JP2019531070A - ツイスティッド・ガストルレーション・ポリペプチドおよびその用途 - Google Patents
ツイスティッド・ガストルレーション・ポリペプチドおよびその用途 Download PDFInfo
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Abstract
Description
本出願は、2016年9月15日付け出願の米国仮特許出願第62/395,088号(その全体を参照により本明細書に組み入れることとする)に基づく優先権の利益を主張するものである。
本出願は、ASCII形式で電子的に提出されている配列表を含み、その全体を参照により本明細書に組み入れることとする。該ASCIIコピーは2017年12月8日付けで作成されたものであり、APH-00125 SL.txtと称され、27,134バイトのサイズを有する。
i)本明細書に記載されているTWSG-Fc融合タンパク質またはポリペプチドをコードするポリヌクレオチドを含む細胞を準備(用意)すること、および
ii)該ポリヌクレオチドによりコードされるTWSG-Fc融合ポリペプチドの発現に適した条件下、該細胞を培養すること、および場合により、
iii)発現されたTWSG-Fc融合ポリペプチドを回収すること
を含む、TWSG-Fc融合タンパク質またはポリペプチドの製造方法を提供する。
1.概要
部分的には、本開示は、動物における鉄利用能ならびに赤血球および/またはヘモグロビンレベルの増加を促進するための新規のTWSGポリペプチドを提供する。TWSGは、トランスフォーミング増殖因子-β(TGF-β)、増殖分化因子(GDF)およびアクチビン/インヒビンをも含むスーパーファミリーにおけるリガンドの主要群である或る骨形成タンパク質(BMP)によるシグナル伝達を調節する分泌タンパク質である。このスーパーファミリーは、共通の配列要素および構造モチーフを共有する種々の増殖因子を含む。これらのタンパク質は、脊椎動物および無脊椎動物の両方において、胚形成中および生後に多種多様な細胞型に生物学的作用をもたらすことが公知である。該スーパーファミリーのメンバーはパターン形成および組織特異化において胚発生中に重要な機能を果たし、脂肪生成、筋形成、軟骨形成、心臓形成、造血、神経形成および上皮細胞分化を含む種々の分化過程に影響を及ぼしうる。TGF-βファミリーのメンバーの活性を操作することにより、生物における有意な生理的変化を引き起こすことがしばしば可能である。例えば、ピエジモンテセ(Piedimontese)およびベルジアンブルー(Belgian Blue)畜牛種は、ミオスタチン(MSTN; GDF8とも称される)をコードする遺伝子に機能喪失突然変異を含有し、これは筋肉量の顕著な増加を引き起こす。Grobetら, Nat Genet. 1997, 17(1):71-4。更に、ヒトにおいては、MSTNの不活性対立遺伝子は筋肉量の増加に関連しており、並外れた強度に関連していると報告されている。Schuelkeら, N Engl J Med 2004, 350:2682-8。
20:R89-92; Riderら, 2010, Biochem J 429:1-12)。現在のところ、TWSG/Tsgに結合することが示されている特異的リガンドはBMP2、BMP4およびBMP7である(Oelgeschlagerら, 2000, Nature 405:757-763; Changら, 2001, Nature 410:483-487; Zakinら, 2005, Development 132:2489-2499)。
ある態様においては、本発明は、例えば、野生型TWSGポリペプチドの断片、機能的変異体および修飾型を含むTWSGポリペプチド、例えば可溶性TWSGポリペプチドに関する。ある実施形態においては、TWSGポリペプチドは、対応野生型TWSGポリペプチドと同じ又は少なくとも1つの類似した生物学的活性を有する。例えば、本発明のTWSGポリペプチドはBMPリガンド(例えば、BMP2、BMP4、BMP6、BMP7またはBMP9)に結合し、その機能を抑制しうる。場合によっては、TWSGポリペプチドは鉄利用性、赤血球数および/または循環ヘモグロビン濃度を増加させる。TWSGポリペプチドの例には、1以上の配列変異を有するヒトTWSG前駆体ポリペプチド(配列番号1)、および1以上の配列変異を有する可溶性ヒトTWSGポリペプチド(例えば、配列番号8、9および13)が含まれる。
リーダー(シグナル)配列および3つの潜在的N結合型グリコシル化部位が下線で示されている。
