JP2012507988A - 加齢黄斑変性における遺伝的多型 - Google Patents
加齢黄斑変性における遺伝的多型 Download PDFInfo
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Abstract
Description
この出願は、2008年11月5日に出願された米国仮出願番号第61/111667号及び2009年5月1日に出願された米国仮出願番号第61/174856号に基づく米国特許法第119条の優先権を主張するものであり、出典明示によりその内容がここに取り込まれる。
ここで使用される場合、単数形「a」、「an」、「the」は文脈が明らかに他の意味になっていない限り、複数形を含む。例えば、「細胞("a" cell)」は複数の「細胞」を含む。
多型
我々は、ラニビツマブを用いた抗VEGF治療の好ましい結果に関連する変化について、種々の多型を試験した。AMD感受性に関連することが以前に報告されている5つの遺伝子座からの8つのアレルであるため、これらの多型を選択し、調べた(表1)。具体的には、補体因子H(CFH)、HTRaセリンペプチダーゼ/加齢黄斑変性感受性2(HTRA1/ARMS2)、補体因子2/補体因子Bプレタンパク質(C2/BF)、補体因子3(C3)からの単一アレル、及びケモカイン(C−X3−Cモチーフ)レセプター(CXCR1)をTaqMan(登録商標)システムを介した定量PCRを用いたDAWN試験からの352AMDサンプルにおいて遺伝子型を同定した。更に、我々は補体因子5(C5)の2つのアレルを調べた(表2)。表1の全てのアッセイの遺伝子型を調べるために、ABIに提供される標準的な実験プロトコルを使用した。簡潔には、アッセイは、次のサイクル条件:50℃で2分、95℃で10分、次いで92℃で15秒及び60℃で1分の40サイクルを用いて、ABI7500装置で行った。
HORIZON伸長試験のDAWN遺伝子サブ試験に参加したLucentis(登録商標)ピボタル試験(MARINA、ANCHOR、及びFOCUS)からの352個の未同定検体からの末梢血サンプルを回収し、ゲノムDNAを単離した。全てのサンプルは血管新生AMDを診断で確認し60%は女性の患者からのものであり、基底における平均年齢は、シャム/PDTについて75.0歳であり、処置したラニビツマブについて75.6歳であった。試験における全ての患者から書面でインフォームド・コンセントを得、試験プロトコルは、治験審査委員会によって承認を得た。DNAをDNeasyTissueキット(Qiagen, Valencia, CA)を用いて抽出した。SNPをTaqMan(登録商標)−ベースのリアルタイム−PCRを用いて遺伝子型同定した。SNPの2つについては、カスタムプライマーを使用し(表4)、他の6つについては、ABI所有権のプライマーを使用した(表3)。2C5SNP(表5に示すオリゴヌクレオチド)をIllumina(登録商標)GoldenGateプラットフォームを用いたカスタム96SNPアッセイパネルの一部として同定した。
MARINA、ANCHOR及びFOCUS Lucentis試験からの臨床情報を調べた。具体的には、自己同定された人種、性別、初期試験ベースラインにおける年齢に関する情報、初期試験治療グループ、Lucentis投与、2年目における治療選択肢に対する交差、投与エラーの存在、試験眼の文字におけるベースライン(BL)の最良の矯正視力(VA)スコア、他眼のBLのVAスコア(文字)、12ヶ月目における試験眼VAスコア(文字)、12ヶ月目における他眼のVAスコア(文字)、BLの他眼における血管新生AMDの存在、及び試験眼のBLのCNV分類。
公共で利用可能な資源から得たコントロールのサンプルに対するDAWNケースのアレルの頻度を比較することにより、8個のアレルの疾患感受性への関係を調べた。コントロールのアレルの頻度のrs10490924、rs1410996、rs9332739、及びrs3732378情報について、アレル頻度は、Wellcome Trust Case Control consortium (WTCCC (2007) Nature 447:661-78)から無料で利用可能な要約統計から得た。コントロールのアレル頻度と残りのSNPに対する遺伝子型のカウントを、rs112006383、rs22301996、rs5471541の関係を報告した論文から得た。関係統計は、標準の2x2の結果表を使用して計算した。
ベースラインの視力(VA)に対する8個のアレルの関係づけは、共変量としてベースラインに付加した年齢の存在下又は非存在下、定量特性として、ベースラインにおける試験眼のVA(文字)を用いて実施した。3つの遺伝子型分類を、平均のベースラインVAにおける重大な差異について調べた。分析は、PLINKソフトウェア (Purcell等 (2007) Am. J. Hum. Genet. 81:559-75)を用いて行った。他眼における血管新生AMDの存在に対する8個のアレルの関係と、ベースラインにおける試験眼の血管新生分類(minimally型、predominantly型、occultなし型)を調べた。臨床特性の頻度は、遺伝子型とt検定で決定した優位性で階層化した。
