JP2017519045A - 酵素的方法による均一抗体薬物コンジュゲート - Google Patents
酵素的方法による均一抗体薬物コンジュゲート Download PDFInfo
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Abstract
Description
本出願は、2014年6月12日に出願された米国特許仮出願第62/011,534号の優先権の利益を主張するものであり、当該仮出願は、参照によりその全体が本明細書に組み入れられる。
本明細書において相互互換的に「TGase」が使用される「トランスグルタミナーゼ」は、トランスグルタミネーション反応を行うことができる酵素を意味する。用語「トランスグルタミネーション」は、本明細書において使用される場合、タンパク質/ペプチド由来のアクセプターグルタミン残基のγ−グルタミニルが、アミン基、例えば、リジンの一級アミンまたはε−アミノ基など、に移される反応を意味する。
本出願は、一態様において、コンジュゲート部分に部位特異的にコンジュゲートしたFc含有ポリペプチド(例えば、抗体など)を含むFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲートなど)を提供する。当該Fc含有ポリペプチド(例えば、抗体など)は、N−グリコシル化Fc領域を含む。当該N−グリコシル化Fc領域は、N−グリコシル化部位に隣接するアクセプターグルタミン残基を含み、当該コンジュゲート部分は、アクセプターグルタミン残基を介してFc含有ポリペプチド(例えば、抗体など)にコンジュゲートしている。
本明細書において説明されるコンジュゲート部分は、いくつかの実施形態において、活性部分を含む。いくつかの実施形態において、当該コンジュゲート部分は、ペプチドまたはポリペプチドである活性部分を含む。いくつかの実施形態において、当該コンジュゲート部分は、生体適合性ポリマーである活性部分を含む。
別の態様において、本出願は、野生型または改変トランスグルタミナーゼを使用することによってFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲートなど)を作製する方法を提供する。
TGaseは、あるタンパク質のリジンドナー残基と別のタンパク質のアクセプターグルタミン残基との間においてプロテイナーゼ抵抗性イソペプチド結合を形成することによって共有結合性のタンパク質の架橋を触媒し、その際に、アンモニアの放出を伴う。トランスグルタミナーゼの触媒メカニズムは、以下のように提案されている。グルタミン含有第1基質(アクセプターまたはQ基質)が酵素に結合した後、それは、アシルコエンザイム中間体として知られる、TGaseの活性中心にシステイン残基を有するγ−グルタミルチオエステルを形成し、その際に、アンモニアの放出を伴う。次いで、第2基質(ドナーまたはK基質)が、当該アシルエンザイム中間体に結合し、チオエステル結合を攻撃する。生成物(Nε(γ−グルタミル)リジンイソペプチドブリッジによって架橋された2つのタンパク質)が形成され、放出される。これは、活性中心である酵素のCys残基をその元の形態に再構築し、それらが触媒の別のサイクルに関与するのを可能にする。共有結合性アシルエンザイム中間体の形成は、この反応における律速段階であると考えられる。多くのトランスグルタミナーゼの触媒三残基は、パパイン様であり、Cys−His−Asp(ここで、Hisはヒスチジンであり、Aspはアスパラギン酸である)および、重要なことに、活性中心Cysから36残基離れて位置するトリプトファン(Trp)残基を含有する。対照的に、ストレプトバーチシリウム属(Streptoverticillium sp)(上記参照)から単離された細菌性TGaseは、非定型的触媒三残基を有し、他のTGaseのパパイン様触媒三残基との配列相同性を示さない。
本出願は、別の態様において、N−グリコシル化部位に近接するアクセプターグルタミンに対してトランスグルタミネーション反応を実施するように特異的に設計された改変トランスグルタミナーゼを提供する。本発明者らは、TGaseの触媒残基Cys64(図3)へのFc領域(Q295特異的)におけるグルタミン残基の接近性を高めるためにTGaseの基質結合ポケットを再モデル化して、Q295においてトランスグルタミネーション反応を特異的に実施する改変TGaseを得た。
