JP2012502113A - 病原性単球の標的化 - Google Patents
病原性単球の標的化 Download PDFInfo
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Abstract
【選択図】なし
Description
本出願は、2008年9月12日に出願された米国特許仮出願第61/096,563号の優先権を請求するものである。
該当しない。
本発明は、一般的に、免疫学、白血球生物学、炎症、癌、血管障害、及び医学の分野に関する。より詳しくは、本発明は、著しい病的状態又は全身性免疫抑制を引き起こさずに、治療選択を決定する方法、治療効能を評価する方法、及び疾患関連白血球を標的とする方法に関する。
従来の免疫学的技術及び分子生物学的技術が関与する方法が、本明細書に記述されている。免疫学的方法(例えば、抗原−Ab複合体を検出及び所在確認するためのアッセイ、免疫沈降、及び免疫ブロット等)は、当技術分野で一般的に知られており、Current Protocols in Immunology,Coligan et al.,ed.,John Wiley&Sons,New York等の方法論文書に記述されている。分子生物学的技術は、Molecular Cloning:A Laboratory Manual,2nd ed.,vol.1−3,Sambrook et al.,ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,2001;及びCurrent Protocols in Molecular Biology,Ausubel et al.,ed.,Greene Publishing and Wiley−Interscience,New York等の文書で詳細に記述されている。Ab法は、Handbook of Therapeutic Antibodies,Dubel,S.,ed.,Wiley−VCH,2007に記述されている。血球分析法は、Flow Cytometry,David Keren,American Society for Clinical Pathology;4th edition,2007及びLichtman et al.,Williams Hematology,McGraw−Hill Professional;7th edition,2005に記述されている。
本発明の種々の方法は、IL−1アルファの機能又は発現を調節する作用剤を、ヒト対象体に投与するステップを特色とする。IL−1アルファの機能又は発現を調節する任意の好適な作用剤を使用することができる。例えば、作用剤は、IL−1アルファ受容体に対するIL−1アルファの結合を妨害する作用剤、又はIL−1アルファをコードする核酸の転写又は翻訳のレベルを調節する作用剤であってもよい。多数のそのような作用剤は、公知であるか、又は当業者であれば、本明細書の教示若しくは当技術分野の知識を使用して製作することができる。これらには、IL−1アルファ又はIL−1アルファ受容体と特異的に結合する抗体(そのためIL−1アルファに対する結合が遮断される)、対象体においてそのような抗体の濃度を増加させるワクチン、IL−1アルファ受容体等のIL−1アルファ結合タンパク質及びそれらの変異体(例えば、断片又はアミノ酸置換突然変異体)、IL−1アルファに結合する核酸(例えば、アプタマー)、IL−1アルファと特異的に結合する有機低分子、IL−1アルファ発現を低減又は調節する核酸、及び前述したものの2つ以上(例えば、2、3、4、又は5つ以上)の組合せが含まれる。
本発明の方法に有用な抗体には、対象体に投与した際に、対象体のCD14+CD16+単球の量又は機能を調節する(例えば、低減する)抗体が含まれる。CD14+CD16+単球はIL−1アルファも発現するため、IL−1アルファ又はIL−1アルファ受容体と特異的に結合するAbを、そのような単球の機能又は量を調節するために使用することができる。抗IL−1アルファ又は抗IL−1アルファ受容体Abは、ポリクローナルであってもよく又はモノクローナルであってもよい。望ましくない反応を防止するために、本発明の方法で使用されるAbは、好ましくはヒト化されているか、又はより好ましくはヒトである。
