JP2017528523A - 線維性疾患の治療 - Google Patents
線維性疾患の治療 Download PDFInfo
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Abstract
Description
本願は、2014年9月16日に出願された米国特許仮出願第62/051,026号の優先権恩典を主張する。米国特許仮出願第62/051,026号は、その全体が参照により本明細書に組み入れられる。
本発明の分野は、概して、RSPO、特に、ヒトRSPO1、RSPO2、およびRSPO3に結合する抗体および他の作用物質を含むが、これに限定されないRSPOアンタゴニストおよびLGRアンタゴニスト、ならびに線維性疾患を治療するためにRSPOアンタゴニストおよび/またはLGRアンタゴニストを使用する方法に関する。
線維症は、先進国世界における死亡のほぼ45%に直接的または間接的に寄与すると見積もられている。線維性疾患は、生理学的組織構造を破壊する細胞外マトリックス成分が過剰に蓄積し、これにより患部臓器が機能不全になることを特徴とする。ある場合では、線維症は慢性的な組織過敏または慢性炎症の結果だと考えられている。ある場合では、線維症は体内での自己免疫反応の結果であると考えられている。強皮症、肺線維症、および肝臓の硬変などの線維性疾患では、徐々に進行する実質組織から細胞外マトリックス成分への置き換わりが観察される。しかしながら、線維カスケードを維持する細胞性因子および分子性因子はまだ十分に理解されていない。
本発明は、治療的有効量のRPSOアンタゴニストおよび/またはLGRアンタゴニスト、例えば、抗RSPO抗体、抗LGR抗体、または可溶性LGR受容体を対象に投与する工程を含む、対象において線維性疾患を治療するための方法を提供する。
(a)
TGYTMH(SEQ ID NO:5)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3を含む、方法を提供する。
(a)
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3を含む、方法を提供する。
(a)
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
を含む軽鎖CDR2、および
を含む軽鎖CDR3を含む、方法を提供する。
本発明は、線維性疾患を治療するための、および創傷治癒に起因する瘢痕を減らすための新規の方法を提供する。本発明は、治療的有効量のヒトRSPOアンタゴニストまたはLGRアンタゴニストを対象に投与する工程を含む、対象における線維性疾患を治療または予防する方法を提供する。前記方法は、RSPO結合物質および/またはLGR結合物質、特に、抗RSPO1抗体、抗RSPO2抗体、抗RSPO3抗体、抗LGR5抗体、またはLGR5-Fc可溶性受容体を、その必要のある対象に投与する工程を含む。RSPO結合物質およびLGR結合物質には、RSPOタンパク質相互作用およびLGRタンパク質相互作用の阻害剤が含まれるが、これに限定されない。
本発明の理解を容易にするために、多数の用語および句を以下で定義する。
本発明は、線維性疾患を予防および/または治療するための方法を提供する。一部の態様において、方法は、本明細書に記載のRSPO結合物質および/またはLGR結合物質(例えば、抗体または可溶性受容体)を使用する工程を含む。ある特定の態様において、RSPO結合物質は、ヒトRSPO1、RSPO2、RSPO3、および/またはRSPO4のアンタゴニストである。ある特定の態様において、LGR結合物質は、ヒトLGR4、LGR5、および/またはLGR6のアンタゴニストである。前記方法はインビトロ方法でもよくエクスビボ方法でもよくインビボ方法でもよい。本発明はまた、線維性疾患を治療するための医薬を製造するための本明細書に記載のRSPO結合物質またはLGR結合物質(例えば、抗体または可溶性受容体)の使用も提供する。
