JP6542433B2 - 単独でのまたは化学療法と組み合わされた変異アクチビン受容体ポリペプチド、およびその使用 - Google Patents
単独でのまたは化学療法と組み合わされた変異アクチビン受容体ポリペプチド、およびその使用 Download PDFInfo
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Description
本願は、2011年12月19日に出願された米国特許出願第13/329,897号に基づく優先権を主張し、その開示は全て、あらゆる目的のためにその全体を参照により本明細書に組み入れられる。
本願は電子形式の配列表を添付して出願されている。配列表は、サイズが265,085バイトであるA-1219-US-CIP_SeqList.txtという名称のファイルとして提供され、2011年12月19日に作成されたものである。配列表の電子形式での情報はその全体を参照により本明細書に組み入れられる。
本発明の技術分野は、トランスフォーミング成長因子-β(TGF-β)ファミリーメンバーおよび可溶性TGF-β受容体、ならびに、さまざまな障害を処置するためにTGF-βファミリーメンバーの活性を調節する方法に関する。
トランスフォーミング成長因子β(TGF-β)タンパク質ファミリーには、トランスフォーミング成長因子-β(TGF-β)、アクチビン、骨形態形成タンパク質(BMP)、神経成長因子(NGF)、脳由来神経栄養因子(BDNF)、および増殖/分化因子(GDF)が含まれる。これらのファミリーメンバーは、細胞増殖、分化、および他の機能を含む広範な生物学的プロセスの調節に関与している。
[本発明1001]
(i)SEQ ID NO:91のアミノ酸配列を含み、かつ、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、変異アクチビンIIB受容体ポリペプチド(vActRIIB)と、(ii)5-フルオロウラシル(5-FU)を含む化学療法剤とを含む、薬学的組成物。
[本発明1002]
(i)位置28における1アミノ酸置換以外はSEQ ID NO:18のポリペプチド配列を含み、かつ、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、変異アクチビンIIB受容体ポリペプチド(vActRIIB)と、(ii)化学療法剤とを含む、薬学的組成物。
[本発明1003]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、F、Q、V、I、L、M、K、H、W、およびYからなる群より選択される、本発明1001または1002の薬学的組成物。
[本発明1004]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、W、およびYからなるアミノ酸の群より選択される、本発明1001〜1003のいずれかの薬学的組成物。
[本発明1005]
前記vActRIIBポリペプチドの位置28における置換がWである、本発明1001〜1004のいずれかの薬学的組成物。
[本発明1006]
ポリペプチドが、SEQ ID NO:91のポリペプチド配列を含むか、またはポリペプチドが、SEQ ID NO:91のポリペプチド配列からなる、本発明1001〜1005のいずれかの薬学的組成物。
[本発明1007]
前記vActRIIBポリペプチドがN末端シグナル配列を欠いている、本発明1001〜1006のいずれかの薬学的組成物。
[本発明1008]
前記化学療法剤がヌクレオシド類似体である、本発明1001〜1007のいずれかの薬学的組成物。
[本発明1009]
前記化学療法剤が5-フルオロウラシルである、本発明1001〜1008のいずれかの薬学的組成物。
[本発明1010]
前記化学療法剤がダカルバジンである、本発明1001〜1009のいずれかの薬学的組成物。
[本発明1011]
薬学的に許容される賦形剤を含む、本発明1001〜1010のいずれかの薬学的組成物。
[本発明1012]
そのような処置を必要とする対象においてアクチビン活性を阻害する方法であって、本発明1001〜1011のいずれかの組成物の治療有効量を該対象に投与する段階を含む、方法。
[本発明1013]
