JP5997134B2 - 安定したフィブロネクチンドメイン組成物、方法及び用途 - Google Patents
安定したフィブロネクチンドメイン組成物、方法及び用途 Download PDFInfo
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Description
ADCC=抗体依存性の細胞傷害性;CDC=補体依存性の細胞毒性;DSC=示差走査熱量計;ΔG=ギブス自由エネルギー;IgG=免疫グロブリンG;Tm=融解温度;
用語「抗体」又は「抗体部分」は、抗体、その消化断片、特定部分及び変異型を含むことを意図し、これには抗体模倣薬が非限定的に挙げられ、又は抗体の構造及び/若しくは機能を模倣する抗体の部分又はその特定断片若しくは一部を含み、単鎖抗体、単一ドメイン抗体、小体、及びその断片が非限定的に挙げられる。機能的断片は、関心対象の標的抗原に結合する、抗原結合断片を含む。例えば、Fab(例えば、パパイン消化による)、Fab’(例えば、ペプシン消化及び部分的還元による)、及びF(ab’)2(例えば、ペプシン消化による)、facb(例えば、プラスミン消化による)、pFc’(例えば、ペプシン又はプラスミン消化による)、Fd(例えば、ペプシン消化、部分的還元、及び再集合による)、Fv又はscFv(例えば、分子生物学的技術による)断片が挙げられるが、これらに限定されない、標的抗原又はその一部に結合できる抗体断片が、用語「抗体」に含まれる。抗体又は断片は、非限定的に、ヒト、マウス、ウサギ、ラット、げっ歯類、霊長類、ラクダ類、ヤギ、又はそれらの任意の組み合わせ等に由来することができ、また、単離したヒト、霊長類、げっ歯類、哺乳類、キメラ、ヒト化、及び/又はCDR移植等の抗体、免疫グロブリン、開裂産物及び他の指定部分、並びにそれらの変異を含む。
本発明は、フィブロネクチン3型(FN3)繰り返し体タンパク質の共通配列に基づく、哺乳類由来スカフォールドを非限定的に含む、単離された組み換え及び/又は合成タンパク質スカフォールド、並びに組成物、及び共通FN3配列に基づくタンパク質スカフォールドをコードする少なくとも1つのポリヌクレオチドを含むコード化核酸分子を提供する。本発明は、例えば発見プラットホームとして、また診断用組成物、治療用組成物、方法及びデバイスを目的として、このような核酸及びタンパク質スカフォールドを製造しかつ使用する方法を非限定的に含む。
本発明の少なくとも1つのスカフォールドタンパク質は、所望により、当該技術分野において周知の細胞株、混合細胞株、不死化細胞又は不死化細胞のクローン集団によって産生することができる。例えば、Ausubel,et al.,ed.,Current Protocols in Molecular Biology,John Wiley & Sons,Inc.,NY,NY(1987〜2001);Sambrook,et al.,Molecular Cloning:A Laboratory Manual,2nd Edition,Cold Spring Harbor,NY(1989);Harlow and Lane,Antibodies,a Laboratory Manual,Cold Spring Harbor,NY(1989);Colligan,etal.,eds.,Current Protocols in Immunology,John Wiley & Sons,Inc.,NY(1994〜2001);Colligan et al.,Current Protocols in Protein Science,John Wiley & Sons,NY,NY,(1997〜2001)を参照されたい。
類似するタンパク質又は断片に特異的に結合する変化に富んだ残基又はドメインを有するスカフォールドベースタンパク質を含む改変スカフォールドベースタンパク質又はライブラリーのスクリーニングを、ヌクレオチド(DNA若しくはRNAディスプレイ)又はペプチドディスプレイライブラリー、例えば、インビトロディスプレイを用いて便利に達成することができる。この方法は、望ましい機能又は構造をもつ個々のメンバーについてペプチドの大規模コレクションをスクリーニングすることを含む。ヌクレオチド配列を有する又は有さない表示されるペプチドの長さは、3〜5000個又はそれ以上のヌクレオチド又はアミノ酸、しばしば5〜100個のアミノ酸、更にしばしば約8〜25個のアミノ酸であり得る。ペプチドライブラリーを作成するための直接的な化学合成方法に加えて、複数の組換えDNA法も記述されている。1つのタイプには、バクテリオファージ又は細胞の、表面上のペプチド配列のディスプレイが関与している。各バクテリオファージ又は細胞は、特定のディスプレイされたペプチド配列をコードするヌクレオチド配列を含有する。
