JP2022513363A - グルカゴン様ペプチド1(glp1)-増殖分化因子15(gdf15)融合タンパク質及びその使用 - Google Patents
グルカゴン様ペプチド1(glp1)-増殖分化因子15(gdf15)融合タンパク質及びその使用 Download PDFInfo
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Abstract
Description
本出願は、2018年10月22日出願の米国特許仮出願第62/784,603号の優先権を主張し、参照によりその開示の全体が本明細書に組み込まれる。
本発明は、概して、新規グルカゴン様ペプチド-1(GLP1)-増殖分化因子15(GDF15)融合タンパク質を対象とする。GLP1-GDF15融合タンパク質は、GLP1R及び/又はGDF15Rを調節する。本発明はまた、医薬組成物及びその使用方法に関する。新規GLP1-GDF15融合タンパク質は、とりわけ、肥満、2型糖尿病、メタボリックシンドローム、インスリン抵抗性、及び脂質異常症などの疾患及び障害を予防する、治療する、又は寛解させるのに有用である。
本出願は、ファイル名「PRD3474配列表」及び2019年10月14日の作成日で、ASCII形式の配列表としてEFS-Webを介して電子的に提出され、327kbのサイズを有する配列表を含む。EFS-Webを介して提出された配列表は、本明細書の一部であり、参照によりその全体が本明細書に組み込まれる。
GDF15及びGLP1シグナル伝達の両方は、食物摂取を低減することができるが、これらの効果は互いに独立しているように見える。例えば、GDF15効果は、マウスにおいてGLP1Rの非存在下で維持され、反対に、GLP1投与は依然として、GFRALの非存在下で食物摂取効果をもたらす(Hsu et al.,Nature 550:255-9(2017),Mullican et al.,Nat Med 23:1150-7(2017))。したがって、両方の機構を同時に標的化することは、いずれかの機構のみよりも大きな食物摂取低減及び体重減少をもたらし得ると仮定される。ヒト血清アルブミンとの融合を通してGDF15及びGLP1アゴニストの、独立しているが相補的な薬理学を組み合わせることは、週1回の投与に好適な単一の完全組換え分子によって体重減少、インスリン感受性、インスリン分泌、及び心血管転帰に利益をもたらすことになる。このアプローチの大きな課題は、全ての所望の効果を得るのに十分な、但し標的上の有害効果を回避する、所望のレベルで対応する受容体と会合する、バランスの取れた様式で分子内のそれぞれのアゴニストを送達することである。このバランスは、分子のアゴニストアームのいずれかの効力及び/又は薬物動態特性を調整することによって微調整され得る。
グルカゴン様ペプチド1(GLP1)は、腸内で合成され、食物摂取に応答して放出されるインスリン分泌促進物質である。これは主にGLP1-(7-37)及びGLP1-(7-36)NH2の2つの形態で分泌され、その両方とも、グルコース刺激によるインスリン分泌を増強する膵臓ベータ細胞を含む多くの組織と、満腹感及び食事量を制御する脳幹に見られる特異的なGLP1受容体(GLP1R)に結合する。
本明細書では、第2の構成要素を含むGLP1-GDF15融合タンパク質が提供され、第2の構成要素は、第1のリンカーペプチド(すなわち、アミノ末端リンカーペプチド)である。第1のリンカーペプチドは、表2に提供される配列のうちの1つを含み得る。第1のリンカーペプチドは、表2に提供される配列のうちの1つと少なくとも75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、又は99%の同一性を含み得る。
本明細書では、第3の構成要素を含むGLP1-GDF15融合タンパク質が提供され、第3の構成要素は、血清アルブミンタンパク質(例えば、ヒト血清アルブミン(HSA)タンパク質又はゴリラ血清アルブミン(GSA)タンパク質)である。天然のヒト血清アルブミンタンパク質は、17個のジスルフィド結合を形成する35個のシステイン(Cys、C)残基を含んでおり、Cysー34残基が分子中で唯一の遊離システインである。この遊離Cysー34は、複数の活性酸素種(ROS)及び活性窒素種(RNS)を捕獲することにより、フリーラジカルスカベンジャーとして機能することがわかっている(Taverna et al.,Ann.Intensive Care 3:4(2013))。この遊離Cysをセリン(Ser)に変異させて酸化による不均一性が生じるリスクを最小化した。