投与によって、リン酸緩衝食塩水(PBS)を投与した対照対象と比較した前記対象における血管新生因子の発現レベルの減少がもたらされる、本発明1012の方法。
[本発明1014]
前記血管新生因子が、血管内皮増殖因子(VEGF)、Ang-1、エンドグリン、オステロポンチン(osteropontin)、IGFBP-1、またはIGFBP-2である、本発明1013の方法。
[本発明1015]
投与によって、PBSを投与した対照対象と比較した前記対象におけるカスパーゼ3活性化の増加がもたらされる、本発明1012〜1014のいずれかの方法。
[本発明1016]
投与によって、PBSを投与した対照対象と比較した前記対象におけるアポトーシスの増加がもたらされる、本発明1012〜1015のいずれかの方法。
[本発明1017]
そのような処置を必要とする対象においてアクチビンが過剰発現している疾患を処置する方法であって、本発明1001〜1011のいずれかの組成物の治療有効量を該対象に投与する段階を含む、方法。
[本発明1018]
前記疾患ががんである、本発明1017の方法。
[本発明1019]
前記疾患が、性腺がん、精巣がん、卵巣がん、皮膚がん、または黒色腫である、本発明1018の方法。
[本発明1020]
投与によって、リン酸緩衝食塩水(PBS)を投与した対照対象と比較した前記対象における血管新生因子の発現レベルの減少がもたらされる、本発明1017〜1019のいずれかの方法。
[本発明1021]
前記血管新生因子が、血管内皮増殖因子(VEGF)、Ang-1、エンドグリン、オステロポンチン、IGFBP-1、またはIGFBP-2である、本発明1020の方法。
[本発明1022]
投与によって、PBSを投与した対照対象と比較した前記対象におけるカスパーゼ3活性化の増加がもたらされる、本発明1017〜1021のいずれかの方法。
[本発明1023]
投与によって、PBSを投与した対照対象と比較した前記対象におけるアポトーシスの増加がもたらされる、本発明1017〜1022のいずれかの方法。
[本発明1024]
投与によって、PBSを投与した対照対象と比較した前記対象におけるがん細胞のアポトーシスの増加がもたらされる、本発明1017〜1023のいずれかの方法。
[本発明1025]
そのような処置を必要とする対象において腫瘍塊のサイズを縮小させる方法であって、本発明1001〜1011のいずれかの組成物の有効量を該対象に投与する段階を含む、方法。
[本発明1026]
前記腫瘍塊が、性腺がん、精巣がん、卵巣がん、皮膚がん、または黒色腫に起因している、本発明1025の方法。
[本発明1027]
そのような処置を必要とする対象に組成物の治療有効量を投与する段階を含む、該対象において性腺がん、精巣がん、卵巣がん、皮膚がん、または黒色腫を処置する方法であって、該組成物が、変異アクチビンIIB受容体ポリペプチド(vActRIIB)を含み、該ポリペプチドが、位置28における1アミノ酸置換以外はSEQ ID NO:18のポリペプチド配列を含み、かつ、該ポリペプチドが、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、方法。
[本発明1028]
前記がんが卵巣がんである、本発明1027の方法。
[本発明1029]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、F、Q、V、I、L、M、K、H、W、およびYからなる群より選択される、本発明1027または1028の方法。
[本発明1030]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、W、およびYからなるアミノ酸の群より選択される、本発明1027〜1029のいずれかの方法。
[本発明1031]
前記vActRIIBポリペプチドの位置28における置換がWである、本発明1027〜1030のいずれかの方法。
[本発明1032]
ポリペプチドが、SEQ ID NO:91のポリペプチド配列を含む、本発明1027〜1031のいずれかの方法。
[本発明1033]
前記vActRIIBポリペプチドがN末端シグナル配列を欠いている、本発明1027〜1032のいずれかの方法。
[本発明1034]