TGYTMH(SEQ ID NO:5)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO1抗体を対象に投与する工程を含み、抗RSPO1抗体は、SEQ ID NO:11と少なくとも90%の配列同一性を有する重鎖可変領域、およびSEQ ID NO:12と少なくとも90%の配列同一性を有する軽鎖可変領域を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO1抗体を対象に投与する工程を含み、抗RSPO1抗体は、SEQ ID NO:56と少なくとも90%の配列同一性を有する重鎖可変領域、およびSEQ ID NO:57と少なくとも90%の配列同一性を有する軽鎖可変領域を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO1抗体を対象に投与する工程を含み、抗RSPO1抗体は、SEQ ID NO:11の重鎖可変領域およびSEQ ID NO:12の軽鎖可変領域を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO1抗体を対象に投与する工程を含み、抗RSPO1抗体は、SEQ ID NO:56の重鎖可変領域およびSEQ ID NO:57の軽鎖可変領域を含む。一部の態様において、抗RSPO1抗体は抗体89M5のヒト化バージョンである。一部の態様において、抗RSPO1抗体は抗体h89M5-H8L5である。一部の態様において、抗RSPO1抗体は抗体h89M5-H2L2である。
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO2抗体を対象に投与する工程を含み、抗RSPO2抗体は、SEQ ID NO:27と少なくとも90%の配列同一性を有する重鎖可変領域、およびSEQ ID NO:28またはSEQ ID NO:66と少なくとも90%の配列同一性を有する軽鎖可変領域を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO2抗体を対象に投与する工程を含み、抗RSPO2抗体は、SEQ ID NO:27の重鎖可変領域およびSEQ ID NO:28またはSEQ ID NO:66の軽鎖可変領域を含む。一部の態様において、抗RSPO2抗体は抗体130M23のヒト化バージョンである。一部の態様において、抗RSPO2抗体は抗体h130M23-H1L6である。一部の態様において、抗RSPO2抗体は抗体h130M23-H1L2である。
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3、ならびに
を含む軽鎖CDR1、
を含む軽鎖CDR2、および
を含む軽鎖CDR3を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO3抗体を対象に投与する工程を含み、抗RSPO3抗体は、SEQ ID NO:46と少なくとも90%の配列同一性を有する重鎖可変領域およびSEQ ID NO:47と少なくとも90%の配列同一性を有する軽鎖可変領域を含む。一部の態様において、線維性疾患を治療または予防する方法は、治療的有効量の抗RSPO3抗体を対象に投与する工程を含み、抗RSPO3抗体は、SEQ ID NO:46の重鎖可変領域およびSEQ ID NO:47の軽鎖可変領域を含む。一部の態様において、抗RSPO3抗体は抗体131R010である。
本発明は、ヒトRSPOタンパク質またはヒトLGRタンパク質に特異的に結合する作用物質を含む方法を提供する。これらの作用物質は、それぞれ、本明細書において「RSPO結合物質」および「LGR結合物質」と呼ばれる。RSPO結合物質およびLGR結合物質の非限定的な例は、米国特許出願公開第2006/0275870号、同第2009/0074782号、同第2009/0191205号、同第2009/0220495号、同第2010/0071078号、同第2012/0039912号、同第2012/0263730号、同第2013/0095116号、同第2013/0336885号、同第2013/0337533号、同第2014/0017253号、同第2014/0302054号、同第2015/0147333、および国際公開番号WO2010/016766、WO2014/012007、WO2014/192974において見られる。一部の態様において、RSPO結合物質は抗体である。一部の態様において、RSPO結合物質はポリペプチドである。ある特定の態様において、RSPO結合物質はRSPO1に結合する(「RSPO1結合物質」)。ある特定の態様において、RSPO結合物質はRSPO2に結合する(「RSPO2結合物質」)。ある特定の態様において、RSPO結合物質はRSPO3に結合する(「RSPO3結合物質」)。ある特定の態様において、RSPO結合物質は1種類または複数種類のヒトRSPOタンパク質に特異的に結合する。ヒトRSPO1、RSPO2、RSPO3、およびRSPO4の完全長アミノ酸(aa)配列は当技術分野において公知であり、本明細書において、SEQ ID NO:1(RSPO1)、SEQ ID NO:2(RSPO2)、SEQ ID NO:3(RSPO3)、およびSEQ ID NO:4(RSPO4)と示される。一部の態様において、RSPO結合物質は可溶性受容体である。一部の態様において、RSPO結合物質は、ヒトLGRタンパク質の細胞外ドメインまたはその断片を含む可溶性受容体である。一部の態様において、ヒトLGRタンパク質はLGR4、LGR5、またはLGR6である。ヒトLGR4、LGR5、およびLGR6の完全長アミノ酸(aa)配列は当技術分野において公知であり、本明細書において、SEQ ID NO:71(LGR4)、SEQ ID NO:72(LGR5)、およびSEQ ID NO:73(LGR6)と示される。
