JP7477905B2 - Cd137に特異的なタンパク質 - Google Patents
Cd137に特異的なタンパク質 Download PDFInfo
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- JP7477905B2 JP7477905B2 JP2022152103A JP2022152103A JP7477905B2 JP 7477905 B2 JP7477905 B2 JP 7477905B2 JP 2022152103 A JP2022152103 A JP 2022152103A JP 2022152103 A JP2022152103 A JP 2022152103A JP 7477905 B2 JP7477905 B2 JP 7477905B2
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Description
CD137は、腫瘍壊死因子受容体(TNFR)スーパーファミリー分子であり、その活性は、免疫が介在する多くの自己免疫疾患および炎症性疾患に関与しうる。これはがん免疫治療のターゲットでもある。
以下の一覧では、本明細書の全体を通して使用される用語、語句、および略号を定義する。本明細書に列挙して定義する用語はいずれも、すべての文法形式を包含するものとする。
[本発明1001]
KDが約300nM以下である親和性でCD137に結合する能力を有するリポカリンムテイン。
[本発明1002]
成熟ヒト涙液リポカリンの直鎖ポリペプチド配列(SEQ ID NO:1)の配列位置5、26~31、33~34、42、46、52、56、58、60~61、65、71、85、94、101、104~106、108、111、114、121、133、148、150および153に少なくとも1つの変異アミノ酸残基を含む、本発明1001のムテイン。
[本発明1003]
ムテインのアミノ酸配列が、成熟ヒト涙液リポカリンの直鎖ポリペプチド配列(SEQ ID NO:1)と比較して以下の変異アミノ酸残基のうちの少なくとも1つを含む、本発明1002のムテイン:
。
[本発明1004]
本質的に実施例4に記載するように表面プラズモン共鳴(SPR)分析によって測定した場合に、KDが約270nM以下である親和性でCD137に結合する、本発明1002または1003のいずれかのムテイン。
[本発明1005]
本質的に実施例6に記載するようにFACS分析によって測定した場合に、約250nM以下のEC50値でCD137に結合する、本発明1002または1003のいずれかのムテイン。
[本発明1006]
ムテインのアミノ酸配列が以下の組のアミノ酸置換のうちの1組を含む、本発明1002~1005のいずれかのムテイン:
。
[本発明1007]
本質的に実施例5に記載するように表面プラズモン共鳴(SPR)アッセイにおいて測定した場合に、CD137へのCD137Lの結合を妨害する能力を有する、本発明1002または1003のいずれかのムテイン。
[本発明1008]
SEQ ID NO:5~11からなる群またはそれらのフラグメントもしくは変異体からなる群より選択されるアミノ酸配列を含む、本発明1002~1005のいずれかのムテイン。
[本発明1009]
SEQ ID NO:5~11からなる群より選択されるアミノ酸配列に対して少なくとも85%の配列同一性を有する、本発明1002~1005のいずれかのリポカリンムテイン。
[本発明1010]
成熟hNGALの直鎖ポリペプチド配列(SEQ ID NO:2)の配列位置28、36、40~41、49、52、65、68、70、72~73、77、79、81、83、87、94、96、100、103、106、125、127、132および134に少なくとも1つの変異アミノ酸残基を含む、本発明1001のムテイン。
[本発明1011]
ムテインのアミノ酸配列が、成熟ヒト涙液リポカリンの直鎖ポリペプチド配列(SEQ ID NO:2)と比較して、以下の変異アミノ酸残基のうちの少なくとも1つを含む、本発明1010のムテイン:
。
[本発明1012]
本質的に実施例4に記載するように表面プラズモン共鳴(SPR)分析によって測定した場合に、KDが約150nM以下である親和性でCD137に結合する、本発明1010または1011のいずれかのムテイン。
[本発明1013]
本質的に実施例6に記載するようにFACS分析によって測定した場合に、約18nM以下のEC50値でCD137に結合する、本発明1010または1011のいずれかのムテイン。
[本発明1014]
本質的に実施例7に記載するように機能的T細胞活性化アッセイにおいて測定した場合に、SEQ ID NO:4の陰性対照と比較して、より高いIL-2濃度を誘導する能力を有する、本発明1010または1011のいずれかのムテイン。
[本発明1015]
本質的に実施例8に記載するように機能的T細胞活性化アッセイにおいて測定した場合に、SEQ ID NO:4の陰性対照と比較して、より高いIL-2濃度をもたらさない、本発明1010または1011のいずれかのムテイン。
[本発明1016]
本質的に実施例9に記載するように機能的T細胞活性化アッセイにおいて測定した場合に、SEQ ID NO:4の陰性対照と比較して、より高いIL-2およびIFN-γ増殖を誘発する能力を有する、本発明1010または1011のいずれかのムテイン。
[本発明1017]
ムテインのアミノ酸配列が、以下の組のアミノ酸置換のうちの1組を含む、本発明1010~1016のいずれかのムテイン:
。
[本発明1018]
本質的に実施例5に記載するように表面プラズモン共鳴(SPR)アッセイにおいて測定した場合に、CD137へのCD137Lの結合を妨害しない、本発明1010または1011のいずれかのムテイン。
[本発明1019]
SEQ ID NO:12~20からなる群またはそれらのフラグメントもしくは変異体からなる群より選択されるアミノ酸配列を含む、本発明1010~1016のいずれかのムテイン。
[本発明1020]
SEQ ID NO:12~20からなる群より選択されるアミノ酸配列に対して少なくとも85%の配列同一性を有する、本発明1010~1016のいずれかのリポカリンムテイン。
[本発明1021]
有機分子、酵素標識、放射性標識、着色標識、蛍光標識、発色標識、発光標識、ハプテン、ジゴキシゲニン、ビオチン、細胞分裂阻害剤、毒素、金属錯体、金属、およびコロイド金からなる群より選択される化合物にコンジュゲートされている、本発明1001~1020のいずれかのリポカリンムテイン。
[本発明1022]
N末および/またはC末において、タンパク質またはタンパク質ドメインもしくはペプチドである融合パートナーに融合されている、本発明1001~1020のいずれかのリポカリンムテイン。
[本発明1023]
ムテインの血清中半減期を延ばす化合物にコンジュゲートされている、本発明1001~1020のいずれかのリポカリンムテイン。
[本発明1024]
血清中半減期を延ばす化合物が、ポリアルキレングリコール分子、ヒドロエチルデンプン(hydroethylstarch)、免疫グロブリンのFc部分、免疫グロブリンのCH3ドメイン、免疫グロブリンのCH4ドメイン、アルブミン結合ペプチド、およびアルブミン結合タンパク質からなる群より選択される、本発明1001~1020のいずれかのリポカリンムテイン。
[本発明1025]
ポリアルキレングリコールがポリエチレン(PEG)またはその活性化誘導体である、本発明1024のリポカリンムテイン。
[本発明1026]
本発明1001~1025のいずれかのムテインをコードするヌクレオチド配列を含む核酸分子。
[本発明1027]
本発明1026の核酸分子を含有する宿主細胞。
[本発明1028]
ムテインをコードする核酸から出発して遺伝子工学の方法を使ってムテインが生産される、本発明1001~1025のいずれかのムテインを生産する方法。
[本発明1029]
本発明1001~1025のいずれかの1つもしくは複数のリポカリンムテインまたはそのようなムテインを含む1つもしくは複数の組成物を適用する工程を含む、CD37の結合方法。