投与によって、リン酸緩衝食塩水(PBS)を投与した対照対象と比較した前記対象における血管新生因子の発現レベルの減少がもたらされる、本発明1027〜1033のいずれかの方法。
[本発明1035]
前記血管新生因子が、血管内皮増殖因子(VEGF)、Ang-1、エンドグリン、オステロポンチン、IGFBP-1、またはIGFBP-2である、本発明1034の方法。
[本発明1036]
投与によって、PBSを投与した対照対象と比較した前記対象におけるカスパーゼ3活性化の増加がもたらされる、本発明1027〜1035のいずれかの方法。
[本発明1037]
投与によって、PBSを投与した対照対象と比較した前記対象におけるアポトーシスの増加がもたらされる、本発明1027〜1036のいずれかの方法。
[本発明1038]
投与によって、PBSを投与した対照対象と比較した前記対象におけるがん細胞のアポトーシスの増加がもたらされる、本発明1027〜1037のいずれかの方法。
[本発明1039]
そのような処置を必要とする対象に、変異アクチビンIIB受容体ポリペプチド(vActRIIB)を含む薬学的組成物の治療有効量を投与する段階を含む、該対象において黒色腫を処置する方法であって、該ポリペプチドが、位置28における1アミノ酸置換以外はSEQ ID NO:18のポリペプチド配列を含み、該ポリペプチドが、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、方法。
[本発明1040]
そのような処置を必要とする対象に、変異アクチビンIIB受容体ポリペプチド(vActRIIB)を含む薬学的組成物の治療有効量を投与する段階を含む、該対象において血管新生因子の過剰発現を有する状態を処置する方法であって、該ポリペプチドが、位置28における1アミノ酸置換以外はSEQ ID NO:18のポリペプチド配列を含み、該ポリペプチドが、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、方法。
[本発明1041]
前記状態ががんである、本発明1040の方法。
[本発明1042]
前記がんが卵巣がんである、本発明1041の方法。
[本発明1043]
VEGF-AまたはAng-1が過剰発現している、本発明1040〜1042のいずれかの方法。
[本発明1044]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、F、Q、V、I、L、M、K、H、W、およびYからなる群より選択される、本発明1040〜1043のいずれかの方法。
[本発明1045]
前記vActRIIBポリペプチドの位置28における置換が、Eの代わりにA、W、およびYからなるアミノ酸の群より選択される、本発明1040〜1044のいずれかの方法。
[本発明1046]
前記vActRIIBポリペプチドの位置28における置換がWである、本発明1040〜1045のいずれかの方法。
[本発明1047]
ポリペプチドが、SEQ ID NO:91のポリペプチド配列を含む、本発明1040〜1046のいずれかの方法。
[本発明1048]
前記vActRIIBポリペプチドがN末端シグナル配列を欠いている、本発明1040〜1047のいずれかの方法。
[本発明1049]
投与によって、リン酸緩衝食塩水(PBS)を投与した対照対象と比較した前記対象における血管新生因子の発現レベルの減少がもたらされる、本発明1040〜1048のいずれかの方法。
[本発明1050]
前記血管新生因子が、血管内皮増殖因子(VEGF)、Ang-1、エンドグリン、オステロポンチン、IGFBP-1、またはIGFBP-2である、本発明1049の方法。
[本発明1051]
投与によって、PBSを投与した対照対象と比較した前記対象におけるカスパーゼ3活性化の増加がもたらされる、本発明1040〜1050のいずれかの方法。
[本発明1052]
投与によって、PBSを投与した対照対象と比較した前記対象におけるアポトーシスの増加がもたらされる、本発明1040〜1051のいずれかの方法。
[本発明1053]
投与によって、PBSを投与した対照対象と比較した前記対象におけるがん細胞のアポトーシスの増加がもたらされる、本発明1040〜1052のいずれかの方法。
