JP2011511638A - 抗tslpr抗体の設計製作 - Google Patents
抗tslpr抗体の設計製作 Download PDFInfo
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- JP2011511638A JP2011511638A JP2010546045A JP2010546045A JP2011511638A JP 2011511638 A JP2011511638 A JP 2011511638A JP 2010546045 A JP2010546045 A JP 2010546045A JP 2010546045 A JP2010546045 A JP 2010546045A JP 2011511638 A JP2011511638 A JP 2011511638A
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Abstract
Description
細胞または受容体に適用する場合、文脈によってまたは明確に他に指示がなければ、「活性化」、「刺激」および「処置」は同じ意味を有し得る(例えば、リガンドによる、細胞または受容体の活性化、刺激、または処置)。「リガンド」は、天然および合成のリガンド、例えばサイトカイン、サイトカイン変異体、アナログ、ムテイン、および抗体由来の結合組成物を包含する。「リガンド」はまた、小分子、例えばサイトカインのペプチド模倣物および抗体のペプチド模倣物を包含する。「活性化」は、内部メカニズムによって、および外部因子または環境因子によって調節される細胞活性化を指し得る。例えば細胞、組織、臓器、または有機体の「反応」は、生化学的または生理学的挙動(例えば、濃度、密度、接着、または生物学的区画内の遊走、遺伝子発現の速度、または分化の状態)の変化を包含し、ここでその変化は、活性化、刺激、または処置と関連するか、または遺伝プログラミングのような内部メカニズムと関連する。
表1
代表的な保存的アミノ酸置換
本発明は、設計製作した抗TSLPR抗体を提供し、そして炎症性疾患、および特にアレルギー性炎症性疾患を治療するためのその使用を提供する。好ましい実施態様において、その炎症性疾患は喘息である。好ましい実施態様において、そのアレルギー性炎症性疾患は、アレルギー性鼻副鼻腔炎、アレルギー性喘息、アレルギー性結膜炎、またはアトピー性皮膚炎である。本発明はまた、線維症、炎症性腸疾患、またはホジキンリンパ腫を治療するための、設計製作した抗TSLPR抗体を提供する。
モノクローナル抗体を産生するための適当な任意の方法を使用し得る。例えば、レシピエントをTSLPRまたはその断片で免疫し得る。任意の適当な免疫方法を使用し得る。そのような方法は、アジュバント、他の免疫賦活薬、反復する追加免疫、および1つまたは複数の免疫経路の使用を含み得る。
超可変領域の供給源として、任意の適当な非ヒト抗体を使用し得る。非ヒト抗体の供給源は、マウス、ウサギ目(ウサギを含む)、ウシ、および霊長類を含むがこれに限らない。ほとんどの部分に関して、ヒト化抗体はヒト免疫グロブリン(レシピエント抗体)であり、ここでレシピエントの超可変領域残基が、望ましい特異性、親和性、およびキャパシティーを有する、マウス、ラット、ウサギ、または非ヒト霊長類のような、非ヒト種(ドナー抗体)由来の超可変領域残基によって置換されている。いくつかの例において、ヒト免疫グロブリンのFvフレームワーク領域(FR)残基が、対応する非ヒト残基で置換される。さらに、ヒト化抗体は、レシピエント抗体またはドナー抗体において見出されない残基を含み得る。望ましい生物学的活性の抗体性能をさらに改良するために、これらの改変を行う。さらなる詳細に関して、Jonesら(1986)Nature 321:522−525;Reichmannら(1988)Nature 332:323−329;およびPresta(1992)Curr.Op.Struct.Biol.2:593−596を参照のこと。
重鎖配列およびドメイン
hu13H5の可変軽鎖の代替配列を、配列番号54において見出し得る(図3B)。位置70のアミノ酸は、DまたはNであり得る。位置92のアミノ酸は、NまたはQであり得る。位置70における潜在的変化の可能性は、マウス抗体に存在するN結合型糖鎖付加部位をヒト化抗体に導入である。
V.ヒト化抗TSLPRの生物学的活性
