JP2008194039A - 新規線維芽細胞増殖因子(fgf23)および使用方法 - Google Patents
新規線維芽細胞増殖因子(fgf23)および使用方法 Download PDFInfo
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- JP2008194039A JP2008194039A JP2008025528A JP2008025528A JP2008194039A JP 2008194039 A JP2008194039 A JP 2008194039A JP 2008025528 A JP2008025528 A JP 2008025528A JP 2008025528 A JP2008025528 A JP 2008025528A JP 2008194039 A JP2008194039 A JP 2008194039A
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Abstract
【解決手段】その中の突然変異が常染色体優性くる病(ADHR)に関係する線維芽細胞増殖因子-23(FGF23)をコードする新規核酸、およびそれによりコードされるタンパク質。患者におけるFGF23の生物学的活性をそれぞれ阻害または刺激することを含む、低リン酸血症および高リン酸血症性障害の診断および治療方法。患者におけるFGF23の生物学的活性を刺激することを含む、骨粗鬆症、皮膚筋炎、および冠状動脈疾患の治療方法。
【選択図】なし
Description
バリン、イソロイシン、ロイシン;
アスパラギン酸、グルタミン酸;
アスパラギン、グルタミン;
セリン、トレオニン;
リシン、アルギニン(タンパク質分解酵素認識部位以外の位置にあるもの);
フェニルアラニン、チロシン。
の抗体を単離するためのこのように作製されたファージのパンニングは、Fab DNAを含むファージライブラリーについて記載された方法と同様にして行われる。
また本発明は、本発明の方法を実施するのに適したFGF23モジュレータの医薬組成物の使用も包含する。この組成物は、適当なFGF23モジュレータおよび製薬上許容可能な担体を含む。
本明細書で使用される以下の用語の各々は、この節にそれに関して記載される意味を有する。
アルパラギン酸 Asp D
グルタミン酸 Glu E
リシン Lys K
アルギニン Arg R
ヒスチジン His H
チロシン Tyr Y
システイン Cys C
アスパラギン Asn N
グルタミン Gln Q
セリン Ser S
トレオニン Thr T
グリシン Gly G
アラニン Ala A
バリン Val V
ロイシン Leu L
イソロイシン Ile I
メチオニン Met M
プロリン Pro P
フェニルアラニン Phe F
トリプトファン Trp W
本明細書で用いられる、FGF23によって媒介されるまたはこれに関係する疾患、障害または状態を「緩和」する。
この実施例のデータは、新規遺伝子FGF23の発見を示す。また以下に示すのは、ADHRが第12番染色の12p13.3の短いアームにマッピングされ、FGF23がこの領域にマッピングされ、およびFGF23がADHRに罹患した個体において突然変異を起こしている、という発見である。
イギリス人(ファミリー2318)、ドイツ人(ファミリー329)およびアメリカ人(ファミリー1406および1478)起源のファミリー系図を分析した。ADHR+ファミリー1406、1478および2318については以前に記載されている(Econsら, 1992, J. Clin. Endocrinol. Metab. 82:674-681; Bainchineら, 1971, Birth Defects Orig. Aric. Ser. 7:287-295; Roweら, 1992, Hum. Genet. 89:539-542)。この研究は、the Indiana University School of Medicineおよびthe Ludwig-Maximilians-Universitat Faculty of Medicine Institutional Review Boardsによって承認されており、全ての患者は参加前に告知に基づいて同意している。
患者のDNAを以下のように評価した。イントロンプライマーを用いてエキソンを増幅し(表2)、増幅断片を直接的な配列決定またはSSCPによって分析した。SSCPは、標準的なポリアクリルアミドまたはSerdogel SSCP 2x(Serva Electrophoresis GmbH,ドイツ国ハイデルベルグ)を用いて20℃にてグリセロール有りまたは無しで行った。Tt4cslistraGreenで染色してFluorlmager(Molecular Dynamics, カリフォルニア州サニーヴェール)で検出することにより、または[32P]dCTPの存在下でエキソンをPCR増幅した後にオートラジオグラフィーを行うことにより、サンプルを可視化した。変異体のバンドを、配列決定のために再び増幅した。Taq DyeDeoxy Terminator Cycle配列決定キット(ABI)を用いて、またはシークエナーゼ・キット(USB)および[33P]ジデオキシヌクレオチドの取込みを用いて、センスプライマーおよびアンチセンスプライマーの両方を用いて直接配列決定した。突然変異分析は、雄性間で遺伝する(male to male transmission)ADHRに相当する臨床的特徴を有する4つのファミリー1406、1478、2318および329のインデックス患者から得たDNA、ならびにPHEX遺伝子の突然変異について陰性である低リン酸血症性くる病患者18人から得たDNAを用いて行った。さらに、低リン酸血症、大頭蓋顔面異常(major craniofacial abnormality)、短上肢症および短下肢症(short upper and lower extremities)(Cabralら, 80th Annual Endocrine Society Meeting 1998)を有するファミリー、ならびに雄性間で遺伝するHBDを有するファミリーについて分析した。