ある態様においては、本発明は、本明細書に開示されているTWSGポリペプチドのいずれかをコードする単離および/または組換え核酸を提供する。配列番号2は、天然に存在するTWSG前駆体ポリペプチドをコードし、一方、配列番号14は可溶性TWSG融合タンパク質をコードする。本核酸は一本鎖または二本鎖でありうる。そのような核酸はDNAまたはRNA分子でありうる。これらの核酸は、例えば、TWSGポリペプチドの製造方法において、または直接的な治療剤として(例えば、遺伝子治療法において)使用されうる。
ある態様においては、本発明は、TWSGポリペプチドのアゴニストまたはアンタゴニストである化合物(物質)を特定するための本TWSGポリペプチド(例えば、可溶性変異体TWSGポリペプチド)の使用に関する。このスクリーニングにより特定された化合物は、インビボまたはインビトロで赤血球、ヘモグロビンおよび/または網状赤血球レベルを調節するそれらの能力を評価するために試験されうる。これらの化合物は、例えば動物モデルにおいて試験されうる。
ある実施形態においては、本発明のTWSGポリペプチドは、哺乳動物、例えば、げっ歯類および霊長類、特にヒト患者において赤血球レベルを増加させるために使用されうる。場合によりEPO受容体アクチベーターと組合されていてもよいTWSGポリペプチドは、無効赤血球生成の治療に有用でありうる。無効赤血球生成は、鉄動力学研究(Rickettsら, 1978, Clin Nucl Med 3:159-164)に基づいて当初は再生不良性貧血、出血または末梢溶血から区別されていたが、無効赤血球生成は、骨髄に存在する赤血球前駆体(赤芽球)の数を考慮した場合に予想されるものより成熟RBCの産生が低い貧血の多様な群を示す(Tannoら, 2010, Adv Hematol 2010:358283)。そのような貧血においては、成熟RBCの無効生成ゆえに、エリスロポエチンレベルの上昇にもかかわらず組織低酸素が持続する。エリスロポエチンレベルの上昇が赤芽球の大量増殖を引き起こして、治療用RBC輸血の非存在下でさえも髄外赤血球生成による脾腫(脾臓肥大)(Aizawaら, 2003, Am J Hematol 74:68-72)、赤芽球誘発性骨病理(Di Matteoら, 2008, J Biol Regul Homeost Agents 22:211-216)および組織鉄過剰を潜在的に招く悪循環が最終的に生じる(Pippardら, 1979, Lancet 2:819-821)。したがって、赤血球生成の有効性を高めることにより、TWSGポリペプチドは前記循環を破ることが可能であり、根底にある貧血だけでなく、エリスロポエチンレベルの関連合併症、脾腫、骨病理および組織鉄過剰を軽減しうる。TWSGポリペプチドは、貧血およびEPOレベルの上昇を含む無効赤血球生成、ならびに合併症、例えば脾腫、赤芽球誘発性骨病理および鉄過剰、ならびにそれらの付随病状を治療しうる。脾腫の場合、そのような病状には胸部または腹部疼痛ならびに細網内皮過形成が含まれる。髄外造血は脾臓だけでなく、髄外造血性偽腫瘍の形態で他の組織でも発生する可能性がある(Musallamら, 2012, Cold Spring Harb Perspect Med 2:a013482)。赤芽球誘発性骨病理の場合、付随病状には低骨密度、骨粗鬆症および骨痛が含まれる(Haidarら, 2011, Bone 48:425-432)。鉄過剰の場合、付随病状にはヘプシジン抑制および食事性鉄の過剰吸収(Musallamら, 2012, Blood Rev 26(Suppl 1):S16-S19)、多発性内分泌障害および肝線維症/肝硬変(Galanelloら, 2010, Orphanet J Rare Dis 5:11)ならびに鉄過剰心筋症(Lekawanvijitら, 2009, Can J Cardiol 25:213-218)が含まれる。
ある実施形態においては、本発明の化合物(例えば、TWSGポリペプチド)は、薬学的に許容される担体と共に製剤化される。例えば、TWSGポリペプチドは、単独で、または医薬製剤(治療用組成物)の成分として投与されうる。本化合物は、ヒトまたは獣医学における使用のための任意の簡便な方法で投与されるように製剤化されうる。
(実施例)
出願人らは、全長ヒトTWSG(図1、配列番号8)がそのC末端において最小リンカーでヒトIgG1 Fcドメイン(配列番号3)に結合されている可溶性TWSG融合タンパク質(TWSG-Fc)を構築した。TWSG-Fc(図2、配列番号9)は最初は、TWSG-FcのN-グリコシル化変異体と同様に、COS細胞における一過性トランスフェクションにより発現された(後記を参照されたい)。簡潔に説明すると、FuGENE(登録商標)6トランスフェクション試薬(Promega)を使用して、COS細胞(ATCC(登録商標))を、TWSG-Fcをコードするプラスミドで一晩トランスフェクトした。翌日、細胞をリン酸緩衝食塩水で洗浄し、無血清培地を加えた。72時間のインキュベーションの後、COS馴化培地を回収し、濾過し、MabSelect SuReカラム(GE Healthcare, UK)上にローディングした。融合タンパク質を0.1M グリシン(pH3.0)で溶出し、1Mトリス(pH8.0)を1:10の比で添加することにより、溶出画分を直ちに中和した。NanoDrop(商標)分光光度計(Thermo Fisher Scientific, Waltham, MA)を使用して、タンパク質を定量した。