ヒト化抗TSLPR抗体において望ましいと本明細書中で同定された特徴を有する抗体を、インビトロにおける生物学的活性の阻害に関してまたは適当な結合親和性に関してスクリーニングし得る。関心のある抗体(例えば、サイトカインのその受容体への結合を阻害するもの)が結合する、ヒトTSLPR上のエピトープに結合する抗体に関してスクリーニングするために、ANTIBODIES、A LABORATORY MANUAL、Cold Spring Harbor Laboratory、Ed HarlowおよびDavid Lane(1988)において記載されたような、通常の交差阻害アッセイを行い得る。同じエピトープに結合する抗体は、そのようなアッセイにおいて交差阻害する可能性が高いが、交差阻害は、近くの、または重複さえしているエピトープに結合した抗体による抗体結合の立体障害に起因し得るので、全ての交差阻害抗体が、必ずしも正確に同じエピトープに結合するわけではない。
医薬組成物または滅菌組成物を調製するために、抗体またはその断片を、薬学的に許容可能な担体または賦形剤と混合する(例えばRemington’s Pharmaceutical SciencesおよびU.S.Pharmacopeia:National Formulary、Mack Publishing Company、Easton、PA(1984)を参照のこと)。治療薬および診断薬の調合を、例えば凍結乾燥粉末、スラリー、水性溶液または懸濁液の形態で、生理学的に許容可能な担体、賦形剤、または安定剤と混合することによって調製し得る(例えばHardmanら(2001)Goodman and Gilman’s The Pharmacological Basis of Therapeutics、MacGraw−Hill、New York、NY;Gennaro(2000)Remington:The Science and Practice of Pharmacy、Lippincott、Williams and Wilkins、New York、NY;Avisら(編)(1993)Pharmaceutical Dosage Forms:Parenteral Medications、Marcel Dekker、NY;Liebermanら(編)(1990)Pharmaceutical Dosage Forms:Tablets、Marcel Dekker、NY;Liebermanら(編)(1990)Pharmaceutical Dosage Forms:Disperse Systems、Marcel Dekker、NY;WeinerおよびKotkoskie(2000)Excipient Toxicity and Safety、Marcel Dekker,Inc.、NYを参照のこと)。
本発明の抗体の組換え産生のために、2つの鎖をコードする核酸を単離し、そしてさらなるクローニング(DNAの増幅)のためまたは発現のために、1つまたは複数の複製可能なベクターに挿入する。モノクローナル抗体をコードするDNAを、従来の手順を用いて容易に単離および配列決定する(例えば抗体の重鎖および軽鎖をコードする遺伝子に特異的に結合し得るオリゴヌクレオチドプローブを用いることによって)。多くのベクターが利用可能である。そのベクター成分は一般的に、1つまたは複数の以下のものを含むがこれに限らない:シグナル配列、複製起点、1つまたは複数のマーカー遺伝子、エンハンサーエレメント、プロモーター、および転写終結配列。1つの実施態様において、本発明のヒト化抗TSLPR抗体の軽鎖および重鎖の両方が、同じベクター、例えばプラスミドまたはアデノウイルスベクターから発現する。
本発明は、炎症性疾患の治療および診断のために、設計製作した抗TSLPRを使用する方法を提供する。
一般的な方法
分子生物学における標準的な方法が記載される(Maniatisら(1982)Molecular Cloning、A Laboratory Manual、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、NY;SambrookおよびRussell(2001)Molecular Cloning、第3版、Cold Spring Harbor Laboratory Press、Cold Spring Harbor、NY;Wu(1993)Recombinant DNA、第217巻、Academic Press、San Diego、CA)。標準的な方法はまた、Ausbelら(2001)Current Protocols in Molecular Biology、第1−4巻、John Wiley and Sons,Inc.、New York、NYにおいても見られ、それは細菌細胞におけるクローニングおよびDNA突然変異誘発(第1巻)、哺乳類細胞および酵母におけるクローニング(第2巻)、複合糖質およびタンパク質発現(第3巻)、およびバイオインフォマティクス(第4巻)を記載する。
マウス抗TSLPR抗体の産生
