JP7075757B2 - 制御放出および持続的放出のためのelp融合タンパク質 - Google Patents
制御放出および持続的放出のためのelp融合タンパク質 Download PDFInfo
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- JP7075757B2 JP7075757B2 JP2017525911A JP2017525911A JP7075757B2 JP 7075757 B2 JP7075757 B2 JP 7075757B2 JP 2017525911 A JP2017525911 A JP 2017525911A JP 2017525911 A JP2017525911 A JP 2017525911A JP 7075757 B2 JP7075757 B2 JP 7075757B2
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- insulin
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Description
本出願は、2014年11月21日に出願の米国特許仮出願第62/082945号および2014年12月31日に出願の米国特許仮出願第62/098624号の権益を主張し、それぞれの内容はあらゆる目的のために参照によりその全体が組み込まれる。
これに添えて電子的に提出されるテキストファイルの内容は、参照によりその全体が本明細書に組み込まれる:配列表のコンピュータ可読フォーマットコピー(ファイル名:PHAS_031_02WO_SEQLIST_ST25.TXT、記録日:2015年11月20日、ファイルサイズ69キロバイト)。
注射部位からの持続的放出または遅い吸収は、対象の体温で水素結合マトリックスを形成することが可能なアミノ酸配列ならびに製剤の成分によって制御される。
一部の実施形態では、体温でマトリックスを形成することが可能なアミノ酸配列は、4~10のアミノ酸の反復単位を有するペプチドである。反復単位は、マトリックスの形成で1つ、2つまたは3つの水素結合を形成することができる。ある特定の実施形態では、体温でマトリックスを形成することが可能なアミノ酸配列は、絹糸、エラスチン、コラーゲン、ケラチンもしくはその模倣物のアミノ酸配列、またはここに参照により組み込まれる米国特許第6,355,776号に開示されるアミノ酸配列である。
(a)テトラペプチドVal-Pro-Gly-GlyまたはVPGG(配列番号1);
(b)テトラペプチドIle-Pro-Gly-GlyまたはIPGG(配列番号2);
(c)ペンタペプチドVal-Pro-Gly-X-Gly(配列番号3)またはVPGXG、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(d)ペンタペプチドAla-Val-Gly-Val-ProまたはAVGVP(配列番号4);
(e)ペンタペプチドIle-Pro-Gly-X-GlyまたはIPGXG(配列番号5)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(e)ペンタペプチドIle-Pro-Gly-Val-GlyまたはIPGVG(配列番号6);
(f)ペンタペプチドLeu-Pro-Gly-X-GlyまたはLPGXG(配列番号7)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる;
(g)ペンタペプチドLeu-Pro-Gly-Val-GlyまたはLPGVG(配列番号8);
(h)ヘキサペプチドVal-Ala-Pro-Gly-Val-GlyまたはVAPGVG(配列番号9);
(i)オクタペプチドGly-Val-Gly-Val-Pro-Gly-Val-GlyまたはGVGVPGVG(配列番号10);
(j)ノナペプチドVal-Pro-Gly-Phe-Gly-Val-Gly-Ala-GlyまたはVPGFGVGAG(配列番号11);
(k)ノナペプチドVal-Pro-Gly-Val-Gly-Val-Pro-Gly-GlyまたはVPGVGVPGG(配列番号12);および
(l)ペンタペプチドXaa-Pro-Gly-Val-GlyまたはXPGVG(配列番号13)、ここでXは任意の天然または非天然のアミノ酸残基であり、Xはポリマーまたはオリゴマー反復配列の間で任意選択により異なる。
ペプチド活性薬剤
