JP6632075B2 - 抗体 - Google Patents
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- JP6632075B2 JP6632075B2 JP2016537262A JP2016537262A JP6632075B2 JP 6632075 B2 JP6632075 B2 JP 6632075B2 JP 2016537262 A JP2016537262 A JP 2016537262A JP 2016537262 A JP2016537262 A JP 2016537262A JP 6632075 B2 JP6632075 B2 JP 6632075B2
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- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
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- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
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- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
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- YFDSDPIBEUFTMI-UHFFFAOYSA-N tribromoethanol Chemical compound OCC(Br)(Br)Br YFDSDPIBEUFTMI-UHFFFAOYSA-N 0.000 description 1
- 229950004616 tribromoethanol Drugs 0.000 description 1
- 210000002993 trophoblast Anatomy 0.000 description 1
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- WFKWXMTUELFFGS-RNFDNDRNSA-N tungsten-188 Chemical compound [188W] WFKWXMTUELFFGS-RNFDNDRNSA-N 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 Substances 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
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- 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
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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- 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
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- 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
- C07K2317/56—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
Description
CDR−H1、CDR−H2、CDR−H3、CDR−L1、CDR−L2、CDR−L3のいずれか1つ;
組合せCDR−H1とH2、CDR−H1とH3、CDR−H1とL1、CDR−H1とL2、CDR−H1とL3、CDR−H2とH3、CDR−H2とL1、CDR−H2とL2、CDR−H2とL3、CDR−H3とL1、CDR−H3とL2、CDR−H3とL3、CDR−L1とL2、CDR−L1とL3、CDR−L2とL3;