ヒトTSLPRに対するマウス抗体を、以下のプロトコールによって産生した:5匹のBALB/cマウスを、1、7、33、48、77、85、92、および99日目に、その右後足蹠において、50マイクロリットルのCorixaMPL+TDMアジュバント(Sigma M6535−1VL)中5マイクログラムのhTSLPR−Ig融合物で免疫した。109日目に、膝窩節および鼠径節の両方由来の細胞を、電気融合を用いて、骨髄腫細胞(ATCC P3×63Ag8.653)と融合した。
ラット抗TSLPR抗体LB1.18B3の産生
ヒトTSLPRに対するラット抗体を、以下のプロトコールによって産生させた:1匹のラットを、1mlの完全フロイントアジュバント中50マイクログラムのhTSLPR−Ig融合物の腹腔内注射によって免疫し、そして不完全フロイントアジュバント中25−50マイクログラムのhTSLPR−Ig融合物で、皮下および/または腹腔内に14日間隔で、7回追加免疫した。脾臓由来の細胞を、PEGを用いて骨髄腫細胞(ATCC P3×63Ag8.653)と融合した。
抗ヒトTSLPR抗体のヒト化
マウス抗ヒトTSLPR抗体13H5のヒト化を、実質的に、参考文献に組み込まれるPCT特許出願公開WO2005/047324およびWO2005/047326に記載されたように行った。
ELISAを用いた、抗ヒトTSLPR抗体のEC50の決定
ELISAは、実施例2によって産生され、そして表4において報告された特定のマウス抗TSLPR抗体のEC50を測定する。その抗体をハイブリドーマ上清から精製し、そしてhis−hTSLPRまたはcTSLPR−Igを用いて、結合親和性を決定した。
−洗浄緩衝液:50mMホウ酸塩を含む4MのNaCl、PH8.0(緩衝液A)
−溶出緩衝液:0.1Mクエン酸ナトリウム、PH3.0(緩衝液B)
プロテインAセファロースカラムを、5CVの緩衝液Aで平衡化した。培養培地を、プロテインAカラムに添加した。そのカラムを、5−10CVの緩衝液Aで洗浄し、そして5−6CVの緩衝液Bでタンパク質を溶出した。約1:5の中和化緩衝液対画分容積の比で、1MのTris PH9.0を加えて、溶出後の画分それぞれを中性にした。その画分を、1×PBSに対して透析した。そのサンプルをろ過し、OD280nmの測定によってタンパク質濃度を決定した。そのサンプルを、SDS−PAGEによって分析した。
Nunc Maxisorp 96U well Immunoplate(Nunc
#449824)
10×リン酸緩衝化生理食塩水(PBS)、pH7.4(Fisher#BP399−20)
Tween−20、酵素グレード(Fisher#BP337−500)
アルブミン、ウシ血清(Sigma#A2153)
コーティング緩衝液:50μL/ウェルでPBS中1μg/mLのTSLP
検出試薬:ヤギ抗マウスIgG(H+L)−Jackson ImmunoResearch−115−035−062
基質溶液:ABTSペルオキシダーゼ基質 1C(Kirkegaard&Perry Labs#50−66−00)
ELISA希釈剤およびアッセイ緩衝液:PBS;0.1% BSA;0.05% Tween−20
ELISA洗浄緩衝液:PBS;0.05% Tween−20
装置:
Molecular Devices Scanwasher300TM
Molecular Devices VersaMaxTMマイクロプレートリーダー。
プレートのコーティングを以下のように行った:PBS中のTSLPR(ウェルあたり50ng)を4℃で一晩インキュベートした。Molecular Devicesプレート洗浄機で、プレートを1サイクル(3回洗浄/サイクル)洗浄した。次いで3倍希釈系列を用いて3000ng/mLから0.4572ng/mLの範囲で、抗体を8ウェルの列で滴定し、そして25℃で60分間インキュベートした。プレートを1サイクル洗浄し、HRP−ヤギ抗マウス(1:2,000希釈)を0.05mL/ウェルで加え、そして25℃で60分間インキュベートした。プレートを1サイクル洗浄した。ABTS基質を0.05mL/ウェルで加え、そして25℃で10分間インキュベートした。プレートをA405nmで測定した。
ELISAによって決定したEC50値
ヒトおよびCynoのTSLPに対する抗ヒトTSLPR抗体の親和性
マウス抗ヒトTSLPR抗体13H5、キメラ抗ヒトTSLPR13H5抗体、ラット抗ヒトTSLPR抗体18B3、およびマウス抗ヒトTSLPR抗体70E8の、ヒト(hu)およびカニクイザル(cyno)のTSLPRの両方に対する、動態学的結合活性を、BIAcore T100システム(BIAcore AB、Upsalla、Sweden)を用いて、表面プラズモン共鳴によって測定した。約70RUのヒトTSLPまたはcynoTSLPを、アミン結合化学によって、Sensor Chip CM5(Research grade、BR−1006−68)に固定化した。HBS−EP緩衝液(BR−1006−69)を、30μL/分の流速で、泳動緩衝液として使用した。0.01から600nMの範囲の様々な濃度の抗体を、30μL/分の流速で、固定化したhuまたはcynoのTSLP表面上へ注入した。各注入サイクルの後、CM5チップ表面を、75μL/分の流速で、一連の溶液(それぞれ10mMのグリシン pH1.5および25mMのNaOH)を用いて再生した。
