JP7142915B2 - ラクトフェリン/アルブミン融合タンパク質及びその製造方法 - Google Patents
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Description
また、血中安定性を上げる方法としてIgGのFc領域を融合させる以外に、血清アルブミン融合タンパク質が開発され(非特許文献5、非特許文献6)、上市もされている。血清アルブミンは分子量約66,000のタンパク質で、血清タンパク質の約6割を占め、血清中のタンパク質で最も含有量の高いタンパク質である。血管中の血清アルブミンの機能は、保水による血管浸透圧の制御であるが、脂肪酸やホルモン、薬物などを結合し、必要な組織に輸送する働きも持つ。また、成人は、一日当たり9グラム前後作られ、約4割が血管に、残り6割が血管外に分布している。
(1) (i)ヒト血清アルブミン(HSA)又はヒト血清アルブミンの断片もしくはペプチドと、
(ii)ラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドとの融合タンパク質であって、
(LF-s-Y)n 又は (Y-s-LF)n
〔式中、LFはラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチド、Yはヒト血清アルブミンもしくはヒト血清アルブミンの断片を含むタンパク質又はペプチド、sは0~10個の任意のアミノ酸の配列、nは1~10の整数を表す〕
で表される融合タンパク質、又はその改変体。
(2)(LF-s-Y)n
で表される前記(1)に記載の融合タンパク質、又はその改変体。
(3)(Y-s-LF)n
で表される上記(1)に記載の融合タンパク質、又はその改変体。
(4) SEQ ID NO: 7に示すアミノ酸配列を含む、上記(1)に記載の融合タンパク質、又はその改変体。
(5) SEQ ID NO: 14に示すアミノ酸配列を含む、上記(1)に記載の融合タンパク質、又はその改変体。
(6) 前記融合タンパク質又はその改変体が、天然又は遺伝子組換え型ラクトフェリンの50%以上の鉄キレート能を保持している、前記(1)~(5)のいずれかに記載の融合タンパク質、又はその改変体。
(7) 前記融合タンパク質又はその改変体は、ラクトフェリン受容体及びアルブミン受容体からなる群より選択される少なくとも1つの受容体を介して取り込まれるものである、前記(1)~(6)のいずれかに記載の融合タンパク質、又はその改変体。
(8) 前記融合タンパク質又はその改変体が、天然又は遺伝子組換え型ラクトフェリンと比べてペプシン耐性が向上したものである、前記(1)~(7)のいずれかに記載の融合タンパク質、又はその改変体。
(9) 前記(1)~(8)のいずれかに記載の融合タンパク質又はその改変体をコードする核酸分子。
(10) 前記(9)に記載の核酸分子を含む発現ベクター。
(11) 前記(10)に記載の発現ベクターを含む宿主細胞。
(12) 前記(9)に記載の核酸分子を含む非ヒト遺伝子組換え動物。
(13) 前記(1)~(8)のいずれかに記載の融合タンパク質又はその改変体によって改善される疾患の治療剤。
(14) 前記(1)~(8)のいずれかに記載の融合タンパク質又はその改変体及び担体を含む、医薬品組成物。
(15)
腫瘍の治療のための、前記(15)に記載の医薬組成物。
(16)
前記腫瘍が肺癌である、前記(16)に記載の医薬組成物。
(17) 前記(1)~(8)のいずれかに記載の融合タンパク質又はその改変体の製造方法であって、この融合タンパク質又はその改変体をコードする遺伝子を含む宿主細胞を培養して融合タンパク質を発現させ、この宿主細胞又はその培地から融合タンパク質又はその改変体を回収することを含む方法。
(18)治療有効量の(1)に記載の融合タンパク質又はその改変体を患者に投与することを含む、腫瘍の治療方法。
(19)前記腫瘍が肺癌である、(18)に記載の方法。
(20)腫瘍の治療に用いるための(1)に記載の融合タンパク質又はその改変体。
(21)前記腫瘍が肺癌である、(20)に記載の融合タンパク質又はその改変体。
(22)腫瘍の治療のための医薬組成物の製造における、(1)に記載の融合タンパク質又はその改変体の使用。
(23)前記腫瘍が肺癌である、(22)に記載の使用。
なお、本明細書において引用した全ての文献、および公開公報、特許公報その他の特許文献は、参照として本明細書に組み込むものとする。また、本明細書は、2016年10月28日に出願された本願優先権主張の基礎となる日本国特許出願(特願2016-212077号)及び2017年3月9日に出願された本願優先権主張の基礎となる日本国特許出願(特願2017-044893号)の明細書及び図面に記載の内容を包含する。
また、本願において、「約」とは、当該用語に続く数値の±10%、±5%、±3%、±2%、±1%の範囲を意味するものとする。
(LF-s-Y)n 又は (Y-s-LF)n 式I
式I中において、LFはラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチド、Yはヒト血清アルブミンもしくはヒト血清アルブミンの断片を含むタンパク質又はペプチドを表し、sは0~10個の任意のアミノ酸の配列表し、ここでnは1~10の整数を表す。また(LF-s-Y)はhLFをN末端側にHSAをC末端側に位置するように融合させたタンパク質を表し、(Y-s-LF)はHSAをN末端側にhLFをC末端側に位置するように融合させたタンパク質を表す。
本発明の融合タンパク質において、アルブミンは、アルブミン全長、あるいはアルブミンの部分ペプチドを使用し、生体に対して適合可能又は薬理学的に不活性であればよい。アルブミンは、ヒト及び種々の動物(ウシ、ウマ、ブ夕、ヒツジ、ヤギ、ラクダ等)由来のものや、鶏卵由来由来のものを用いることができるが、好ましくはヒト血清アルブミン(HSA)が好ましい。ヒト血清アルブミンのアミノ酸配列(GenBank: AAA98797.1、SEQ ID NO: 2)及びCDS配列(GenBank: M12523.1、SEQ ID NO: 1)は公知である。
本発明において使用される場合、ヒト血清アルブミンは天然の配列(SEQ ID NO: 2)と同一であってもよく、また、変異を有していてもよい。また、変異を有するヒト血清アルブミンとしては、SEQ ID NO: 2のアミノ酸配列と90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、99%以上、99.1%以上、99.2%以上、99.3%以上、99.4%以上、99.5%以上、99.6%以上、99.7%以上、99.8%以上、または99.9%以上の配列同一性を有するアミノ酸配列を有するタンパク質が挙げられる。上記配列同一性の数値は一般的に大きい程好ましい。ヒト血清アルブミンの断片もしくはペプチドとしては、SEQ ID NO: 2のアミノ酸配列の10%以上、20%以上、30%以上、40%以上、50%以上、60%以上、70%以上、80%以上、または90%以上を占める配列からなるものを用いることができる。
本発明で用いるラクトフェリンは、ヒト及び種々の動物(ウシ、ウマ、ブ夕、ヒツジ、ヤギ、ラクダ等)から得られる天然のラクトフェリンと同一のアミノ酸配列を有していてもよいし、目的とするラクトフェリンの生理活性を有する限りにおいて、一部のアミノ酸が欠失、付加、置換した変異を有していてもよい。ヒトのラクトフェリンの(GenBank: AAN75578.2、SEQ ID NO: 4)及びCDS配列(GenBank: AY178998.2、SEQ ID NO: 3)は公知である。ラクトフェリンの機能的(生物活性を有する)断片、ペプチドは、種々のものが公知であり(例えば、「プログラム・抄録集第2回臨床ラクトフェリンシンポジウム2009」、21~ 27頁(島崎敬一))などの文献の記載をもとに、必要に応じて設計することができる。変異を有するラクトフェリンを用いる場合、SEQ ID NO: 4のアミノ酸配列と90%以上、91%以上、92%以上、93%以上、94%以上、95%以上、96%以上、97%以上、98%以上、99%以上、99.1%以上、99.2%以上、99.3%以上、99.4%以上、99.5%以上、99.6%以上、99.7%以上、99.8%以上、または99.9%以上の配列同一性を有するアミノ酸配列を有するタンパク質が挙げられる。上記配列同一性の数値は一般的に大きい程好ましい。
本発明の融合タンパク質は、さらに、付加的なアミノ酸配列を含んでいてもよい。ヒト血清アルブミンと、ラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドとの聞に、スペーサー配列として適切な長さの任意のアミノ酸配列を有することができる。スペーサー配列( s )は、例えば0~10個、又は0~5個の任意のアミノ酸の配列であることができる。その他の付加的な配列は、スペーサー配列のような立体構造上の利点を提供するものであってもよく、また、例えばシグナルペプチドや精製に利用されるタグ配列のように、何らかの機能を融合タンパク質に与えるものであってもよい。
本発明の融合タンパク質は、ペプシン耐性の向上したものである。ペプシンは、胃液の主要なタンパク質分解酵素であるので、ペプシン耐性を向上させることにより、胃において消化されにくい融合タンパク質を提供することができる。ペプシン耐性は、公知の手法により測定することができる。例えば、適宜濃度を調整したタンパク質溶液にペプシン溶液を添加して、消化させた後、SDS-PAGE法などのゲル電気泳動法などにより、消化されたタンパク質を検出または、計量することにより、ペプシン耐性を測定することができる(Yasuhiro Nojima, Yosuke Suzuki, Kazuhiro Yoshida, Fumiko Abe, Tuneo Shiga, Takashi Takeuchi, Akihiko Sugiyama, Hirohiko Shimizu, and Atsushi Sato, Pharmaceutical Research, Vol. 26, No. 9, September 2009 2125-2132)。例えば、上記ペプシン処理をした後に、ゲル電気泳動法により、顕著な分解産物が観察されなかった場合を、ペプシン耐性があるとすることができる。また、融合タンパク質が、天然又は遺伝子組み換え型ラクトフェリンと比べ、ペプシン処理による、タンパク質分解産物が減少した場合を、ペプシン耐性が向上したとすることができる。
本発明の融合タンパク質は、抗腫瘍活性を有する。ここで抗腫瘍活性とは、腫瘍細胞の増殖を阻害する活性を言う。抗腫瘍活性は、本明細書において抗腫瘍効果と称する場合もある。
本発明の融合タンパク質の抗腫瘍活性は、本発明の融合タンパク質の存在下(サンプル群)及び非存在下(対照群)で同数の腫瘍細胞の培養を開始し、一定期間後(例えば24時間後、48時間後、72時間後)にサンプル群の腫瘍細胞数が対照群の腫瘍細胞数よりも少なくなっていることにより確認することができる。
ここで腫瘍とは、良性腫瘍又は悪性腫瘍のいずれでもよい。このような腫瘍の例としては、(1)骨肉腫や軟部組織肉腫等の肉腫、(2)乳癌腫、肺癌腫、膀胱癌腫、甲状腺癌腫、前立腺癌腫、結腸癌腫、結腸直腸癌腫、膵臓癌腫、胃癌腫、肝臓癌腫、子宮癌腫、子宮頸癌腫、卵巣癌腫等の癌腫、(3)ホジキンや非ホジキンリンパ腫等のリンパ腫、(4)神経芽細胞腫、(5)メラノーマ、(6)ミエローマ、(7)ウィルムス腫瘍、(8)急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)及び慢性リンパ性白血病(CLL)等の白血病、(9)グリオーマ、(10)網膜芽細胞腫等が挙げられるが、これらに限定されるものではない。ある実施態様では、腫瘍は肺癌種であり、さらには肺腺癌である。また、腫瘍細胞は分化型、低分化型、未分化型のいずれであってもよいが、ある実施形態では分化型及び低分化型に対して特に強い抗腫瘍効果を示す。
本発明は、本発明の融合タンパク質を含む、ラクトフェリン関連疾患を治療するための医薬組成物を提供する。
ここでラクトフェリン関連疾患には、生活習慣病(動脈硬化、高コレステロール血症、高脂血症、高血圧、糖尿病、脂肪肝など)、がん(発がん予防、がんの二次予防、転移抑制、制癌剤の作用増強など)、自己免疫疾患(シェーグレン症候群によるドライアイ及びドライマウス、リウマチ性関節炎、悪性関節リウマチ、膠原病、多発性硬化症、全身性エリテマトーデス、全身性紅斑性狼蒼など)、精神神経疾患(痴呆、アルツハイマー病、パーキンソン病、テンカン、うつ病、ヒキコモリ、統合失調症、各種ストレス性疾患、更年期障害など)、疼痛緩和(モルヒネ等のオピオイド増強作用、がん性疼痛、神経因性疼痛、ヘルペス後疼痛、線維筋痛症、術後疼痛、舌痛症、生理痛、歯痛、関節痛、更年期障害など)、肝炎(各種ウイルス性肝炎、非アルコール性肝炎、肝硬変など)、炎症性腸疾患(大腸性潰瘍炎、クローン病など)、過敏性腸症候群、前立腺肥大、頻尿、不眠症、便秘等が挙げられ、さらに、ラクトフェリンのウイルス作用及び免疫能賦活作用に基づいて治療され得る、ヘリコバクター・ピロリ菌の胃粘膜感染、歯周病、歯槽膿漏、口臭、口腔カンジダ症、口内炎、口角炎、鼻炎、食道炎、胆嚢炎、尿路感染症、膣感染症、水虫、ニキビ、ヘルペス属ウイルスの感染症、老人性肺炎、術後感染症、さらにはラクトフェリンの免疫寛容作用に基づいて治療可能な花粉症、アトピー性皮膚炎、脂漏症、蕁麻疹等のアレルギー性疾患が挙げられる。ラクトフェリン関連疾患のさらなる例としては、ラクトフェリンの抗酸化ストレス作用に基づいて治療可能な、ウィルソン病、劇症肝炎などや、肌や眼の抗加齢・若返り作用、加齢性黄斑変性症、糖尿病性網膜症が含まれる。
また、本発明は、本発明の融合タンパク質を含む、腫瘍を治療するための医薬組成物を提供する。腫瘍については上で述べたとおりである。
例えば、経口投与の場合、治療上有効量は、ラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドの量として0.001~10 g/kg/日、0.005~10 g/kg/日、0.01~10 g/kg/日、0.01~5 g/kg/日とすることができる。ヒトに投与する場合、一般的には、治療上有効量として、一日あたりラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドの量として10 mg~15,000 mg、10 mg~12,000 mg、10 mg~10,000 mg、20 mg~10,000 mg、20 mg~8,000 mg、30 mg~8,000 mg、30 mg~6,000 mgの量である。また、経皮投与の場合、治療上有効量は、ラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドの量として0.001~10 g/kg/日、0.005~10 g/kg/日、0.01~10 g/kg/日、0.01~5 g/kg/日とすることができる。ヒトに投与する場合、一般的には、治療上有効量として、一日あたりラクトフェリン又はラクトフェリンの生物活性断片もしくはペプチドの量として10 mg~15,000 mg、10 mg~12,000 mg、10 mg~10,000 mg、20 mg~10,000 mg、20 mg~8,000 mg、30 mg~8,000 mg、30 mg~6,000 mgの量である。このような一日あたりの用量を一度にまたは分割して、治療を必要とする患者に投与することができる。
