JP5330398B2 - サイトカインムテイン - Google Patents
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- JP5330398B2 JP5330398B2 JP2010530226A JP2010530226A JP5330398B2 JP 5330398 B2 JP5330398 B2 JP 5330398B2 JP 2010530226 A JP2010530226 A JP 2010530226A JP 2010530226 A JP2010530226 A JP 2010530226A JP 5330398 B2 JP5330398 B2 JP 5330398B2
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Description
本出願は、2007年10月26日に提出された米国仮特許出願第61/000,576号と関連し、かつそれによる優先権を主張するものであり、その全内容は参照により本明細書に組み入れられる。
本発明は一般に、インターロイキン-11(IL-11)媒介性状態の治療に関する。より詳細には、本発明は、IL-11媒介性状態の治療における、IL-11シグナル伝達をモジュレートする改変型のIL-11の使用を提供する。
本明細書中に提示している参考文献の文献学的詳細は、明細書の最後に列記されている。
本明細書の全体を通じて、文脈が別のものを要求しない限り、「含む(comprise)」という用語、または「含む(comprises)」もしくは「含むこと(comprising)」などの変形物は、言及した要素または整数または要素もしくは整数の群を含むものの、他の要素または整数または要素もしくは整数の群を除外しないことを意味するものと解釈されるものとする。
以下に、本発明の基本的な諸特徴および種々の態様を列挙する。
[1]
野生型哺乳動物IL-11の58〜62位のアミノ酸配列AMSAGが、アミノ酸配列PAIDYまたはFMQIQに置き換えられている、IL-11ムテイン。
[2]
アミノ酸配列AMSAGがPAIDYに置き換えられている、[1]記載のIL-11ムテイン。
[3]
アミノ酸配列AMSAGがFMQIQに置き換えられている、[1]記載のIL-11ムテイン。
[4]
そのgp130との結合を阻害するかまたは低下させるさらなる突然変異を含む、[1]または[2]または[3]のいずれか一項記載のIL-11ムテイン。
[5]
前記さらなる突然変異が、野生型IL-11のアミノ酸147位におけるトリプトファン(W)のアミノ酸置換である、[4]記載のIL-11ムテイン。
[6]
前記トリプトファン(W)がアラニン(A)またはシステイン(C)に置換されている、[5]記載のIL-11ムテイン。
[7]
SEQ ID NO:4、SEQ ID NO:4のアミノ酸10〜178位、SEQ ID NO:4のアミノ酸10〜175位、SEQ ID NO:5、SEQ ID NO:5のアミノ酸10〜178位、SEQ ID NO:5のアミノ酸10〜175位、SEQ ID NO:6、SEQ ID NO:6のアミノ酸10〜178位、SEQ ID NO:6のアミノ酸10〜175位、SEQ ID NO:7、SEQ ID NO:7のアミノ酸10〜178位、SEQ ID NO:7のアミノ酸10〜175位、SEQ ID NO:8、SEQ ID NO:8のアミノ酸10〜178位、SEQ ID NO:8のアミノ酸10〜175位、SEQ ID NO:13、SEQ ID NO:13のアミノ酸10〜178位およびSEQ ID NO:13のアミノ酸10〜175位から選択されるアミノ酸配列を含む、[1]記載のIL-11ムテイン。
[8]
SEQ ID NO:9、SEQ ID NO:9のアミノ酸10〜178位、SEQ ID NO:9のアミノ酸10〜175位、SEQ ID NO:10、SEQ ID NO:10のアミノ酸10〜178位、SEQ ID NO:10のアミノ酸10〜175位、SEQ ID NO:11、SEQ ID NO:11のアミノ酸10〜178位、SEQ ID NO:11のアミノ酸10〜175位、SEQ ID NO:12、SEQ ID NO:12のアミノ酸10〜178位、SEQ ID NO:12のアミノ酸10〜175位、SEQ ID NO:14、SEQ ID NO:14のアミノ酸10〜178位、SEQ ID NO:14のアミノ酸10〜175位、SEQ ID NO:15、SEQ ID NO:15のアミノ酸10〜178位、SEQ ID NO:15のアミノ酸10〜175位、SEQ ID NO:16、SEQ ID NO:16のアミノ酸10〜178位、SEQ ID NO:16のアミノ酸10〜175位、SEQ ID NO:17、SEQ ID NO:17のアミノ酸10〜178位、SEQ ID NO:17のアミノ酸10〜175位、SEQ ID NO:18、SEQ ID NO:18のアミノ酸10〜178位、SEQ ID NO:18のアミノ酸10〜175位、SEQ ID NO:19、SEQ ID NO:19のアミノ酸10〜178位、SEQ ID NO:19のアミノ酸10〜175位、SEQ ID NO:20、SEQ ID NO:20のアミノ酸10〜178位、SEQ ID NO:20のアミノ酸10〜175位、SEQ ID NO:21、SEQ ID NO:21のアミノ酸10〜178位およびSEQ ID NO:21のアミノ酸10〜175位から選択されるアミノ酸配列を含む、[1]記載のIL-11ムテイン。
[9]
PEG化されている、[1]または[7]または[8]のいずれか一項記載のIL-11ムテイン。
[10]
[1]〜[9]のいずれか一項記載のIL-11ムテイン、ならびに1つまたは複数の薬学的に許容される担体、希釈剤および/または添加剤を含む、薬学的組成物。
[11]
[1]〜[9]のいずれか一項記載のIL-11ムテインの有効量を対象に投与する段階を含む、IL-11媒介性状態を治療するための方法。
[12]
IL-11媒介性状態の治療のための医薬の製造における、[1]〜[9]のいずれか一項記載のIL-11ムテインの使用。
本明細書で用いる場合、単数形の「1つの(a)」、「1つの(an)」および「その(the)」は、文脈で明らかに別の指示がなされない限り、複数の局面を含む。したがって、例えば、「1つのムテイン(a mutein)」に対する言及は、単一のムテインのほかに、2つまたはそれ以上のムテインを含み;「1つの薬剤(an agent)」に対する言及は、単一の薬剤のほかに、2つまたはそれ以上の薬剤を含み;「本発明」に対する言及は、本発明の単一または複数の局面を含み;その他についても同様である。
IL-11突然変異タンパク質
A.可溶性IL-11突然変異タンパク質の組換え生産
IL-11突然変異体1.21(SEQ ID NO:10)、1B.382(SEQ ID NO:17)およびmIL-11-W147Aを、改変型のpET15bベクター(Novagen Cat #69661-3)中にクローニングした。pET15bベクターは、トロンビン切断部位およびマルチクローニング部位をAscIおよびEcoRI制限部位に置き換えること、ならびにM13複製起点を挿入することによって改変しており、そのためこのベクターはファージミドとして用いることができた。
突然変異IL-11タンパク質がIL-11生物活性を阻止する能力を調べるために、IL-11応答性Ba/F3細胞系を作製した。通常はIL-11Rαもgp130も発現せず、IL-11に応答して増殖することもない、マウスのプロBリンパ球細胞系であるBa/F3細胞に対して、野生型マウスIL-11Rαおよび補助受容体マウスgp130をコードする構築物を安定的にトランスフェクトし、IL-11を含む培地中での増殖によって選択した。クローン化細胞系を限界希釈クローニングによって導き出した。安定的にトランスフェクトされたさまざまなクローンを、IL-11の存在下で培養した場合のそれらの用量応答性増殖(MTTアッセイを用いて)に関して分析し、1つを以降の検討のために選択した。
PEG化IL-11ムテイン
PEG化IL-11ムテインの生産
マウスIL-11の成熟タンパク質配列は、トロンビンによって切断可能であって、その結果として最初の9個のアミノ酸の除去が起こる、アミノ酸配列を含む。最初の9個のアミノ酸を有するIL-11ムテイン1.21(SEQ ID NO:10)とそれを有しないものとの比較では同一な活性が示され、このことからマウスIL-11の最初の9個の残基はIL-11 Rα結合には必要でないことが指し示された。その内部トロンビン部位を、効率的な切断を可能にするための部位指定突然変異誘発により、残基6および7位の、それぞれLeu(L)およびVal(V)への突然変異によって最適化した。SEQ ID NO:12のアミノ酸10〜178位のPEG化IL-11ムテインの大規模生産のために、改変mIL-11配列のアミノ末端Hisタグおよび最初の9個の残基をトロンビン消化によって除去した。
小型タンパク質のインビボ使用の制約となるのは、血行からのそれらの迅速な排除である。排除の主な経路の1つは腎臓を通しての濾過を介したものであり、その効率は分子量と反比例する。小型タンパク質のインビボでの排除速度を低下させるための1つの戦略は、ポリエチレングリコールによる化学的改変を通じてのものであるが(Tsutsumi et al, Thjromb. Haemost. 77.1:168-73, 1997)、これは、不適切な部位に結び付いた場合にはタンパク質の活性を低下させ、さらにはそれを消失させてしまう恐れがある。