BIAcore分析
中和化抗TSLPR抗体の評価のための増殖バイオアッセイ
モノクローナル抗体の、TSLPRを生物学的に中和する能力を、組換えヒトまたは非ヒト霊長類のTSLP受容体を発現する細胞を用いる、短期間増殖バイオアッセイの適用によって評価した。トランスフェクタントBa/F3−hTSLPR(Ba/F3−hTSLPR−hIL7Ra)細胞およびBa/F3−cyTSLPR(Ba/F3−cTSLPR−cIL7Ra)は、それぞれhTSLPまたはcTSLPに反応して増殖し、そしてその反応を、中和抗TSLPR抗体が阻害し得る。各抗体を、TSLP用量−反応曲線の直線領域内、プラトー付近、およびTSLP EC50より上で選択したTSLPの濃度に対して滴定した。増殖、またはその欠如を、Alamar Blue(代謝活性の検出に基づく増殖指標色素)を用いて、比色法によって測定する。TSLPを中和する抗体の能力を、そのEC50値、またはTSLP増殖の最大半量阻害を誘導する抗体の濃度によって評価する。
増殖の阻害
Claims (23)
- ヒトTSLPRおよびcyno TSLPRに特異的に結合する結合化合物であって:
配列番号1、2、3、73、7、8、9、13、14、15、19、20、21、25、26、27、31、32、33、37、38、39、43、44および45、または任意の該配列の変異体から成る群から選択される少なくとも1つのCDR配列を含む、少なくとも1つの抗体重鎖可変領域またはそのTSLPR結合断片;あるいは
配列番号4、5、6、74、10、11、12、16、17、18、22、23、24、28、29、30、34、35、36、40、41、42、46、47、および48、または任意の該配列の変異体から成る群から選択される少なくとも1つのCDR配列を含む、少なくとも1つの抗体軽鎖可変領域またはそのTSLPR結合断片
を含む、結合化合物。 - 配列番号1、2、3、73、7、8、9、13、14、15、19、20、21、25、26、27、31、32、33、37、38、39、43、44および45、または任意の該配列の変異体から成る群から選択される少なくとも1つのCDR配列を含む、少なくとも1つの抗体重鎖可変領域またはそのTSLPR結合断片;および
配列番号4、5、6、74、10、11、12、16、17、18、22、23、24、28、29、30、34、35、36、40、41、42、46、47、および48、または任意の該配列の変異体から成る群から選択される少なくとも1つのCDR配列を含む、少なくとも1つの抗体軽鎖可変領域またはそのTSLPR結合断片
を含む、請求項1に記載の結合化合物。 - 前記抗体重鎖可変領域またはそのTSLPR結合断片が、配列番号1、2、3、73、7、8、9、13、14、15、19、20、21、25、26、27、31、32、33、37、38、39、43、44および45、または任意の該配列の変異体から成る群から選択される少なくとも2つのCDR配列を含み;そして
前記抗体軽鎖可変領域またはそのTSLPR結合断片が、配列番号4、5、6、74、10、11、12、16、17、18、22、23、24、28、29、30、34、35、36、40、41、42、46、47、および48、または任意の該配列の変異体から成る群から選択される少なくとも2つのCDR配列を含む、
請求項2に記載の結合化合物。 - 前記抗体重鎖可変領域またはそのTSLPR結合断片が、配列番号1、2、3、73、7、8、9、13、14、15、19、20、21、25、26、27、31、32、33、37、38、39、43、44および45、または任意の該配列の変異体から成る群から選択される3つのCDR配列を含み;そして
前記抗体軽鎖可変領域またはそのTSLPR結合断片が、配列番号4、5、6、74、10、11、12、16、17、18、22、23、24、28、29、30、34、35、36、40、41、42、46、47、および48、または任意の該配列の変異体から成る群から選択される3つのCDR配列を含む、
請求項2に記載の結合化合物。 - 前記抗体重鎖可変領域またはそのTSLPR結合断片が、配列番号1のCDR−H1配列またはその変異体、配列番号2のCDR−H2配列またはその変異体、および配列番号3または配列番号73のCDR−H3配列またはその変異体を含み;そして