RT-PCRは、1〜2 ngのヒトもしくはマウスFGF23 cDNA(図5または図6)を鋳型として用いて行った。RACEは、マラソンcDNA増幅キット(ClonTech Inc. Palo Alto, CA)を用いて行った。推定cDNA配列から設計したプライマーを0.2〜3.5kb産物の増幅に使用した(表2)。これらのプライマーは必要に応じて入手することができる。Bonaventureら, 1994, Exp. Cell Res 212:97-104によって記載されているように、ヒト胎児軟骨細胞培養物を調製し、COL2A1の発現について調べた。
この実施例のデータは、ヒト組織および癌細胞系におけるFGF23の発現を示す。また、この実施例では、FGF23に特異的な抗体の作製、ならびに細菌および哺乳動物細胞の中で生成されるFGF23を検出するためのその使用を示す。この実施例で提供されるデータはさらに、FGF23が分泌タンパク質であること、およびFGF23が腫瘍形成性低リン酸血症性骨軟化症(OHO)腫瘍において豊富に発現されることを示す。
各組織から得た2μgのポリA+-RNAを含む多数の組織ノーザンブロット(ClonTech Inc. Palo Alto, CA)を、ハイブリダイゼーション緩衝液(270 mM NaCl, 15 mM Na2HPO4、15 mM EDTA、1% SDS、10% 硫酸デキストラン、0.5% 脱脂粉乳)中の全長FGF23(図5Aまたは6A)プローブと一緒に、60℃の0.01 X SSCで洗浄しながら65℃にてインキュベートした。
Pfuポリメラーゼ(Gibco-BRL, Rockville, MD)を用いて、ヒト心臓から得たRNA(ClonTech Inc. Palo Alto, CA)をPCR増幅することにより、ヒトFGF23cDNAを生成した。Type IV Qiaexpress Kit(Qiagen, Inc., Valencia, CA)を用いて、第7番〜第756番ヌクレオチドを含む挿入体(推定シグナルペプチドを含まない全長FGF23をコードする)を、方向を合わせてpQE30ベクター中にN末端6xHisタグにインフレームでクローニングした。次に、M15[pREP4]細胞を形質転換するためにプラスミドFGF23-6xHis pQEを用い、4時間かけてIPTGを加えてタンパク質発現を誘導した。ニッケルクロマトグラフィーミニプレップによってその製造業者(Qiagen Inc., Valencia, CA)の指示どおりに、FGF23-6xHisタンパク質を精製した。
タンパク質のサンプルおよび標準物質を15%SDS-PAGEミニ-ゲル(BioRad)上で電気泳動にかけ、ニトロセルロース膜にエレクトロブロット(electroblot)を行った。膜を2.5μg/mlの抗ヒトFGF23抗体およびマウス抗5xHis抗体と一緒にインキュベートした後、HRP標識ヤギ抗ウサギもしくは抗マウス2次抗体(1:1000)(Amersham, Inc., Piscataway, NJ)と一緒にインキュベートし、化学発光増幅法(ECL)(Amersham, Inc., Piscataway, NJ)によって可視化した。
哺乳動物細胞内でFGF23を産生するために、ヒトFGF23を発現するプラスミド(pFGF23と呼ぶ)でOK-E、COS-7およびHEK293細胞を一過的にトランスフェクトした。pFGF23を構築するために、RT-PCRにより心臓全長RNAからコザック配列(bp3〜756)後方のFGF23のORFを増幅した。得られたcDNAを、方向を合わせて発現プラスミドpcDNA3.1(+)(Invitrogen)中に挿入した。pFGF23の完全性をDNA配列決定によって確認した。
OHO患者からの6つの異なる腫瘍を、以下に挙げる部位から外科手術により取り出した:a)左大腿(血管周囲細胞腫);b) 下顎骨(混合型結合組織腫瘍);c)左大腿(血管形成異常);d)足裏(血管周囲細胞腫);e)鼻(血管周囲細胞腫);およびf) 遠位大腿(骨芽細胞骨肉腫)(図8A)。全ての患者は、OHOに特徴的な生化学的異常を示し、これらは腫瘍を除去した後に消散した。約100mgの腫瘍サンプルを、75μg/ml AEBSFプロテアーゼインヒビターを加えた0.5mlの氷冷リン酸緩衝食塩水(PBS)の中に再懸濁した。サンプルを氷上で30秒間ホモジナイズした後、1500 x gで遠心分離し、その後、上清のホモジネートを更なる実験で用いた。ウシ血清アルブミンを標準物質として用いてブラッドフォード・プロテインアッセイ(Bio-Rad, Inc., Hercules, CA)によってタンパク質濃度を測定した。
この実施例のデータは、ADHRに関係するFGF23突然変異により、プロテアーゼが共通SPC部位でFGF23を効率良く切断することができなくなるので、FGF23の大きい方のタンパク質種のレベルが上昇することを示している。またこの実施例では、FGF23突然変異型が野生型FGF23に匹敵するレベルでヘパリンに結合し得ることが示される。
