JP2022542151A - FGF21 Fc融合タンパク質、GLP-1 Fc融合タンパク質、それらの併用治療剤および使用 - Google Patents
FGF21 Fc融合タンパク質、GLP-1 Fc融合タンパク質、それらの併用治療剤および使用 Download PDFInfo
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Abstract
Description
そのアミノ酸配列は、
(1)SEQ ID NO:4に示されるとおりであり、または
(2)上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である、
FGF21 Fc融合タンパク質を提供する。
そのアミノ酸配列は、
(1)SEQ ID NO:5、SEQ ID NO:6、またはSEQ ID NO:7に示されるとおりであり、または
(2)上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である、
GLP-1 Fc融合タンパク質を提供する。
前記併用治療剤は、長期間作用型FGF21 Fc融合タンパク質を含む第1医薬組成物と、長期間作用型GLP-1 Fc融合タンパク質を含む第2医薬組成物とで構成され、長期間作用型FGF21 Fc融合タンパク質のアミノ酸配列は、SEQ ID NO:4に示される配列、または上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である配列から選ばれ、前記長期間作用型GLP-1 Fc融合タンパク質のアミノ酸配列は、SEQ ID NO:5、SEQ ID NO:6もしくはSEQ ID NO:7に示される配列、または上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である配列から選ばれる。
長期間作用型FGF21-Fc融合タンパク質は、FP4Iと命名され、調製方法はCN107995914Aを参照し、本発明において、そのアミノ酸配列はSEQ ID NO:4に示すとおりであり、デュラグルチド(アメリカのLily社)は、本発明において、そのアミノ酸配列はSEQ ID NO:5に示すとおりであり、Ex(1-39)-L3-CTP1-vFcγ2-3は、FP-Aと命名され、調製方法は中国特許CN106117370Bを参照し、本発明において、そのアミノ酸配列はSEQ ID NO:6に示すとおりであり、Ex-(1-45)-L-vFcは、FP-Bと命名され、調製方法は中国特許CN106279430Bを参照し、本発明において、そのアミノ酸配列はSEQ ID NO:7に示すとおりである。
8週齢のC57BL/6J雄マウスは、上海SLAC実験動物有限責任公司から購入した。飼育環境22~24℃、相対湿度45%~65%、照明時間12h/日とした。D12492飼料(脂肪カロリー60%、アメリカResearch Diets社の製品)で20週間飼育した後、体質量によって、マウスを溶媒対照グループ、FP4I-5mg/kgグループ(FP4Iグループと略称する)、デュラグルチド-1.5mg/kgグループ(デュラグルチドグループと略称する)、FP-B-1.5mg/kgグループ(FP-Bグループと略称する)、FP-A-1.5mg/kgグループ(FP-Aグループと略称する)、FP4I-5mg+デュラグルチド-1.5mg/kgグループ(FP4I+デュラグルチドグループと略称する)、FP4I-5mg/kg+FP-B-1.5mg/kgグループ(FP4I+FP-Bグループと略称する)、およびFP4I-5mg+FP-A-1.5mg/kgグループ(FP4I+FP-Aグループと略称する)にランダムに分け、グループ毎に8匹のマウスとした。溶媒対照グループおよび単剤治療グループの頸背部皮下に、対応するタンパク質溶液または緩衝液を注射投与し、併用投与グループの頸背部皮下にFP4Iを注射投与し、腹部皮下にデュラグルチド、FP-A、またはFP-Bをそれぞれ注射投与した。6日に1回投与し、合計4回投与した。最終回の投与周期後に、各グループのマウスを16h断食させ、眼窩から全血を採取し、2000gで15分間遠心し、分離して血清サンプルを得た。肝臓組織を分離し、重量を秤量し、肝左外側葉を液体窒素で急凍結した後、-80℃の冷蔵庫に移して保存し、肝右葉を10%のホルマリン溶液に保存した。
全自動生化学分析装置(ALFRA XL-200全自動生化学分析装置、ドイツALFRA社の製品)およびセットとなる試薬キット(寧波美康バイオテクノロジー有限公司の製品)でマウス血清のALT、AST、TG、TC、LDL-c、HDL-cの含有量を検出した。ELISA法(マウス超高感度インスリンELISA検出試薬キット、アメリカALPCO社の製品)でマウスの空腹時の血清中のインスリン含有量を検出した。マウス肝左外側葉組織を約55mg取り、Floch法で単位肝質量あたりのトリグリセリド含有量を検出した。マウス肝右葉を取り、HE染色を行い、組織病理学的検査を行った。
