JP6290845B2 - 補体活性化の阻害剤 - Google Patents
補体活性化の阻害剤 Download PDFInfo
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- JP6290845B2 JP6290845B2 JP2015203735A JP2015203735A JP6290845B2 JP 6290845 B2 JP6290845 B2 JP 6290845B2 JP 2015203735 A JP2015203735 A JP 2015203735A JP 2015203735 A JP2015203735 A JP 2015203735A JP 6290845 B2 JP6290845 B2 JP 6290845B2
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Description
APの活性化は異種表面上で生じ、C3の緩徐の自然加水分解及び機能的C3転換酵素C3bBbを形成するためのプロパージン因子、B因子及びD因子の活性によって引き起こされる。APはまた、2つの他の経路の増幅経路(増幅ループ)として機能する。近頃、代替の酵素アセンブリーがプロパージンの標的表面への非共有結合によって開始され得ることもまた示された。一方、CPの活性化は、C1qが抗原と複合体を形成して免疫グロブリンに結合する場合に開始され、Clq結合セリンプロテアーゼC1r及びC1sの活性化を誘発する。C1sは、C4及びC2を切断して活性化し、CPC3転換酵素C4b2aを形成する。LCPは、例えば、微生物の表面上でマンノース結合レクチン(MBL)又はフィコリンが炭水化物又はアセチル化化合物の制限型に結合する場合又は臨死の宿主細胞上に曝露される場合に活性化される。結合セリンプロテアーゼMASP-2はリガンドに結合すると、C4及びC2を活性化し切断し、LCPC3転換酵素C4b2aを形成する。MASP-1の機能は、C2のMASP-2切断の安定化を含み、C3の低度の切断を指示すると示唆されている。しかしながら、他の研究は、MASP-1及びMASP-2の機能及び活性をプロトロンビン、フィブリノゲン及び第XIII因子を含む凝固系クロストークと関連付けている。MASP1/3ノックアウトマウスを使用して、実際にMASP-1が補体活性に寄与することが近頃示された。極最近に発見されたMBL結合セリンプロテアーゼMASP-3の正確な機能は、解明されていない。MASP-3が制限範囲のMBLオリゴマーと結合し、MASP-3及び低分子MBL結合タンパク質(sMAP)がMBL依存性LCP補体活性化の制御又は抑制に関与することを示す研究が報告されている。
本発明の実施形態は、炎症、アポトーシス、自己免疫、凝固、及び/又は血栓性又は凝固障害関連疾患と関連した病状の治療に適したポリペプチドを供することを目的とする。本発明のポリペプチドはさらに、これらの徴候の診断及び/又は予後診断、及び癌等の悪性疾患に適したバイオマーカーとなり得る。
a) 生物試料を得る工程;
b) 生物試料を本発明抗体と接触させる工程;
c) 抗体とポリペプチドとの複合体が存在する場合、試料中のポリペプチドの存在の指標として、当該複合体を検出する工程、
を含む。
a) 生物試料を得る工程;
b) 生物試料を本発明の核酸プローブと接触させる工程;
c) 核酸プローブとポリペプチドをコードする核酸との複合体が存在する場合、試料におけるポリペプチドをコードする核酸の存在の指標として、当該複合体を検出する工程、
を含む。
本願明細書において用語「フィコリン結合ポリペプチド」とは、天然のヒトフィコリン結合タンパク質(FAP)(配列番号 1)のアミノ酸配列20-380又は配列番号9の16-363のアミノ酸配列を含む任意のタンパク質又はポリペプチド、それらの機能的変異体、機能的切断型、及び機能的誘導体又は複合物であって、ポリペプチドが補体活性を有しないが、フィコリン-3、MBL、C1q、肺サーファクタントタンパク質SP-A及び/又はSP-D及び/又はCL-L1(及び他のコレクチンファミリーメンバー)への結合のためのMASP-1、MASP-2、又はMASP-3と競合する能力を有するものを意味する。これは、配列番号1を有するヒトフィコリン結合ポリペプチド(FAP)及びその変異体を含むがこれらに限定されない。
1) 疎水性: ノルロイシン、Met、Ala、VaI、Leu、Ile;