本発明のタンパク質スカフォールドをコードする核酸分子は、mRNA、hnRNA、tRNA若しくは任意の他の形態などのRNAの形態、又はクローニングにより得られる若しくは合成的に生成されるcDNA及びゲノムDNAが挙げられるがこれらに限定されないDNAの形態、又はこれらの任意の組み合わせであってよい。DNAは、三本鎖、二本鎖、若しくは一本鎖、又はこれらの任意の組み合わせであってもよい。DNA又はRNAの少なくとも1本の鎖の任意の部分は、センス鎖としても知られるコード鎖であってもよく、又はアンチセンス鎖と呼ばれる、非コード鎖であってもよい。
本発明はまた、単離したポリヌクレオチドとして、又は原核細胞、真核性、又は繊維状のファージ発現、組成物の分泌及び/又はそれらの定方向突然変異誘発物質又は組成物のディスプレイと適合するベクターを含む発現ベクターの部分として、本発明の組成物をコードする核酸を提供する。
(a)組換え方法、(b)合成方法、(c)精製方法、及び/又は、
(d)これらの組み合わせ、を使用して作ることができる。
G:グアニン
A:アデニン
T:チミン
C:シトシン
R(A又はG)
Y(C又はT)
M(A又はC)
K(G又はT)
S(C又はG)
W(A又はT)
H(A又はC又はT)
B(C又はG又はT)
V(A又はC又はG)
D(A又はG又はT)
N(A又はC又はG又はT)
本発明の修飾されたタンパク質スカフォールド及び断片は、直接的又は間接的に別のタンパク質に共有結合される1つ以上の部分を含むことができる。
本明細書に記載されるように、スカフォールドベースタンパク質の発現に対して選択される宿主細胞は、最終組成物に対する重要な寄与因子であり、存在する場合に、例えば免疫グロブリンCH2ドメインにおいてタンパク質を修飾するオリゴ糖部分の組成物における変異を含むが、これに限定されない。したがって、本発明の1つの態様は、所望の治療用タンパク質を発現する産生細胞の使用及び/又は開発のために適切な、宿主細胞の選択を含む。
ポリペプチド又は融合タンパク質あるいはその成分及びドメインは、そのようなドメイン又は成分のライブラリー、例えば、ファージライブラリーから選択することにより得られてもよい。ファージライブラリーは、免疫化された動物又はヒトのB細胞から抗体ドメインのような、ランダムオリゴヌクレオチドのライブラリー又は目的の配列を含有するポリヌクレオチドのライブラリーを挿入することによって、作成され得る(Smith,G.P.1985.Science 228:1315〜1317)。抗体ファージライブラリーは、1つのファージに重鎖(H)及び軽鎖(L)可変領域対を含有し、単鎖Fv断片又はFab断片の発現を可能にする(Hoogenboom,et al.2000,Immunol.Today 21(8)371〜8)。ファージミドライブラリーの多様性は、後に追加の、望ましい分子特性及びそれらをコードするポリヌクレオチドを生成しその後同定するために、ライブラリーのポリペプチドの特異性を増大及び/又は変更するように操作することができる。
本明細書に記載され、上述の方法のいずれかで作成されるスカフォールドベースの分子の組成物は、ヒトの疾病の症状、又は細胞、組織、臓器、体液、若しくは一般には宿主の特定の病変を、診断し、監視し、調節し、治療し、緩和し、発生の防止を助け、又は軽減するために使用され得る。特定の目的のために改変されたスカフォールドベースの分子を使用して、免疫介在疾患又は免疫不全症、代謝性疾患、心臓血管傷害又は疾患;悪性疾患;神経障害又は疾患;細菌感染症、ウイルス感染症又は寄生虫感染症などの感染症;あるいは、腫脹、疼痛、及び組織壊死又は線維症などのその他の既知又は特定の関連疾患、を治療することができる。
修飾されている又は修飾されていない、一価、二価、又は多価の、単一標的、重標的、多標的である標的結合スカフォールドタンパク質は、捕捉、固定化、分割、又は沈殿のための当該技術分野において周知の分離法を用いて単離され、商業的応用に必要な程度まで精製され得る。
Tenconの設計
ヒトテネイシンの第3 FN3ドメイン(配列番号3)を、抗体の相補性決定領域(CDR)に構造的に類似する表面露出ループを介して特定の標的分子に結合するよう改変することができる代替スカフォールドとして使用することができる。天然型のこのドメインの融解温度はPBS中で54℃である。類似構造及び改善された物理学的特性、例えば改善された熱安定性を有するスカフォールド分子を製造するため、ヒトテネイシンの15のFN3ドメイン(配列番号1〜15)の配列比較に基づいて共通配列を設計した。
