JP5836130B2 - ヒトil−13に結合特異性を有する抗体分子 - Google Patents
ヒトil−13に結合特異性を有する抗体分子 Download PDFInfo
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- JP5836130B2 JP5836130B2 JP2011553509A JP2011553509A JP5836130B2 JP 5836130 B2 JP5836130 B2 JP 5836130B2 JP 2011553509 A JP2011553509 A JP 2011553509A JP 2011553509 A JP2011553509 A JP 2011553509A JP 5836130 B2 JP5836130 B2 JP 5836130B2
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000003151 transfection method Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- WFKWXMTUELFFGS-RNFDNDRNSA-N tungsten-188 Chemical compound [188W] WFKWXMTUELFFGS-RNFDNDRNSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/244—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/544—Mucosal route to the airways
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/515—Complete light chain, i.e. VL + CL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Description
・ヒトB細胞におけるIgEへの免疫グロブリンアイソタイプスイッチング(Punnonen,Aversaら 1993 Proc Natl Acad Sci USA 90 3730−4)、及び
・ヒトとマウスの両方における炎症性サイトカイン産生の抑制(de Waal Malefyt,Figdorら 1993 J Immunol 151 6370−81;Doherty,Kasteleinら 1993 J Immunol 151 7151−60)。
フェニルアラニン、チロシン及びトリプトファン(芳香族側鎖を有するアミノ酸);
リシン、アルギニン及びヒスチジン(塩基性側鎖を有するアミノ酸);
アスパラギン酸及びグルタミン酸(酸性側鎖を有するアミノ酸);
アスパラギン及びグルタミン(アミド側鎖を有するアミノ酸);並びに
システイン及びメチオニン(硫黄含有側鎖を有するアミノ酸)
が含まれる。同一性及び類似性の程度は容易に計算することができる(Computational Molecular Biology,Lesk,A.M.編,Oxford University Press,New York,1988;Biocomputing.Informatics and Genome Projects,Smith,D.W.編,Academic Press,New York,1993;Computer Analysis of Sequence Data,Part 1,Griffin,A.M.,及びGriffin,H.G.編,Humana Press,New Jersey,1994;Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987,Sequence Analysis Primer,Gribskov,M.及びDevereux,J.編,M Stockton Press,New York,1991,NCBIから入手可能なBLAST(商標)software(Altschul,S.F.ら,1990,J.Mol.Biol.215:403−410;Gish,W.& States,D.J.1993,Nature Genet.3:266−272.Madden,T.L.ら,1996,Meth.Enzymol.266:131−141;Altschul,S.F.ら,1997,Nucleic Acids Res.25:3389−3402;Zhang,J.& Madden,T.L.1997,Genome Res.7:649−656)。
不純物がカラムに保持され、抗体が非結合画分に維持されるように、非結合モードで陰イオン交換クロマトグラフィーを行うステップ
を含む上記方法が提供される。このステップは、例えば、pHが約6〜8で行われてもよい。