以前に公表された見解を確認すると、全ての8遺伝子座からのアレルが、P<0.05で血管新生AMDのリスクに関係した。しかし、CX3CR1遺伝子座からのアレルだけが、当所の報告に一致した関係を示さなかった。DAWNサンプルのうち、CX3CR1遺伝子座が1.12のオッズ比を有し、当所の報告の3より大きいオッズ比に反する。有意な関係がrs17216529(C5 I145V)とAMDを伴う個体の他眼における脈絡膜新生血管(CNV)の発生の間で観察された。更に、rs17611(C5 I802V)と滲出性AMD、GA AMDを伴う非滲出性、又は両者の発生との間で関係が観察された(表7)。その関係はGA AMDの場合よりもAMDの場合(p=0.0014)によりも強固であった。
ベースラインにおける視力に対する8アレルの有意な関係性は見出されなかった。CFH Y402HアレルとHTRA1 A69Sアレルのリスクアレルの数は、サンプルの他眼の血管新生AMDの有病率に関連し、これらの遺伝子座の遺伝子型と疾患の重大さの関係を示唆した。CFH Y402Hアレルは、ベースラインの試験眼の血管新生AMDの「predminantly型」サブタイプに関係した。rs1410996のイントロンCFHアレルは、CNVと古典的CNVにおける損傷の領域に関係し、C5 I802Vアレルは古典的CNVの損傷の領域に関連した。
DAWNサンプルをMARINA、ANCHOR及びFOCUS試験の間の治療状況に基づき3つのグループに分類した。ラニビツマブで処理したグループは、0.3mg、0.5mg又は0.5mg+PDTの投与を受ける患者を含んだ。SHAM/PDTグループは、モック注射(SHAM)又は光線力学療法(PDT)のみを受ける個体から構成された。12ヶ月の治療後の視力(VA、文字で測定した)の変化の関係を8個のアレルのそれぞれの遺伝子型に対する関係について試験した。治療応答における有意な差がCFH Y402H、C5 I802V、及びHTRA1 A69S遺伝子座における遺伝子型と関係した(表8、9及び10)。これらの変化は、毎月ラニビツマブで処理した患者のVAの変化に関連した。12ヶ月目のVAの平均の変化は、Y402H CC、CT及びTTの遺伝子型についてそれぞれ、+14.5、+10.8及び+7.0文字;I802V AA、AG及びGGの遺伝子型についてそれぞれ、+15.6、+12.2及び+8.8;A69S GG、GT及びTTの遺伝子型についてそれぞれ+9.3、+14.1及び+10.5であった。CFH Y402Hアレルについて、12ヶ月目におけるY402H CC、CT、及びTTについてのそれぞれ−4.8、−10.2及び−11.5のBCVAの平均変化を伴うコントロールグループ(SHAM/PDT)における、逆対応する傾向が観察された。コントロールとラニビツマブ治療グループの間の平均BCVA12ヶ月の結果における差異は、Y402Hリスク遺伝子型の全てで同じであった。
Claims (21)
- 滲出性AMD患者が高親和性の抗VEGF抗体を用いた治療の利益を得る見込みが増加しているかどうかを予測する方法において、rs1061170に対応する補体H因子遺伝子(CFH)Y402Hアレルにおける前記患者から単離したサンプルの遺伝子多型のスクリーニングを含み、ここで、対応する遺伝子型がCC又はCTを含む場合、該患者は、前記治療の利益を得る見込みが増加している方法。
- 滲出性AMD患者が抗VEGF抗体を用いた治療の利益を得る見込みが増加しているかどうかを予測する方法において、rs17611に対応する補体C5因子遺伝子(C5)1802Vアレルにおける前記患者から単離したサンプルの遺伝子多型のスクリーニングを含み、ここで、対応する遺伝子型がAA又はAGを含む場合、該患者は、前記治療の利益を得る見込みが増加している方法。
- 滲出性AMD患者が抗VEGF抗体を用いた治療の利益を得る見込みが増加しているかどうかを予測する方法において、rs10490924に対応するHTRA1 A69Sアレルにおける前記患者から単離したサンプルの遺伝子多型のスクリーニングを含み、ここで、対応する遺伝子型がGTを含む場合、該患者は、前記治療の利益を得る見込みが増加している方法。
- 前記抗VEGF抗体がハイブリドーマATCC(登録商標)HB10709によって産生されるモノクローナル抗VEGF抗体A4.6.1として同一のエピトープに結合する、請求項1から3の何れか一項の方法。
- 前記抗VEGF抗体が、次の重鎖相補性決定領域(CDR)アミノ酸配列:CDRH1(GYDFTHYGMN;配列番号:1)、CDRH2(WINTYTGEPTYAADFKR;配列番号:2)及びCDRH3(YPYYYGTSHWYFDV;配列番号:3)を含む重鎖可変ドメイン並びに次の軽鎖CDRアミノ酸配列:CDRL1(SASQDISNYLN;配列番号:4)、CDRL2(FTSSLHS;配列番号:5)及びCDRL3(QQYSTVPWT;配列番号:6)を含む軽鎖可変ドメインを有する、請求項4の方法。
