JP6152380B2 - 代謝障害を処置するためのデュアル機能性タンパク質 - Google Patents
代謝障害を処置するためのデュアル機能性タンパク質 Download PDFInfo
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- JP6152380B2 JP6152380B2 JP2014532112A JP2014532112A JP6152380B2 JP 6152380 B2 JP6152380 B2 JP 6152380B2 JP 2014532112 A JP2014532112 A JP 2014532112A JP 2014532112 A JP2014532112 A JP 2014532112A JP 6152380 B2 JP6152380 B2 JP 6152380B2
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
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Description
本発明は、投与される対象における代謝プロフィールを改善することが知られている線維芽細胞増殖因子21(FGF21)および他の代謝レギュレーターを含む新規タンパク質に関する。
線維芽細胞増殖因子(FGF)ファミリーは、7つのサブファミリーにグループ分けされる22個の遺伝的に異なる同種リガンドにより特徴付けられる。FGF−21は、FGF−19およびFGF−23に非常に近く、これらとサブファミリーを形成する。このFGFサブファミリーは、古典的FGFに珍しい種々の生理学的プロセス、すなわちエネルギーおよび胆汁酸ホメオスタシス、グルコースおよび脂質代謝およびリン酸塩ならびにビタミンDホメオスタシスを制御する。さらに、他のFGFとは違って、該サブファミリーは、内分泌腺様式において作用する(Moore, D.D. (2007) Science 316, 1436-8)(Beenkenら (2009) Nature Reviews Drug Discovery 8, 235)。
本発明は、新規タンパク質、例えば、線維芽細胞増殖因子21(FGF21)および他の代謝レギュレーター、例えば、GLP−1およびエキセンディン−4を含む融合タンパク質の同定に関し、これは、医薬製剤条件下で構成成分の製剤を超える改善された医薬特性を有し、例えば、より安定であり、投与される対象に対する代謝パラメーターを改善する能力を有し、タンパク質分解および酵素分解されにくく、複合体を凝集および形成する可能性が低く、免疫原性が起こる可能性が低い。本発明のタンパク質は、FGF21受容体アゴニストおよびGLP−1受容体アゴニスト活性の両方を有し;該タンパク質は、FGF21の切断体および変異体を含み、例えば、グルカゴン様ペプチド−1(GLP−1)、エキセンディン−4または他の代謝レギュレーターまたはそれらの変異体の1つ以上をさらに含む。
本発明のタンパク質は、当分野で知られている全長野生型FGF21ポリペプチドの修飾バージョンを示す。例えば、FGF21野生型配列とタンパク質変異体との間の比較が必要であるとき、FGF21野生型配列は、参照配列(配列番号:1)となる。FGF21野生型配列は、NCBI参照配列番号NP_061986.1を有し、例えば、Chiron CorporationによるUS6,716,626B1のような発行済み特許において見いだすことができる(配列番号:1)。
本発明の典型的なデュアル機能性タンパク質配列は、表1に記載されている。該アゴニストの記載は、リンカーを適用する場合、個々の構成アゴニストを含む。変異体が構成アゴニストとして使用されるとき、作られる変化または置換は、それらの野生型対応物と比較して番号付けされる。一例として、「デュアル機能1−タンパク質」(配列番号:9)は、本明細書に記載されている野生型GLP−1配列の残基7−35(すなわち、GLP−1受容体アゴニスト)、リンカー配列、および本明細書に記載されているFGF21野生型配列(配列番号:1)に対する多くの挙げられている変化を有するFGF21変異体(すなわち、FGF21受容体アゴニスト)を含む。
種々の定義が、本明細書を通して使用される。多数の用語は、当業者がそれらの用語に帰属すると考える意味を有する。下記で、または本明細書の他の場所で具体的に定義された用語は、全体として、本発明の文脈で提供される意味を有し、一般的には、当業者により理解されるものである。