[本発明1030]
本発明1001~1025のいずれかの1つもしくは複数のリポカリンムテインまたはそのようなムテインを含む1つもしくは複数の組成物を適用する工程を含む、CD137の下流シグナリング経路を活性化する方法。
[本発明1031]
本発明1001~1025のいずれかの1つもしくは複数のリポカリンムテインまたはそのようなムテインを含む1つもしくは複数の組成物を適用する工程を含む、Tリンパ球増殖を誘発する方法。
[本発明1032]
本発明1007の1つもしくは複数のリポカリンムテインまたはそのようなムテインを含む1つもしくは複数の組成物を適用する工程を含む、CD137へのCD137Lの結合を妨害する方法。
[本発明1033]
本発明1007の1つもしくは複数のリポカリンムテインまたはそのようなムテインを含む1つもしくは複数の組成物を適用する工程を含む、炎症誘発性サイトカインおよびケモカインの生産を低減する方法。
本明細書にいう「リポカリン」は、複数(好ましくは4つ)のループにより一端においてペアワイズに接続されることで結合ポケットを規定している複数(好ましくは8つ)のβストランドを含む円柱状のβプリーツシート超二次構造領域を有する、重量が約18~20kDAの単量体型タンパク質と定義される。サイズ、形状、および化学的特徴が異なるターゲットを収容する能力をそれぞれが有するリポカリンファミリーメンバー間に、さまざまな異なる結合様式を生じさせるのは、他の点では剛直なリポカリンスキャフォールドにおけるループの多様性である(例えばFlower, D.R.(1996)、前掲、Flower, D.R. et al.(2000)、前掲、またはSkerra, A.(2000)Biochim. Biophys. Acta 1482, 337-350に概説されている)。事実、リポカリンタンパク質ファミリーは、広範なリガンドに結合するように自然に進化しており、それらが共有する全体的配列保存のレベルは異常に低い(多くの場合、配列同一性は20%未満である)にもかかわらず、高度に保存された全体的フォールディングパターンを保っている。さまざまなリポカリンにおける位置間の対応は当業者には周知である。例えば米国特許第7,250,297号を参照されたい。
一局面において、本開示は、CD137に結合するヒトリポカリンムテイン、およびその有用な応用を提供する。本開示は、本明細書に記載するCD137結合タンパク質を作製する方法、ならびにそのようなタンパク質を含む組成物も提供する。本開示のCD137結合タンパク質およびその組成物は、試料中のCD137を検出する方法において、または対象におけるCD137の結合方法において、使用されうる。本開示が提供する用途に付随するこれらの特徴を有するそのようなヒトリポカリンムテインが、以前に記載されたことはなかった。
本開示の一態様は、例えば本質的に実施例4に記載するように表面プラズモン共鳴(SPR)分析によって決定した場合に、KDで測って約300nM、100nM、75nM、50nM、25nM、10nMまたはそれ未満の、例えば2nMの親和性で、CD137に結合する能力を有するリポカリンムテインに関する。
。いくつかの態様において、本開示によるTlcムテインは、成熟ヒト涙液リポカリンのこれらの配列位置における変異アミノ酸残基を、2つまたはそれ以上、例えば3、4、5、6、7、8、9、10、11、12個、さらにそれ以上、例えば13、14、15、16、17、18、19、20、21、22、23、24、25、26個、またはすべて含む。
。
CD137は、T細胞受容体(TCR)活性化時に誘導されるT細胞共刺激受容体である(Nam et al., Curr. Cancer Drug Targets, 5:357-363(2005); Watts et al., Annu. Rev. Immunol., 23:23-68(2005))。CD137は、活性化CD4+およびCD8+ T細胞におけるその発現に加えて、CD4+CD25+制御性T細胞、ナチュラルキラー(NK)およびNK-T細胞、単球、好中球、および樹状細胞でも発現する。その天然リガンドであるCD137Lは、B細胞、単球/マクロファージ、および樹状細胞を含む抗原提示細胞での記載がある(Watts et al., Annu. Rev. Immunol., 23:23-68(2005))。CD137は、そのリガンドと相互作用すると、増加したTCR誘発性T細胞増殖、サイトカイン生産、機能的成熟、および長期間にわたるCD8+ T細胞生存をもたらす(Nam et al., Curr. Cancer Drug Targets, 5:357-363(2005), Watts et al., Annu. Rev. Immunol., 23:23-68(2005))。
リポカリンは、リガンドに結合するように自然に進化したタンパク質結合分子である。リポカリンは、脊椎動物、昆虫、植物および細菌を含む多くの生物に見いだされる。リポカリンタンパク質ファミリーのメンバー(Pervaiz, S., & Brew, K.(1987)FASEB J. 1, 209-214)は、典型的には、小さな分泌タンパク質であり、単一のポリペプチド鎖を有する。それらは一連の異なる分子認識特性、すなわち、さまざまな、主として疎水性の分子(レチノイド、脂肪酸、コレステロール、プロスタグランジン、ビリベルジン、フェロモン、味物質、およびにおい物質など)に結合するそれらの能力、特異的細胞表面受容体へのそれらの結合、およびそれらの高分子複合体形成によって特徴づけられる。リポカリンは以前は主に輸送タンパク質として分類されていたが、リポカリンはさまざまな生理学的機能を果たすことが、現在では明らかになっている。それらには、レチノール輸送、嗅覚、フェロモンシグナリング、およびプロスタグランジンの合成における役割が含まれる。リポカリンは、免疫応答の制御および細胞ホメオスタシスの媒介にも関係づけられている(例えばFlower, D.R.(1996)Biochem. J. 318, 1-14およびFlower, D.R. et al.(2000)Biochim. Biophys. Acta 1482, 9-24に概説されている)。
である。他の置換も許容され、それらは実験的に決定することができるか、または他の公知の保存的もしくは非保存的置換に一致しうる。さらなる指針として、以下の8つのグループは、それぞれが、典型的には互いに保存的置換を規定すると解釈することができるアミノ酸を含んでいる:
a.アラニン(Ala)、グリシン(Gly);
b.アスパラギン酸(Asp)、グルタミン酸(Glu);
c.アスパラギン(Asn)、グルタミン(Gln);
d.アルギニン(Arg)、リジン(Lys);
e.イソロイシン(Ile)、ロイシン(Leu)、メチオニン(Met)、バリン(Val);
f.フェニルアラニン(Phe)、チロシン(Tyr)、トリプトファン(Trp);
g.セリン(Ser)、スレオニン(Thr)、および
h.システイン(Cys)、メチオニン(Met)。
である。
実施例1:CD137に特異的に結合するムテインの選択および最適化
本願において開示する代表的なCD137特異的リポカリンムテインは、ヒトNGALおよびヒトTLcに基づくナイーブ突然変異体ライブラリーから選択された。CD137結合性ムテインを得るために異なる戦略および異なるターゲットを使用した。利用した組換えターゲットは、ヒトからのCD137の全細胞外ドメインの市販Fc融合物(huCD137-Fc、R&D Systems 838-4B)およびいずれもヒトFcフラグメントへの融合物として作製されたヒトCD137の個々のサブドメインである。代替的非Fc融合物ターゲットとして、本発明者らはHisタグ付きヒトCD137細胞外ドメイン(Invitrogen、10041-H08H-250)を使用した。あるいは、ヒトCD137の全cDNAをトランスフェクトしたCHO細胞を用いる細胞ベースのパニングを使用した。タンパク質ベースおよび細胞ベースのパニングは標準的手法を使って行った。選択後に得られたクローンを、実施例2に記載するスクリーニング工程に付した。
