JP2018510147A - Cd47に結合する抗体医薬 - Google Patents
Cd47に結合する抗体医薬 Download PDFInfo
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Abstract
Description
用語「ペプチド」、「ポリペプチド」および「タンパク質」はそれぞれ、ペプチド結合により互いに繋がれている2つ以上のアミノ酸残基を含む分子を意味する。これらの用語は、例えば、タンパク質配列の天然および人工のタンパク質、タンパク質断片およびポリペプチド類似体(例えば、突然変異体、改変体および融合タンパク質)、ならびに翻訳後修飾、または他には共有結合もしくは非共有結合的に修飾されたタンパク質を包含する。ペプチド、ポリペプチドまたはタンパク質は、単量体または重合体であってもよい。
本発明は、CD47、例えば、ヒトCD47に結合するCD47結合タンパク質、特に抗CD47抗体またはそれらの抗原結合部分、およびその使用に関する。本発明の様々な態様は、抗体および抗体断片、医薬組成物、核酸、組換え発現ベクター、ならびにこのような抗体および断片を作製するための宿主細胞に関する。ヒトCD47を検出するため、インビトロまたはインビボのいずれかでCD47活性を抑制するため、およびがんのような障害を予防または治療するための本発明の抗体の使用方法はまた、本発明により包含される。
ある種の実施形態において、本発明の結合ポリペプチドは、翻訳後修飾をさらに含み得る。タンパク質の翻訳後修飾の例としては、リン酸化、アセチル化、メチル化、ADP−リボシル化、ユビキチン化、グリコシル化、カルボニル化、SUMO化(sumoylation)、ビオチン化またはポリペプチド側鎖もしくは疎水性基の付加が挙げられる。結果として、修飾された可溶性ポリペプチドは、脂質、多糖または単糖、およびリン酸塩のような非アミノ酸エレメントを含み得る。グリコシル化の好ましい形態は、1つ以上のシアル酸部分をポリペプチドにコンジュゲートさせるシアリル化である。シアル酸部分は、溶解性および血清半減期を改善し、一方、タンパク質の免疫遺伝学的解析の可能性を減少させる。Rajuら、Biochemistry.2001年、31;40(30):8868−76頁を参照されたい。
特定の実施形態において、本開示はさらに、抗CD47ポリペプチドを投与することを含む、免疫応答または免疫抑制のいずれかの刺激を必要とする、広範囲の哺乳動物のがんまたは広範囲の線維性疾患を治療する方法を提供する。本明細書に開示される抗体のいずれも、このような方法において使用され得る。例えば、本方法は、少なくとも10−6Mの結合親和性でCD47エピトープに結合するIgGクラスの完全ヒト抗体、重鎖由来の可変ドメイン領域および軽鎖由来の可変ドメイン領域を有するFab完全ヒト抗体断片、重鎖由来の可変ドメイン領域および軽鎖由来の可変ドメイン領域ならびに重鎖と軽鎖可変ドメイン領域を連結するペプチドリンカーを有する一本鎖ヒト抗体であって、配列番号1−32(表5)に記載される重鎖および軽鎖可変領域(および該配列内のCDR)を含む一本鎖抗体からなる群から選択される抗CD47ポリペプチドを使用して行われてもよい。
抗体C47B10、C47A8、C47A11およびC47D8を含む、ヒト抗CD47抗体由来の重鎖および軽鎖可変ドメインアミノ酸配列が同定された。これらの抗体の重鎖および軽鎖可変ドメイン配列は、以下の表5に記載される(表5は、本明細書において開示されているすべての配列の要約である。)。
C47B10抗体(または「B10」抗体)の生殖系列突然変異を実施して、安定性を高め、免疫原性の危険性を減少させた。B10抗体の生殖系列化は、生殖系列配列と一致するように、特定のフレームワーク残基を変化させることを伴った。生殖系列配列と比較すると、軽鎖の第3のアミノ酸は生殖系列配列と異なっていた。これは、既知の生殖系列データベースを用いて同定された。したがって、B10抗体の軽鎖中の第3のアミノ酸はVからAに変化させた。以下の表1は、C47B10野生型配列(配列番号1/配列番号4)およびC47B10−1生殖細胞系列を変化させた配列(配列番号1/配列番号8)を示す。
