JP5498566B2 - アルファ−4−ベータ−7ヘテロ二量体特異的アンタゴニスト抗体 - Google Patents
アルファ−4−ベータ−7ヘテロ二量体特異的アンタゴニスト抗体 Download PDFInfo
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Description
本出願は、35U.S.C.119(e)に基づいて、2009年3月20日出願の米国特許出願第61/162,154号および2010年2月22日出願の米国特許出願第61/306,829号の優先権を主張し、これらの出願は本明細書に援用される。
本出願は、アルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質に関する組成物および方法を提供する。
用語「単離された分子」は(分子が、例えばポリペプチド、ポリヌクレオチド、または抗体である場合)、その起源または派生供給源によって、(1)天然状態で該分子に付随する、天然に関連する構成要素と関連していないか、(2)同じ種由来の他の分子を実質的に含まないか、(3)異なる種由来の細胞によって発現されるか、または(4)人の介入なしに天然には存在しない分子である。したがって、化学的に合成されたか、または天然に由来する細胞とは異なる細胞系において合成される分子は、天然に関連する構成要素から「単離されている」であろう。分子はまた、当該技術分野に周知の精製技術を用いた単離によって、天然に関連する構成要素を実質的に含まないようにされうる。当該技術分野に周知のいくつかの手段によって、分子純度または均一性をアッセイしてもよい。例えば、当該技術分野に周知の技術を用いて、ポリアクリルアミドゲル電気泳動を用い、そしてゲルを染色してポリペプチドを視覚化して、ポリペプチド試料の純度をアッセイしてもよい。特定の目的のため、HPLCまたは当該技術分野に周知の精製のための他の手段を用いることによって、より高い解像度を提供してもよい。
1つの側面において、本発明は、アルファ4ベータ7、例えばヒト・アルファ4ベータ7に結合する、抗原結合タンパク質(例えば抗体、抗体断片、抗体誘導体、抗体突然変異タンパク質、および抗体変異体)を提供する。
1つの側面において、本発明は、単離核酸分子を提供する。該核酸は、例えば、抗原結合タンパク質のすべてまたは一部、例えば本発明の抗体の一方または両方の鎖、あるいはその断片、誘導体、突然変異タンパク質、または変異体をコードするポリヌクレオチド、ポリペプチドをコードするポリヌクレオチドを同定するか、分析するか、突然変異させるかまたは増幅するための、ハイブリダイゼーション・プローブ、PCRプライマーまたは配列決定プライマーとして使用するのに十分なポリヌクレオチド、ポリヌクレオチドの発現を阻害するためのアンチセンス核酸、および前述のものの相補配列を含む。核酸はいかなる長さであってもよい。これらは、例えば、長さ5、10、15、20、25、30、35、40、45、50、75、100、125、150、175、200、250、300、350、400、450、500、750、1,000、1,500、3,000、5,000またはそれより長いヌクレオチドであってもよく、そして/または1以上のさらなる配列、例えば制御配列を含んでもよく、そして/またはより大きい核酸、例えばベクターの一部であってもよい。核酸は、一本鎖または二本鎖であってもよく、そしてRNAおよび/またはDNAヌクレオチド、ならびにその人工的変異体(例えばペプチド核酸)を含んでもよい。
1つの側面において、本発明は被験体を治療する方法を提供する。該方法は、例えば、被験体に対して、一般的に健康によい効果を有することも可能であり、例えば被験体の予期される寿命を増加させることも可能である。あるいは、該方法は、例えば、疾患、障害、状態、または疾病(「状態」)を治療するか、防止するか、治癒させるか、軽減するか、または改善する(「治療する」)ことも可能である。本発明にしたがって治療すべき状態の中には、アルファ4ベータ7の不適切な発現または活性によって特徴付けられる状態がある。こうした状態には、細胞の不適切な輸送、例えばMAdCAM−1を発現する細胞を含む胃腸管または他の組織への白血球(例えばリンパ球または単球)の輸送に関連するもの(MAdCAM−1を発現する細胞への白血球の結合の結果として)が含まれる。適宜治療可能な疾患には、炎症性腸疾患、例えば潰瘍性大腸炎、クローン病、セリアック病(非熱帯性スプルー)、血清陰性関節症に関連する腸疾患、顕微鏡的またはコラーゲン性大腸炎、好酸球性胃腸炎、あるいは直腸結腸切除術および回腸肛門吻合術後に生じる嚢炎が含まれる。本発明にしたがって治療可能なさらなる状態には、膵炎、インスリン依存性糖尿病、乳腺炎、胆嚢炎、胆管炎、胆管周囲炎、慢性気管支炎、慢性副鼻腔炎、喘息および移植片対宿主病が含まれる。
本明細書に提供する特定の方法は、被験体にアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質を投与し、それによって、特定の状態において役割を果たす、アルファ4ベータ7が誘導する生物学的応答を減少させる工程を含む。特定の態様において、本発明の方法は、例えば、被験体への投与を介して、またはex vivo法において、アルファ4ベータ7抗原結合タンパク質と、内因性アルファ4ベータ7を接触させることを伴う。
別の側面において、本発明は、アルファ4ベータ7阻害性抗原結合タンパク質および1以上の他の治療で、被験体を治療する方法を提供する。1つの態様において、こうした併用療法は、例えば腫瘍の多数の部位または分子ターゲットを攻撃することによって、相乗効果または付加的効果を達成する。本発明と関連して使用可能な併用療法のタイプには、単一の疾患関連経路、ターゲット細胞における多数の経路、およびターゲット組織内の多数の細胞種における多数のノードを阻害するかまたは活性化する(適切なように)ことが含まれる。
XenoMouseTM XG2カッパラムダ(kl)およびXG4klマウス(それぞれ、ヒトIgG2またはIgG4を発現するトランスジェニックマウス、ならびにヒト・カッパおよびラムダ軽鎖を発現するトランスジェニックマウス; Abgenix Inc.、カリフォルニア州フレモント)を、一過性トランスフェクションされたヒト胚性腎(HEK)293細胞(293−a4b7)または安定トランスフェクションされたチャイニーズ・ハムスター卵巣(CHO)細胞(CHO−a4b7)いずれかの、ヒト・アルファ4ベータ7を発現している細胞で免疫することによって、ヒト・アルファ4ベータ7に対するモノクローナル抗体を創出した。アルファ4ベータ7トランスフェクション細胞をそれぞれの親対照細胞に比較する、蛍光活性化細胞分取装置(FACS)分析によって、血清力価を監視した。いずれかの免疫キャンペーン由来の過免疫動物を屠殺し、そして脾臓およびリンパ節組織をハイブリドーマ融合に供した。
得た抗体分泌細胞をクローニングし、そして抗体がコードする核酸を単離し、そして配列決定した。部位特異的突然変異誘発を用いて、1以上のアミノ酸残基が単離配列と異なる変異体を調製した。抗体および変異体の軽鎖および重鎖のアミノ酸配列を以下の表1および2に示す。CDRおよびFR領域の境界は、本明細書において、先に論じたように、以下に示すものとは異なっている可能性もあることが認識される。
本実施例は、抗体を特徴付けるために用いた多様なアッセイを記載する。
リン酸緩衝液pH9.0で希釈した20μG/mL MAdCAM−1(またはコーティング対照としての類似の濃度のヒトIgG1)で4℃で一晩、96ウェルプレートをコーティングすることによって、コーティングプレート(例えばCostar(登録商標)3368 96ウェルプレート; Corning Incorporated Life Sciences、マサチューセッツ州ローウェル)を調製する。コーティングを取り除き、そして100μLの3%BSA/PBSでプレートをブロッキングし、室温で1時間以上インキュベーションする。ハンクス平衡塩溶液(HBSS)でプレートを3回洗浄する。
プレートを、ヒトMAdCAM−1−FcまたはヒトIgG(20mMリン酸緩衝液、pH9.0、130mM NaCl中、3μG/ml)、100μL/ウェルで4℃で一晩コーティングし、次いで、200μL/ウェルのブロッキング試薬(PBS中の3%ウシ胎児血清アルブミン(albumen))で、室温で少なくとも2時間、ブロッキングする。次いで、接着緩衝液(30mM HEPES、pH7.4、120mM NaCl、1mM MnCl2、10g/mlヒトIgG)でプレートを3回洗浄する。
ヒト末梢血単核細胞(PBMC;例えば2%FBSを含むリン酸緩衝生理食塩水中の、新鮮なものまたは凍結融解したもの)を、1%BSAを含み、1mM MnCl2を含むまたは含まない(実験に応じる; Mn2+はMAdCAM−1結合に必要である)HEPES緩衝液(30mM HEPES+140nM NaCl)中で洗浄し、そして再懸濁し、そして96ウェルプレート内にプレーティングする(106細胞/ウェル)。細胞を10μG/mlのヒトIgGと氷上で30分間インキュベーションして、非特異的結合をブロッキングする。次いで、細胞を96ウェルプレート中のビオチン化抗アルファ4ベータ7抗体の連続希釈と氷上で1時間インキュベーションし、その後、1:100希釈のストレプトアビジン−フィコエリトリン(PE; Jackson ImmunoResearch Laboratories Inc.、ペンシルバニア州ウェストグローブ)、4μL CD3−Pacific Blue、CD4−PerCP−Cy5.5およびCD45RA−フルオレセインイソチオシアネート(FITC)(BD Biosciences、カリフォルニア州サンノゼ)を添加して、最終体積100μLにし、そして氷上でさらに1時間インキュベーションする。細胞をHEPES緩衝液(対応して、MnCl2を含むまたは含まない)で2回洗浄し、そして次いで、200μL HEPES緩衝液+0.5%パラホルムアルデヒド(やはり、対応して、MnCl2を含むまたは含まない)中で固定した。蛍光活性化細胞分取装置(FACS)、例えばBDTM LSR IIベンチトップ・フローサイトメーター(BD Biosciences、カリフォルニア州サンノゼ)を用いて、陽性アルファ4ベータ7抗体結合性CD4+CD45RA−メモリーT細胞の割合を決定する。EC50を、CD4CD45RA−メモリー細胞上のアルファ4ベータ7部位の50%にアルファ4ベータ7抗体が結合する、アルファ4ベータ7の濃度として定義する。
PBMC(先に記載する通り、新鮮または凍結)を洗浄し、そして1%BSAおよび1mM MnClを含むHEPES緩衝液(30mM HEPES+140nM NaCl)中、最終濃度107細胞/mlに再懸濁する。先に記載するように細胞をブロッキングし;ブロッキング後、細胞を、96ウェルプレート中、抗アルファ4ベータ7抗体(または適切な対照)の連続希釈と氷上で30分間インキュベーションし、そして次いで、0.3μG/mlビオチン化MAdCAM−1−Fcタンパク質とさらに1時間インキュベーションする。
レチノイン酸(1000nM)の存在下または非存在下で、抗CD3(プレート結合、5μG/ml)、ヒトIL−2(20ng/ml)によって、単離ヒトPBMCを7日間活性化する。活性化された細胞を染色緩衝液(0.5%BSAおよび1mM MnClを加えたPBS)で2回洗浄し、そして100μG/mlヒトIgと30分間インキュベーションして、非特異的結合をブロッキングする。細胞をまず、抗アルファ4ベータ7抗体の連続希釈中で、氷上で30分間、インキュベーションし、そして次いで、1μG/mlビオチン化MAdCAM−1−Fcでさらに30分間染色する。染色緩衝液で2回洗浄した後、細胞をストレプトアビジン−PE(1:1000)で30分間染色する。蛍光活性化細胞分取によって、例えばFACSCaliburTM(BD Biosciences、カリフォルニア州サンノゼ)を用いて細胞を分析する。この方式で調製した細胞は、競合アッセイなどのさらなる実験のために使用可能である。
また、実質的にFiscellaら, Nature Biotechnology 21:302−307; 2003に実質的に記載されるような、蛍光分析微量アッセイ技術またはFMATによって、アルファ4ベータ7を発現している細胞への結合に際して、他の抗アルファ4ベータ7および/またはベータ7抗体と競合する能力に関して、アルファ4ベータ7抗体を調べた。簡潔には、例えばアルファ4をコードする核酸およびベータ7を発現する核酸で、細胞を一過性同時トランスフェクションすることによって、高レベルのアルファ4ベータ7を発現している細胞を調製する。安定トランスフェクションに適した細胞およびプロトコルを用いて、類似の方式で、安定細胞株を調製する。トランスフェクトされた細胞を、例えばFACSによって、アルファ4に対する抗体、ベータ7に対する抗体、および/またはリガンド(すなわちMAdCAM−1、例えばMAdCAM−1−Fc融合タンパク質)を用いて、スクリーニングする。細胞はいくつかの周期の分取および選択を経て、再現性がある上昇したレベルのアルファ4ベータ7発現を伴うクローン性細胞株を得てもよい。
ACT−1結合に非常に重要であることが知られる(J Immunol. 159:1497, 1997)、ベータ7鎖中のS250N点突然変異体を認識する能力に関してもまた、抗体を評価した。高レベルのアルファ4ベータ7を発現している細胞の調製に関して、先に記載するのと類似の方式で、ベータ鎖中にS250N突然変異を有するアルファ4ベータ7を一過性同時発現する293細胞(参照)を調製する。
α4サブユニットのSNP分析のため、異なる民族群を代表する90人の個体(180の一倍体ゲノム)からα4遺伝子エクソン1〜28をポリメラーゼ連鎖反応(PCR)によって増幅し、そして続いて配列決定した。α4遺伝子のコード領域中の3つの候補SNPが同定され、そして3つのうちの1つはアミノ酸変化(Arg878Gln)を生じた。同様に、β7サブユニットSNP分析のため、異なる民族群を代表する90人の個体(180の一倍体ゲノム)からβ7遺伝子エクソン2〜15のコード領域をPCR増幅し、そして続いて配列決定した。3つのSNPが同定され、そしてそのうちの2つはアミノ酸変化を生じた。社内SNP分析データをNCBIデータベース(NCBI:全米バイオテクノロジー情報センター、米国衛生研究所(NIH)の国立医学図書館(NLM)の一部門)中の情報と比較した。α4サブユニット中のGln878Argを生じるA/G突然変異のみが高頻度で生じ、社内SNPおよび公的データベースの両方で、それぞれ、20%または30%生じる。もう一方のSNPは低頻度で生じる。この情報を以下の表4に要約する。
前述の機能アッセイにおいて異なる特性を持つ、いくつかの代表的な抗体を、以下に記載するようなさらなる分析のために選択した。
ヒト抗アルファ4ベータ7抗体の細胞結合アフィニティを測定するため、溶液相中の結合事象を測定する動力学排除アッセイを用いて、平衡解離定数、Kdを計算してもよい。KinExA(登録商標)技術(Sapidyne Instruments、アイダホ州ボイズ)を、実質的に、以前、Xieら J. Imm, Methods 304:1(2005)およびRathanaswamiら Anal. Biochem. 373:52(2008)に記載されるように、用いた。簡潔には、ヒト・アルファ4ベータ7を発現しているHUT78細胞を、3つ中1つで、〜506細胞/mLから〜400細胞/mLで滴定し、そして次いで2または30pMのmAb 2F12または18A11、および17C8に関しては30または500pMの最終濃度で、4℃で18時間、平衡化した。平衡時に上清中に留まる未結合抗体を、KinExA(登録商標)技術によって、ヤギ抗ヒトFcであらかじめコーティングしたPMMAビーズ上に上清を通過させることによって測定し、そしてヤギ抗ヒト(H+L)Cy5で検出した(実質的に、Rathanaswamiら Biochem Biophys Research Commun:1004(2005)に記載される通り)。KinExA(登録商標)ソフトウェアを用いて、所定の曲線をすべて同時に単一のKd値に適合させる、「n曲線分析」によって平衡解離定数(Kd)を得る(Rathanswamiら 2005およびXieら、上記)。
雄カニクイザルにおいて、3つの完全ヒト抗アルファ4ベータ7抗体の単回用量薬力学(PK)および薬物動態学(PD)研究によって、以下の静脈内(IV; 5mg/kg)または皮下(SC; 0.5または5mg/kg)投与を行った。類似の初期PK曝露(C0; 時間ゼロにおける濃度)および5mg/kg IV後の中枢循環内での分布を観察した。SC投与後、Cmax(血清中の最大濃度)およびAUC(濃度−時間曲線下の面積)は、3つの抗体すべてに関して、0.5〜5mg/kg SC用量範囲内で、用量比例性を示した。試験した3つの抗体に関して、SC後の絶対生物学的利用能は、44〜68%の範囲であった。
Claims (21)
- 配列番号37由来のCDR1、CDR2およびCDR3を含む重鎖可変領域、ならびに配列番号9由来のCDR1、CDR2およびCDR3を含む軽鎖可変領域を有する、単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- 軽鎖可変領域が配列番号9に少なくとも90%同一であり、そして重鎖可変領域が配列番号37に少なくとも90%同一である、請求項1のヘテロ二量体特異的抗原結合タンパク質。
- 軽鎖可変領域が配列番号9を含み、そして重鎖可変領域が配列番号37を含み、ここにおいて、N末端のアミノ酸がピログルタミン酸に変換されている、請求項2のヘテロ二量体特異的抗原結合タンパク質。
- さらに軽鎖定常領域および重鎖定常領域を含む、請求項1〜3のいずれか1項の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- 軽鎖定常領域がカッパ型軽鎖定常領域であり;
そして重鎖定常領域が:
a’)IgD抗体由来の定常領域;
b’)IgE抗体由来の定常領域;
c’)IgM抗体由来の定常領域;
d’)IgG1抗体由来の定常領域;
e’)IgG2抗体由来の定常領域;
f’)IgG3抗体由来の定常領域;
g’)IgG4抗体由来の定常領域;および
h’)ヒンジ領域中に、H鎖内ジスルフィド結合を形成する傾向を軽減させる、少なくとも1つの突然変異を有する、IgG4抗体由来の定常領域;
からなる群より選択される、請求項4の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。 - 軽鎖定常領域が:
a)配列番号70を含むポリペプチド;
b)配列番号70に少なくとも90%同一であるポリペプチド;
c)1以上の翻訳後修飾を取り込む、a)のポリペプチド;ならびに
d)1つ、2つ、3つ、4つまたは5つのN末端および/またはC末端アミノ酸が取り除かれている、配列番号70に示すようなアミノ酸配列を有するポリペプチド
からなる群より選択され、
そして重鎖定常領域が:
a’)配列番号72を含むポリペプチド;
b’)配列番号72に少なくとも90%同一であるポリペプチド;
c’)1以上の翻訳後修飾を取り込む、a’)のポリペプチド;ならびに
d’)1つ、2つ、3つ、4つまたは5つのN末端および/またはC末端アミノ酸が取り除かれている、配列番号72に示すようなアミノ酸配列を有するポリペプチド
からなる群より選択される、請求項4の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。 - 重鎖可変領域および軽鎖可変領域を有する単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質であって、ここにおいて、重鎖可変領域は配列番号37をコードする核酸によってコードされ、そして、軽鎖可変領域は配列番号9をコードする核酸によってコードされる、前記単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- 重鎖可変領域をコードする核酸が配列番号64を含み、軽鎖可変領域をコードする核酸が配列番号63を含む、請求項7の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- さらに軽鎖定常領域および重鎖定常領域を含む、ここにおいて、軽鎖定常領域は配列番号70をコードする核酸によってコードされ、そして、重鎖定常領域は配列番号72をコードする核酸によってコードされる、請求項7又は8の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- 重鎖定常領域が配列番号69を含む核酸によってコードされ、そして、軽鎖定常領域が配列番号71を含む核酸によってコードされる、請求項9の単離されたアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質。
- 請求項1〜10のいずれか1項のタンパク質、および生理学的に許容されうる希釈剤、賦形剤またはキャリアーを含む、組成物。
- 請求項1〜10のいずれか1項のタンパク質をコードする単離された核酸。
- 請求項12の核酸を含むベクター。
- 請求項13のベクターでトランスフェクションまたは形質転換されている、単離された宿主細胞。
- 発現を促進する条件下で請求項14の宿主細胞を培養し、そして培地からタンパク質を回収することを含む、抗原結合タンパク質を産生するための方法。
- アルファ4ベータ7の少なくとも1つの活性を阻害するインビトロの方法であって、アルファ4ベータ7を発現している細胞と、請求項1〜10のいずれか1項記載のタンパク質とを、MAdCAM−1への細胞の接着が部分的にまたは完全に阻害されるように、接触させることを含む、前記方法。
- アルファ4ベータ7を発現している細胞が、MAdCAM−1を発現する細胞を含む組織に輸送されるのを阻害するインビトロの方法であって、アルファ4ベータ7を発現している細胞と、請求項1〜10のいずれか1項記載のアルファ4ベータ7ヘテロ二量体特異的抗原結合タンパク質とを、MAdCAM−1への細胞の接着が部分的にまたは完全に阻害されるように、接触させることを含む、前記方法。
- アルファ4ベータ7を発現している細胞が、MAdCAM−1を発現している細胞を含む組織に不適切に輸送されることによって特徴付けられる状態に罹患している個体を治療するための、請求項11の組成物。
- 状態が炎症性腸疾患である、請求項18の組成物。
- 状態が、潰瘍性大腸炎、クローン病、セリアック病(非熱帯性スプルー)、血清陰性関節症に関連する腸疾患、顕微鏡的またはコラーゲン性大腸炎、好酸球性胃腸炎、ならびに直腸結腸切除術および回腸肛門吻合術後に生じる嚢炎からなる群より選択される、請求項19の組成物。
- 状態が、膵炎、インスリン依存性糖尿病、乳腺炎、胆嚢炎、胆管炎、胆管周囲炎、慢性気管支炎、慢性副鼻腔炎、喘息および移植片対宿主病からなる群より選択される、請求項18の組成物。
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