(i)ミツバチメリチン(HBML)のリーダー配列:MKFLVNVALVFMVVYISYIYA(配列番号10);
(ii)組織プラスミノーゲンアクチベーター(TPA)のリーダー配列:MDAMKRGLCCVLLLCGAVFVSP(配列番号11);
(iii)天然ヒトTWSGのリーダー配列:MKLHYVAVLTLAILMFLTWLPESLS(配列番号12)。
表面プラズモン共鳴およびレポーター遺伝子アッセイによる後続の特徴づけのために、CHO細胞において発現されたヒトTWSG-Fcを以下のとおりに精製した。hTWSG-hFcを含有する馴化培地を濃縮し、濾過し、予めPBSで平衡化されたMAb SelectSuReカラムにローディングした。ついで樹脂をPBSで洗浄し、タンパク質を0.1M グリシン(pH3.5)で溶出した。タンパク質を含有する画分を5%(v/v)1Mトリス(pH8.0)で中和した。バッファーA(50mM Tris pH 8.0)およびB(50mM Tris、1M NaCl pH 8.0)で予め平衡化されたQ Sepharose FF 10mLカラム(GE Healthcare)上に溶出プールをローディングした。10% B(100mM NaCl)で洗浄し、ついで20% B(200mM NaCl)で溶出した。50mMアルギニン(pH7.22)を含有するPBSで平衡化されたHiLoad(商標)26/60 Superdex(GE Healthcare)でタンパク質を更に処理した。画分を分析用サイズ排除クロマトグラフィーにより評価し、そして90%を超える単量体を含有する画分をプールし、濃縮し、特徴づけした。サンプルの純度を分析用サイズ排除クロマトグラフィー、およびクーマシー染色を用いるSDS-PAGEにより評価した。分析は、該成熟タンパク質がCNKAL(配列番号15)のN末端配列を有することを示した。
過去の研究は、TWSGまたはその非哺乳類ホモログTsgがBMP2、BMP4およびBMP7に高いアフィニティで結合することを決定している(Oelgeschlagerら, 2000, Nature 405:757-763; Scottら, 2001, Nature 410:475-478; Changら, 2001, Nature 410:483-487)。これらの研究は、他のTGFβスーパーファミリーリガンドへのTWSG(またはTsg)の結合を系統的には評価していないため、本出願人らは表面プラズモン共鳴を用いて、そのような結合を調べ、特徴づけした。初期定性スクリーニングにおいて、組換えマウスTWSG(mTWSG; R&D Systems, Minneapolis, MN)をBIACORE(商標)CM5チップ上に共有結合により固定化し、社内で作製した又はR&D Systemsから入手した30個を超えるリガンドを捕捉mTWSG上に個々に注入して、室温でのそれらの結合の度合を特徴づけした。このスクリーニングの結果に基づいて、本出願人らは、選択されたリガンドを生理的温度でのヒトTWSG融合タンパク質への結合の定量的特徴づけに付した。この分析のために、TWSG-FcをCHO細胞において発現させ、実施例1に記載されているとおりに精製し、BIACORE(商標)チップ上で抗Fc抗体で捕捉し、37℃で以下のリガンドを使用する表面プラズモン共鳴により試験した。
レポーター遺伝子アッセイを用いて、BMP2、BMP4、BMP6、BMP7、BMP9およびBMP10によるシグナル伝達を抑制するヒトTWSG-Fcの能力を測定した。これらのアッセイは、pGL3 BRE(BMP応答要素)レポータープラスミド(Korchynskyiら, 2002, J Biol Chem 277:4883-4891)およびトランスフェクション効率を制御するためのウミシイタケ(Renilla)レポータープラスミド(pRLCMV)でトランスフェクトされたヒト神経膠芽腫(T98G)または肝細胞癌(HepG2)細胞株に基づく。Id1プロモーターからのBMP応答要素はpGL3 BREレポータープラスミドのプロモーター内に存在し、したがって、このベクターは、Smad1およびSmad5を介してシグナル伝達する因子に一般的に有用である。