変異ヒトアクチビンIIB受容体(vActRIIB;sActRIIBともいう)ポリペプチドを含むタンパク質を開示する。これらのタンパク質およびポリペプチドは、3つのTGF-βタンパク質、ミオスタチン(GDF-8)、アクチビンA、およびGDF-11の少なくとも一つに結合し、これらのタンパク質の活性を阻害するその能力を特徴とする。これらのタンパク質およびポリペプチドは、本明細書において開示する修飾を含有しないポリペプチドと比較して、低下した凝集傾向も呈する。修飾は、アクセッション番号NP_001097の野生型ActRIIB(SEQ ID NO:47)およびActRIIBの細胞外ドメイン(SEQ ID NO:18)またはActRIIB5の細胞外ドメイン(SEQ ID NO:2)を基準として、位置28、40、または28と40の両方におけるアミノ酸置換からなる。
本明細書において使用する場合、アクチビンII型B受容体(ActRIIB)という用語は、アクセッション番号NP_001097(SEQ ID NO:47)を有するヒトアクチビン受容体を指す。可溶性ActRIIBという用語には、ActRIIBの細胞外ドメイン(SEQ ID NO:18)、ActRIIB5の細胞外ドメイン(SEQ ID NO:2)および位置64のアルギニンがアラニンで置換されているこれらの配列も包含される。
本発明は、可溶性のヒト変異ActIIB受容体ポリペプチド(本明細書では、vActRIIBポリペプチド、または変異ポリペプチドもしくはsActRIIBという)を含む単離されたタンパク質を提供する。本明細書において使用する場合、「vActRIIBタンパク質」という用語は、vActRIIBポリペプチドを含むタンパク質を指す。本明細書において使用する場合、「単離された」という用語は、内在性物質からある程度精製されたタンパク質またはポリペプチド分子を指す。これらのポリペプチドおよびタンパク質は、アクチビンA、ミオスタチン、またはGDF-11のいずれか一つを結合させて、それらの活性を阻害する能力を有すると特徴決定される。いくつかの態様では、アクチビンA、ミオスタチン、またはGDF-11に対する変異ポリペプチドの結合アフィニティが、野生型ポリペプチドと比較して改善される。
本発明はさらに、本発明のvActRIIBポリペプチドに特異的に結合するものを含めて、変異ActRIIBポリペプチドに結合する抗体を包含する。本明細書において使用する場合、「特異的に結合する」という用語は、抗体が、vActRIIBポリペプチドに対して106M-1またはそれより大きい結合アフィニティ(Ka)を有することを指す。本明細書において使用する場合、「抗体」という用語は、ポリクローナル抗体(例えばAntibodies: A Laboratory Manual, Harlow and Lane (eds), Cold Spring Harbor Press, (1988)参照)およびモノクローナル抗体(例えば米国再発行特許第32,011号、米国特許第4,902,614号、同第4,543,439号、および同第4,411,993号、ならびにMonoclonal Antibodies: A New Dimension in Biological Analysis, Plenum Press, Kennett, McKearn and Bechtol (eds.) (1980)を参照されたい)を含む、無傷の抗体を指す。本明細書において使用する場合、「抗体」という用語は、抗体のフラグメント、例えば組換えDNA技法によって産生されるか、無傷の抗体の酵素的または化学的切断によって産生される、F(ab)、F(ab')、F(ab')2、Fv、Fc、および単鎖抗体なども指す。「抗体」という用語は、2つの異なる重鎖/軽鎖対と2つの異なる結合部位とを有する人工的なハイブリッド抗体である二重特異性抗体または二機能性抗体も指す。二重特異性抗体は、ハイブリドーマの融合またはFab'フラグメントの連結などといった、さまざまな方法によって産生することができる(Songsivilai et al., Clin. Exp. Immunol. 79:315-321 (1990)、Kostelny et al., J. Immunol.148:1547-1553 (1992)参照)。
