JP2017517272A - Fgf23融合タンパク質 - Google Patents
Fgf23融合タンパク質 Download PDFInfo
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- JP2017517272A JP2017517272A JP2017502954A JP2017502954A JP2017517272A JP 2017517272 A JP2017517272 A JP 2017517272A JP 2017502954 A JP2017502954 A JP 2017502954A JP 2017502954 A JP2017502954 A JP 2017502954A JP 2017517272 A JP2017517272 A JP 2017517272A
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Abstract
Description
から選択して良い。
本明細書において別段の規定がない限り、本発明に関連して用いられる科学用語及び技術用語は、当業者によって一般に理解されている意味を有するものとする。更に、文脈による別段の必要性がない限り、単数形の用語は複数形を含み、複数形の用語は単数形を含む。一般に、本明細書に記載する、細胞培養及び組織培養、分子生物学、免疫学、微生物学、遺伝学、ならびにタンパク質化学及び核酸化学、ならびにハイブリダイゼーションに関連して用いられる命名法と、これらの技術とは、当技術分野において周知であり、一般的に用いられている。
FGF23は、176RXXR179モチーフでの部位特異的なタンパク質分解切断によってインビボで失活され、C末端(cテール)及びN末端断片を産生する(Shimada,(2002)、White,((2001)Kidney Int.60(6)):2079−86、Goetzら,(2007)Mol Cell Biol,27(9):3417−28、Goetzら,(2010)Proc Natl Acad Sci USA 107:407−412)。FGFR/αKlothoの二元複合体に対するFGF23結合部位を含むC末端タンパク分解断片(FGF23 cテール)は、二元受容体複合体に対する結合を完全長FGF23と有効に競合できるが、完全長リガンドとは対照的に、受容体の活性化は誘発しない(Goetzら,(2010)Proc Natl Acad Sci USA 107:407−412)。したがって、タンパク質分解切断により、2つの機構、即ち二元受容体複合体に対する結合部位をFGF23から除去すること、及びFGF23に対する内因性の競合的拮抗薬を生成することによってFGF23は失活する。ただし、72aa cテールペプチドの半減期は極めて短く、概算の半減期は10分である(Goetzら,(2010)Proc Natl Acad Sci USA 107:407−412)。
本出願は、実質的に改善された有用な特徴を有するFGF23 cテール融合タンパク質を開示する。このような融合タンパク質は、例えば、FGF23活性の拮抗薬として使用することができる。
本発明の融合タンパク質を形成するときに、リンカーを使用できるが、これは必須ではない。リンカーは、ペプチド結合、即ち、ペプチドリンカーによって共に連結されたアミノ酸を構成できる。本発明のいくつかの実施形態では、リンカーは、ペプチド結合によって連結された1〜20またはそれ以上のアミノ酸から構成され、この場合のアミノ酸は20の天然に存在するアミノ酸から選択される。いくつかの実施形態では、アミノ酸は、アミノ酸グリシン、セリン及びグルタミン酸から選択される。いくつかの実施形態では、好適なリンカーとして、
が挙げられる。5つのアミノ酸残基からなるリンカーが、本明細書で開示するFGF23 cテール融合タンパク質で機能することが見出されているが、本発明はいかなる長さまたは組成のリンカーも企図する。例示的なリンカーを表2に示す。
本発明のいくつかの実施形態では、FGF23 cテールタンパク質は、Fcドメイン、例えばヒトIgGのFc領域の1つ以上のドメインに融合される。抗体は、抗原と結合する可変ドメイン(通称「Fab」)と、特にエフェクター機能、例えば食細胞による補体活性化及び攻撃に関与する定常ドメイン(通称「Fc」)という2つの機能的に独立した部分を含む。Fcは長い血清半減期を有しており(Caponら,1989,Nature 337:525−31)、その結果、Fcドメインが治療的タンパク質と結合されると、半減期の延長をもたらすか、あるいはFc受容体結合、プロテインA結合、補体結合及び治療的なタンパク質に望まれるその他の特性のようなエフェクター機能を組み込むことができる。
本発明のFGF23融合タンパク質は、1,25VitD血清濃度を実質的に変化させる、または変化をもたらすことなく血清リン酸濃度を調節する。
