JP6845237B2 - 抗−ヒトil−3抗体、il−3の高められた発現又はレベルに関連する疾患又は機能障害へのそれらの使用、及びヒトil−3の検出方法へのそれらの使用 - Google Patents
抗−ヒトil−3抗体、il−3の高められた発現又はレベルに関連する疾患又は機能障害へのそれらの使用、及びヒトil−3の検出方法へのそれらの使用 Download PDFInfo
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Description
APMTQTTSLK TSWVNCSNMI DEIITHLKQP PLPLLDFNNL NGEDQDILME NNLRRPNLEA FNRAVKSLQN ASAIESILKN LLPCLPLATA APTRHPIHIK DGDWNEFRRK LTFYLKTLEN AQAQQTTLSL AIF(グリコシル化部位は太字である)。
が100ng/ml又はそれ以下であるように、グリコシル化hIL−3に対する阻害活性を有することが重要であることが見出された。好ましくは、IC50は、40ng/ml又はそれ以下、好ましくは10ng/ml又はそれ以下である。IC50を決定するための方法は、当業者に知られており、そして既知の何れかの方法が本試験に使用され得る。
ミョウバン中、ヒト真核生物グリコシル化IL−3の少なくとも6回のi.p.注射を用いて、4週間隔でBalb/cマウスを免疫化することにより、抗−IL−3抗体を生成した。細胞融合の2日前、PBS中、IL−3を腹腔内注射した。免疫化されたマウスから得られた抗体−産生脾細胞(HAT培地上で増殖できるHGPRT陽性)を、ポリエチレングリコール(PEG)の存在下で、骨髄腫細胞系xx63Ag8.6.5.3と融合され、そしてハイブリドーマの選択を、HAT選択培地において実施した。ハイブリドーマを、10%FCS(純粋に不活性された、NIA)、P/S及びグルタミン(1:100)により補充されたRPMI−1640培地において培養した。得られたば細胞は、懸濁状態で増殖することができ、そして1:4の比で3日ごとに分けた。
タイプIgG1の得られた抗体のいくつかを、ハイブリドーマクローンから単離し、そしてそれらの濃度を決定した。濃度の決定を、以下の方法に従って実施した:96ウェルプレートを、室温で一晩、100μl/ウェルの濃度での抗−マウスIgG(pBS中、1:100)により被覆する。遮断を、PBS中、2%BSA100μl/ウェルを添加し、そして室温で2時間、インキュベートすることにより実施する。遮断反応の後、プレートを2度、洗浄する。クローン3.47.20、6.38.14、.36.38、 10.12.4、 11.14.6の上清液の2つのサンプル及びブランクをそれぞれ、希釈せずに、並びに1:3、 1:9、1:27、1:81、1:243、1:729 及び 1:2187(ウェル当たり100μl、PBS中、2%BSAでの希釈)の希釈度で、室温でインキュベートする。1mg/mlの開始濃度でのマウスIgG1を標準として用いるが、20ng/mlの濃度を、1:2、 1:4、 1:8、1:16、1:32、1:64 及び1:128の希釈度で適用する。
ゲルの調製及びウェスターンブロット分析の実施のために、標準方法を用いる。12%PAA分解ゲルを注ぎ、約1−2mlの水により被覆し、そして認識可能な「ライン」が形成されるまで、重合を30〜45分間、行う。水を除去し、スタッキングゲルを分解ゲル上に注ぎ、そしてテフロン櫛を挿入する。重合を30分間、実施し、次に櫛を注意して除く。
a)IL−3に対する抗体の親和性
得られた抗体のIL−3に対する親和性を、ELISAアッセイで測定した。ELIsAプレートを、異なった濃度(2μg/ml、0.66μg/ml、0.22μg/ml、0μg/ml)の抗−ヒトIL−3抗体(RD、ヤギIgG 抗−ヒト IL−3 AF−203−NA)、により一晩、被覆した。各濃度について、二重反復を用いた(2×12ウェル)。このためには、第1の濃度(2μg/ml)をPBSにより希釈し、IgGの全濃度を一定に保つために、さらなる希釈を、2μg/mlの対照ヤギIgGを含むPBSで行う。2%BSAによる遮断を、室温で2時間、実施し、続いてPBSを用いての5回の洗浄工程を行う。
診断アッセイのための得られたモノクローナル抗体の有用性を決定するためには、患者の血液、血漿、血清又は他の体液にも存在する密接に関連するサイトカインとの交差反応を排除できないことは重要である。この目的のために、ELISAプレートのウェルを、PBS中、100μg/ウェルのヒトIL−3(1μg/ml)又はIL−5(1μg/ml)を添加することにより被覆した。負の対照として、PBSを使用した(100μl/ウェル)。試験された各抗体に関して、異なる希釈液を、hIL−3、hGM−CSF、hIL−5及びPBSを有する共通プレート上で強制的に試験した。
