JP6121330B2 - 作用持続時間が増した改変ポリペプチド - Google Patents
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Description
本願は、2010年9月28日出願の米国特許仮出願第61/387,391号および2010年12月10日出願の同第61/422,085号の恩典を主張するものであり、前記各米国特許仮出願は、それら全体があらゆる目的のため出典明示により本明細書に援用されている。
「肥満」および「過体重」は、通常予測される体重より重い体重を有する哺乳動物を指し、例えば、外見、当該技術分野において公知のボディーマス指数(BMI)、ウエスト周囲径とヒップ周囲径の比、皮下脂肪厚、ウエスト周囲径、およびこれらに類するものによって判定することができる。米国疾病管理予防センター(The Centers for Disease Control and Prevention:CDC)は、過体重を25から29.9のBMIを有する成人と定義しており、肥満を30以上のBMIを有する成人と定義している。肥満判定のためのさらなる測定基準が存在する。例えば、CDCは、1.0より大きいウエスト対ヒップ比を有する人は過体重であると述べている。
II. 化合物
HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2(配列番号1);
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2(配列番号2)。
GVSD X5 YK X8 X9 I X11 X12 A X14 TVEGV X20 AL X23 X24 X25 I(配列番号119)
(式中、互いに独立して、
X5は、YおよびFから選択され;
X8は、N、 RおよびSから選択され;
X9は、V、I、L、M、FおよびYから選択され;
X11は、N、S、EおよびDから選択され;
X12は、R、KおよびNから選択され;
X14は、KおよびRから選択され;
X20は、D、N、Q、E、H、S、RおよびKから選択され;
X23は、K、IおよびTから選択され;
X24は、A、S、T、G、H、LおよびDから選択され;ならびに
X25は、H、EおよびDから選択される)。
アルブミン半減期(日)=3.75 * 体重(kg)0.368。
III. 設計および生産方法
IV. 使用方法および疾患処置方法
V. アッセイ
VI. 医薬組成物
A. 製剤
KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY(配列番号6);
KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY(配列番号7);
KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY(配列番号8)。
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP(配列番号9);
CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP(配列番号10);
KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(配列番号11)。
B. 有効投薬量
C. 毒性
以下の実施例において有用なペプチドとしては、次のものが挙げられる:HaPGTFTSDLSKQMEEE AVRLFIEWLKNGGPSSGAPPPSTGGGGSASLAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP; HAEGTFTSDVSSYLEGQAAKEFIAWLVKLAEAKVLAN RELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP(配列番号164);HGEGTFTSDLSKQMEEEAVRLFIEWLKLAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP(配列番号165);HGEGTFTSDLSKQMEEEAVRLFIEW LKNGGPSSGAPPPSGGSLKNAKEDAIAELKKAGITSDFYFNAVNKAKTVEEVNALKNEILKALP (化合物22)(配列番号168);H(Aib)QGTFTSDYSKYLDEQAAKEFIAWLMN TYGVSDFYKRLINKAKTVEGVEALKLHILAALP(配列番号171);HSQGTFTSDYSKYLDEQAAKEFIAWLMNTYGVSDFYKRLINKAKTVEGVEALKLHILAALP(配列番号172);HSQGTFTSDYSKYLDEQAAKEFIAWLMNTGGGSYGVSD FYKRLINKAKTVEGVEALKLHILAALP(配列番号173);HaPGTFTSDLSKQMEEE AVRLFIEWLKNGGPSSGAPPPSTGGGGSASLAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP(化合物14)、および[[Lys27#]HGEGTFTSDLSKQMEEEA VRLFIEWLKNGGPSSGAPPPS][LAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP-GGG-#](化合物30)。当該技術分野において通例であるように、小文字1文字アミノ酸略号(例えば、「a」)は、D−アミノ酸(例えば、D−Ala)を示す。側鎖連結ペプチド化合物の命名法では、角カッコ(「[]」)は、独立した断片を示し、クロスハッチ(「#」)は、連結位置を示す。
方法。配列:MAHHHHHHVGTGSNENLYFQHGEGTFTSDLSKQLEEEAVRLFIEW LKQGGPSKEIISTGGGGSASLAEAKVLANRELDKYGVSDFYKRLINKAKTVEGVEALKLHILAALP (配列番号50)を有する、、当該技術分野において公知のHis6(配列番号49)「タグ」が組み込まれたN末端伸長部を有する例示的化合物15(配列番号163)を最初に製造した。
