JP6093712B2 - インターロイキン2のスーパーアゴニストおよびアンタゴニスト - Google Patents
インターロイキン2のスーパーアゴニストおよびアンタゴニスト Download PDFInfo
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Description
[0028]本明細書で引用される全ての参考文献は、全体が示されたと仮定した場合と同様に、参照によりそれらの全体において組み込まれる。別段に規定しない限り、本明細書で用いられる技術用語および科学用語は、本発明が属する技術分野の当業者により一般的に理解されるのと同じ意味を有する。Singletonら、「Dictionary of Microbiology and Molecular Biology」、3版、J.Wiley & Sons(New York、NY 2001);March、「Advanced Organic Chemistry:Reactions,Mechanisms and Structure」、5版、J.Wiley & Sons(New York、NY 2001);ならびにSambrookおよびRussell、「Molecular Cloning:A Laboratory Manual」、3版、Cold Spring Harbor Laboratory Press(Cold Spring Harbor、NY 2001)は、当業者に、本開示で用いられる多くの用語への一般的な指針をもたらす。必要に応じ、市販のキットおよび試薬の使用を伴う手順は、別段に言及しない限り、一般に製造元により規定されたプロトコールおよび/またはパラメータに従い実行する。
[0044] 多様な実施形態では、本開示は、実質的に精製されうるが必ずしも精製されていないIL−2ポリペプチドであって、IL−2の生物学的活性のうちの1または複数(例えば、細胞増殖の刺激)を果たし、野生型IL−2のアゴニストとして機能しうる、IL−2ポリペプチドを提供する。IL−2は、抗原により活性化したT細胞の増殖およびNK細胞の刺激を誘導する、T細胞成長因子として特徴づけられている。
IL−2ムテイン、発現ベクター、および宿主細胞の組換え発現
[0058] 多様な実施形態では、本発明を実施するのに用いられるポリペプチドが、合成であるか、または組換え核酸分子の発現を介して生成する。キメラ(例えば、少なくとも突然変異体のIL−2ポリペプチドおよび異種ポリペプチドを含有する融合タンパク質)である場合、ポリペプチドは、突然変異体IL−2の全部または一部をコードする1つの配列、および異種ポリペプチドの全部または一部をコードする第2の配列を含有するハイブリッドの核酸分子によりコードされうる。例えば、突然変異体のIL−2ポリペプチドは、ヘキサヒスチジンタグと融合させて、細菌により発現されるタンパク質の精製を容易にすることもでき、ヘマグルチニンタグと融合させて、真核細胞により発現されるタンパク質の精製を容易にすることもできる。
[0064] 上記で言及した通り、例示的な突然変異体のIL−2ポリペプチドは、突然変異体のIL−2ポリペプチドおよび異種ポリペプチド(すなわち、IL-2またはその突然変異体でないポリペプチド)(例えば、米国特許第6,451,308号を参照されたい)を包含する融合ポリペプチドまたはキメラポリペプチドとして調製することができる。例示的な異種ポリペプチドは、in vivoにおいて、キメラポリペプチドの循環半減期を延長することが可能であり、したがって、突然変異体のIL−2ポリペプチドの特性をさらに増強することが可能である。多様な実施形態では、循環半減期を延長するポリペプチドが、ヒト血清アルブミンなどの血清アルブミンの場合もあり、IgGの重鎖可変領域を欠く抗体のIgGサブクラスのFc領域の場合もある。例示的なFc領域は、補体の結合およびFc受容体の結合を阻害する突然変異を包含する場合もあり、溶解性の場合もある、すなわち、補体に結合する場合もあり、抗体依存性補体溶解(ADCC;1994年12月12日に出願されたUSSN08/355,502)などの別の機構を介して細胞を溶解させる場合もある。
