JP2021168699A - I型及びii型細胞外ドメインを異種キメラタンパク質として連結する組成物及び方法 - Google Patents
I型及びii型細胞外ドメインを異種キメラタンパク質として連結する組成物及び方法 Download PDFInfo
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Abstract
Description
本出願は、2015年10月1日出願の米国仮出願第62/235,727号、2015年12月4日出願の米国仮出願第62/263,313号、2016年8月9日出願の米国仮出願第62/372,574号に対する利益及び優先権を主張するものであり、そのすべてが全体として参照により本明細書に組み込まれる。
電子的に提出されたテキストファイルに関する説明事項
本明細書とともに電子的に提出されたテキストファイルの内容は、その全体が参照により本明細書に組み込まれる:配列表のコンピューター可読形式コピー(ファイル名:HTB−023PC−SequenceListing.txt;記録日:2016年9月29日;ファイルサイズ:140KB)。
一態様では、本発明は、(a)N末端またはその近傍にI型膜貫通タンパク質の第1の細胞外ドメイン、(b)C末端またはその近傍にII型膜貫通タンパク質の第2の細胞外ドメイン、及び(c)リンカーを含み、第1及び第2の細胞外ドメインの一方が免疫抑制シグナルであり、かつ第1及び第2の細胞外ドメインの一方が免疫刺激シグナルであるキメラタンパク質に関する。
様々な実施形態において、本発明は、癌及び/または腫瘍に関し、例えば、癌及び/または腫瘍の治療または予防に関する。本明細書で別記するように、癌の治療は、様々な実施形態において、本発明のキメラタンパク質を用いて免疫抑制よりも免疫刺激を有利にするように免疫系を調節することを含み得る。
いくつかの実施形態では、本発明は、キメラタンパク質、及び追加薬剤を対象に投与することをさらに含む方法を提供する。いくつかの実施形態では、本発明は、共投与及び/または共製剤化に関する。本明細書に記載のいずれの組成物も、共製剤化及び/または共投与することができる。
本明細書に記載のキメラタンパク質(及び/または追加薬剤)は、無機酸もしくは有機酸と反応することができる十分な塩基性の官能基、または無機塩基もしくは有機塩基と反応することができるカルボキシル基を有し、薬学的に許容される塩を形成することができる。薬学的に許容される酸付加塩は、当技術分野で周知のように、薬学的に許容される酸から形成される。そのような塩として、例えば、Journal of Pharmaceutical Science,66,2−19(1977)及びThe Handbook of Pharmaceutical Salts;Properties,Selection,and Use.P.H.Stahl and C.G.Wermuth(eds.),Verlag,Zurich(Switzerland)2002に列記されている薬学的に許容される塩が挙げられ、各文献はその全体が参照により本明細書に組み込まれる。
本発明は、記載されたキメラタンパク質(及び/または追加薬剤)を様々な製剤に含む。本明細書に記載のいずれのキメラタンパク質(及び/または追加薬剤)も、溶液、懸濁液、乳濁液、滴剤、錠剤、丸薬、ペレット、カプセル、液体を含有するカプセル、散剤、徐放性製剤、坐剤、乳濁液、エアゾール、スプレー、懸濁液の形態、または使用に適した他の任意の形態をとることができる。タンパク質配列をコードするDNAまたはRNA構築物もまた使用することができる。一実施形態では、組成物はカプセルの形態である(例えば、米国特許第5,698,155号を参照)。好適な医薬賦形剤の他の例は、Remington’s Pharmaceutical Sciences 1447−1676(Alfonso R.Gennaro eds.,19th ed.1995)に記載されており、それは参照により本明細書に組み込まれる。
様々な実施形態において、本発明は、本明細書に記載のキメラタンパク質をコードする核酸を含む発現ベクターを提供する。様々な実施形態において、発現ベクターはDNAまたはRNAを含む。様々な実施形態において、発現ベクターは哺乳動物の発現ベクターである。
いくつかの実施形態では、対象及び/または動物は、哺乳動物、例えば、ヒト、マウス、ラット、モルモット、イヌ、ネコ、ウマ、ウシ、ブタ、ウサギ、ヒツジ、またはサル、チンパンジー、もしくはヒヒなどの非ヒト霊長類である。他の実施形態では、対象及び/または動物は、非哺乳動物、例えばゼブラフィッシュなどである。いくつかの実施形態では、対象及び/または動物は、蛍光標識細胞(例えば、GFPによる)を含み得る。いくつかの実施形態では、対象及び/または動物は、蛍光細胞を含むトランスジェニック動物である。