本発明のvActRIIBタンパク質およびポリペプチドを含有する薬学的組成物も提供される。そのような組成物は、薬学的に許容される材料および生理学的に許容される製剤材料と混合された治療有効量または予防的有効量のポリペプチドまたはタンパク質を含む。薬学的組成物は、例えば組成物のpH、オスモル濃度、粘度、透明性、色、等張性、匂い、滅菌性、安定性、溶解もしくは放出速度、吸着または浸透などを修飾し、維持しまたは保存するための製剤材料を含有しうる。好適な製剤材料には、アミノ酸(例えばグリシン、グルタミン、アスパラギン、アルギニンまたはリジン);抗微生物剤;酸化防止剤(例えばアスコルビン酸、亜硫酸ナトリウムまたは亜硫酸水素ナトリウム);緩衝剤(例えばボラート、重炭酸塩、トリス-HCl、シトラート、フォスフェート、他の有機酸);充填剤(例えばマンニトールまたはグリシン)、キレート剤(例えばエチレンジアミン四酢酸(EDTA));錯化剤(例えばカフェイン、ポリビニルピロリドン、β-シクロデキストリンまたはヒドロキシプロピル-β-シクロデキストリン);充填剤;単糖;二糖および他の糖質(例えばグルコース、マンノース、またはデキストリン);タンパク質(例えば血清アルブミン、ゼラチンまたは免疫グロブリン);着色剤;矯味矯臭剤および希釈剤;乳化剤;親水性ポリマー(例えばポリビニルピロリドン);低分子量ポリペプチド;塩形成対イオン(例えばナトリウム);保存剤(例えば塩化ベンザルコニウム、安息香酸、サリチル酸、チメロサール、フェネチルアルコール、メチルパラベン、プロピルパラベン、クロルヘキシジン、ソルビン酸または過酸化水素);溶媒(例えばグリセリン、プロピレングリコールまたはポリエチレングリコール);糖アルコール(例えばマンニトールまたはソルビトール);懸濁剤;界面活性剤または湿潤剤(例えばプルロニック、PEG、ソルビタンエステル、ポリソルベート、例えばポリソルベート20、ポリソルベート80、トリトン、トロメタミン、レシチン、コレステロール、チロキサパール(tyloxapal));安定性強化剤(スクロースまたはソルビトール);張性強化剤(例えばハロゲン化アルカリ金属(好ましくは塩化ナトリウムまたは塩化カリウム、マンニトールソルビトール);送達ビヒクル;希釈剤;賦形剤および/または薬学的佐剤などがあるが、それらに限定されるわけではない(Remington's Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, ed., Mack Publishing Company, 1990)。
本発明は、前記ポリペプチドをvActRIIBポリペプチドと接触させることによって、インビボおよびインビトロでミオスタチン、アクチビンA、またはGDF-11の量または活性を減少させるかまたは中和するための方法および薬学的組成物を提供する。vActRIIBポリペプチドはミオスタチン、アクチビンA、およびGDF-11に対して高いアフィニティを有し、ミオスタチン、アクチビンA、およびGDF-11のうちの少なくとも一つの生物学的活性を減少させかつ阻害することができる。いくつかの態様では、vActRIIBポリペプチドが、野生型ActRIIBポリペプチドと比較して向上した活性を呈する。これを後述の実施例において実証する。
変異ActRIIBポリペプチドの発現と精製には以下の方法を使用した。
構造解析、分子モデリング、および質量分析のアプローチを併用することにより、ActRIIBでは、非グリコシル化ActRIIB分子間の静電相互作用およびH結合相互作用によって惹起される分子間ジスルフィド結合形成を介して、凝集(オリゴマー化)が起こりうることが示された。残基28および40は、ActRIIB:ActRIIB相互作用に関与し、ActRIIBとそのリガンドとの相互作用には関与しないことが決定された。
細胞バンクを、選択したクローンから、次の手順に従って作製した。増幅した安定トランスフェクト細胞のプールを96ウェルプレートに播種し、小スケール試験で、成長および生産性能について、候補クローンを評価した。約60バイアルのプレマスター細胞バンク(PMCB)を、選ばれたクローンから調製した。全てのPMCBを無菌性、マイコプラズマおよびウイルスについて試験した。