なお、本発明の組成物の投与量及び投与頻度は、対象の種、体重、性別、年齢、疾患の進行度、投与経路といった種々の要因に依存して変化するが、医師、獣医師、歯科医師又は薬剤師等の当業者であれば、それぞれの要因を考慮して投与量を決定することができる。
上記の治療上有効量、投与量及び投与頻度は、典型的な数値を列挙したものであり、これを超える数値又は下回る数値であっても治療効果を奏する場合も十分に考えられる。従って、上記の治療上有効量、投与量及び投与頻度を超える数値又は下回る数値であっても、本発明の組成物の治療上有効量、投与量及び投与頻度として包含される。
ヒトラクトフェリン(hLF)とヒト血清アルブミン(HSA)との融合タンパク質については、hLFをN末端側にHSAをC末端側に位置するように融合させたタンパク質をhLF-HSA、逆にHSAをN末端側にhLFをC末端側に位置するように融合させたタンパク質をHSA-hLF、と命名した。また、本明細書中で、rhLFとは、Aspergillus由来の組換え型hLFを意味する。
シグナル配列を含むhLF cDNA断片は、公知のDHFR欠損チャイニーズハムスター卵巣由来細胞(CHO[DG44])用発現ベクターpOptiVEC/hLF-dFc(Shiga, Yら Eur J Pharm Sci. Vol.67, 136-143, 2015)をXho IとBamH Iで消化することで調製した。
シグナル配列を含むHSA cDNAは、ヒト肝癌由来細胞株であるHepG2からTotal RNAを抽出し、そのTotal RNAを鋳型としたRT-PCR法で取得した。HepG2は10% ウシ胎児血清(FBS)を含むD-MEM(low glucose)培地(和光純薬社製)で培養した。1x106cells分のHepG2細胞から、RNA 抽出用試薬ISOGEN(商品名、ニッポンジーン社製)を用いて、Total RNAを抽出した。その方法は試薬に添付されているプロトコールに従った。得られた2μg分のTotal RNAを鋳型として、オリゴdTプライマー (oligo (dT)15、プロメガ社製)、逆転写酵素 (ReverTra Ace、商品名、東洋紡社製)を用いてTotal cDNAを合成した。その方法は試薬に添付されているプロトコールに従った。HSA cDNA断片は、得られたTotal cDNAを鋳型としたPCR法により取得した。フォーワード側プライマーとして、N-EcoRI-HSA(5’-CGGAATTCATGAAGTGGGTAACCTTTAT-3’: SEQ ID NO: 10;[開始コドンであるATGの上流に下線部EcoR Iサイトを導入])、リバース側プライマーとして、HSA-XhoI-C(5’-CCGCTCGAGTAAGCCTAAGGCAGCTTGAC-3’: SEQ ID NO: 11)[3’末端側に下線部Xho Iサイトを導入]を用い、DNA合成酵素は「PrimeStar(登録商標) HS(premix)」(商品名、タカラバイオ社製)を使用して、HSA cDNAを増幅した。得られたDNA断片に、rTaq DNA polymerase (商品名、東洋紡社製)でAを付加し、「pGEM-T(登録商標) Easyベクター」(商品名、プロメガ社製)にTAクローニングした。HSA cDNAの塩基配列は、ジデオキシ法シークエンシングで確認した。その後、このベクターをEcoR IとXho Iで消化することにより、シグナル配列を含むヒトHSAのDNA断片を切り出した。
hLF-HSA、HSA-hLF融合タンパク質の安定発現細胞株構築のために、CHO細胞の一種であるDHFR欠損チャイニーズハムスター卵巣由来細胞(DG44)を用いた。DHFRとは、ジヒドロ葉酸還元酵素であり、核酸の生合成には必須である。DHFRのアンタゴニストであるメトトレキサート(MTX)の存在下で細胞を培養すると、DHFRの産生が阻害される。その際、細胞は生き残るためにDHFR遺伝子を増幅し、DHFR遺伝子の近傍に存在する遺伝子も増幅されるために、その遺伝子のタンパク質発現が増幅することが知られている。このようにして、目的とするタンパク質を高発現させることが可能である。
大量発現は、175cm2のTフラスコ(グライナー社製)を用いた静置培養で行った。DG44(hLF-HSA)細胞、およびDG44(HSA-hLF)は、10%FBSを含むリボヌクレオシド、デオキシリボヌクレオシド不含MEMα培地(和光純薬社製)で70%confluentになるまで培養した。培地上清を除去し、付着している細胞をPBSで洗浄した後、「Hybridoma Serum Free Medium」(商品名、Invitrogen社)を30ml加えて37℃、5%CO2で4日間培養した。4日後、培養上清液を50 ml遠沈菅に移し、10,000×gで10分間遠心して上清を保存容器に移した。細胞には新しい「Hybridoma Serum Free Medium」(商品名、Invitrogen社)を30ml加えて、37℃、5%CO2で更に4日間培養して、培養上清を調製した。培養後、細胞を遠心分離で取り除き、得られた培養上清には最終濃度0.02%のアジ化ナトリウムを加え、4℃にて保存した。
精製には、大量発現で得られたhLF-HSA、HSA-hLF融合タンパク質を含む培地上清(最終濃度0.02%アジ化ナトリウムを含む)をそのまま使用した。ヒトラクトフェリン(hLF)は、ヘパリンに強く結合する性質が知られているため、Heparin Sepharose 6 Fast Flow(商品名、GEヘルスケア社)を用いるアフィニティー精製で、hLF-HSA、HSA-hLF融合タンパク質の精製を行った。「Heparin Sepharose 6 Fast Flow」(商品名、GEヘルスケア社)2 ml分を「Poly-Prep Chromatography Columns」(商品名、バイオラッド社)に充填して、5カラム容量(CV)分の10mMリン酸ナトリウム緩衝液(pH 7.0)で平衡化した。10℃にて、培養上清500mL分を還流させる形で、Heparin Sepharose 6 Fast Flowと接触させて、融合タンパク質を「Heparin Sepharose 6 Fast Flow」に吸着させた。還流後、還流させていた培養上清は素通り画分として回収した。融合タンパク質を吸着させたヘパリン担体を含む「Poly-Prep Chromatography Columns」を、「UV DETECTOR」(東京理化器械社、280nmの吸光度を測定)、マイクロチューブポンプ(東京理化器械社)と接続し、ポンプの流速を1ml/minに設定し、10mMリン酸ナトリウム緩衝液(pH7.0)を流して担体を洗浄した。「UV DETECTOR」の280nmの吸光度が上昇し始めた時点から、排出液を回収した(洗浄画分)。この回収は280nmの吸光度が0になるまで続けた。その後、溶液を0.5M NaClを含む10mMリン酸ナトリウム緩衝液(pH7.0)に換えて同様の操作を行った(0.5M NaCl溶出画分)。さらに、溶液を2M NaClを含む10mMリン酸ナトリウム緩衝液(pH7.0)に換えて同様の操作を行った(2M NaCl溶出画分)。回収した各溶出液は、4℃にて保存した。各画分溶液12μlに非還元の4×サンプル緩衝液を4μl混合し、95℃で5分間熱処理を行い、7.5%SDS-PAGEで解析した。バンドの染色にはCBBを用いた。hLF-HSA融合タンパク質の精製結果を図3、HSA-hLF融合タンパク質の精製結果を図4に示す。両融合タンパク質とも、素通り画分、および洗浄画分にはバンドは見られず、0.5M NaCl溶出画分に、約140kDaの融合タンパク質のバンドが認められる。2M NaCl溶出画分にはバンドが認められないことから、Heparin Sepharose 6 Fast Flowに吸着した両融合タンパク質は、0.5M NaClで完全に溶出されることがわかった。4.に記載の方法で発現させた場合、hLF-HSA、HSA-hLF融合タンパク質はともに、1Lの培養上清から精製タンパク質として約10~15mg分得られることがわかった。
ラクトフェリン(LF)は分子量8万の非ヘム性の鉄結合性糖タンパク質で、Nローブ、Cローブと呼ばれる二つの領域からなり、炭酸イオン(CO3 2-)存在下でタンパク質1分子当たり2個の鉄イオン(Fe3+)を可逆的にキレート結合する能力を有する(Andersonら., Nature, 344, 784-78 (1990))。まず、4.、5.で調製したhLF-HSA、HSA-hLF両融合タンパク質に結合している脱鉄操作前の鉄イオン(Fe3+)量を、和光純薬社製「Fe C-テストワコー」で測定した。その結果、hLF換算タンパク質1mgあたりhLF-HSAは1302ng、HSA-hLFは1161ngのFe3+が結合しており、これはタンパク質1分子当たり2個の鉄イオン(Fe3+)が結合した場合の理論値(hLF 1mgあたりFe3+が約1400ng結合する)にほぼ近い値であった。したがって、両hLF-HSA、HSA-hLF融合タンパク質は鉄イオンと結合する能力を有していることが示された。さらに以下の方法で、hLF-HSA融合タンパク質の鉄結合能を測定した。調製した各融合タンパク質から、10mM HCl(pH 2.0)と0.1% EDTAを含むリン酸バッファー(pH7.5)を用いて鉄イオン(Fe3+)を遊離させ、アポ(apo)型ラクトフェリン(鉄除去型ラクトフェリン)を調製した。次いで炭酸イオン(CO3 2-)存在下で鉄イオン(Fe3+)を付加させた鉄再結合ラクトフェリンを調製した。鉄除去型ラクトフェリン及び鉄再結合ラクトフェリンの鉄含量及びタンパク質濃度を測定し、hLFタンパク質1mg(HSA融合タンパク質の場合は、分子量を用いて算出したhLF換算で1mg)あたりに結合している鉄の結合量を算出した。
HSA-hLF、hLF-HSA融合タンパク質の熱安定性を、円偏光二色性(CD)スペクトルで解析した。円偏光二色性(CD)スペクトルとは、物質にある波長をあてた場合の右円偏光と左円偏光の吸収の差を測定する方法で、タンパク質の二次構造の有無や種類、含量を推定することが可能である。
まず、PBS(-)に0.1mg/mlで懸濁したAspergillus由来の組換え型hLF(rhLF)、ヒト血清アルブミン(HSA、和光純薬社製)、hLF-HSA、HSA-hLF融合タンパク質を用意して、25℃で、波長200nm~250nmのCDスペクトルを測定した(円二色性分散計J-1500使用、日本分光社製)。その結果を、図5に示す。HSA-hLF、hLF-HSA両融合タンパク質の二次構造が確認され、hLF とHSAとの融合により、hLFの二次構造に大きな変化は起こっていないことが確認された。次に、各タンパク質の熱安定性を調べた。タンパク質溶液の温度を低温から高温へ変化させながらCDスペクトルを測定すると、ある温度で[θ]が上昇し一定の値を取る。この現象は、熱によりタンパク質の変性が起きて、二次構造が変化することに起因している。熱安定性を観察する場合は、一般に測定する波長は225nm付近を用いる。PBS(-)に0.1mg/mlで懸濁したAspergillus由来の組換え型hLF(rhLF)、ヒト血清アルブミン(HSA、和光純薬社製)、hLF-HSA、HSA-hLF融合タンパク質を用意して、30~90℃まで1℃ずつ上昇させながら、波長225nmのCDスペクトルを測定した(円二色性分散計J-1500使用、日本分光社製)。二次構造が変化した際の変性温度 (Tm値)は、日本分光社の熱変性解析プログラムSpectra Manager Ver.2を用いて算出した。なお、hLFに結合する鉄量が多いほど、高い熱安定性を示すことが報告されているため (Spreedhara, A. et al., Biometals 23, 1159-1170, 2010)、測定に使用したサンプルの鉄含有量を「Fe C-テストワコー」(商品名、和光純薬社製)を用いて測定した。その結果、各サンプルは、rhLF:1222ng/mg、hLF-HSA:1302ng/mg、HSA-hLF 1161ng/mgとほぼ同じ量の鉄を結合していた。各タンパク質の熱安定性の結果を図6に示す。各タンパク質の変性温度(Tm値)は、rhLF:90℃以上、HSA:61.6℃、hLF-HSA:82.2℃、HSA-hLF:64.5℃であり、両融合タンパク質のTm値はrhLFより低下したが、hLF-HSA融合タンパク質はHSA-hLFと比較して、高い熱安定性を保持していた。
1.2mg/mlの濃度に調整した各タンパク質溶液(Aspergillus由来の組換え型hLF(rhLF)、ヒト血清アルブミン(HSA、和光純薬社製)、hLF-HSA、HSA-hLF融合タンパク質)35μl、10mM HCl(pH 2.0)40.6μlを混合して、37℃で5分間静置した。その後、8.4μlの200ng/mlペプシン溶液(和光純薬社製のブタ胃由来のペプシンを10mM HCl(pH 2.0)に溶解)を添加して、消化反応を開始した。経時的に反応サンプル12μlを回収し、あらかじめ用意しておいた還元4xSample Buffer (0.1 M Tris-HCl(pH6.8)、8% SDS、40% Glycerol、20%2-Mercaptoethanol、0.1%BPB)4μlに加え、消化反応を停止させた。その後、サンプルは95℃で5分間熱処理を行い、そのうちの4 μlを7.5% SDS-PAGEで泳動した。ゲルはCBBで染色した。図7は、左から順に、各タンパク質にペプシンを加えずに37℃で0、5、10、20、40、80分間静置反応させたサンプル (Pepsin(-)と表記)、各タンパク質にペプシンを加えて37℃で0、5、10、20、40、80分間静置反応させたサンプル(Pepsin(+)と表記)の泳動結果である。染色したバンドの濃さを数値化するためのソフトウエアであるCS Analyzer(ATTO社製)を用いて、各バンドの濃さを解析した。各タンパク質の消化時間0分におけるバンドの濃さを100%として、相対濃度をグラフ化した(図8)。コントロールであるhLFは5分間以内で完全に分解されたのに対して、hLF-HSAとHSA-hLFの両融合タンパク質は消化耐性を示した。ペプシンによる各タンパク質の消化分解半減期は、hLFは5分以内、HSAは3.1分、hLF-HSAは80分以上、HSA-hLFは9.3分と算出され、特にhLF-HSAはペプシンに対して顕著な消化耐性を示した。
LFは完全な分子の形で腸管から取り込まれ、完全な分子の形で胸管リンパ液へ移行し、その後大静脈から全身へ移行することが知られている(Takeuchiら, Exp Physiol., Vol.89, 263-270, 2004)。またヒト小腸上皮様細胞Caco-2へのLFの細胞内取り込み、および細胞外放出は、LFの腸管吸収を模倣する現象であると考えられている。そこで、Aspergillus由来の組換え型hLF(rhLF)、hLF-HSA、HSA-hLF融合タンパク質を蛍光プローブで標識して、Caco-2細胞と反応させ、細胞内に取り込まれた様子を共焦点レーザースキャン顕微鏡で観察した。また、各非標識タンパク質をCaco-2細胞へ取り込ませて、その後Caco-2細胞のcell lysateを調製し、各タンパク質の細胞内での状態をLFに対するポリクローナル抗体を用いたウエスタンブロット法で解析した。さらに、各非標識タンパク質をCaco-2細胞へ取り込ませた後、細胞から放出される各タンパク質をhLFに対するポリクローナル抗体を用いたウエスタンブロット法で解析した。