様々な実施形態では、活性薬剤は、それ自体で短い循環半減期、例えば約30秒~約1時間を有することができるタンパク質またはペプチドである。治療剤は、タンパク質活性薬剤と、対象の体温で水素結合マトリックスを形成することが可能なアミノ酸配列(例えば、ELP)との間の組換え融合タンパク質であってもよい。任意の適当なペプチド活性薬剤を、本開示の治療剤で使用することができる。例示的なペプチド活性薬剤には、GIP受容体アゴニスト、例えばグルコース依存性インスリン分泌性ペプチド(GIP)またはその誘導体が含まれる。さらなる例示的なペプチド活性薬剤には、GLP1受容体アゴニスト、例えばGLP-1またはその誘導体(GLP1 7-36またはGLP1 7-37を含む)またはエキセンディン-4またはその誘導体が含まれる。他の実施形態では、タンパク質またはペプチド薬剤は、グルカゴン受容体アゴニストである(グルカゴン、オキシントモジュリンまたはその誘導体を含む)。他の実施形態では、本開示は、GLP1受容体アゴニスト、グルカゴン受容体アゴニスト、GIP受容体アゴニスト、VPAC2選択的アゴニスト、例えば血管作用性小腸ペプチド(VIP)もしくはその誘導体、凝固因子、例えば第VII因子、第VIII因子もしくは第IX因子、インスリン(例えば、ここに参照により組み込まれる、米国特許出願公開第2013/0150291号に記載される、単鎖インスリンまたはA鎖もしくはB鎖融合タンパク質)、またはモノクローナル抗体もしくは単鎖抗体のうちの任意の2つの共製剤を提供する。あるいは、活性薬剤は、ここに参照により組み込まれる、米国特許出願公開第2011/0123487号に記載されている通りである。
本開示のある特定の実施形態では、治療剤は、GLP-1受容体アゴニスト、例えばGLP-1、エキセンディン-4またはその機能的類似体に融合またはコンジュゲートしているELP成分を含む。
一部の態様では、タンパク質活性薬剤は、成長ホルモンである。例示的な成長ホルモン配列には、図24、26、28および30の下線付きの配列が含まれる(例えば配列番号22)。追加の適する配列には、Seeburgら、「The human growth hormone gene family:nucleotide sequences show recent divergence and predict a new polypeptide hormone:DNA1(3)239-249(1982)に記載されるものが含まれ、それは受託番号AAA98618に関連する配列を含む。AAA98616の正確な配列に加えて、他の誘導体を使用することができる。例えば、成長ホルモンは、最高3アミノ酸、最高5アミノ酸、最高10アミノ酸、最高15アミノ酸、最高20アミノ酸、最高25アミノ酸、最高30アミノ酸、最高35アミノ酸または最高40アミノ酸がN末端でトランケーションされてもよい。特定の態様では、約15~約30アミノ酸をN末端から欠失させることができる。他の態様では、成長ホルモンは、最高3アミノ酸、最高5アミノ酸、最高10アミノ酸、最高15アミノ酸、最高20アミノ酸、最高25アミノ酸、最高30アミノ酸、最高35アミノ酸または最高40アミノ酸がC末端でトランケーションされてもよい。特定の態様では、約20~約30アミノ酸をC末端から欠失させることができる。
ヒトプロインスリンは、31アミノ酸Cペプチド(配列番号44または46)に連結されるAおよびB鎖からなる。プレプロインスリンが小胞体に到達すると、プロテアーゼがシグナルペプチドを切断してプロインスリンを形成する。具体的には、AとB鎖の間でジスルフィド結合が形成されると、プロインスリンは、トリプシン/カルボキシペプチダーゼB様系によるCペプチドの除去によってin vivoで成熟インスリンに変換される。ヒトインスリンは、2つのジスルフィド架橋によって連結される鎖A(21アミノ酸-GIVEQCCTSICSLYQLENYCN)(配列番号47)および鎖B(30アミノ酸FVNQHLCGSHLVEALYLVCGERGFFYTPKT)(配列番号48)という名称のアミノ酸の2つの鎖で構成される。A鎖の6番目および11番目の残基を連結する第3のジスルフィド架橋がA鎖の中にある。ほとんどの種では、鎖AおよびBの長さならびにアミノ酸組成は類似し、3つのジスルフィド結合の位置は高度に保存されている。この理由から、ブタインスリンは、糖尿病患者で欠損したヒトインスリンレベルを元に戻すことができる。今日、ブタのインスリンは、細菌によるヒトプロインスリンの大量生産(組換えインスリン)によってほとんど置き換えられている。
血管作用性小腸ペプチド(VIP)は、気道、小腸、精巣および膵臓を含む様々な組織で見出される、2つの受容体VPAC1およびVPAC2に結合する28アミノ酸ニューロペプチドである。VIPおよびその機能的および構造的に関係する類似体は、気道平滑筋を弛緩させ、それによって気管支拡張剤として作用すること、気道粘膜下腺で液分泌を刺激すること、ならびに腸および膵臓で水および電解質分泌を調節することを含む、多くの生理機能を有することが公知である(Wine(2007);Wu(2011);Derand(2004))。