[0070] 一部の実施形態では、上記の突然変異体のIL−2ポリペプチドなど、単独の、またはキメラポリペプチドの一部としての突然変異体のIL−2ポリペプチドは、核酸分子を発現させることにより得ることができる。突然変異体のIL−2ポリペプチドが、それらの野生型IL−2ポリペプチドとの同一性との関係で記載しうるのと全く同様に、それらをコードする核酸分子も、野生型IL−2をコードする核酸分子との一定の同一性を必然的に有する。例えば、突然変異体のIL−2ポリペプチドをコードする核酸分子は、野生型IL−2をコードする核酸(例えば、配列番号2)と少なくとも50%、少なくとも65%、好ましくは少なくとも75%、より好ましくは少なくとも85%、および最も好ましくは少なくとも95%(例えば、99%)同一でありうる。成熟IL−2およびそのシグナル配列をコードする核酸配列は、配列番号17に見出される。
[0076] 上記の核酸分子は、例えば、それを形質導入した細胞における核酸分子の発現を指示することが可能なベクター内に含有させることができる。したがって、発現ベクターは、突然変異体のIL−2ポリペプチドに加えて、突然変異体のIL−2ポリペプチドをコードする核酸分子も含有し、これらのベクターでトランスフェクトした細胞も、好ましい実施形態のうちにある。
[00100] 一部の実施形態では、突然変異体IL−2のポリペプチドおよび/またはそれらを発現する核酸を対象に投与して、アポトーシス過程または分化過程の異常と関連する障害を治療する(例えば、能動的免疫または受動的免疫を生成させることにより、例えば、がんなどの細胞増殖障害または細胞分化障害を治療する)ことができる。このような疾患の治療において、開示されるIL−2ムテインは、血管漏出症候群の軽減などの有利な特性を保有する。
[00108] 一部の実施形態では、突然変異体のIL−2ポリペプチドおよび核酸を、医薬組成物を含めた組成物へと組み込むことができる。このような組成物は、ポリペプチドまたは核酸分子および薬学的に許容可能な担体を包含することが典型的である。
酵母の表面におけるIL−2の機能的発現
[00123] IL−2は既にバクテリオファージ上で提示されている(Buchliら、Arch. Biochem. Biophys. 339:79-84、1997)が、このかつての系は、指向的進化に適さず、したがって、IL−2Rのサブユニットに対する結合を改善したIL−2の突然変異体を得るのには適切でない。これを克服するため、IL−2を、酵母細胞の表面で発現させた。ヒトIL−2 DNAを、酵母用ディスプレイベクターであるpCT302へとクローニングした。Saccharomyces cerevisiaeのEBY100株を、pCT302_IL−2ベクターで形質転換し、SD−CAAプレート上、30℃で3日間にわたり増殖させた。IL−2酵母の個別のコロニーを、SD−CAA中、30℃で一晩にわたり増殖させ、次いで、20℃で2日間にわたりSGCAAに導入した。酵母を、四量体化されたビオチニル化IL−2Rβ、ビオチニル化γ、またはビオチニル化γの存在下におけるビオチニル化IL−2Rβで染色した。IL−2Rβおよびγの細胞外ドメインをC末端においてビオチニル化し、染色分取試薬として用いられるフィコエリトリンコンジュゲートストレプトアビジンに連結した。IL−2Rβの四量体は、2μΜのビオチニル化IL−2Rβを、氷上で15分間にわたり470nMのストレプトアビジン−フィコエリトリン(SA-PE、Invitrogen)と共にインキュベートすることにより形成した。これらの受容体の「四量体」は、単量体の細胞外ドメイン(ECD)によるIL−2との低アフィニティーの相互作用のアビディティーを増強し、ライブラリーからのIL−2変異体の最大限の回収を可能とした。溶体の野生型IL−2と同様に、IL−2Rβ単独に弱く結合する、酵母により提示されるIL−2は、γ単独には全く結合せず、フローサイトメトリー(データは示さない)により見られる対角染色を介して証拠立てられる通り、IL−2Rβの存在下ではγに結合した。したがって、酵母により提示されるIL−2は、可溶性のIL−2と共に見られる、細胞上におけるヘテロ二量体の受容体複合体の協調的アセンブリーを再現する(recapitulate)ものであり、したがって、ライブラリーによる選択のためのプラットフォームとして適する。