ActRIIB-Fc(IgG1とIgG2の両方)、ActRIIB5-Fc(IgG1とIgG2の両方)、およびそれらの変異体を含有する約5Lの条件培地を、5ft2の10Kメンブレンタンジェンシャルフローフィルタ(Pall)を使って濃縮した。濃縮された材料を、PBS(塩化マグネシウムも塩化カルシウムも含まないダルベッコ)で平衡化しておいた5mLのプロテインA High Performance Column(商標)(GE Healthcare)に適用した。280nmにおける吸光度(OD280)が0.1未満になるまでカラムを平衡化緩衝液で洗浄した後、結合しているタンパク質を0.1Mグリシン-HCl、pH2.7で溶出し、1Mトリス-HCl、pH8.5で直ちに中和した。中和した溶出物のプールを1mlの体積まで濃縮し、PBS(塩化マグネシウムも塩化カルシウムも含まないダルベッコ)で平衡化した320mlのSephacryl-200カラム(GE Healthcare)に適用した。4〜20%SDS PAGEゲル(Invitrogen)で泳動することで、プールする画分を決定した。これらのポリペプチドを、活性、凝集度について、以下に示すように試験した。
上述のように精製したvActRIIBポリペプチドの試料を、リン酸緩衝食塩水(PBS:2.67mM塩化カリウム、138mM塩化ナトリウム、1.47mMリン酸カリウム一塩基性、8.1mMリン酸ナトリウム二塩基性、pH7.4)で0.2mg/mlまで希釈し、37℃で6日間インキュベートしてから、MALDI-MS(マトリックス支援レーザー脱離/イオン化質量分析)、SECおよび/またはSEC-LS分析にかけた。プロテインA精製段階後の野生型ポリペプチドおよび変異ポリペプチドの凝集を、SECまたはSEC-LSを使って決定し、分子の分子量を後述のMALDI-MS法で確認した。
vActRIIB5-IgG1 FcおよびvActRIIB-IgG1 Fc変異体を、上述のように生成させた。アクチビンIIB受容体へのアクチビンAまたはミオスタチンの結合を阻害するこれらの変異体の能力を、以下に説明する細胞ベースの活性アッセイ法を使って試験した。
以下の動物試験は、いずれも成熟切断型vActRIIB-IgG2 Fc(E28W)ポリペプチド(SEQ ID NO:91)を使用し、下記の手順に従って行った。
インヒビン-αはアクチビンAの天然の阻害剤である。インヒビン-αを欠いているマウスは、循環中に著しく上昇したアクチビンAレベルを示し、卵巣がん、精巣がん、および副腎がんなどの腫瘍の自然発生的形成に関連する致死的な消耗症候群を患う(Matzuk et al., PNAS 91(19):8817-21 (1994)、Cipriano et al. Endocrinology 121(7): 2319-27(2000)、Matzuk et al., Nature 360(6402):313-9 (1992))。以下の実験のために、インヒビン-αノックアウトマウス(C57BL/6J)をCharles River Laboratoriesから入手した。体重および筋量に対するvActRIIB-IgG2 Fc E28W(SEQ ID NO:91)(以下、E28W、またはE28Wポリペプチド、または可溶性受容体E28Wという)の効果を、インヒビン-αノックアウトマウスで調べた。8週齢雄インヒビン-αノックアウトマウスにおいて、14日間の単回注射試験を行った。雄インヒビン-αノックアウトマウスは、8週齢時に、同齢野生型同腹仔対照マウスと比較して、体重の25%超を失っていた。0日目に、ノックアウトマウスのうちの5匹に、E28W(30mg/kg)の単回皮下注射を与え、5匹のノックアウトマウスに等体積のPBS(ビヒクル)を皮下投与した。ベースライン対照として、0日目に、5匹の同齢野生型マウスにビヒクルの単回皮下注射を投与した。0日目、7日目および14日目にマウスの体重を測定した。14日目の最後に、全てのマウスを屠殺し、その除脂肪枝肉重量および腓腹筋量を剖検によって分析した。14日間の試験期間中に、ビヒクル処置ノックアウトマウスの平均体重は、0日目の22.5gから14日目の21.4gまで約1.1g低下した。対照的に、E28W処置ノックアウトマウスの平均体重は、0日目の22.1gから14日目の33.1gまで11gの劇的な増加を示した。終了時剖検分析により、E28Wポリペプチドは、インヒビン-αノックアウトマウスにおける除脂肪枝肉重量および腓腹筋量を、以下に示すように、事実上二倍にすることが明らかになった。E28W処置ノックアウトマウスの平均除脂肪枝肉重量は、ビヒクル処置ノックアウトマウスが約8.0g、ビヒクル処置野生型対照マウスが約12.1gであるのと比較して、約14.9gであった。E28W処置ノックアウトマウスの平均腓腹筋重量(両脚から)は、ビヒクル処置ノックアウトマウスの約209mg、ビヒクル処置野生型対照マウスの約324mgと比較して、約426mgであった。これらの結果は、体重減少および筋消耗の疾患状態の処置に関するE28Wポリペプチドの有効性を実証しており、これらの結果を下記の表に要約する。