インビボ半減期
雌性C57BL/6Jマウス(8週齡前後および20±2g)を、PEG化ムテイン(Δ1.21)およびPEG化していないトロンビン切断したムテイン1.21(すなわち、SEQ ID NO:10のアミノ酸10〜178位)のインビボ半減期の決定のために用いた。各マウスに1回のIP注射を行った。マウスに対して、トロンビン切断したムテイン1.21を1mg/kgの用量(動物個体当たり20ug)で、または等モル用量のΔ1.21を3.2mg/kg(動物個体当たり64ug)の用量で注射した。IP注射後の適切な時点で、マウスをCO2吸入およびその後の頸椎脱臼によって殺処理し、心臓穿刺によって血液を採取した。37℃での1時間のインキュベーション、および続いて4℃で一晩置くことによって血清を血液から分離させ、その後に遠心によって赤血球をペレット化した。血液は、トロンビン切断したムテイン1.21を注射したマウスからは5分、10分、30分、1時間、2時間および5時間の時点で採取し、Δ1.21を注射したマウスからは10分、1時間、2時間、6時間、24時間、48時間および72時間の時点で採取した。各時点について合計4匹のマウスを用いた。
PEG化ヒトIL-11ムテイン
PEG化ヒトIL-11ムテインを、SEQ ID NO:11に基づいて調製した。マウスIL-11ムテインに関して上述した一般的アプローチを用いて、これを記載した通りに発現させ、精製して、リフォールディングさせた上で、Cys147(番号付けはSEQ ID NO:11に基づく)において部位特異的にPEG化した。ヒトIL-11は内部トロンビン部位を含まないため、ヒトIL-11配列の最初の9個のアミノ酸ならびにベクター由来のタグ配列は保持されてSEQ ID NO:22のムテインが得られた。
Claims (10)
- 野生型ヒトIL-11の58〜62位のアミノ酸配列AMSAGが、アミノ酸配列PAIDYまたはFMQIQに置き換えられている、IL-11ムテイン。
- アミノ酸配列AMSAGがPAIDYに置き換えられている、請求項1記載のIL-11ムテイン。
- アミノ酸配列AMSAGがFMQIQに置き換えられている、請求項1記載のIL-11ムテイン。
- gp130に結合する能力を阻害するかまたは低下させるさらなる突然変異を含む、請求項1または2または3のいずれか一項記載のIL-11ムテインであって、前記さらなる突然変異が、野生型IL-11のアミノ酸147位におけるトリプトファン(W)のアミノ酸置換であり、ここで該トリプトファン(W)がアラニン(A)またはシステイン(C)に置換されている、IL-11ムテイン。
- SEQ ID NO:4、SEQ ID NO:4のアミノ酸10〜178位、SEQ ID NO:4のアミノ酸10〜175位、SEQ ID NO:5、SEQ ID NO:5のアミノ酸10〜178位、SEQ ID NO:5のアミノ酸10〜175位、SEQ ID NO:6、SEQ ID NO:6のアミノ酸10〜178位、SEQ ID NO:6のアミノ酸10〜175位、SEQ ID NO:7、SEQ ID NO:7のアミノ酸10〜178位、SEQ ID NO:7のアミノ酸10〜175位、SEQ ID NO:8、SEQ ID NO:8のアミノ酸10〜178位、SEQ ID NO:8のアミノ酸10〜175位、SEQ ID NO:13、SEQ ID NO:13のアミノ酸10〜178位およびSEQ ID NO:13のアミノ酸10〜175位から選択されるアミノ酸配列を含む、請求項1記載のIL-11ムテイン。
- SEQ ID NO:9、SEQ ID NO:9のアミノ酸10〜178位、SEQ ID NO:9のアミノ酸10〜175位、SEQ ID NO:10、SEQ ID NO:10のアミノ酸10〜178位、SEQ ID NO:10のアミノ酸10〜175位、SEQ ID NO:11、SEQ ID NO:11のアミノ酸10〜178位、SEQ ID NO:11のアミノ酸10〜175位、SEQ ID NO:12、SEQ ID NO:12のアミノ酸10〜178位、SEQ ID NO:12のアミノ酸10〜175位、SEQ ID NO:14、SEQ ID NO:14のアミノ酸10〜178位、SEQ ID NO:14のアミノ酸10〜175位、SEQ ID NO:15、SEQ ID NO:15のアミノ酸10〜178位、SEQ ID NO:15のアミノ酸10〜175位、SEQ ID NO:16、SEQ ID