各タンパク質は蛍光プローブであるAlexa Fluor(登録商標)488 (Thermo Fisher Scientific社製)で標識した。1mg のAlexa Fluor(登録商標)488にDMSO 100μlを加え、その後、1M NaHCO3を加えた各タンパク質とAlexa Fluor(登録商標)488をモル比1:10で混合して、室温で、1 時間反応させた。反応後、反応液を1×PBS(-)に対して24時間透析を行い、タンパク質に結合しなかったフリーのAlexa Fluor(登録商標) 488を除去して、Alexa Fluor(登録商標)488標識タンパク質とした。
Caco-2細胞を12well plateに細胞濃度5×104cells/mlになるように撒き込み、37℃,5% CO2で2日おきに培地交換しながら1週間培養した。Caco-2細胞にPBS(-)を500μl/well加えて、3回洗浄を行い、培地成分を完全に取り除いた。次に、PBS(-)に懸濁した各タンパク質を15μg/well加えて、4℃と37℃で1時間反応させた。反応後、冷却したPBS(-)を500μl/well加えて、3回洗浄を行った。洗浄後、0.25%Trypsin/1mM EDTAを用いてplateから細胞を剥がして、細胞を1.5ml遠心チューブに回収した。冷却したPBS(-)を 500μl/ml加えて細胞を洗浄し、その後、200×g,2分間,4℃で遠心を行うことで細胞を回収した。この洗浄操作を3回行い、最終的に、細胞には100 μlの冷却したLysis buffer(1% Triton X-100とプロテインインヒビターを含むPBS(-)溶液)を添加して、4℃で30分間反応させることで、細胞を破壊した。その後、18,700×g,15分間,4℃で遠心を行い、上清をcell lysateとして回収した。10%SDS-PAGEに、1レーンあたり36μg 分の各cell lysateを非還元状態で泳動した。泳動後、常法に従い、各レーンのタンパク質をニトロセルロース ブロッテイングメンブレン(Protran(登録商標) Premium 0.45μm NC、GEヘルスケア社製)へ転写し、1次抗体としてHuman Lactoferrin antibody(Rabbit polyclonal、A80-144A、Betheyl社製)、2次抗体としてAnti Rabbit IgG(Fc),Monoclonal Antibody, Peroxidase Conjugated,016-23943、和光純薬社製)を反応させた。バンドの検出は化学発光法(イムノゼータ、和光純薬社製)で行った。その結果、37℃で細胞内に取り込まれたrhLFは、コントロールであるrhLFと同じ位置に、完全な分子として検出された。一方、4℃で細胞と反応させたrhLFは、37℃で細胞と反応させた場合より検出されるバンドが薄かった(図10左、rhLF)。rhLFと同様に、37℃で細胞内に取り込まれたhLF-HSAは、コントロールであるhLF-HSAと同じ位置に、完全な分子として検出された。一方、4℃で細胞と反応させたhLF-HSAは、37℃で細胞と反応させた場合より検出されるバンドが薄かった(図10中央、hLF-HSA)。以上の結果からhLF-HSAは、rhLFと同様に完全な形でCaco2細胞へ取り込まれることが確認された。一方、約140kDaの分子量であるHSA-hLFは、37℃で細胞と反応させた場合、主に約80kDaの位置にバンドが検出された(図10右、HSA-hLF)。これは、HSA-hLFが細胞内に取り込まれる際、HSAとhLFとの結合部位が分解され、80kDaであるhLFが抗hLF抗体により検出されたものと推察される。したがって、HSA-hLFは、Caco2細胞へ取り込まれると分解することが判明した。
Caco-2細胞を12well plateに細胞濃度5×104 cells/mlになるように撒き込み、37℃,5%CO2で2日おきに培地交換しながら1週間培養した。Caco-2細胞にPBS(-)を500μl/well加えて、3回洗浄を行い、培地成分を完全に取り除いた。次に、PBS(-)に懸濁した各タンパク質を15 μg/well加えて、37℃で1時間反応させた。反応後、冷却したPBS(-)を 500 μl/well加えて、3回洗浄を行った。洗浄後、0.25% Trypsin/1mM EDTAを用いてplateから細胞を剥がして、細胞を1.5ml遠心チューブに回収した。冷却したPBS(-)を1ml加えて細胞を3回洗浄し、その後、200×g,2分間,4℃で遠心を行うことで細胞を回収した(3回目の洗浄液は、ウエスタンブロット法で解析した)。D-MEM培地(和光純薬社製)を200μl加えて、37℃で30、60、120分間反応させ、培地中に各タンパク質を放出させた。培地は6000rpmで10分間遠心を行い、上清をhLFに対するポリクローナル抗体を用いたウエスタンブロット法で解析した。ウエスタンブロット法は上記細胞内取り込みに記載した方法で行った。結果を図11に示す。rhLFは80kDaの完全な形で培地中に放出された。またhLF-HSAは、rhLFと同様に完全な形で培地中に放出された。一方、細胞内取り込みにおいて、HSAとhLFとの結合部位の分解が示唆されたHSA-hLFは、分解したhLFのみが培地中に放出された。
8週齢のWistar系ラット(雄)5頭に、ペントバルビタールナトリウムによる麻酔下にて、外頸静脈に採血用カニューレを留置した。大腿静脈内注射により、hLF換算で1mg/kg体重となるようhLF-HSAとHSA-hLF両融合タンパク質を投与した。投与前及び投与後1、5、10、15、30、60、120、180、240分後に外頸静脈に留置したカニューレから採血し、血漿中のhLF濃度はELISA(「AssayMax Human Lactoferrin ELISA kit」、Assaypro社製)により測定した。なお、予備検討により、採血時に使用した抗凝固剤であるEDTA、及び血漿は、このELISA測定に影響を及ぼさないことを確認している。
まず、ブラッドフォード法により濃度既知であるhLF-HSAとHSA-hLF両融合タンパク質を用いて、各検量線を作成した。hLF-HSAとHSA-hLF両融合タンパク質は、0.24~15.0ng/mlで直線性が得られたので、この範囲に測定値が入るように各血漿サンプルを希釈してタンパク質濃度を測定した。
統計解析ソフトウエア「GraphPad Prism(登録商標) 4」(GraphPad Software社)を用いて、血中半減期と時間曲線下面積(area under the curve、AUC)を算出した。Aspergillus由来の組換え型hLF投与群の半減期は12.6分であるのに対し、hLF-HSA、HSA-hLF両融合タンパク質投与群の半減期はそれぞれ64分、404分とhLF投与群の約5.1倍、32.1倍に延長した(図13)。AUCについては、hLF-HSA、HSA-hLF両融合タンパク質投与群では、hLF投与群の約1.8倍、4.2倍に増加という血中安定性の著しい向上を示した。
4.、5.で示した方法で調製したhLF-HSA、HSA-hLF両融合タンパク質、さらにrhLFに結合している脱鉄操作前の鉄イオン(Fe3+)量を、和光純薬社製「Fe C-テストワコー」で測定すると、hLF換算タンパク質1mgあたりhLF-HSAは1207ng、HSA-hLFは819ng、rhLFは1966ngのFe3+が結合していた。HSA-hLFは酸性状態では沈殿してしまうために、6.で示した塩酸を用いる脱鉄方法は適さない。そこで、中性条件下で脱鉄する方法として、カオトロピック塩であるチオシアン酸ナトリウムを用いる方法を試みた。 rhLF、hLF-HSA、HSA-hLF両融合タンパク質溶液に最終濃度で5 Mになるようにチオシアン酸ナトリウム、最終濃度で0.1% になるようにEDTAを添加して、室温で16時間インキュベートした。その後、150mM NaClを含む50 mMリン酸バッファー(pH 6.6) に対して24時間透析することで脱鉄を行った。鉄の再結合は脱鉄後、0.001%クエン酸鉄アンモニウム、50mM炭酸水素ナトリウム及び150mM NaClを含むリン酸バッファー(pH 7.5)に対して24時間透析、150mM NaClを含む50mMリン酸バッファー(pH 6.6) に対して24時間の透析を1回行うことで、鉄再結合ラクトフェリンとした。タンパク質に結合している鉄イオンは、血清鉄測定キット「Fe C-テストワコー」(商品名、和光純薬社製)を用いて測定した。鉄の結合能は、ブラッドフォード法で定量したhLFタンパク質1mg(HSA融合タンパク質の場合は、分子量を用いて算出したhLF換算で1mg)あたりに結合する鉄の結合量として算出した。その結果を表に示す。rhLFの結合活性を100%とすると、rhLF-HSA、rHSA-hLF融合タンパク質は147%、69.5%の鉄結合能を示した。
低分化型ヒト肺腺ガン細胞株PC-14 は(株)免疫生物研究所(IBL)より購入して、10% FBSを含むRPMI-1640(和光純薬社製)で培養した。細胞培養用96 well plateに0.1% ブタゼラチン(岩城硝子社製)溶液を100 μl/well加えて1時間静置し、plateをゼラチンコートした。PC-14を10% FBSを含むRPMI-1640培地に2.5×104 cells/mlになるように懸濁して、200 μl/wellで細胞を撒き、37℃、5% CO2で一晩培養した。rhLF、ヒト血清アルブミン(HSA、和光純薬社製)、hLF-HSA、HSA-hLF融合タンパク質を10% FBSを含むRPMI-1640(和光純薬社製)を用いて0、5、10 μM (HSA-hLFは0、5 μM)となるように調製した。Plateに接着した細胞の培地を捨てて、調製した各タンパク質溶液を100 μl/wellで加え、37℃、5% CO2で96時間培養した。その後、Cell Counting Kit-8 (同仁化学社製)を加え37℃、5% CO2で2時間発色させた。発色後、450 nmにおける吸光度により細胞増殖を評価した。細胞増殖は、培地にタンパク質を加えない場合の吸光度を100%とした場合の相対値(n=2の平均値)で示した(図14)。10 μM HSAで多少の細胞増殖阻害が観察されたが、rhLFでは細胞増殖阻害は観察されなかった。一方、hLF-HSA、HSA-hLF融合タンパク質では顕著な細胞増殖阻害が認められ、特にHSA-hLFはhLF-HSA と比較して強い細胞増殖阻害を示した。以上のことから、HSA融合によるhLFの抗腫瘍作用の増強が示された。
次にこの抗腫瘍作用の増強には、HSAとrhLFの共存が必要なのか、それとも両分子が共有結合により融合されていることが必要であるのかを明らかとするために、HSAとrhLFの両方を各成分が10 μMの濃度となるように同じウエルに加えて、実施例8と同様の方法でPC-14細胞の増殖を評価した。ただし、今回は各タンパク質を細胞に加え72時間培養し、その後、Cell Counting Kit-8 (同仁化学社製)で2時間発色させた。細胞増殖は、培地にタンパク質を加えない場合の吸光度を100%とした場合の相対値(n=3,平均値±標準偏差 SD)で示した(図15)。10 μM HSA単体、10 μM rhLF単体を加えた場合に多少の細胞増殖阻害が観察されたが、HSAとrhLFの両者を各成分が10 μMの濃度で同じウエルに加えた場合では、10 μM HSA単体、10 μM rhLF単体の場合と同様に増殖阻害をほとんど示さなかった。一方、融合タンパク質ではhLF-HSA及びHSA-hLFのいずれにも顕著な細胞増殖阻害が認められ、特にHSA-hLFはhLF-HSA と比べても強い細胞増殖阻害を示した。このことから、hLFの抗腫瘍作用の増強には、hLFにHSAを共有結合で融合させることが必要であることが示された。
分化型ヒト肺腺ガン細胞株PC-9は(株)免疫生物研究所 (IBL)より購入して、10% FBSを含むRPMI-1640(和光純薬社製)で培養した。細胞培養用96 well plateに0.1% ブタゼラチン(岩城硝子社製)溶液を100 μl/well加えて1時間静置し、plateをゼラチンコートした。PC-9を10% FBSを含むRPMI-1640培地に2.5×104 cells/mlになるように懸濁して、200 μl/wellで細胞を撒き、37℃、5% CO2で一晩培養した。rhLF、ヒト血清アルブミン(HSA、和光純薬社製)、hLF-HSA、HSA-hLF融合タンパク質を10% FBSを含むRPMI-1640(和光純薬社製)を用いて0、5、10 μM (HSA-hLFは0、5 μM)となるように調製した。Plateに接着した細胞の培地を捨てて、調製した各タンパク質溶液を100 μl/wellで加え、37℃、5% CO2で72時間培養した。その後、Cell Counting Kit-8 (同仁化学社製)を加え37℃、5% CO2で2時間発色させた。発色後、450 nmにおける吸光度により細胞増殖を評価した。細胞増殖は、培地にタンパク質を加えない場合の吸光度を100%とした場合の相対値(n=3,平均値±標準偏差 SD)で示した(図16)。10 μM HSA、10 μM rhLFでは細胞増殖阻害は観察されなかったが、hLF-HSA、HSA-hLF融合タンパク質では顕著な細胞増殖阻害が認められ、特にHSA-hLFはhLF-HSA と比較して強い細胞増殖阻害を示した。以上のことから、本発明の融合タンパク質は分化型のヒト肺腺ガン細胞に対しても抗腫瘍作用を有することが確認された。
次にhLF-HSA、HSA-hLF融合タンパク質のヒト肺正常細胞株WI-38への影響を調べた。WI-38 はJCRB細胞バンクより購入して、10% FBSを含むD-MEM low glucose(和光純薬社製)で培養した。細胞培養用96 well plateに0.1% ブタゼラチン(岩城硝子社製)溶液を100 μl/well加えて1時間静置し、plateをゼラチンコートした。WI-38を10% FBSを含むD-MEM low glucose培地に2.5×104 cells/mlとなるように懸濁して、200 μl/wellで細胞を撒き、37℃、5% CO2で一晩培養した。10% FBSを含むD-MEM low glucose(和光純薬社製)を用いてrhLF、HSA、hLF-HSA融合タンパク質は10 μM 、HSA-hLFは5 μMとなるようにタンパク質溶液を調製した。Plateに接着した細胞の培地を捨てて、調製した各タンパク質溶液を100 μl/wellで加え、37℃、5% CO2で72時間培養した。その後、Cell Counting Kit-8(同仁化学社製)を加え37℃、5% CO2で2時間発色させた。発色後、450 nmにおける吸光度により細胞増殖を評価した。細胞増殖は、培地にタンパク質を加えない場合の吸光度を100%とした場合の相対値(n=3の平均値 ± 標準偏差)で示した(図17)。10 μM hLF-HSAで細胞の増殖促進が観察されたが、10 μM rhLF、HSA、5 μM HSA-hLFでは細胞増殖阻害はまったく観察されなかった。以上のことから、HSA融合によりhLFの抗腫瘍作用が増強されること、さらにその抗腫瘍作用は正常細胞では示されないことが明らかとなった。