タンパク質医薬の開発における重要な挑戦が、タンパク質の物理化学的不安定性に取り組むことであることは、当分野でよく知られている。このことは、タンパク質医薬製剤が多数の使用を意図されるとき、さらになおさら明らかであり、注射製剤は、安定な濃縮された保存溶液を必要とすると同時に、好ましい生物活性プロフィールを維持する。文献における野生型FGF21の生物物理学特性化は、濃縮タンパク質溶液(>5mg/ml)は、ストレス条件、例えば、高い温度または低いpHに暴露されたとき、加速された会合および凝集(すなわち、乏しい物理的安定性および生物医薬特性)を引き起こすことを確立した。医薬防腐剤(例えば、m−クレゾール)へのFGF21の濃縮タンパク質溶液の暴露はまた、物理的安定性に対するネガティブな影響を有した。
いくつかの態様において、本発明の融合タンパク質は、GLP−1またはエキセンディン−4のさらなる突然変異体、GLP−1/グルカゴンハイブリッドペプチド、(ペグ化または他の目的のためにDPP−4耐性を与えるために)非天然アミノ酸を有するGLP−1類似体を含む。
例えば、本明細書に記載されているデュアル機能融合タンパク質の切断および変異体形態を含む本明細書に記載されている融合タンパク質の化学的に修飾された形態は、本明細書に記載されている記載を考慮して、当業者により調製することができる。このような化学的に修飾されたデュアル機能性タンパク質は、化学的に修飾された突然変異体が、修飾されていない突然変異体と、突然変異体に天然に結合された分子の型または位置のいずれかにおいて異なるように改変される。化学的に修飾された突然変異体は、1つ以上の天然に結合された化学基の欠失により形成される分子を含むことができる。
本発明のデュアル機能性タンパク質を含む治療組成物は、本発明の範囲内であり、具体的には、増強された特性を示すいくつかの突然変異体デュアル機能性タンパク質配列の同定を踏まえて考慮される。このようなデュアル機能性タンパク質突然変異体医薬組成物は、投与様式との適合性に対して選択される薬学的または生理学的に許容される製剤との混合物中に治療有効量のデュアル機能性タンパク質タンパク質変異体を含むことができる。
治療に使用される本発明の医薬組成物の有効量は、例えば、治療状況および目的に依存する。当業者は、したがって、処置に対して適当な用量レベルが、一部分において、送達される分子、融合タンパク質変異体が使用される適応症、投与経路、ならびに患者のサイズ(体重、体表面または臓器サイズ)および状態(年齢および全般的な健康状態)に依存することを理解している。したがって、臨床医は、最適な治療効果を得るために用量を滴定し、投与経路を修飾することができる。典型的な用量は、上記因子に依存して、約0.1μg/kgから最大約100mg/kgまたはそれ以上の範囲であり得る。他の態様において、用量は、0.1μg/kgから最大約100mg/kg;または1μg/kgから最大約100mg/kgの範囲であり得る。
本発明のタンパク質は、限定はしないが代謝障害を含む、多くの疾患、障害または状態を処置、診断、改善または予防するために使用することができる。1つの態様において、処置される代謝障害は、糖尿病、例えば、2型糖尿病である。別の態様において、代謝障害は肥満である。他の態様は、代謝状態または障害、例えば、1型糖尿病、膵炎、脂質異常症、非アルコール性脂肪肝疾患(NAFLD)、非アルコール性脂肪性肝炎(NASH)、インスリン耐性、高インスリン血症、耐糖能障害、高血糖、メタボリック・シンドローム、高血圧、心臓血管疾患、急性心筋梗塞、アテローム性動脈硬化症、末梢動脈疾患、卒中、心不全、冠動脈性心臓疾患、腎臓疾患、糖尿病性合併症、ニューロパシー、インスリン受容体における重度の不活性化突然変異と関連する障害、HIV関連リポジストロフィーを含むリポジストロフィー、胃不全まひおよび他の代謝障害を含む。
本発明はまた、本明細書に記載されている本発明のデュアル機能性タンパク質または突然変異体の1つ以上および薬学的に許容される担体を含む医薬組成物を提供する。いくつかの態様において、医薬組成物は、液体溶液または懸濁液としてのいずれかで注射用として製造され;注射前に、液体ビヒクルでの溶液または懸濁液に対して適当な固体形態もまた製造することができる。リポソームは、薬学的に許容される担体の定義に含まれる。薬学的に許容される塩、例えば、鉱酸塩、例えば、塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩など;および有機酸の塩、例えば、酢酸塩、プロピオン酸塩、マロン酸塩、安息香酸エステル塩などもまた、医薬組成物に存在することができる。薬学的に許容される賦形剤の徹底的な議論は、Remington: The Science and Practice of Pharmacy (1995) Alfonso Gennaro, Lippincott, Williams, & Wilkinsで利用できる。