nested-PCR、部位特異的突然変異誘発法を用いて、FGF23 cDNA中にADHRミスセンス変異R176Q、R179W、R179Qを導入した。全てのPCR反応において、pFGF23(pcDNA3.1主鎖)と鋳型として用い、高性能再現性(high-fidelity)DNAポリメラーゼPfu(Promega, Inc., Madison, WI)を用いた。PCRの最初のサイクルでは、適当なミスセンスを含む各順方向突然変異誘発プライマーを逆方向3'FGF23プライマーと塩基対形成させ、各逆方向突然変異誘発プライマーを順方向5'FGF23プライマーと塩基対形成させた。突然変異誘発プライマーを以下の表2に挙げる。5'FGF23および3'FGF23プライマーの中に位置しているBamHIおよびEcoRI部位はそれぞれ、イタリック体およびアンダーラインで示される。各プライマーの中の突然変異塩基にはアンダーラインを付してある。
以下のプライマーを用いてpFGF23およびpR176Qを別々に増幅した:
順方向プライマー(EcoRI部位(下線部)を含む)
5'GGAATTCATATCCCAATGCCTCCCCA3'(配列番号7);および
逆方向プライマー(BamHI部位(下線部)を含む)
5'CGGGATCCCTAGATGAACTTGGCGAA3'(配列番号6)。得られたcDNAをEcoRIおよびBamHIで消化し、方向を合わせてpFLAG-CMV-3発現ベクター(Sigma-Aldrich, Inc., St. Louis, MO)中にライゲートし、FLAG-FGF23およびFLAG-R176Qを発現するプラスミドを作製した。親pFLAG-CMV-3ベクターは、N末端FLAGタグ付け融合タンパク質の分泌を可能とするためにプレプロトリプシン(preprotrypsin)リーダー配列を用いることに留意されたい。クローン挿入体を配列決定し、この融合タンパク質の正しいリーディングフレームを確認した。
トランスフェクトしたHEK293細胞から得た馴化培地(0.5ml)を、1×PBS(pH7.4)(1:1)およびヘパリンセファロースの1×PBS(Amersham Pharmacia, Inc., Piscataway, NJ)懸濁液(1:1)50μlと一緒にインキュベートした。この混合物を4℃の回転台(rotating platform)に4時間載せた後、1分間遠心分離した。上清を取り出し、氷冷した1×PBSでセファロースを4回洗浄した。Laemmliサンプル緩衝液(50μl)をセファロースに加え、懸濁液をボルテックス装置で短時間攪拌した後、5分間沸騰させた。このサンプルを1分間遠心分離にかけ、上清を取り出した。この上清10μl(ヘパリンセルロースに結合した物質)を、抗-FGF23抗体を用いたウェスタンブロット分析により分析した。
この実施例のデータは、FGF23を過剰発現するマウス、FF23の突然変異型を発現するマウス、またはリン酸塩欠乏食(phosphate-depleted diet)またはリン酸塩増量食(phosphate-enriched diet)を与えたマウスの作製および分析を示す。
この実施例で提供されるデータは、患者において腫瘍誘導型骨軟化症を診断するためのFGF23検出プロトコールの使用を示す。
この実施例で示すデータは、ヒトにおけるFGF23の安全性を示す。
Claims (62)
- 線維芽細胞増殖因子-23(FGF23)もしくはその突然変異体、変異体、相同体またはこれらの断片をコードする単離核酸。
- 配列番号1および配列番号3のうち少なくとも一方の核酸配列と少なくとも約50%の配列同一性を有する、線維芽細胞増殖因子-23(FGF23)をコードする単離核酸。
- 配列番号2および配列番号4のうち少なくとも一方のアミノ酸配列と少なくとも約40%の配列同一性を有するアミノ酸配列を有するポリペプチドをコードする、線維芽細胞増殖因子-23(FGF23)をコードする単離核酸。
- DSMZ受託番号DSM13530に含まれる単離核酸。
- さらにタグポリペプチドをコードする核酸が共有結合により連結されている、請求項1記載の単離核酸。
- 前記タグポリペプチドが、myc-タグポリペプチド、グルタチオン-S-トランスフェラーゼ・タグポリペプチド、グリーン蛍光タンパク質タグポリペプチド、myc-ピルビン酸キナーゼ・タグポリペプチド、His6タグポリペプチド、インフルエンザウイルス赤血球凝集素タグポリペプチド、flagタグポリペプチド、およびマルトース結合性タンパク質タグポリペプチドからなる群より選択される、請求項5記載の単離核酸。
- さらにプロモーター/調節配列を指定する核酸が機能しうる形で連結されている、請求項1記載の単離核酸。
- 請求項1記載の単離核酸を含むベクター。
- さらにプロモーター/調節配列を指定する核酸が機能しうる形で連結されている、請求項8記載のベクター。
- 請求項1記載の単離核酸を含む組換え細胞。
- 請求項8記載のベクターを含む組換え細胞。
- 線維芽細胞増殖因子-23(FGF23)もしくはその突然変異体、変異体、相同体またはこれらの断片をコードする核酸にアンチセンス方向で相補的である単離核酸。
- 前記相補的核酸が、配列番号1および配列番号3のうち少なくとも一方の配列を有する核酸に相補的な核酸と少なくとも約50%の配列同一性を有する、請求項12記載の単離核酸。
- 請求項12記載の単離核酸を含むベクター。
- さらにプロモーター/調節配列を指定する核酸が機能しうる形で連結されている、請求項14記載のベクター。
- 請求項12記載の単離核酸を含む組換え細胞。
- 線維芽細胞増殖因子-23(FGF23)もしくはその突然変異体、変異体、相同体またはこれらの断片をコードする単離核酸を含むトランスジェニック非ヒト哺乳動物。
- 線維芽細胞増殖因子-23(FGF23)もしくはその突然変異体、変異体、相同体またはこれらの断片を含む単離ポリペプチド。