NO:16のアミノ酸10〜178位、SEQ ID NO:16のアミノ酸10〜175位、SEQ ID NO:17、SEQ ID NO:17のアミノ酸10〜178位、SEQ ID NO:17のアミノ酸10〜175位、SEQ ID NO:18、SEQ ID NO:18のアミノ酸10〜178位、SEQ ID NO:18のアミノ酸10〜175位、SEQ ID NO:19、SEQ ID NO:19のアミノ酸10〜178位、SEQ ID NO:19のアミノ酸10〜175位、SEQ ID NO:20、SEQ ID NO:20のアミノ酸10〜178位、SEQ ID NO:20のアミノ酸10〜175位、SEQ ID NO:21、SEQ ID NO:21のアミノ酸10〜178位およびSEQ ID NO:21のアミノ酸10〜175位から選択されるアミノ酸配列を含む、請求項1記載のIL-11ムテイン。
- PEG化されている、請求項1または5または6のいずれか一項記載のIL-11ムテイン。
- 請求項1〜7のいずれか一項記載のIL-11ムテイン、ならびに1つまたは複数の薬学的に許容される担体、希釈剤および/または添加剤を含む、薬学的組成物。
- 転移性骨癌、骨髄腫、ページェット骨病、もしくは骨粗鬆症の治療のため、または避妊を誘導するための薬学的組成物であって、請求項1〜7のいずれか一項記載のIL-11ムテインの有効量を含む、薬学的組成物。
- 転移性骨癌、骨髄腫、ページェット骨病、もしくは骨粗鬆症の治療のため、または避妊を誘導するための医薬の製造における、請求項1〜7のいずれか一項記載のIL-11ムテインの使用。
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GB201522186D0 (en) | 2015-12-16 | 2016-01-27 | Singapore Health Services Pte Ltd And Nat University Of Singapore The | Treatment of fibrosis |
GB201621439D0 (en) | 2016-12-16 | 2017-02-01 | Singapore Health Services Pte Ltd And Nat Univ Of Singapore | IL-11Ra Antibodies |
WO2018109174A2 (en) | 2016-12-16 | 2018-06-21 | Singapore Health Services Pte Ltd | Il-11 antibodies |
GB201621431D0 (en) | 2016-12-16 | 2017-02-01 | Singapore Health Services Pte Ltd And Nat Univ Of Singapore The | Decoy cytokine receptor |
CA3126322A1 (en) | 2019-01-21 | 2020-07-30 | Singapore Health Services Pte. Ltd. | Treatment of hepatotoxicity |
GB201902419D0 (en) | 2019-02-22 | 2019-04-10 | Singapore Health Serv Pte Ltd | Treatment of kidney injury |
GB201906291D0 (en) | 2019-05-03 | 2019-06-19 | Singapore Health Serv Pte Ltd | Treatment and prevention of metabolic diseases |
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GB202017244D0 (en) | 2020-10-30 | 2020-12-16 | Nat Univ Singapore | Methods to extend health-span and treat age-related diseases |
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US4959455A (en) | 1986-07-14 | 1990-09-25 | Genetics Institute, Inc. | Primate hematopoietic growth factors IL-3 and pharmaceutical compositions |
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