*:P<0.05、対野生型+ビヒクル;#:P<0.05、対KO+ビヒクル
colon-26腫瘍を有するマウスは、がん悪液質を研究するために広く使用されている前臨床動物モデルである(Fujita et al., Int J Cancer 68(5):637-43 (1996)、Kwak et al., Cancer Research 64(22):8193-8 (2004))。体重変化、筋量および生存率に対するE28Wポリペプチドの効果を、腫瘍を有するマウスで調べた。colon-26(C-26)腫瘍細胞を、40匹の10週齢雄CDF1マウスの皮下に、1匹あたり0.5×106細胞の割合で移植した。腫瘍移植は0日目に行った。腫瘍移植後5日目から、毎週、20匹のC-26マウスを10mg/kgのvActRIIB IgG2 Fc E28W(SEQ ID NO:91)の皮下注射で処置すると共に、20匹のC-26マウスをビヒクル(PBS)で処置した。同時に、10匹の同齢および同体重正常マウスをビヒクル(PBS)だけで処置した。体重および食物摂取量を週に3回決定した。腫瘍を有するマウスの生死を毎日2回、点検した。腫瘍サイズは、PCコンピュータに接続したカリパス(Ultra-Cal IV IP65電子カリパス、Fred V Fowler Co.、マサチューセッツ州ボストン)を使って測定され、値は、マイクロソフトExcelデータファイルのワークシートに、自動的に記録された。図5に示すように、腫瘍移植の2週間後に、C-26腫瘍を有するマウスは重度の悪液質を発症し、その体重を劇的に失った。E28W処置は、腫瘍を有するマウスにおける体重減少を効果的に緩和した。E28Wで処置した腫瘍を有するマウスの平均体重は、ビヒクルで処置した、腫瘍を有するマウスの平均体重より、有意に高かった(p<0.001、腫瘍接種後7日目から33日目まで。対応のないT検定、Graph pad Software Inc.、カリフォルニア州サンディエゴ)。
後肢懸垂マウスモデルを使って、不使用状態における筋量に対するvActRIIB-IgG2 Fc E28W(SEQ ID NO:91)の効果を調べた。後肢懸垂法は、Carlson CJらが以前に報告したもの(Carlson CJ, Booth FW and Gordon SE: Am J Physiol Regul Integr Comp Physiol. 277:R601-RR606, 1999)と本質的に同じである。この試験には9週齢の雌C57BL/6マウスを使用した。合計60匹のマウスを次のとおり3群に分割した:1.ビヒクル(PBS)で処置される非懸垂ベースライン対照群(20匹)、2.ビヒクルで処置される後肢懸垂群(20匹)、および3. vActRIIB-IgG2 Fc,E28Wで処置される後肢懸垂群(20匹)。具体的には、後肢懸垂の開始時に、30mg/kgのvActRIIB-IgG2 Fc E28Wかビヒクルかどちらか一方の単回SC注射を、上述の群のそれぞれに与えた。体重変化を、週に2〜3回、経時的に測定した。次に挙げる4つの異なる時点において、各群からの5匹を屠殺した:1日目、3日目、7日目および14日目。腓腹筋重量を剖検によって決定した。