ラット抗体の軽鎖可変領域についてのアミノ酸配列(配列番号7)、
ラット抗体軽鎖の可変領域についてのDNA配列(配列番号8)、及び
シグナル配列を有するラット抗体の軽鎖可変領域についてのアミノ酸配列(配列番号9)
を示す。
ラット抗体の軽鎖可変領域及び定常領域についてのアミノ酸配列(配列番号11)、
ラット抗体の軽鎖可変領域及び定常領域についてのDNA配列(配列番号12)、及び
シグナル配列を有するラット抗体の軽鎖についてのアミノ酸配列(配列番号13)
を示す。
ラット抗体の重鎖可変領域についてのアミノ酸配列(配列番号15)、
ラット抗体の重鎖可変領域についてのDNA配列(配列番号16)、及び
シグナル配列を有するラット抗体の重鎖可変領域についてのアミノ酸配列(配列番号17)
を示す。
ラット抗体の重鎖可変領域及び定常領域についてのアミノ酸配列(配列番号19)
を示す。
シグナル配列を有するラット抗体の重鎖可変領域及び定常領域についてのアミノ酸配列(配列番号21)
を示す。
ヒト化抗体の軽鎖可変領域についてのDNA配列(配列番号24)、
シグナル配列を有するヒト化抗体の軽鎖可変領域についてのアミノ酸配列(配列番号25)、
シグナル配列を有するヒト化抗体の軽鎖可変領域についてのDNA配列(配列番号26)、及び
ヒト化抗体の軽鎖可変領域及び定常領域についてのアミノ酸配列(配列番号27)
を示す。
シグナル配列を有するヒト化抗体の軽鎖可変領域及び定常領域についてのアミノ酸配列(配列番号29)、及び
シグナル配列を有するヒト化抗体の軽鎖可変領域及び定常領域についてのDNA配列(配列番号30)、
を示す。
ヒト化抗体の重鎖可変領域についてのDNA配列(配列番号32)、
シグナル配列を有するヒト化抗体の重鎖可変領域についてのアミノ酸配列(配列番号33)、
シグナル配列を有するヒト化抗体の重鎖可変領域についてのDNA配列(配列番号34)、及び
ヒト化抗体の重鎖可変領域及び定常領域についてのアミノ酸配列(配列番号35)
を示す。
シグナル配列を有するヒト化抗体の重鎖可変領域及び定常領域についてのアミノ酸配列(配列番号37)、及び
ヒト化抗体の重鎖可変領域及び定常領域についてのDNA配列(配列番号38)
を示す。
精製されたヒトIL−13(Peprotech)若しくはヒトIL−13を発現しているラット線維芽細胞(培養上清中に約1μg/mlで発現している)のいずれか、又はある場合にはこれらの2つの組み合わせでラットを免疫した。3〜6回の注射後、動物を屠殺し、PBMC、脾臓、骨髄及びリンパ節を回収した。血清は、ELISAにおいてヒトIL−13への結合について、さらに、HEK−293 STAT−6レポーター細胞アッセイ(HEK−Blueアッセイ、Invivogen社)においてhIL−13を中和する能力について監視された。
本明細書に例証されたヒト化抗体は(Ab652)、ヒト生殖系列抗体のV領域フレームワークに、ラット抗体のV領域(配列番号7及び15)由来のCDR(配列1から6において本明細書に開示されたCDR)をグラフトすることによって調製された。ラット抗体(ドナー)のV領域配列とヒト生殖系列抗体(アクセプター)のV領域配列とのアラインメントは、設計されたヒト化配列とともに、図12に示される。アクセプター配列にドナーからグラフトされたCDRは、Kabat(Kabatら,Sequence of proteins of immunological interest(1987).Bethesda MD,National Institutes of Health,US)によって定義されている通りであるが、組み合わせたChothia/Kabat定義が使用される場合にはCDR−H1は除かれる(Adairら(1991)Humanised antibodies WO91/09967参照)。ヒトV領域のVH2 3−12−26プラスJH4 J領域(V BASE、http://vbase.mrc-cpe.cam.ac.uk/)は、重鎖CDRのためのアクセプターとして選ばれた。重鎖フレームワーク残基は全て、ヒト生殖系列遺伝子由来であるが、ドナー残基グリシン(G49)及びアルギニン(R71)が保持される場合には、それぞれ残基49及び71(Kabat番号付け)を除く。これらの2つのドナー残基の保持は、ヒト化抗体の完全な活性に本質的である。ヒトV領域VK1 2−1−(1)02プラスJK4 J領域(V BASE、http://vbase.mrc-cpe.cam.ac.uk/)は、軽鎖CDRのためのアクセプターとして選ばれた。軽鎖フレームワーク残基は全て、ヒト生殖系列遺伝子由来である。