本発明のエキセンディン−ABD改変ポリペプチドは、in vitro細胞活性化アッセイにおいて十分なエキセンディン活性を保持した。加えて、これらの改変ポリペプチドは、哺乳動物に単回用量として投与されたとき、エキセンディン−4と比較して、血糖降下および体重減少についての劇的に向上した作用持続時間をもたらした。驚くべきことに、作用持続時間を齧歯動物モデルにおいて少なくとも1日、さらには少なくとも4日、およびさらには少なくとも7日、またはそれ以上延長することができ、これはヒト対象では少なくとも1週間の作用持続時間ということになるため、1日2回、1日1回、週3回、週2回またはさらに週1回の投与に好適である。
グルコース経管栄養(1.5k/kg デキストロース)の前およびグルコース経管栄養の30分後の血糖に対する効果を、様々な量の化合物15を伴うペプチド化合物の投与の1日後に調査した。結果を図1A−1Bに示す。図9に示すように、25nmol/kgでの化合物31も投与後24時間の時点で活性を示した。4時間絶食させたNIH/Swissマウスに、図に示す用量で薬物を投与した。バーは、平均±sdを表す。ペプチドをt=−1日の時点でIP注射した。4時間絶食させたNIH/Swiss雌マウスにt=0の時点でグルコース経管栄養(1.5g/kg)を施した。OneTouch(登録商標)Ultra(登録商標)(Johnson & Johnson Companyの傘下のLifeScan, Inc.、カリフォルニア州ミルピータス)で血糖を測定した。*ビヒクル対照に対してp<0.05;ANOVA、ダネット検定。このOGTT DOAは、薬物を投与した少なくとも24時間後に薬物活性が存在することを示す。(コンジュゲートしていない)エキセンディン−4は、このアッセイにおいて、t−24時間(グルコースアッセイの1日前)に投与したとき、およびより高い用量ででさえ効果がなかった。
経管栄養(1.5k/kg デキストロース)の前および30分の時点での血糖に対する効果を、様々な量の化合物15の投与の2日後に調査した。結果を図2A−2Bに示す。4時間絶食させたNIH/Swissマウスに、図に示す用量で薬物を投与した。このOGTT DOAは、薬物を投与した少なくとも48時間後に薬物活性が存在することを示す。
血糖に対する化合物15の効果と化合物8の効果の比較を行った。結果を図3A−3Bに示す。4時間絶食させたNIH/Swissマウスに、図に示す用量で薬物を投与した。このOGTT DOAは、薬物を投与した少なくとも24時間後に薬物活性が存在することを示す。
化合物15(240nmol/kg)での処置の効果を投与の5日後にSprague Dawley給餌麻酔ラットにおいて調査した。IVGTT後の血漿中グルコースの経時変化を図4Aに示す。積分(AUC0−60)血糖値を図4Bのヒストグラムに示す。被験対象におけるインスリンレベルの経時的変化を図4Cに示した。積分インスリンレベル(AUC0−30)を図4Dに示す。被験対象についての経時的体重変化(ベースラインからの変化%)を図4Eに示す。被験対象についての毎日の食物摂取量のヒストグラムの描画を図4Fに提供する。このIVGTT DOAは、薬物を投与した少なくとも5日時間(5 days hours)後に、特に、体重および毎日の食物摂取量に対する効果について、薬物活性が存在することを示す。
ob/obマウスにおける体重、グルコースおよびHbA1cに対する化合物15の効果の経時変化を投与後に調査した。図5Aに示すように、顕著な体重減少が250nmol/kgの化合物15での処置の結果として起こる。グルコースの変化(前処理%)およびHbA1cの変化(前処理%)を図5B−5Cに示す。点は、平均±s.d.(標準偏差)を表す。絶食させていない雄ob/obマウスに日=0でのベースライン試料採集直後に化合物15をsc注射した。別の指示がない限り、本明細書に記載する血糖測定にはOneTouch(登録商標)Ultra(登録商標)デバイス(LifeScan, Inc.、カリフォルニア州Miliptas)を用いた。化合物21も体重減少およびHbA1c低下を示した。
本明細書に記載する例示的化合物の体重およびグルコース低下の複合的有効性を評定するために、約14週齢雄ZDFラットにおいて化合物15の用量依存効果を調査した。ベースライングルコースは426mg/dLであり、ベースライン体重は431gであった。群の大きさn=8。図6Aは、処置後の体重の経時的変化(ビヒクル補正%)を示す。図6Bは、血漿グルコースの経時変化を示す。
図7に示すように、30分の時点での血糖の変化(経管栄養前%)に対する化合物15、8および10の効果を調査した。図中、バーは、平均±s.d.を表す。被験化合物をt=−1日の時点でIP注射した。4時間絶食させたNIH/Swiss雌マウスにt=0の時点でグルコース経管栄養(1.5g/kg)を施した。本明細書中で説明するとおりに血糖を測定した。このOGTT DOAは、薬物を投与した少なくとも24時間後に薬物活性が存在することを示す。
30分の時点で血糖の変化(経管栄養前%)に対する本明細書に開示する化合物の効果を調査した。被験化合物を25nmol/kgで、t=−1日の時点で、IP注射した。4時間絶食させたNIH/Swiss雌マウスにt=0の時点でグルコース経管栄養(1.5g/kg)を施した。本明細書中で説明するとおりに血糖を測定した。このOGTT DOAは、薬物を投与した少なくとも24時間後に薬物活性が存在することを示す。結果を下記の表6に示す。化合物30(リシン27連結)および化合物32は、血糖降下をもたらさなかった。これは、これらの条件下、24時間の時点での存在の欠如を示す。(コンジュゲートしていない)エキセンディン−4は、このアッセイにおいて、t−24時間に投与したとき、およびより高い用量ででさえ効果がなかった。位置3にプロリンを有する化合物14は、in vitro機能アッセイにおいて本質的に不活性であり、血糖降下OGTTアッセイにおいて不活性(およびおそらく体重増加促進性(weight promoting))であった(データを示さない)。P.マグヌス(P. magnus)からのPABタンパク質であるアルブミン結合配列を有する化合物22は、上記のアッセイにおいて体重低下性を殆ど有さず、あったとしても3%しか有さなかった。切頭型ABDを有する化合物19および化合物20は、持続時間は短縮されるが、in vitro活性を依然として維持し、OGTT DOAアッセイにおいてそれぞれ6%および8%血糖を降下させた。