したがって、本発明の融合タンパク質は抗腫瘍活性を示しながらも、副作用を生じない、あるいは生じたとしても低い副作用に留まることが分かる。
SEQUENCE LISTING
<110> NRL Pharma Inc
<120> lactorerrin/albumin fusion protein and method of producing them
<130> G1649WO
<150> JP 2016-212077
<151> 2016-10-28
<150> JP 2017-044893
<151> 2017-03-09
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 1830
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(1830)
<400> 1
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Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
gac tgc tgt gca aaa caa gaa cct gag aga aat gaa tgc ttc ttg caa 384
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
cac aaa gat gac aac cca aac ctc ccc cga ttg gtg aga cca gag gtt 432
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
gat gtg atg tgc act gct ttt cat gac aat gaa gag aca ttt ttg aaa 480
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
aaa tac tta tat gaa att gcc aga aga cat cct tac ttt tat gcc ccg 528
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
gaa ctc ctt ttc ttt gct aaa agg tat aaa gct gct ttt aca gaa tgt 576
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
tgc caa gct gct gat aaa gct gcc tgc ctg ttg cca aag ctc gat gaa 624
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
ctt cgg gat gaa ggg aag gct tcg tct gcc aaa cag aga ctc aag tgt 672
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
gcc agt ctc caa aaa ttt gga gaa aga gct ttc aaa gca tgg gca gta 720
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
gct cgc ctg agc cag aga ttt ccc aaa gct gag ttt gca gaa gtt tcc 768
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
aag tta gtg aca gat ctt acc aaa gtc cac acg gaa tgc tgc cat gga 816
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
gat ctg ctt gaa tgt gct gat gac agg gcg gac ctt gcc aag tat atc 864
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
tgt gaa aat caa gat tcg atc tcc agt aaa ctg aag gaa tgc tgt gaa 912
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
aaa cct ctg ttg gaa aaa tcc cac tgc att gcc gaa gtg gaa aat gat 960
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
gag atg cct gct gac ttg cct tca tta gct gct gat ttt gtt gaa agt 1008
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
aag gat gtt tgc aaa aac tat gct gag gca aag gat gtc ttc ctg ggc 1056
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
atg ttt ttg tat gaa tat gca aga agg cat cct gat tac tct gtc gtg 1104
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
ctg ctg ctg aga ctt gcc aag aca tat gaa acc act cta gag aag tgc 1152
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
tgt gcc gct gca gat cct cat gaa tgc tat gcc aaa gtg ttc gat gaa 1200
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
ttt aaa cct ctt gtg gaa gag cct cag aat tta atc aaa caa aat tgt 1248
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
gag ctt ttt gag cag ctt gga gag tac aaa ttc cag aat gcg cta tta 1296
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
gtt cgt tac acc aag aaa gta ccc caa gtg tca act cca act ctt gta 1344
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
gag gtc tca aga aac cta gga aaa gtg ggc agc aaa tgt tgt aaa cat 1392
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
cct gaa gca aaa aga atg ccc tgt gca gaa gac tat cta tcc gtg gtc 1440
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
ctg aac cag tta tgt gtg ttg cat gag aaa acg cca gta agt gac aga 1488
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
gtc acc aaa tgc tgc aca gaa tcc ttg gtg aac agg cga cca tgc ttt 1536
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
tca gct ctg gaa gtc gat gaa aca tac gtt ccc aaa gag ttt aat gct 1584
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
gaa aca ttc acc ttc cat gca gat ata tgc aca ctt tct gag aag gag 1632
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
aga caa atc aag aaa caa act gca ctt gtt gag ctc gtg aaa cac aag 1680
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
ccc aag gca aca aaa gag caa ctg aaa gct gtt atg gat gat ttc gca 1728
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
gct ttt gta gag aag tgc tgc aag gct gac gat aag gag acc tgc ttt 1776
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
gcc gag gag ggt aaa aaa ctt gtt gct gca agt caa gct gcc tta ggc 1824
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
tta taa 1830
Leu
<210> 2
<211> 609
<212> PRT
<213> Homo sapiens
<400> 2
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 3
<211> 2136
<212> DNA
<213> Homo sapiens
<220>
<221> CDS
<222> (1)..(2136)
<400> 3
atg aaa ctt gtc ttc ctc gtc ctg ctg ttc ctc ggg gcc ctc gga ctg 48
Met Lys Leu Val Phe Leu Val Leu Leu Phe Leu Gly Ala Leu Gly Leu
1 5 10 15
tgt ctg gct ggc cgt agg aga agg agt gtt cag tgg tgc acc gta tcc 96
Cys Leu Ala Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Thr Val Ser
20 25 30
caa ccc gag gcc aca aaa tgc ttc caa tgg caa agg aat atg aga aga 144
Gln Pro Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Arg
35 40 45
gtg cgt ggc cct cct gtc agc tgc ata aag aga gac tcc ccc atc cag 192
Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln
50 55 60
tgt atc cag gcc att gcg gaa aac agg gcc gat gct gtg acc ctt gat 240
Cys Ile Gln Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu Asp
65 70 75 80
ggt ggt ttc ata tac gag gca ggc ctg gcc ccc tac aaa ctg cga cct 288
Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg Pro
85 90 95
gta gcg gcg gaa gtc tac ggg acc gaa aga cag cca cga act cac tat 336
Val Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr
100 105 110
tat gcc gtg gct gtg gtg aag aag ggc ggc agc ttt cag ctg aac gaa 384
Tyr Ala Val Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn Glu
115 120 125
ctg caa ggt ctg aag tcc tgc cac aca ggc ctt cgc agg acc gct gga 432
Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala Gly
130 135 140
tgg aat gtc cct ata ggg aca ctt cgt cca ttc ttg aat tgg acg ggt 480
Trp Asn Val Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly
145 150 155 160
cca cct gag ccc att gag gca gct gtg gcc agg ttc ttc tca gcc agc 528
Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala Ser
165 170 175
tgt gtt ccc ggt gca gat aaa gga cag ttc ccc aac ctg tgt cgc ctg 576
Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu
180 185 190
tgt gcg ggg aca ggg gaa aac aaa tgt gcc ttc tcc tcc cag gaa ccg 624
Cys Ala Gly Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro
195 200 205
tac ttc agc tac tct ggt gcc ttc aag tgt ctg aga gac ggg gct gga 672
Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala Gly