BIAcore技術により、リアルタイムで、しかも標識を必要とせずに生体分子間の結合が監視される。相互作用物の1つは、リガンドと呼ばれ、固相化された表面上に直接固相化されるか又は捕捉され、他方は、分析物と呼ばれ、捕捉された表面全体に溶液で流れる。センサーは、分析物がリガンドに結合し、表面上で複合体を形成するため、センサー表面上での質量変化を検出する。これは、結合プロセスに対応する。リガンドからの分析物の解離は、分析物が緩衝液によって置き換わる場合に監視される。親和性BIAcoreアッセイにおいては、リガンドはAb652であり、分析物はヒトIL−13である。
Biacore受容体交差ブロッキングアッセイは、抗IL−13Fabの捕捉、次に、捕捉されたリガンド全体に流れるIL−13(第一分析物として)を必要とし、センサー表面上で安定な複合体を形成する。次に、第二分析物(組換え可溶性IL−13受容体)は、この安定な複合体全体に流される。安定な複合体への第二分析物の結合量を監視する。安定な抗体:IL−13複合体への第二分析物の結合を許容しない抗IL−13抗体は、サイト1競合物質として分類される。安定な抗体:IL−13複合体への第二分析物の結合を許容するそれらの抗IL−13抗体は、サイト2競合物質として分類される。
装置
Biacore(登録商標)3000,Biacore AB,Uppsala,Sweden
センサーチップ
CM5(リサーチ等級)カタログ番号:BR−1001−14,Biacore AB,Uppsala,Sweden
チップを4℃で保存した。
アミンカップリングキット
カタログ番号:BR−1000−50,Biacore AB,Uppsala,Sweden
エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩(EDC)。蒸留水で75mg/mLにし、−70℃にて200μLアリコートで保存した。
N−ヒドロキシスクシンイミド(NHS)。蒸留水で11.5mg/mLにし、−70℃にて200μLアリコートで保存した。
1Mエタノールアミン塩酸塩−NaOH pH8.5。−70℃にて200μLアリコートで保存した。
緩衝液
泳動緩衝液:HBS−EP(0.01M HEPES pH7.4、0.15M NaCl、3mM EDTA、0.005%サーファクタントP20である)。カタログ番号:BR−1001−88,Biacore AB,Uppsala,Sweden.緩衝液を4℃で保存した。
固相化緩衝液:酢酸塩5.0(10mM酢酸ナトリウム pH5.0である)。カタログ番号:BR−1003−51,Biacore AB,Uppsala,Sweden。緩衝液を4℃で保存した。
リガンド捕捉
Affinipure F(ab’)2断片ヤギ抗ヒトIgG、F(ab’)2断片特異的。
Jackson ImmunoResearch Inc(Pennsylvania,USA)カタログ番号:109−006−097。試薬を4℃で保存した。
リガンド
Ab652(2.51、21.7及び3.86mg/ml Fab)を4℃で保存した。
抗hIL−13mIgG(R&D Systems Europe Ltd,Abingdon,Oxon.カタログ番号MAB−213、ロット番号RL04)。
分析物
組換えヒトIL−13(0.2mg/ml、D.Lightwoodより;R&D Systems Europe Ltd,Abingdon,Oxon.カタログ番号213−IL−050)を−70℃で保存し、各アッセイについて一度解凍した。
組換えヒトIL−13受容体1 hFc(R&D Systems Europe Ltd,Abingdon,Oxon.カタログ番号146−IL−100)。−70℃で保存し、各アッセイについて一度解凍した。
組換えヒトIL−13受容体2 hFc(R&D Systems Europe Ltd,Abingdon,Oxon.カタログ番号614−IL−100)。−70℃で保存し、各アッセイについて一度解凍した。
再生溶液
11.6M保存溶液(BDH,Poole,England.カタログ番号:101254H)から蒸留水を用いた希釈によって調製された40mM HCl。
50mM保存溶液から蒸留水を用いて希釈によって調製された5mM NaOH。
カタログ番号:BR−1003−58、Biacore AB,Uppsala,Sweden。
主要装置
Biacore 3000 Biosensor,GE Healthcare Ltd,Amersham Place,Little Chalfont,Buckinghamshire,HP7 9NA。この装置は、製造業者のプロコールにしたがって維持される。
アッセイフォーマットは、固相化された抗ヒトF(ab’)2によるAb652の捕捉、続く、捕捉された表面全体でヒトhIL−13の滴定であった。