TGYTMH(SEQ ID NO:5)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3を含む、方法を提供する。一部の態様において、RSPO1結合物質は、
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3をさらに含む。一部の態様において、RSPO1結合物質は、
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3を含む。ある特定の態様において、RSPO1結合物質は、
(a)
TGYTMH(SEQ ID NO:5)を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3
を含む。
(a)
TGYTMH(SEQ ID NO:5)を含む重鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(b)
を含む重鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(c)
を含む重鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(d)
を含む軽鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(e)
WASTRHT(SEQ ID NO:9)を含む軽鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;および
(f)
QQHYSTPW(SEQ ID NO:10)を含む軽鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種を含む、方法を提供する。ある特定の態様において、アミノ酸置換は保存的置換である。一部の態様において、置換は生殖系列ヒト化プロセスの一環としてなされる。
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3を含む、方法を提供する。一部の態様において、RSPO2結合物質は、
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3をさらに含む。一部の態様において、RSPO2結合物質は、
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3を含む。ある特定の態様において、RSPO2結合物質は、
(a)
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3を含む。
(a)
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(b)
を含む重鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(c)
を含む重鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(d)
を含む軽鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(e)
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;および
(f)
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種を含む、方法を提供する。ある特定の態様において、アミノ酸置換は保存的置換である。一部の態様において、置換は生殖系列ヒト化プロセスの一環としてなされる。
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3
を含む、方法を提供する。一部の態様において、RSPO3結合物質は、
を含む軽鎖CDR1、
を含む軽鎖CDR2、および
を含む軽鎖CDR3
をさらに含む。一部の態様において、RSPO3結合物質は、
を含む軽鎖CDR1、