CDR−H1、H2とH3、CDR−H1、H2とL1、CDR−H1、H2とL2、CDR−H1、H2とL3、CDR−H2、H3とL1、CDR−H2、H3とL2、CDR−H2、H3とL3、CDR−H3、L1とL2、CDR−H3、L1とL3、CDR−L1、L2、L3のいずれか1つ;
組合せCDR−H1、H2、H3とL1、CDR−H1、H2、H3とL2、CDR−H1、H2、H3とL3、CDR−H2、H3、L1とL2、CDR−H2、H3、L2とL3、CDR−H3、L1、L2とL3、CDR−L1、L2、L3とH1、CDR−L1、L2、L3とH2、CDR−L1、L2、L3とH3、CDR−L2、L3、H1とH2、
CDR−H1、H2、H3、L1とL2、CDR−H1、H2、H3、L1とL3、CDR−H1、H2、H3、L2とL3、CDR−L1、L2、L3、H1とH2、CDR−L1、L2、L3、H1とH3、CDR−L1、L2、L3、H2とH3のいずれか1つ;及び
組合せCDR−H1、H2、H3、L1、L2とL3
からなる群から選択される1つ又は複数のCDRで、少なくとも1つのアミノ酸が保存的置換によって置き換えられる。
− 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)。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.ed.,Oxford University Press,New York,1988;Biocomputing.Informatics and Genome Projects,Smith,D.W.ed.,Academic Press,New York,1993;Computer Analysis of Sequence Data,Part1,Griffin,A.M.and Griffin,H.G.eds.,Humana Press,New Jersey,1994;Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987,Sequence Analysis Primer,Gribskov,M. and Devereux,J.,eds.,M Stockton Press,New York,1991,NCBIから入手できるBLAST(商標)ソフトウェア(Altschul,S.F.et al.,1990,J.Mol.Biol.215:403−410;Gish,W.及びStates,D.J.1993,Nature Genet.3:266−272。Madden,T.L.et al.,1996,Meth.Enzymol.266:131−141;Altschul,S.F.et al.,1997,Nucleic Acids Res.25:3389−3402;Zhang,J.及びMadden,T.L.1997,Genome Res.7:649−656)。
すなわち、各PEGは、約20,000Daである。
1)CSF−1Rタンパク質(又はその結合断片)の精製−基質にコンジュゲートされて、親和性カラムとして、又は(抗CSF−1Rの改変形態として)抗Fc試薬によって任意選択で沈殿される、沈殿剤(例えば、改変されてもよい別の分子によって認識されるドメインで改変される形態として)として使用される
2)生きているか又は固定された細胞上又は細胞中のCSF−1Rの検出及び/又は数量化(in vitro又は組織中又は細胞切片中の細胞)。これのための用途には、抗CSF−1R処置の効果を追跡するためのバイオマーカーとしてのCSF−1Rの数量化を含めることができる。これらの目的のために、候補は改変形態で使用されてもよい(例えば、遺伝子融合タンパク質又は化学的コンジュゲートとして別の部分の付加、例えばレポーター分子、例えば検出目的で使用される蛍光性タグの付加による)。
3)(1)及び(2)で例示される方法によって改変される候補への結合によって標識されるCSF−1Rを有する細胞の精製又は選別。
免疫化:
グリコシルホスファチジルイノシトール(GPI)アンカーに連結したヒトCSF−1R細胞外ドメインを発現するベクターで一時的にトランスフェクトさせた同系RFL6ラット線維芽細胞で、雌SDラットを免疫化した。図3は、ラットの免疫化で使用したヒトCSF−1R細胞外ドメイン配列である配列番号39を示す。