210 215 220
gac gtg gct ttt atc aga gag agc aca gtg ttt gag gac ctg tca gac 720
Asp Val Ala Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp
225 230 235 240
gag gct gaa agg gac gag tat gag tta ctc tgc cca gac aac act cgg 768
Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr Arg
245 250 255
aag cca gtg gac aag ttc aaa gac tgc cat ctg gcc cgg gtc cct tct 816
Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser
260 265 270
cat gcc gtt gtg gca cga agt gtg aat ggc aag gag gat gcc atc tgg 864
His Ala Val Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp
275 280 285
aat ctt ctc cgc cag gca cag gaa aag ttt gga aag gac aag tca ccg 912
Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser Pro
290 295 300
aaa ttc cag ctc ttt ggc tcc cct agt ggg cag aaa gat ctg ctg ttc 960
Lys Phe Gln Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe
305 310 315 320
aag gac tct gcc att ggg ttt tcg agg gtg ccc ccg agg ata gat tct 1008
Lys Asp Ser Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp Ser
325 330 335
ggg ctg tac ctt ggc tcc ggc tac ttc act gcc atc cag aac ttg agg 1056
Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu Arg
340 345 350
aaa agt gag gag gaa gtg gct gcc cgg cgt gcg cgg gtc gtg tgg tgt 1104
Lys Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys
355 360 365
gcg gtg ggc gag cag gag ctg cgc aag tgt aac cag tgg agt ggc ttg 1152
Ala Val Gly Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly Leu
370 375 380
agc gaa ggc agc gtg acc tgc tcc tcg gcc tcc acc aca gag gac tgc 1200
Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys
385 390 395 400
atc gcc ctg gtg ctg aaa gga gaa gct gat gcc atg agt ttg gat gga 1248
Ile Ala Leu Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly
405 410 415
gga tat gtg tac act gca ggc aaa tgt ggt ttg gtg cct gtc ctg gca 1296
Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala
420 425 430
gag aac tac aaa tcc caa caa agc agt gac cct gat cct aac tgt gtg 1344
Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val
435 440 445
gat aga cct gtg gaa gga tat ctt gct gtg gcg gtg gtt agg aga tca 1392
Asp Arg Pro Val Glu Gly Tyr Leu Ala Val Ala Val Val Arg Arg Ser
450 455 460
gac act agc ctt acc tgg aac tct gtg aaa ggc aag aag tcc tgc cac 1440
Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys His
465 470 475 480
acc gcc gtg gac agg act gca ggc tgg aat atc ccc atg ggc ctg ctc 1488
Thr Ala Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu
485 490 495
ttc aac cag acg ggc tcc tgc aaa ttt gat gaa tat ttc agt caa agc 1536
Phe Asn Gln Thr Gly Ser Cys Lys Phe Asp Glu Tyr Phe Ser Gln Ser
500 505 510
tgt gcc cct ggg tct gac ccg aga tct aat ctc tgt gct ctg tgt att 1584
Cys Ala Pro Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu Cys Ile
515 520 525
ggc gac gag cag ggt gag aat aag tgc gtg ccc aac agc aat gag aga 1632
Gly Asp Glu Gln Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg
530 535 540
tac tac ggc tac act ggg gct ttc cgg tgc ctg gct gag aat gct gga 1680
Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly
545 550 555 560
gac gtt gca ttt gtg aaa gat gtc act gtc ttg cag aac act gat gga 1728
Asp Val Ala Phe Val Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly
565 570 575
aat aac aat gac gca tgg gct aag gat ttg aag ctg gca gac ttt gcg 1776
Asn Asn Asn Asp Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala
580 585 590
ctg ctg tgc ctc gat ggc aaa cgg aag cct gtg act gag gct aga agc 1824
Leu Leu Cys Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser
595 600 605
tgc cat ctt gcc atg gcc ccg aat cat gcc gtg gtg tct cgg atg gat 1872
Cys His Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp
610 615 620
aag gtg gaa cgc ctg aaa cag gtg ttg ctc cac caa cag gct aaa ttt 1920
Lys Val Glu Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe
625 630 635 640
ggg aga aat gga tct gac tgc ccg gac aag ttt tgc tta ttc cag tct 1968
Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser
645 650 655
gaa acc aaa aac ctt ctg ttc aat gac aac act gag tgt ctg gcc aga 2016
Glu Thr Lys Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg
660 665 670
ctc cat ggc aaa aca aca tat gaa aaa tat ttg gga cca cag tat gtc 2064
Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro Gln Tyr Val
675 680 685
gca ggc att act aat ctg aaa aag tgc tca acc tcc ccc ctc ctg gaa 2112
Ala Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu
690 695 700
gcc tgt gaa ttc ctc agg aag taa 2136
Ala Cys Glu Phe Leu Arg Lys
705 710
<210> 4
<211> 711
<212> PRT
<213> Homo sapiens
<400> 4
Met Lys Leu Val Phe Leu Val Leu Leu Phe Leu Gly Ala Leu Gly Leu
1 5 10 15
Cys Leu Ala Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Thr Val Ser
20 25 30
Gln Pro Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Arg
35 40 45
Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln
50 55 60
Cys Ile Gln Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu Asp
65 70 75 80
Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg Pro
85 90 95
Val Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr
100 105 110
Tyr Ala Val Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn Glu
115 120 125
Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala Gly
130 135 140
Trp Asn Val Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly
145 150 155 160
Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala Ser
165 170 175
Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu
180 185 190
Cys Ala Gly Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro
195 200 205
Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala Gly
210 215 220
Asp Val Ala Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp
225 230 235 240
Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr Arg
245 250 255
Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser
260 265 270
His Ala Val Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp
275 280 285
Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser Pro
290 295 300
Lys Phe Gln Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe
305 310 315 320
Lys Asp Ser Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp Ser
325 330 335
Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu Arg
340 345 350
Lys Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys
355 360 365
Ala Val Gly Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly Leu
370 375 380
Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys
385 390 395 400
Ile Ala Leu Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly
405 410 415
Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala
420 425 430
Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val
435 440 445
Asp Arg Pro Val Glu Gly Tyr Leu Ala Val Ala Val Val Arg Arg Ser
450 455 460
Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys His
465 470 475 480
Thr Ala Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu
485 490 495
Phe Asn Gln Thr Gly Ser Cys Lys Phe Asp Glu Tyr Phe Ser Gln Ser
500 505 510
Cys Ala Pro Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu Cys Ile
515 520 525
Gly Asp Glu Gln Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg
530 535 540
Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly
545 550 555 560
Asp Val Ala Phe Val Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly
565 570 575
Asn Asn Asn Asp Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala
580 585 590
Leu Leu Cys Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser
595 600 605
Cys His Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp
610 615 620
Lys Val Glu Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe
625 630 635 640
Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser
645 650 655
Glu Thr Lys Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg
660 665 670
Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro Gln Tyr Val
675 680 685
Ala Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu
690 695 700
Ala Cys Glu Phe Leu Arg Lys
705 710
<210> 5
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 5
cgcggatccc gatgcacaca agagtgaggt 30
<210> 6
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 6
aaggaaaaaa gcggccgctt ataagcctaa ggcagctt 38
<210> 7
<211> 1298
<212> PRT
<213> Artificial Sequence
<220>
<223> hLF-HSA fusion protein
<400> 7
Met Lys Leu Val Phe Leu Val Leu Leu Phe Leu Gly Ala Leu Gly Leu
1 5 10 15
Cys Leu Ala Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Ala Val Ser
20 25 30
Gln Pro Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lys
35 40 45
Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln
50 55 60
Cys Ile Gln Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu Asp
65 70 75 80
Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg Pro
85 90 95
Val Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr
100 105 110
Tyr Ala Val Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn Glu
115 120 125
Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala Gly
130 135 140
Trp Asn Val Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly
145 150 155 160
Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala Ser
165 170 175
Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu
180 185 190
Cys Ala Gly Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro
195 200 205
Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala Gly
210 215 220
Asp Val Ala Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp
225 230 235 240
Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr Arg
245 250 255
Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser
260 265 270
His Ala Val Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp
275 280 285
Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser Pro
290 295 300
Lys Phe Gln Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe
305 310 315 320
Lys Asp Ser Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp Ser
325 330 335
Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu Arg
340 345 350
Lys Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys
355 360 365
Ala Val Gly Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly Leu
370 375 380
Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys
385 390 395 400
Ile Ala Leu Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly
405 410 415
Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala
420 425 430
Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val
435 440 445
Asp Arg Pro Val Glu Gly Tyr Leu Ala Val Ala Val Val Arg Arg Ser
450 455 460
Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys His
465 470 475 480
Thr Ala Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu
485 490 495
Phe Asn Gln Thr Gly Ser Cys Lys Phe Asp Glu Tyr Phe Ser Gln Ser
500 505 510
Cys Ala Pro Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu Cys Ile
515 520 525
Gly Asp Glu Gln Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg
530 535 540
Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly
545 550 555 560
Asp Val Ala Phe Val Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly
565 570 575
Asn Asn Asn Glu Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala
580 585 590
Leu Leu Cys Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser
595 600 605
Cys His Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp
610 615 620
Lys Val Glu Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe
625 630 635 640
Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser
645 650 655
Glu Thr Lys Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg
660 665 670
Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro Gln Tyr Val
675 680 685
Ala Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu
690 695 700
Ala Cys Glu Phe Leu Arg Lys Asp Pro Asp Ala His Lys Ser Glu Val
705 710 715 720
Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val
725 730 735
Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His
740 745 750
Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala
755 760 765
Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly
770 775 780
Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met
785 790 795 800
Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu
805 810 815
Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu
820 825 830
Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu
835 840 845
Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala
850 855 860
Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu
865 870 875 880
Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp
885 890 895
Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys
900 905 910
Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala
915 920 925
Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val
930 935 940
Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His
945 950 955 960
Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr
965 970 975
Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys
980 985 990
Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn
995 1000 1005
Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
1010 1015 1020
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val
1025 1030 1035
Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp
1040 1045 1050
Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr
1055 1060 1065
Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr
1070 1075 1080
Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln
1085 1090 1095
Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
1100 1105 1110