- 前記抗VEGF抗体がY0317の重鎖可変ドメイン及び軽鎖可変ドメインを有する請求項5の方法。
- 前記抗VEGF抗体がラニビツマブである、請求項1から3の何れか一項の方法。
- 対応する遺伝子型がCCを含む請求項1の方法。
- 対応する遺伝子型がCTを含む請求項1の方法。
- 対応する遺伝子型がAAを含む請求項2の方法。
- 対応する遺伝子型がAGを含む請求項2の方法。
- 滲出性AMD患者が、rs1061170に対応するCFH Y402HアレルにおけるC/T遺伝子多型に特異的な第一のオリゴヌクレオチド及び第二のオリゴヌクレオチドを含む、ラニビツマブを用いた治療の利益を得る見込みが増加しているかどうかを予測するためのキット。
- 前記第一のオリゴヌクレオチド及び前記第二のオリゴヌクレオチドを、CFH Y402HアレルにおけるC/T遺伝子多型を含むCFH遺伝子の一部を増幅するために用いてもよい請求項12のキット。
- 滲出性AMD患者が、rs17216529に対応するC5 I802VアレルにおけるA/G遺伝子多型に特異的な第一のオリゴヌクレオチド及び第二のオリゴヌクレオチドを含む、抗VEGF抗体を用いた治療の利益を得る見込みが増加しているかどうかを予測するためのキット。
- 前記第一のオリゴヌクレオチド及び前記第二のオリゴヌクレオチドを、I802V C5アレルにおけるA/G遺伝子多型を含むCFH遺伝子の一部を増幅するために用いてもよい請求項14のキット。
- 滲出性AMD患者が、rs10490924に対応するHTRA1 A69SアレルにおけるG/T遺伝子多型に特異的な第一のオリゴヌクレオチド及び第二のオリゴヌクレオチドを含む、抗VEGF抗体を用いた治療の利益を得る見込みが増加しているかどうかを予測するためのキット。
- 前記第一のオリゴヌクレオチド及び前記第二のオリゴヌクレオチドを、HTRA1 A69SアレルにおけるA/G遺伝子多型を含むCFH遺伝子の一部を増幅するために用いてもよい請求項16のキット。
- 患者がAMDを発症する見込みが増加しているかどうかを予測する方法において、rs17216529に対応するC5I145Vアレルにおける前記患者から単離したサンプルの遺伝子多型のスクリーニングを含み、ここで、対応する遺伝子型がGG又はAGを含む場合、該患者は、AMDを発症する見込みが増加している方法。
- 対応する遺伝子型がGGを含む請求項18の方法。
- 対応する遺伝子型がAGを含む請求項18の方法。
- 患者が滲出性又はGA AMDを伴う非滲出性AMDを発症する見込みが増加しているかどうかを予測する方法において、rs17611に対応するC5 I802Vアレルにおける前記患者から単離したサンプルの遺伝子多型のスクリーニングを含み、ここで、対応する遺伝子型がアレルT(ile)含む場合、該患者は、AMDを発症する見込みが増加している方法。
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CN102203296A (zh) | 2011-09-28 |
EP2356250A2 (en) | 2011-08-17 |
DK2540843T3 (da) | 2014-09-01 |
BRPI0914368A2 (pt) | 2015-10-20 |
MX2011004763A (es) | 2011-06-01 |
HK1173751A1 (en) | 2013-05-24 |
PL2540843T3 (pl) | 2014-12-31 |
KR101719376B1 (ko) | 2017-03-23 |
WO2010054110A2 (en) | 2010-05-14 |
EP2540843A2 (en) | 2013-01-02 |
AU2009313475B2 (en) | 2016-06-02 |
EP2540843B1 (en) | 2014-07-02 |
CA2740242A1 (en) | 2010-05-14 |
KR20110081836A (ko) | 2011-07-14 |
EP2540843A3 (en) | 2013-05-29 |
ES2498274T3 (es) | 2014-09-24 |
CN102203296B (zh) | 2014-12-03 |
CN103333952B (zh) | 2015-07-29 |
JP5701216B2 (ja) | 2015-04-15 |
CN103333952A (zh) | 2013-10-02 |
SI2540843T1 (sl) | 2014-10-30 |
IL211995A (en) | 2014-04-30 |
AU2009313475A1 (en) | 2010-05-14 |
WO2010054110A3 (en) | 2010-08-19 |
IL211995A0 (en) | 2011-06-30 |
US20170159114A1 (en) | 2017-06-08 |
US20120003641A1 (en) | 2012-01-05 |
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