抗体上清は、トランスフェクトされたHEK293細胞上で発現されたヒトCSF−1Rに結合するそれらの能力について、蛍光微量アッセイ技術(FMAT)によって最初にスクリーニングした。
中和抗CSF−1R活性を含有したFMAT陽性ウェル、すなわちヒトCSF−1R受容体へのヒトCSF−1結合を阻止する能力を有する抗体を同定するように、中間スループットアッセイを考案した。ヒトCSF−1とのインキュベーションの前に、CSF−1Rを発現するTHP−1細胞と抗体上清をインキュベートした。THP−1細胞へのCSF−1結合のレベルは、抗CSF−1ポリクローナル抗体を使用するフローサイトメトリーによって測定した。無関係の抗体上清を、陰性対照として使用した。
二次スクリーニングで中和活性を示していた抗体上清を、一次ヒト単球のCSF−1依存性生存を阻止するそれらの能力について試験した。ヒト血液から単球を精製し、20ng/mlのヒトCSF−1の存在下で1×104個の細胞を各抗体上清とインキュベートした。72時間のインキュベーションの後、生存可能な単球の数を、CellTiter Gloアッセイによって測定した。
CSF−1中和活性を実証した18個の抗体ウェルから、可変領域(V領域)のクローニングを試みた。ラット抗体定常領域に特異的なプライマー及びラット免疫グロブリンリーダーペプチドをコードする配列にアニールする冗長なプライマーセットを用いて、重鎖及び軽鎖の免疫グロブリンV領域をRT−PCRによって増幅した。V領域遺伝子は14個の抗体から回収し、重鎖及び軽鎖のヒトIgG4発現ベクターにクローニングした。
配列多様性を評価するために、9つの中和抗体で配列決定をした。全ての9つの抗体は特異であった。さらなるプロファイリング研究のために、これらの抗体をクローニングし、発現させた。
i)キメラAb969の発現
例1で同定された9つの中和抗体の可変領域を別々の重鎖及び軽鎖発現ベクターにクローニングし、完全長ヒトIgG4抗体として発現させた。
THP−1細胞へのCSF−1結合を阻害する9つの抗体の各々の能力は、フローサイトメトリーによって評価した。THP−1細胞は、0.5、0.125、0.031、0.0078及び0.00195μg/mlで各抗体と30分間インキュベートした。無関係なIgG4抗体は、アイソタイプ対照の役目をした。洗浄後、細胞を30分間、0.5μg/mlヒトCSF−1とインキュベートした。さらなる洗浄の後、ビオチン化抗CSF−1抗体及びAlexa488コンジュゲートストレプトアビジンとの逐次的なインキュベーションによって、結合したCSF−1を検出した。受容体結合リガンドをフローサイトメトリーによって測定し、蛍光強度中央値(MFI)をプロットした。
抗ヒトCSF−1R:
一次ヒト単球のCSF−1及びIL−34駆動型の生存及び増殖を阻害するそれらの能力について、精製された抗ヒトCSF−1R抗体を試験した。各アッセイで、単球の最大刺激を与える濃度でマイトジェン(CSF−1又はIL−34)を使用した。
一次マウスCD11b+単球をマウス脾臓から精製した。次に、単球を24時間、漸増量のマウスCSF−1(mCSF−1)とインキュベートした。細胞培地へのMCP−1の放出をELISAによって測定し、mCSF−1によるMCP−1の用量依存的放出が実証された。研究の別の群では、10μg/mlの抗マウスCSF−1R Ab535を漸増量のmCSF−1と一緒に加えた。MCP−1の放出は、試験したCSF−1の全ての濃度でAb535によって完全に阻害された(図6)。
精製された組換えCSF−1R/Fc融合タンパク質への結合動態の測定によるBIAcoreアッセイで、CSF−1Rに結合するそれらの能力について抗体を試験した。
THP−1細胞へのCSF−1結合を阻害するそれらの相対力価を測定することによって、4つの抗体を分析した。このアッセイフォーマットで、全ての4つの抗体はCSF−1結合の強力な阻害を示し、IC50値は5ng/ml未満(約30pM)であった。