さらに、本明細書において説明されるFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲート)を含む医薬組成物も提供される。いくつかの実施形態において、当該医薬組成物はさらに、薬学的に許容される担体も含む。いくつかの実施形態において、当該医薬組成物中のFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲートなど)の少なくとも約50%(例えば、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約95%、または少なくとも約99%のいずれかなど)は、当該Fc含有ポリペプチド(例えば、抗体など)に付着された1つのコンジュゲート部分を有する。いくつかの実施形態において、当該医薬組成物中のFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲートなど)の少なくとも約50%(例えば、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約95%、または少なくとも約99%のいずれかなど)は、当該Fc含有ポリペプチド(例えば、抗体など)に付着された2つのコンジュゲート部分を有する。いくつかの実施形態において、当該医薬組成物中のFc含有ポリペプチドコンジュゲート(例えば、抗体薬物コンジュゲートなど)の少なくとも約50%(例えば、少なくとも約60%、少なくとも約70%、少なくとも約80%、少なくとも約90%、少なくとも約95%、または少なくとも約99%のいずれかなど)は、当該Fc含有ポリペプチド(例えば、抗体など)に付着された1つまたは2つのコンジュゲート部分を有する。
この実施例は、TGase変異体の生成について説明するものである。図3を参照すると、活性部位入口に近い3つの領域が、基質結合性ポケットを拡大するために欠失または変異されていた。野生型TG_SLを、過剰なプロリンと共にNdeIおよびXhoIを使用してpET39+ベクター中へとクローンした(配列番号17)。以下の欠失変異体を、IgG1およびTG_SMのドッキングに基づいて作製した:変異体1:P1〜E5からの欠失、変異体2:P245〜P248からの欠失、変異体3:N283〜L286からの欠失、変異体4:P1〜E5およびN283〜L286の欠失、変異体5:変異体1,2、および3によって特定される3つ全ての領域の欠失、変異体6:P1〜E5の欠失およびGによるH280〜A288の置換、変異体7:P1〜E5の欠失およびGによるA281〜H290の置換。欠失エリアは、図3に示されるように、灰色に着色されるか、下線または取り消し線が引かれる。これらの変異体は、IgG1に向けてより活性であった。
MDCは一級アミンを有しており、ならびにその蛍光は容易にモニターすることができるため、この実験にMDCを選択した。ここでは、mABへのコンジュゲーションを実証するために、MDCを使用する。Tris緩衝液(pH6.5〜8.5)中における精製されたIgG1(1〜10mg/ml)に、1〜5mMの最終濃度(最終的なDMSOは2〜10%)まで、DMSO中におけるMDC(Sigma−Aldrich)を加えた。0.05〜1.0mg/mlの最終濃度まで、精製した野生型TG_SLまたはその変異体を加えた。当該反応混合物を37℃においてインキュベートする。反応後に、フェニル疎水性相互作用カラム(PHIC、Tosoh Bioscience LLC)を使用してHPLCを行った。反応の開始時、生成物は、IgG1の1つの重鎖のみがMDCとカップリングしたDAR1が支配的であった。反応が進行するに従い、IgG1の両方の重鎖がMDCとカップリングしたDAR2が、主要生成物となった。反応の終わりに向かって(pH7において0.2mg/mlのmTGaseで8時間)、コンジュゲーション収率は,DAR2の80%および残存DAR1の20%に達し、または、試料が10mMのTCEPによって還元され、C4−1000Aカラム(Vydac)において分析される場合には重鎖(HC)の90%に達した(図6を参照されたい)。HCへのMDCの選択的コンジュゲーションは、SDS PAGEにおいて可視化した(図7)。他のmTGase、例えば、ストレプトマイセス・モバラエンシス由来のTG_SM(AjinomotoのActiva TIから精製した)なども試験した。変異体は、IgG1に対して野生型よりも活性が高かったが、野生型TGaseも、高濃度(>0.1mg/ml)においてADC反応を触媒することができた。TG_SM(Ajinomotoによって販売され、PfizerおよびInnate Pharmaによって使用される)も、高濃度において機能するが、TG_SLと比べて約30%の活性しか有していないこともさらに見出された。