また、本方法では、IL−1アルファの機能又は発現を調節(例えば、阻害)する作用剤は、対象体のIL−1アルファと特異的に結合する抗体の濃度を増加させるワクチンであってもよい。好適なワクチンは、薬学的に許容される担体中に免疫原性形態のIL−1アルファを含むことができる。アルミニウム塩等のアジュバントが、同様に含まれていてもよい。免疫原性形態のIL−1アルファは、完全なタンパク質又はそのようなタンパク質のペプチド断片を含んでいてもよい。免疫応答を増強するために、免疫原性形態のIL−1アルファは、キーホールリンペットヘモシニアン又はシュードモナス菌体外毒素等の担体タンパク質と結合されていてもよい。ワクチン投与の結果として産生されるAbは、上述のように収集及び使用することができる。
直接標的化によりIL−1アルファの発現及び/又は機能を調節するタンパク質の例には、IL−1RI、IL−1RII、及びそのIL−1アルファ結合変異体(例えば、組換え形態、断片、模倣体、突然変異体、及びそれらの結合体)等のIL−I受容体(IL−1R)が含まれる。可溶性形態のIL−1Rは、投与が容易であるため好ましい。IL−1アルファの発現及び/又は機能を間接的に調節することができるタンパク質の例には、IL−1R等のリガンド結合を単球関連IL−1アルファと競合することができるタンパク質(例えば、活性化シグナルを伝達しないタンパク質)が含まれる。これらには、修飾された非活性化IL−1アルファ(前駆IL−1アルファ、膜結合型IL−1アルファ、及び組換えIL−1アルファを含む)、修飾された非活性化IL−1ベータ(前駆IL−1ベータ及び成熟IL−1ベータを含む)、IL−I受容体拮抗剤(IL−1Ra;可溶性IL−1Ra、icIL−1RaI、及びicIL−1RaIIを含む)、及びそれらの変異体が含まれていてもよい。
また、IL−1アルファの発現/活性を調節する作用剤は、核酸であってもよい。例えば、核酸は、IL−1アルファタンパク質をコードするセンス核酸であってもよい(例えば、細胞に導入することにより、細胞のIL−1アルファ活性を増加させることができる)。また、核酸は、IL−1アルファをコードするmRNAにハイブリダイズして、翻訳を阻害し、タンパク質の発現を減少させるアンチセンス核酸であってもよい。本発明で使用するためのアンチセンス核酸分子は、例えば転写及び/又は翻訳を阻害することによりIL−1アルファタンパク質の発現を阻害するように、IL−1アルファタンパク質をコードする細胞性mRNA及び/又はゲノムDNAと、細胞性条件下で特異的にハイブリダイズする(例えば、結合する)アンチセンス核酸分子である。結合は、従来の塩基対相補性によるものであってもよく、又は例えばDNA二本鎖に結合する場合は、二重らせんの主溝における特異的相互作用によるものであってもよい。
一連の選択(例えば、SELEXによる;指数関数的な濃縮によるリガンドの系統的進化)を繰り返すことによりIL−1アルファに結合するように遺伝子操作されたアプタマー又は核酸種を、IL−1アルファの機能を調節するために、本発明で使用することもできる。特定のマーカーに対するアプタマーを製作及び使用する方法は、例えば、米国特許第5,670,637号;第6,331,398号;及び第5,270,163号;第5,567,588号に記述されている。
低分子(一般的には有機)も、IL−1アルファの発現又は機能を調節することができる。コルチコステロイド、シクロオキシゲナーゼ阻害剤、リノミド(ロキニメックス)、サリドマイド、ペントキシフィリン、及びゲニステイン等の、抗炎症作用を有する公知の低分子を使用することができる。低分子のライブラリーをスクリーニングして、単球中でIL−1アルファの発現を調節する(上方制御又は下方制御する)分子を特定することにより、他の分子を特定することができる。
本発明の1つの方法は、IL−1アルファの発現及び/又は機能を調節する作用剤の投与が、対象体のCD14+CD16+単球の量を調節するかどうかを決定するステップが、投与前後の対象体のCD14+CD16+単球の量(例えば、数、全血球百分率数での白血球のパーセント、濃度、CD14++単球等の他の血球に対する比率)を決定することを含むことができることを特色とする。投与前後の対象体のCD14+CD16+単球の量を決定することは、任意の好適な方法により実施することができる。例えば、末梢血単核細胞(PBMC)をヒト対象体から単離し、その後CD14及びCD16に特異的な抗体を使用して、フローサイトメトリーにかけることができる。末梢血細胞を遠心分離して細胞を濃縮し、免疫組織化学的技術を使用してCD14+CD16+集団を特定及び定量化することもできる。