他の実施形態では、治療剤は、活性薬剤と、対象の体温でマトリックスを形成することが可能なアミノ酸配列(例えば、ELP)との間の化学コンジュゲートである。例えば、活性薬剤は、化学療法剤、例えばメトトレキサート、ダウノマイシン、マイトマイシン、シスプラチン、ビンクリスチン、エピルビシン、フルオロウラシル、ベラパミル、シクロホスファミド、シトシンアラビノシド、アミノプテリン、ブレオマイシン、マイトマイシンC、デモコルシン、エトポシド、ミトラマイシン、クロラムブシル、メルファラン、ダウノルビシン、ドキソルビシン、タモキシフェン、パクリタキセル、ビンブラスチン、カンプトセシン、アクチノマイシンD、シタラビンおよびコンブレタスタチンから選択される化学療法剤であってよい。あるいは、薬剤は、免疫原性分子、または免疫調節物質、または抗炎症剤、例えば、ここに参照により完全に組み込まれる米国特許出願公開第2009/0004104号に記載される薬剤であってもよい。さらに、薬剤は、オピオイド分子、例えばオキシコドン、モルヒネまたはコデイン、例えば、ここに参照により組み込まれる米国特許仮出願第61/597,898号に記載されるようなものであってもよい。化学コンジュゲートは開裂可能なリンカーを通すものであってよく、その多数のタイプが当技術分野で公知である。ここに参照により完全に組み込まれる、米国特許第6,328,996号を参照。
本開示は、本明細書に開示される治療剤ならびに1つまたは複数の薬学的に許容される賦形剤および/または希釈剤を含む持続的放出製剤を提供する。例えば、そのような賦形剤には、塩および水素結合を安定させる作用をすることができる他の賦形剤が含まれる。当技術分野で公知である任意の適当な賦形剤を使用することができる。例示的な賦形剤には、限定されずに、ヒスチジン、グリシンまたはアルギニンなどのアミノ酸;グリセロール;スクロースなどの糖;ポリソルベート20およびポリソルベート80などの界面活性剤;クエン酸;クエン酸ナトリウム;抗酸化剤;ナトリウム、カリウムおよびカルシウムなどのアルカリ土類金属塩を含む塩;塩化物およびリン酸塩などの対イオン;糖アルコール(例えばマンニトール);保存剤;糖アルコール(例えばマンニトール、ソルビトール);ならびに緩衝剤が含まれる。例示的な塩には、塩化ナトリウム、塩化カリウム、塩化マグネシウム、塩化カルシウム、二塩基リン酸ナトリウム、一塩基リン酸ナトリウム、リン酸ナトリウムおよびリン酸カリウムが含まれる。
ある特定のアミノ酸配列が示す相転移特性を、図1(ELP1)および図2(ELP4)に例示する。相転移は、濁度の増加として観察することができる。図3は、理論によって縛られることを望まないが、所与の濃度の相転移温度より高い温度での水シェルの排除および水素結合の形成によって推進される、相転移の潜在的機構を例示する。
ELPモチーフのVPGXG配列でゲスト残基位置Xのアミノ酸を変更することは、転移状態のELPバイオポリマーのコアセルベートの安定性または強度を変更し、皮下に投薬したときに薬物のより遅い放出および延長された貯蔵をもたらすことができる。9つのVPGXG五量体(9量体)ブロック(アルファ、ベータおよびベータv2)で使用されるゲストアミノ酸の比を変えることによって、異なるコアセルベーション強度を有するELPバイオポリマーのコレクションを構築した。VPGXGのゲスト残基を置換することに加えて、モチーフXPGVGを有する五量体も構築した(デルタ)。ELP五量体は任意の長さに組み合わせることができるが、DNAの合成および操作の例示および容易さのために、9つのELP五量体(9量体)のサブユニットを構築した。これらの9量体は任意の長さのポリマーを作製するために組み合わせることができるが、ゲスト残基位置のバリンと他のアミノ酸との全体的な比は同じままである。図4は、これらの9量体(アルファ、ベータ、ベータv2およびデルタ)のアラインメントを示す。9量体は、疎水性を有する、したがって、以前に検査したELP1シリーズ(VPGXG:V5A2G3)およびELP4シリーズ(VPGXG:V-5)のバイオポリマーの間の転移温度を有するELPバイオポリマーを形成するように設計した。図10に表されない別のELPポリマーが開発された。このポリマー(ELPガンマ)は、V5:A2:G2の比でVPGXG五量体モチーフを含む。表1は、新しいELPシリーズと1および4シリーズの9量体の間の、ゲスト残基占有率の比を比較する。
ヒト成長ホルモン(hGH)配列を合成し、制限酵素PflM1/BglIで消化し、次にプラスミドpE0362にサブクローニングしてプラスミドpPE0429を提供し、ELPベータV2-144をhGH配列のN末端に置いた。図23は、pPE0429のプラスミドマップを示す。図24は、融合タンパク質の配列を示す。この構築物は、ELPベータV2 9量体の16個の反復配列を有するELPを提供する。