- 前記FGF23のアミノ酸配列が、配列番号2および配列番号4のうち少なくとも一方のアミノ酸配列と少なくとも約40%の配列同一性を有する、請求項18記載の単離ポリペプチド。
- 線維芽細胞増殖因子-23(FGF23)ポリペプチドもしくはその突然変異体、変異体、相同体またはこれらの断片に特異的に結合する抗体。
- ポリクローナル抗体、モノクローナル抗体、ヒト化抗体、キメラ抗体、および合成抗体からなる群より選択される、請求項20記載の抗体。
- 突然変異を含む、線維芽細胞増殖因子-23(FGF23)をコードする単離核酸。
- 前記突然変異により前記FGF23が高い安定性を獲得している、請求項22記載の単離核酸。
- 前記突然変異が、配列番号2における第176位のアミノ酸(アルギニン)をコードする核酸における突然変異および配列番号2における第179位のアミノ酸(アルギニン)をコードする核酸における突然変異からなる群より選択されるものである、請求項22記載の単離核酸。
- 突然変異を含む単離された線維芽細胞増殖因子-23(FGF23)ポリペプチド。
- 前記FGF23に対して高い安定性を付与する突然変異を含む、単離された線維芽細胞増殖因子-23(FGF23)ポリペプチド。
- 前記突然変異が、配列番号2における第176位のアミノ酸(アルギニン)での突然変異および配列番号2における第179位のアミノ酸(アルギニン)での突然変異からなる群より選択される、請求項26記載の単離されたポリペプチド。
- FGF23ポリペプチドをコードするmRNAのレベルを低下させる分子、FGF23ポリペプチドのレベルを低下させる分子、およびFGF23の生物学的活性を低下させる分子からなる群より選択されることを特徴とする、線維芽細胞増殖因子-23(FGF23)のインヒビター。
- アンチセンス核酸、リボザイム、抗体、ペプチド、およびペプチド模倣体からなる群より選択される、請求項28記載のインヒビター。
- FGF23に特異的に結合する抗体およびFGF23受容体に特異的に結合する抗体からなる群より選択される抗体である、請求項28記載のインヒビター。
- RNA干渉によりFGF23ポリペプチドをコードするmRNAのレベルを低下させる二本鎖RNAである、請求項28記載のインヒビター。
- 請求項1記載の単離核酸および製薬上許容可能な担体を含む組成物。
- 請求項12記載の単離核酸および製薬上許容可能な担体を含む組成物。
- 請求項18記載の単離ポリペプチドおよび製薬上許容可能な担体を含む組成物。
- 請求項20記載の抗体および製薬上許容可能な担体を含む組成物。
- 請求項22記載の単離核酸および製薬上許容可能な担体を含む組成物。
- 請求項23記載の単離核酸および製薬上許容可能な担体を含む組成物。
- 請求項24記載の単離核酸および製薬上許容可能な担体を含む組成物。
- 請求項25記載の単離されたFGF23ポリペプチドおよび製薬上許容可能な担体を含む組成物。
- 請求項26記載の単離されたFGF23ポリペプチドおよび製薬上許容可能な担体を含む組成物。
- 請求項27記載の単離されたFGF23ポリペプチドおよび製薬上許容可能な担体を含む組成物。
- 請求項28記載のインヒビターおよび製薬上許容可能な担体を含む組成物。
- 線維芽細胞増殖因子-23(FGF23)の生物学的活性を有する単離タンパク質の作製方法であって、(a)前記タンパク質が発現されるような条件下で請求項11記載の組換え細胞を培養する工程、および(b)前記タンパク質を回収する工程を含む、上記方法。
- 哺乳動物において低リン酸血症性障害を診断する方法であって、(a)前記哺乳動物から生物学的サンプルを得る工程、および(b) 線維芽細胞増殖因子-23(FGF23)をコードする核酸中の突然変異の存否を検出する試薬に前記生物学的サンプルを接触させる工程を含み、前記突然変異が存在すると前記哺乳動物が低リン酸血症性障害に罹っていることを示すことによって、前記哺乳動物における低リン酸血症性障害を診断する、上記診断方法。
- 前記低リン酸血症性障害が常染色体優性低リン酸血症性くる病(ADHR)である、請求項44記載の方法。
- 前記生物学的サンプルが、血液および尿からなる群から選択される、請求項44記載の方法。
- 前記試薬が核酸である、請求項44記載の方法。
- 前記試薬が検出可能に標識されたものである、請求項44記載の方法。
- 放射性同位元素、生物発光化合物、化学発光化合物、蛍光化合物、金属キレート、および酵素からなる群より選択される標識で前記試薬が検出可能に標識されている、請求項44記載の方法。
- 哺乳動物において低リン酸血症性障害を診断する方法であって、(a)前記哺乳動物から生物学的サンプルを得る工程、および(b)線維芽細胞増殖因子-23(FGF23)ポリペプチドの突然変異体の存否を検出する試薬に前記生物学的サンプルを接触させる工程を含み、前記FGF23ポリペプチドの突然変異体が存在すると、前記哺乳動物が前記低リン酸血症性障害に罹っていることを示すことによって、前記哺乳動物における前記低リン酸血症性障害を診断する、上記診断方法。
- 前記低リン酸血症性障害が、常染色体優性低リン酸血症性くる病(ADHR)である、請求項50記載の方法。
- 前記生物学的サンプルが、血液および尿からなる群より選択される、請求項50記載の方法。
- 前記試薬が抗体である、請求項50記載の方法。