本発明は、本明細書に記載の任意の薬剤の投与を容易にすることができるキットを提供する。本発明の例示的なキットは、本明細書に記載の任意の組成物を単位剤形で含む。一実施形態では、単位剤形は、本明細書に記載の任意の薬剤及び薬学的に許容される担体、希釈剤、賦形剤、またはビヒクルを収容する、滅菌できるプレフィルドシリンジなどの容器である。キットは、本明細書に記載の任意の薬剤の使用法を指示するラベルまたは印刷された説明書をさらに含むことができる。キットはまた、開瞼器、局所麻酔剤、及び投与場所の清浄剤を含み得る。キットはまた、本明細書に記載の1つ以上の追加薬剤をさらに含み得る。一実施形態では、キットは、有効量の本発明の組成物及び有効量の本明細書に記載されるような別の組成物を収容する容器を含む。以下の実施例で本発明をさらに説明するが、これは特許請求の範囲に記載された本発明の範囲を限定するものではない。
キメラマウスPD−1−Fc−OX40L構築物を作製し、マウスIgG捕捉ELISAアッセイを使用してCHO−K1細胞での発現を確認した(ここでのFcはIgG1に由来する)。具体的には、CHO−K1細胞を、Fcに融合したPD−1のマウス細胞外ドメイン(ECD)(mPD−1−Fc)またはOX40LのECDに融合したmPD−1−Fc(mPD−1−Fc−OX40L)のいずれかを発現するpVITRO2−GS−hygroベクターまたはpcDNA3.4ベクターで安定的にヌクレオフェクションした。抗生物質耐性単一細胞クローンを、限界希釈法によって単離した。培地に分泌された各キメラタンパク質の濃度を、mIgG捕捉ELISAによって図5に示すように決定した。
IgG1由来のヒンジ−CH2−CH3 Fcドメインを介してOX40LのECDに融合したPD−1のマウス細胞外ドメイン(ECD)(mPD−1−Fc−OX40L)を含めた、mPD−1−Fc−OX40L構築物を作製した。mPD−1−Fc−OX40L構築物を293細胞中で一過性発現させ、プロテインAアフィニティークロマトグラフィーを使用して精製した。ウェスタンブロット法及び機能的ELISA分析を実施して、mPD−1−Fc−OX40Lの3つの構成要素すべての検出及び結合を確認した(図10のパネルA)。mPD1−Fc−OX40Lの定量は、マウスIgG捕捉及び検出ELISAを使用して評価することができる(図10のパネルB)。mPD−L1−Fcを用いてmPD−1−Fc−OX40Lを捕捉し、それをmOX40−His、続いてHis−HRPで化学発光定量を検出することにより、mPD−1及びmOX40LのそれぞれのパートナーであるmPD−L1及びmOX40への結合を同時に実証した(図8のパネルC)。mPD−1−Fc−OX40Lの単量体及び二量体の立体構造が存在することも示された。
ヒト免疫グロブリン4(IgG4)抗体由来のヒンジ−CH2−CH3 Fcドメインを介してOX40Lに連結したヒトPD−1を含むヒトPD−1−Fc−OX40Lを構築した。この構築物をSL−279252と称した。
先のデータは、SL−279252が低ナノモル親和性で固定化標的に結合することを示し、複数のタンパク質アッセイによって検出可能であった。SL−279252が、生細胞表面にある標的にin vitroで結合できるかどうかを決定する追加の分析を実施した。ヒトOX40受容体へのSL−279252の結合を評価するために、ヒトAML T細胞株Jurkatを、OX40を過剰発現するように遺伝子操作し、Jurkat/hOX40細胞を作製した(フローサイトメトリーにより確認;図15のパネルA)。PD−L1への結合を評価するために、ヒトPD−L1を発現しないチャイニーズハムスター卵巣細胞株CHO−K1をトランスフェクトして、ヒトPD−L1を安定的に発現させた(図15のパネルB)。ヒトCD47への結合を評価するために、CHO−K1細胞をトランスフェクトして、ヒトCD47を安定的に発現させた(図15のパネルC)。
追加のヒトPD−1−Fc−OX40L構築物、ならびにヒトhCD172a−Fc−OX40L、hPD1−Fc−TL1A、hBTLA−Fc−OX40L、hTMIGD2−Fc−OX40L、hTIM3−Fc−OX40L、mPD1−Fc−GITRL、mPD1−Fc−41BBL、mPD1−Fc−TL1A、mCD172a−Fc−CD40L、hTIGIT−Fc−OX40L、及びイヌPD−1−Fc−OX40Lを含む追加の構築物を作製した。これらの構築物のそれぞれを、チャイニーズハムスター卵巣(CHO)細胞の発現にコドン最適化して、CHO細胞にトランスフェクトし、個々のクローンから高発現したものを選抜した。次いで、高発現クローンを、無血清培地中の撹拌バイオリアクターでの小規模製造に使用し、関連するキメラ融合タンパク質をプロテインA結合樹脂カラムで精製した。図17のパネルAは、hCD172a−Fc−OX40L、hPD1−Fc−TL1A、hBTLA−Fc−OX40L、hTMIGD2−Fc−OX40L、hTIM3−Fc−OX40L、mPD1−Fc−GITRL、mPD1−Fc−41BBL、mPD1−Fc−TL1A、mCD172a−Fc−CD40L、hTIGIT−Fc−OX40Lを含む、種々のキメラタンパク質のウェスタンブロットによる特性決定を示す。