Tenconのアミノ酸配列(配列番号16)を逆翻訳すると、配列番号17に示すDNA配列が得られた。この配列をオーバーラッピングPCRにより構築し、修飾されたpET15ベクターにサブクローンし、BL21Star(DE3)大腸菌(Invitrogen)に形質転換し、75μg/mLカルベニシリン含有LB寒天平板上で培養した。コロニーを1つ取り、37℃で、2%グルコース及び100μg/mLカルベニシリンを含有するTB培地50mL中で一晩培養した。この培養液を用いて、2.5L容のUltra Yieldフラスコ(Thomson Instrument Company)中の自己誘導培地(Overnight Express Instant TB media,Novagen)500mLに播種した。増殖及び発現は、ATR Multitron振盪培養機の二重プログラム(37℃、300rpmで3時間、続いて30℃、250rpmで16時間)を用いて行った。
Tenconの構造及び安定性を、それぞれ円偏光二色性分光法及び示差走査熱量測定法によって特徴づけた。PBS中濃度0.2mg/mLで、20℃において、AVIV分光計でCD測定を実施した。図8のスペクトルは218nmで最小を示し、設計したとおり、FN3ファミリーに属するタンパク質に予測されるβシート構造が示唆される。溶液のテネイシン第3 FN3ドメイン又はTenconのPBS溶液0.5mg/mLを、N−DSCII熱量計(Applied Thermodynamics)において、35℃から95℃まで、1℃/分の速度で加熱することによりDSCデータを得た。最初に、緩衝剤のみの曲線を差し引き、図3に示す特性を得た。このデータから、第3 FN3ドメイン及びTenconそれぞれについて、CpCalc(Applied Thermodynamics)ソフトウェアを用い、54℃及び78℃の融解温度が計算された。両ドメインの折り畳み及び変性は、これらの温度で可逆的である。
ヒトに対するアミノ酸配列の免疫原性をモデリングするコンピュータプログラムを用い、ヒトテネイシンの第3 FN3ドメイン、Tencon、及び種々の治療用抗体(表2に示す)を表すアミノ酸配列の予測される免疫原性を比較した。このプログラムで解析したキメラmAb及びヒトmAb(アダリムマブ)に、続いて寛容限界を適用した(ヒト生殖細胞系にコードされた配列に100%同一である9マーのペプチドを除去する)。寛容限界は、テネイシン又はTenconに適用しなかった。寛容限界は、ヒト生殖細胞系にコードされたmAb配列に対する幅広いT細胞寛容を仮定し、主にCDR及び隣接ドメインにおける新規配列に関する解析に焦点を当てる。
Tenconのアミノ酸配列をコードする遺伝子を、PCR及び制限消化クローニングによりファージミド発現ベクターpPep9にサブクローニングし、ベクターpTencon−pIXを得た。この系は、C末端がM13 pIXタンパク質のN末端に融合するN末端Myc−タグ化Tenconを発現する(図4)。Lacプロモーターにより、IPTGがない状態で発現レベルが低く、IPTGの添加後に発現を増加することができる。OmpAシグナル配列をTenconのN末端に追加し、周辺質への効率的な移動を促進した。短いTSGGGGSリンカー(配列番号141)をTenconとpIXとの間に構築し、これらのタンパク質間における立体相互作用を防止した。
Tencon変異体ライブラリーを所望の複雑度、及び分子内における変異体の相対位置に応じて、様々な方法で作成することができる。Tencon遺伝子全体に点在する変異体を作るには、DNA合成法が好ましい。遺伝子の異なる領域に変異を含有するDNA断片を組み換えるための、制限酵素クローニングも用いることができる。単一のTenconループなど、小さく定められた領域における飽和突然変異誘発は、縮重オリゴヌクレオチド及びオリゴヌクレオチド指定突然変異誘発を用いて導入することができる(Kunkel et al.,1987)。
GAATACACCGTTTCTATCTACGGTGTTNNSNNSNNSNNSNNSNNSNNSCCGCTGTCTGCGGAATTCAC
gactctctgcgtctgtcttggNNSNNSNNSNNSNNSNNSTTCGACTCTTTCCTGATCCAGTACC
GTGAATTCCGCAGACAGCGGSNNSNNSNNSNNSNNSNNSNNAACACCGTAGATAGAAACGGTG