改善されたC47B10抗体
C47B10−1は、さらなる突然変異のための親抗体として用いて親和性特性を改良しようと試みた。簡単には、C47B10−1(Ch47B10またはC47B10−1抗体は、軽鎖可変領域中の1つのフレームワーク残基のみが異なるため、CDRが同じであることに留意されたい。)のCDR内の単一アミノ酸(ChothiaまたはKabat番号付けのいずれかによって定義される。)は、各々のCDR内の各位置がすべての可能な20アミノ酸に突然変異されるように突然変異させた。次に、これらのB10改変体抗体は、C47B10−1親抗体と比較した親和性変化についてスクリーニングされ、結合の差異を示す抗体を配列決定した。C47B10−1と比較したCD47に対する親和性がより低いことを示した特定の改変体を同定した。これらのより低い親和性改変体は、C47B10−1に対して単一の突然変異のみを有し、抗体C47B10 H3−D4、C47B10 L1A−A10、C47B10H3−D3、C47B10 L1A−A4およびC47B10L3−B2として同定された。抗体C47B10H3−D4およびC47B10L1A−A10は、ELISAに従って選択および試験された改変体のうち最も低い親和性を示した(以下により詳細に説明する。)。また、増加した親和性を有するヒットが配列決定され、コンビナトリアルライブラリーに含まれ、次に、これは、さらに改善された親和性抗体について発現およびスクリーニングされた。C47B10−1改変体の軽鎖および重鎖可変ドメインアミノ酸配列(増加および減少した親和性改変体;上記されないものは高親和性改変体である。)は、以下の表2に記載される。
改善された抗体はまたC47A8抗体から生成された。C47A8は、インビトロでの赤血球凝集アッセイ(上記)の低赤血球凝集を示したため選択された。
ELISAは、抗体C47A8およびC47A8改変体(表3に示される。)のヒトCD47への結合を評価するために行われた。ELISAプレートは、PBS中の1μg/mlのヤギ抗ヒトFD抗体で一晩4℃にて被覆された。翌日、プレートをカゼインで1.5時間ブロックし、洗浄し、抗CD47 IgG抗体をカゼイン中で1μg/ml添加して2時間放置した。ビオチニル化されたCD47をニュートラアビジン−APを用いて20分間プレ複合体化し、カゼインで連続希釈し、ELISAプレートに添加した。室温で1時間インキュベートした後、プレートを洗浄し、p−ニトロフェニルホスフェート(PNPP)基質で発色させ、吸光度を測定した。結果を図2に示す。図2に示されるように、C47A8−CLはC47A8よりも多くのCD47受容体に結合した。これらの条件下で、C47 A8−CLは、C47 A8と比較して抗原に対する結合が良好であると考えられたが、他の抗体は、親抗体C47A8よりもCD47抗原に対してわずかに低い親和性を有した。
本出願を通して引用されたすべての参考文献、特許、係属中の特許出願および公開された特許の内容は、参照により本明細書に明示的に組み込まれる。
Claims (17)
- CD47エピトープに結合するIgGクラスの単離された完全ヒト抗CD47抗体であって、配列番号1、配列番号7、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号16、配列番号17、配列番号18、配列番号22、配列番号24、および配列番号32からなる群から選択されるアミノ酸配列と少なくとも95%同一である重鎖可変ドメイン配列、ならびに配列番号2、配列番号4、配列番号5、配列番号6、配列番号8、配列番号15、配列番号19、配列番号20、配列番号21、配列番号23、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、および配列番号30からなる群から選択されるアミノ酸配列と少なくとも95%同一である軽鎖可変ドメイン配列を含む完全ヒト抗CD47抗体。