モノクローナル抗体のさらなる性質として、他の種からのIL−3とのそれらの交差反応性を決定した。それぞれのアッセイに関しては、ELISAプレートのウェルを、PBS中、ヒト、ネズミ、ラット及びアガゲザルIL−3(1μg/ml)、及びバックグラウンドとしての100μl/ウェルのPBSにより被覆し、そして冷蔵庫で一晩インキュベートした。各抗体に関しては、異なる希釈溶液を、hIL−3、ネズミIL−3、ラットIL−3、アカゲザルIL−3及び負の対照としてのPBSを有する共通プレート上で強制的に試験した。
実施例1に従って得られた抗体のIL−3活性を遮断する能力を分析するために、いくつかの異なる実験を実施した。
TF1細胞はヒト赤芽球であり、そして重度の汎血球減少症に罹患している35歳の日本人男性の骨髄からの細胞系が1987年、T.K.Kitamuraにより確立されている。TF1細胞の増殖は、IL−3又はGM−CSFの存在に完全に依存している。従って、TF1細胞の細胞増殖に基く試験を用いて、TF1細胞の増殖の低下又はさらに、完全な阻害を導くIL−3活性の遮断を決定することができる。そのような試験に関しては、MTT−細胞−増殖アッセイを行い、ミトコンドリアデヒドロゲナーゼの活性に基いて細胞の生存性を決定する。溶液中で黄色を示すデヒドロゲナーゼの基質MTT(3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロミド)は、酵素活性によりテトラゾリウム環で切断され、紫色のMTTホルマザン結晶の形成が導かれる。そのような結晶は、イソプロパノールに溶解され、紫色の溶液が分光計で測定され、そしてその結果は、生存TF1細胞の量と相関する。
TF1細胞を、培養培地(10%FCS(HIA)、P/S及びグルタミン(1:100)を含み、そして5ng/mlのIL−3又は5ng/mlのGM−CSFのいずれかにより補充されたRPMI−1640)において増殖し、そして3日ごとに1:4に分割した。
上記プロトコルに従って3日ごとに分割されたTF−1細胞を、実験が行われる前日、5ng/mlのヒトIL−3を含む培養培地中に1:2に分割する。
上記のように、TF1細胞の増殖は、IL−3又はGM−CSFの存在に依存する。実施例5aに示されるように、抗−IL−3抗体は、TFF1細胞の増殖に対して負の効果を有する。IL−3は、70kDaのα鎖及び約130kDaのβ鎖から構成されるIL−3受容体に結合する。同じβ鎖がまた、IL−5及びGM−CSFの受容体上に存在する。従って、別の実験において、抗−IL−3抗体がまた、GM−CSFの存在下でTF1細胞の増殖にも影響を及ぼすかどうかを試験した。このためには、上記実験を、抗−IL−3抗体と共にプレインキュベートされた、GM−CSF、IL−3及びそれらの混合物の、TF1細胞の培養培地への添加を反復した。GM−CSF及びIL−3を含まない対照も含まれていた。
ヒト好塩基球顆粒球は、CD203c及びCD11bのIL−3誘発されたアップレギュレーションを示す。この実験においては、抗−IL−3抗体もまた、この点でIL−3の効果を阻害できるかどうかを決定した。
ELISAプレートを、PBS中、10μg/mlの濃度で、ヒトIL−3由来の種々のペプチドにより一晩、被覆した。PBS単独による被覆を、負の対照として使用した。洗浄し、PBS/1%BSA(ウシ血清アルブミン)により遮断した後、クローンP8C11C8−6(40μg/ml)を、室温で1時間、適用した。洗浄の後、結合されたP8C11C8−6抗体を、二次HRP−標識されたウサギ抗−マウスポリクローナル抗体及び色基質反応により検出した(図30を参照のこと)。
IL3−1A (aa 1−24 、2つの突然変異に下線を引く): APMTQTTPLKTSWAKCSNMIDEII (配列番号3)
IL3−1B (aa 1−24 、2つの突然変異に下線を引く): APMTQTTSLKTSWVNCSNMIDEII (配列番号4)
IL3−2 (aa 22−48): EIITHLKQPPLPLLDFNNLNGEDQDIL (配列番号1)
IL3−3 (aa 43−69): EDQDILMENNLRRPNLEAFNRAVKSLQ (配列番号5)
IL3−4 (aa 64−90): AVKSLQNASAIESILKNLLPCLPLATA (配列番号6)
IL3−5 (aa 85−111): LPLATAAPTRHPIHIKDGDWNEFRRKL (配列番号7)
IL3−6 (aa 106−133): EFRRKLTFYLKTLENAQAQQTTLSLAIF (配列番号8)
IL3−2 (aa 22−48): EIITHLKQPPLPLLDFNNLNGEDQDIL (配列番号1)
IL3−2a (aa 30−48):PPLPLLDFNNLNGEDQDIL (配列番号9)
IL3−26 (aa 26−48): HLKQPPLPLLDFNNLNGEDQDIL 配列番号11)