2) 中性の親水性: Cys、Ser、Thr、Asn、Gln;
3) 酸性: Asp、Glu;
4) 塩基性: His、Lys、Arg;
5) 鎖の方向性に影響する残基: Gly、Pro;
6) 芳香族: Trp、Tyr、Phe。
イソロイシン(+4.5); バリン(+4.2); ロイシン (+3.8); フェニルアラニン (+2.8); システイン/シスチン (+2.5); メチオニン (+1.9); アラニン (+1.8); グリシン (- 0.4); スレオニン (-0.7); セリン (-0.8); トリプトファン (-0.9); チロシン (-1.3); プロリン (-1.6); ヒスチジン (-3.2); グルタマート (-3.5); グルタミン (-3.5); アスパルタート (-3.5); アスパラギン (-3.5); リジン (-3.9); 及びアルギニン (-4.5)。
本発明はまた、上記の本発明のヒトフィコリン結合ポリペプチド及び他のポリペプチドを調製する方法に関する。本明細書において説明する本発明のフィコリン結合ポリペプチド及び他のポリペプチドは、組換え型核酸技術によって産生することができる。一般に、クローン化野生型FAP核酸配列は、目的のタンパク質をコードするために修飾される。続いてこの修飾された配列は、順に発現ベクター中に挿入され、形質転換又は宿主細胞中に形質移入される。より高等の真核細胞、特に培養哺乳類細胞は、宿主細胞として好適である。ヒトFAPに関する完全なアミノ酸及びヌクレオチド配列を、配列番号1及び配列番号2で供する。
本発明のフィコリン結合ポリペプチド及び他のポリペプチドを、細胞培地又は乳から回収することができる。本発明のフィコリン結合ポリペプチド及び他のポリペプチドは、クロマトグラフィー(例えば、イオン交換性, 親和性, 疎水性, 等電点電気泳動, 及び分子ふるいクロマトグラフィー)、電気泳動手順(例えば、調製用等電点電気泳動(IEF), 選択的溶解(例えば、硫酸アンモニウム沈殿)、又は抽出(例えば、Protein Purification, J.-C. Janson and Lars Ryden, editors, VCH Publishers, New York, 1989を参照されたい)を含むがそれに限定されない、当技術分野で周知の様々な手順によって精製することができる。好ましくは、抗FAP抗体カラム上で親和性クロマトグラフィーによってそれらを精製することができる。例えば高速液体クロマトグラフィー等の、従来の化学精製手段によってさらなる精製を達成することができる。クエン酸バリウム沈殿を含む精製の他の方法は、当技術分野で周知であり、本明細書の新規フィコリン結合ポリペプチド及び他のポリペプチドの精製に適用することができる(例えば、Scopes, R., Protein Purification, Springer-Verlag, N.Y., 1982を参照されたい)。
SDS-PAGE及びウエスタンブロッティングのための一般的な手順:
電気泳動を、10 % 又は4-12 % (w/v) Bis-トリス ポリアクリルアミド-ゲル上で非連続的緩衝液と共に、NuPAGE(R)システム(Invitrogen)を使用して製造者に推奨されるとおり行った。ポリビニリデンジフルオリド膜(PVDF-HyBond, GE-healthcare, Hilleroed, Denmark, cat. no. RPN303F)、2 μg/mlのビオチン標識一次モノクローナル抗体及びPBS、0.05 % Tween20中で1 : 1500に希釈したHRP 複合ストレプトアビジン(P0397, Dako, Glostrup, Denmark) による二次可視化を使用して、ウエスタンブロッティングを行った。アセトン中の0.04 % 3-アミノ-9-エチルカルバゾール(Sigma-aldrich, Broenby, Denmark, cat. no. A5754-100G)及び50 mM 酢酸ナトリウム緩衝液 pH 5中の0.015 % H2O2で膜を展開した。
マンノース結合レクチン(MBL)血清複合体の免疫沈降: 1 mlの正常ヒト血清をTBS(10 mM トリス, 140 mM NaCl, pH 7.5)中で1: 1に希釈し、5 μgのMBL 特異的マウスモノクローナル抗体Hyb 131-11(Bioporto, Gentofte, Denmark)で4℃で1時間回転してインキュベートした。