IgGに結合するTenconライブラリーメンバーの選択を実施するため、組み換えIgG(ヒトIgG1サブタイプ)をスルホ−NHS−LC−ビオチン(Pierce)を用いてビオチン化し、PBS内に透析した。選択には、200μLのファージディスプレイライブラリーFG7又はBC6/FG7を200μLのケミブロッカーでブロッキングした後、500nM(1回目)又は100nM(2回目及び3回目)の濃度のビオチン化IgGを添加した。結合したファージを、1回目はNeutravidin磁気ビーズ(Seradyne)で、2回目及び3回目はストレプトアビジン磁気ビーズ(Promega)で回収した。未結合のファージを、tween含有Tris緩衝生理食塩水(TBST)1mLで5〜10回洗浄し、続いてTris緩衝生理食塩水(TBS)1mLで2回洗浄し、ビーズから洗い流した。対数増殖期中期の大腸菌MC1061F’を添加することにより、結合したファージをビーズから溶出させた。カルベニシリンとグルコースとを添加したLB寒天プレート上に感染細胞を蒔いた。翌日、細胞をプレートからかき取り、対数期の中間部まで増殖させた後、VCSM13ヘルパーファージで回復させ、一晩増殖した。PEG/NaCl沈殿で単離したファージ粒子を、次の選択回で用いた。
配列番号1:
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tylpapeglkfksiketsvevewdpldiafetweiifrnmnkedegeitkslrrpetsyrqtglapgqeyeislhivknntrgpglkrvtttrld
dapsqievkdvtdttalitwfkplaeidgieltygikdvpgdrttidltedenqysignlkpdteyevslisrrgdmssnpaketftt
tgldaprnlrrvsqtdnsitlewrngkaaidsyrikyapisggdhaevdvpksqqattkttltglrpgteygigvsavkedkesnpatinaateldtpkd
dtpkdlqvsetaetsltllwktplakfdryrlnyslptgqwvgvqlprnttsyvlrglepgqeynvlltaekgrhkskpakskparvk
qapelenltvtevgwdglrlnwtaadqayehfiiqvqeankveaarnltvpgslravdipglkaatpytvsiygviqgyrtpvlsaeastge
etpnlgevvvaevgwdalklnwtapegayeyffiqvqeadtveaaqnltvpgglrstdlpglkaathytitirgvtqdfsttplsvevlte
evpdmgnltvtevswdalrlnwttpdgtydqftiqvqeadqveeahnltvpgslrsmeipglragtpytvtlhgevrghstrplavevvte
dlpqlgdlavsevgwdglrlnwtaadnayehfviqvqevnkveaaqnltlpgslravdipgleaatpyrvsiygvirgyrtpvlsaeastakepe
kepeignlnvsditpesfnlswmatdgifetftieiidsnrlletveynisgaertahisglppstdfivylsglapsirtktisatatte
alpllenltisdinpygftvswmasenafdsflvtvvdsgklldpqeftlsgtqrklelrglitgigyevmvsgftqghqtkplraeivte
aepevdnllvsdatpdgfrlswtadegvfdnfvlkirdtkkqsepleitllapertrdltglreateyeielygiskgrrsqtvsaiattam
gspkevifsditensatvswraptaqvesfrityvpitggtpsmvtvdgtktqtrlvklipgveylvsiiamkgfeesepvsgsfttal
dgpsglvtanitdsealarwqpaiatvdsyvisytgekvpeitrtvsgntveyaltdlepateytlrifaekgpqksstitakfttdl
dsprdltatevqsetalltwrpprasvtgyllvyesvdgtvkevivgpdttsysladlspsthytakiqalngplrsnmiqtifttigl
LPAPKNLVVSEVTEDSLRLSWTAPDAAFDSFLIQYQESEKVGEAINLTVPGSERSYDLTGLKPGTEYTVSIYGVKGGHRSNPLSAEFTT
ctgccggcgccgaaaaacctggttgtttctgaagttaccgaagactctctgcgtctgtcttggaccgcgccggacgcggcgttcgactctttcctgatccagtaccaggaatctgaaaaagttggtgaagcgatcaacctgaccgttccgggttctgaacgttcttacgacctgaccggtctgaaaccgggtaccgaatacaccgtttctatctacggtgttaaaggtggtcaccgttctaacccgctgtctgcggaattcaccacc