アカゲザル、カニクイザル及びイヌ完全長CSF−1Rでの交差反応性について、4つの抗体を試験した。全ての4つの抗体はヒトCSF−1Rに加えてアカゲザル及びカニクイザルのCSF−1Rに結合し、アイソタイプ対照のレベルより有意に高い明らかな結合を実証した。
Ab969:
THP−1細胞を0、0.5、2、4、24及び48時間、Ab969とインキュベートした。細胞は、それぞれ陽性及び陰性対照としての役目をしたヒトCSF−1及びアイソタイプ対照によっても処置した。各時点で、細胞表面CSF−1Rのレベルをフローサイトメトリーによって測定した(図7)。アイソタイプ対照と比較してAb969で処置した細胞上の細胞表面CSF−1Rの相対レベルを計算したものを、図8に示す。
マウス白血病単球/マクロファージ細胞系RAW264.7は、高レベルのマウスCSF−1R(mCSF−1R)を発現し、抗マウスCSF−1R抗体Ab535が受容体の内在化を導き出すことができるかどうかについて試験するのに適する細胞ベースの系を代表する。
CSF−1はCSF−1Rに結合して受容体二量体の形成を引き起こし、それはキナーゼドメインを近接させることによって急速な受容体リン酸化を誘発する。これはその後、受容体内在化、及びRas−MAPK経路を含むいくつかのよく特徴付けられたシグナル伝達経路の活性化につながる。抗CSF−1R抗体が受容体クラスタリングを導き出し、下流のシグナル伝達カスケードを誘発することができるかもしれない。これは受容体シグナル伝達を阻害するべきである抗体にとって望ましくない特性であるかもしれないので、Ab969による受容体アゴニズムを2つの独立したin vitroアッセイフォーマットを使用して試験した。
例2で測定されたそれらの親和性及び特性に基づき、ヒト化について4つの抗CSF−1R抗体を選択した。
ヒト生殖細胞系抗体V領域フレームワークの上へラット抗体V領域からのCDRを移植することによって、抗体969及び970をヒト化した。
各ヒト化移植片は、(i)BIAcoreによるヒトCSF−1Rへの結合親和性、及び(ii)ThermoFluor分析によって測定する融点(Tm)について、両方とも親のキメラ抗体と比較して評価した。融点は抗体分子の安定性の初期の指標を提供すると考えられ、不安定な抗体は一般的に75.0℃未満のTmを示す。
培養中の単球の活性化及び生存のために、CSF−1が必要とされる。CSF−1が除去されると、単球はアポトーシスを速やかに受ける。読出しとしてMCP−1(単球化学走性タンパク質−1;別名CCL2、ケモカインC−Cモチーフリガンド2)を使用したアッセイを考案した。CSF−1刺激の結果、ヒト単球はMCP−1を分泌し、それは一般的に刺激の24時間後にELISAによって細胞上清中に検出することができる。CSF−1結合をブロックする抗体によるCSF−1Rシグナル伝達の阻害は、MCP−1分泌の低減を引き起こす。
in vitro活性を比較することができるように、一時的な発現によって一群のAb969ヒト化中間体移植片を調製した(表8)。同じバッチの中で抗体特性の直接比較ができるように、対応するキメラ抗体(Ab969.g0)及び完全ヒト化移植片(Ab969.g5)も一時的発現に含まれた。
各Ab969ヒト化抗体移植片及び親のキメラ抗体の親和性をBIAcoreによって測定し(表10)、そこでは3つの独立した実験を実行して、平均値を計算した。データは、親和性(KD)が、キメラ分子(Ab969.g0)から「完全ヒト化」抗体Ab969.g5まで、ヒト化の過程で変化しないようであることを示す。しかし、ヒト化がAb969.g2移植片を越えて進行するとき、抗体「オンレート」は減少する。Ab969.g4及びAb969.g5の両方は、前の移植片より低いKa値を有する。さらに、Ab969.g5のKaはAb969.g4より低く、SGへのDG異性化部位の突然変異がなおさらに抗体オンレートを低減することを潜在的に示す。
いくつかのアッセイでの一群のAb969ヒト化移植片の試験は、軽鎖の中の71位のチロシン残基(例えばY71)が抗体の活性を改善することを明らかにした。例えばY71のフェニルアラニンでの置換は、親のキメラ分子と比較して抗体オンレートの低減(Kaの減少)をもたらす。これは、一次ヒト単球でのCSF−1Rの活性を監視するアッセイ(MCP−1阻害アッセイ)で明らかにされた、CSF−1RへのCSF−1結合をブロックする抗体の能力の低下をもたらす。