本明細書に記載するBiacoreのものを含めて、アルブミンへの改変ポリペプチドの結合の特性確認を行い得る方法はいくらでもある。この実施例では、25℃でGLCセンサーチップを使用してBioRad ProteOn XPR36システム(Bio-Rad Laboratories、米国カリフォルニア州ハーキュリーズ;ProteOn XPR36 Protein Interaction Array Systemカタログ番号#176-0100)で結合測定を行った。アミンカップリングのために、下で示すように水中で最初のストックから30倍希釈したスルホ−NHS/EDCの1:1混合物を使用して5分間、GLCチップを活性化した。各アルブミン試料を10mM 酢酸Na pH5.0中25ug/mLに希釈して、離れたセンサー表面に5分間注射した。その後、各表面を1Mエタノールアミン pH8.5でブロックした。各アルブミンをレゾナンスユニットでの2000−5000の密度でカップリングした。3倍希釈系列で5nMを最高濃度として使用して、改変ポリペプチドの結合を試験した。泳動緩衝液は、10mM HEPES pH7.4、150 mM NaCl、3 mM EDTAおよび0.005% tween−20を含有した。3倍希釈系列を用いてすべての試料を試験した。各濃度系列を二重反復で試験した。最高濃度についての解離相を3時間、モニターした。
血清アルブミンの存在下での前記改変ポリペプチドのin vitro活性の特性確認を実証した。アルブミン、特にヒト血清アルブミンの存在および不存在下で、アッセイを実行することができる。上のデータは、約0.1%ウシ血清アルブミン(BSA)の存在下で判定したものである。下記の表は、上で説明した、ただし様々な種からの血清アルブミンの存在下での、受容体活性化(cAMP誘導)アッセイの機能活性を提示するものである。明らかなように、驚くべきことに、化合物がヒト血清アルブミンなどの血清アルブミンに結合しているときでさえ、アルブミン結合の結果として起こる化合物の立体障害およびさらには見かけのストークス半径の変化に関する可能性を伴う、大きな血清アルブミンの存在にもかかわらず、前記改変ポリペプチドはGLP−1受容体アゴニスト活性を保持している。一部の種の血清アルブミン、例えばヒト血清アルブミンへのABDおよび前記改変ポリペプチドのピコモル親和性を考えると、前記改変ポリペプチドは、このアッセイに(そしてまた、循環血中in vivoで)存在するアルブミンに有効かつ十分に結合すると考えられる。(上記のような)アルブミンへの化合物の極めて高い結合親和性および血液中の高濃度の血清アルブミンの存在のため、該化合物は、本質的にin vivo結合状態で存在することとなると予想されるが、驚くべきことに、(ここで実証するように)十分なエキセンディン機能を提供する。
化合物をヒト血漿およびヒト細胞膜プロテアーゼに対する安定性について検査した。ヒト血漿中での代表ペプチドの安定性が次のように実現された:ゼロ時点で開始して、その期間(5時間)の間、10分毎に100μL試料を取り出すのに十分な量でヒト血漿中の10μg/mLの化合物を調製した。ヒト血漿への化合物の添加後、その試料を穏やかに混合し、その混合物の100μL試料を微量遠心チューブに移して、ゼロ時点とした。試料の残りを37℃のインキュベーターに入れ、600RPMで60分間混合した。10分間隔で、前記混合物の100μL試料を取り出し、別の微量遠心チューブに移した。ゼロ時点で、および各10分間隔で100μLの試料を移した後、混合しながら100μLの冷0.2%ギ酸:アセトニトリルをゆっくりと添加することにより、回収した各試料を抽出した。アセトニトリル溶液の添加後、試料を高速で15秒間ボルテックス混合した。抽出試料を−20℃で少なくとも20分間保存し、その後、11,000×gで10分間、5℃で遠心分離した。各試料の上清を新たな微量遠心チューブに移し、再び遠心分離し、最後にLC/MS分析のために移した。0.1%トリフルオロ酢酸を含有する水中の5−95%アセトニトリル(acetonitile)勾配を用いて、Agilent HLPC(LC/MS 1200)で試料分析を行った。表9は、標準物質(100%)に正規化した結果を示す。図8は、5時間の時間経過にわたってヒト血漿中の化合物残存率の時間プロファイルを表すものである。
一部の薬物、例えば一部のPEG化タンパク質に関しては、近位曲尿細管の内側を覆う上皮細胞の細胞質中で望ましくない空胞が形成することがあり、これは望ましくない毒性の尺度となる。本願の改変アルブミン結合化合物は、腎臓空胞を形成しない。C57BL6雌マウス(n=2ケージ、3マウス/ケージ)を毎日消灯の3時間前に計量した。第0−6日の計量直後にマウスに被験化合物を皮下注射した。第7日にマウスを殺し、腎臓を病理組織診断に付した。腎皮質尿細管上皮細胞の細胞質空胞化についての重症度スコアは、次のとおりであった:スコア1=極微(8−15%);2=軽度(16−35%);3=中等度(36−60%);4=顕著(>60%)。空砲形成を誘発することが公知の陽性対照化合物には3のスコアを付けた。ABDポリペプチド自体は、0スコアであった。化合物15は、0スコアであった。
正常マウスの食物摂取抑制に対する被験化合物の効果の経時変化を判定した。図10Aに示すように、用量依存性の顕著な体重減少が6時間にわたって化合物31での処置の結果として起こる。図10Bは、正常マウスにおいて少なくとも54時間、化合物の単回投与後の用量依存性、持続性食物摂取抑制を示している。エキセンディン類似体の効果は、24時間以内に無くなる。化合物31は、最高用量で3日後でさえ食物摂取を依然として顕著に抑制する。点は、n=4ケージ(3マウス/ケージ)の平均±標準偏差を表す。ペプチドをt=0の時点でIP注射した。注射後直ちに餌を導入し、消費量をt=30、60、120、180、240、300、360分、24時間、30時間、48時間および54時間の時点で測定した。*ビヒクル対照に対してp<0.05;ANOVA、ダネット検定。ED50は、化合物31については約10nmol/kg、および[Leu14]エキセンディン−4については2nmol/kgであった。
