチジン、イミダゾアセチルデスヒスチジン、デスアミノヒスチジン、β−ヒドロキシイミダゾプロピオニルデスヒスチジン、N−ジメチルヒスチジン又はβ−カルボキシイミダゾプロピオニルデスヒスチジンであり、
X2はアラニン、グリシン又はAib(2-aminoisobutyric acid)であり、
X30はリシン又はアルギニンであり、
X34は不在であるか、リシン、アルギニン、グルタミン、ヒスチジン、6−アジドリシン又はシステインであるが、
一般式1のアミノ酸配列のうち配列番号1と同じ配列は除く。) - 前記GLP−2誘導体は、(1)X2がグリシンであるか、(2)X30がアルギニンであるか、又は(3)X2がグリシンであり、X30がアルギニンである、請求項11に記載のGLP−2誘導体。
- 前記GLP−2誘導体は、
(1)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34がシステインであるか、
(2)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34がリシンであるか、
(3)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がアルギニンであり、X34がリシンであるか、
(4)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がリシンであり、X34が6−アジドリシンであるか、
(5)X1がイミダゾアセチルデスヒスチジンであり、X2がグリシンであり、X30がアルギニンであり、X34がシステインであるか、
(6)X1がイミダゾアセチルデスヒスチジンであり、X2がAibであり、X30がリシンであり、X34がシステインであるか、又は
(7)X1がヒスチジンであり、X2がAibであり、X30がリシンであり、X34がシステインである、請求項11又は12に記載のGLP−2誘導体。 - 請求項11〜13のいずれか一項に記載のGLP−2誘導体をコードする分離された核酸。
- 請求項14に記載の核酸を含む組換え発現ベクター。
- 請求項15に記載の組換え発現ベクターを含む形質転換体。
- a)請求項11〜13のいずれか一項に記載のGLP−2誘導体をコードする核酸を含む形質転換体を培養してGLP−2誘導体を発現させるステップと、
b)発現したGLP−2誘導体を分離及び精製するステップとを含む、請求項11〜13のいずれか一項に記載のGLP−2誘導体の製造方法。 - (a)少なくとも2つの末端反応基を有する非ペプチド性重合体と、請求項11〜13のいずれか一項に記載のGLP−2誘導体と免疫グロブリンFc領域のいずれか一方とを反応させ、一末端にGLP−2誘導体又は免疫グロブリンFc領域が結合され、他末端に反応基を有する連結体を作製するステップと、
(b)前記(a)ステップで作製した連結体と、免疫グロブリンFc領域とGLP−2誘導体のうち連結体に結合されていない他方とを反応させ、GLP−2誘導体と免疫グロブリンFc領域が非ペプチド性重合体を介して連結された結合体を製造するステップとを含む、GLP−2結合体の製造方法。 - 前記非ペプチド性重合体は、アルデヒド基、プロピオンアルデヒド基、ブチルアルデヒド基、マレイミド基及びスクシンイミド誘導体からなる群から選択される少なくとも1つの反応基を有する、請求項18に記載のGLP−2結合体の製造方法。
- 前記スクシンイミド誘導体は、スクシンイミジルカルボキシメチル、スクシンイミジルバレレート、スクシンイミジルメチルブタノエート、スクシンイミジルメチルプロピオネート、スクシンイミジルブタノエート、スクシンイミジルプロピオネート、N−ヒドロキシスクシンイミド又はスクシンイミジルカーボネートである、請求項19に記載のGLP−2結合体の製造方法。
- 請求項1〜10のいずれかのGLP−2結合体、又は請求項11〜13のいずれか一項に記載のGLP−2誘導体を含む、腸疾患、腸損傷及び胃疾患から選択される少なくとも1つの疾患の予防又は治療用薬学的組成物。
- 前記腸疾患は、短腸症候群、過敏性腸疾患、炎症性腸疾患、クローン病、結腸炎、大腸炎、膵炎、回腸炎、粘膜炎又は腸萎縮である、請求項21に記載の薬学的組成物。
- 前記胃疾患は、胃痙攣、胃炎、胃潰瘍、十二指腸炎又は十二指腸潰瘍である、請求項21に記載の薬学的組成物。
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