-ハイブリダイゼーションに基づく方法
ダイナミックアレル特異的ハイブリダイゼーション
分子ビーコン
SNPマイクロアレイ
-酵素に基づく方法
制限断片長多型
PCRに基づく方法
Flap エンドヌクレアーゼ
プライマー伸長
5'-ヌクレアーゼ
オリゴヌクレオチドリガーゼアッセイ
-DNAの物理的特性に基づく他の増幅後の方法
一本鎖立体構造多型
温度勾配ゲル電気泳動
変性高速液体クロマトグラフィー
増幅産物全体の高分解能融解
SNPIex
-配列決定
組合せ処置
本明細書に定義されるフィコリン結合ポリペプチドは、フィコリン-1、2、3、及びマンノース結合レクチン(MBL)から選択される1又は2以上のタンパク質と共に、同時又は経時的に投与することができる。因子を、単一用量形態が両方の化合物を含む単一用量形態、又は第一の単位用量形態としてのフィコリン結合ポリペプチドの製剤及び第二の単位用量形態としての1又は2以上の他の化合物の製剤を含むキットの一部分の形態中に供給することができる。本明細書を通して第一、第二又は第三等の単位用量に言及する場合、これは好適な投与順番を示すものではなく、単に好都合な目的とするものである。
上記の通り、本発明は、単離フィコリン結合ポリペプチド及び配列番号4のアミノ酸配列又はその変異体又は免疫性断片を含むポリペプチドに関する。一部の実施形態において、本発明のポリペプチドは実質的に純粋である。
MASPl遺伝子の代替転写の検出
方法: MASPlの3つの転写変異体: MASPl, MASP3及び FAPを検出するために、各変異体のための特異的プライマーをデザインした。PCRを、エクソン6における共通の順方向プライマー(5'-gcacccagagccacagtg-3')及び特異的逆方向プライマー: エクソン12におけるMASPl(5'-gccttccagtgtgtgggc-3')、エクソン11におけるMASP3(5-gccttccagagtgtggtca-3') 及びエクソン8aにおけるFAP (5'-cgatctggagagcgaactc-3') でセットアップした(図1)。50 ng 肝臓cDNA (クロンテック) 、0.25 μMの各プライマー、2.5 mM MgCl2、0.2 mM dNTP、50 mM KCl、10 mM トリス-HCl、pH 8.4、及び0.4 単位の白金 Taq DNAポリメラーゼ (Invitrogen)、を含有する20-μl容積中でPCR増幅を実行した。次のサイクルパラメータでPCR反応を行った: 10分94℃、30又は40サイクル(30秒94℃, 50秒58℃, 90秒72℃) 、10分72℃。2% アガロースゲル上で試料を分析した。
方法: 上記のように同一のPCRアッセイで、MASPl、MASP3、及び FAP 発現に関して市販のヒト組織cDNAパネル(クロンテック)を調べた。2% アガロースゲル上で試料を分析した。
方法: 翻訳ATG開始部位に関連する位置+44,083から+44,431に及ぶMASP1/MASP3/FAP 遺伝子のイントロン-エクソン境界を含むエクソン8aの直接配列決定を、100人の健常なコーカサス人由来のゲノムDNAテンプレート上で行った。順方向プライマーが5'-T7 配列(5'-ttatacgactcacta-3') を含有する、単一プライマーセット(順方向: 5'-ctgttcttcacactggctg-3'、逆方向: 5'-ctgctgagatcatgttgttc-3') を使用して、断片を増幅した。50 ng ゲノムDNA、0.25μM の各プライマー、2.5 mM MgCl2、0.2 mM dNTP、50 mM KCl、10 mM トリス-HCl、pH 8.4、及び白金Taq DNA ポリメラーゼの0.4単位(Invitrogen) を含有する20-μl容積中で、PCR増幅を実行した。以下のサイクルパラメータ: 2分94℃、15サイクル(30秒94℃, 60秒64℃, 60秒72℃) 、15サイクル(30秒94℃, 60秒58℃, 60秒72℃) 、5分72℃、でPCR反応を行い、そして5'-ビオチン標識配列プライマーを使用して、ABI BigDyeサイクル配列決定ターミネーターキット(Applied Biosystems, Foster City, CA) を使用してプロトコールに従って順方向に配列決定した。ストレプトアビジンビーズ(GenoVision) を使用してPyroMark Vacuum Prep Workstation (Biotage)上で、配列反応物を精製した。