慢性疾患、自己免疫疾患および感染に関連する炎症は貧血を促進する可能性があり、それに対しては、限られた治療選択肢しか存在しない(Roy, 2010, Hematology Am Soc Hematol Educ Program, 2010:276-80; Kwaan, 2011, Infect Disord Drug Targets 11:40-44)。トランスジェニックマウスモデルにより示されているとおり(Royら, 2007, Blood 109:4038-4044)、現在ではヘプシジン産生の上昇が炎症性貧血の主要原因とみなされている(Roy, 2010, Hematology Am Soc Hematol Educ Program, 2010:276-80; Ganzら, 2012, Biochim Biophys Acta 1823:1434-1443)。そしてBMP6はヘプシジン発現の重要な内因性調節因子であることが確認されている(Camaschella, 2009, Nat Genet 41:386-388; Meynardら, 2009, Nat Genet 41:478-481; Andriopoulosら, 2009, Nat Genet 41:482-487)。
本明細書中で挙げられている全ての刊行物および特許を、各個の刊行物または特許が参照により本明細書中に組み入れられると具体的かつ個別に示されている場合と同様に、参照により本明細書中に組み入れることとする。
Claims (100)
- ツイスティッド・ガストルレーション(TWSG)ポリペプチドおよびフラグメント結晶化可能領域(Fc)ポリペプチドを含むポリペプチド。
- TWSGポリペプチドがヒトまたは非ヒト脊椎動物TWSGポリペプチドである、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、配列番号2の核酸配列を含むポリヌクレオチドによりコードされうる、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、高度にストリンジェントな条件下、配列番号2の配列に相補的である核酸配列にハイブリダイズするポリヌクレオチドによりコードされうる、請求項1に記載のポリペプチド。
- 高度にストリンジェントな条件が、6×塩化ナトリウム/クエン酸ナトリウム(SSC)中、約65℃でのハイブリダイゼーション、およびそれに続く、0.2×SSC中、約65℃での洗浄を含む、請求項4に記載のポリペプチド。
- TWSGポリペプチドが、配列番号8の配列に対して少なくとも約80%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、配列番号8の配列に対して少なくとも約90%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、配列番号8の配列に対して少なくとも約95%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、配列番号8の配列に対して少なくとも約99%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドが配列番号8のアミノ酸配列を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドが、野生型TWSGポリペプチドと比較してアミノ酸置換を含む、請求項1に記載のポリペプチド。
- TWSGポリペプチドがシグナル配列を含む、請求項1〜11のいずれか1項に記載のポリペプチド。
- FcポリペプチドがIgG1、IgG2、IgG3、IgG4またはキメラIgGサブクラスに由来する、請求項1〜12のいずれか1項に記載のポリペプチド。
- Fcポリペプチドが、高度にストリンジェントな条件下、配列番号3、4、5、6または7のアミノ酸配列を含むポリペプチドをコードするポリヌクレオチドの配列に相補的である核酸配列にハイブリダイズするポリヌクレオチドによりコードされうる、請求項1〜13のいずれか1項に記載のポリペプチド。
- 高度にストリンジェントな条件が、6×塩化ナトリウム/クエン酸ナトリウム(SSC)中、約65℃でのハイブリダイゼーション、およびそれに続く、0.2×SSC中、約65℃での洗浄を含む、請求項14に記載のポリペプチド。
- Fcポリペプチドが、配列番号3、4、5、6または7の配列に対して少なくとも約80%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- Fcポリペプチドが、配列番号3、4、5、6または7の配列に対して少なくとも約90%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- Fcポリペプチドが、配列番号3、4、5、6または7の配列に対して少なくとも約95%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- Fcポリペプチドが、配列番号3、4、5、6または7の配列に対して少なくとも約99%同一であるアミノ酸配列を含む、請求項1に記載のポリペプチド。