IL3−28 (aa28−48): KQPPLPLLDFNNLNGEDQDIL (配列番号12)。
ELISAウェルを、PBS中、ヒトIL−3(0.5μg/ml)により一晩、被覆した。洗浄、及びPBS/1%BSA(ウシ血清アルブミン)による遮断の後、標識されていない抗体クローン13又はクローンP8C11C8−6を、室温で1時間、種々の濃度で適用した。洗浄、又は標識されていない抗体の除去なしで、HRP−標識された抗体クローン13(0.4μg/ml)を、室温で1時間、添加した。洗浄の後、色基質反応を、ABTSにより行い、そして光学密度(OD)を測定した。図36−38に示される結果からわかるように、クローンP8C11C8−6及びクローン13は、お互いと競争しない。クローンP3C11C8−6はまた、クローン13又はクローン11のIL−3への結合を妨げない(図37を参照のこと)。
図39に示されるように、ヒト好塩基球に対するE.コリ又は昆虫細胞由来のIL−3の活性は同等である。昆虫細胞(Biolegend)又はE.コリ(Peprotech)、又は負の対照としてのPBSにおいて生成された種々の濃度のIL−3を、新鮮なヒトEDTA血液に、37℃で1時間、添加した。次に、細胞を、CD11b、C203c、CD123及びHLA−DRに対する、直接的に標識された抗体により、氷上で20分間、染色し、そしてフローサイトメトリーにより分析し、好塩基球を同定し、そして好塩基球に対するCD203cのアップレギュレーションを定量化した。
図41に示されるように、クローン11及びR&D mab203は単に、E.コリ由来の活性を遮断するが、しかし好塩基球によるアッセイにおける昆虫細胞由来のIL−3の活性は遮断しない。
図47A−Cに示されるように、種々の供給源からのIL−3がサンドイッチELISAにより検出され、そしてクローン13+P8C11C8−6の対のみがHEK293細胞において発現されたIL−3を検出する。
Claims (11)
- 治療に用いる、抗ヒトIL−3(抗hIL−3)抗体、又はその抗原結合部位を有するフラグメントであって、当該抗hIL−3抗体が、グリコシル化hIL−3に対する阻害活性を有し、当該抗hIL−3抗体のIC50が100ng/ml以下であり、当該抗hIL−3抗体のIL−5及びGM−CSFと非ヒトIL−3との交差反応性が5%未満であり、当該抗hIL−3抗体が、ハイブリドーマ細胞株DSM ACC3281によって生産された抗体の相補性決定領域(CDR)を6個全て含む、当該抗体、又はその抗原結合部位を有するフラグメント。
- 前記抗体が、ハイブリドーマ細胞株DSM ACC3281によって生産された抗体である、請求項1に記載の抗hIL−3抗体。
- 前記抗体とhIL−3との結合と比較して、IL−5又はGM−CSFとの結合の程度が5%未満、2%未満、又は1%未満である;及び/又はマウス又はラットIL−3と交差反応しない;及び/又はキメラ又はヒト化抗体である、請求項1に記載の抗hIL−3抗体。
- 40ng/ml以下、又は10ng/ml以下のIC50でhIL−3に対して阻害活性を有する、請求項1〜3のいずれか1項に記載の抗hIL−3抗体。
- 前記抗体が、患者のhIL−3の発現又はレベルの増大に関連する疾患又は機能不全の治療又は予防に使用され、ここで当該疾患又は機能不全が、炎症性又は自己免疫性疾患、リウマチ性関節炎、慢性移植片対宿主疾患、多発性硬化症、全身性エリテマトーデス、抗好中球細胞質抗体関連脈管炎、又は乾癬性関節炎である、請求項1〜4のいずれか1項に記載の抗hIL−3抗体。
- ハイブリドーマ細胞株DSM ACC3281によって生産された抗hIL−3抗体、又はハイブリドーマ細胞株DSM ACC3281によって生産された抗体のCDRを6個全て含む抗hIL−3抗体。
- 請求項1〜6のいずれか1項に記載の抗hIL−3抗体、又はその抗原結合部位を有するフラグメントをコードすることを特徴とする核酸。
- 医薬として有効な量の、請求項1〜6のいずれか1項に記載の抗hIL−3抗体、又はその抗原結合部位を有するフラグメント、及び医薬として許容される助剤及び/又は担体を含有する、医薬組成物。
- 患者のhIL−3の発現又はレベルの増大に関連する疾患又は機能不全の治療又は予防に使用され、当該疾患または機能不全が、炎症性又は自己免疫性疾患、リウマチ性関節炎、慢性移植片対宿主疾患、多発性硬化症、全身性エリテマトーデス、抗好中球細胞質抗体関連脈管炎、又は乾癬性関節炎である、請求項8に記載の医薬組成物。
- ヒト細胞中又は患者試料中のhIL−3を検出するための、請求項1〜6のいずれか1項に記載の抗hIL−3抗体又はその抗原結合部位を有するフラグメントのインビトロでの使用。
- 前記検出がELISA法によって行われる、請求項10に記載の使用。
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