IL−2突然変異体ライブラリーの構築およびスクリーニング
[00124] 第1世代のin vitro戦略は、IL−2遺伝子全体のエラープローンPCRライブラリーを創出することであった。第1世代の突然変異体IL−2ライブラリーは、以下の通りに構築した。野生型ヒトインターロイキン2(IL-2)を、製造元の指示書に従いGeneMorph(登録商標)II Random Mutagenesisキットを用いるエラープローン突然変異誘発にかけた。エラープローンPCRには、以下のプライマーを用いた:5’−GCACCTACTTCAAGTTCTAC−3’(IL-2_errprone_for)および5’−GCCACCAGAGGATCC−3’(IL-2_errprone_rev)。次いで、以下のプライマー:5’−AGTGGTGGTGGTGGTTCTGGTGGTGGTGGTTCTGGTGGTGGTGGTTCTGCTAGCGCACCTACTTCAAGTTCTAC−3’および5’−ACACTGTTGTTATCAGATCTCGAGCAAGTCTTCTTCGGAGATAAGCTTTTGTTCGCCACCAGAGGATCC−3’を用いて、エラープローンPCR反応の産物を増幅して、DNA約130μgを得た。酵母ディスプレイベクターであるpCT302を、制限酵素NheIおよびBamHIで二重消化し、ゲル精製した。IL−2 DNAおよびpCT302 DNAを併せて、エレクトロコンピテントのEBY100酵母と5:1μgの比で混合した。酵母を電気穿孔して、ライブラリーDNAの酵母への移入を容易にした。この電気穿孔を約20回にわたり繰り返し、最終ライブラリーサイズ1×108の形質転換体を得た。
PCR増幅オリゴ(50bpの相同性を包む)
IL−2ムテインタンパク質の発現および精製
[00125] ヒトIL−2変異体(アミノ酸1〜133)、IL−2Rβ細胞外ドメイン(アミノ酸1〜214)、およびγc(アミノ酸34〜232)を、N末端のgp67シグナル配列およびC末端のヘキサヒスチジンタグとインフレームでpAcGP67−Aベクター(BD Biosciences)へとクローニングし、バキュロウイルスによる発現系を用いて生成させた。バキュロウイルスの原液は、SF900II培地(Invitrogen)中で増殖させたSpodoptera frugiperda(Sf9)細胞におけるトランスフェクションおよび増幅により調製し、タンパク質の発現は、BioWhittaker(登録商標)昆虫 XPRESS(商標)培地(Lonza)中で増殖させたTrichoplusia ni(High Five(商標))細胞懸濁液中で実行した。タンパク質を発現させ、ニッケルアガロース(QIAGEN)を介する48〜60時間後のHigh Five(商標)上清から捕捉し、10mMのHEPES(pH7.2)および150mMのNaCl中で平衡化したSuperdex(商標)200カラム(GE Healthcare)によるサイズ除外クロマトグラフィーを介して濃縮および精製した。SPRおよび細胞ベースのアッセイで用いられるIL−2変異体は、完全にグリコシル化させて発現させた。ビオチニル化させた受容体の発現では、IL−2Rβおよびγcを、C末端ビオチンアクセプターペプチド(BAP)(LNDIFEAQKIEWHE)およびヘキサヒスチジンタグと共にpAcGP67−Aベクターへとクローニングした。受容体タンパク質は、過剰なビオチン(100uM)を伴うBirAリガーゼと共に共発現させた。
CD25−ナチュラルキラー(YT-1)細胞およびCD25+ナチュラルキラー(YT-1)細胞の刺激
[00126]YT−1細胞およびCD25+YT−1細胞を、10%のウシ胎仔血清、2mMのL−グルタミン、最小限の非必須アミノ酸、ピルビン酸ナトリウム、25mMのHEPES、およびペニシリン−ストレプトマイシン(Gibco)を補充したRPMI 1640培地中で培養した。CD25+YT−1細胞は、以下の通りに精製した:1×107個の細胞をFACS緩衝液(リン酸緩衝生理食塩液+2%のウシ血清アルブミン)で洗浄し、FACS緩衝液1mL中、4℃で20分間にわたり、PEとコンジュゲートした抗ヒトCD25(1:20; Biolegend、San Diego、CA)で染色した。染色された細胞を抗PE IgGへと連結された常磁性マイクロビーズで標識し、製造元(Miltenyi Biotec、Bergisch Gladbach、Germany)の指示書に従い、LS MACS(登録商標)分離カラムにより分離した。溶出させた細胞を、完全RPMI培地中に1×105個の細胞濃度で再懸濁させ、後続の実験のために増殖させた。細胞の濃縮は、Accuri(登録商標)C6フローサイトメーターを用いて、FL−2チャネルによるフローサイトメトリーを介してモニタリングした。