FGF23 cテール融合タンパク質を含む医薬組成物は、本発明の範囲内であり、特性の亢進を呈するいくつかの融合タンパク質の同定という観点から具体的に企図される。このような医薬組成物は、治療有効量のFGF23 cテール融合タンパク質を、投与様式との適合性に応じて選択される薬学的に、または生理学的に許容される製剤化剤と混合して含むことができる。許容される製剤化剤は、使用される用量及び濃度でレシピエントにとって非毒性であることが好ましい。
FGF23 cテール融合タンパク質及びFGF23 cテール融合タンパク質を含む医薬組成物を使用して、FGF23媒介性またはFGF受容体(FGFR)/α−Klotho複合体媒介性の調節により、リン酸及びカルシウムなどのミネラルイオン、ならびに1,25VitDを調節することができる。したがって、本発明のタンパク質は、FGF23活性の阻害に使用できるため、FGF23とFGF受容体(FGFR)/α−Klotho複合体との相互作用によって媒介される、様々な疾患または障害の治療に使用することができる。加えて、本発明は、FGF23媒介性またはFGF受容体(FGFR)/α−Klotho複合体媒介性の障害の治療または予防に使用される薬剤の製造に、本開示のFGF23 cテール融合タンパク質、またはその医薬組成物を使用するために提供する。別の実施形態では、本発明は、α−Klothoに依存しない、または別の共受容体を利用するFGF23媒介性の障害の治療または予防に使用される薬剤の製造に、本開示のFGF23 cテール融合タンパク質またはその医薬組成物を使用するために提供する。治療が可能な、FGF23媒介性またはFGF受容体(FGFR)/α−Klotho複合体媒介性障害の例として、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)が挙げられるが、これらに限定されない。
本発明を以下の実験的実施例を参照して更に詳細に説明する。これら実施例は、例示のみを目的として提供するものであり、別段の指定のない限り、限定的であることを意図しない。したがって、本発明は、いかなる場合も以下の実施例に限定されると解釈されるべきではなく、むしろ、本明細書に示す教示の結果として明らかにされる一部及び全ての変更を包含すると解釈されるべきである。
本実施例は、本明細書に記載するFc−FGF23融合タンパク質の生成及び発現について示す。
C末端またはN末端のいずれかで種々のPEG部分をFGF23 cテールペプチドにコンジュゲートすると、ペプチドの阻害活性が抹消または大幅に低減されたため、PEG化は実行可能性のない選択肢であった。対照的に、FGF23 cテールペプチドとエフェクターのないヒトFcとの融合は、ペプチドの阻害活性に有意な影響を及ぼさなかった。興味深いことには、SPRによる競合的結合アッセイでは、従来的でないC末端融合が、N末端融合よりも大きな阻害力価を示した(図1)。加えて、C末端及びN末端でのFc融合物の力価はほぼ同等であったが、精製収率はC末端融合において有意に高かった。
本実施例は、上記実施例1に記載の実験から得た融合タンパク質の精製及び性質決定について示す。
C末端FGF23 cテール−Fc及びN末端FGF23 cテール−Fcの両方の分子的性質決定から、切り詰めの形跡は示したが、切り詰めの存在は試料内で不均質であった。N末端の切り詰めは、切り詰めが発生した分子の活性を損なうことが予測された。C末端融合物の切り詰めの不均質性を図4に示す。FGF23 cテールペプチドのC末端からの最初の2〜3aaの欠失がペプチドの阻害力価に影響を及ぼすかどうかを評価するために、α−Klothoを過剰発現するように操作されたHEK293細胞を用いて競合的結合アッセイを実施した。HEK293細胞は、FGF23の同族FGFRを含めた、内因的にいくつかのFGFRを発現するヒト細胞胚腎細胞である(Kurosuら、(2006)J Biol Chem 281:6120−6123、Yamazakiら、(2010)J Cell Biochem 111:1210−1221)。これら細胞のα−Klothoの異所性発現は、FGF23の強力な結合、及びシグナル伝達を可能にしている(Kurosuら、(2006)J Biol Chem 281:6120−6123)。72aa FGF23 cテールによるHEK293−Klotho細胞の前処理(合成ペプチド形態及びFc融合形態の両方)は、フローサイトメトリーで評価したように、準飽和量のFGF23とこの細胞との結合能を用量応答様式で阻害する。FGF23タンパク質(本明細書に記載のヒト及びマウス両方)を、マウスミエローマ細胞株(NS0)を使用して産生した。72、70若しくは69aa(ペプチド)または69及び67aa(Fc融合)のFGF23 cテールで構成された、合成FGF23 cテールペプチド及びFGF23 cテール−Fc融合タンパク質を生成した。図5に示すように、FGF23 cテール−Fc融合物のFGF23 cテールペプチド成分を2〜3aa単位でC末端から切り詰めても、融合タンパク質の競合的結合活性に影響を与えなかった。質量分析は、69または67aaのFGF23 cテール−Fc融合物の生成が、分子の付加的な刈り込みを阻止することを示している(表7)。したがって、こうした融合タンパク質を、XLH治療の潜在的治療法として使用することもできる。