この実験は、実質的に、実施例2において説明される通りに実施した。アシルアクセプターMDCに代えて、1〜2mMの最終濃度のpH7.0における1kDaのメトキシ−PEG−アミン(JenKem、米国)によってPEG化IgG1を得た。37℃で終夜反応させた反応物をTCEPで還元した後にC4カラムにおいて試料分析した結果、重鎖の90%修飾を示した。
mTGaseの除去を単純化して酵素の再利用を可能にするために、固定されたmTGaseを触媒作用において使用した。固定されたmTGaseのカラムの調製において、カーボネート緩衝液(pH8.3)中における15mg/mlのmTGaseの1mlを、製造元のプロトコルに従って、1.0ml(GE)のNHS活性化HITRAP(登録商標) HPカラムそれぞれに対して使用した。1〜5mMのMDCを伴うTris緩衝液(pH6〜8.0)中における1〜10mg/mlの精製したIgG1の0.5mlを、HITRAP(登録商標)−mTGaseカラムに注入した。当該カラムの両端を密封し、37℃で一晩インキュベートした。次の日、反応混合物をTris緩衝液で溶出させた。当該カラムは、次のコンジュゲーション反応のために、1〜20mMのTCEPで再生させた。各使用後に、固定されたmTGaseの活性の損失はなかった。mTGaseを用いない場合に得られた収率と同様に、90%HCの収率が各実施において達成された。
MDCと全く同じように、アミンリンカーを有する毒素を一段階プロトコルにおいてIgG1にコンジュゲートさせることができた(図4)。リンカーは−(CH2)n−NH2(リジン側鎖と同様にn≧4である)のように単純であるが、エチレングリコール足場の使用は、リンカー−薬物の溶解性を増加させ、コンジュゲーション反応を容易にすることができた。この実施例は、IgG1へのMAY−PEG4(非切断性リンカー、図8)およびMAY−PVCL(切断性リンカー、図9)のコンジュゲーションを実証するものである。
グリカン鎖の異質性に起因して、IgG1は、その質量分析スペクトルにおいて複数のピークを示すであろう。質量分析を簡素化するために、全てのmABコンジュゲートを、PNGaseF(Promega、マディソン、ウィスコンシン州)を使用した質量分析の前に脱グリコシル化し、それにより、単一のピークが、同じ荷電のそれぞれの種に対して観察されるであろう。そうすることにより、元のグリカン結合アスパラギン(N)が、アスパルテート(D)に変換される。
Tris緩衝液(pH7.0〜8.0)中における1〜10mg/mlの精製したヒトIgG2またはIgG4を、2〜5mMのMDCと反応させた後、0.1〜1mg/mLの精製したmTGaseを加えた。当該混合物を37℃において8〜16時間インキュベートし、次いで、フェニル疎水性相互作用カラムにおいて分析するか、またはC4カラムにおいて10mMのTCEPによって還元した。IgG1と同様に、IgG2およびIgG4をMDCとコンジュゲートしたところ、時間と共にDAR1およびDAR2の蓄積を示した(図6)
一段階コンジュゲーション反応は単純で容易であるが、収率は、薬物の溶解性に影響される。薬物濃度が低い場合、脱アミド化の副産物を無視することができない。脱アミド化を抑制するために、化学ハンドルを含む高可溶性アミンを、mTGaseによって触媒される第一段階コンジュゲーションにおいて、過剰(化学ハンドル:mABのモル比>10)に使用した。次いで、第二段階において化学選択的連結反応によって、薬物分子をmABに架橋させた(図5)。以下の多くの化学選択的対を使用することができる。
アミノオキシー/アルデヒドまたはケトン
スルフヒドリル/マレイミド
アジド/アルキン
SK−BR−3細胞を、96ウェルの黒色透明底プレートに10k細胞/ウェルにおいて播種し、24時間培養した。三連において、細胞を、2倍に連続的に希釈した抗体薬物コンジュゲートによって96時間処理した。細胞生存率を、CELLTITER(商標) Blue Cell Viability Assay(Promega、マディソン、ウィスコンシン州)によって特定した。相対的細胞生存率を、未処理の対照の割合として特定した。XLfitからの4パラメータロジスティックモデルを使用して、IC50を計算した。表3は、抗体に対する薬物の比率と、様々なトラスツズマブ−薬物コンジュゲートを使用したSK−BR−3細胞でのIC50を示している。