- 抗体が、配列番号1/配列番号2(C47A8)、配列番号1/配列番号4(C47B10)、配列番号1/配列番号8(C47B10−1)、配列番号1/配列番号5(C47B10−1H4S)、配列番号1/配列番号6(C47B10−1F6S)、配列番号7/配列番号8(C47B10−2A9S)、配列番号9/配列番号8(C47B10−2B11S)、配列番号10/配列番号4(C47B10−2B8S)、配列番号11/配列番号4(C47B10−2C1S)、配列番号12/配列番号4(C47B10−2B9S)、配列番号13/配列番号4(2C4S)、配列番号14/配列番号15(C47B10−B1C)、配列番号16/配列番号15(C47B10−C6C)、配列番号17/配列番号15(C47B10−D3C)、配列番号18/配列番号15(C47B10−C11C)、配列番号19/配列番号15(C47B10−C11C)、配列番号1/配列番号20(C47KD8)、配列番号1/配列番号21(C47KD9)、配列番号1/配列番号8(C47B10−1H4S2)、配列番号32/配列番号15(C47B10−C3C)、配列番号1/配列番号19(C47K11)、配列番号22/配列番号8(C47B10−H3−D4)、配列番号1/配列番号23(C47B10−L1A−A10)、配列番号24/配列番号8(C47B10−H3−D3)、配列番号1/配列番号25(C47B10−L1A−A4)、配列番号1/配列番号26(C47B10−L3−B2)、配列番号1/配列番号27(C47A8−CA)、配列番号1/配列番号28(C47A8−CL)、配列番号1/配列番号29(C47−A8−CQ)、および配列番号1/配列番号30(C47A8−CS)からなる群から選択される重鎖/軽鎖可変ドメイン配列を含む、請求項1に記載の完全ヒト抗体。
- 抗体が少なくとも1×10−6MのKDを有する、請求項1または2に記載の完全ヒト抗体。
- 配列番号1、配列番号7、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号16、配列番号17、配列番号18、配列番号22、配列番号24、および配列番号32からなる群から選択されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含む重鎖可変ドメイン;ならびに配列番号2、配列番号4、配列番号5、配列番号6、配列番号8、配列番号15、配列番号19、配列番号20、配列番号21、配列番号23、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、および配列番号30からなる群から選択されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含む軽鎖可変ドメインを含む抗CD47完全ヒト抗体Fab断片。
- 抗体が、配列番号1/配列番号2、配列番号1/配列番号4、配列番号1/配列番号5、配列番号1/配列番号8、配列番号1/配列番号6、配列番号7/配列番号8、配列番号9/配列番号8、配列番号10/配列番号4、配列番号11/配列番号4、配列番号12/配列番号4、配列番号13/配列番号4、配列番号14/配列番号15、配列番号16/配列番号15、配列番号17/配列番号15、配列番号18/配列番号15、配列番号1/配列番号20、配列番号1/配列番号21、配列番号1/配列番号22、配列番号1/配列番号8、配列番号32/配列番号15、配列番号1/配列番号19、配列番号22/配列番号8、配列番号1/配列番号23、配列番号24/配列番号8、配列番号1/配列番号25、配列番号1/配列番号26、配列番号1/配列番号27、配列番号1/配列番号28、配列番号1/配列番号29、および配列番号1/配列番号30からなる群から選択される重鎖/軽鎖可変ドメイン配列を含む、請求項4に記載の完全ヒト抗体Fab断片。
- 抗体が少なくとも1×10−6MのKDを有する、請求項5に記載の完全ヒト抗体Fab断片。