C末Strep-tag(SEQ ID NO:23、実施例3参照)に融合された個々のリポカリンムテインを使って、2×YT/Amp培地に接種し、定常期まで終夜(14~18時間)成長させた。次に、定常期培養物から50μLの2×YT/Ampに接種し、37℃で3時間インキュベートした後、OD595が0.6~0.8に達するまで22℃に移行した。1.2μg/mlアンヒドロテトラサイクリンを補足した2×YT/Ampを10μL添加することによって、ムテインの生産を誘発した。培養物を翌日まで22℃でインキュベートした。PBS/T中の5%(w/v)BSA 40μLを添加し、25℃で1時間インキュベートした時点で、培養物はスクリーニングアッセイに使用する準備が整った。
発現後にStreptactinアフィニティークロマトグラフィーおよび分取用サイズ排除クロマトグラフィーを使ってムテインを精製するために、SAまたはPSAリンカーとStrep-tag(登録商標)II、WSHPQFEK(SEQ ID NO:23)とを含むC末タグ
を持つユニークなムテインを、2YT-Amp培地中、大腸菌で発現させた。最後に、Mustang Eカラムを利用するエンドトキシン枯渇工程に、リポカリンムテインを付した。次に、精製されたリポカリンムテインを、以下のすべての実施例において詳述するように特徴づけた。
表面プラズモン共鳴(SPR)を使って、本明細書において開示する代表的なリポカリンムテインの結合速度および親和性を測定した。
CD137に結合する本願記載のリポカリンムテインについては、一般に、2つの結合様式が可能である。第1の場合は、ムテインの結合部位がCD137へのヒトCD137リガンド(CD137L)の結合部位とオーバーラップする。そのようなリポカリンムテインがCD137に結合する場合、これは、CD137へのCD137Lの結合を妨害し、それに伴って、天然CD137Lシグナリングの妨害をもたらす(「競合結合」)。第2の場合は、ムテインの結合部位がCD137Lの結合部位とオーバーラップせず、そのようなリポカリンムテインは、CD137L結合および天然のCD137Lシグナリングを妨害することなく、CD137に結合することができる(「非競合結合」)。
ヒトCD137が安定にトランスフェクトされたチャイニーズハムスター卵巣(CHO)細胞(CHO-huCD137)へのリポカリンムテインおよび陰性対照の特異的結合を評価するために、本発明者らはFACS研究を使用した。細胞株は、Flp-Inシステム(Invitrogen)を製造者の説明書に従って使用することによって作製した。モックトランスフェクトFlp-In CHO細胞を陰性対照とした。
本発明者らはT細胞活性化アッセイを使って、一組の代表的CD137結合性リポカリンムテインの、T細胞応答を共刺激する能力を評価した。試験したムテイン(SEQ ID NO:13、SEQ ID NO:14、およびSEQ ID NO:15)は、実施例4において、2nMから>23nMまでの範囲のSPR親和性にまたがる(表1参照)。実施例5で述べたように、CD137のクラスター化を誘発するにはいくつかの方法があり、この実験では固定化CD137結合作用物質を適用した。リポカリンムテインを抗ヒトCD3抗体(ムロノマブ(Muronomab)、Janssen-Cilag)と一緒にプラスチック製ディッシュにコーティングし、次にその被覆表面上で、精製T細胞を可溶性抗ヒトCD28抗体(クローン28.2; eBioscience)の存在下でインキュベートした。CD137共刺激による共刺激を受けうるT細胞に閾値未満の刺激を与えるために、
抗CD3抗体および抗CD28抗体を使用した。読み出し情報として、本発明者らは上清インターロイキン2(IL-2)レベルを測定した。IL-2生産の増加はT細胞活性化の特徴の一つであり、抗CD137抗体での共刺激によるIL-2レベルの増加は文献に記載されている(Fisher T.S. et al., Cancer Immunol Immunother(2012)61:1721-1733)。陰性対照として、SEQ ID NO:4を利用した。以下に、この実験を詳細に説明する。
代表的リポカリンムテインがクラスター化なしで単に結合するだけでもCD137を活性化できるかどうかを試験するために、実施例7のアッセイを、実施例5と同様の方法で、ただし捕捉されたリポカリンムテインではなく可溶性リポカリンムテインを使用することによって実行した。このアッセイでは、平底組織培養プレートを上述のように、ただし抗CD3抗体だけを使ってコーティングした。T細胞添加工程(2μg/mL hCD28を含む)後まではプレートを上述のように処理し、次に、溶解状態にある濃度25μg/mLのリポカリンムテイン50μLを添加した。
SEQ ID NO:13のムテインが持つT細胞応答共刺激能力をさらに詳細に調べるために、本発明者らは実施例7と同様のT細胞活性化アッセイを使用した。本発明者らは、読み出し情報として、3日間のインキュベーション後のT細胞増殖の継続を、4時間BrdUパルスを使って評価し、上清のIL-2レベルおよびインターフェロンガンマ(IFN-g)レベルを測定した。増殖およびIL-2生産に加えて、IFN-g生産の増加もT細胞活性化のさらなる特徴であり、抗CD137抗体での共刺激によるIFN-γレベルの増加は文献に記載がある(Jure-Kunkel, M.らの米国特許第7288638号)。
SEQUENCE LISTING
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Val Val Gly Gln Ala Gly Asn Ile Arg Leu Arg Glu Asp Lys Asp Pro
35 40 45
Ile Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Met Val Lys Phe Asp Asp Lys Lys Cys Met Tyr Asp Ile
65 70 75 80
Trp Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 14
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 14
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Arg Leu Arg Glu Asp Lys Asp Pro
35 40 45
Asn Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Ala Val Ala Phe Asp Asp Lys Lys Cys Thr Tyr Asp Ile
65 70 75 80
Trp Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 15
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin muein
<400> 15
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Lys Leu Arg Glu Asp Lys Asp Pro
35 40 45
Asn Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Ala Val Ala Phe Asp Asp Lys Lys Cys Thr Tyr Asp Ile
65 70 75 80
Trp Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 16
<211> 175
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 16
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Lys Leu Arg Glu Asp Ser Lys Met
35 40 45
Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr Asp Val Thr
50 55 60
Gly Val Ser Phe Asp Asp Lys Lys Cys Thr Tyr Ala Ile Met Thr Phe
65 70 75 80
Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys Ile Lys Ser
85 90 95
Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser Thr Asn Tyr
100 105 110
Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln Asn Arg Glu
115 120 125
Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu Thr Ser Glu
130 135 140
Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly Leu Pro Glu
145 150 155 160
Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile Asp Gly
165 170 175
<210> 17
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 17
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Lys Leu Arg Glu Asp Lys Asp Pro
35 40 45
Val Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Gly Val Thr Phe Asp Asp Lys Lys Cys Arg Tyr Asp Ile
65 70 75 80
Ser Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Phe Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 18
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 18
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Arg Leu Arg Glu Asp Lys Asp Pro
35 40 45
His Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Gly Val Thr Phe Asp Asp Lys Lys Cys Thr Tyr Ala Ile
65 70 75 80
Ser Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 19
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 19
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Lys Leu Arg Glu Asp Lys Asp Pro
35 40 45
Asn Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Gly Val Thr Phe Asp Asp Lys Lys Cys Thr Tyr Ala Ile
65 70 75 80
Ser Thr Leu Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Phe Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 20
<211> 178
<212> PRT
<213> artificial
<220>
<223> lipocalin mutein
<400> 20
Gln Asp Ser Thr Ser Asp Leu Ile Pro Ala Pro Pro Leu Ser Lys Val
1 5 10 15
Pro Leu Gln Gln Asn Phe Gln Asp Asn Gln Phe His Gly Lys Trp Tyr
20 25 30
Val Val Gly Gln Ala Gly Asn Ile Arg Leu Arg Glu Asp Lys Asp Pro
35 40 45
Ser Lys Met Met Ala Thr Ile Tyr Glu Leu Lys Glu Asp Lys Ser Tyr
50 55 60
Asp Val Thr Ala Val Thr Phe Asp Asp Lys Lys Cys Asn Tyr Ala Ile
65 70 75 80
Ser Thr Phe Val Pro Gly Ser Gln Pro Gly Glu Phe Thr Leu Gly Lys
85 90 95
Ile Lys Ser Phe Pro Gly His Thr Ser Ser Leu Val Arg Val Val Ser
100 105 110
Thr Asn Tyr Asn Gln His Ala Met Val Phe Phe Lys Phe Val Phe Gln
115 120 125
Asn Arg Glu Glu Phe Tyr Ile Thr Leu Tyr Gly Arg Thr Lys Glu Leu
130 135 140
Thr Ser Glu Leu Lys Glu Asn Phe Ile Arg Phe Ser Lys Ser Leu Gly
145 150 155 160
Leu Pro Glu Asn His Ile Val Phe Pro Val Pro Ile Asp Gln Cys Ile
165 170 175
Asp Gly
<210> 21
<211> 10
<212> PRT
<213> artificial
<220>
<223> C-terminal tag 1
<400> 21
Ser Ala Trp Ser His Pro Gln Phe Glu Lys
1 5 10
<210> 22
<211> 11
<212> PRT
<213> artificial
<220>
<223> C-terminal tag 2
<400> 22
Pro Ser Ala Trp Ser His Pro Gln Phe Glu Lys
1 5 10
<210> 23
<211> 8
<212> PRT
<213> artificial
<220>
<223> Strep-tag
<400> 23
Trp Ser His Pro Gln Phe Glu Lys
1 5
<210> 24
<211> 456
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 24
gcctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc catgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaaggcggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
aaagcagtgt tagagaagac agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtgaaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc aggggtgtgg ctcgtgggca gagaccccaa gaacaacctg 360
gaagccttgg aggactttga gaaagccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca ggcagagcga aaccagctct ccaggg 456