- Fcポリペプチドが配列番号3、4、5、6または7のアミノ酸配列を含む、請求項1に記載のポリペプチド。
- Fcポリペプチドが、野生型Fcポリペプチドと比較して少なくとも1つのアミノ酸置換を含む、請求項1〜20のいずれか1項に記載のポリペプチド。
- ポリペプチドがTWSGポリペプチドとFcポリペプチドとの融合ポリペプチドである、請求項1〜21のいずれか1項に記載のポリペプチド。
- TWSGポリペプチドとFcポリペプチドとの間にリンカー配列を更に含む、請求項22に記載のポリペプチド。
- リンカー配列がX-(G)n-Y(式中、Xは存在しない、または少なくとも1つのアミノ酸残基、好ましくはTもしくはSであり、nは、少なくとも1の値を有する整数、好ましくは3または4であり、Yは存在しない、または少なくとも1つのアミノ酸残基、好ましくはSである)の構造を含む、請求項23に記載のポリペプチド。
- リンカー配列がTGGG(配列番号16)、SGGG(配列番号17)、TGGGG(配列番号18)、SGGGG(配列番号19)、GGGGS(配列番号20)、GGGG(配列番号21)またはGGGを含む、請求項24に記載のポリペプチド。
- リンカー配列がTGGG(配列番号16)を含む、請求項25に記載のポリペプチド。
- ポリペプチドが、配列番号14の配列に対して少なくとも約80%同一である核酸配列を含むポリヌクレオチドによりコードされうる、請求項22に記載のポリペプチド。
- ポリペプチドが、配列番号14の配列に対して少なくとも約90%同一である核酸配列を含むポリヌクレオチドによりコードされうる、請求項22に記載のポリペプチド。
- ポリペプチドが、配列番号14の配列に対して少なくとも約95%同一である核酸配列を含むポリヌクレオチドによりコードされうる、請求項22に記載のポリペプチド。
- ポリペプチドが、配列番号14の配列に対して少なくとも約99%同一である核酸配列を含むポリヌクレオチドによりコードされうる、請求項22に記載のポリペプチド。
- ポリペプチドが配列番号14の核酸配列によりコードされうる、請求項22に記載のポリペプチド。
- ポリペプチドが、高度にストリンジェントな条件下、配列番号14の配列に相補的である核酸配列にハイブリダイズするポリヌクレオチドによりコードされうる、請求項22に記載のポリペプチド。
- 高度にストリンジェントな条件が、6×塩化ナトリウム/クエン酸ナトリウム(SSC)中、約65℃でのハイブリダイゼーション、およびそれに続く、0.2×SSC中、約65℃での洗浄を含む、請求項32に記載のポリペプチド。
- 配列番号9または13の配列に対して少なくとも約80%同一であるアミノ酸配列を含む、請求項22に記載のポリペプチド。
- 配列番号9または13の配列に対して少なくとも約90%同一であるアミノ酸配列を含む、請求項22に記載のポリペプチド。
- 配列番号9または13の配列に対して少なくとも約95%同一であるアミノ酸配列を含む、請求項22に記載のポリペプチド。
- 配列番号9または13の配列に対して少なくとも約99%同一であるアミノ酸配列を含む、請求項22に記載のポリペプチド。
- 配列番号9のアミノ酸配列を含む、請求項22に記載のポリペプチド。
- 配列番号13のアミノ酸配列を含む、請求項22に記載のポリペプチド。
- アミノ酸配列が配列番号9における少なくとも1つのN結合グリコシル化部位において少なくとも1つのアミノ酸置換を含む、請求項22〜37のいずれか1項に記載のポリペプチド。
- ポリペプチドが少なくとも1つの骨形成タンパク質(BMP)に結合しうる、請求項1〜40のいずれか1項に記載のポリペプチド。
- ポリペプチドが、BMP2、BMP4、BMP6、BMP7およびBMP9から選択される少なくとも1つのBMPに結合しうる、請求項41に記載のポリペプチド。
- BMP2、BMP4、BMP6およびBMP7から選択されるBMPの少なくとも1つに多くとも1nM、0.5nMまたは0.33nMのKDで結合しうる、請求項41に記載のポリペプチド。
- BMP2、BMP4、BMP6およびBMP7に多くとも1nM、0.5nMまたは0.33nMのKDで結合しうる、請求項43に記載のポリペプチド。
- 結合が表面プラズモン共鳴により検出される、請求項41〜44のいずれか1項に記載のポリペプチド。
- 少なくとも1つのBMPを抑制しうる、請求項1〜45のいずれか1項に記載のポリペプチド。
- 少なくとも1つのBMPがBMP2、BMP4、BMP6およびBMP7から選択される、請求項46に記載のポリペプチド。