前記抗体軽鎖可変領域またはそのTSLPR結合断片が、配列番号4のCDR−L1配列またはその変異体、配列番号5のCDR−L2配列またはその変異体、および配列番号6または配列番号74のCDR−L3配列またはその変異体を含む、
請求項4に記載の結合化合物。 - 配列番号53の残基1〜116を含む重鎖可変領域またはその変異体;および
配列番号54の残基1〜108を含む軽鎖可変領域またはその変異体を含む、請求項5に記載の結合化合物。 - 配列番号51の残基1〜116を含む重鎖可変領域またはその変異体;および
配列番号52の残基1〜108を含む軽鎖可変領域またはその変異体を含む、請求項5に記載の結合化合物。 - 前記変異体が、3個までの保存的に改変されたアミノ酸残基を含む、請求項6に記載の結合化合物。
- ヒトTSLPおよびcyno TSLPに特異的に結合する結合化合物であって:
配列番号51のアミノ酸配列と少なくとも90%の相同性を有する重鎖可変領域;および
配列番号52のアミノ酸配列と少なくとも90%の相同性を有する軽鎖可変領域
を含む、結合化合物。 - 請求項1に記載の結合化合物の重鎖可変領域または軽鎖可変領域のうちの少なくとも一つをコードする単離された核酸。
- 請求項10に記載の核酸配列を含む発現ベクターであって、宿主細胞が該ベクターでトランスフェクトされる場合、該宿主細胞により認識されるコントロール配列に作動可能に連結する、発現ベクター。
- 請求項11に記載の発現ベクターを含む、宿主細胞。
- ポリペプチドを産生する方法であって:
核酸配列が発現される条件下で培地において請求項12に記載の宿主細胞を培養し、それによって軽鎖可変領域および重鎖可変領域を含むポリペプチドを産生する工程;および
該ポリペプチドを該宿主細胞または培地から回収する工程
を含む、方法。 - ヒト重鎖定常領域または20個までの保存的に改変されたアミノ酸置換を含むその変異体;あるいは
ヒト軽鎖定常領域または20個までの保存的に改変されたアミノ酸置換を含むその変異体
をさらに含む、請求項1に記載の結合化合物。 - 前記ヒト重鎖定常領域が、γ4またはγ1のヒト重鎖定常領域またはその変異体を含み、ここで該変異体は、20個までの保存的に改変されたアミノ酸置換を含む、請求項14に記載の結合化合物。
- Fab、Fab’、Fab’−SH、Fv、scFv、F(ab’)2、およびダイアボディから成る群から選択される、TSLPR結合抗体断片である、請求項1に記載の結合化合物。
- ヒト対象において免疫応答を抑制する方法であって、該抑制を必要とする対象に、TSLPRの生物学的活性を阻害するのに有効な量で、請求項1に記載の結合化合物またはそのTSLPR結合断片を投与する工程を含む、方法。
- 前記免疫応答が、炎症性応答である、請求項17に記載の方法。
- 薬剤学的に許容可能な担体または希釈剤と組み合わせた、請求項1に記載の結合化合物を含む、組成物。
- 抗体13H5、70E8、54C11、49A5、4G8、54A11、61C11および18B3からなる群から選択される抗体により結合される、ヒトTSLP上のエピトープに特異的に結合する抗体またはその抗原結合断片。
- 抗体13H5、70E8、54C11、49A5、4G8、54A11、61C11および18B3から成る群から選択される抗体へのTSLPRの結合を競合的に阻害する抗体またはその抗原結合断片。
- 交差阻害アッセイにおいて、TSLPR媒介性活性を阻害するかまたはTSLPのTSLPRへの結合を阻害する、請求項1に記載の結合化合物。
- 免疫応答を抑制するための医薬の調製のための、請求項1に記載の結合化合物またはそのTSLPR結合断片の使用。
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US8475793B2 (en) | 2013-07-02 |
AR070346A1 (es) | 2010-03-31 |
US20110020369A1 (en) | 2011-01-27 |
CA2713935C (en) | 2016-11-01 |
CA2713935A1 (en) | 2009-08-13 |
EP2250199A1 (en) | 2010-11-17 |
WO2009100324A1 (en) | 2009-08-13 |
JP2013223516A (ja) | 2013-10-31 |
EP2250199B1 (en) | 2015-09-02 |
CN101986784A (zh) | 2011-03-16 |
MX2010008688A (es) | 2010-08-30 |
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