結果は、図1に示すように、溶媒対照グループと比べ、デュラグルチドグループ、FP-Aグループ、FP-Bグループ、およびFP4Iグループのマウスの体質量は著しく低下した。FGF21 Fc融合タンパク質またはGLP-1 Fc融合タンパク質の単独投与と比べ、併用投与グループのマウスの体質量は更に著しく低下した。結果は、図2および図3に示すように、併用投与グループのマウスの肝機能の改善程度は、単独投与グループよりも著しく優れ、肝臓トリグリセリドの含有量は単独投与グループよりも著しく低かった。
8週齢のC57BL/6J雄マウスは、北京華阜康バイオテクノロジー股フン有限公司から購入した。飼育環境22~24℃、相対湿度45%~65%、照明時間12h/日とした。D09100301飼料(脂肪カロリー40%、果糖カロリー40%、コレステロール質量2%、アメリカResearch Diets社の製品)で30週間飼育した後、12h断食し、眼角静脈叢から全血を約120μl採取し、血清を分離してALTレベルを検出した。体質量および血清のALTレベルによって、マウスを溶媒対照グループ、FP4I-5mg/kgグループ(FP4Iグループと略称する)、デュラグルチド-1.5mg/kgグループ(デュラグルチドグループと略称する)、FP-B-1.5mg/kgグループ(FP-Bグループと略称する)、FP-A-1.5mg/kgグループ(FP-Aグループと略称する)、FP4I-5mg+デュラグルチド-1.5mg/kgグループ(FP4I+デュラグルチドグループと略称する)、FP4I-5mg/kg+FP-B-1.5mg/kg(FP4I+FP-Bグループと略称する)、およびFP4I-5mg+FP-A-1.5mg/kgグループ(FP4I+FP-Aグループと略称する)にランダムに分け、グループ毎に8匹のマウスとした。溶媒対照グループおよび単剤治療グループの頸背部皮下に、対応するタンパク質溶液または緩衝液を注射投与し、併用投与グループの頸背部皮下にFP4Iを注射投与し、腹部皮下にデュラグルチド、FP-A、またはFP-Bをそれぞれ注射投与した。6日に1回投与し、合計8回投与した。最終回の投与周期後に、各グループのマウスを16h断食し、眼角静脈叢から全血を採取し、2000gで15分間遠心し、分離して血清サンプルを得た。肝臓組織を分離し、重量を秤量し、肝左外側葉を液体窒素で急凍結した後、-80℃の冷蔵庫に移して保存し、肝右葉を10%のホルマリン溶液に保存した。
非アルコール性脂肪性肝炎のスコア系(NASポイント)で治療効果を評価し、標準は、アメリカ国立衛生研究所の病理ワークグループマニュアルを参照し、具体的に、肝細胞脂肪変性は、0点(<5%)、1点(5%~33%)、2点(34%~66%)、3点(>66%)であり、20倍顕微鏡下の小葉内炎症は、0点(無し)、1点(<2つ)、2点(2~4つ)、3点(<4つ)であり、肝細胞の風船様変性は、0点(無し)、1点(少ない)、2点(多い)であった。血清生化学検査、肝臓トリグリセリド含有量の検出、組織病理学的検査、統計学的分析方法は、実施例1における対応する部分と同様であった。
図6および図7に示すように、単独投与の治療の基、併用投与グループは、非アルコール性脂肪性肝炎マウスの肝機能を更に改善し、肝臓トリグリセリドの含有量を低減することができる。
6週齢のdb/db雄マウスは、江蘇Gempharmatech有限公司から購入した。飼育環境22~24℃、相対湿度45%~65%、照明時間12h/日とした。D12450B飼料で14週齢まで飼育した後、眼角静脈叢から全血を約20μl採取し、糖化ヘモグロビンの含有量を検出した。体質量および糖化ヘモグロビンレベルによって、db/dbマウスを、溶媒対照グループ、FP4I-5mg/kgグループ(FP4Iグループと略称する)、デュラグルチド-1.5mg/kgグループ(デュラグルチドグループと略称する)、FP-B-1.5mg/kgグループ(FP-Bグループと略称する)、FP-A-1.5mg/kgグループ(FP-Aグループと略称する)、FP4I-5mg+デュラグルチド-1.5mg/kgグループ(FP4I+デュラグルチドグループと略称する)、FP4I-5mg/kg+FP-B-1.5mg/kg(FP4I+FP-Bグループと略称する)、およびFP4I-5mg+FP-A-1.5mg/kgグループ(FP4I+FP-Aグループと略称する)にランダムに分け、同じ週齢のdb/mマウスを正常対照グループとし、グループ毎に8匹のマウスとした。対照グループおよび単剤治療グループの頸背部皮下に、対応するタンパク質溶液または緩衝液を注射投与し、併用投与グループの頸背部皮下にFP4Iを注射投与し、腹部皮下にデュラグルチド、FP-A、またはFP-Bをそれぞれ注射投与した。3日に1回投与し、合計12回投与した。最終回の投与周期後に、各グループのマウスを一晩断食させ、眼角静脈叢から全血を採取し、糖化ヘモグロビンの含有量を検出し、採血後に頸椎を外してマウスを殺し、マウスの心臓組織を分離し、心臓全体の質量を秤量した。