<210> 25
<211> 459
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 25
acctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaaggcggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
agagcagtgt tagagaagac agatgaaccg ggtaaatata cggccgacgg cggtaaacat 240
gatgcctata tcattcgcag ccatgtgaaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gagaccccga gaacaacctg 360
gaagccttgg aggactttga gaaaaccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca ggcagagcga aaccagctct ccagggcca 459
<210> 26
<211> 456
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 26
gcctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaaggcggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
aacgcagtgt tagagaagac agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtgaga gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gggaccccga gaacaacctg 360
gaagccttgg aggactttga gaaaaccgca ggagcccgcg gactcagcac ggagagcatt 420
ctcattccca ggcagagcga aaccagctct ccaggg 456
<210> 27
<211> 459
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 27
gtctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaaggcggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
agagcagtgt tagagaagac agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtggaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gagaccccga gaacaacctg 360
gaagccttgg aggactttga gaaaaccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca ggcagagcga aaccagctct ccagggcca 459
<210> 28
<211> 459
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 28
gcctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gtctaccctt 120
gaaggcggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
aaagcagtgt tagagaagac agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtgaaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gagaccccaa gaacaacctg 360
gaagccttgg aggactttga gaaagccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca ggcagatcga aaccagctct ccagggcca 459
<210> 29
<211> 459
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 29
gcctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaaggcggca atctggaggc tgaggtcacc atggcaatag atgggccggc acaggaggtg 180
aaagcagtgt tagagaaggc agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtgaaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gagaccccaa gaacaacctg 360
gaagccttgg aggactttga gaaaaccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca gtcagatcga aaccagctct ccagggcca 459
<210> 30
<211> 459
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 30
acctcagacg aggagattca ggatgtgtca gggacgtggt atctgaaggc gatgacggtg 60
gatgaggggt gtcgtccttg gaatatattt tcagttacgc caatgactct gactaccctt 120
gaagacggca atctggaggc taaggtcacc atggcaatag atgggccggc acaggaggtg 180
aaagcagtgt tagagaaggc agatgaaccg ggtaaatata cggccgatgg cggtaaacat 240
gttgcctata tcattcgcag ccatgtgaaa gatcattaca tcttttatag cgagggcgtg 300
tgcgatgggt ctcctgttcc gggggtgtgg ctcgtgggca gagaccccaa gaacaacctg 360
gaagccttgg aggactttga gaaagccgca ggagcccgcg gactcagcac ggagagcatc 420
ctcatcccca ggcagatcga aaccagctct ccagggcca 459
<210> 31
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 31
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaag tggtatgtgg taggtcaggc agggaatatc 120
aaactcagag aagacaaaga cccgaacaag atgatggcca ccatctatga gctgaaagaa 180
gacaagagct acaatgtcac cggtgtcact tttgacgaca agaagtgtac ttacgctatc 240
tctacttttg ttccaggttc ccagccaggc gagttcacgc tgggcaaaat taagagtttc 300
cctggacata cgagttctct cgtccgagtg gtgagcacca actacaacca gcatgctatg 360
gtgttcttca agttcgtttt ccaaaacagg gaggaattct acatcaccct ctacgggaga 420