血糖降下、HbA1c低下および体重低下に対する、本明細書に記載するエキセンディン−アルブミン結合ドメイン改変ポリペプチドの慢性的曝露の効果を実証するために、糖尿病ob/ob/マウスを化合物15および化合物21で処置した。ob/obマウスにおける体重、血糖降下およびHbA1c低下に対する被験化合物の効果の経時変化を投与後に調査し、4週間後での値を図11A、11B、11Cおよび11Dに示した。図11A(化合物15)および11B(化合物21)は、リラグルチドと比較した血糖の変化を示す図であり、すべての化合物を週2回(BIW)与えた。そして図11Cは、持続皮下注入(CSI)によって与えたエキセンディン−4と比較した、週2回(BIW)与えた化合物15および化合物21についてのHbA1cの低下(基線からの変化%)を示す図である。図11Dは、持続皮下注入(CSI)によって与えたエキセンディン−4と比較した、週2回(BIW)与えた化合物15および化合物21についての体重の低下(基線からの変化%)を示す図である。驚くべきことに、図11Aおよび11Bからわかるように、各化合物は、慢性的曝露による血糖降下について、等モル(equimoloar)投与でのリラグルチドより優れている。さらに、リラグルチドと等モル投与で、化合物15および化合物21は、それぞれ、長時間作用性アルブミン結合GLP−1誘導体であるリラグルチド[N−イプシロン−(ガンマ−Glu(N−α−ヘキサデカノイル))−Lys26,Arg34]−GLP−1−(7−37)−酸よりHbA1c低下および体重減少の点で有効であった(データを示さない)。図11Cに示すように顕著なHbA1c低下が、および図11Dに示すように顕著な体重減少が、28日間、各週2回、腹腔内に(IP)施した25および250nmol/kgの各化合物での処置の結果として生ずる。点は、平均±s.d.(標準偏差)を表す。絶食させていない雄ob/obマウスに日=0でのベースライン試料採集直後に各被験化合物をIP注射した。25nmol/kg biw(週2回)投与について観察された効果は、エキセンディン−4について最大効力をもたらすことが知られている用量である約7.2nmol/kg/日での持続注入(CSI)によって与えたエキセンディン−4について観察された効果より大きかった。したがって、匹敵する等モル用量で、化合物15および化合物21は、最大有効用量のエキセンディン−4の糖血および体重減少効果より優れていた。250nmol/kgで、化合物15は、最大有効用量のエキセンディン−4より顕著に優れており、化合物21は、最大有効用量のエキセンディン−4の2倍有効であった。別の指示がない限り、本明細書に記載する血糖測定にはOneTouch(登録商標)Ultra(登録商標)デバイス(LifeScan, Inc.、カリフォルニア州Miliptas)を用いた。
本明細書に記載する改変ポリペプチドの長い半減期および長い活性持続時間をさらに実証するために、ラットを使用して薬物動態(PK)特性および薬力学的(PD)特性を判定した。正常Harlan Sprague−Dawley(HSD)ラットに皮下投与した例示的改変ポリペプチド化合物15および化合物21の薬物動態プロファイルおよび生物活性を提示する。組換え改変化合物である化合物21および化合物15をt=0の時点で25nmol/kgで正常HSDラットに皮下注射した。給餌HSD雄ラットからt=1時間、3時間、6時間、24時間、48時間、72時間、96時間および168時間の時点で尾出血によって血液を採集した。餌重量および体重を毎日測定した。図12Aは、食物摂取量を低減させる化合物15および化合物21の効果を示す図である。図12Bは、体重を低下させる化合物15および化合物21の効果を示す図である。図12Cは、化合物15および化合物21の単回投与後のPKプロファイルを示す図である。点は、平均±sdを表す。
腸管取り込みを伴う経口送達を、代表的改変化合物を使用して調査した。糖尿病db/dbマウスに次の化合物を240nmol/kgで経口(経管栄養により経口)投与した:エキセンディン類似体 [Leu14,Gln28]エキセンディン−4−(1−32)−fGLP−1−(33−37)酸および化合物15。データは、前記改変ペプチドが、送達および取り込みを増進し得る他の特定の賦形剤不存在の製剤PBS/プロピレングリコール(50:50)の場合でさえ、経口的に生物学的利用能を示すことを明示する。前記エキセンディン類似体と比較すると、エキセンディン類似体の分子量の2倍より大きい化合物15も、(両方とも1mg/kg用量で)、同製剤で経口的に生物学的利用能を示す。これらの結果は、両方の化合物が、経口投与されたとき活性であり、試験した条件下で120分まで同等に効果的であったことを示す。結果を図14に提示する。点は、平均+/−sdを表す。ベースライン試料の採取直後、t=0の時点で、ペプチドを経管栄養により経口投与した。マウスは、2時間絶食させたdb/dbマウスであった。したがって、本明細書に提示する化合物は、特にヒト対象において、少なくとも1日2回(例えば朝晩)、少なくとも毎日、週3回、週2回、およびさらには週1回経口の投与を必要とする。
VIII. 実施形態
Claims (9)
- 配列番号35を含むアルブミン結合ドメインポリペプチド(ABD)と;配列番号3と少なくとも90%の配列同一性を有し、エキセンディンの生物活性を有する第一のペプチドホルモンドメイン(HD1)と;ABDおよびHD1を共有結合で連結するリンカー基(L1)とを含み;前記ABDはC−末端部分であり、前記HD1はN−末端部分である、改変ポリペプチド。
- L1が、G;GGG;GGS;配列番号192;配列番号193;配列番号194;または配列番号195である、請求項1に記載の改変ポリペプチド。
- 配列番号95を含む、請求項1に記載の改変ポリペプチド。