本発明はその特定の実施形態に関連して説明されているが、さらなる改変が可能であること、ならびに本出願が、本発明の原理に一般的に従う本発明のいかなる変形例、使用法、または適合例も包含し、また本発明が関係する技術分野の範囲内で既知の慣例または慣行の範囲内で考案されるような本開示からの逸脱、及び添付の特許請求の範囲の範囲内に定められ、それに従う上記の本質的な特徴に該当し得るような逸脱を含むことを意図するものであることが理解されよう。
本明細書で参照するすべての特許及び刊行物は、その全体が参照により本明細書に組み込まれる。
本発明の実施形態の例として、以下の項目が挙げられる。
(項目1)
(a)N末端またはその近傍にI型膜貫通タンパク質の第1の細胞外ドメイン、(b)C末端またはその近傍にII型膜貫通タンパク質の第2の細胞外ドメイン、及び(c)リンカーを含み、第1及び第2の細胞外ドメインの一方が免疫抑制シグナルであり、かつ第1及び第2の細胞外ドメインの一方が免疫刺激シグナルである、異種キメラタンパク質。
(項目2)
前記免疫抑制シグナルが、TIM−3、BTLA、PD−1、TMIGD2、TIGIT、CD172a/SIRPα、VSIG8、またはその変種のうちの1つ以上である、項目1に記載の異種キメラタンパク質。
(項目3)
前記免疫抑制シグナルがPD−1またはその変種である、項目1に記載の異種キメラタンパク質。
(項目4)
前記免疫刺激シグナルが、4−1BBリガンド、GITRリガンド、OX−40リガンド、LIGHT(CD258)、CD70、CD30リガンド、CD40リガンド、TRAIL、及びTL1A、またはその変種のうちの1つ以上である、項目1に記載の異種キメラタンパク質。
(項目5)
前記免疫抑制シグナルがOX40リガンドまたはその変種である、項目4に記載の異種キメラタンパク質。
(項目6)
前記キメラタンパク質が、(i)PD−1の細胞外ドメインと、(ii)OX40Lの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目7)
前記キメラタンパク質が、配列番号22と少なくとも95%の配列類似性を有するアミノ酸配列を含む、項目6に記載の異種キメラタンパク質。
(項目8)
前記キメラタンパク質が、(i)PD−1の細胞外ドメインと、(ii)GITRLの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目9)
前記キメラタンパク質が、(i)BTLAの細胞外ドメインと、(ii)OX40Lの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目10)
前記キメラタンパク質が、(i)TIGITの細胞外ドメインと、(ii)OX40Lの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目11)
前記キメラタンパク質が、(i)TIM3の細胞外ドメインと、(ii)OX40Lの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目12)
前記キメラタンパク質が、(i)CD172aの細胞外ドメインと、(ii)CD40Lの細胞外ドメインとを含む、項目1に記載の異種キメラタンパク質。
(項目13)
前記融合体が、(i)CD115の細胞外ドメインと、(ii)CD40Lの細胞外ドメインとを含む、項目1に記載のキメラタンパク質。
(項目14)
前記キメラタンパク質が、組換え融合タンパク質である、項目1に記載の異種キメラタンパク質。
(項目15)
前記細胞外ドメインの1つが抑制性免疫シグナルを減少させる、遮断する、または消失させることができる、項目1に記載の異種キメラタンパク質。
(項目16)
前記細胞外ドメインの1つが、免疫刺激シグナルを増加させる、模擬する、または活性化させることができる、項目1に記載の異種キメラタンパク質。
(項目17)
前記キメラタンパク質が、(i)免疫抑制シグナルを減少または消失させること、かつ(ii)免疫刺激シグナルを増加または活性化させることができる、項目1に記載の異種キメラタンパク質。
(項目18)
前記キメラタンパク質が、制御性T細胞に対するエフェクターT細胞の比率を増加させることができる、項目1に記載の異種キメラタンパク質。
(項目19)
前記キメラタンパク質が、細胞傷害性T細胞の亜集団;エフェクターメモリーT細胞;セントラルメモリーT細胞;CD8+幹細胞メモリーエフェクター細胞;TH1エフェクターT細胞;TH2エフェクターT細胞;TH9エフェクターT細胞;TH17エフェクターT細胞;ならびに/またはIL−2、IL−4、及び/もしくはIFN−γを分泌するエフェクターT細胞を増加させる、及び/または減少を妨げることができる、項目1に記載の異種キメラタンパク質。