- ペプチドリンカーによって連結された重鎖可変ドメインおよび軽鎖可変ドメインを含む抗CD47一本鎖ヒト抗体であって、重鎖可変ドメインが、配列番号1、配列番号7、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号16、配列番号17、配列番号18、配列番号22、配列番号24、および配列番号32からなる群から選択されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含み;軽鎖可変ドメインが、配列番号2、配列番号4、配列番号5、配列番号6、配列番号8、配列番号15、配列番号19、配列番号20、配列番号21、配列番号23、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、および配列番号30からなる群から選択されるアミノ酸配列と少なくとも95%同一であるアミノ酸配列を含む、抗CD47一本鎖ヒト抗体。
- 一本鎖完全ヒト抗体が、配列番号1/配列番号2、配列番号1/配列番号4、配列番号1/配列番号5、配列番号1/配列番号8、配列番号1/配列番号6、配列番号7/配列番号8、配列番号9/配列番号8、配列番号10/配列番号4、配列番号11/配列番号4、配列番号12/配列番号4、配列番号13/配列番号4、配列番号14/配列番号15、配列番号16/配列番号15、配列番号17/配列番号15、配列番号18/配列番号15、配列番号19/配列番号15、配列番号1/配列番号20、配列番号1/配列番号21、配列番号1/配列番号22、配列番号1/配列番号8、配列番号32/配列番号15、配列番号1/配列番号19、配列番号22/配列番号8、配列番号1/配列番号23、配列番号24/配列番号8、配列番号1/配列番号25、配列番号1/配列番号26、配列番号1/配列番号27、配列番号1/配列番号28、配列番号1/配列番号29、および配列番号1/配列番号30からなる群から選択される重鎖/軽鎖可変ドメイン配列を含む、請求項7に記載の完全ヒト一本鎖抗体。
- 抗体が少なくとも1×10−6MのKDを有する、請求項7または8に記載の完全ヒト一本鎖抗体。
- 請求項1から9のいずれか一項に記載の有効量の抗CD47抗体または抗体断片を、それを必要とする対象に投与することを含む、がんまたは線維性疾患を治療する方法。
- がんが、卵巣がん、結腸がん、乳がん、肺がん、骨髄腫、神経芽球由来のCNS腫瘍、単球性白血病、B細胞由来の白血病、T細胞由来の白血病、B細胞由来のリンパ腫、T細胞由来のリンパ腫、および肥満細胞由来の腫瘍からなる群から選択される、請求項10に記載の方法。
- 線維性疾患が、心筋梗塞、狭心症、変形性関節症、肺線維症、喘息、嚢胞性線維症、気管支炎および喘息からなる群から選択される、請求項10に記載の方法。
- 配列番号1、配列番号7、配列番号9、配列番号10、配列番号11、配列番号12、配列番号13、配列番号14、配列番号16、配列番号17、配列番号18、配列番号22、配列番号24、および配列番号32からなる群から選択される重鎖可変ドメインアミノ酸配列に記載される相補性決定領域(CDR)を含む重鎖可変ドメイン;ならびに配列番号2、配列番号4、配列番号5、配列番号6、配列番号8、配列番号15、配列番号19、配列番号20、配列番号21、配列番号23、配列番号25、配列番号26、配列番号27、配列番号28、配列番号29、および配列番号30からなる群から選択される軽鎖可変領域アミノ酸配列に記載されるCDRを含む軽鎖可変ドメインを含む、単離された抗CD47抗体またはその抗原結合断片。
- 請求項1から9または13のいずれか一項に記載の抗CD47抗体または抗体断片、および医薬として許容される担体を含む医薬組成物。
- 請求項13に記載の有効量の抗CD47抗体またはその抗原結合断片を対象に投与し、それによりがんまたは線維性疾患を治療することを含む、それを必要とするヒト対象においてがんまたは線維性疾患を治療する方法。
- がんが、卵巣がん、結腸がん、乳がん、肺がん、骨髄腫、神経芽球由来のCNS腫瘍、単球性白血病、B細胞由来の白血病、T細胞由来の白血病、B細胞由来のリンパ腫、T細胞由来のリンパ腫、および肥満細胞由来の腫瘍からなる群から選択される、請求項15に記載の方法。
- 線維性疾患が、心筋梗塞、狭心症、変形性関節症、肺線維症、喘息、嚢胞性線維症、気管支炎および喘息からなる群から選択される、請求項15に記載の方法。
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