免疫沈降
血清由来のMAP-1の特異的免疫沈降を、MAP-1特異的mAb 20C4 (17 MAP-1特異的C末端ペプチドに対して産生された)又はmAb 8B3で行い、モノクローナル抗体は対照沈殿抗体として使用したMASP-1/3の共通の重鎖に対して反応した。総量10μgの抗MAP-1又はMASP-1/3 抗体を、ヒツジ抗マウス又はウサギIgG Dynaビーズ (M-280, cat. 112.02D/112.04D, Dynal/Invitrogen) に結合させた。洗浄工程後、ビーズを正常ヒト血清のプール (TBS中に1 : 1に希釈した) に適用し、4℃で1時間回転させながらインキュベートした。最終洗浄工程及び磁気分離後、ビーズを緩衝液を負荷したSDS中で沸騰し、SDS-PAGE及び、MAP-1、MBL、及びフィコリン-3への抗体でプローブしたウエスタンブロッティングに供した。
rMAP-1を発現しているCHO細胞を、培養フラスコ中でRPMI+10%中で成長させた。80-90% コンフルエンスで細胞を回収し、4% ホルムアルデヒド-PBS中で24時間固定し、続いてパラフィン中に包埋した。6つの異なるヒト肝臓組織及び2つの異なる心筋組織、2つの骨格筋組織由来の試料及びヒト大動脈から得た2つの試料もまた固定し、上記のようにパラフィン包埋した。Leitz Wetzlar ミクロトームで5 μm の切片を得て、スライドガラス上に置き、アッセイを行うまで4℃で保管した。前処理及び分析を上述の通り行った。一次抗体はMAP-1特異的モノクローナル抗体mAb 12B11又は親和性精製した、モノ特異的ウサギ抗MAP-1であり、これらは全て5 μg/mlに希釈したものであった。アイソタイプ抗体対照を、同一濃度で組織に適用した。二次抗体は、Envision(登録商標)抗体(HRP-抗マウス又はHRP-抗ウサギ, Dako, Glostrup, Denmark)であった。Leica DMLB2 顕微鏡下で染色パターン分析を行った。
本質的には製造者によって説明されるように、NuPAGE(R)システム(Invitrogen) を使用して、10%又は4-12% (w/v) Bis-トリスポリアクリルアミドゲル上で非連続的緩衝液で電気泳動を行った。ポリビニリデンジフルオリド膜 (PVDF-HyBond, Amersham Bioscience)、2μg/mlの一次mAbsを使用したウエスタンブロッティング、及びPBS、0.05% Tween20中で1: 1500に希釈したHRP複合ストレプトアビジン(P0397, Dako) 又はPBS、0.05% Tween20中で1: 1000に希釈したHRP-ウサギ抗マウスIgG (PO260, Dako)による二次可視化を行った。5OmM酢酸ナトリウム緩衝液 pH 5中の3-アミノ-9-エチルカルバゾール(Sigma)(アセトン中に0.04%) 及び0.015% H2O2で膜を展開した。
本質的に上述のように、MBL及びフィコリン-3媒介補体因子C4析出へのMAP-1の影響を評価した。簡潔には、マンナン(MBLリガンド)(Sigma-Aldrich M7504)又はアセチル化ウシ血清アルブミン(フィコリン-3リガンド)をlOμg/ml でMaxisorp ELISA プレート(Nunc, Denmark)に固定した。洗浄後、rMBL又はrフィコリン-3(0.4μg/ml)を添加し、1.5時間インキュベートした。rMAP-1又はrMASP-2の2倍の段階希釈物を一方の次元に沿って1時間加え、他方の次元に沿ってMBL又はフィコリン-3の血清欠乏の段階希釈物を添加し37℃で45分間インキュベーションした。C4cへのpAbを使用してC4析出を測定した(Q0369, Dako, Glostrup/Denmark)。
MAP-1は、フィコリン-2、フィコリン-3及びMBLと共沈殿する。