トラスツズマブ(10mg/ml)およびモノメチルオーリスタチンE(MMAE)を、9種の非切断性のPEGリンカー(CH2CH2O)x(x=2、4、6、8、10、12、16、20、および24、図12)のそれぞれを用いて、実施例5において説明されるように、それぞれコンジュゲートさせた。ADCは、プロテインAカラムによって精製し、mTGaseおよび過剰なMMAEを除去した。還元されたADC試料をC4カラムを使用してHPLCにおいて分析した場合、平均DARは約1.9である。SK−BR−3細胞ベースのアッセイにおいて、これらのADCは全て強力で、38〜148pMのIC50を有する(表4)。
トラスツズマブ(10mg/ml)およびMMAEを切断性PEG3cリンカー(図12)によってコンジュゲートし、実施例10において説明されるように精製した。TP3cEと命名されたこのADCは、1.9のDARおよびインビトロでの高い効力を有する(表4)。NCI N87異種移植モデルおよびSK_Ov3異種移植モデルの両方においてTDM−1(Genentech)と比較するためにインビボ研究を行った。NCI N87モデルにおいて、TP3cEは、単回静脈内注入によるTDM−1より4倍有効である(図15)。血液試料分析は、TP3cEが21日まで血液中において完全に安定していることを示しているが、TDM−1は、5日でその毒素の50%を失っていた(図16)。SK_Ov3異種移植片において、TP3cEは、15mg/kgまたは8mg/kgのいずれかの3週間投与により、結果として、完全な腫瘍寛解を生じたが、その一方で、TDM−1は、15mg/kgのみにおいて有効性を示した(図17)。
トラスツズマブ(10mg/ml)と、1つのアミン基および2つのアジド基を有する3アームPEGリンカー(1〜5kDa)の基のいずれか(図18、上側、Conju−probeおよびJenkem)(4〜8mg/ml)とをコンジュゲートさせ、それぞれ、実施例10において説明されるように精製した。当該抗体−リンカーコンジュゲーション反応は、C4カラムを用いてHPLCにより分析し還元した場合、>90%変換率に達した。
Claims (29)
- 抗体上の内因性アクセプターグルタミン残基を介してコンジュゲート部分にコンジュゲートした該抗体を含む抗体薬物コンジュゲートであって、Fc領域においてグリコシル化されている抗体薬物コンジュゲート。
- 前記抗体薬物コンジュゲートがFc領域においてN−グリコシル化されている、請求項1に記載の抗体薬物コンジュゲート。
- 前記抗体がヒト抗体である、請求項1または2に記載の抗体薬物コンジュゲート。
- 前記抗体がヒト化抗体である、請求項1または2に記載の抗体薬物コンジュゲート。
- 前記抗体の両重鎖が、前記コンジュゲート部分にコンジュゲートされている、請求項1〜4に記載の抗体薬物コンジュゲート。
- 前記コンジュゲート部分が、前記抗体の薬物動態特性を向上させる部分、治療的部分、および診断的部分からなる群より選択される活性部分を含む、請求項1〜5に記載の抗体薬物コンジュゲート。
- 前記活性部分が毒素である、請求項6に記載の抗体薬物コンジュゲート。
- 前記抗体および前記コンジュゲート部分が、リンカーを介してコンジュゲートされている、請求項1〜7のいずれか一項に記載の抗体薬物コンジュゲート。
- 前記リンカーが、切断性リンカーである、請求項8に記載の抗体薬物コンジュゲート。
- 前記リンカーが、非切断性リンカーである、請求項8に記載の抗体薬物コンジュゲート。
- 請求項1〜10のいずれか一項に記載の抗体薬物コンジュゲートを含む組成物であって、前記組成物中の抗体薬物コンジュゲートの少なくとも約50%が、前記Fc領域においてグリコシル化されている組成物。
- 前記組成物中の前記抗体薬物コンジュゲートの少なくとも80%が、1:1または1:2である前記抗体とコンジュゲート部分とのモル比を有する、請求項11に記載の組成物。
- コンジュゲート部分に特異的にコンジュゲートした抗体を含む抗体薬物コンジュゲートを製造する方法であって、該抗体薬物コンジュゲートを生じるのに十分な条件下において、トランスグルタミナーゼの存在下で、抗体組成物を該コンジュゲート部分に接触させる工程を含み、該組成物中の該抗体の少なくとも約50%が、前記Fc領域においてグリコシル化されており、該コンジュゲート部分が、該抗体上の内因性アクセプターグルタミン残基にコンジュゲートされる、方法。