本明細書では、第4の構成要素を含むGLP1-GDF15融合タンパク質が提供され、第4の構成要素は、第2のリンカーペプチド(すなわち、カルボキシ末端リンカーペプチド)である。第2のリンカーペプチドは、表4に提供される配列のうちの1つを含み得る。第2のリンカーペプチドは、表4に提供される配列のうちの1つと少なくとも75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、又は99%の同一性を含み得る。
増殖分化因子15(GDF15)は、トランスフォーミング増殖因子β(TGF-β)スーパーファミリーに属するタンパク質である。GDF15は、25-kDa二量体として循環する分泌タンパク質である。GDF15は、前立腺由来因子(PDF)、マクロファージ阻害性サイトカイン-1(MIC-1)、NSAID(非ステロイド性抗炎症薬)活性化遺伝子(NAG-1)及び胎盤TGF-β(PTGFβ)とも称される。
本明細書では、前述のように第1、第2、第3、第4、及び第5の構成要素を含むGLP1-GDF15融合タンパク質が提供される。第1の構成要素は、GLP1又はGLP1変異体ペプチドであり、第2の構成要素は第1のリンカーペプチドであり、第3の構成要素は血清アルブミンタンパク質であり、第4の構成要素は第2のリンカーペプチドであり、第5の構成要素はGDF15又はGDF15変異体タンパク質である。GLP1-GDF15融合タンパク質は、表6に提供される配列のうちの1つを含み得る。GLP1-GDF15融合タンパク質は、表6に提供される配列のうちの1つと少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、又は99%の同一性を含み得る。GLP1-GDF15融合タンパク質は、以下の基準:(i)発現収率及び純度、(ii)インビトロ効力、(iii)インビトロ安定性、(iv)セリンキシロシル化の欠如、(v)GLP1-GDF15融合タンパク質の物理的特性(例えば、インビボ安定性及びインビボ効力(すなわち、GLP1又はGLP1変異体ペプチド及びGDF15又はGDF15変異体タンパク質が、それぞれ、GLP1R及びGDF15Rに対するアゴニスト活性を有することができるかどうか))、並びに(vi)インビボにおける二重アゴニズム薬理学の所望のバランスのうちの少なくとも1つに基づいて選択され得る。
別の一般的な態様において、本発明は、本発明のGLP1-GDF15融合タンパク質をコードする単離核酸に関する。タンパク質のアミノ酸配列を変えることなく、タンパク質のコード配列を変える(例えば置換する、欠失する、挿入するなど)ことができることが、当業者には理解されよう。したがって、本発明の融合タンパク質をコードする核酸配列を、タンパク質のアミノ酸配列を変えずに変化させることができる点は当業者には理解されるであろう。
別の一般的な態様では、本発明は、本発明のGLP1-GDF15融合タンパク質及び/又はGLP1-GDF15融合ポリヌクレオチド、並びに医薬上許容できる担体を含む医薬組成物に関する。本明細書で使用されるとき、用語「医薬組成物」は、医薬上許容できる担体と一緒に本発明のGLP1-GDF15融合タンパク質及び/又はGLP1-GDF15融合ポリヌクレオチドを含む生成物を意味する。本発明のGLP1-GDF15融合タンパク質及び/又はGLP1-GDF15融合ポリヌクレオチド、並びにそれらを含む組成物は、本明細書で言及される治療用途のための薬剤の製造にも有用である。
本発明は、GDF15受容体(GDF15F、GFRAL)媒介症候群及び/又はGLP1受容体媒介症候群、障害、又は疾患を予防する、治療する、又は寛解させることを、それを必要とする対象において行う方法であって、有効量の本発明のGLP1-GDF15融合タンパク質、GLP1-GDF15融合ポリヌクレオチド、及び/又は医薬組成物を、それを必要とする対象に投与することを含む、方法を目的とする。
本発明は以下の非限定的な実施形態も提供する。
実施形態1は、グルカゴン様ペプチド-1(GLP1)/増殖文化因子15(GDF15)融合タンパク質であり、GLP1-GDF15融合タンパク質は、GLP1ペプチド、第1のリンカーペプチド、血清アルブミンタンパク質、第2のリンカーペプチド、及びGDF15タンパク質を含む。