を含む軽鎖CDR2、および
を含む軽鎖CDR3を含む。ある特定の態様において、RSPO3結合物質は、
(a)
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、
を含む重鎖CDR2、および
TYFANNFD(SEQ ID NO:39)
を含む重鎖CDR3;ならびに
(b)
を含む軽鎖CDR1、
AASNLES (SEQ ID NO:42)
を含む軽鎖CDR2、および
を含む軽鎖CDR3を含む。
(a)
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(b)
を含む重鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(c)
を含む重鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(d)
を含む軽鎖CDR1、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;
(e)
を含む軽鎖CDR2、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種;および
(f)
を含む軽鎖CDR3、または1個、2個、3個、もしくは4個のアミノ酸置換を含む、その変種を含む、方法を提供する。ある特定の態様において、アミノ酸置換は保存的置換である。一部の態様において、置換は生殖系列ヒト化プロセスの一環としてなされる。
ある特定の態様において、本発明は、少なくとも1種類のヒトRSPOタンパク質または少なくとも1種類のヒトLGRタンパク質に特異的に結合するポリペプチド(またはポリペプチドの断片)をコードするポリヌクレオチドを含むポリヌクレオチドを包含する。「ポリペプチドをコードするポリヌクレオチド」という用語は、ポリペプチドのコード配列しか含まないポリヌクレオチド、ならびにさらなるコード配列および/または非コード配列を含むポリヌクレオチドを包含する。例えば、一部の態様において、本発明は、ヒトRSPOタンパク質に対する抗体をコードするか、またはこのような抗体の断片(例えば、抗原結合部位を含む断片)をコードするポリヌクレオチド配列を含むポリヌクレオチドを提供する。一部の態様において、本発明は、ヒトLGRタンパク質に対する抗体をコードするか、またはこのような抗体の断片(例えば、抗原結合部位を含む断片)をコードするポリヌクレオチド配列を含むポリヌクレオチドを提供する。本発明のポリヌクレオチドはRNAの形をとってもよく、DNAの形をとってもよい。DNAはcDNA、ゲノムDNA、および合成DNAを含み、二本鎖でも一本鎖でもよく、一本鎖であればコード鎖でもよく非コード(アンチセンス)鎖でもよい。
本発明は、本明細書に記載のRSPO結合物質またはLGR結合物質(例えば、抗体または可溶性受容体)を備え、本明細書に記載の方法を実施するのに使用することができるキットを提供する。ある特定の態様において、キットは、1つまたは複数の容器の中に、少なくとも1種類のヒトRSPOタンパク質に対する少なくとも1種類の精製された抗体を含む。ある特定の態様において、キットは、1つまたは複数の容器の中に、少なくとも1種類のヒトLGRタンパク質に対する少なくとも1種類の精製された抗体を含む。ある特定の態様において、キットは、1つまたは複数の容器の中に、少なくとも1種類のヒトRSPOタンパク質に結合する少なくとも1種類の精製された可溶性受容体を含む。一部の態様において、キットは、全対照を含む、検出アッセイを実施するのに必要および/または十分な成分、アッセイを実施するための指示、ならびに分析するための、および結果を提示するための任意の必要なソフトウェアを全て備える。当業者は、本発明の開示されたRSPO結合物質および/またはLGR結合タンパク質を、当技術分野において周知の確立したキットの形式の1つに容易に組み入れることができることを容易に認識する。
肺線維症モデル
マウスモデルにおける肺線維症の誘導は、Baran et al., 2011, Am. J. Respir. Cell Mol. Biol., 45:999-1006およびDakhlallah et al., 2013, Am J. Respir. Crit. Care Med., 187:397-405に記載されている。おおむね、このモデルに従った。簡単に述べると、6〜8週齢C57BL/6Nマウスに0.035U/gブレオマイシンまたはビヒクル(食塩水)を腹腔内注射した。1日目、4日目、9日目、12日目、15日目、18日目、22日目、25日目、29日目、および32日目に、0.9%NaClに溶解した濃度が7U/mlのブレオマイシン100μlをマウスに投与した。9日目、16日目、22日目、29日目、および33日目に、5匹の代表的なマウスを安楽死させた。肺からの組織断片を遺伝子発現分析のために収集した。残った肺組織にはホルマリンを灌流し、組織学的分析のために保管した。