卵巣切除雌C57Bl6マウス(OVX)は、女性の性腺機能低下症および骨粗しょう症のモデルであるとみなされている。24匹の雌C57Bl6マウスを3月齢時に卵巣切除し、3ヶ月間、回復させた。6月齢時に、24匹のOVXマウスならびに24匹の同齢シャム手術対照C57Bl6マウスを、3ヶ月の処置期間にわたる体重、筋量、およびNMRによる脂肪量、骨量(PIXImus-GE LUNAR Corporation)の経時変化について測定した。期間の終了時に動物を屠殺し、終了時剖検中に骨組織を収穫し、Faxitron X線およびマイクロCT(Faxitron X-ray CorporationおよびGE Medical system)分析に供した。E28W変異受容体(SEQ ID NO:91)は、体重、具体的には除脂肪骨格筋量、および骨量を増加させると同時に、マウスの脂肪含量を非卵巣切除マウスに見られるレベルにまで減少させるのに有効であることが実証された。具体的には、12週間の期間で、除脂肪筋量は、E28Wで処置したシャム手術マウスの20gから27.5gと比較して、また、OVX+ビヒクルまたはシャム+ビヒクルでは除脂肪筋量の増加がほとんどなかったこと(OVX+ビヒクルの場合で約19グラム、野生型+ビヒクルの場合で約20g)と比較して、E28Wで処置したOVXマウスでは20gから27.0gまで増加した。同じ試験において、E28Wで処置したOVXマウスは、12週間の試験の終了時までに、1匹あたり8g平均から、シャム手術動物に匹敵する1匹あたり約4g平均へと脂肪量の減少を示した。ビヒクルで処置したOVXマウスは、対照的に、試験中どの時点においても、脂肪量の喪失がなかった。最後に骨量は、E28Wで処置したOVXマウス処置では、ビヒクル処置OVXマウスと比較して増加した。終了時剖検の際に収穫した切離骨の大腿骨/脛骨BMC(骨塩含量)の分析は、pQCT分析(末梢定量的コンピュータ断層撮影法)で行った。E28Wで処置したOVXマウスは、約0.045g/cmのBMCが、12週間の試験の終了時に、シャム手術ビヒクル処置動物の最終BMCに匹敵する約0.055g/cmまで増加した。ビヒクルで処置したOVXマウスは、12週間の試験の終了時に0.045g/cmというほぼ同じBMCを示した。E28W処置野生型マウスは、12週間の試験の終了時に、約0.054g/cmから約0.065g/cmへのBMCの増加を示した。これらの試験は、加齢に伴う虚弱、骨粗しょう症および肥満の潜在的処置としてのE28Wポリペプチドの有効性を実証している。
卵巣がん(OC)を持つマウスにおけるアクチビンレベルを知らべた(図7A)。循環アクチビンAレベルは、卵巣がん(OC)を持つマウスでは、正常対照対象(正常)と比較して有意に上昇していた。血清中アクチビンAはELISAで測定した。sActRIIB(E28W)(SEQ ID.NO:91)による卵巣がん処置の効果を図7B〜7Dに示す。樹立した卵巣腫瘍を持つ12週齢の雌KOマウスを、sActRIIBまたはPBSの単回注射で、14日間処置した。対照同齢雌野生型同腹仔にはPBSを与えた。KOマウスにおけるアクチビンAの上昇した循環レベルは、sActRIIB処置によって、野生型対照レベルまで迅速に減少したことが、図7Bからわかる。血清中アクチビンAは、処置後0日目、1日目および14日目に、ELISAによって測定した。
PBSまたはsActRIIBで2週間処置された10週齢雄および14週齢雌インヒビン-αKOマウスならびに同齢野生型対照における卵巣および精巣腫瘍の組織学的試験を行った。8週齢雄および12週齢雌インヒビン-αKOマウスには、sActRIIBまたはPBSの単回注射を行った。処置の14日後に、卵巣器官および精巣器官を剖検によって収集した。組織切片を、卵巣については過ヨウ素酸シッフ染色、精巣についてはマッソン三色染色に付した。
ヌードマウス中のTOV21G腫瘍性超阻害に対するアクチビンアンタゴニストsActRIIBおよび細胞毒性化学療法剤5-フルオロウラシルの効果。(図9A)TOV-21G異種移植片を有するヌードマウスを、腫瘍移植後12日目に、それぞれsActRIIB、5-Fu、またはsActRIIBと5-Fuとの組み合わせで処置した。腫瘍体積の変化を経時的に記録した。sActRIIBは単独で腫瘍体積を34%減少させ、5-フルオロウラシル(5-FU)は単独で腫瘍体積を49%減少させることが、図9Aでわかる。しかし、これら2つを組み合わせると、腫瘍体積は74%減少する。
Claims (1)
- (i)SEQ ID NO:91のアミノ酸配列を含み、かつ、ミオスタチン、アクチビンA、またはGDF-11を結合させることができる、変異アクチビンIIB受容体ポリペプチド(vActRIIB)と、(ii)5-フルオロウラシル(5-FU)を含む化学療法剤とを含む、薬学的組成物。
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