i)熱安定性
熱安定性(融点Tmで測定される)は、2つの独立した方法によって判定した。1つの方法は、露出した疎水性表面への蛍光色素の結合によるアンフォールディングを監視し(Thermofluor方法)、他は熱量測定(DSC)、直交技術による。
保存中の試料の安定性の予測因子として、PBS pH7.4中の安定性に及ぼす抗体濃度の影響を調べた。
抗体を10mg/ml超に濃縮し、室温で5日間インキュベートした。濃縮直後(T0)に、969.g7は濁っているようであり、969.g8はわずかに乳白色に見えた。対照的に、969.g5試料は、目視検査によって透明であると判断された。室温で5日間のインキュベーションの後、965.g5試料は透明なままであったが、969.g7及び969.g8の凝集はさらに進行し、各々重い沈殿物を示した。
濃縮の前に、乳白色に見える969.g6(4.68mg/ml)を除いて、全ての3つの抗体試料は目視検査で透明であった。16mg/mlへの濃縮の結果、室温及び4℃の両方で24時間の保存の後に969.g6の沈殿が注目された。しかし、969.g1及び969.g4の両方は目視で透明のままだった。5日間のさらなるインキュベーションの後、室温及び4℃の両方において試料969.g1で大きな粒子が明白であった。目視検査によって判断された通り、室温又は4℃において試料969.g4で凝集は観察されなかった。
濃縮直後(T0)、一晩のインキュベーションの後及び濃縮から5日後に、試料分析を実施した。全ての試料は濃縮前に目視検査で透明であり、粒子形成の証拠はなかった。23.07mg/mlへの濃縮の直後に、969.g7試料は、実験1で以前に観察された沈殿を示した。969.g9でわずかな乳白光が観察され、それは室温又は4℃で24時間の保存の後により目立つようになった。他の969移植片の全ては、濃縮直後に目視検査によって透明に見えた。
i)Ab969.g2の配列
Ab969.g2は、gL7軽鎖移植片及びgH2重鎖移植片を含有する。ラット抗体(ドナー)V領域配列とヒト生殖細胞系(アクセプター)V領域配列とのアラインメントを、軽鎖移植片gL7及び重鎖移植片gH2の最終ヒト化配列と一緒に図2A及び2Bに示す。
IL−34依存性ヒト単球アッセイで、969.g0と比較したAb969.g2の活性を評価した。2つの別々の単球ドナーを使用して実験を実施し、IL−34媒介単球刺激の阻害の平均IC50を計算した(表12)。Ab969.g2とAb969.g0の間にIC50の有意差はなかった。
ヒト母集団で報告された、ヒトCSF−1R遺伝子のリガンド結合ドメインに位置する4つの非同義の一塩基多型(SNP)がある。これらのSNPは、V32G、A245S、H247P及びV279Mである(図1F)。ヒトCSF−1Rの各SNP変異体を生成し、細胞系で安定して発現させた。各SNPへのAb969.g2の結合は、フローサイトメトリーによって確認した。
ヒト以外の霊長類(カニクイザル)で抗体の薬理活性を実証するために、ヒト化モノクローナル抗CSF−1R抗体969.g2による薬物動態学的/薬力学的(PK/PD)研究を実施した。3匹のカニクイザルの群に、7mg/kg(第1群)又は1.5mg/kg(第2群)の969.g2抗体の単一用量を静脈内投与した。抗体は、有害な臨床徴候がなく、良好な耐容性を示した。25日間の研究全体で複数の時点に血清試料を採取した。
t1/2は、血清中の抗体の半減期である。
Cmaxは、血清中の抗体のピーク濃度である。
AUCは曲線下面積(濃度−時間曲線の積分)であり、薬物への全曝露の指標を提供する。
クリアランスは、単位時間あたりの薬物が取り除かれた血漿の容積である。
Vol.Dist.は分布容積であり、薬物が分配される見掛け容積のことである。
抗体969.g2は、マウスCSF−1Rに結合することができない。したがって、がん及び線維症を処置するAb969.g2の有用性を示すために、抗マウスCSF−1R抗体Ab535を使用してin vivoマウス研究を実行した。いくつかのin vitro実験で、Ab535はAb969.g2と同等の特性及び活性を有することが示された。