GLP1及びGDF15アゴニストを組み合わせた潜在的な相加的体重減少効果を、食餌誘導性肥満(DIO)マウスで試験した。リラグルチド、GLP1アゴニストを単独で、又はHSA-GDF15(配列番号81)分子と組み合わせて8日間投与した。HSA-GDF15を2日毎に与える一方、リラグルチドを毎日皮下投与した。体重減少は、これらの独立した機構を組み合わせたときの相加性の可能性を実証するいずれかの単一薬剤と比較して、両方のアゴニストを受容した動物においてより大きかった(図1)。
GLP1ペプチド又はGLP1変異体ペプチド、血清アルブミンタンパク質、及びGDF15タンパク質又はGDF15変異体タンパク質からなる組換え融合タンパク質を以下のように設計した:GLP1ペプチド又はGLP1変異体ペプチドを、GLP1ペプチド又はGLP1変異体ペプチドのC末端にある第1のリンカーペプチドを介して、ヒト血清アルブミンのN末端に結合した。ヒト血清アルブミンを、C末端で、第2のリンカーペプチドを介してGDF15タンパク質又はGDF15タンパク質変異体のN末端に結合する。この設計は、GDF15二量体化界面を乱さないようにし、天然の鎖間ジスルフィドの形成を可能にし、約170KDaのホモ二量体をもたらすことを目的としている。分子全体が組換えによって作製されるように設計されており、1つの遺伝子のみを必要とした(図3)。
GLP1-GDF15融合タンパク質、GLP1-第1のリンカー-血清アルブミン(例えば、HSA、GSA)タンパク質、血清アルブミン(例えば、HSA、GSA)-第2のリンカー-GDF15タンパク質、及び/又は上記実施例で利用されるGDF15タンパク質を、HEK Expi293F(商標)(ThermoFisher Scientific、カタログ番号A14527)又はExpiCHO-S(商標)(ThermoFisher Scientific、カタログ番号A29127;Waltham,MA)のいずれかで発現させた。HEK Expi293F(商標)での発現のために、GLP1-GDF15融合タンパク質をコードしているプラスミドを、製造元の推奨に従って一過性トランスフェクションによって細胞にトランスフェクトした。簡潔に述べると、Expi293F細胞を、37℃、8%CO2及び125RPMに設定した振盪インキュベータ内で、Expi293(商標)発現培地(ThermoFisher Scientific)中の懸濁液中に維持した。トランスフェクションの日に、1mL当たり2.5×106細胞に希釈することができるように細胞を継代し、細胞生存率を95%以上に維持した。一過性トランスフェクションは、ExpiFectamine(商標)293トランスフェクションキット(ThermoFisher Scientific)を使用して行った。トランスフェクトされる希釈細胞1mL毎に1マイクログラムのプラスミドDNAをOptiMEM(商標)SFM複合体化培地に希釈した。ExpiFectamine(商標)293試薬を、1:2.6の比(v/v、DNA:試薬)で使用し、これもOptiMEM(商標)に希釈し、室温で5分間インキュベートさせた。希釈したDNA及びトランスフェクション試薬を20分間合わせ、DNA/脂質複合体を形成させ、次いで、細胞に添加した。一晩インキュベートした後、Expi293(商標)フィード及びExpiFectamine(商標)293エンハンサーを細胞に添加した。細胞を37℃で4日間振盪しながら培養した後で、培養上清を採取した。
1分子上にGLP1及びGDF15の両アゴニストを送達することによって相加効果を得る可能性を、ゴリラ血清アルブミン(GSA)とのアゴニストの融合を8日間投与したDIOマウスの体重減少を評価することによって試験した。GSAは、これらのツール分子中のHSAの代用物として使用した。マウスは、8nmol/kgのGLP1-GSA-GDF15(配列番号72)、GLP1-GSA-GDF15(I89R)(配列番号73、I89R変異はGDF15活性を消失させる)、GLP1(9-36)-GSA-GDF15(配列番号74、又はGSA-GDF15(配列番号75)の皮下投与を受け、後者の2つはいずれも、分解したGLP1を再現するように設計された。2つの追加の動物群を対照及び基準とし、一方の群には、溶媒のみを与え、別の群には、GLP1アゴニストのデュラグルチドを投与した。GLP1-GSA-GDF15(配列番号72)を投与されたマウスは、GLP1(9-36)-GSA-GDF15(配列番号74)、GLP1-GSA-GDF15(I89R)(配列番号73)、及びGSA-GDF15(配列番号75)を投与されたマウスより大きく体重が減少し、GLP1R及びGFRALの両方が単一分子によりアゴナイズされ、結果として相加効果が得られ得るという概念の証明をもたらした(図2)。