accaaggagc tgacttcgga actaaaggag aacttcatcc gcttctccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 32
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 32
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aggctgcgtg aggataagga tccgattaaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac catggtgaag tttgatgata agaaatgcat gtacgatatt 240
tggacctttg tgccggggag ccagccgggc gagtttactt taggcaagat taaaagtttt 300
ccgggccata catcatcgtt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 33
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 33
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aggctgcgtg aggataagga tccgaataaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cgcggtggcg tttgatgata agaaatgcac gtacgatatt 240
tggacctttg tgccggggag ccagccgggc gagtttactt taggcaagat taaaagtttt 300
ccgggccata catcatcgtt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 34
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 34
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aagctgcgtg aggataagga tccgaataaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cgcggtggcg tttgatgata agaaatgcac gtacgatatt 240
tggacctttg tgccggggag ccagccgggc gagtttactt taggcaagat taaaagtttt 300
ccgggccata catcatcttt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 35
<211> 525
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 35
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aagctgcgtg aggatagtaa aatgatggcg accatttacg agttgaaaga agataaatca 180
tatgacgtca ccggtgtgag ttttgatgat aagaaatgca cgtacgctat tatgaccttt 240
gtgccgggga gccagccggg cgagtttact ttaggcaaga ttaaaagttt tccgggccat 300
acatcatcgt tggtccgcgt cgtgagcacc aactacaacc agcatgccat ggtgttcttc 360
aagtttgtgt ttcagaaccg cgaggagttt tatatcacac tgtacgggcg cacgaaagaa 420
ctgacaagcg agctgaagga aaattttatc cgcttttcca aatctctggg cctccctgaa 480
aaccacatcg tcttccctgt cccaatcgac cagtgtatcg acggc 525
<210> 36
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 36
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aagctgcgtg aggataagga tccggttaaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cggggtgacg tttgatgata agaaatgcag gtacgatatt 240
tcgacctttg tgccggggag ccagccgggc gagtttactt ttggcaagat taaaagtttt 300
ccgggccata catcatcgtt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 37
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 37
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aggctgcgtg aggataagga tccgcataaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cggggtgact tttgatgata agaaatgcac gtacgctatt 240
tcgacctttg tgccggggag ccagccgggc gagtttactt taggcaagat taaaagtttt 300
ccgggccata catcatcttt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 38
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 38
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aagctgcgtg aggataagga tccgaataaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cggggtgact tttgatgata agaaatgcac gtacgctatt 240
tctacccttg tgccggggag ccagccgggc gagtttactt ttggcaagat taaaagtttt 300
ccgggccata catcatcgtt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
<210> 39
<211> 534
<212> DNA
<213> artificial
<220>
<223> lipocalin mutein
<400> 39
caggactcca cctcagacct gatcccagcc ccacctctga gcaaggtccc tctgcagcag 60
aacttccagg acaaccaatt ccatgggaaa tggtacgttg tcgggcaggc cggaaatatt 120
aggctgcgtg aggataagga tccgtctaaa atgatggcga ccatttacga gttgaaagaa 180
gataaatcat atgacgtcac cgctgtgacg tttgatgata agaaatgcaa ttacgctatt 240
tctacctttg tgccggggag ccagccgggc gagtttactt taggcaagat taaaagtttt 300
ccgggccata catcatcgtt ggtccgcgtc gtgagcacca actacaacca gcatgccatg 360