本実施例は、細胞ベースのアッセイでのヒト72aa FGF23 cテール−Fc融合物の阻害力価について示す。
本実施例は、野生型マウスでのヒトFGF23 cテール−Fcの、血清リン及び1,25VitDに対する効果について示す。
本実施例は、NaPi2A発現の制御を介した、Hypマウス中のリン酸濃度に対するマウスFGF23 cテール−Fcの治療効果について示す。
本実施例は、Hypマウスでの1,25VitD及びカルシウムの血清濃度に対する、マウスFGF23 cテール−Fcの治療的効果について示す。
muFGF23 cテール−Fcを用いて長期的に処置されたHypマウスに軟組織の石灰化がない例を示す。
本実施例は、海綿骨及び骨塩量に対するFGF23 cテール−Fc融合タンパク質の効果について示す。
本実施例は、本発明のFGF23 cテール−Fc融合タンパク質の血清半減期の延長について示す。
現在まで、FGF23の同族受容体複合体にわたるFGF23 cテールペプチドの結合親和性及びそれ自体の結合性質は、十分に定義されていない。この情報がない限り、Fc分子に対する融合がFGF23 cテールペプチドの本質的な結合性質に影響を及ぼすかどうか、また何らかの潜在的な変化が様々なFGFR/αKlotho受容体複合体にわたって一貫しているかどうかを予測することは困難だった。これらの問題に対処するために、BAF3細胞(内因性のFGFRまたはKlothoを発現しないマウスプロB細胞株)を操作して、異なる受容体複合体を発現させ、これら細胞株にわたって組換えヒトFGF23の結合を評価した。上記のように、FGF23タンパク質(本明細書に記載のヒト及びマウス両方)を、マウスミエローマ細胞株(NS0)を使用して産生した。続いて、FGF23 cテールペプチドまたはFGF23 cテール−Fcのいずれかが、FGF23結合を競合的に阻害する能力を評価した。これらの実験から得た第1の予備的結果を、図17A〜17Bに示している。
[本発明1001]
異種アミノ酸配列と融合された線維芽細胞増殖因子23 cテール(FGF23 cテール)タンパク質を含む、融合タンパク質であって、血清リン酸濃度を調節するが、血清1,25−ジヒドロキシコレカルシフェロール(1,25VitD)濃度を実質的に調節しない、前記融合タンパク質。
[本発明1002]
二量体化ドメインを更に含む、本発明1001の融合タンパク質。
[本発明1003]
前記FGF23 cテールタンパク質が、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6またはSEQ ID NO:7に示す配列を含む、本発明1001の融合タンパク質。
[本発明1004]
前記FGF23 cテールタンパク質が、SEQ ID NO:2に示す配列を含む、本発明1001の融合タンパク質。
[本発明1005]
前記FGF23 cテールタンパク質が、リンカーを介して異種アミノ酸配列と融合される、本発明1001の融合タンパク質。
[本発明1006]
前記リンカーが、
から選択される配列を含むペプチドリンカーである、本発明1005の融合タンパク質。
[本発明1007]
前記リンカーがSEQ ID NO:12に示すアミノ酸配列を含む、本発明1006の融合タンパク質。
[本発明1008]
前記異種アミノ酸配列が、ヒトIgG1 Fcドメインを含む、本発明1001の融合タンパク質。
[本発明1009]
前記Fcドメインが、SEQ ID NO:13に示すアミノ酸配列を含む、本発明1008の融合タンパク質。
[本発明1010]
前記Fcドメインが、前記ドメインのエフェクター機能を変更するように改変されている、本発明1008の融合タンパク質。
[本発明1011]
前記Fcドメインが、残基242、243及び245でアミノ酸置換を含むように改変され、位置242の該置換アミノ酸がアラニンであり、位置243の該置換アミノ酸がアラニンであり、かつ位置245の該置換アミノ酸がアラニンである、本発明1010の融合タンパク質。
[本発明1012]
前記Fcドメインが、SEQ ID NO:14に示すアミノ酸配列を含む、本発明1011の融合タンパク質。
[本発明1013]
前記Fcドメインが、融合タンパク質の半減期を延長するために改変される、本発明1008の融合タンパク質。
[本発明1014]
SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19またはSEQ ID NO:20に示す配列からなる群から選択されるアミノ酸配列を含む、本発明1001の融合タンパク質。
[本発明1015]
SEQ ID NO:14に示すアミノ酸配列を含む、融合タンパク質。
[本発明1016]
本発明1001〜1015のいずれかの融合タンパク質と、薬学的に許容される剤とを含む、医薬組成物。
[本発明1017]
本発明1001〜1015のいずれかの融合タンパク質をコードする単離核酸。