皮膚線維症モデル
ブレオマイシンを用いたマウスモデルにおける皮膚線維症の誘導は、Distler et al., 2007, Arthritis & Rheumatism, 56(1):311-322に記載されている。おおむね、このモデルに従った。簡単に述べると、6〜8週齢マウスの上背の規定された領域にブレオマイシンを皮下注射で注射した。注射部位領域は大きさが約1cm2であり、マウス背中の背側外側領域(脊髄から約2cm側方)に位置する。一匹のマウスにつき2箇所の注射部位があった。1日目、3日目、5日目、8日目、および10日目に、0.9%NaClに溶解した濃度が0.5mg/mlのブレオマイシン100μlを投与した。2日目、5日目、8日目、および12日目に、4匹の代表的なマウスを安楽死させた。注射部位からの組織断片を遺伝子発現分析のために収集し、組織学的分析のためにホルマリン固定した。
ブレオマイシンによる皮膚病変部の誘導に対する抗RSPO抗体の効果
前記の実施例2に記載のようにマウスに皮膚線維症を誘導した。6〜8週齢マウスの上背の2カ所の規定された領域にブレオマイシンを皮下注射で注射した。1日目、3日目、5日目、8日目、および10日目に、0.9%NaClに溶解した濃度が0.5mg/mlのブレオマイシン100μlを投与した。1日目および8日目に、対照抗体1B7.11、抗RSPO2抗体130M23、抗RSPO3抗体131R010、または抗RSPO2抗体130M23と抗RSPO3抗体131R010の組み合わせを25mg/kgの用量で投与した。対照抗体群では4匹のマウスを治療し、それぞれの抗RSPO抗体群では8匹のマウスを治療した。
シグナル配列があるヒトRSPO1アミノ酸配列(SEQ ID NO:1)
シグナル配列があるヒトRSPO2アミノ酸配列(SEQ ID NO:2)
シグナル配列があるヒトRSPO3アミノ酸配列(SEQ ID NO:3)
シグナル配列があるヒトRSPO4アミノ酸配列(SEQ ID NO:4)
89M5重鎖CDR1(SEQ ID NO:5)
TGYTMH
89M5重鎖CDR2(SEQ ID NO:6)
89M5重鎖CDR3(SEQ ID NO:7)
89M5軽鎖CDR1(SEQ ID NO:8)
89M5軽鎖CDR2(SEQ ID NO:9)
WASTRHT
89M5軽鎖CDR3(SEQ ID NO:10)
QQHYSTPW
h89M5-H8L5重鎖可変領域アミノ酸配列(SEQ ID NO:11)
h89M5-H8L5軽鎖可変領域アミノ酸配列(SEQ ID NO:12)
下線を引いた推定シグナル配列があるh89M5-H8L5重鎖アミノ酸配列(SEQ ID NO:13)
推定シグナル配列がないh89M5-H8L5重鎖アミノ酸配列(SEQ ID NO:14)
下線を引いた推定シグナル配列があるh89M5-H8L5軽鎖アミノ酸配列(SEQ ID NO:15)
推定シグナル配列がないh89M5-H8L5軽鎖アミノ酸配列(SEQ ID NO:16)
h89M5-H8L5重鎖可変領域ヌクレオチド配列(SEQ ID NO:17)
h89M5-H8L5軽鎖可変領域ヌクレオチド配列(SEQ ID NO:18)
h89M5-H8L5重鎖ヌクレオチド配列(SEQ ID NO:19)
h89M5-H8L5軽鎖ヌクレオチド配列(SEQ ID NO:20)
130M23重鎖CDR1(SEQ ID NO:21)
SSYAMS
130M23重鎖CDR2(SEQ ID NO:22)
130M23重鎖CDR3(SEQ ID NO:23)
130M23軽鎖CDR1(SEQ ID NO:24)
130M23軽鎖CDR2(SEQ ID NO:25)
WASTRHT
130M23軽鎖CDR3(SEQ ID NO:26)
QQHYSTP
h130M23-H1L6重鎖可変領域アミノ酸配列(SEQ ID NO:27)
h130M23-H1L6軽鎖可変領域アミノ酸配列(SEQ ID NO:28)
下線を引いた推定シグナル配列があるh130M23-H1L6重鎖アミノ酸配列(SEQ ID NO:29)
推定シグナル配列がないh130M23-H1L6重鎖アミノ酸配列(SEQ ID NO:30)
下線を引いた推定シグナル配列があるh130M23-H1L6軽鎖アミノ酸配列(SEQ ID NO:31)
推定シグナル配列がないh130M23-H1L6軽鎖アミノ酸配列(SEQ ID NO:32)