本明細書で上述されたTenconスカフォールド(配列番号16)の折畳み安定性を改善するために突然変異体を設計した。点突然変異を生じさせて、配列番号16の個々の残基の置換、例えば、N46V(Tencon17−配列番号142)、E14P(Tencon18−配列番号143)、E11N(Tencon19−配列番号144)、E37P(Tencon20−配列番号145)、及びG73Y(Tencon21−配列番号146)を生じさせ、これらはプログラムPoPMuSiC v2.0(Dehouck,Grosfils et al.,2009)によって安定性を改善すると予想された。突然変異体E86I(Tencon22−配列番号147)は、相同タンパク質、ヒトテネイシンの第3 FN3ドメインを安定させることが以前に見出されている(WO2009/086116A2)。最後に、Tenconの全てのループ残基が独立してアラニンで置換されるアラニン走査実験中に、L17A変異体がTenconを有意に安定させることが見出された(データは示されず)。安定性アッセイの初回の後(下記参照)、安定性を更に増加させるために、コンビナトリアル突然変異体N46V/E86I(Tencon 23−配列番号148)、E14P/N46V/E86I(Tencon24−配列番号149)、及びL17A/N46V/E86I(Tencon25−配列番号150)を生成した。
QuikChange変異誘発キット(Stratagene)を使用して、Tenconコード配列の突然変異体を生成した。得られたプラスミドをBL21−GOLD(DE3)大腸菌(Stratagene)に形質転換して発現させた。単一コロニーを取り、100μg/mLアンピシリンを含有するTB培地2mL中で37℃で一晩培養した。この培養液を用いて、500mLのバッフルフラスコ中の自己誘導培地(Overnight Express Instant TB media,Novagen)100mLに播種し、37℃で16時間培養した。
本発明のTencon及び各突然変異体の熱安定性を、毛細示差走査熱量法(DSC)によって測定した。各サンプルをPBS(pH 7.4)に対して透析し、2〜3mg/mLの濃度まで希釈した。オートサンプラー(MicroCal,LLC)を備えたVP−DSC機器を使用して、これらサンプルの融解温度を測定した。サンプルを10℃から95℃又は100℃まで毎分1℃の速度で加熱した。積分のためのベースラインを計算するために、各サンプルの走査の間に緩衝液のみの走査を行った。データは、緩衝液のみのシグナルを差し引いた後の二状態変性モデルに合致していた。各サンプルをセルから取り出すことなく走査を繰り返すことによって、熱変性の可逆性を決定した。可逆性は、1回目の走査曲線の下の面積を2回目の走査曲線の下の面積と比較することによって計算された。DSC実験の結果は、完全な融解曲線から導かれた値として表5に示されている。単一の突然変異体Tencon17、Tencon18、Tencon19、及びTencon22は、親Tencon配列と比べて熱安定性を改善した。Tencon21だけが有意に不安定化した。コンビナトリアル突然変異体サンプルTencon23、Tencon24、及びTencon25は全て、安定性の向上が有意に大きく、設計された変異は熱安定性の改善に対して相加的に作用することが示された。
トリプトファン蛍光で測定した場合の、高濃度の塩酸グアニジン(GdmCl)で処理された際にTencon及び各突然変異体が折り畳みを維持するの能力を用いて、安定性を評価した。Tenconはトリプトファン残基を1個だけ含有している。トリプトファン残基は疎水性コアの中に埋め込まれ、したがって、360nmの蛍光放射は、このタンパク質の折り畳み状態の感度の高い測定となる。17点滴定のために、50mMのリン酸ナトリウム(pH 7.0)、150mMのNaCl、及び0.48〜6.63Mの可変濃度のGdmClを含有する200μLの溶液を、黒色で非結合の96個のウェルプレート(Greiner)にピペットで入れた。Tencon突然変異体を含有している10μLの溶液を、最終タンパク質濃度が23uMになるようにプレートにわたり各ウェルに加え、ピペットをゆっくりと上下に操作することによって混合した。室温で24時間インキュベーションした後、SpectraMax M5プレートリーダー(Molecular Devices)によって、280nmでの励起及び360nmでの発光により蛍光を読み取った。かかる曲線から作成されたデータが図8に示されている。次の式(Pace 1986 Methods Enzymol 131:266〜80)を用いて蛍光シグナルを折り畳みが壊れた割合に変換した。