CD25−T細胞およびCD25+T細胞刺激
[00129]ヒトおよびマウスのCD4 T細胞を、BALB/CマウスのPBMC(Stanford Blood Bank)、脾臓、およびリンパ節から、それぞれ、抗体でコーティングされたCD4 T細胞単離用磁気ビーズ(Stem Cell TechnologiesおよびMiltenyi Biotec)を用いて調製した。天然細胞刺激アッセイでは、細胞を即座に用いた。in vitroにおいて「抗原経験のある(experienced)」T細胞世代を生成するために、100ng/mLの抗CD3(ヒトにはOKT3であり、マウスには2C11である;eBiosciences)でプレートをコーティングする前に、ウェルを、pH9.6の重炭酸緩衝液中の二次抗体(Vector Labs)であらかじめコーティングした。T細胞を、可溶性の抗CD28(ヒトにはCD28.2であり、マウスには37.51である;eBiosciences)と共に、ウェル1つ当たり0.1×106個の細胞で播種した。細胞を、刺激された完全なTCRと共に3日間にわたり培養した後、条件付け培地中で2日間にわたり静置し(rest)、新鮮な培養培地中で2日間にわたり静置した。使用前に、Lympholyte−M(Cederlane)による遠心分離を介して生細胞を回収し、カウントした。
NK細胞による細胞傷害作用アッセイ
[00132] EGFR(内皮成長因子受容体)を発現する扁平上皮がん細胞系(SCC6)と、EGFRに対するモノクローナル抗体であるセツキシマブとを用いて、D10 IL−2ムテインの、ナチュラルキラー細胞の機能、とりわけ、自発的な抗体依存性細胞介在性細胞毒性(ADCC)に対する効果を評価した。ヒトEGFR陽性扁平上皮細胞がん細胞系であるSCC6は、J.Sunwoo研究室(Stanford、CA)から恵与された。SCC6細胞系は、加熱により不活化した10%のFCS(HyClone Laboratories)、100U/mLのペニシリンおよび100μg/mLのストレプトマイシン(いずれもInvitrogen Life Technologies製)を補充したDMEM/F12培地(Invitrogen Life Technologies)中で培養した。細胞は、5%CO2中37℃の培養物中で接着させて増殖させた。セツキシマブ(マウスキメラ抗ヒト表皮成長因子受容体(EGFR)IgG1; IMC-C225; Erbitux(登録商標))は、Bristol−Myers Squibbから購入した。
IL−2ムテインは、抑制型T細胞(Tregs)の刺激を比較的低下させながら、メモリー表現型増殖の増強を結果としてもたらす
[00134] IL−2ムテインであるH9の、CD25は低レベルで発現するがIL−2Rβγは高レベルで発現するメモリー表現型CD8+T細胞の増殖に対する効力を、in vivoにおいて評価した。C57B1/6マウスに、PBS、IL−2 20μg、H9 20μg、またはIL−2/抗IL−2モノクローナル抗体の複合体1.5μgを施し、脾臓のCD3+CD8+CD44highメモリー表現型T細胞の全細胞カウントをフローサイトメトリーにより評価した。脾臓細胞の懸濁液を調製し、蛍光色素をコンジュゲートしたモノクローナル抗体で、CD3(クローン145-2C11、eBioscience)、CD4(クローンRM4-5、Caltag Laboratories)、CD8a(クローン53-6.7、BD Biosciences)、CD25(クローンPC61、BD Biosciences)、CD44(クローンIM7、eBioscience)、NK1.1(クローンPK136、BD Biosciences)、およびThy1.1(クローンHIS51、eBioscience)を染色した。BD FACSCanto(商標)IIフローサイトメーターを用いて少なくとも100,000個の生細胞を収集し、FlowJoソフトウェア(TriStar, Inc.)を用いて解析した。図10(A)に示される通り、開示されるIL−2ムテインによる処置は、他の処置モダリティーと比べて大幅な、メモリー表現型T細胞の増殖を結果としてもたらしたが、CD3+CD4+CD25highT細胞である制御性T細胞の増殖は制限された(図10(B))。