BIA(Biamolecular Interaction Analysis)はBIAcore 3000(BIAcore AB)を用いて行われた。Affinipure F(ab’)2断片、ヤギ抗ヒトIgG、F(ab’)2断片特異的(Jackson ImmunoResearch)は、約4000反応単位(RU)の捕捉レベルまでアミンカップリング化学を介してCM5センサーチップ上に固相化された。ブランク表面は、この手法からF(ab’)2断片を除いて、同様の方法により調製された。HBS−EP緩衝液(10mM HEPES pH7.4、0.15M NaCl、3mM EDTA、0.005%サーファクタントP20、BIAcore AB)は、泳動緩衝液として使用され、流速は10μl/分であった。約0.2μg/mLでAb652 Fabの10μl注入は、固相化された抗ヒトIgG−F(ab’)2による捕捉のために用いられ、十分なIL−13結合を可能にしたが、物質移動に制限された結合効果を最小限にもした。ヒトIL13は、流速を30μL/分にして、種々の濃度(10nM〜0.31nM)の捕捉されたAb652全体で滴定された。表面は、流速を10μL/分にして、40μM HClの10μL注入、続く5mM NaOHの5μL注入によって再生された。
BIAcore受容体交差ブロッキングアッセイは、抗IL−13Fabの捕捉、続く、センサー表面に安定な複合体を形成するために捕捉リガンド全体に流されるIL−13(第一分析物として)を必要とする。次に、第二分析物(組換え可溶性IL−13受容体)をこの安定な複合体上に流す。その後、安定な複合体への第二分析物の結合量を監視する。第二分析物による安定な抗体:IL−13複合体への結合を可能にしない抗IL−13抗体は、Axis1競合物質として分類される。第二分析物による安定な抗体:IL−13複合体への結合を可能にするそれらの抗IL−13抗体は、Axis2競合物質として分類される。
IL−13を中和するAb652 Fabのインビトロ有効性は、HEK−BLUE(商標)STAT−6アッセイ(Invivogen社)を用いて調べられた。このアッセイは、4つのSTAT−6結合部位に融合されたIFN−β最小プロモータの調節下で、ヒトSTAT−6を安定に発現し、分泌性胚アルカリホスファターゼ(SEAP)を安定に発現するHED293細胞を含む。Ab652の中和有効性(IC50)は、250pg/mLでアッセイに使用されるヒトIL−13の異なるタイプを用いて評価された。中和有効性は、細菌(大腸菌)及び哺乳動物(ラット線維芽細胞)宿主細胞から生成された組換え野生型ヒトIL−13に対して評価された。中和有効性は、ヒトTリンパ球から生成された天然の野生型及びR130Qバリアント ヒトIL−13に対して、及び哺乳動物細胞において生成された組換えカニクイザルIL−13に対して評価された。R130Q hIL−13を精製せず、その濃縮物をhIL−13 ELISAによって決定した。カニクイザルIL−13を精製せず、250pg/mLのhIL−13と、アッセイにおいて同等の応答を与える濃度で使用した。さらに、CA154_652.g2 Fabの中和有効性は、PARI eFLOW(登録商標)メッシュ噴霧器を用いて、噴霧後に測定された。表4:HEK BlueアッセイにおけるIL−13の複数形態に対するAb652 FabのIC50値。機能性親和性の決定のため、IL−13滴定は、Ab652の固定濃度の存在下で行われた。シルドプロット分析は、組換えヒト野生型IL−13及び組換えカニクイザルIL−13の中和のためのKD値を決定するデータに適用された。表5:HEK BlueアッセイにおけるIL−13の複数形態に対するAb652 FabのIC50及びKD値。
上記した通り、可変領域をグラフトされた8つの異なる抗体は、選択されたラット抗体由来のCDR(配列番号1〜6、図1)を用いて生じさせた。それらの8つのグラフトからのAb652(gL1gH2)の選択は、上記に記載された有効性及び生物物理学的特徴に基づいていた。試験された、グラフトされた可変領域の全てについて生じさせたデータに基づいて、抗体652は以下の理由で選ばれた:
・hIL−13及びバリアントIL−13に対する最も高い親和性を維持していた
・最も高い融解温度、Tm(より高い安定性の指標)を有していた
・最も高いpH安定性(円偏光二色性による)、即ち、低pHで少ない乱れを示した
・振とう又は噴霧時に凝集なし
Ab652が噴霧に適しているかどうかを決定するために、PARI eFLOW(登録商標)噴霧器を用いた。50mM酢酸ナトリウム/125mM塩化ナトリウム、pH5中の体積2.5mLのAb652溶液は、周囲温度(約21℃)で噴霧され、冷却された回収チューブに噴霧物を濃縮することによって回収された。その後の分析は、明らかな分解を示さなかった。また、この研究は、PBS、pH7中の溶液を用いて繰り返された。IgG4の陽性対照を含め、噴霧中に凝集されることが見出された。噴霧された試料の分析は、存在する凝集した材料を検出するという特定の目的で、サイズ排除、SDS−PAGE、動的光散乱及びリガンド結合によってなされた。それらの技術のいずれによっても変化はみられず、これは、Ab652が噴霧中の損傷に耐性であることを示した。
