JP6626892B2 - ヒト化抗タウ抗体 - Google Patents
ヒト化抗タウ抗体 Download PDFInfo
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- JP6626892B2 JP6626892B2 JP2017520755A JP2017520755A JP6626892B2 JP 6626892 B2 JP6626892 B2 JP 6626892B2 JP 2017520755 A JP2017520755 A JP 2017520755A JP 2017520755 A JP2017520755 A JP 2017520755A JP 6626892 B2 JP6626892 B2 JP 6626892B2
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Description
本出願は、2015年6月2日に出願された米国特許出願第62/170,036号、2014年11月17日に出願された米国特許出願第62/080,903号および2014年6月27日に出願された米国特許出願第62/018,436号の35 U.S.C.§119(e)の下での優先権の利益を主張するものであり、これらの内容全体が参照により本明細書に組み込まれる。
添付の配列表の内容は、参照により本出願に組み込まれる。付属の配列表のテキストファイル、名称C2N1120_4WO_Sequence_Listingは、2015年6月26日に作成され、9kbである。このファイルは、Windows OSを使用するコンピュータ上でMicrosoft Wordを用いて評価することができる。
この実施例は、マウス抗タウ抗体HJ8.5のヒト化のための取り組みと結果を述べる。この取り組みは、4つのヒト化軽鎖可変領域(VLまたはVK)および4つのヒト化重鎖可変領域(VH)を生じた。
この試験は、組換えヒトタウ−412タンパク質と、6つの完全ヒト化(実施例1で上述した、VH1/VK2、VH1/VK3、VH2/VK2、VH2/VK3、VH3/VK2およびVH3/VK3)モノクローナル抗体ならびにHJ8.5に基づく1つのキメラモノクローナル抗体との間の相互作用の結合特性を測定し、比較するためのBiacore T200の使用を説明する。この試験の目的は、タウ−412とこれら7つのmAbとの間の相互作用の高分解能の動態特性づけのためにBiacore T200表面プラズモン共鳴装置を使用することであった。
Biacore保守保全キット2 BR−1006−51
シリーズS CM5センサーチップ BR−1006−68
アミンカップリングキット BR−1000−50
10mMアセテート pH4.5 BR−1003−51
HBS−EPランニング緩衝液 BR−1006−69
10mMグリシン−HCl pH1.5 BR−1003−54
10mMグリシン−HCl pH2.0 BR−1003−55
プロテインA(Sigma) P6031
4M MgCl2ヘキサハイドレート(Sigma) M9272−500G
図6は、サンドイッチ型ELISAにおける可溶性ヒトタウへの4つのヒト化抗体変異体の結合を示す。受動吸着に依存するアッセイ方法は、人為的結合結果を作り出す潜在的可能性を有する。この可能性を克服するため、ヒト化抗体変異体の結合活性を測定する溶液ベースの方法を用いた。このアッセイ形式では、抗原(ヒトタウ)を、HJ8.5とは異なるエピトープを認識するモノクローナル抗ヒトタウ抗体によって捕捉する。捕捉されたヒトタウへのヒト化抗タウ抗体のこの後の結合は抗原濃度に依存するが、IgG4アイソタイプ対照は全く結合を示さない。このアッセイは、ヒトタウへのヒト化抗タウ抗体の結合が特異的であり、抗体が可溶性ヒトタウに結合することを明らかにする。
図7(A−H)は、野生型マウス(陰性対照組織)、P301Sマウス(P301S変異を有するヒトタウを発現し、加齢に関連するタウ病変を発症する。)およびアルツハイマー病または進行性核上性麻痺(PSP)のいずれかを有するヒト由来の組織へのヒト化抗体および対照抗体の結合を示す。この試験の目的は、ヒト化抗体が、キメラ形態のHJ8.5と比較して組織中の凝集タウに結合する能力を保持することを確認することであった。図は、ヒト化HJ8.5抗体の種々の変異体でヒトおよびマウス脳を染色した代表的な画像を示す。4か月齢および9か月齢のP301Sマウスを試験し、両方の時点のマウスがタウの病的凝集体を示し、9か月齢のマウスは4か月齢のマウスよりも多くのタウ病変を有していた。ヒト染色に関しては、PSPを有する1名の被験者由来の脳組織の試料およびADを有する1名の被験者由来の脳組織の試料を検査した。図7Aは、マウスおよびヒトAD組織に関するキメラHJ8.5での染色を例示する。図7Bは、陰性対照抗体(非特異的ヒトIgG4)での染色を例示する。図7C−7Hは、6つのヒト化抗体での染色を例示する。マウスHJ8.5抗体のすべてのヒト化変異体は、P301Sマウス脳において認められるタウ凝集体ならびにADまたはPSPのいずれかを有すると診断された被験者の脳組織中で認められるタウ凝集体に結合する。
図8は、ヒトタウ中のHJ8.5のエピトープを示す。酵母ディスプレイを用いてエピトープをマッピングした。この方法のために、酵母を使用してヒトタウの配列をカバーする様々なペプチドを発現させた。培養下の酵母へのHJ8.5抗体の結合を免疫蛍光検査によって測定した。最初の34個のアミノ酸を含むタウの変異体を発現する酵母への結合が認められたが、酵母がタウの最初の32個のアミノ酸だけを発現する場合は結合が認められなかった。これは、エピトープが最初の34個のアミノ酸内に存在することを示唆する。加えて、HJ8.5は、ペプチドがアミノ酸27−135個を含む場合は結合するが、ペプチドがアミノ酸30−135個にわたる場合は結合しない。これは、エピトープがアミノ酸27個より大きいアミノ酸を含むことを示唆する。このデータに基づき、エピトープはヒトタウの27−34個の配列(GYTMHQDQ)(配列番号10)内に含まれる。図8はまた、アカゲザルおよびマウスタウ配列も示し、ヒトタウからのアミノ酸変化を赤色でハイライトする。
図10は、ヒトまたはアカゲザルタウのいずれかへの種々の抗ヒトタウ抗体の結合結果を例示する。ヒト化変異体VH1/VK2(C 2 N−8E12とも称される。)と共にマウス抗ヒトタウ抗体HJ8.5およびHJ8.7を試験した。図8は、特許請求される結合エピトープ配列GYTM(H/L)QDQ(配列番号57)において、ヒトとアカゲザルタウの間で32位に1個のアミノ酸相違が存在することを示す。図8は、特許請求される結合エピトープ配列DQ(G/E)GYT(配列番号58)において、ヒトとアカゲザルタウの間で27位に1個のアミノ酸相違が存在することを示す。2つの種のタウの間でのこれらのアミノ酸相違が抗体HJ8.5/C2N−8E12の結合能力に影響を及ぼすかどうかを調べるため、以下の実験を実施した。ヒトおよびアカゲザルタウへのC 2 N−8E12、HJ8.5(C 2 N−8E12のマウス前駆体)およびHJ8.7(ヒトとアカゲザルのアミノ酸配列が100%保存されているタウのエピトープに結合するマウス抗ヒトタウ抗体)の結合を、96ウェルELISAプレートを様々な濃度のヒトタウまたはアカゲザルタウのいずれかで被覆することによって測定した。本発明者らの結果は、C2N−8E12およびHJ8.5はアカゲザルタウには結合しないが、これらがヒトタウへの明確な結合を示すことを明らかにした。予想されたように、HJ8.7はヒトおよびアカゲザルの両方のタウに結合する。
図11は、様々なタウオパチーを有するヒト被験者由来のCSF中のタウへのヒト化抗タウ抗体の結合を示す。様々なタウオパチーを有すると診断された被験者ならびに年齢がマッチする健常対照および若年健常対照被験者由来のCSF試料中のタウへのC2N−8E12の結合を評価した。サンドイッチELISAを使用して、AD、CBD、FTDまたはPSPを有する被験者ならびに年齢がマッチするおよび若年/成人対照由来のヒトCSF中のタウへのC2N−8E12の結合を明らかにした。C2N−8E12を、CSF試料中のタウを捕捉するための被覆抗体として使用した。ビオチン化マウスモノクローナルタウ抗体HJ8.7を検出抗体として使用した。対照ヒトIgG4で被覆したウェルは実験の陰性対照としての役割を果たした。C2N−8E12被覆ウェルと対照IgG4被覆ウェルからのシグナルには大きな差が観察され、ヒトCSF試料中のタウへのC2N−8E12の特異的結合を明らかにした。標準曲線(組換えタウ)を含めることにより、これらのCSF試料中のタウ濃度に関する定量的情報を得ることが可能である。
この試験は、最大10施設までで実施される無作為化、二重盲検、プラセボ対照、単回増加量(SAD)第1相試験である。C2N−8E12の単回与の安全性、耐容性、免疫原性およびPKを評価し、今後の反復投与試験において使用されるMTDを確立するように設計されている。
(#)注入完了から15分以内;
(@)28日目以降、以下の事象のいずれかの早期発生まで28日ごとにPK試料を採取する:(i)試験中止;(ii)C2N−8E12の検出可能な血液レベルの不在。
Claims (12)
- 単離されたモノクローナル抗タウ抗体であって、
配列番号2のアミノ酸配列を含む軽鎖、及び、
配列番号5のアミノ酸配列を含む重鎖
を含む、抗タウ抗体。 - ヒト化IgG1、IgG2、IgG3又はIgG4抗体である、請求項1に記載の抗体。
- S241Pヒンジ安定化変異を含むヒト化IgG4抗体である、請求項1に記載の抗体。
- 配列番号9のアミノ酸配列を含むエピトープに結合する請求項1に記載の抗体。
- 請求項1に記載の抗タウ抗体と、薬理学的に許容される担体とを含む、医薬組成物。
- 単離されたモノクローナル抗タウ抗体であって、
配列番号18のアミノ酸配列を含む軽鎖、及び、
配列番号13のアミノ酸配列を含む重鎖
を含む、抗タウ抗体。 - 請求項6に記載の抗タウ抗体と、薬理学的に許容される担体とを含む、医薬組成物。
- 配列番号9のアミノ酸配列を含むエピトープに結合する請求項6に記載の抗体。
- 配列番号2のアミノ酸配列を含む抗体軽鎖と、配列番号5のアミノ酸配列を含む抗体重鎖とをコードする核酸分子。
- 配列番号18のアミノ酸配列を含む軽鎖と、配列番号13のアミノ酸配列を含む重鎖とをコードする請求項9に記載の核酸分子。
- ヒトアイソタイプκの軽鎖定常領域を含む、請求項1に記載の抗体。
- 請求項3に記載の抗タウ抗体と、薬理学的に許容される担体とを含む、医薬組成物。
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