正常位前立腺がんモデルPC−3を使用して、in vivoで抗体Ab535の抗腫瘍及び転移抑制効力も試験した。ルシフェラーゼを連続的に発現してin vivo生物発光画像分析を可能にするようにPC−3細胞系を遺伝子改変し、これはin vivoで腫瘍増殖を監視すること及び選択された器官でex vivo転移分析を実施することを可能にした。
ブレオマイシンはストレプトミセス・ベルチシラタス(Streptomyces verticillatus)から最初に単離された抗生物質であり、様々ながんのための化学療法薬として使用されている。肺線維症のブレオマイシンモデルは確立されたモデルであり、本質的にMadtes、DK et al.,1999,Am J Respir Cell Mol Biol,20,924−34に記載されているように使用された。詳細なプロトコールは、以下の参考文献Morschl,E.,Molina,J.G.,Volmer,J.,Mohsenin,A.,Pero,R.S.,Hong、J.S.,Kheradmand,F.,Lee,J.J.及びBlackburn,M.R.(2008)、A3 adenosine receptor signaling influences pulmonary inflammation and fibrosis.Am.J.Respir.Cell Mol.Biol.39:697−705に見出すことができる。
アデノシンは強力なシグナル伝達ヌクレオシドであり、そのレベルは細胞がストレスを受けるか又は傷害を受けるときに増加し、アデノシンがその特異的Gタンパク質結合受容体と係合するときに多種多様な応答が起こる。アデノシンデアミナーゼ(ADA)は、アデノシンをイノシンに変換するプリン異化作用酵素である。ADAノックアウトマウスが作製され、血清並びに腎臓、肝臓及び肺などの組織でのアデノシンレベルの増加を有することが示された(Blackburn,MR et al.,1998,J Biol Chem,273(9):5093−5100)。これらのマウスは、肺でのアデノシンレベルの増加と関連する、慢性肺疾患、例えば肺胞破壊、気道炎症及び過剰な粘液生成の特徴を示す(Blackburn MR et al.,2000,J Exp Med,192:159−70)。影響は、マウスが呼吸窮迫により3週齢までに死ぬというようなものである。低用量レジメンを用いた外因性ADAの投与は、アデノシンレベルを低減し、これらのマウスの寿命を延長し、肺線維症モデルの開発を可能にする(Chunn JL et al.,2005,J Immunol 175:1937−46、Pedrosa M et al.,2011,PLoS One,6(7号):e22667)。このモデルでは、アデノシンレベルの慢性的上昇は、肺でのTGF□を含む線維症促進媒介物の増加、肺組織でのコラーゲン沈着の増加及び線維性肺病状の増加と関連する。抗線維症能力を有する分子の効果を調査するために、ADA欠損マウスを数週間低用量外因性ADAレジメンで維持し、その後ADA処置を停止し、潜在的抗線維症剤を投与する。
Claims (29)
- 配列番号23に記載の配列を含む重鎖と、配列番号15に記載の配列を含む軽鎖とを有する、抗CSF−1R抗体。
- 前記抗体が、完全長重鎖及び軽鎖を有する完全な抗体分子又はその断片からなる群から選択される、請求項1に記載の抗CSF−1R抗体。
- 前記抗体分子が、Fab、改変Fab’、Fab’、F(ab’)2、Fv、VH、VL及びscFv断片を含む群から選択される、請求項2に記載の抗CSF−1R抗体。
- 軽鎖のフレームワーク領域が、請求項1に記載の抗体の軽鎖のフレームワーク領域と少なくとも90%の同一性を有する配列を含み、重鎖のフレームワーク領域が、請求項1に記載の抗体の重鎖のフレームワーク領域と少なくとも90%の同一性を有する配列を含み、10pM又は10pM未満のヒトCSF−1Rへの結合親和性を有する、抗CSF−1R抗体。
- 配列番号27に記載の配列を含む重鎖と、配列番号19に記載の配列とを含む軽鎖を有する、抗CSF−1R抗体。
- 重鎖及び軽鎖のフレームワーク領域が、請求項5に記載の抗体の対応する重鎖及び軽鎖のフレームワーク領域と少なくとも90%同一であり、10pM又は10pM未満のヒトCSF−1Rへの結合親和性を有する、抗CSF−1R抗体。