MAP-1のMBL及びフィコリン-3との結合の可能性を検討するために、抗MAP-1 mAb20C4及びMASP-1及びMASP-3の共通の重鎖に対するmAb (mAb8B3)を共に使用して血清複合体を沈殿させた。続いて沈殿物を、MAP-1、MBL、及びフィコリン-3それぞれへの抗体でプローブしたウエスタンブロッティングによって分析した。明確なフィコリン-3共沈殿バンドを観察したが、それより弱いバンドもまたMBLで観察された(図 24A)。フィコリン-2に対する抗体はウエスタンブロットにおいて機能しなかったので、試料はフィコリン-2に対する抗体でプローブされなかった。続いて、MBL、フィコリン-2及びフィコリン-3に対するmAbsを使用して免疫沈降を逆行させ、1 ml、300 μl及び100 μlの血清をそれぞれ沈殿させたが、これはMBLの血清濃度(2 μg/ml) 、フィコリン-2の血清濃度(5 μg/ml) 及びフィコリン-3の血清濃度(20 μg/ml)の違いの調整に機能する。続いて試料をMAP-1への抗体でプローブしたウエスタンブロッティングによって分析した。顕著なMAP-1バンドがフィコリン-2及び-3由来の沈殿物中で観察され、はるかに弱いバンドがMBL沈殿物中に生じ、免疫沈降rMAP-1及び血清MAP-1は対照として機能した(図24B)。
rMBL及びrフィコリン-3との組合せでのMBL及びフィコリン-3欠乏血清を、MBL及びフィコリン-3補体C4活性化活性のための再構成のために使用した。マンナン及びアセチル化BSAはMBL及びフィコリン-3のリガンドとしてそれぞれ機能した。rMBL及びrフィコリン-3は共に、MBL及び フィコリン-3欠乏血清中でC4析出をそれぞれ開始することができた(図25A及び25D)。rMASP-2の適用は、フィコリン-3及びMBL活性化経路の双方を介して、C4析出の強度の正の用量依存性の増強をもたらす(図25B及び25E)。一方、rMAP-1の適用は、双方の経路を介してC4析出の明白な用量依存性抑制をもたらす(図25C及び25F)。
新規MBL/フィコリン結合タンパク質1(MAP-1)の血清濃度及び結合特性の決定
MAP-1の全長の非標識組換え型コンストラクトがCHO-DG44 細胞中で生成され、安定に発現された。MAP-1に対する特異的モノクローナル抗体が産生された。また、MAP-1血清測定のための定量的ELISAを確立し、血清MAP-1とフィコリン-2、-3及びMBLと間の結合をELISA及び密度勾配分画で調べた。
PowerCHO1 血清不含有培地(Lonza, Vallensbaek/Denmark, www.lonza.com) を発現培地として使用した変更を行ってが、他で説明されるように非標識ヒトMAP-1の全長コンストラクトがCHO-DG44 細胞中で発現された(Hummelshoj et al., MoI Immunol 44, 401-11, 2007; Larsen et al., J Biol Chem 279, 21302-11, 2004; Ma et al., 2009 J Biol Chem, Oct 9;284(41))。これまで記載されるように(Skjoedt et al., 2009; Immunobiology, Nov 23)、rMAP-1を生成するために抗体親和性精製を使用した。簡潔に言えば、本質的にはPfeiffer等によって説明されるように(Pfeiffer et al., J Immunol Methods 97, 1-9, 1987)、15 mgの抗MAP-1 抗体(mAb 20C4) をCNBr活性化セファロースに共有結合で結合させ、精製マトリックスとして使用した。抗MAP-1カラムもまた、血清からMAP-1を除去するために使用した。
統計(スピアマンノンパラメトリック相関関係, ノンパラメトリック両側t-検定)及びMAP-1、MBL、フィコリン-2及び-3血清レベルを、Prism4 ソフトウェア (GraphPad Software, Inc., La Jolla/CA/US, www.gaphpad.com)を使用して算出した。
rMAP-1の精製及び特性決定
CHO DG44 細胞におけるrMAP-1の発現は、150 nM メトトレキサートの存在下で高産生量となった(産生量: 血清非含有培地中、10-20 μg/ml)。精製後、rMAP-1をSDS-PAGEで分析し、続いてクーマシーブリリアントブルー染色又は免疫ブロッティングを行った。SDS-PAGE/クーマシー染色分析から、推定-45 kDa減少の分子量のバンドが明らかとなった(図27)。rMAP-1のN-グリコシダーゼ Fでの脱グリコシル化は、シグナルペプチドを含まない理論的質量に相当する〜40 kDaへの分子量変化をもたらす。このパターンはまた、MAP-1への特異的抗体を使用した免疫ブロットで観察された。