- ポリペプチドが、BMP4、BMP6およびBMP7から選択される少なくとも1つのBMPを多くとも5nMまたは3.7nMのIC50で抑制しうる、請求項46に記載のポリペプチド。
- ポリペプチドがBMP4、BMP6およびBMP7を多くとも5nMまたは3.7nMのIC50で抑制しうる、請求項48に記載のポリペプチド。
- ポリペプチドが、Smad 1および/またはSmad 5を介する細胞シグナル伝達の少なくとも1つの態様を抑制しうる、請求項46〜49のいずれか1項に記載のポリペプチド。
- 細胞シグナル伝達の少なくとも1つの態様の抑制が、細胞に基づくアッセイにより測定される、請求項50に記載のポリペプチド。
- 細胞に基づくアッセイが、pGL3 BREレポータープラスミドにおけるBMP応答要素を使用するインビトロアッセイである、請求項51に記載のポリペプチド。
- 請求項1〜52のいずれか1項に記載のポリペプチドを含む多量体ポリペプチド複合体。
- Fcポリペプチドが該多量体ポリペプチド複合体における少なくとも1つのポリペプチドと相互作用する、請求項53に記載の多量体ポリペプチド複合体。
- 多量体ポリペプチド複合体が二量体である、請求項53または54に記載の多量体ポリペプチド複合体。
- 多量体ポリペプチド複合体がホモ二量体である、請求項55に記載の多量体ポリペプチド複合体。
- 請求項1〜52のいずれか1項に記載のポリペプチドと薬学的に許容される担体とを含む組成物。
- 請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体と薬学的に許容される担体とを含む組成物。
- 請求項1〜52のいずれか1項に記載のポリペプチドまたは請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体をコードするポリヌクレオチド。
- ポリヌクレオチドがmRNA分子である、請求項59に記載のポリヌクレオチド。
- 請求項59または60に記載のポリヌクレオチドと薬学的に許容される担体とを含む組成物。
- 請求項59または60に記載のポリヌクレオチドに機能的に連結された少なくとも1つの調節配列を含むベクター。
- 請求項62に記載のベクターを発現する宿主細胞。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクター、および/または請求項63に記載の宿主細胞、および場合により投与装置を含むキット。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、および/または請求項59もしくは60に記載のポリヌクレオチドを発現または過剰発現するように操作された非ヒト動物。
- i)請求項59または60に記載のポリヌクレオチドを含む細胞を準備すること、および
ii)該ポリヌクレオチドによりコードされるTWSG-Fc融合ポリペプチドの発現に適した条件下、該細胞を培養すること
を含む、TWSG-Fc融合ポリペプチドの製造方法。 - iii)発現されたTWSG-Fc融合ポリペプチドを回収することを更に含む、請求項66に記載の製造方法。
- 細胞が哺乳類細胞である、請求項66または67に記載の製造方法。
- 哺乳類細胞がCHO細胞である、請求項68に記載の製造方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を投与することを含む、細胞、組織または器官におけるBMPシグナル伝達を抑制する方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象において赤血球および/もしくはヘモグロビンレベルを増加させる、または輸血依存(TD)を低減する方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象において鉄レベルを増加させる方法。
- 対象における鉄レベルの増加が脾臓においては生じるが、他の組織においては生じない、請求項72に記載の方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象における鉄過剰症の治療方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象における鉄過剰症の予防方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象におけるBMPシグナル伝達の調節不全の治療方法。
- 該調節不全の治療が対象における無効赤血球生成の治療を含む、請求項76に記載の方法。
- 該調節不全の治療が貧血、脾腫、赤芽球誘発性骨病理、鉄過剰症およびサラセミア症候群の治療を含む、請求項76に記載の方法。