異なるGLP1ペプチド又はGLP1ペプチド変異体及び異なる第1のリンカーペプチドは、hGLP1過剰発現HEK細胞中の環状アデノシンモノリン酸(cAMP)レベルを測定するアッセイにおいて、インビトロhGLP1受容体効力に対して異なる効果を有する。キットの指示書に従って、Lance競合cAMPイムノアッセイ(Perkin Elmer,Waltham,MA)を使用した細胞内cAMP生成を測定する細胞ベースのアッセイにおいて、インビトロGLP1R効力について融合をスクリーニングした。マウス又はヒトGLP1Rを安定的に発現するクローンHEK293細胞をアッセイで使用した。得られたデータを使用して、Prism統計ソフトウェア(GraphPad Software,San Diego,CA)を用いて化合物EC50値を計算した。一般に、GLP1変異体(配列番号1)は、インビトロhGLP1Rアッセイにおいて、他の2つのGLP1変異体(配列番号2及び配列番号3)よりも効力がない。
キシロースグリカンがグリシシン-セリンリンカーに付着することが報告されていることから(Spahr et.al,mAbs 6(4):904-914)、グリシシン-セリンリンカーを含有する分子のO-結合型キシロースレベルを試験した。簡潔に述べると、試料は、変性のためにpH8.0で緩衝されたグアニジン-HClに希釈し、続いて還元のためにDTTを添加し、37℃で1時間インキュベートすることによって調製した。還元後、試料を、新たに調製されたヨードアセトアミドを使用して暗所にて室温で60分間アルキル化した。次いで、DTTを試料に添加して、未反応のヨードアセトアミドをキレート化した。次に、試料を50mMトリス、1mM CaCl2、pH8.0中で、製造元のプロトコルに従ってZeba Spin Desaltingカラムを使用して脱塩し、37℃で4時間、トリプシン(Promega)で消化した。消化後、消化反応をクエンチするため、TFAをそれぞれの試料に添加した。消化した試料を4℃に保ち、24時間以内にLC/MSに注入した。
GLP1-GDF15融合タンパク質のインビトロ活性を、細胞系アッセイにおけるGLP1R効力及びGDF15R効力の両方について試験した。GDF15R(GFRAL)活性を、ヒト又はカニクイザルGFRALのいずれかを過剰発現させるために安定的にトランスフェクトされたSK-N-ASヒト神経芽腫細胞中のリン酸化AKT(Ser473)レベルを測定することによって決定した。様々な濃度の融合分子を有するGFRAL発現細胞を処理した後のAKTのリン酸化を、製造元の指示に従ってPhospho-AKT(Ser473)Assayキット(Cisbio,Beford,MA)を使用して測定した。得られたデータを使用して、Prism統計ソフトウェア(GraphPad Software San Diego)を用い化合物EC50値を計算した。表9で試験したGLP1-GDF15融合タンパク質は、EC50が4.6~6.9nMの範囲で、GDF15Rと同様の効力を有する。
サイズ排除高性能液体クロマトグラフィー(SE-HPLC)を使用して、主種、並びに凝集体を表す高分子量(HMW)種とフラグメントを表す低分子量(LMW)種との両方の割合を定量化することによって、分子の純度及び安定性を調べた。簡潔に言えば、タンパク質純度を決定するために、20μgのタンパク質を1x DPBS、pH7.2(Gibco、カタログ番号14190-136)移動相を有するTosoh TSKgel BioAssist G3SWXL(カタログ番号20026)カラムに注入した。タンパク質種を、室温にて1mL/分の流量で溶出し、UV-280nm吸光度値を、可変波長検出器を備えたDionex Ultimate3000 HPLCシステムを使用してモニタリングした。タンパク質安定性を決定するために、100μgのタンパク質を、0.2Mのリン酸ナトリウム、pH7.0移動相を有するTosoh TSKgel BioAssist G3SWXL(カタログ番号20026)カラムに注入した。タンパク質種を、室温にて0.7mL/分の流量で溶出し、UV-280nm吸光度値を、可変波長検出器を備えたDionex Ultimate3000 HPLCシステムを使用してモニタリングした。Chromeleonソフトウェアを用いてデータを解析した。