[本発明1018]
SEQ ID NO:22に示す核酸配列を含む、単離核酸。
[本発明1019]
本発明1018の核酸を含むベクター。
[本発明1020]
本発明1018の核酸または本発明1019のベクターを含む宿主細胞。
[本発明1021]
FGF23 cテール融合タンパク質を産生する方法であって、前記核酸によってコードされるタンパク質が発現する条件下で、本発明1020の宿主細胞を増殖させることを含む、前記方法。
[本発明1022]
前記タンパク質を単離することを更に含む、本発明1021の方法。
[本発明1023]
SEQ ID NO:15に示すアミノ酸配列からなるアミノ酸配列を含む、FGF23 cテール Fc融合タンパク質。
[本発明1024]
本発明1001〜1015または1023のいずれかの融合タンパク質を、それを必要とする患者に投与することを含む、FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療方法。
[本発明1025]
前記疾患または障害が腎臓リン酸消耗障害である、本発明1024の方法。
[本発明1026]
前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、本発明1024の方法。
[本発明1027]
FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療のための薬剤の製造における、本発明1001〜1015または1023のいずれかのFGF23 cテール融合タンパク質の使用。
[本発明1028]
前記疾患または障害が腎臓リン酸消耗疾患または障害である、本発明1027の使用。
[本発明1029]
前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、本発明1027の使用。
[本発明1030]
それを必要とする患者での、FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療のための、本発明1016の医薬組成物の使用。
[本発明1031]
前記疾患または障害が腎臓リン酸消耗疾患または障害である、本発明1030の使用。
[本発明1032]
前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、本発明1030の使用。
[本発明1033]
左心室肥大または副甲状腺機能亢進症の治療方法であって、本発明1001〜1015または1023のいずれかの融合タンパク質を、それを必要とする患者に投与することを含む、前記方法。
[本発明1034]
左心室肥大または副甲状腺機能亢進症の治療のための薬剤の製造における、本発明1001〜1015または1023のいずれかのFGF23 cテール融合タンパク質の使用。
[本発明1035]
それを必要とする患者での、左心室肥大または副甲状腺機能亢進症の治療のための、本発明1016の医薬組成物の使用。
Claims (35)
- 異種アミノ酸配列と融合された線維芽細胞増殖因子23 cテール(FGF23 cテール)タンパク質を含む、融合タンパク質であって、血清リン酸濃度を調節するが、血清1,25−ジヒドロキシコレカルシフェロール(1,25VitD)濃度を実質的に調節しない、前記融合タンパク質。
- 二量体化ドメインを更に含む、請求項1に記載の融合タンパク質。
- 前記FGF23 cテールタンパク質が、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6またはSEQ ID NO:7に示す配列を含む、請求項1に記載の融合タンパク質。
- 前記FGF23 cテールタンパク質が、SEQ ID NO:2に示す配列を含む、請求項1に記載の融合タンパク質。
- 前記FGF23 cテールタンパク質が、リンカーを介して異種アミノ酸配列と融合される、請求項1に記載の融合タンパク質。
- 前記リンカーがSEQ ID NO:12に示すアミノ酸配列を含む、請求項6に記載の融合タンパク質。
- 前記異種アミノ酸配列が、ヒトIgG1 Fcドメインを含む、請求項1に記載の融合タンパク質。
- 前記Fcドメインが、SEQ ID NO:13に示すアミノ酸配列を含む、請求項8に記載の融合タンパク質。
- 前記Fcドメインが、前記ドメインのエフェクター機能を変更するように改変されている、請求項8に記載の融合タンパク質。
- 前記Fcドメインが、残基242、243及び245でアミノ酸置換を含むように改変され、位置242の該置換アミノ酸がアラニンであり、位置243の該置換アミノ酸がアラニンであり、かつ位置245の該置換アミノ酸がアラニンである、請求項10に記載の融合タンパク質。
- 前記Fcドメインが、SEQ ID NO:14に示すアミノ酸配列を含む、請求項11に記載の融合タンパク質。
- 前記Fcドメインが、融合タンパク質の半減期を延長するために改変される、請求項8に記載の融合タンパク質。
- SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19またはSEQ ID NO:20に示す配列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に記載の融合タンパク質。
- SEQ ID NO:14に示すアミノ酸配列を含む、融合タンパク質。
- 請求項1〜15のいずれか一項に記載の融合タンパク質と、薬学的に許容される剤とを含む、医薬組成物。
- 請求項1〜15のいずれか一項に記載の融合タンパク質をコードする単離核酸。
- SEQ ID NO:22に示す核酸配列を含む、単離核酸。
- 請求項18に記載の核酸を含むベクター。
- 請求項18に記載の核酸または請求項19に記載のベクターを含む宿主細胞。
- FGF23 cテール融合タンパク質を産生する方法であって、前記核酸によってコードされるタンパク質が発現する条件下で、請求項20に記載の宿主細胞を増殖させることを含む、前記方法。
- 前記タンパク質を単離することを更に含む、請求項21に記載の方法。
- SEQ ID NO:15に示すアミノ酸配列からなるアミノ酸配列を含む、FGF23 cテール Fc融合タンパク質。
- 請求項1〜15または23のいずれか一項に記載の融合タンパク質を、それを必要とする患者に投与することを含む、FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療方法。
- 前記疾患または障害が腎臓リン酸消耗障害である、請求項24に記載の方法。
- 前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、請求項24に記載の方法。
- FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療のための薬剤の製造における、請求項1〜15または23のいずれか一項に記載のFGF23 cテール融合タンパク質の使用。
- 前記疾患または障害が腎臓リン酸消耗疾患または障害である、請求項27に記載の使用。
- 前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、請求項27に記載の使用。
- それを必要とする患者での、FGF23とFGFR/α−Klotho複合体との相互作用によって媒介される疾患または障害の治療のための、請求項16に記載の医薬組成物の使用。
- 前記疾患または障害が腎臓リン酸消耗疾患または障害である、請求項30に記載の使用。
- 前記疾患または障害が、常染色体優性低リン血症性くる病(ADHR)、X染色体連鎖性低リン血症性くる病(XLH)、腫瘍誘発性骨軟化症(TIO)、繊維性骨異形成症(FD)及び慢性腎臓病(CKD)からなる群から選択される、請求項30に記載の使用。
- 左心室肥大または副甲状腺機能亢進症の治療方法であって、請求項1〜15または23のいずれか一項に記載の融合タンパク質を、それを必要とする患者に投与することを含む、前記方法。
- 左心室肥大または副甲状腺機能亢進症の治療のための薬剤の製造における、請求項1〜15または23のいずれか一項に記載のFGF23 cテール融合タンパク質の使用。
- それを必要とする患者での、左心室肥大または副甲状腺機能亢進症の治療のための、請求項16に記載の医薬組成物の使用。
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2015
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Cited By (2)
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JP2021506792A (ja) * | 2017-12-13 | 2021-02-22 | イエール ユニバーシティ | 内分泌型fgf23関連疾患を処置または防止するための組成物および方法 |
JP2021527439A (ja) * | 2018-06-22 | 2021-10-14 | ウニベルジテート ウルム | 補体阻害剤及びその使用 |
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AU2015237176A1 (en) | 2016-10-20 |
AU2015237176A2 (en) | 2016-11-10 |
US20170226172A1 (en) | 2017-08-10 |
CN106456714A (zh) | 2017-02-22 |
EP3122371A1 (en) | 2017-02-01 |
EP3122371A4 (en) | 2017-09-06 |
WO2015149069A1 (en) | 2015-10-01 |
US10464979B2 (en) | 2019-11-05 |
CA2943361A1 (en) | 2015-10-01 |
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