- 哺乳動物において低リン酸血症性障害を診断する方法であって、前記方法が、(a)前記哺乳動物から生物学的サンプルを得る工程、および(b)前記サンプル中の線維芽細胞増殖因子-23(FGF23)ポリペプチドのレベルを検出する試薬に前記生物学的サンプルを接触させる工程を含み、前記サンプル中のFGF23ポリペプチドのレベルが対照哺乳動物から得たサンプル中のFGF23ポリペプチドのレベルに比べて上昇していると、前記哺乳動物が低リン酸血症性障害に罹っていることを示すことによって、前記哺乳動物における前記低リン酸血症性障害を診断する、上記診断方法。
- 前記低リン酸血症性障害が、X連鎖遺伝性くる病(XLH)、遺伝性低リン酸血症性くる病(HHRH)、低リン酸血症性骨疾患(HBD)、常染色体優性低リン酸血症性くる病(ADHR)、腫瘍誘導型骨軟化症、表皮母斑症候群、線維性異形成症、および腎石症からなる群より選択される、請求項54記載の方法。
- 前記生物学的サンプルが、血液および尿からなる群より選択される、請求項54記載の方法。
- 前記試薬がFGF23抗体である、請求項54記載の方法。
- 前記試薬が検出可能に標識されている、請求項54記載の方法。
- 前記試薬が、放射性同位元素、生物発光化合物、化学発光化合物、蛍光化合物、金属キレート、および酵素からなる群より選択される標識で検出可能に標識されている、請求項54記載の方法。
- 患者における腫瘍誘導型骨軟化症の診断方法であって、(a)前記患者から腫瘍サンプルを得る工程、および(b)前記腫瘍中のFGF23の発現の有無を検出する工程を含み、FGF23の発現が前記患者が腫瘍誘導型骨軟化症を有することを示す、上記診断方法。
- 哺乳動物における低リン酸血症性障害の治療方法であって、前記障害に罹った哺乳動物に治療に有効な量の線維芽細胞増殖因子-23(FGF23)インヒビターを投与する工程を含み、前記インヒビターは、前記哺乳動物においてFGF23ポリペプチドをコードするmRNAのレベルを低下させるインヒビター、前記哺乳動物においてFGF23ポリペプチドのレベルを低下させるインヒビター、および前記哺乳動物におけるFGF23の生物学的活性のインヒビターからなる群より選択される、上記治療方法。
- 前記低リン酸血症性障害が、X連鎖遺伝性くる病(XLH)、遺伝性低リン酸血症性くる病(HHRH)、低リン酸血症性骨疾患(HBD)、常染色体優性低リン酸血症性くる病(ADHR)、腫瘍誘導型骨軟化症、表皮母斑症候群、線維性異形成症、および腎石症からなる群より選択される、請求項61記載の方法。
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US (5) | US7223563B2 (ja) |
EP (2) | EP1303536B1 (ja) |
JP (2) | JP2004504063A (ja) |
KR (2) | KR20090036151A (ja) |
CN (1) | CN1446227B (ja) |
AT (1) | ATE461213T1 (ja) |
AU (2) | AU2001273323B2 (ja) |
CA (1) | CA2418215A1 (ja) |
DE (1) | DE60141582D1 (ja) |
ES (1) | ES2340662T3 (ja) |
WO (1) | WO2002008271A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Families Citing this family (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020137890A1 (en) * | 1997-03-31 | 2002-09-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20060160181A1 (en) * | 2000-02-15 | 2006-07-20 | Amgen Inc. | Fibroblast Growth Factor-23 molecules and uses thereof |
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US6838264B2 (en) | 2000-12-05 | 2005-01-04 | Immutopics, Inc. | Antibodies and peptide antigens for producing antibodies having a selective binding specificity to bioactive intact parathyroid hormone (PTH) 1-84 |
JPWO2002052009A1 (ja) * | 2000-12-26 | 2004-04-30 | 中外製薬株式会社 | 血中リン濃度を低下させるヒトfgf23タンパク質変異体 |
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EP1466925B1 (en) * | 2001-12-28 | 2009-09-02 | Kyowa Hakko Kirin Co., Ltd. | Antibodies against fibroblast growth factor 23 |
US7094551B2 (en) | 2002-09-17 | 2006-08-22 | Zahradnik Richard J | Immunoassays, assay methods, antibodies and method of creating antibodies for detecting FGF-23 |
US20090093398A1 (en) * | 2003-11-07 | 2009-04-09 | Jacques Bollekens | Use of Fibroblast Growth Factor Fragments |