GLP1-GDF15融合タンパク質の安定性を、ヒト血漿中にてエクスビボで評価した。簡潔に言えば、新鮮な非凍結ヒト血漿を遠心分離によってヘパリン添加血から生成した。融合タンパク質を、静かに混合しながらこの基質中で、0、4、24、48、72、及び96時間、37℃でインキュベートした。ヒト血漿中の融合分子の経時的な濃度を、抗GDF15抗体による免疫親和性捕獲、及び抗HSA抗体(「全体形式」)又は抗GLP1 N末端特異性抗体(「GLP1活性形式」)のいずれかによる免疫検出によってモニタリングした。表13及び14は、これら2つのイムノアッセイの結果を示す。
マウスにおける薬物動態
配列番号50、45、46、及び44に由来するGLP1-GDF15融合タンパク質を、PBS、pH7中、5mg/kgのIV及びSC用量で雌性C57Bl/6マウスに投与した。両方の投与経路後に、血液試料を採取し、血漿を処理して、薬剤濃度を4日間にわたって測定した。IV及びSC投与後の血漿中の被検質の濃度も免疫親和性捕獲-トリプシン消化-LC-MS/MS分析によって測定した。選択されたトリプシンペプチド、すなわち、ALV(ALVLIAFAQYLQQSPFEDHVK)(配列番号79)、HGE-1(HGEGTFTSDVSSYLEEQAAK)(配列番号77)、及びHGE-2(HGEGTFTSDLSK)(配列番号78)、並びにTDT(TDTGVSLQTYDDLLAK)(配列番号80)は、HSAタンパク質のN末端、GLP1ペプチド又はGLP1ペプチド変異体のN末端、及びGDF15タンパク質又はGDF15タンパク質変異体のC末端の付近にそれぞれ位置する。これらの代理ペプチドをモニタリングすることにより、GLP1-GDF15融合タンパク質のそれぞれの領域(GLP1、HSA、GDF15)の薬物動態評価を可能にした。血漿中薬物濃度-時間プロファイルを表15~22に要約する。
配列番号33、50、45、46、及び44に由来するGLP1-GDF15融合タンパク質を、PBS、pH7中、0.5mg/kg SCの用量でナイーブ型雄性カニクイザル(Macaca fascicularis)に投与した。血液試料を採取し、血漿を処理し、イムノアッセイバイオアナリシスを用いて薬物濃度を21日目まで測定した。イムノアッセイ方法には、抗GDF15捕獲抗体、及び無傷のGLP1を認識する抗体(「活性」)又はHSAを認識する抗体(「全体」)のいずれかによる検出が含まれた。血漿中薬剤濃度-時間プロファイルを表24及び25に要約する。
C57BL/6雄性マウスにおける食物摂取の評価:この実験の目的は、C57BL/6マウスにおける食物摂取の阻害に対する配列番号50、33、49、45、46、及び44に対応する分子のインビボ薬物動態効果を実証することであった。24時間の食物摂取を、4:00~5:00pmのGLP1-GDF15融合タンパク質(試験物品)又は対照(PBS溶媒又はデュラグルチド)の皮下投与の前後に測定した。ケージ毎の食物重量の変化を24時間毎に記録した。結果は、投与24時間前と比較した食物摂取の変化率として表され、検査で使用されるそれぞれの試験物品の循環濃度に部分的に依存する(図4)。試験物品の循環濃度を、免疫親和性捕獲-トリプシン消化-LC-MS/MS分析によって投与から24時間後に測定した。選択されたトリプシンペプチド、すなわち、HSAタンパク質のN末端、GLP1ペプチド又はGLP1ペプチド変異体のN末端、及びGDF15タンパク質又はGDF15タンパク質変異体のC末端の付近にそれぞれ位置するALV(ALVLIAFAQYLQQSPFEDHVK)(配列番号79)、HGE-1(HGEGTFTSDVSSYLEEQAAK)(配列番号77)、及びHGE-2(HGEGTFTSDLSK)(配列番号78)、並びにTDT(TDTGVSLQTYDDLLAK)(配列番号80)をモニタリングした。VVSペプチド(VVSVLTVLHQDWLNGK)(配列番号82)は、デュラグルチドのFc部分に位置する。これらの代理ペプチドをモニタリングすることにより、GLP1-GDF15融合タンパク質のそれぞれの領域(GLP1、HSA、GDF15)の薬物動態評価を可能にした。血漿中薬物濃度を図5に示す。結果は、配列番号50、33、49、45、46、及び44のC57BL/6マウスへの皮下投与が、溶媒投与動物と比較して食物摂取を著しく阻害したことを示した。