in vivoにおけるIL−2ムテインの毒性の低減
[00135] IL−2による処置は、急性肺浮腫などの重度の有害作用をもたらしうることが知られ、これは、現在のところIL−2の有効な使用を阻止する制約となっている。したがって、開示されるIL−2ムテインのIL−2と比べた毒性を評価した(図11A)。C57B1/6マウスに、PBS、IL−2 20μg、H9 20μg、またはIL−2/抗IL−2モノクローナル抗体の複合体1.5μgによる毎日の腹腔内注射を、連続5日間にわたり施した。養子(adoptive)細胞移入の6日後、肺を摘出し、真空下58℃で一晩にわたる乾燥の前および乾燥の後に秤量した。肺の湿潤重量は、初期の肺重量を脱水後の肺重量から減じることにより計算した。
in vivoにおけるIL−2ムテインの抗腫瘍活性の増大
[00136] 開示されるIL−2ムテインの腫瘍細胞に対する効力をin vivoにおいて調べた。RPMI 100μl中に106個のB16F10黒色腫細胞を、マウス(群1つ当たりのマウス3〜4匹)背部の真皮上層へと注射した。処置は、PBS、IL−2 20μg、H9 20μg、またはIL−2/抗IL−2モノクローナル抗体の複合体(IL-2/mAb)1.5μgによる5回にわたる毎日の注射からなり、腫瘍小塊が約15mm2のサイズではっきりと目視可能および触知可能となって1日後に開始した。図11(B)で裏付けられる通り、開示されるIL−2ムテインは、in vivoにおける抗腫瘍活性の増強を結果としてもたらした。
IL−2ムテインとIL−2との構造比較
[00137] 表面プラズモン共鳴(SPR)によりIL−2Rβに対するそれらの結合アフィニティーおよび反応速度を測定するために、IL−2ムテインのうちのいくつかを組換えにより発現させた。IL−2とIL−2Rβとのアフィニティーは、KD=280nMであった。IL−2ムテインを、低アフィニティーのクラス、中程度のアフィニティーのクラス、および高アフィニティーのクラスへとクラスター分割した。低アフィニティーのIL−2ムテイン(5−2および6−6)は、それぞれ、50〜70nMのKDでIL−2Rβに結合し、野生型IL−2の4〜6倍のアフィニティーの増分は、ほぼ完全にL85V置換を介するものであった。第2の部位指向的ライブラリーから選択された、アフィニティーが中程度の突然変異体および高アフィニティーの突然変異体のKDは、それぞれ、10〜15nM(C5、H4)および1.2〜1.7nM(B1、D10、E10、G8、H9)であった。アフィニティーの増大は、オフ速度の低減により一様に明示され、高アフィニティーのIL−2ムテインは、L80F/R81D/L85V/I86V/I92Fのうちの無作為化された位置にコンセンサス配列を含有した。
[00143] 本発明をその詳細な記載と共に記載してきたが、前出の記載は、添付の特許請求の範囲により規定される、本発明の範囲を例示することを意図するものであり、これを限定するものではないことを理解されたい。他の態様、利点、および改変は、以下の特許請求の範囲の範囲内にある。例えば、IL−2は、明細書の全体において言及されているが、当業者であれば、本明細書で記載される方法および組成物が、他のサイトカイン、例えば、この特性を伴う顆粒球マクロファージコロニー刺激因子(GM-CSF)、IL−2、IL−3、IL−5、IL−6、またはIL−15にも同等に適用可能であることを理解するであろう。したがって、本発明はまた、それらのそれぞれの受容体に対する結合アフィニティーを野生型と比較して増大させた、GM−CSF、IL−2、IL−3、IL−5、IL−6、およびIL−15の突然変異体、ならびにこれらの突然変異体を同定する方法および用いる方法も包含する。