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AU2006236335A1 (en) * | 2005-04-18 | 2006-10-26 | Clearplay, Inc. | Apparatus, system and method for associating one or more filter files with a particular multimedia presentation |
KR100760525B1 (ko) * | 2006-04-13 | 2007-10-04 | 김재만 | 병원성 미생물의 무증폭 다중 정량 검출킷트 및 검출방법 |
US8012694B2 (en) | 2006-09-14 | 2011-09-06 | Immutopics, Inc. | Assay for the detection of phosphorylated PTH |
WO2008089936A1 (en) * | 2007-01-22 | 2008-07-31 | Medizinische Universität Innsbruck | Novel markers for chronic kidney disease |
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US20110183434A1 (en) * | 2008-01-17 | 2011-07-28 | Myles Wolf | Diagnostic methods and kits using fibroblast growth factor-23 |
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US20110195077A1 (en) | 2010-01-29 | 2011-08-11 | Novartis Ag | Methods and compositions using fgf23 fusion ppolypeptides |
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US10800843B2 (en) | 2015-07-29 | 2020-10-13 | Ngm Biopharmaceuticals, Inc. | Beta klotho-binding proteins |
ES2871036T3 (es) | 2015-11-09 | 2021-10-28 | Ngm Biopharmaceuticals Inc | Método para el tratamiento de trastornos relacionados con ácidos biliares |
US11370841B2 (en) | 2016-08-26 | 2022-06-28 | Ngm Biopharmaceuticals, Inc. | Methods of treating fibroblast growth factor 19-mediated cancers and tumors |
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US20200080995A1 (en) | 2017-05-31 | 2020-03-12 | Hitachi Chemical Diagnostics Systems Co., Ltd. | Measurement Method for Fibroblast Growth Factor-23, Measurement Reagent, and Measurement Kit |
WO2020047475A1 (en) * | 2018-08-30 | 2020-03-05 | The Uab Research Foundation | Drug screening for fgf23-fgfr4 inhibitors |
BR112021019337A2 (pt) * | 2019-03-29 | 2021-12-07 | Atarga Llc | Anticorpo anti-fgf23 |
AU2020257570A1 (en) * | 2019-04-19 | 2021-10-28 | Genethon | Gene therapy of fibroblast growth factor 23 related hypophosphatemic diseases |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000073454A1 (en) * | 1999-06-02 | 2000-12-07 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001040466A2 (en) * | 1999-12-01 | 2001-06-07 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001042451A2 (en) * | 1999-12-08 | 2001-06-14 | Genset | FULL-LENGTH HUMAN cDNAs ENCODING POTENTIALLY SECRETED PROTEINS |
WO2001049740A1 (en) * | 2000-01-05 | 2001-07-12 | Zymogenetics, Inc. | Novel fgf homolog zfgf12 |