- それに付着したエフェクター又はレポーター分子を有する、請求項1から6までのいずれか一項に記載の抗CSF−1R抗体。
- 10pM又は10pM未満のヒトCSF−1Rへの結合親和性を有する、請求項1から7までのいずれか一項に記載の抗CSF−1R抗体。
- 請求項1に記載の抗体の結合を交差ブロックし、CSF−1Rに対して100pM以下の結合親和性を有する、抗CSF−1R抗体。
- 請求項1から9までのいずれか一項に記載の抗体の重鎖及び/又は軽鎖(単数又は複数)をコードする単離されたDNA。
- 請求項10に記載の1つ又は複数のDNAを含むクローニング又は発現ベクター。
- 配列番号28及び/又は配列番号20に記載の配列を含む、請求項11に記載のベクター。
- 請求項12に記載の1つ又は複数のクローニング又は発現ベクターを含む宿主細胞。
- 請求項13に記載の宿主細胞を培養して抗体を単離することを含む、請求項1から9までのいずれか一項に記載の抗体の生成方法。
- 請求項1から9までのいずれか一項に記載の抗体を、薬学的に許容される賦形剤、希釈剤又は担体の1つ又は複数と一緒に含む医薬組成物。
- 他の有効成分をさらに含む、請求項15に記載の医薬組成物。
- 医薬として使用するための、請求項15又は16に記載の医薬組成物。
- がんの処置のための、請求項15又は16に記載の医薬組成物。
- 線維性疾患の処置のための、請求項15又は16に記載の医薬組成物。
- がんの治療又は予防のための医薬の製造における請求項1から9までのいずれか一項に記載の抗体又は請求項15若しくは16に記載の組成物の使用。
- 線維性疾患の治療又は予防のための医薬の製造における請求項1から9までのいずれか一項に記載の抗体又は請求項15若しくは16に記載の組成物の使用。
- がんを患っているか又はその危険があるヒト対象の処置のための、請求項15又は16に記載の医薬組成物。
- 線維性疾患を患っているか又はその危険があるヒト対象の処置のための、請求項15又は16に記載の医薬組成物。
- 前記がんが、乳がん、前立腺がん、骨がん、結腸直腸がん、白血病、リンパ腫、皮膚がん、食道がん、胃がん、星状細胞がん、子宮体がん、子宮頸がん、膀胱がん、腎臓がん、肺がん、肝がん、甲状腺がん、頭頚部がん、膵がん及び卵巣がんからなる群から選択される、請求項18に記載の医薬組成物。
- 前記がんが、乳がん、前立腺がん、骨がん、結腸直腸がん、白血病、リンパ腫、皮膚がん、食道がん、胃がん、星状細胞がん、子宮体がん、子宮頸がん、膀胱がん、腎臓がん、肺がん、肝がん、甲状腺がん、頭頚部がん、膵がん及び卵巣がんからなる群から選択される、請求項20に記載の使用。
- 前記がんが、乳がん、前立腺がん、骨がん、結腸直腸がん、白血病、リンパ腫、皮膚がん、食道がん、胃がん、星状細胞がん、子宮体がん、子宮頸がん、膀胱がん、腎臓がん、肺がん、肝がん、甲状腺がん、頭頚部がん、膵がん及び卵巣がんからなる群から選択される、請求項22に記載の医薬組成物。
- 前記線維性疾患が、肺線維症、例えば特発性肺線維症及び嚢胞性線維症、腎臓線維症、肝硬変、心内膜心筋線維症、縦隔線維症、骨髄線維症、後腹膜線維化症、進行性の大規模な線維症、腎原性の全身性線維症、クローン病、ケロイド、心筋梗塞、強皮症及び関節線維症からなる群から選択される、請求項19に記載の医薬組成物。
- 前記線維性疾患が、肺線維症、例えば特発性肺線維症及び嚢胞性線維症、腎臓線維症、肝硬変、心内膜心筋線維症、縦隔線維症、骨髄線維症、後腹膜線維化症、進行性の大規模な線維症、腎原性の全身性線維症、クローン病、ケロイド、心筋梗塞、強皮症及び関節線維症からなる群から選択される、請求項21に記載の使用。
- 前記線維性疾患が、肺線維症、例えば特発性肺線維症及び嚢胞性線維症、腎臓線維症、肝硬変、心内膜心筋線維症、縦隔線維症、骨髄線維症、後腹膜線維化症、進行性の大規模な線維症、腎原性の全身性線維症、クローン病、ケロイド、心筋梗塞、強皮症及び関節線維症からなる群から選択される、請求項23に記載の医薬組成物。
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