NycoCard Reader II特殊タンパク質ゴールドラベル検査機(ノルウェーAlere Technologies AS社の製品)を用い、微粒子クロマトグラフィでマウスの糖化ヘモグロビン含有量を検出した。統計学的分析方法は、実施例1の対応する部分と同様であった。
結果は、表4に示すように、FGF21 Fc融合タンパク質またはGLP-1 Fc融合タンパク質の単独投与は、db/dbマウスに対して良好な血糖制御作用を表したが、正常血糖マウスのレベルよりも高かった。併用投与後のdb/dbマウスの糖化ヘモグロビン含有量は、単独治療グループよりも著しく低く、そのレベルはほぼ正常マウスの血糖レベルに回復した。
Claims (10)
- FGF21 Fc融合タンパク質であって、そのアミノ酸配列は、
(1)SEQ ID NO:4に示されるとおりであり、または
(2)上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である、FGF21 Fc融合タンパク質。 - GLP-1 Fc融合タンパク質であって、そのアミノ酸配列は、
(1)SEQ ID NO:5、SEQ ID NO:6、またはSEQ ID NO:7に示されるとおりであり、または
(2)上記配列のいずれかと実質的に同一(例えば、少なくとも80%、85%、90%、92%、95%、97%、98%、99%以上の同一性を有するか、または1つ以上のアミノ酸の置換(例えば、保存的置換)、欠失および/または付加を有する配列)である、GLP-1 Fc融合タンパク質。 - 請求項1に記載のFGF21 Fc融合タンパク質を含む第1医薬組成物と、請求項2に記載のGLP-1 Fc融合タンパク質を含む第2医薬組成物とで構成される、ことを特徴とする併用治療剤。
- 前記FGF21 Fc融合タンパク質およびGLP-1 Fc融合タンパク質は、予防有効量または治療有効量で前記第1医薬組成物および第2医薬組成物に含まれ得る、ことを特徴とする請求項3に記載の併用治療剤。
- 前記第1医薬組成物は、医薬的に許容される担体、および/または賦形剤、および/または安定剤を更に含む、ことを特徴とする請求項3に記載の併用治療剤。
- 前記第2医薬組成物は、医薬的に許容される担体、および/または賦形剤、および/または安定剤を更に含む、ことを特徴とする請求項3に記載の併用治療剤。
- 前記第1医薬組成物および第2医薬組成物は、経口投与または注射投与に適した剤形で製剤化される、請求項3~6のいずれか1項に記載の併用治療剤。
- 前記第1医薬組成物および第2医薬組成物は、経口投与または注射投与に適した剤形で別々に製剤化される、請求項3~6のいずれか1項に記載の併用治療剤。
- 請求項1に記載のFGF21 Fc融合タンパク質および/または請求項2に記載のGLP-1 Fc融合タンパク質の、心血管および/または代謝系疾患を予防または治療するための薬剤(好ましくは、請求項3~8のいずれか1項に記載の併用治療剤)の調製における使用。
- 前記心血管および/または代謝系疾患は、肥満、高脂血症、アテローム性動脈硬化症、非アルコール性脂肪性肝疾患、糖尿病、糖尿病性心筋症、冠状アテローム性動脈硬化性心臓病、およびインスリン抵抗性に関連する他の疾患を含むが、これらに限定されない、ことを特徴とする請求項9に記載の使用。
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CN110028587A (zh) * | 2018-01-11 | 2019-07-19 | 安源生物科技(上海)有限公司 | 用于调节血糖和脂质的增效型双功能蛋白 |
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CA3145475A1 (en) | 2021-01-28 |
EP4006058A4 (en) | 2023-11-01 |
JP7360751B2 (ja) | 2023-10-13 |
CN112279920B (zh) | 2024-01-16 |
KR20220039790A (ko) | 2022-03-29 |
MX2022000984A (es) | 2022-03-02 |
WO2021012947A1 (zh) | 2021-01-28 |
AU2020317780A1 (en) | 2022-02-24 |
EP4006058A1 (en) | 2022-06-01 |
US20220242926A1 (en) | 2022-08-04 |
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CN112279920A (zh) | 2021-01-29 |
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