WO2001060850A1 (en) * | 2000-02-14 | 2001-08-23 | Smithkline Beecham Corporation | Novel compounds |
WO2001061007A2 (en) * | 2000-02-15 | 2001-08-23 | Amgen, Inc. | Fibroblast growth factor-23 molecules and uses thereof |
WO2001066595A2 (en) * | 2000-03-08 | 2001-09-13 | Chiron Corporation | Human fgf-23 gene and gene expression products |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4256108A (en) | 1977-04-07 | 1981-03-17 | Alza Corporation | Microporous-semipermeable laminated osmotic system |
US4160452A (en) | 1977-04-07 | 1979-07-10 | Alza Corporation | Osmotic system having laminated wall comprising semipermeable lamina and microporous lamina |
US4265874A (en) | 1980-04-25 | 1981-05-05 | Alza Corporation | Method of delivering drug with aid of effervescent activity generated in environment of use |
WO1994017810A1 (en) | 1993-02-12 | 1994-08-18 | The Wistar Institute Of Anatomy And Biology | Recombinant cytomegalovirus vaccine |
CA2160583A1 (en) | 1993-04-16 | 1994-10-27 | Stanley A. Plotkin | Recombinant cytomegalovirus vaccine |
US5693775A (en) * | 1995-05-12 | 1997-12-02 | The Johns Hopkins University School Of Medicine | Fibroblast growth factor homologous factor-1 (FHF-1) and methods of use |
WO2002076467A1 (en) * | 2001-03-22 | 2002-10-03 | Genzyme Corporation | Compositions and methods to regulate bone and mineral metabolism |
-
2001
- 2001-07-10 AT AT01952590T patent/ATE461213T1/de not_active IP Right Cessation
- 2001-07-10 US US09/901,938 patent/US7223563B2/en not_active Expired - Lifetime
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- 2001-07-10 WO PCT/US2001/021738 patent/WO2002008271A1/en active IP Right Grant
- 2001-07-10 CN CN018140572A patent/CN1446227B/zh not_active Expired - Lifetime
- 2001-07-10 JP JP2002514175A patent/JP2004504063A/ja active Pending
- 2001-07-10 CA CA002418215A patent/CA2418215A1/en not_active Abandoned
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- 2001-07-10 EP EP10001442A patent/EP2184296A1/en not_active Withdrawn
- 2001-07-10 KR KR1020097006051A patent/KR20090036151A/ko not_active Application Discontinuation
- 2001-07-10 AU AU7332301A patent/AU7332301A/xx active Pending
- 2001-07-10 DE DE60141582T patent/DE60141582D1/de not_active Expired - Lifetime
-
2003
- 2003-01-18 KR KR1020037000821A patent/KR100924183B1/ko active IP Right Grant
- 2003-03-04 US US10/379,334 patent/US7314618B2/en not_active Expired - Lifetime
-