- 請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターおよび/または請求項63に記載の宿主細胞を対象に投与することを含む、対象における貧血の治療方法。
- ツイスティッド・ガストルレーション(TWSG)ポリペプチドとフラグメント結晶化可能領域(Fc)ポリペプチドとを含む融合タンパク質を対象に投与することを含む、対象における貧血の治療方法。
- ツイスティッド・ガストルレーション(TWSG)ポリペプチドとフラグメント結晶化可能領域(Fc)ポリペプチドとを含む融合タンパク質を含む多量体ポリペプチド複合体を対象に投与することを含む、対象における貧血の治療方法。
- 多量体ポリペプチド複合体が二量体である、請求項81に記載の方法。
- 多量体ポリペプチド複合体がホモ二量体である、請求項82に記載の方法。
- 多量体ポリペプチド複合体がヘテロ二量体である、請求項82に記載の方法。
- 融合タンパク質が配列番号9の配列を含む、請求項80〜84のいずれか1項に記載の方法。
- 融合タンパク質が配列番号13の配列を含む、請求項80〜84のいずれか1項に記載の方法。
- 貧血が、遺伝性貧血、後天性貧血、慢性疾患または炎症の貧血、赤血球異形成貧血(I型およびII型)、鎌状赤血球貧血、遺伝性球状赤血球症、ピルビン酸キナーゼ欠乏関連貧血または巨赤芽球性貧血から選択される少なくとも1つである、請求項79〜86のいずれか1項に記載の方法。
- 投与が局所、経腸または非経口である、請求項70〜87のいずれか1項に記載の方法。
- 投与が経口または鼻腔内である、請求項70〜87のいずれか1項に記載の方法。
- 投与が静脈内、皮下、動脈内、腹腔内または筋肉内である、請求項70〜87のいずれか1項に記載の方法。
- 第2の薬剤または第2の治療行為を共に投与若しくは実施することを更に含む、請求項70〜87のいずれか1項に記載の方法。
- 第2の薬剤がEPOまたはそのアゴニストもしくは類似体である、請求項91に記載の方法。
- 第2の治療行為が輸血である、請求項91に記載の方法。
- 対象がヒトである、請求項71〜93のいずれか1項に記載の方法。
- 対象におけるBMPシグナル伝達の抑制、赤血球および/またはヘモグロビンレベルの増加、輸血依存(TD)の低減、鉄レベルの増加、鉄過剰症の治療または予防、あるいはBMPシグナル伝達の調節不全の治療のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞。
- 対象におけるBMPシグナル伝達の抑制、赤血球および/またはヘモグロビンレベルの増加、輸血依存(TD)の低減、鉄レベルの増加、鉄過剰症の治療または予防、あるいはBMPシグナル伝達の調節不全の治療のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞の使用。
- 対象におけるBMPシグナル伝達の調節不全に関連した疾患または障害の治療のための医薬の製造のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞の使用。
- 対象における貧血の治療のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞。
- 対象における貧血の治療のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞の使用。
- 対象における貧血の治療のための医薬の製造のための、請求項1〜52のいずれか1項に記載のポリペプチド、請求項53〜56のいずれか1項に記載の多量体ポリペプチド複合体、請求項59もしくは60に記載のポリヌクレオチド、請求項57、58もしくは61に記載の組成物、請求項62に記載のベクターまたは請求項63に記載の宿主細胞の使用。
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US20190218262A1 (en) | 2019-07-18 |
EP3512887A4 (en) | 2020-04-15 |
CN109996817A (zh) | 2019-07-09 |
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US20230234998A1 (en) | 2023-07-27 |
WO2018053234A1 (en) | 2018-03-22 |
AU2017325973A1 (en) | 2019-03-07 |
JP2022116031A (ja) | 2022-08-09 |
CA3036104A1 (en) | 2018-03-22 |
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