別の態様において、本発明のタンパク質は、本発明のデュアル機能性タンパク質アミノ酸配列に由来する融合タンパク質またはペプチド化合物に作り替えることができる。このような融合タンパク質およびペプチド化合物は、当分野で知られている標準技術を使用して作製することができる。例えば、ペプチド化合物は、標準ペプチド合成技術を使用する化学合成により作製し、次に、ペプチドを細胞(例えば、リポソームなど)に導入するための当分野で知られている種々の手段により細胞に導入することができる。
GLP−1およびFGF21一緒の有効性を試験するために、融合分子を設計した。受容体結合および活性化のために、GLP−1はフリーなN−末端を必要とし、FGF21はフリーなC−末端を必要とするため、2つをN−GLP−1−リンカー−FGF21−Cの順にクローニングした。最初の構築物は、GLP−1残基7−35を有し、DPP−4保護のためのN−末端へのいくつかの修飾を有するか、または該修飾を有さない構築物を作製した(以下で述べる)。GLP−1のさらなる修飾(点突然変異または欠失)を試験し、インビトロ効力によりスコア化した。
FGF21は、2型糖尿病のob/obマウスモデルにおいて血糖レベル、肝臓脂質レベルおよび体重を改善することを示されている(T2D;例えば、A. Kharitonenkovら (2005) Journal of Clinical Investigation 115, 1627; T. Coskunら (2008) Endocrinology 149, 6018;およびE. D. Berglundら (2009) Endocrinology 150, 4084参照)。同様に、GLP−1類似体は、この遺伝的マウス糖尿病モデルにおいてグルコースコントロール、ベータ細胞機能および肝臓健康状態を改善することを示されている(Gallwitz B., Glucagon-like peptide-1 as a treatment option for type 2 diabetes and its role in restoring beta-cell mass. Diabetes Technol Ther. 2005, 7:651-7)。
融合物を、本明細書において「変異体76」または「V76」と称される以下のFGF21変異体配列で作製した:
本発明のGLP−1−FGF21−PEGデュアル活性タンパク質をさらに最適化およびランク付けするため、および共投与モデルを超えるそれらの改善された有効性の完全な評価を得るために、融合物を有効性のob/obモデルにおいて試験する。これらは、血清安定性または活性を改善するために、より長いまたはより短いリンカー、本発明のさらなるタンパク質(これは、変異体76に基づく突然変異体、または、開発におけるさらなる変異体、例えば、さらなるまたは異なる点突然変異、挿入または欠失、二量体化分子、代替ペグ化戦略、さらなるジスルフィド架橋を有する分子、異なる発現系において生産される分子を含み得るが、これらに限定されない)、およびエキセンディン−4またはGLP−1の変異体を有する分子を含むが、これらに限定されない。候補物も、コンピューター内での最終産物の免疫原性予測、発現レベルおよび質(溶解度、凝集および安定性に関する)により、フィルターをかける。
構築物を、代替リンカー(例えば、SGGGGSGGGGSGGGGSA(配列番号:138)、GGGGS(配列番号:173)、GG、およびGGGGSGGGGSGGGGS(配列番号:174))、FGF21変異体、およびGLP−1−関連ペプチドで作製した。一般的に、Fcドメインを含むデュアル機能性タンパク質をHEK293細胞において発現させた。これらの融合物のDNAコード配列を、分泌のためにタンパク質を指向するリーダーペプチドをコードする配列を含み、所望の産物のmRNA合成およびタンパク質発現を促進するために必要とされる配列をさらに含むベクターにクローニングした。HEK293細胞を、ベクターで一時的にトランスフェクトした。これらの細胞培養物から培地を回収し、濾過し、プロテインAアフィニティークロマトグラフィーにより精製した。溶出液を中性pHに至らせ、サイズ排除クロマトグラフィーによりさらに精製した。次に、産物を濃縮し、種々のアッセイのために保管した。