gtgttcttca agtttgtgtt tcagaaccgc gaggagtttt atatcacact gtacgggcgc 420
acgaaagaac tgacaagcga gctgaaggaa aattttatcc gcttttccaa atctctgggc 480
ctccctgaaa accacatcgt cttccctgtc ccaatcgacc agtgtatcga cggc 534
Claims (16)
- CD137に結合する能力を有するリポカリンムテインであって、
(i)該ムテインのアミノ酸配列が、成熟ヒト涙液リポカリンの直鎖ポリペプチド配列(SEQ ID NO:1)と比較して、
以下の変異アミノ酸残基:Arg 26 → Glu; Glu 27 → Gly; Phe 28 → Cys; Pro 29 → Arg; Glu 30 → Pro; Met 31 → Trp; Leu 33 → Ile; Glu 34 → Phe; Leu 56 → Ala; Ser 58 → Asp; Arg 60 → Pro; Cys 61 → Ala; Cys 101 → Ser; Glu 104 → Val; Leu 105 → Cys; His 106 → Asp; Lys 108 → Ser; Arg 111 → Pro; Lys 114 → Trp; およびCys 153 → Serを含み、ならびに
以下の変異アミノ酸残基:Ala 5 → Val もしくは Thr; Thr 42 → Ser; Gly 46 → Asp; Lys 52 → Glu; Lys 65 → Arg もしくは Asn; Thr 71 → Ala; Val 85 → Asp; Lys 94 → Arg もしくは Glu; Lys 121 → Glu; Ala 133 → Thr; Arg 148 → Ser; およびSer 150 → Ileの1つまたは複数をさらに含み、かつ
該ムテインが、SEQ ID NO: 5~11からなる群より選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するアミノ酸配列を含むか、または
(ii)該ムテインのアミノ酸配列が、成熟hNGALの直鎖ポリペプチド配列(SEQ ID NO:2)と比較して、
以下の変異アミノ残基:Gln 28 → His; Leu 36 → Gln; Ala 40 → Ile; Tyr 52 → Met; Arg 72 → Asp; Lys 73 → Asp; Cys 87 → Ser; Asn 96 → Lys; Tyr 100 → Phe; Leu 103 → His; Tyr 106 → Ser; Lys 125 → Phe; Ser 127 → Phe; Tyr 132 → Glu および Lys 134 → Tyrを含み、ならびに
以下の変異アミノ酸残基:Ile 41 → Arg もしくは Lys; Gln 49 → Val, Ile, His, Ser, もしくは Asn; Asn 65 → Asp; Ser 68 → Met, Ala, もしくは Gly; Leu 70 → Ala, Lys, Ser, もしくは Thr; Asp 77 → Met, Arg, Thr, もしくは Asn; Trp 79 → Ala もしくは Asp; Arg 81 → Met, Trp, もしくは Ser; Phe 83 → Leu; およびLeu 94 → Pheの1つまたは複数をさらに含み、かつ
該ムテインが、SEQ ID NO: 12~20からなる群より選択されるアミノ酸配列に対して少なくとも90%の配列同一性を有するアミノ酸配列を含む、
リポカリンムテイン。 - ムテインが、成熟ヒト涙液リポカリンの直鎖ポリペプチド配列(SEQ ID NO:1)と比較して、以下の変異アミノ酸残基の組のうちの1組を含む、請求項1記載のムテイン:
(a) Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, および Cys 153 → Ser;
(b) Ala 5 → Thr, Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Lys 65 → Arg, Val 85 → Asp, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Lys 121 → Glu, Ala 133 → Thr, および Cys 153 → Ser;
(c) Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Lys 65 → Asn, Lys 94 → Arg, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Lys 121 → Glu, Ala 133 → Thr, および Cys 153 → Ser;
(d) Ala 5 → Val, Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Lys 65 → Arg, Lys 94 → Glu, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Lys 121 → Glu, Ala 133 → Thr, および Cys 153 → Ser;
(e) Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Thr 42 → Ser, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Ser 150 → Ile, および Cys 153 → Ser;
(f) Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Lys 52 → Glu, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Thr 71 → Ala, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Ala 133 → Thr, Arg 148 → Ser, Ser 150 → Ile, および Cys 153 → Ser; または
(g) Ala 5 → Thr, Arg 26 → Glu, Glu 27 → Gly, Phe 28 → Cys, Pro 29 → Arg, Glu 30 → Pro, Met 31 → Trp, Leu 33 → Ile, Glu 34 → Phe, Gly 46 → Asp, Leu 56 → Ala, Ser 58 → Asp, Arg 60 → Pro, Cys 61 → Ala, Thr 71 → Ala, Cys 101 → Ser, Glu 104 → Val, Leu 105 → Cys, His 106 → Asp, Lys 108 → Ser, Arg 111 → Pro, Lys 114 → Trp, Ser 150 → Ile, および Cys 153 → Ser。 - ムテインのアミノ酸配列が、成熟hNGALの直鎖ポリペプチド配列(SEQ ID NO:2)と比較して、以下の変異アミノ酸残基の組のうちの1組を含む、請求項1記載のムテイン:
(a) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Lys, Gln 49 → Asn, Tyr 52 → Met, Ser 68 → Gly, Leu 70 → Thr, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Ala, Arg 81 → Ser, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(b) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Arg, Gln 49 → Ile, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Met, Leu 70 → Lys, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Met, Trp 79 → Asp, Arg 81 → Trp, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(c) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Arg, Gln 49 → Asn, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Ala, Leu 70 → Ala, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Asp, Arg 81 → Trp, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(d) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Lys, Gln 49 → Asn, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Ala, Leu 70 → Ala, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Asp, Arg 81 → Trp, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(e) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Lys, Gln 49 → Ser, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Gly, Leu 70 → Ser, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Ala, Arg 81 → Met, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(f) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Lys, Gln 49 → Val, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Gly, Leu 70 → Thr, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Arg, Trp 79 → Asp, Arg 81 → Ser, Cys 87 → Ser, Leu 94 → Phe, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(g) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Arg, Gln 49 → His, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Gly, Leu 70 → Thr, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Ala, Arg 81 → Ser, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr;
(h) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Lys, Gln 49 → Asn, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Gly, Leu 70 → Thr, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Thr, Trp 79 → Ala, Arg 81 → Ser, Phe 83 → Leu, Cys 87 → Ser, Leu 94 → Phe, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr; または
(i) Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Arg, Gln 49 → Ser, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Ala, Leu 70 → Thr, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Asn, Trp 79 → Ala, Arg 81 → Ser, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, および Lys 134 → Tyr。 - ムテインのアミノ酸配列が、成熟hNGALの直鎖ポリペプチド配列(SEQ ID NO:2)と比較して、以下の変異アミノ酸残基の組を含む、請求項1記載のムテイン:
Gln 28 → His, Leu 36 → Gln, Ala 40 → Ile, Ile 41 → Arg, Gln 49 → Ile, Tyr 52 → Met, Asn 65 → Asp, Ser 68 → Met, Leu 70 → Lys, Arg 72 → Asp, Lys 73 → Asp, Asp 77 → Met, Trp 79 → Asp, Arg 81 → Trp, Cys 87 → Ser, Asn 96 → Lys, Tyr 100 → Phe, Leu 103 → His, Tyr 106 → Ser, Lys 125 → Phe, Ser 127 → Phe, Tyr 132 → Glu, およびLys 134 → Tyr。 - SEQ ID NO:5~20からなる群より選択されるアミノ酸配列に対して少なくとも95%の配列同一性を有するアミノ酸配列を含む、請求項1記載のムテイン。
- ムテインが、SEQ ID NO:13のアミノ酸配列に対して少なくとも90%の配列同一性を有するアミノ酸配列を含む、請求項1記載のムテイン。
- ムテインが、SEQ ID NO:13のアミノ酸配列に対して少なくとも95%の配列同一性を有するアミノ酸配列を含む、請求項1記載のムテイン。
- 請求項1~7のいずれか一項記載のリポカリンムテインをコードするヌクレオチド配列を含む核酸分子。
- 請求項8記載の核酸分子を含有する宿主細胞。
- 原核細胞または真核細胞である、請求項9記載の宿主細胞。
- 大腸菌(Escherichia coli)(E. coli)、枯草菌(Bacillus subtilis)、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)、ピキア・パストリス(Pichia pastoris)、SF9またはHigh5昆虫細胞、不死化哺乳動物細胞株、HeLa細胞、CHO細胞、および初代哺乳動物細胞からなる群より選択される、請求項9または10記載の宿主細胞。
- リポカリンムテインをコードする核酸から出発してリポカリンムテインが生産される、請求項1~7のいずれか一項記載のリポカリンムテインを生産する方法。
- CD137の結合に使用するための、請求項1~7のいずれか一項記載のリポカリンムテイン。
- CD137の下流シグナリング経路活性化に使用するための、請求項1~7のいずれか一項記載のリポカリンムテイン。
- Tリンパ球増殖の誘発に使用するための、請求項1~7のいずれか一項記載のリポカリンムテイン。
- 請求項1~7のいずれか一項記載のリポカリンムテイン、請求項8記載の核酸分子、または請求項9~11のいずれか一項記載の宿主細胞を含む、薬学的組成物。
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