本発明の1つの方法は、IL−1アルファを標的とする作用剤の投与が対象体のCD14+CD16+単球の機能を調節するかどうかを決定するステップが、投与前後の対象体のCD14+CD16+単球の機能を評価することを含むことができることを特色とする。投与前後の対象体のCD14+CD16+単球の機能を決定することは、任意の好適な方法により実施することができる。例えば、CD14+CD16+単球は、ヒト対象体から収集された末梢血単核細胞から単離することができる。その後、単離された単球を、人工膜基材に接着したヒト臍帯静脈内皮細胞を使用するin vitro結合及び経内皮遊走アッセイにかけることができる。例えば、Etingin et al.(1991)Proc.Nat’l.Acad.Sci.USA,88:7200−7203を参照されたい。
本発明の方法は、任意の好適なヒト対象体に対して実施することができる。しかしながら、好ましくは、対象体は、CD14+CD16+単球のレベル異常又は機能異常に関連する状態を罹患している対象体だろう。そのような対象体の例には、炎症状態、自己免疫状態、癌(例えば、乳癌、結腸直腸癌、前立腺癌、卵巣癌、白血病、肺癌、子宮内膜癌、又は肝臓癌)、アテローム性動脈硬化、関節炎(例えば、骨関節炎又は関節リウマチ)、炎症性腸疾患(例えば、潰瘍性大腸炎又はクローン病)、末梢血管疾患、脳血管発作(脳卒中)、慢性炎症が存在する病態、単球/マクロファージ浸潤を示す病変を特徴とする病態、アミロイド斑が脳に存在する病態(例えば、アルツハイマー病)、骨粗しょう症、筋萎縮性側索硬化症、又は多発性硬化症等の、CD14+CD16+単球の機能異常又はレベル異常に関連する病態を示す対象体が含まれる。
方法:健常ドナーから全血を無菌条件下で収集した。2.5mlの全血を、溶解緩衝液(150mM酢酸アンモニウム 0.1mM EDTA)で10倍に希釈した。細胞を、氷上で10分間緩衝液中で維持し、その後1000Gで5分間遠心沈降した。細胞を、氷冷FACS緩衝液(1%粉乳で補完されたPBS、0.2μmフィルターでろ過されている)に再懸濁した。細胞を、FACS緩衝液で2回洗浄した。ペレット化した細胞を、2.8mlのFACS緩衝液に再懸濁し、血球計を使用して計数し、以下のスキームに従って蛍光性標識抗体を薄明りの下で添加した:
1)PerCP−Cy5.5結合抗CD14(eBioscience(商標)親和性精製、マウス抗ヒトIgG、カッパ、45−109番)
2)PE結合抗CD16(eBioscience(商標)親和性精製、マウス抗ヒトIgG1、12−0168番)
3)FITC結合抗IL−1a(eBioscience(商標)親和性精製、マウスIgG1、抗ヒトIL−1a、11−718番)
4)FITC結合抗KLH(eBioscience(商標)親和性精製、マウスIgG1、カッパ、11−4714番)
5)抗CD14、抗CD16
6)抗CD14、抗CD16、抗IL−1a
7)抗CD14、抗CD16、抗IL−1a、抗KLH
MABp1は、内皮細胞の表面における細胞接着分子の発現誘導を阻害することができる。2つの重要な接着分子CD54(ICAM−1)及びCD62E(E−セレクチン)のMABP1媒介性阻害を、ヒト臍帯静脈内皮細胞(HUVEC)をモデル系として使用して観察した。MABp1効果は、HUVECが、可溶性組換えヒトIL1アルファによってではなく、遺伝子操作されたDG44 CHO細胞(GPI−IL1A細胞)の表面にグリコシル−ホスファチジルイノシトール(GPI)により係留された膜性IL1アルファによって刺激される場合に、最も著しい。代表的な実験では、6ウエルプレート中のHUVEC細胞のコンフルエント培養を、M−200培地中で5×106個のGPI−IL1A DG44細胞と共に、単独で、10μg/mL MABP1の存在下で、又は10μg/mL D5ヒトIgG1アイソタイプ対照抗体の存在下で、終夜共培養した。17〜20時間後、HUVEC単層を、ダルベッコPBSでよく洗浄し、その後CellStripper試薬(Cellgro Mediatech社製)を用いた20分間の非酵素処理により取り上げた。標準的フローサイトメトリープロトコールを使用して、CD62E(E−セレクチン)発現について、細胞を直ちに分析した。染色緩衝液は、2%加熱不活性化ウシ胎仔血清で補完されたダルベッコPBSを含んでいた。PE結合マウス抗ヒトCD62Eモノクローナル抗体(eBioscience社製、クローンP2H3)又はPE結合マウスIgG1kアイソタイプ対照(eBioscience社製、クローンP3)を、製造業者の説明書に従って使用して、室温、暗所で20分間100マイクロリットルの染色容積中でHUVEC細胞を染色した。その後、染色緩衝液で2回の洗浄を実施し、次にFACSCaliburフローサイトメーター(BD Biosciences社製)で試料を取得した。n=3の実験で、膜性GPI−IL1Aにより誘導されたHUVEC細胞表面上にあるE−セレクチンの上方制御は、MABP1により、未刺激HUVEC細胞が示すような基線レベルに中和された。