- 血漿中でおよび血漿プロテアーゼに対して安定している、請求項1−3のいずれか一項に記載の改変ポリペプチド。
- 前記リンカーL1が、配列(Gly)4(配列番号196)または(Gly)5(配列番号197)を含む、請求項1に記載の改変ポリペプチド。
- 前記リンカーL1が、配列(Gly)3Lys(Gly)4(配列番号131);(Gly)3AsnGlySer(Gly)2(配列番号132);(Gly)3Cys(Gly)4(配列番号133);またはGlyProAsnGlyGly(配列番号134)を含む、請求項1に記載の改変ポリペプチド。
- 前記リンカーL1が、TG−(GGGS)1(配列番号198)、TG−(GGGS)2(配列番号199)、TG(GGGS)3(配列番号200)、TG−(GGGS)4(配列番号201)、TG−(GGGS)5(配列番号202)、(GGGS)1−AS(配列番号203)、(GGGS)2−AS(配列番号204)、(GGGS)3−AS(配列番号205)、(GGGS)4−AS(配列番号206)、(GGGS)5−AS(配列番号207)、TG−(GGGS)1−AS(配列番号208)、TG−(GGGS)2−AS(配列番号209)、TG−(GGGS)3−AS(配列番号210)、TG(GGGS)4−AS(配列番号211)およびTG−(GGGS)5−AS(配列番号212)から成る群より選択された配列を含む、請求項1に記載の改変ポリペプチド。
- 請求項1−7のいずれか一項に記載の改変ポリペプチドと医薬的に許容され得る賦形剤とを含む医薬組成物。
- 糖尿病、過体重、肥満、アルツハイマー病、短腸症候群、脂肪性肝疾患、脂質異常症、冠動脈疾患、卒中、高脂血症またはパーキンソン病を処置するための、請求項8に記載の医薬組成物。
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Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX345245B (es) * | 2010-09-28 | 2017-01-23 | Amylin Pharmaceuticals Llc | Polipeptidos manipulados que tienen duracion de accion incrementada. |
DK2621515T3 (en) | 2010-09-28 | 2017-07-17 | Aegerion Pharmaceuticals Inc | Chimeric seal-human leptin polypeptide with increased solubility |
DK2729160T3 (da) | 2011-07-08 | 2019-07-01 | Aegerion Pharmaceuticals Inc | Manipulerede polypeptider, der har forbedret virkningstid og reduceret immunogenicitet |
US20160009767A9 (en) * | 2012-03-28 | 2016-01-14 | Affibody Ab | Oral administration |
WO2013148966A1 (en) * | 2012-03-28 | 2013-10-03 | Amylin Pharmaceuticals, Llc | Transmucosal delivery of engineered polypeptides |
UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
SI2934567T1 (sl) | 2012-12-21 | 2018-10-30 | Sanofi | Derivati eksendina-4 kot dualni GLP1/GIP ali trigonalni agonisti GLP1/GIP/glukagon |
EP2986306A4 (en) | 2013-04-18 | 2016-12-07 | Armo Biosciences Inc | METHOD FOR USE OF INTERLEUKIN-10 FOR THE TREATMENT OF ILLNESSES AND SUFFERING |
EP3434277A1 (en) | 2013-06-17 | 2019-01-30 | Armo Biosciences, Inc. | Method for assessing protein identity and stability |
US10010588B2 (en) | 2013-08-30 | 2018-07-03 | Armo Biosciences, Inc. | Methods of using pegylated interleukin-10 for treating hyperlipidemia |
CN105848674A (zh) | 2013-11-11 | 2016-08-10 | 阿尔莫生物科技股份有限公司 | 将白细胞介素-10用于治疗疾病和病症的方法 |
WO2015086729A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/gip receptor agonists |
WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
EP3080149A1 (en) | 2013-12-13 | 2016-10-19 | Sanofi | Dual glp-1/glucagon receptor agonists |
EP3080150B1 (en) | 2013-12-13 | 2018-08-01 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自exendin-4之雙重glp-1/升糖素受體促效劑 |
TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重glp-1/昇糖素受體激動劑之艾塞那肽-4衍生物 |
TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽-4(Exendin-4)之肽類雙重GLP-1/升糖素受體促效劑 |
WO2015187295A2 (en) | 2014-06-02 | 2015-12-10 | Armo Biosciences, Inc. | Methods of lowering serum cholesterol |
US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
MX2017004838A (es) | 2014-10-14 | 2017-10-16 | Armo Biosciences Inc | Composiciones de interleucina-15 y usos de estas. |
KR20170084033A (ko) | 2014-10-22 | 2017-07-19 | 아르모 바이오사이언시스 인코포레이티드 | 질환 및 장애를 치료하기 위해 인터루킨-10을 사용하는 방법 |
US10618970B2 (en) | 2015-02-03 | 2020-04-14 | Armo Biosciences, Inc. | Method of treating cancer with IL-10 and antibodies that induce ADCC |
WO2016191587A1 (en) | 2015-05-28 | 2016-12-01 | Armo Biosciences, Inc. | Pegylated interleukin-10 for use in treating cancer |
AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重glp-1/升糖素受體促效劑之新毒蜥外泌肽(exendin-4)衍生物 |
AU2016312510A1 (en) | 2015-08-25 | 2018-03-08 | Armo Biosciences, Inc. | Methods of using Interleukin-10 for treating diseases and disorders |
CA2998528A1 (en) | 2015-09-22 | 2017-03-30 | The Regents Of The University Of California | Modified cytotoxins and their therapeutic use |
US10286079B2 (en) | 2015-09-22 | 2019-05-14 | The Regents Of The University Of California | Modified cytotoxins and their therapeutic use |
EP3393496B1 (en) | 2015-12-23 | 2023-10-11 | The Johns Hopkins University | Long-acting glp-1r agonist as a therapy of neurological and neurodegenerative conditions |
EP3426284A1 (en) | 2016-03-10 | 2019-01-16 | Medimmune Limited | Glucagon and glp-1 co-agonists for the treatment of obesity |
KR20200135618A (ko) * | 2019-05-23 | 2020-12-03 | ㈜ 디앤디파마텍 | 폴리펩티드를 포함하는 비알코올성 지방간 질환의 예방 또는 치료용 약학 조성물 |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6936694B1 (en) | 1982-05-06 | 2005-08-30 | Intermune, Inc. | Manufacture and expression of large structural genes |
US6319685B1 (en) | 1984-09-27 | 2001-11-20 | Unigene Laboratories, Inc. | Alpha-amidating enzyme compositions and processes for their production and use |
SE509359C2 (sv) | 1989-08-01 | 1999-01-18 | Cemu Bioteknik Ab | Användning av stabiliserade protein- eller peptidkonjugat för framställning av ett läkemedel |
FR2672128B1 (fr) | 1991-01-28 | 1995-08-18 | Cis Bio Int | Procede de mesure de la luminescence emise dans un dosage par luminescence. |
HU222249B1 (hu) | 1991-03-08 | 2003-05-28 | Amylin Pharmaceuticals Inc. | Eljárás amilin agonista peptidszármazékok és ezeket tartalmazó gyógyszerkészítmények előállítására |
US5912015A (en) | 1992-03-12 | 1999-06-15 | Alkermes Controlled Therapeutics, Inc. | Modulated release from biocompatible polymers |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