エキセンディン-4コード配列を合成し、制限酵素Xbal/BsrGlで消化し、次にプラスミドpE0362にサブクローニングしてプラスミドpPE0364を提供し、エキセンディン-4配列をELPベータV2-144配列のN末端に置いた。図31は、pPE0364のプラスミドマップを示す。図32は、融合タンパク質の配列を示す。この構築物は、ELPベータV2 9量体の16個の反復配列を有するELPを提供する。
本明細書で参照される全ての特許および刊行物は、以下で開示される刊行物を含め、ここに参照により完全に組み込まれる。
Claims (47)
- 全身投与のための治療剤であって、活性薬剤、および(i)少なくとも90個の[VPGXG]の構造単位を含むエラスチン様ペプチド(ELP)であって、各XはV、GおよびAから選択され、V:G:Aの比は
a)7:2:0;
b)7:0:2;
c)6:0:3;および
d)5:2:2、からなる群から選択される、ELP、または、
(ii)少なくとも90個の[XPGVG]の構造単位を含むELPであって、各XはV、GおよびAから選択され、V:G:Aの比は5:0:4である、ELP、を含む、治療剤
ならびに
1つまたは複数の薬学的に許容される賦形剤
を含む持続的放出医薬製剤。 - 投与すると注射部位からの遅い吸収を提供する、請求項1に記載の医薬製剤。
- PKプロファイルが浅いCmaxおよび/または低いピーク対トラフ比および/または長いTmaxを有する、請求項2に記載の医薬製剤。
- 体温での可逆的マトリックスの形成がタンパク質濃度の低下に従って反転する、請求項1~3のいずれか一項に記載の医薬製剤。
- 前記ELPが[VPGXG]144を含む、請求項1~4のいずれか一項に記載の医薬製剤。
- 対象がヒトである、請求項1~5のいずれか一項に記載の医薬製剤。
- 対象が非ヒト哺乳動物である、請求項1~5のいずれか一項に記載の医薬製剤。
- 前記活性薬剤がタンパク質である、請求項1~7のいずれか一項に記載の医薬製剤。
- 前記治療剤が、前記タンパク質活性薬剤とELPの間の組換え融合タンパク質である、請求項8に記載の医薬製剤。
- 前記タンパク質活性薬剤が30秒~10時間、または30秒~1時間の範囲内の循環半減期を有する、請求項8に記載の医薬製剤。
- 前記タンパク質活性薬剤が、GLP-1受容体アゴニストもしくはその誘導体、VPAC2選択的アゴニストもしくはその誘導体、GIP受容体アゴニストもしくはその誘導体、グルカゴン受容体アゴニストもしくはその誘導体、エキセンディン-4もしくはその誘導体またはインスリンもしくはその誘導体である、請求項8に記載の医薬製剤。
- 前記活性薬剤が、GLP1受容体アゴニスト、グルカゴン受容体アゴニスト、GIP受容体アゴニスト、エキセンディン-4およびインスリンのうちの少なくとも2つを含む共製剤である、請求項8に記載の医薬製剤。
- 前記治療剤が、前記活性薬剤とELPの間の化学的コンジュゲートである、請求項1~8および10~12のいずれか一項に記載の医薬製剤。
- 前記活性薬剤が、メトトレキサート、ダウノマイシン、マイトマイシン、シスプラチン、ビンクリスチン、エピルビシン、フルオロウラシル、ベラパミル、シクロホスファミド、シトシンアラビノシド、アミノプテリン、ブレオマイシン、マイトマイシンC、デモコルシン、エトポシド、ミトラマイシン、クロラムブシル、メルファラン、ダウノルビシン、ドキソルビシン、タモキシフェン、パクリタキセル、ビンブラスチン、カンプトセシン、アクチノマイシンD、シタラビンおよびコンブレスタチンから選択される化学療法剤である、請求項13に記載の医薬製剤。
- 前記治療剤が0.5mg/mL~200mg/mLの範囲内で存在する、請求項1~14のいずれか一項に記載の医薬製剤。
- 前記治療剤が30mg/mL~150mg/mLの範囲内で存在する、請求項15に記載の医薬製剤。
- 前記治療剤が50mg/mL~125mg/mL、または75mg/mL~110mg/mLの範囲内で存在する、請求項16に記載の医薬製剤。
- 前記治療剤が100mg/mLの量で存在する、請求項17に記載の医薬製剤。
- 前記治療剤が貯蔵条件で相転移マトリックスを形成しない、請求項1~18のいずれか一項に記載の医薬製剤。
- 前記貯蔵条件が30℃未満、27℃未満、または25℃未満である、請求項19に記載の医薬製剤。
- 前記貯蔵条件で1カ月を超えて安定している、請求項20に記載の医薬製剤。
- 25℃で1カ月を超えて安定している、請求項21に記載の医薬製剤。
