JP7058670B2 - 増殖分化因子15融合タンパク質 - Google Patents
増殖分化因子15融合タンパク質 Download PDFInfo
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- JP7058670B2 JP7058670B2 JP2019562592A JP2019562592A JP7058670B2 JP 7058670 B2 JP7058670 B2 JP 7058670B2 JP 2019562592 A JP2019562592 A JP 2019562592A JP 2019562592 A JP2019562592 A JP 2019562592A JP 7058670 B2 JP7058670 B2 JP 7058670B2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- 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
- C07K14/475—Growth factors; Growth regulators
- C07K14/495—Transforming growth factor [TGF]
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
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- 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
Description
本出願は、その全体を本明細書に援用する、2018年4月9日に出願された米国仮特許出願第62/655,108号明細書の利益を主張する。
本出願は、電子フォーマットの配列表と共に提出されている。配列表は、2019年3月15日に作成されたA-2239-WO-PCT_SeqList_ST25.txtという名称のファイル(サイズは109kb)として提供される。配列表の電子フォーマットにおける情報は、その全体を本明細書に援用する。
本開示は、GDF15融合タンパク質などのGDF15分子、その組成物、並びにそうしたタンパク質を作製及び使用するための方法に関する。
アルゴリズム:Needleman et al.,1970,J.Mol.Biol.48:443-453;
比較マトリックス:Henikoff et al.,1992,supraによるBLOSUM62;
ギャップペナルティー:12(但し、エンドギャップにペナルティーはない)
ギャップ長ペナルティー:4
類似性の閾値:0
scFc-GDF15(配列番号38)及びFcΔ10(-)-(G4S)4-GDF15(配列番号39)のGDF15分子を産生し、分子の活性を試験した。
実施例1に記載されているようなFcΔ10(-)-(G4S)4-GDF15(配列番号39)分子及びFcΔ10(+)-(G4)-GDF15(配列番号40)について、その安定性及び製造性(たとえば、商業生産のため)に影響を与え得る属性を解析した。GDF15分子(たとえば、FcΔ10(-)-(G4S)4-GDF15及びFcΔ10(+)-(G4)-GDF15)は、分子の製造性に望ましくない特徴、非常に不均一であること(たとえば、FcΔ10(-)-(G4S)4-GDF15のイオン交換カラム画分の解析から、分子が非常に不均一であることが示される、図3)が確認された。非常に不均一な集団が生じるGDF15分子の属性を決定するため、サイズ排除クロマトグラフィー、SDS PAGEゲル及び質量分析法による分子の解析を行った。サイズ排除クロマトグラフィーによる保持時間に差がないことから、凝集又は著しい分解が不均一性の原因ではなさそうであることが示された。SDS PAGEゲルにも差がなかったことから、ジスルフィド対の誤り又は著しい分解も不均一性の原因ではなさそうであることが示された。
実施例2に記載した不均一性問題に対応するため、1)GDF15領域とFc領域との間のリンカーを除去し、2)野生型ヒトGDF15の活性フラグメントのN末端残基を除去又は置換した新規なGDF15-Fc融合タンパク質(たとえば、野生型ヒトGDF15の活性フラグメントの最初の3アミノ酸が欠失されるGDF15(Δ3)(配列番号13)、又は野生型ヒトGDF15の活性フラグメントの5位のアスパルテートがグルタメートに変異されたGDF15(D5E)(配列番号16))。
製造性及び安定性の属性が改善された新設計の分子が前世代分子と同様の効力特性及びPK特性を有したため、起こり得る不均一性を低下させ、Fcエフェクター機能を低下させて効力を増大させるように分子をさらに操作した。
実施例4のGDF15-Fc融合タンパク質は、実施例1のGDF15-Fc融合タンパク質と比較して、表7に示すような以下の相違を有した。
食物摂取量アッセイを用いて、2つの異なるGDF15-Fc融合タンパク質の有効性を評価した。7~8週齢の個別飼育した雄ob/obマウスを、各群が同程度の処置前体重レベル及び食物摂取レベルを有する種々の処置群(各群n=5)に分けた。動物を皮下注射により0.32ug/kg、1.6ug/kg、8ug/kg、40ug/kg、0.2mg/kg、1mg/kg又は5mg/kgのヘテロ二量体FcΔ16(-)-(G4Q)4-GDF15(N3Q/D5E):FcΔ16(+、K)又はFcΔ10(-、L234A/L235A)-(G4Q)4-GDF15(N3Q/D5E):FcΔ10(+、K、L234A/L235A)で処置し、夜間の食物摂取量を測定した。各GDF15-Fc融合タンパク質の代表的な実験の結果を、FcΔ16(-)-(G4Q)4-GDF15(N3Q/D5E)(図9)及びFcΔ10(-、L234A/L235A)-(G4Q)4-GDF15(N3Q/D5E)(図10)の用量反応曲線で示す。結果から、どちらのGDF15-Fc融合タンパク質も、急性ob/obマウスにおいて食物摂取量を減少させることが示される。本アッセイにおけるED50を表8に示す。
Claims (16)
- リンカーを介してFc領域に連結されたGDF15領域を含む融合タンパク質であって、前記GDF15領域は、配列番号16又は18のアミノ酸配列を含み、前記リンカーは、(G4S)nリンカー又は(G4Q)nリンカーであり、nは、0より大きい、融合タンパク質。
- nは、1又は2である、請求項1に記載の融合タンパク質。
- 請求項1に記載の融合タンパク質であって、nは、2より大きい、融合タンパク質。
- 前記nは、3又は4である、請求項3に記載の融合タンパク質。
- リンカーが(G4Q)nリンカーである、請求項1~4のいずれかに記載の融合タンパク質。
- 前記Fc領域は、K392D変異、K409D変異、E356K変異、D399K変異又はこれらのいかなる組み合わせを含む、請求項1~5のいずれか1項に記載の融合タンパク質。
- 前記Fc領域は、配列番号26から37で表されるアミノ酸配列から選択される、請求項1~6のいずれか1項に記載の融合タンパク質。
- 配列番号50のアミノ酸配列を含む、請求項1に記載の融合タンパク質。
- 請求項1~8のいずれか1項に記載の融合タンパク質を含む、代謝障害を治療するための医薬組成物。
- 代謝症候又は障害が、糖尿病、肥満、脂質代謝異常、高グルコースレベル、高インスリンレベル又は糖尿病性ニューロパチーである、請求項9に記載の医薬組成物。
- 代謝症候又は障害が、2型糖尿病である、請求項10に記載の医薬組成物。
- 100mg/dL以上の空腹時血糖レベルを有する被検体を治療するための、請求項1~8のいずれか1項に記載の融合タンパク質を含む医薬組成物。
- 少なくとも125mg/dLの空腹時血糖レベルを有する被検体を治療するための、請求項1~8のいずれか1項に記載の融合タンパク質を含む医薬組成物。
- 請求項1~8のいずれか1項に記載の融合タンパク質及び配列番号32から37で表されるアミノ酸配列から選択されるFc分子を含む二量体。
- 融合タンパク質が配列番号46、47、50、52、54及び57で表されるアミノ酸配列から選択される、請求項14に記載の二量体。
- GDF15-Fc融合体が配列番号50のアミノ酸配列を含み、Fc分子が配列番号36のアミノ酸配列を含む、請求項15に記載の二量体。
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