US5766627A (en) | 1993-11-16 | 1998-06-16 | Depotech | Multivescular liposomes with controlled release of encapsulated biologically active substances |
WO1998005351A1 (en) | 1996-08-08 | 1998-02-12 | Amylin Pharmaceuticals, Inc. | Methods for regulating gastrointestinal motility |
EP1629849B2 (en) | 1997-01-07 | 2017-10-04 | Amylin Pharmaceuticals, LLC | Pharmaceutical compositions comprising exendins and agonists thereof |
ATE354584T1 (de) | 1997-06-13 | 2007-03-15 | Gryphon Therapeutics Inc | Festphasige native chemische ligation von ungeschützten oder n-cystein-geschützten peptiden in wässrigen lösungen |
DE69838791T3 (de) | 1997-08-08 | 2011-06-22 | Amylin Pharmaceuticals, Inc., Calif. | Neue exendinagonist verbindungen |
WO1999025728A1 (en) | 1997-11-14 | 1999-05-27 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
US7223725B1 (en) | 1997-11-14 | 2007-05-29 | Amylin Pharmaceuticals, Inc. | Exendin agonist compounds |
NZ504258A (en) | 1997-11-14 | 2002-12-20 | Amylin Pharmaceuticals Inc | Exendin 3 and 4 agonist compounds for the treatment of diabetes |
AU759058C (en) | 1998-02-13 | 2005-09-15 | Amylin Pharmaceuticals, Inc. | Inotropic and diuretic effects of exendin and GLP-1 |
US6194006B1 (en) | 1998-12-30 | 2001-02-27 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of microparticles having a selected release profile |
PT1143989E (pt) | 1999-01-14 | 2007-03-30 | Amylin Pharmaceuticals Inc | Exendinas para supressão de glucagon |
US6902744B1 (en) | 1999-01-14 | 2005-06-07 | Amylin Pharmaceuticals, Inc. | Exendin agonist formulations and methods of administration thereof |
US6514500B1 (en) * | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
US6528486B1 (en) | 1999-07-12 | 2003-03-04 | Zealand Pharma A/S | Peptide agonists of GLP-1 activity |
PT1240337E (pt) | 1999-12-24 | 2007-01-31 | Genentech Inc | Métodos e composições para prolongar as meias-vidas de eliminação de compostos bioactivos |
US6264987B1 (en) | 2000-05-19 | 2001-07-24 | Alkermes Controlled Therapeutics Inc. Ii | Method for preparing microparticles having a selected polymer molecular weight |
US6296842B1 (en) | 2000-08-10 | 2001-10-02 | Alkermes Controlled Therapeutics, Inc. | Process for the preparation of polymer-based sustained release compositions |
WO2004035623A2 (en) | 2002-10-02 | 2004-04-29 | Zealand Pharma A/S | Stabilized exendin-4 compounds |
NZ571824A (en) | 2004-02-11 | 2010-04-30 | Amylin Pharmaceuticals Inc | Amylin family peptides and methods for making and using them |
US7399744B2 (en) | 2004-03-04 | 2008-07-15 | Amylin Pharmaceuticals, Inc. | Methods for affecting body composition |
US8394765B2 (en) | 2004-11-01 | 2013-03-12 | Amylin Pharmaceuticals Llc | Methods of treating obesity with two different anti-obesity agents |