本発明は、その詳細な説明と共に記述されているが、前述の説明は例示を目的としており、添付の特許請求の範囲により定義される本発明の範囲を限定しないことが理解されるべきである。他の態様、利点、及び改変は、添付の請求項の範囲内にある。
Claims (16)
- (a)IL−1アルファの機能又は発現を調節する作用剤を、ヒト対象体に投与するステップと、
(b)そのような作用剤の投与が、前記対象体のCD14+CD16+単球の量又は機能を調節するかどうかを決定するステップとを含む方法。 - 前記IL−1アルファの機能又は発現を調節する作用剤が、IL−1アルファ受容体に対するIL−1アルファの結合を妨害する作用剤である、請求項1に記載の方法。
- 前記作用剤が、IL−1アルファと特異的に結合する抗体である、請求項1に記載の方法。
- 前記抗体が、IL−1アルファと特異的に結合するモノクローナル抗体である、請求項3に記載の方法。
- 前記モノクローナル抗体がヒト抗体である、請求項4に記載の方法。
- 前記ヒト抗体がIgG1である、請求項5に記載の方法。
- 前記ヒト抗体が、配列番号3のアミノ酸配列を含む重鎖と、配列番号4のアミノ酸配列を含む軽鎖とを有する、請求項6に記載の方法。
- 前記ヒト対象体が、CD14+CD16+単球の機能異常又はレベル異常に関連する病態を示す、請求項1に記載の方法。
- 前記病態が炎症状態である、請求項8に記載の方法。
- 前記病態が自己免疫状態である、請求項8に記載の方法。
- 前記作用剤の投与前には、前記ヒト対象体の末梢血白血球の少なくとも1.5%がCD14+CD16+単球であり、前記作用剤の投与後には、前記ヒト対象体の末梢血白血球細胞の1.5%未満がCD14+CD16+単球である、請求項1に記載の方法。
- 前記作用剤の投与が、その結果として、全血球百分率数で少なくとも10%のCD14+CD16+単球パーセントの低減をもたらす、請求項1に記載の方法。
- そのような投与が前記対象体のCD14+CD16+単球の量又は機能を調節するかどうかを決定するステップが、前記作用剤の投与前後の前記対象体のCD14+CD16+単球の機能を評価することを含む、請求項1に記載の方法。
- 前記作用剤の投与が、その結果として、少なくとも10%のCD14+CD16+単球機能の低減をもたらす、請求項13に記載の方法。
- (a)疾患又は病理学的障害を有するヒト対象体が、前記疾患又は病理学的障害に寄与するCD14+/CD16+単球を有することを決定するステップと、
(b)IL−1アルファの機能又は発現を調節する作用剤を、前記ヒト対象体に投与するステップと、
(c)そのような作用剤の投与が、前記対象体のCD14+CD16+単球の量を調節するかどうかを決定するステップとを含む方法。 - 対象体のCD14+CD16+単球の量又は機能を調節する薬剤を調製するための、IL−1アルファと特異的に結合する抗体の使用。
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CA2737056C (en) | 2018-10-30 |
US8546331B2 (en) | 2013-10-01 |
US20100068212A1 (en) | 2010-03-18 |
US8242074B2 (en) | 2012-08-14 |
US20120276110A1 (en) | 2012-11-01 |
CN102209557A (zh) | 2011-10-05 |
CA2737056A1 (en) | 2010-03-18 |
AU2009291536B2 (en) | 2012-08-16 |
JP5976319B2 (ja) | 2016-08-23 |
EP2326347A2 (en) | 2011-06-01 |
WO2010030979A3 (en) | 2011-04-14 |
WO2010030979A2 (en) | 2010-03-18 |
AU2009291536A1 (en) | 2010-03-18 |
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