h130M23-H1L6重鎖可変領域ヌクレオチド配列(SEQ ID NO:33)
h130M23-H1L6軽鎖可変領域ヌクレオチド配列(SEQ ID NO:34)
h130M23-H1L6重鎖ヌクレオチド配列(SEQ ID NO:35)
h130M23-H1L6軽鎖ヌクレオチド配列(SEQ ID NO:36)
131R010重鎖CDR1(SEQ ID NO:37)
DYSIH
131R010重鎖CDR2(SEQ ID NO:38)
131R010重鎖CDR3(SEQ ID NO:39)
TYFANNFD
131R010別の重鎖CDR3(SEQ ID NO:40)
131R010軽鎖CDR1(SEQ ID NO:41)
131R010軽鎖CDR2(SEQ ID NO:42)
AASNLES
131R010別の軽鎖CDR2(SEQ ID NO:43)
AAS
131R010軽鎖CDR3(SEQ ID NO:44)
131R010別の軽鎖CDR3(SEQ ID NO:45)
131R010重鎖可変領域アミノ酸配列(SEQ ID NO:46)
131R010軽鎖可変領域アミノ酸配列(SEQ ID NO:47)
下線を引いた推定シグナル配列がある131R010重鎖アミノ酸配列(SEQ ID NO:48)
推定シグナル配列がない131R010重鎖アミノ酸配列(SEQ ID NO:49)
下線を引いた推定シグナル配列がある131R010軽鎖アミノ酸配列(SEQ ID NO:50)
推定シグナル配列がない131R010軽鎖アミノ酸配列(SEQ ID NO:51)
131R010重鎖可変領域ヌクレオチド配列(SEQ ID NO:52)
131R010軽鎖可変領域ヌクレオチド配列(SEQ ID NO:53)
131R010重鎖ヌクレオチド配列(SEQ ID NO:54)
131R010軽鎖ヌクレオチド配列(SEQ ID NO:55)
h89M5-H2L2重鎖可変領域アミノ酸配列(SEQ ID NO:56)
h89M5-H2L2軽鎖可変領域アミノ酸配列(SEQ ID NO:57)
下線を引いた推定シグナル配列があるh89M5-H2L2重鎖アミノ酸配列(SEQ ID NO:58)
推定シグナル配列がないh89M5-H2L2重鎖アミノ酸配列(SEQ ID NO:59)
下線を引いた推定シグナル配列があるh89M5-H2L2軽鎖アミノ酸配列(SEQ ID NO:60)
推定シグナル配列がないh89M5-H2L2軽鎖アミノ酸配列 (SEQ ID NO:61)
h89M5-H2L2重鎖可変領域ヌクレオチド配列(SEQ ID NO:62)
h89M5-H2L2軽鎖可変領域ヌクレオチド配列(SEQ ID NO:63)
h89M5-H2L2重鎖ヌクレオチド配列(SEQ ID NO:64)
h89M5-H2L2軽鎖ヌクレオチド配列(SEQ ID NO:65)
h130M23-H1L2軽鎖可変領域アミノ酸配列(SEQ ID NO:66)
下線を引いた推定シグナル配列があるh130M23-H1L2軽鎖アミノ酸配列(SEQ ID NO:67)
下線を引いた推定シグナル配列がないh130M23-H1L2軽鎖アミノ酸配列(SEQ ID NO:68)
h130M23-H1L2軽鎖可変領域ヌクレオチド配列(SEQ ID NO:69)
h130M23-H1L2軽鎖ヌクレオチド配列(SEQ ID NO:70)
ヒトLGR4タンパク質配列(SEQ ID NO:71)
ヒトLGR5タンパク質配列(SEQ ID NO:72)
ヒトLGR6タンパク質配列(SEQ ID NO:73)
LGR5 ECDアミノ酸22〜564(SEQ ID NO:74)
LGR5-Fcタンパク質配列(SEQ ID NO:75)
ヒトIgG1Fc領域(SEQ ID NO:76)
ヒトIgG1Fc領域(SEQ ID NO:77)
ヒトIgG1Fc領域(SEQ ID NO:78)
ヒトIgG1Fc領域(SEQ ID NO:79)
ヒトIgG2Fc領域(SEQ ID NO:80)
Claims (20)
- 治療的有効量のヒトR-スポンジン(RSPO)アンタゴニストまたはLGRアンタゴニストを対象に投与する工程を含む、対象における線維性疾患を治療または予防する方法。
- RSPOアンタゴニストまたはLGRアンタゴニストが抗体である、請求項1記載の方法。
- 前記抗体が、ヒトRSPO3、ヒトRSPO2、ヒトRSPO1、またはヒトRSPO4からなる群より選択される少なくとも1種類のRSPOタンパク質に特異的に結合する、請求項2記載の方法。
- 前記抗体がRSPO3に特異的に結合し、かつ
(a)
DYSIH(SEQ ID NO:37)
を含む重鎖CDR1、
を含む重鎖CDR2、および
TYFANNFD(SEQ ID NO:39)