サイズ排除クロマトグラフィー(SEC)を用いて、WT Tencon及び各突然変異体の凝集状態を評価した。5μLの各サンプルを、PBS移動相を用いて0.3mL/分の流量でSuperdex 75 5/150カラム(GE Healthcare)上に注入した。カラムからの溶出を280nmの吸光度でモニターした。凝集状態を評価するために、球状分子量標準品(globular molecular weight standards)(Sigma)でカラムを予め較正した。Tencon21を除く試験した全てのサンプルは、モノマーサンプルの溶出体積と一致する溶出体積で単一ピークに溶出された。Tencon21は2つのピークに溶出され、凝集の存在を示していた。
Claims (8)
- ループドメインを含むタンパク質スカフォールドであって、前記スカフォールドは、配列番号16の共通アミノ酸配列に基づくアミノ酸配列を有し、配列番号16の1つ以上の特定の残基が置換され、配列番号16のアミノ酸配列を有するタンパク質スカフォールドの融解温度(Tm)及び化学安定性と比べて前記タンパク質スカフォールドの融解温度(Tm)及び化学安定性が増強されたものであり、配列番号16の置換が、N46V、E14P、L17A、E86I、N46VとE86Iとの組み合わせ、E14PとN46VとE86Iとの組み合わせ、及びL17AとN46VとE86Iとの組み合わせからなる群から選択されるものである、タンパク質スカフォールド。
- 前記融解温度(Tm)が示差走査熱量計によって測定され、前記化学安定性が塩化グアニジニウム変性に対する抵抗性により[D]として測定され、前記Tmが、配列番号16のアミノ酸配列を有する前記タンパク質スカフォールドと比べて、約1Kcal〜約12Kcal増加する、請求項1に記載のタンパク質スカフォールド。
- 標的タンパク質と接触するループ領域を含み、前記ループ領域が、配列番号16、142、143及び147〜151からなる群から選択されるアミノ酸配列の残基13、15及び16、22〜28、38〜43、51〜54、60〜64、及び75〜81からなる群から選択される1つ以上の位置に変異を含む、請求項1に記載のタンパク質スカフォールド。
- 前記タンパク質スカフォールドが、表面プラズモン共鳴又は結合平衡除外法で測定されるとき、少なくとも10-9M以下、少なくとも10-10M以下、少なくとも10-11M以下、及び少なくとも10-12M以下、少なくとも10-13M以下、少なくとも10-14M以下、及び少なくとも10-15MであるKDから選択される少なくとも1つの親和性で標的タンパク質に結合する、請求項3に記載のタンパク質スカフォールド。
- 配列番号142〜144及び147〜151からなる群から選択されるアミノ酸配列を含む、タンパク質スカフォールド。
- ポリペプチド変異体を製造するためにランダム化コドンを導入するフィブロネクチン3型ドメインの安定性が強化された共通配列に由来するスカフォールドベースタンパク質のライブラリーの構築方法であって、
フィブロネクチン3型ドメインの安定性が強化された共通配列を含むポリペプチドをコードするポリヌクレオチド配列を提供するステップであって、前記安定性が強化された共通配列が配列番号142〜144及び147〜151からなる群から選択されるものである、ステップと、
ランダム化コドンを、少なくとも1つのループ領域をコードする位置において前記ポリヌクレオチド配列に導入するステップと、
変異スカフォールドタンパク質をコードするポリヌクレオチドのライブラリーを形成するために、ポリヌクレオチド配列のコピーを増幅するステップと、を含む方法。 - 前記ランダム化コドンが、NNS及びNNKからなる群から選択される、請求項6に記載の方法。
- 前記ランダム化コドンが、配列番号142〜144及び147〜151の残基13〜16、22〜28、38〜43、51〜54、60〜64、及び75〜81の位置の残基からなる群から選択される少なくとも1つのループ領域をコードする位置に導入される、請求項7に記載の方法。
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JP2018183143A (ja) * | 2010-04-30 | 2018-11-22 | ヤンセン バイオテツク,インコーポレーテツド | 安定したフィブロネクチンドメイン組成物、方法及び用途 |
JP2021010368A (ja) * | 2010-04-30 | 2021-02-04 | ヤンセン バイオテツク,インコーポレーテツド | 安定したフィブロネクチンドメイン組成物、方法及び用途 |
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