EP3363810A1 (en) * | 2005-11-28 | 2018-08-22 | The Trustees Of The University Of Pennsylvania | Potent compstatin analogs |
WO2007082264A2 (en) | 2006-01-11 | 2007-07-19 | Bristol-Myers Squibb Company | Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions |
KR20080106950A (ko) | 2006-03-31 | 2008-12-09 | 아밀린 파마슈티칼스, 인크. | 정신의학적 질환 및 장애를 치료하기 위한 아밀린 및 아밀린 효능제 |
WO2007139589A1 (en) | 2006-05-26 | 2007-12-06 | Bristol-Myers Squibb Company | Sustained release glp-1 receptor modulators |
AU2007267833B2 (en) | 2006-05-26 | 2012-07-26 | Amylin Pharmaceuticals, Llc | Composition and methods for treatment of congestive heart failure |
DK2046820T3 (da) * | 2006-08-01 | 2011-02-07 | Pieris Ag | Muteiner af tåre-lipocalin og fremgangsmåder til opnåelse deraf |
JP2008169195A (ja) | 2007-01-05 | 2008-07-24 | Hanmi Pharmaceutical Co Ltd | キャリア物質を用いたインスリン分泌ペプチド薬物結合体 |
JP2009003340A (ja) | 2007-06-25 | 2009-01-08 | Oki Data Corp | 画像形成装置 |
JP2009019027A (ja) | 2007-07-16 | 2009-01-29 | Hanmi Pharmaceutical Co Ltd | アミノ末端のアミノ酸が変異したインスリン分泌ペプチド誘導体 |
ES2346178T3 (es) * | 2007-07-31 | 2015-11-02 | Affibody Ab | Nuevas composiciones, procedimientos y usos de unión de la albúmina |
KR20100132535A (ko) * | 2008-03-31 | 2010-12-17 | 글락소 그룹 리미티드 | 약물 융합체 및 컨주게이트 |
US8329419B2 (en) | 2008-05-23 | 2012-12-11 | Amylin Pharmaceuticals, Llc | GLP-1 receptor agonist bioassays |
WO2010054699A1 (en) * | 2008-11-17 | 2010-05-20 | Affibody Ab | Conjugates of albumin binding domain |
EP2398825B1 (en) * | 2009-02-19 | 2017-10-25 | Glaxo Group Limited | Single variable domain against serum albumin |
US8642544B2 (en) | 2009-04-01 | 2014-02-04 | Amylin Pharmaceuticals, Llc | N-terminus conformationally constrained GLP-1 receptor agonist compounds |
MX345245B (es) | 2010-09-28 | 2017-01-23 | Amylin Pharmaceuticals Llc | Polipeptidos manipulados que tienen duracion de accion incrementada. |
WO2013148966A1 (en) * | 2012-03-28 | 2013-10-03 | Amylin Pharmaceuticals, Llc | Transmucosal delivery of engineered polypeptides |
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CN103370083B (zh) | 2016-11-16 |
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US9593154B2 (en) | 2017-03-14 |
HK1188710A1 (zh) | 2014-05-16 |
CN103370083A (zh) | 2013-10-23 |
MX2013003481A (es) | 2013-10-25 |
CN106986940A (zh) | 2017-07-28 |
BR112013007442A2 (pt) | 2019-09-24 |
ES2563091T3 (es) | 2016-03-10 |
US20140107019A1 (en) | 2014-04-17 |
EP3028720A1 (en) | 2016-06-08 |
US20170114114A1 (en) | 2017-04-27 |
WO2012050923A3 (en) | 2012-07-19 |
CA2812951A1 (en) | 2012-04-19 |
MX345245B (es) | 2017-01-23 |
EA201390450A1 (ru) | 2013-07-30 |
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