(項目20)
前記キメラタンパク質がもたらす動物の末梢血におけるサイトカイン応答を前記キメラタンパク質の適切な用量を決定する手段として使用することができる、項目1に記載の異種キメラタンパク質。
(項目21)
前記リンカーが、可動性のアミノ酸配列、IgGヒンジ領域、または抗体配列から場合に応じて選択されるポリペプチドである、項目1に記載の異種キメラタンパク質。
(項目22)
前記リンカーが合成リンカー、場合によりPEGである、項目1に記載の異種キメラタンパク質。
(項目23)
前記リンカーが、IgG1、場合によりヒトIgG1に由来するヒンジ−CH2−CH3 Fcドメインを含む、項目21に記載の異種キメラタンパク質。
(項目24)
前記リンカーが、IgG1、場合によりヒトIgG4に由来するヒンジ−CH2−CH3 Fcドメインを含む、項目21に記載の異種キメラタンパク質。
(項目25)
前記キメラタンパク質が、哺乳動物宿主細胞において、分泌可能かつ完全に機能する単一ポリペプチド鎖として産生可能である、項目1に記載の異種キメラタンパク質。
(項目26)
先行項目のいずれかに記載の異種キメラタンパク質を含む、医薬組成物。
(項目27)
先行項目のいずれかに記載の異種キメラタンパク質をコードする核酸を含む、発現ベクター。
(項目28)
前記発現ベクターが哺乳動物の発現ベクターである、項目27に記載の発現ベクター。
(項目29)
前記発現ベクターがDNAまたはRNAを含む、項目28に記載の発現ベクター。
(項目30)
項目27〜29のいずれか1項に記載の発現ベクターを含む、宿主細胞。
(項目31)
先行項目のいずれかに記載のキメラタンパク質をコードする核酸配列を含む、ウイルス。
(項目32)
項目26に記載の医薬組成物の有効量を、それを必要とする対象に投与することを含む、癌の治療方法。
(項目33)
項目26に記載の医薬組成物の有効量を、それを必要とする対象に投与することを含む、自己免疫疾患または自己免疫障害の治療方法。
(項目34)
項目26に記載の医薬組成物の有効量を、それを必要とする対象に投与することを含む、患者の免疫応答を調節する方法。
(項目35)
前記患者のT細胞が、免疫刺激シグナルを有する前記細胞外ドメインによって活性化される、項目32〜34のいずれか1項に記載の方法。
(項目36)
前記患者が腫瘍を有し、かつ1つ以上の腫瘍細胞が、免疫抑制シグナルを有する前記細胞外ドメインによって活性化される免疫抑制シグナルを伝達できない、項目32〜35のいずれか1項に記載の方法。
(項目37)
(i)配列番号39〜55のうちの1つ、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列と;
(ii)配列番号56〜69のうちの1つ、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列とを含む、異種キメラタンパク質。
(項目38)
(iii)配列番号70〜72のうちの1つ、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列をさらに含み、(iii)が(i)と(ii)との間に転置されている、項目37に記載の異種キメラタンパク質。
(項目39)
(iv)配列番号73〜78のうちの1つのアミノ酸配列の1つ以上をさらに含み、(iv)が(iii)に隣接している、項目37に記載の異種キメラタンパク質。
(項目40)
配列番号2のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目41)
配列番号5のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目42)
配列番号7のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目43)
配列番号9のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目44)
配列番号11のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目45)
配列番号13のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目46)
配列番号15のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目47)
配列番号22のアミノ酸配列、またはそれと少なくとも90%、もしくは93%、もしくは95%、もしくは97%、もしくは98%、もしくは99%同一であるアミノ酸配列を含む、異種キメラタンパク質。
(項目48)
項目37〜47のいずれか1項に記載の異種キメラタンパク質を含む、医薬組成物。
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