Claims (20)
- グルカゴン様ペプチド-1(GLP1)/増殖分化因子15(GDF15)融合タンパク質であって、前記GLP1-GDF15融合タンパク質は、GLP1ペプチドと、第1のリンカーペプチドと、血清アルブミンタンパク質と、第2のリンカーペプチドと、GDF15タンパク質と、を含む、GLP1-GDF15融合タンパク質。
- GLP1ペプチドが、配列番号1~4からなる群から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 前記第1のリンカーペプチドが、配列番号5~25からなる群から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 前記血清アルブミンタンパク質が、配列番号26又は配列番号27から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 前記第2のリンカーペプチドが、配列番号28~30からなる群から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 前記GDF15タンパク質が、配列番号31又は配列番号32から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 前記GLP1-GDF15融合タンパク質が、配列番号33~74及び84からなる群から選択されるアミノ酸配列を含む、請求項1に記載のGLP1-GDF15融合タンパク質。
- 請求項1に記載のGLP1-GDF15融合タンパク質をコードする、単離核酸。
- 請求項8に記載の単離核酸を含む、ベクター。
- 請求項8に記載の単離核酸又は請求項9に記載のベクターを含む、宿主細胞。
- 請求項1に記載のGLP1-GDF15融合タンパク質と、医薬上許容できる担体と、を含む、医薬組成物。
- 疾患又は障害を治療又は予防することを、それを必要とする対象において行う方法であって、前記疾患又は障害は、肥満、I型又はII型糖尿病、メタボリックシンドローム、インスリン抵抗性、耐糖能異常、高血糖症、高インスリン血症、高トリグリセリド血症、先天性高インスリン症(CHI)による低血糖、脂質異常症、アテローム性動脈硬化症、糖尿病性腎症、並びに管理されていないコレステロール及び/又は脂質レベルに関連する高血圧及び心血管危険因子などの他の心血管危険因子、骨粗鬆症、炎症、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)、腎疾患、並びに湿疹からなる群から選択され、前記方法は、有効量の請求項11に記載の医薬組成物を、それを必要とする前記対象に投与することを含む、方法。
- 食物摂取を低減することを、それを必要とする対象において行う方法であって、前記方法は、有効量の請求項11に記載の医薬組成物を、それを必要とする前記対象に投与することを含む、方法。
- GLP1受容体活性を調節することを、それを必要とする対象において行う方法であって、前記方法は、有効量の請求項11に記載の医薬組成物を、それを必要とする前記対象に投与することを含む、方法。
- GDF15受容体(GFRAL)活性を調節することを、それを必要とする対象において行う方法であって、前記方法は、有効量の請求項11に記載の医薬組成物を、それを必要とする前記対象に投与することを含む、方法。
- 前記医薬組成物が注射により投与される、請求項12に記載の方法。
- 請求項1に記載のGLP1-GDF15融合タンパク質、請求項8に記載の単離核酸、及び/又は請求項9に記載のベクターを含む、キット。
- 前記キットが注射用デバイスを更に含む、請求項17に記載のキット。
- 請求項1に記載のGLP1-GDF15融合タンパク質を含む医薬組成物を生成する方法であって、前記GLP1-GDF15融合タンパク質を医薬上許容できる担体と組み合わせて前記医薬組成物を得ることを含む、方法。
- 請求項1に記載のGLP1-GDF15融合タンパク質を生成する方法であって、前記GLP1-GDF15融合タンパク質を生成するための条件下で前記GLP1-GDF15融合タンパク質をコードする核酸を含む細胞を培養することと、前記細胞又は培養物から前記GLP1-GDF15融合タンパク質を回収することと、を含む、方法。
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