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- 2007-11-07 US US11/983,137 patent/US7745406B2/en not_active Expired - Fee Related
- 2007-11-07 US US11/983,190 patent/US7947810B2/en not_active Expired - Fee Related
-
2008
- 2008-02-05 JP JP2008025528A patent/JP2008194039A/ja active Pending
-
2011
- 2011-04-11 US US13/084,203 patent/US8586317B2/en not_active Expired - Lifetime
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000073454A1 (en) * | 1999-06-02 | 2000-12-07 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001040466A2 (en) * | 1999-12-01 | 2001-06-07 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2001042451A2 (en) * | 1999-12-08 | 2001-06-14 | Genset | FULL-LENGTH HUMAN cDNAs ENCODING POTENTIALLY SECRETED PROTEINS |
WO2001049740A1 (en) * | 2000-01-05 | 2001-07-12 | Zymogenetics, Inc. | Novel fgf homolog zfgf12 |
WO2001060850A1 (en) * | 2000-02-14 | 2001-08-23 | Smithkline Beecham Corporation | Novel compounds |
WO2001061007A2 (en) * | 2000-02-15 | 2001-08-23 | Amgen, Inc. | Fibroblast growth factor-23 molecules and uses thereof |
WO2001066595A2 (en) * | 2000-03-08 | 2001-09-13 | Chiron Corporation | Human fgf-23 gene and gene expression products |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013517781A (ja) * | 2010-01-29 | 2013-05-20 | ノバルティス アーゲー | Fgf23融合ポリペプチドを使用する方法および組成物 |
JP2016190847A (ja) * | 2010-01-29 | 2016-11-10 | ノバルティス アーゲー | Fgf23融合ポリペプチドを使用する方法および組成物 |
US10654909B2 (en) | 2014-12-04 | 2020-05-19 | Novartis Ag | Soluble alpha klotho and serum albumin fusion protein |
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CA2418215A1 (en) | 2002-01-31 |
EP1303536B1 (en) | 2010-03-17 |
US7223563B2 (en) | 2007-05-29 |
US20030181379A1 (en) | 2003-09-25 |
EP2184296A1 (en) | 2010-05-12 |
AU7332301A (en) | 2002-02-05 |
ES2340662T3 (es) | 2010-06-08 |
US20080241946A1 (en) | 2008-10-02 |
EP1303536A1 (en) | 2003-04-23 |
US8586317B2 (en) | 2013-11-19 |
WO2002008271A1 (en) | 2002-01-31 |
US7745406B2 (en) | 2010-06-29 |
KR100924183B1 (ko) | 2009-10-28 |
US20090311792A1 (en) | 2009-12-17 |
CN1446227B (zh) | 2011-10-05 |
US20020156001A1 (en) | 2002-10-24 |
DE60141582D1 (de) | 2010-04-29 |
US7947810B2 (en) | 2011-05-24 |
CN1446227A (zh) | 2003-10-01 |
AU2001273323B2 (en) | 2005-11-10 |
EP1303536A4 (en) | 2005-01-05 |
US7314618B2 (en) | 2008-01-01 |
KR20030029111A (ko) | 2003-04-11 |
KR20090036151A (ko) | 2009-04-13 |
US20120064544A1 (en) | 2012-03-15 |
JP2004504063A (ja) | 2004-02-12 |
ATE461213T1 (de) | 2010-04-15 |
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