- 塩化カルシウム、塩化マグネシウム、塩化カリウム、一塩基リン酸カリウム、塩化ナトリウム、ポリソルベート20、リン酸ナトリウム、一塩基リン酸ナトリウムおよび二塩基リン酸ナトリウムのうちの2つ以上を含む、請求項1~22のいずれか一項に記載の医薬製剤。
- リン酸ナトリウム、塩化ナトリウムおよびポリソルベート20を含む、請求項23に記載の医薬製剤。
- 10mMリン酸ナトリウム、110mM塩化ナトリウムおよび0.1%ポリソルベート20を含む、請求項24に記載の医薬製剤。
- 1週につき1回、1週につき2回または1カ月につき1~8回の投与のために前充填された(pre-dosed)ペンまたはシリンジの形で詰め込まれる、請求項1~25のいずれか一項に記載の医薬製剤。
- 活性薬剤およびELPアミノ酸配列を含む治療剤であって、前記ELPアミノ酸配列が、(i)[VPGXG]144であって、各XはV、GおよびAから選択され、V:G:Aの比は、
a)7:2:0;
b)7:0:2;
c)6:0:3;および
d)5:2:2、からなる群から選択される、[VPGXG]144、または、
(ii)[XPGVG]144であって、各XはV、GおよびAから選択され、V:G:Aの比は5:0:4である、[XPGVG]144、を含む
治療剤、ならびに
1つまたは複数の薬学的に許容される賦形剤
を含む持続的放出医薬製剤。 - 投与すると注射部位からの遅い吸収を提供する、請求項27に記載の医薬製剤。
- PKプロファイルが浅いCmaxおよび/または低いピーク対トラフ比および/または長いTmaxを有する、請求項28に記載の医薬製剤。
- 体温での可逆的マトリックスの形成がタンパク質濃度の低下に従って反転する、請求項27~29のいずれか一項に記載の医薬製剤。
- 前記活性薬剤がタンパク質である、請求項27~30のいずれか一項に記載の医薬製剤。
- 前記治療剤が、前記タンパク質活性薬剤と前記アミノ酸配列の間の組換え融合タンパク質である、請求項31に記載の医薬製剤。
- 前記タンパク質活性薬剤が30秒~10時間、または30秒~1時間の範囲内の循環半減期を有する、請求項31に記載の医薬製剤。
- 前記活性薬剤が、GLP-1受容体アゴニストもしくはその誘導体、VPAC2選択的アゴニストもしくはその誘導体、GIP受容体アゴニストもしくはその誘導体、グルカゴン受容体アゴニストもしくはその誘導体、エキセンディン-4もしくはその誘導体またはインスリンもしくはその誘導体である、請求項31に記載の医薬製剤。
- 前記活性薬剤が、GLP1受容体アゴニスト、グルカゴン受容体アゴニスト、GIP受容体アゴニスト、エキセンディン-4およびインスリンのうちの少なくとも2つを含む共製剤である、請求項31に記載の医薬製剤。
- 前記治療剤が前記活性薬剤と前記アミノ酸配列の間の化学的コンジュゲートである、請求項27~31および33~35のいずれか一項に記載の医薬製剤。
- 前記活性薬剤が、メトトレキサート、ダウノマイシン、マイトマイシン、シスプラチン、ビンクリスチン、エピルビシン、フルオロウラシル、ベラパミル、シクロホスファミド、シトシンアラビノシド、アミノプテリン、ブレオマイシン、マイトマイシンC、デモコルシン、エトポシド、ミトラマイシン、クロラムブシル、メルファラン、ダウノルビシン、ドキソルビシン、タモキシフェン、パクリタキセル、ビンブラスチン、カンプトセシン、アクチノマイシンD、シタラビンおよびコンブレスタチンから選択される化学療法剤である、請求項36に記載の医薬製剤。
- 前記治療剤が0.5mg/mL~200mg/mLの範囲内で存在する、請求項27~37のいずれか一項に記載の医薬製剤。
- 前記治療剤が30mg/mL~150mg/mLの範囲内で存在する、請求項38に記載の医薬製剤。
- 前記治療剤が50mg/mL~125mg/mLの範囲、または75mg/mL~110mg/mLの範囲内で存在する、請求項39に記載の医薬製剤。
- 前記治療剤が100mg/mLの範囲内で存在する、請求項40に記載の医薬製剤。
- 前記治療剤が貯蔵条件でマトリックスを形成しない、請求項27~41のいずれか一項に記載の医薬製剤。
- 前記貯蔵条件が30℃未満、27℃未満、または25℃未満である、請求項42に記載の医薬製剤。
- 塩化カルシウム、塩化マグネシウム、塩化カリウム、一塩基リン酸カリウム、塩化ナトリウム、ポリソルベート20、リン酸ナトリウム、一塩基リン酸ナトリウムおよび二塩基リン酸ナトリウムのうちの2つ以上を含む、請求項27~43のいずれか一項に記載の医薬製剤。
- リン酸ナトリウム、塩化ナトリウムおよびポリソルベート20を含む、請求項44に記載の医薬製剤。
- 10mMリン酸ナトリウム、110mM塩化ナトリウムおよび0.1%ポリソルベート20を含む、請求項45に記載の医薬製剤。