- 低分子ハンドルおよび活性部分を含むコンジュゲート部分に特異的にコンジュゲートした抗体を含む抗体薬物コンジュゲートを製造する方法であって、
a)該低分子ハンドルに特異的にコンジュゲートした抗体を含む中間コンジュゲートを生じるのに十分な条件下において、トランスグルタミナーゼの存在下で、抗体組成物を該低分子ハンドルに接触させる工程と、
b)該中間コンジュゲートを活性部分に接触させ、それにより、該抗体薬物コンジュゲートを得る工程であって、該組成物中の該抗体の少なくとも約50%が、Fc領域においてグリコシル化されており、該コンジュゲート部分が、該抗体上の内因性アクセプターグルタミン残基にコンジュゲートされる、工程と、
を含む方法。 - 前記トランスグルタミナーゼが、野生型トランスグルタミナーゼである、請求項13または14に記載の方法。
- 前記野生型トランスグルタミナーゼが、配列番号16のアミノ酸配列を有する、請求項15に記載の方法。
- 前記トランスグルタミナーゼが、改変トランスグルタミナーゼである、請求項13または14に記載の方法。
- 前記改変トランスグルタミナーゼが、配列番号16に対して少なくとも約80%の同一性を有するアミノ酸配列を含む、請求項17に記載の方法。
- 前記トランスグルタミナーゼが、少なくとも約90%の純度を有する、請求項13〜18のいずれか一項に記載の方法。
- 前記トランスグルタミナーゼと前記抗体組成物のモル比が、約10:1から約1:10である、請求項13〜19のいずれか一項に記載の方法。
- 前記トランスグルタミナーゼが、固体支持体に固定されている、請求項13〜20のいずれか一項に記載の方法。
- 前記抗体が、固体支持体に固定されている、請求項13〜20のいずれか一項に記載の方法。
- 前記抗体が、ヒト抗体またはヒト化抗体である、請求項13〜22のいずれか一項に記載の方法。
- 前記コンジュゲート部分が、前記抗体組成物の薬物動態特性を向上させる部分、治療的部分、および診断的部分からなる群より選択される活性部分を含む、請求項13〜23のいずれか一項に記載の方法。
- 前記活性部分が毒素である、請求項24に記載の方法。
- Fc含有ポリペプチドをコンジュゲート部分にコンジュゲートさせることができる改変トランスグルタミナーゼであって、
該Fc含有ポリペプチドがN−グリコシル化Fc領域を含み、
該N−グリコシル化Fc領域が、N−グリコシル化部位に隣接するアクセプターグルタミン残基を含み、
反応の際、該コンジュゲート部分が、該アクセプターグルタミン残基を介して該Fc含有ポリペプチドにコンジュゲートされ、ならびに、
該コンジュゲーションが、同じ反応条件下において野生型トランスグルタミナーゼよりも少なくとも約10%活性が高い、
改変トランスグルタミナーゼ。 - 配列番号16に対して少なくとも約80%の同一性を有するアミノ酸配列を含む改変トランスグルタミナーゼであって、D1〜E4、P244〜P247、およびN282〜L285からなる群より選択される欠失を含む、改変トランスグルタミナーゼ。
- コンジュゲート部分に特異的にコンジュゲートした抗体を含む抗体薬物コンジュゲートを製造する方法であって、該抗体薬物コンジュゲートを生じるのに十分な条件下において、請求項26または27に記載の改変トランスグルタミナーゼの存在下で、抗体組成物を該コンジュゲート部分に接触させる工程を含み、該コンジュゲート部分が、該抗体上の内因性アクセプターグルタミン残基にコンジュゲートされる、方法。
- 低分子ハンドルおよび活性部分を含むコンジュゲート部分に特異的にコンジュゲートした抗体を含む抗体薬物コンジュゲートを製造する方法であって、
a)該低分子ハンドルに特異的にコンジュゲートした抗体を含む中間コンジュゲートを生じるのに十分な条件下において、請求項26または27に記載の改変トランスグルタミナーゼの存在下で、抗体組成物を該低分子ハンドルに接触させる工程と、
b)該中間コンジュゲートを活性部分に接触させ、それにより、抗体薬物コンジュゲートを得る工程であって、該コンジュゲート部分が、該抗体上の内因性アクセプターグルタミン残基にコンジュゲートされる、工程と、
を含む方法。
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |