JP5844772B2 - ヒトil−4受容体に対する高親和性ヒト抗体 - Google Patents
ヒトil−4受容体に対する高親和性ヒト抗体 Download PDFInfo
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- JP5844772B2 JP5844772B2 JP2013097263A JP2013097263A JP5844772B2 JP 5844772 B2 JP5844772 B2 JP 5844772B2 JP 2013097263 A JP2013097263 A JP 2013097263A JP 2013097263 A JP2013097263 A JP 2013097263A JP 5844772 B2 JP5844772 B2 JP 5844772B2
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Description
グメントを提供する。これらのHCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3配列を有する典型的な抗体としては、H4H098P(配列番号:148/150/152/156/158/160)、H4H083P(配列番号:196/198/200/204/206/208)、及びH4H095P(配列番号:4/6/8/12/14/16)と呼ばれる抗体が挙げられる。
そしてX11=Tyrであるか又は存在せず;LCDR2は式X1−X2−X3(配列番号269)のアミノ酸配列を含み、式中X1=Leu、Ala又はVal、X2=Ala又はGly、そしてX3=Serであり;そしてLCDR3は式X1−X2−X3−X4−X5−X6−X7−X8−X9(配列番号270)のアミノ酸配列を含み、式中X1=Gln又はMet、X2=Gln、X3=Ala又はTyr、X4=Leu又はAsn、X5=Gln又はSer、X6=Thr、Phe又はHis、X7=Pro、X8=Tyr、Ile又はTrp、
そしてX9=Thrである。
X8=Glyであるか又は存在せず;X9=Tyrであるか又は存在せず;X10=Asnであるか又は存在せず;そしてX11=Tyrであるか又は存在せず;LCDR2は式X1−X2−X3(配列番号269)のアミノ酸配列を含み、式中X1=Leu又はAla、X2=Ala又はGly、そしてX3=Serであり;そしてLCDR3は式X1−X2−X3−X4−X5−X6−X7−X8−X9(配列番号270)のアミノ酸配列を含み、式中X1=Gln又はMet、X2=Gln、X3=Ala又はTyr、X4=Leu又はAsn、X5=Gln又はSer、X6=Thr又はHis、X7=Pro、X8=Tyr又はTrp、そしてX9=Thrである。
X7=Ileであるか又は存在せず;X8=Glyであるか又は存在せず;X9=Tyrであるか又は存在せず;X10=Asnであるか又は存在せず;そしてX11=Tyrであるか又は存在せず;LCDR2は式X1−X2−X3(配列番号269)のアミノ酸配列を含み、式中X1=Leu又はVal、X2=Ala又はGly、そしてX3=Serであり;そしてLCDR3は式X1−X2−X3−X4−X5−X6−X7−X8−X9(配列番号270)のアミノ酸配列を含み、式中X1=Gln又はMet、X2=Gln、X3=Ala、X4=Leu又はAsn、X5=Gln又はSer、X6=Thr又はPhe、X7=Pro、X8=Tyr又はIle、そしてX9=Thrである。
本発明の方法を説明する前に、当然のことながら、本発明は記載される特定の方法及び実験条件に限定されず、そのようなものとして方法及び条件は変動し得る。また当然のことながら、本発明の範囲は添付の特許請求の範囲によってのみ限定されるので、本明細書で使用される用語は、特定の実施態様を記載する目的のためのみのものであって、限定することを意図されない。
本明細書で使用される用語「ヒトIL4R」(hIL−4R)は、インターロイキン−4(IL−4)、IL−4Rα(配列番号274)に特異的に結合するヒトサイトカイン受容体を指すことを意図される。用語「ヒトインターロイキン−13」(hIL−13)は、IL−13受容体に特異的に結合するサイトカインを指し、そして「hIL−13/hIL−13R1複合体」は、hIL−13R1複合体にhIL−13が結合することにより形成される複合体を指し、この複合体はhIL−4受容体に結合して生物学的活性を開始する。
例えば、Holliger et al.(1993)Proc.Natl.Acad Sci.USA 90:6444−6448を参照のこと)。
ヒト抗体を生成する方法としては、例えばUS 6,596,541、Green et al.(1994) Nature Genetics 7:13−21)、US 5,545,807、US 6,787,637に記載される方法が挙げられる。
Techniques、Academic Press、CAを参照のこと)。本発明の抗体は、好ましくはVELOCIMMUNETM 技術(US6,596,541)を使用して製造される。内因性免疫グロブリン重鎖及び軽鎖可変領域が対応するヒト可変領域で置き換えられているトランスジェニックマウスを、目的の抗原で攻撃し、そして抗体を発現するマウスからリンパ球(例えばB細胞)を回収する。リンパ球を骨髄腫細胞株と融合させて不死ハイブリドーマ細胞株を製造し得、そしてこのようなハイブリドーマ細胞株をスクリーニング、そして選択し、目的の抗原に対して特異的な抗体を産生するハイブリドーマ細胞株を同定する。重鎖及び軽鎖の可変領域をコードするDNAを単離して、重鎖及び軽鎖の所望のアイソタイプ定常領域に連結し得る。このような抗体タンパク質は、CHO細胞のような細胞で産生され得る。あるいは、抗原特異的キメラ抗体又は軽鎖及び重鎖の可変領域をコードするDNAは、抗原特異的リンパ球から直接単離され得る。
特定のエピトープに結合する抗体をスクリーニングするために、Harlow and Lane(前出)に記載されるアッセイのような交差遮断(cross−blocking)アッセイを行うことができる。他の方法としては、アラニンスキャニング変異体、ペプチドブロット(Reineke(2004) Methods Mol Biol 248:443−63)、又はペプチド切断分析が挙げられる。さらに、エピトープ切除、エピトープ抽出及び抗原の化学的改変のような方法を使用することができる(Tomer(2000) Protein Science:9:487−496)。
本発明の抗体は、単一特異性、二重特異性、又は多重特異性であり得る。多重特異性抗体は、1つの標的ポリペプチドの異なるエピトープに対して特異的でもよいし、1つより多くの標的ポリペプチドに対して特異的な抗原結合ドメインを含有していてもよい。例えば、Tutt et al.(1991)J.Immunol.147:60−69を参照のこと。ヒト抗IL−4R抗体を、別の機能的分子、例えば別のペプチド又はタンパク質に連結しても、又は別の機能的分子と同時発現(co−expressed)してもよい。例えば、抗体又はそのフラグメントは、1つ又はそれ以上の他の分子実体、例えば別の抗体又は抗体フラグメントに(例えば、化学的カップリング、遺伝子融合、非共有結合又はその他により)連結されて、第二の結合特異性を有する二重特異性又は多重特異性抗体を生じ得る。
本発明は、本発明の抗IL−4R抗体又はその抗原結合フラグメントを含む治療用組成物を提供する。本発明に従う治療用組成物の投与は、適切な担体、添加剤及び改善された輸送、送達、耐性などをもたらすために製剤に組み込まれる他の薬剤と共に投与される。多数の適切な製剤が、全ての薬剤師に知られる処方集:Remington's Pha
rmaceutical Sciences、Mack Publishing Company、Easton、PAにおいて見出され得る。これらの製剤としては、例えば、散剤、ペースト剤、軟膏、ゼリー、ろう、オイル、脂質、脂質(カチオン性又はアニオン性)含有小胞(例えばLIPOFECTINTM)、DNAコンジュゲート、無水吸収ペースト、水中油及び油中水乳剤、carbowax(種々の分子量のポチエチレングリコール)乳剤、半固形ゲル、並びにcarbowaxを含有する半固形混合物が挙げられる。Powell et al.「Compendium of excipients for parenteral formulations」 PDA(1998)J Pharm Sci Technol 52:238−311も参照のこと。
VELOCIMMUNETMマウス(Regeneron Pharmaceuticals、Inc.;US6,596,541)をヒトIL−4R(hIL−4R、配列番号274)、又はhIL−4R及びサル(Macaca fascicularis)のIL−4R(mfIL−4R、配列番号275)タンパク質若しくはDNAの組み合わせで免疫した。最適な免疫応答を得るために、続いて動物を3〜4週ごとにブーストし、そして抗抗原応答の進行を評価するために各ブーストの10日後に採血した。
25℃又は37℃のいずれかで、hIL−4Rに関して選択された抗体の結合親和性(KD)を、実時間バイオセンサー表面プラズモン共鳴アッセイ(BIACORETM2000)を使用して決定した。手短には、抗体を、BIACORETMチップへの直接カップリングにより作出したヤギ抗hFcポリクローナル抗体表面上に捕捉して、捕捉抗体表面を形成した。種々の濃度(50nMから12.5nMの範囲)のモノマーhIL−4R(R&D Systems)又はダイマーhIL−4R−mFcを、25℃又は37℃のいずれかで捕捉抗体表面上に10μl/分で2.5分間注入した。抗体に対する抗原の結合及び結合複合体の解離を実時間でモニタリングした。平行解離定数(KD)及び解離速度定数を、BIA評価ソフトウェアを使用して動態解析を行うことにより確認した。BIA評価ソフトウェアを、抗原/抗体複合体解離の半減期(T1/2)を計算するためにも使用した。結果を表1に示す。NB:抗体−抗原結合が実験条件下で観察されなかった。コントロール:完全ヒト抗IL−4R抗体(米国特許第7,186、809号;配列番号:10及び12)。
精製した抗hIL−4R抗体のhIL−4R仲介細胞機能を中和する能力をインビトロで決定するためにヒトSTAT6及びSTAT6ルシフェラーゼレポーターを含有するよう操作したHK293細胞株を使用するバイオアッセイを開発した。hIL−4R誘導ルシフェラーゼ活性の阻害を以下のように決定した:細胞を96ウェルプレートに培地中1×104細胞/ウェルで播種し、そして終夜37℃、5%CO2でインキュベートした。段階希釈で0〜20nMの範囲の抗体タンパク質を、10pMのhIL−4又は40pMのhIL−13のいずれかとともに細胞に加えた。次いで細胞を37℃、5%CO2で6時間インキュベートした。細胞応答の程度をルシフェラーゼアッセイ(Promega Biotech)で測定した。結果を表3に示す。NB:ルシフェラーゼ活性が上記の実験条件下で遮断されなかった。さらに、H4H098PはmfIL−4R仲介細胞機能を360fM mfIL−4の存在下で150nMのIC50で遮断することができた。
Claims (10)
- 疾患又は障害の処置のための医薬の製造における、重鎖可変領域(HCVR)及び軽鎖可変領域(LCVR)を含み、重鎖可変領域が配列番号162を含み、そして軽鎖可変領域が配列番号164を含む、抗体又は抗原結合フラグメントの使用であって、ここで疾患又は障害がヒトインターロイキン−4(hIL−4)活性の除去、阻害又は低減により改善、軽減又は抑制される、使用。
- 疾患又は障害が、関節炎、疱疹状疾患、慢性特発性蕁麻疹、強皮症、肥厚性瘢痕化、ウィップル病、良性前立腺肥大、肺障害、喘息、炎症性障害、アレルギー反応、川崎病、鎌状赤血球症、チャーグ・ストラウス症候群、グレーブズ病、子癇前症、シェーグレン症候群、自己免疫性リンパ増殖症候群、自己免疫性溶血性貧血、バレット食道、自己免疫性ブドウ膜炎、結核、及びネフローゼからなる群より選択される、請求項1に定義される使用。
- 疾患又は障害が喘息又はアトピー性皮膚炎である、請求項1に定義される使用。
- ヒトインターロイキン−4(hIL−4)活性の除去、阻害又は低減により改善、軽減又は抑制される、疾患又は障害を処置するための医薬であって、重鎖可変領域(HCVR)及び軽鎖可変領域(LCVR)を含み、重鎖可変領域が配列番号162を含み、そして軽鎖可変領域が配列番号164を含む、抗体又は抗原結合フラグメントを含む、上記医薬。
- 疾患又は障害が、関節炎、疱疹状疾患、慢性特発性蕁麻疹、強皮症、肥厚性瘢痕化、ウィップル病、良性前立腺肥大、肺障害、喘息、炎症性障害、アレルギー反応、川崎病、鎌状赤血球症、チャーグ・ストラウス症候群、グレーブズ病、子癇前症、シェーグレン症候群、自己免疫性リンパ増殖症候群、自己免疫性溶血性貧血、バレット食道、自己免疫性ブドウ膜炎、結核、及びネフローゼからなる群より選択される、請求項4に記載の医薬。
- 疾患又は障害が喘息又はアトピー性皮膚炎である、請求項4に記載の医薬。
- 抗体又はその抗原結合フラグメントの製造のための宿主−ベクターシステムであって、以下:
(i)HCVRを含む抗体又はその抗原結合フラグメントをコードする核酸を含むベクターであって、ここで、HCVRが配列番号162のアミノ酸配列を含み;そして
(ii)LCVRを含む抗体又はその抗原結合フラグメントをコードする核酸を含むベクターであって、ここで、LCVRが配列番号164のアミノ酸配列を含む;
前記宿主−ベクターシステム。 - ヒトインターロイキン−4受容体アルファ(hIL−4R)に特異的に結合する抗体又はその抗原結合フラグメントを製造する方法であって、請求項7に記載の宿主−ベクターシステムにより構成される細胞を、前記抗体又はフラグメントが発現する条件で成長させること、及び発現した抗−hIL−4R抗体を回収することを含む、前記方法。
- 宿主細胞が原核細胞又は真核細胞である、請求項8記載の方法。
- 宿主細胞がE.coli細胞又はCHO細胞である、請求項9記載の方法。
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