変異体を、以下の4つのアッセイにおいてインビトロでの活性について試験した:GLP−1Rを介する活性を測定するために、GLP−1RでトランスフェクトされたHEK293におけるCRE−ルシフェラーゼ発現誘導(表3)およびINS1E細胞におけるグルコース刺激インスリン分泌(表6);FGF21活性を測定するために、ベータ−クロトーでトランスフェクトされたHEK293におけるERKリン酸化誘導(表4)および3T3L1細胞による2−デオキシグルコース摂取(表5)。GLP−1(A8S)および15個のアミノ酸リンカーを有する変異体は、GLP−1およびより短いリンカーを有する変異体よりも、より活性であった。試験された全てのリンカーを有するエキセンディン−4(1−39)変異体が活性であった。エキセンディン−4(1−30)を含む変異体は、エキセンディン−4(1−39)を含む構築物と同様のインビトロ効力を有した。エキセンディン−4(1−39)のタンデムリピートを有する変異体は、GLP−1−関連ペプチドの単一のコピーを有する変異体ほど強力でなかった。
例えば、図9において示されているとおり、本発明のデュアルアゴニストタンパク質を、ベータ−クロトーでトランスフェクトされたHEK293においてERKリン酸化を誘導する能力について、FGF21およびエクセナチドの種々の形態と比較した。10分で、GLP−1(A8S)−FGF21(V76)−PEG(V272)で処置された細胞は、FGF21(V76)−PEG プラス エクセナチドで処置された細胞と比較したとき、より高い効力および全ERKに対するホスホ−ERKのより高い最大比率を示した。より高い最大ホスホ−ERKシグナルは、恐らく受容体とのより良い相互作用(例えば、N−末端延長が、デュアル機能性タンパク質を受容体結合または活性化のためにより好ましい構造に達成させる)によって、デュアル機能性タンパク質V272が、FGF21(V76)−PEG分子と比較したとき、FGFR1c/ベータ−クロトーを介するシグナル伝達に対して優れたアゴニストであることを示す。
RIP−DTAトランスジェニックマウス(9−10週齢)を、3日間ドキシサイクリンで処置し、コントロールされたベータ−細胞切除を誘導した(Thorelら, Nature 2010(464)1149-1154と同様)。次に、マウスを3週間、週に2回、FGF21(V76)−PEG、FGF21(V76)−PEG+GLP−1(A8S)−PEG(V253)またはGLP−1(A8S)−FGF21(V76)−PEG(V272)で処置した。全3つの群における処置動物は、試験中、より低い基礎食餌グルコースレベルを示した。デュアル機能性タンパク質処置は、組合せ処置(ビヒクルから55%減少)と比較して、有意に低いグルコースAUC(ビヒクルから64%減少)をもたらした。絶食後、マウスにグルコースボーラス投与し、グルコース周遊を測定した。全3つの処置は、ビヒクル処置動物と比較して血糖レベルを低下させ、デュアル機能性タンパク質処置は、組合せ処置に対する66%と比較して76%減少をもたらした。全ての処置群は、ビヒクルと比較して膵臓インスリン量を増加させ、デュアル機能性タンパク質処置は、組合せ処置よりも76%良いインスリン量をもたらした。
mAbおよび他の治療タンパク質に対する抗薬物抗体(ADA)の形成は、潜在的に、重度の免疫毒性学的応答、例えば、IgE−介在アナフィラキシー応答(Chungら (2008) N Eng J Med, 358, 1109-17)または免疫複合体病、例えば、脈管炎、糸球体腎炎(Descotes and Gouraud (2008) Expert Opin Drug Metab Toxicol 4, 1537-49)ならびに臨床的暴露(exposure)および有効性の喪失を引き起こし得る。治療タンパク質、PEG化巨核球増殖発達因子(PEG−MGDF)およびエリスロポエチン(EPO;Eprex)で処置されたいくつかの患者は、それらのそれぞれの内因性対応物と交差反応性である中和するADAを発生させ、PEG−MGDFで重度の血小板減少症およびEprexで赤芽球癆を引き起こした(Liら (2007) Blood 98, 3241-8; Casadevallら (2002) N Engl J Med 346, 469-75)。したがって、ヒト試験の前に免疫原性の危険性を評価することが重要である。臨床開発段階において、免疫原性の危険性を評価することおよび確かな(solid)免疫原性の危険性の緩和計画を適所に置くことは、修飾された非ヒト配列、例えば、本発明の対象であるFGF21変異体を含む治療タンパク質に対してとりわけ重要である。
以下に、本願の当初の特許請求の範囲に記載された発明を付記する。
[1] GLP−1受容体アゴニスト領域およびFGF21受容体アゴニスト領域を含む、デュアル(dual)機能性融合タンパク質。[2] FGF21変異体に融合されたGLP−1受容体アゴニストペプチド、リンカー、および該GLP−1受容体アゴニストまたはFGF21変異体の生物学的機能を増強するような様式において結合されたPEG基を含む、[1]に記載のデュアル機能性融合タンパク質。
[3] FGF21変異体が変異体76である、[2]に記載のデュアル機能性融合タンパク質。
[4] リンカーがFcである、[3]に記載のデュアル機能性融合タンパク質。
[5] リンカーがFc変異体である、[3]に記載のデュアル機能性融合タンパク質。
[6] 変異体208、変異体209、変異体211、変異体214、変異体272、変異体277または変異体311をさらに含む、[1]に記載のデュアル機能性融合タンパク質。
[7] GLP−1受容体アゴニストおよびFGF21受容体アゴニストを含むデュアル機能性融合タンパク質を必要とする対象に投与することによる、代謝障害を処置する方法。
[8] 該デュアル機能性融合タンパク質が、個々のGLP−1受容体アゴニストおよびFGF21受容体アゴニストの組み合わせての投与を超える、対象における代謝パラメーターを改善する、[7]に記載の方法。
[9] 該デュアル機能性融合タンパク質が、変異体208、変異体209、変異体211、変異体214、変異体272、変異体277または変異体311をさらに含む、[7]に記載の方法。
Claims (11)
- GLP−1受容体アゴニスト領域およびFGF21受容体アゴニスト領域を含む、デュアル(dual)機能性融合タンパク質であって、
配列番号32に示される変異体208、配列番号36に示される変異体209、配列番号134に示される変異体211、配列番号135に示される変異体214、配列番号9に示される変異体272、配列番号11に示される変異体277または配列番号154に示される変異体311を含む、デュアル機能性融合タンパク質。 - デュアル機能性融合タンパク質が、配列番号32に示される変異体208、配列番号36に示される変異体209、配列番号134に示される変異体211、配列番号135に示される変異体214、配列番号9に示される変異体272、配列番号11に示される変異体277または配列番号154に示される変異体311である、請求項1に記載のデュアル機能性融合タンパク質。
- 配列番号32に示される変異体208、配列番号36に示される変異体209または配列番号135に示される変異体214である、請求項1または2に記載のデュアル機能性融合タンパク質。
- 配列番号32に示される変異体208または配列番号36に示される変異体209である、請求項1〜3のいずれか一項に記載のデュアル機能性融合タンパク質。
- 配列番号36に示される変異体209である、請求項1〜4のいずれか一項に記載のデュアル機能性融合タンパク質。
- 配列番号9に示される変異体272、配列番号11に示される変異体277または配列番号154に示される変異体311である、請求項1または2に記載のデュアル機能性融合タンパク質。
- 配列番号9に示される変異体272または配列番号11に示される変異体277である、請求項6に記載のデュアル機能性融合タンパク質。
- 代謝障害を処置するための、GLP−1受容体アゴニスト領域およびFGF21受容体アゴニスト領域を含む、デュアル機能性融合タンパク質であって、
配列番号32に示される変異体208、配列番号36に示される変異体209、配列番号134に示される変異体211、配列番号135に示される変異体214、配列番号9に示される変異体272、配列番号11に示される変異体277または配列番号154に示される変異体311である、デュアル機能性融合タンパク質。 - 該デュアル機能性融合タンパク質が、個々のGLP−1受容体アゴニストおよびFGF21受容体アゴニストの組み合わせての投与を超える、対象における代謝パラメーターを改善する、請求項8に記載のデュアル機能性融合タンパク質。
- 代謝障害を処置するための医薬製剤の調製のための請求項1〜7のいずれか一項にデュアル機能性融合タンパク質の使用。
- 該デュアル機能性融合タンパク質が、個々のGLP−1受容体アゴニストおよびFGF21受容体アゴニストの組み合わせての投与を超える、対象における代謝パラメーターを改善する、請求項10に記載の使用。
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