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val
1115 1120 1125
Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu
1130 1135 1140
Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg
1145 1150 1155
Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu
1160 1165 1170
Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys
1175 1180 1185
Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala
1190 1195 1200
Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu
1205 1210 1215
Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
1220 1225 1230
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His
1235 1240 1245
Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp
1250 1255 1260
Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu
1265 1270 1275
Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln
1280 1285 1290
Ala Ala Leu Gly Leu
1295
<210> 8
<211> 711
<212> PRT
<213> Artificial Sequence
<220>
<223> hLF plus signal sequence
<400> 8
Met Lys Leu Val Phe Leu Val Leu Leu Phe Leu Gly Ala Leu Gly Leu
1 5 10 15
Cys Leu Ala Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Ala Val Ser
20 25 30
Gln Pro Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lys
35 40 45
Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln
50 55 60
Cys Ile Gln Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu Asp
65 70 75 80
Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg Pro
85 90 95
Val Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr
100 105 110
Tyr Ala Val Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn Glu
115 120 125
Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala Gly
130 135 140
Trp Asn Val Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly
145 150 155 160
Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala Ser
165 170 175
Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu
180 185 190
Cys Ala Gly Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro
195 200 205
Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala Gly
210 215 220
Asp Val Ala Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp
225 230 235 240
Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr Arg
245 250 255
Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser
260 265 270
His Ala Val Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp
275 280 285
Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser Pro
290 295 300
Lys Phe Gln Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe
305 310 315 320
Lys Asp Ser Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp Ser
325 330 335
Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu Arg
340 345 350
Lys Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys
355 360 365
Ala Val Gly Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly Leu
370 375 380
Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys
385 390 395 400
Ile Ala Leu Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly
405 410 415
Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala
420 425 430
Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val
435 440 445
Asp Arg Pro Val Glu Gly Tyr Leu Ala Val Ala Val Val Arg Arg Ser
450 455 460
Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys His
465 470 475 480
Thr Ala Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu
485 490 495
Phe Asn Gln Thr Gly Ser Cys Lys Phe Asp Glu Tyr Phe Ser Gln Ser
500 505 510
Cys Ala Pro Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu Cys Ile
515 520 525
Gly Asp Glu Gln Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg
530 535 540
Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly
545 550 555 560
Asp Val Ala Phe Val Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly
565 570 575
Asn Asn Asn Glu Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala
580 585 590
Leu Leu Cys Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser
595 600 605
Cys His Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp
610 615 620
Lys Val Glu Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe
625 630 635 640
Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser
645 650 655
Glu Thr Lys Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg
660 665 670
Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro Gln Tyr Val
675 680 685
Ala Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu
690 695 700
Ala Cys Glu Phe Leu Arg Lys
705 710
<210> 9
<211> 585
<212> PRT
<213> Artificial Sequence
<220>
<223> HSA
<400> 9
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 10
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 10
cggaattcat gaagtgggta acctttat 28
<210> 11
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 11
ccgctcgagt aagcctaagg cagcttgac 29
<210> 12
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 12
ctcgagatgg gccgtagga 19
<210> 13
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> primer
<400> 13
gcggccgctt acttcctgag gaactcac 28
<210> 14
<211> 1304
<212> PRT
<213> Artificial Sequence
<220>
<223> HSA-hLF fusion protein
<400> 14
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu Leu Glu Met Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Ala Val
610 615 620
Ser Gln Pro Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg
625 630 635 640
Lys Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile
645 650 655
Gln Cys Ile Gln Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu
660 665 670
Asp Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg
675 680 685
Pro Val Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His
690 695 700
Tyr Tyr Ala Val Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn
705 710 715 720
Glu Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala
725 730 735
Gly Trp Asn Val Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr
740 745 750
Gly Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala
755 760 765
Ser Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg
770 775 780
Leu Cys Ala Gly Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu
785 790 795 800
Pro Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala
805 810 815
Gly Asp Val Ala Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser
820 825 830
Asp Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr
835 840 845
Arg Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro
850 855 860
Ser His Ala Val Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile
865 870 875 880
Trp Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser
885 890 895
Pro Lys Phe Gln Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu
900 905 910
Phe Lys Asp Ser Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp
915 920 925
Ser Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu
930 935 940
Arg Lys Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp
945 950 955 960
Cys Ala Val Gly Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly
965 970 975
Leu Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp
980 985 990
Cys Ile Ala Leu Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp
995 1000 1005
Gly Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val
1010 1015 1020
Leu Ala Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro
1025 1030 1035
Asn Cys Val Asp Arg Pro Val Glu Gly Tyr Leu Ala Val Ala Val
1040 1045 1050
Val Arg Arg Ser Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly
1055 1060 1065
Lys Lys Ser Cys His Thr Ala Val Asp Arg Thr Ala Gly Trp Asn
1070 1075 1080
Ile Pro Met Gly Leu Leu Phe Asn Gln Thr Gly Ser Cys Lys Phe
1085 1090 1095
Asp Glu Tyr Phe Ser Gln Ser Cys Ala Pro Gly Ser Asp Pro Arg
1100 1105 1110
Ser Asn Leu Cys Ala Leu Cys Ile Gly Asp Glu Gln Gly Glu Asn
1115 1120 1125
Lys Cys Val Pro Asn Ser Asn Glu Arg Tyr Tyr Gly Tyr Thr Gly
1130 1135 1140
Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly Asp Val Ala Phe Val
1145 1150 1155
Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly Asn Asn Asn Glu
1160 1165 1170
Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala Leu Leu Cys
1175 1180 1185
Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser Cys His
1190 1195 1200
Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp Lys
1205 1210 1215
Val Glu Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe
1220 1225 1230
Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln
1235 1240 1245
Ser Glu Thr Lys Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu
1250 1255 1260
Ala Arg Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro
1265 1270 1275
Gln Tyr Val Ala Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser
1280 1285 1290
Pro Leu Leu Glu Ala Cys Glu Phe Leu Arg Lys
1295 1300
<210> 15
<211> 609
<212> PRT
<213> Artificial Sequence
<220>
<223> HSA plus signal sequence
<400> 15
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 16
<211> 692
<212> PRT
<213> Artificial Sequence
<220>
<223> hLF
<400> 16
Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Ala Val Ser Gln Pro Glu
1 5 10 15
Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg Gly
20 25 30
Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln Cys Ile Gln
35 40 45
Ala Ile Ala Glu Asn Arg Ala Asp Ala Val Thr Leu Asp Gly Gly Phe
50 55 60
Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys Leu Arg Pro Val Ala Ala
65 70 75 80
Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr Tyr Ala Val
85 90 95
Ala Val Val Lys Lys Gly Gly Ser Phe Gln Leu Asn Glu Leu Gln Gly
100 105 110
Leu Lys Ser Cys His Thr Gly Leu Arg Arg Thr Ala Gly Trp Asn Val
115 120 125
Pro Ile Gly Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly Pro Pro Glu
130 135 140
Pro Ile Glu Ala Ala Val Ala Arg Phe Phe Ser Ala Ser Cys Val Pro
145 150 155 160
Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu Cys Ala Gly
165 170 175
Thr Gly Glu Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro Tyr Phe Ser
180 185 190
Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly Ala Gly Asp Val Ala
195 200 205
Phe Ile Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp Glu Ala Glu
210 215 220
Arg Asp Glu Tyr Glu Leu Leu Cys Pro Asp Asn Thr Arg Lys Pro Val
225 230 235 240
Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser His Ala Val
245 250 255
Val Ala Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp Asn Leu Leu
260 265 270
Arg Gln Ala Gln Glu Lys Phe Gly Lys Asp Lys Ser Pro Lys Phe Gln
275 280 285
Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe Lys Asp Ser
290 295 300
Ala Ile Gly Phe Ser Arg Val Pro Pro Arg Ile Asp Ser Gly Leu Tyr
305 310 315 320
Leu Gly Ser Gly Tyr Phe Thr Ala Ile Gln Asn Leu Arg Lys Ser Glu
325 330 335
Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys Ala Val Gly
340 345 350
Glu Gln Glu Leu Arg Lys Cys Asn Gln Trp Ser Gly Leu Ser Glu Gly
355 360 365
Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys Ile Ala Leu
370 375 380
Val Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly Gly Tyr Val
385 390 395 400
Tyr Thr Ala Gly Lys Cys Gly Leu Val Pro Val Leu Ala Glu Asn Tyr
405 410 415
Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val Asp Arg Pro
420 425 430
Val Glu Gly Tyr Leu Ala Val Ala Val Val Arg Arg Ser Asp Thr Ser
435 440 445
Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys His Thr Ala Val
450 455 460
Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu Phe Asn Gln
465 470 475 480
Thr Gly Ser Cys Lys Phe Asp Glu Tyr Phe Ser Gln Ser Cys Ala Pro
485 490 495
Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu Cys Ile Gly Asp Glu
500 505 510
Gln Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg Tyr Tyr Gly
515 520 525
Tyr Thr Gly Ala Phe Arg Cys Leu Ala Glu Asn Ala Gly Asp Val Ala
530 535 540
Phe Val Lys Asp Val Thr Val Leu Gln Asn Thr Asp Gly Asn Asn Asn
545 550 555 560
Glu Ala Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala Leu Leu Cys
565 570 575
Leu Asp Gly Lys Arg Lys Pro Val Thr Glu Ala Arg Ser Cys His Leu
580 585 590
Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp Lys Val Glu
595 600 605
Arg Leu Lys Gln Val Leu Leu His Gln Gln Ala Lys Phe Gly Arg Asn
610 615 620
Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser Glu Thr Lys
625 630 635 640
Asn Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg Leu His Gly
645 650 655
Lys Thr Thr Tyr Glu Lys Tyr Leu Gly Pro Gln Tyr Val Ala Gly Ile
660 665 670
Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu Ala Cys Glu
675 680 685
Phe Leu Arg Lys
690
Claims (17)
- (1)ヒト血清アルブミン(HSA)又はヒト血清アルブミンの断片もしくはペプチドと、
(2)ラクトフェリン又はラクトフェリンの生物活性断片との融合タンパク質であって、
(LF-s-Y)n 又は (Y-s-LF)n
〔式中、LFはラクトフェリン又はラクトフェリンの生物活性断片、Yはヒト血清アルブミンもしくはヒト血清アルブミンの断片を含むタンパク質又はペプチド、sは0~10個の任意のアミノ酸の配列、nは1~10の整数を表す〕
で表され、SEQ ID NO: 7又は14に示すアミノ酸配列と90%以上の配列同一性を有するアミノ酸配列からなり、かつラクトフェリンの生物活性を保持する融合タンパク質。 - (LF-s-Y)n
で表される請求項1に記載の融合タンパク質。 - (Y-s-LF)n
で表される請求項1に記載の融合タンパク質。 - SEQ ID NO: 7に示すアミノ酸配列からなる、請求項1に記載の融合タンパク質。
- SEQ ID NO: 14に示すアミノ酸配列からなる、請求項1に記載の融合タンパク質。
- 前記融合タンパク質が、天然又は遺伝子組換え型ラクトフェリンの50%以上の鉄キレート能を保持している、請求項1~5のいずれか一項に記載の融合タンパク質。
- 前記融合タンパク質は、ラクトフェリン受容体及びアルブミン受容体からなる群より選択される少なくとも1つの受容体を介して細胞に取り込まれるものである、請求項1~6のいずれか一項に記載の融合タンパク質。
- 前記融合タンパク質が、天然又は遺伝子組換え型ラクトフェリンと比べてペプシン耐性が向上したものである、請求項1~7のいずれか一項に記載の融合タンパク質。
- 請求項1~8のいずれか一項に記載の融合タンパク質をコードする核酸分子。
- 請求項9記載の核酸分子を含む発現ベクター。
- 請求項10記載の発現ベクターを含む宿主細胞。
- 請求項9記載の核酸分子を含む非ヒト遺伝子組換え動物。
- 請求項1~8のいずれか一項に記載の融合タンパク質によって改善される疾患の治療剤。
- 請求項1~8のいずれか一項に記載の融合タンパク質及び担体を含む、医薬組成物。
- 腫瘍の治療のための、請求項14に記載の医薬組成物。
- 前記腫瘍が肺癌である、請求項15に記載の医薬組成物。
- 請求項1~8のいずれか一項に記載の融合タンパク質の製造方法であって、この融合タンパク質をコードする遺伝子を含む宿主細胞を培養して融合タンパク質を発現させ、この宿主細胞又はその培地から融合タンパク質を回収することを含む方法。
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