- 1週につき1回、1週につき2回または1カ月につき1~8回の投与のために前充填された(pre-dosed)ペンまたはシリンジの形で詰め込まれる、請求項27~46のいずれか一項に記載の医薬製剤。
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AU2015255752B2 (en) | 2014-05-08 | 2020-07-23 | Immunoforge Co., Ltd. | Methods and compositions for treating Cystic Fibrosis |
US10722590B2 (en) | 2014-11-21 | 2020-07-28 | Phasebio Pharmaceuticals, Inc. | ELP fusion proteins for controlled and sustained release |
US10688156B2 (en) | 2015-02-09 | 2020-06-23 | Phasebio Pharmaceuticals, Inc. | Methods and compositions for treating muscle disease and disorders |
CN108135968A (zh) | 2015-08-28 | 2018-06-08 | 阿穆尼克斯运营公司 | 嵌合多肽组装体及其制备和使用方法 |
JP7325075B2 (ja) * | 2018-09-21 | 2023-08-14 | 学校法人 埼玉医科大学 | フリズルド3発現細胞の細胞数増加剤若しくは低下剤、糖尿病予防若しくは治療剤、インスリノーマ予防若しくは治療剤、及びインスリン分泌促進剤若しくは分泌抑制剤よりなる群から選択される少なくとも1つの剤をスクリーニングするためのスクリーニング剤、スクリーニング用キット、及びスクリーニング方法 |
WO2020081716A2 (en) * | 2018-10-16 | 2020-04-23 | Texas Tech University System | Biomaterials for 3d cell growth and differentiation |
WO2021030196A1 (en) * | 2019-08-09 | 2021-02-18 | Phasebio Pharmaceuticals, Inc. | Elp fusion proteins comprising parathyroid hormone for controlled and sustained release |
WO2021226244A1 (en) * | 2020-05-05 | 2021-11-11 | Phasebio Pharmaceuticals, Inc. | Vasoactive intestinal peptide fusion proteins for the treatment of covid-19 |
CN113735941B (zh) * | 2021-08-13 | 2024-01-30 | 江南大学 | 一种蛋白纯化方法及其应用 |
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US10722590B2 (en) | 2020-07-28 |
JP2018500291A (ja) | 2018-01-11 |
CA2967394A1 (en) | 2016-05-26 |
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JP2022176986A (ja) | 2022-11-30 |
AU2021229233A1 (en) | 2021-10-28 |
WO2016081884A3 (en) | 2016-09-15 |
US20200353091A1 (en) | 2020-11-12 |
EP3220936A2 (en) | 2017-09-27 |
US20230414773A1 (en) | 2023-12-28 |
US20190015523A1 (en) | 2019-01-17 |
WO2016081884A2 (en) | 2016-05-26 |
AU2015349743B2 (en) | 2021-06-10 |
JP2021008501A (ja) | 2021-01-28 |
JP7461997B2 (ja) | 2024-04-04 |
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EP3220936A4 (en) | 2018-08-22 |
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