Claims (15)
- IL−2Rβに対する平衡解離定数が、野生型のヒトIL−2(hIL−2)のものより小さい、IL−2Rβ結合タンパク質であって、
野生型のhIL−2に従い番号付けされたL80F、R81D、L85V、I86VおよびI92Fのアミノ酸置換を含むIL−2ムテインである、結合タンパク質。 - 前記ムテインが、I24V、F42A、K43N、P65H、Q74R、Q74H、Q74N、Q74S、I89VおよびV93Iからなる群から選択される1または複数のアミノ酸置換をさらに含む、請求項1に記載の結合タンパク質。
- 前記ムテインがQ74Rのアミノ酸置換を含む、請求項2に記載の結合タンパク質。
- 前記ムテインが、Q74N、L80F、R81D、L85V、I86V、I89VおよびI92Fのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- 前記ムテインが、L80F、R81D、L85V、I86V、I89V、I92F、およびV93Iのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- 前記ムテインが、Q74H、L80F、R81D、L85V、I86VおよびI92Fのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- 前記ムテインが、IL−2RβとIL−2Rγとの間の相互作用を阻害する、請求項1〜6のいずれか一項に記載の結合タンパク質。
- 前記ムテインが、Q74S、L80F、R81D、L85V、I86VおよびI92Fのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- 前記ムテインが、L18R、Q22E、L80F、R81D、L85V、I86V、I89V、I92F、V93I、およびQ126Tのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- IL−2Rβに対する平衡解離定数が、野生型のヒトIL−2(hIL−2)のものより小さい、IL−2Rβ結合タンパク質であって、野生型のhIL−2に従い番号付けされたL18R、Q22E、Q74S、L80F、R81T、L85V、I86V、I89V、I92F、V93IおよびQ126Tのアミノ酸置換を含むIL−2ムテインである、結合タンパク質。
- 前記ムテインが、Q74N、L80F、R81D、L85V、I86VおよびI92Fのアミノ酸置換を有する、請求項1に記載の結合タンパク質。
- 前記IL−2ムテインがヒトIL−2ムテインである、請求項1または10に記載の結合タンパク質。
- ヒトIL−2を突然変異させ、これにより、第1世代のIL−2ムテインを生成させる工程と、野生型のヒトIL−2のものより小さい、インターロイキン2受容体βに対する平衡解離定数を有する第1世代のIL−2ムテインを同定する工程と、同定された第1世代のIL−2ムテインを突然変異させ、これにより、第2世代のIL−2ムテインを生成させる工程と、野生型のhIL−2に従い番号付けされたL80F、R81D、L85V、I86VおよびI92Fのアミノ酸置換を含む第2世代のIL−2ムテインを同定し、さらに野生型のIL−2と比較してより低い程度で、インターロイキン2受容体γに結合し、かつ/またはインターロイキン2受容体γを介してシグナル伝達する第2世代のIL−2ムテインを同定し、これにより、IL−2βアンタゴニストタンパク質を生成させる工程と、を含む、IL−2結合タンパク質の生成方法。
- 野生型IL−2と比べて低減したインターロイキン2受容体αへの結合を示す、請求項1、2または10に記載の結合タンパク質。
- 野生型IL−2と比べて低減したインターロイキン2受容体γへの結合および/またはインターロイキン2受容体γを介するシグナル伝達を示す、請求項1、10または14に記載の結合タンパク質。
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JP2014502967A (ja) | 2014-02-06 |
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