MAP-1の血清レベルを測定するために、定量的ELISAを展開した。アッセイは、捕捉用抗体及びMASP-1、-3及びMAP-1の共通の重鎖を認識する検出抗体(mAb 8B3)としてのMAP-1 特異的mAb 20C4に基づく。既知濃度の精製rMAP-1 検量用試料及び精製MAP-1添加のMAP-1欠乏血清間で、完全な平行が検量線で観察された(図28A)。100人のデンマーク人の供血者において、MAP-1の血清レベルを分析し、範囲115-466 ng/ml、平均値240 ng/mlと分かった(図29A)。以前に説明されるように(Skjoedt et al., 2009) 同一群でMASP-3血清レベルを測定し、MAP-1及びMASP-3濃度をプロットした(図29B)。MAP-1及びMASP-3の血清は同一遺伝子由来の代替転写物を表すにもかかわらず、MAP-1及びMASP-3の血清濃度間に、相関関係がないことが分かった。
MAP-1及びMBL、フィコリン-2及び-3の間の相互作用を測定するために、捕捉用抗体としてmAb 20C4 を使用し且つビオチン標識mAbs: FCN-219 (フィコリン-2特異的)、FCN-334 (フィコリン-3 特異的)又はHyb 131-11 (MBL特異的)でプローブして、3つの異なるELISAを展開した。MAP-1測定に使用した同一の100人のドナー血清試料を分析し、MAP-1及びフィコリン-2、-3及びMBL間の血清結合レベルを、相対的O.D.490-650nmとして評価した(図30A)。さらに、以前に記載のように(Skjoedt et al., 2009)、MBL、フィコリン-2及び-3の血清濃度を測定した。
結合分子に関してMAP-1の分布を検討し、どれほど関係が無いか調べるために、10-30% スクロース勾配及び超遠心分離法を使用して正常ヒト血清を密度分画に供した。続いて、採取した画分をMAP-1、MASP-3、MBL、フィコリン-2及び-3に関してELISAで(図31A)、MAP-1、MASP-1、-2及び-3、sMAP、MBL、フィコリン-2及び-3に関してウエスタンブロッティングで分析した(図31B)。結果は、血清MAP-1がフィコリンを有する画分に唯一存在することを示し、MBLはMAP-1が非結合分子として存在しないことを示した。sMAP、MASP-1、-2及び-3に関して、同一のパターンが観察された。さらに、データは、MAP-1、sMAP及びMASP-1、-2及び-3の大部分がフィコリン-3のピーク画分中に共局在することを示す。この分布をまた、サイズ排除クロマトグラフィーによってsephadex-200 カラム上で分析した。分子の等価な分布パターンが観察された(データは図示せず)。
新規MBL/フィコリン結合タンパク質1 (MAP-1) 構造側面を検討し血清レベルを証明するために、非標識、組換え型MAP-1を発現させ、それに対する特異的抗体を産生した。N-グリコシダーゼ F 処理及びSDS-PAGE 分析は、MAP-1がグリコシル化され、シグナルペプチドのない推定アミノ酸配列から算出される分子量に等価な、N-グリカンを有する分子量-45 kDa及び脱グリコシル化後の-40 kDaを生じることを示した。
Claims (5)
- 補体活性化を阻害するための、配列番号4のアミノ酸配列をC末端に有するフィコリン結合ポリペプチドを含む医薬組成物であって、該フィコリン結合ポリペプチドが、配列番号1のアミノ酸配列の位置20〜380のアミノ酸残基を含むか、又は配列番号1の配列と少なくとも90 % 配列同一性を有するポリペプチドを含み、該フィコリン結合ポリペプチドがシグナルペプチドを含まない、医薬組成物。
- 前記フィコリン結合ポリペプチドが、配列番号1の配列と少なくとも95 % 配列同一性を有する、請求項1に記載の医薬組成物。
- 前記フィコリン結合ポリペプチドが、マンノース結合レクチン(MBL)、フィコリン-1、フィコリン-2、及びフィコリン-3のいずれか1つとの結合能を有する、請求項1又は2に記載の医薬組成物。
- 前記フィコリン結合ポリペプチドが遺伝子組換えタンパク質である、請求項1〜3のいずれか1項に記載の医薬組成物。
- 前記フィコリン結合ポリペプチドが、配列番号1のアミノ酸配列の位置20〜380のアミノ酸残基から成るか、又は配列番号1の配列と少なくとも90 % 配列同一性を有するポリペプチドから成る、請求項1〜4のいずれか1項に記載の医薬組成物。
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