pI(等電点) 8(2測定の平均)
熱安定性 Tm84℃
抗体を凝集/振とう又は噴霧に供した場合にAb652の凝集は観察されなかった。
目的
本研究の目的は、喘息の非ヒト霊長類モデルにおけるAb652の有効性を評価することであった。主要評価項目には、気管支肺胞洗浄(BAL)細胞カウント、ケモカインレベル、並びに肺耐性によって評価される初期及び後期肺機能変化(RL)に対する効果が含まれた。
Ab652は、メッシュ噴霧器を用いて送達された。呼吸シミュレーション研究は、典型的な換気パラメータ及び研究施設で使用される管設定を用いて行われた。呼吸シミュレーション研究の結果は、噴霧器における40.4%の材料変化が気管内チューブのレベルで送達されたことを示した。
噴霧されたAb652は、低mg/日投薬でBALエオタキシン−3の増加を有意に阻害した(図13)。噴霧されたAb652は、スクリーニングセッションと処置セッションとの間で測定されたBAL好酸球の増加を投薬量依存的な阻害を引き起こした(図14)。噴霧されたAb652は、処置セッションにおける回虫接種後の最大15分まで測定された2日目のピーク初期反応を有意に且つ投薬量依存的に阻害した(図15)。噴霧されたAb652は、2日目のアレルゲン接種後の24時間で測定された後期反応を有意に且つ投薬量依存的に阻害した(図16)。
カニクイザルにおける喘息の回虫モデルでの噴霧されたAb652により生じたデータは、IL−13誘導のアレルギー性肺炎症が、エアロゾルにおける気道に直接的に送達される中和抗IL−13Fab断片によって、薬理学的調節に感受性であることを示している。顕著には、Ab652は有力であり、低mg/日投薬量で有効性を示した。
Claims (16)
- 配列番号31に示される配列を含む重鎖、及び配列番号23に示される配列を含む軽鎖を有する、ヒトIL−13に結合するアンタゴニスト抗体。
- 配列番号35に示される配列を含む重鎖、及び配列番号27に示される配列を含む軽鎖を有する、ヒトIL−13に結合するアンタゴニスト抗体。
- 前記アンタゴニスト抗体が、
全長の重鎖及び軽鎖を有する完全な抗体分子;又は
Fab、修飾されたFab’、Fab’、F(ab’)2、Fv、又はscFv断片から選択される、その断片;
からなる群から選択される、請求項1又は2に記載のアンタゴニスト抗体分子。 - エフェクター分子又はレポーター分子が結合している、請求項1から3までのいずれか一項に記載のアンタゴニスト抗体。
- 30pM又はそれより良好である、単離されたヒトIL−13に対する結合親和性を有する請求項1から4までのいずれか一項に記載のアンタゴニスト抗体。
- 請求項1から5までのいずれか一項に記載の抗体の重鎖及び軽鎖をコードする単離されたDNA。
- 請求項6に記載の1又は複数のDNAを含むクローニングベクター又は発現ベクター。
- 前記ベクターが配列番号36及び配列番号28に示される配列を含む、請求項7に記載のベクター。
- 請求項8に記載の1又は複数のクローニングベクター又は発現ベクターを含む宿主細胞。
- 請求項9に記載の宿主細胞を培養すること、及び抗体を単離することを含む、請求項1から5までのいずれか一項に記載の抗体を産生するための方法。
- 請求項1から5までのいずれか一項に記載の抗体を、1又は複数の薬学的に許容される賦形剤、希釈剤又は担体と組み合わせて含む医薬組成物。
- 他の有効成分をさらに含む、請求項11に記載の医薬組成物。
- 治療用途のための、請求項11又は12に記載の医薬組成物。
- IL−13によって媒介されるか又はIL−13レベルの増加と関連している病的障害の治療又は予防において使用するための、請求項11又は12に記載の医薬組成物。
- 吸入により投与される、請求項14に記載の医薬組成物。
- 前記病的障害が、喘息疾患、アトピー性疾患、慢性閉塞性肺疾患(COPD)、気道炎症に関連した状態、好酸球増加症、線維症及び過剰粘液産生、炎症状態、自己免疫状態、腫瘍又は癌、ウイルス感染及び防御性1型免疫応答の発現抑制からなる群から選択される、請求項14又は15に記載の医薬組成物。
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JP2016025856A (ja) * | 2009-03-11 | 2016-02-12 | ユセベ ファルマ ソシエテ アノニム | ヒトil−13に結合特異性を有する抗体分子 |
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