を含む重鎖CDR3、ならびに
を含む軽鎖CDR1、
AASNLES(SEQ ID NO:42)
を含む軽鎖CDR2、および
を含む軽鎖CDR3;
(b)
SEQ ID NO:46と少なくとも90%の配列同一性を有する重鎖可変領域およびSEQ ID NO:47と少なくとも90%の配列同一性を有する軽鎖可変領域;または
(c)
SEQ ID NO:46の重鎖可変領域およびSEQ ID NO:47の軽鎖可変領域
を含む、請求項2または請求項3記載の方法。 - 前記抗体がRSPO2に特異的に結合し、かつ
(a)
SSYAMS(SEQ ID NO:21)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3、ならびに
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:25)
を含む軽鎖CDR2、および
QQHYSTP(SEQ ID NO:26)
を含む軽鎖CDR3;
(b)
SEQ ID NO:27と少なくとも90%の配列同一性を有する重鎖可変領域およびSEQ ID NO:28もしくはSEQ ID NO:66と少なくとも90%の配列同一性を有する軽鎖可変領域;または
(c)SEQ ID NO:27の重鎖可変領域およびSEQ ID NO:28もしくはSEQ ID NO:66の軽鎖可変領域
を含む、請求項2または請求項3記載の方法。 - 前記抗体がRSPO1に特異的に結合し、かつ
(a)
TGYTMH(SEQ ID NO:5)
を含む重鎖CDR1、
を含む重鎖CDR2、および
を含む重鎖CDR3、ならびに
を含む軽鎖CDR1、
WASTRHT(SEQ ID NO:9)
を含む軽鎖CDR2、および
QQHYSTPW(SEQ ID NO:10)
を含む軽鎖CDR3;
(b)
SEQ ID NO:11と少なくとも90%の配列同一性を有する重鎖可変領域およびSEQ ID NO:12と少なくとも90%の配列同一性を有する軽鎖可変領域、もしくはSEQ ID NO:56と少なくとも90%の配列同一性を有する重鎖可変領域およびSEQ ID NO:57と少なくとも90%の配列同一性を有する軽鎖可変領域;または
(c)
SEQ ID NO:11の重鎖可変領域およびSEQ ID NO:12の軽鎖可変領域、もしくはSEQ ID NO:56の重鎖可変領域およびSEQ ID NO:57の軽鎖可変領域
を含む、請求項2または請求項3記載の方法。 - 前記抗体が少なくとも1種類のヒトLGRタンパク質に特異的に結合する、請求項2記載の方法。
- 前記抗体が、LGR4、LGR5、およびLGR6からなる群より選択される少なくとも1種類のヒトLGRタンパク質に特異的に結合する、請求項7記載の方法。
- 前記抗体が、組換え抗体、モノクローナル抗体、キメラ抗体、単一特異性抗体、二重特異性抗体、ヒト化抗体、ヒト抗体、IgG1抗体、IgG2抗体、または抗原結合部位を含む抗体断片である、請求項2〜8のいずれか一項記載の方法。
- RSPOアンタゴニストまたはLGRアンタゴニストが、ヒトLGRタンパク質の細胞外ドメインを含む可溶性受容体であり、該細胞外ドメインがヒトRSPOタンパク質に結合することができる、請求項1記載の方法。
- ヒトLGRタンパク質がLGR5である、請求項10記載の方法。
- ヒトLGRタンパク質の細胞外ドメインがヒトLGR5のアミノ酸22〜564(SEQ ID NO:74)を含む、請求項10または請求項11記載の方法。
- 前記可溶性受容体が非LGRポリペプチドを含む、請求項10〜12のいずれか一項記載の方法。
- 非LGRポリペプチドがヒトFc領域を含む、請求項13記載の方法。
- 非LGRポリペプチドがSEQ ID NO:76、SEQ ID NO:77、SEQ ID NO:78、SEQ ID NO:79、またはSEQ ID NO:80を含む、請求項13または請求項14記載の方法。
- 少なくとも1種類のさらなる治療剤の投与を含む、請求項1〜15のいずれか一項記載の方法。
- さらなる治療剤が第2の抗体または抗炎症剤である、請求項16記載の方法。
- 線維性疾患が、肺線維症、腎線維症、肝線維症、皮膚線維症、心臓線維症、および癒着からなる群より選択される、請求項1〜17のいずれか一項記載の方法。
- 皮膚線維症が、強皮症、全身性硬化症、強皮症様疾患、皮膚硬化のない強皮症(sine scleroderma)、ケロイド形成、または肥厚性瘢痕である、請求項18記載の方法。
- 腎線維症が慢性腎疾患である、請求項18記載の方法。
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