JP6654781B2 - Kir2ds1に対するモノクローナル抗体 - Google Patents
Kir2ds1に対するモノクローナル抗体 Download PDFInfo
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- JP6654781B2 JP6654781B2 JP2016545624A JP2016545624A JP6654781B2 JP 6654781 B2 JP6654781 B2 JP 6654781B2 JP 2016545624 A JP2016545624 A JP 2016545624A JP 2016545624 A JP2016545624 A JP 2016545624A JP 6654781 B2 JP6654781 B2 JP 6654781B2
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Classifications
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
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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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- 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
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/02—Preparation of hybrid cells by fusion of two or more cells, e.g. protoplast fusion
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Description
CDR1として配列番号1のアミノ酸配列を有し、CDR2として配列番号2のアミノ酸配列を有し、CDR3として配列番号3のアミノ酸配列を有するVLと、
CDR1として配列番号4若しくは配列番号5のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号7、配列番号8及び配列番号9からなる群より選択されるいずれか1つのアミノ酸配列を有するVHと、
を有する。
KIR2DS1のアゴニストとして作用せず、かつ、KIR2DS1のアンタゴニストとして作用しない本発明の第1及び第2の観点に係るモノクローナル抗体又はその抗原結合領域を含むフラグメントをKIR2DS1およびKIR2DL1を発現している培養細胞集団に投与する工程と、
前記細胞集団の、KIR2DL1の活性の度合Aを測定する工程と、
候補物質を更に前記細胞集団に投与する工程と、
前記候補物質を前記細胞集団に投与した後の、KIR2DL1の活性の度合Bを測定する工程と、
前記度合Aと前記度合Bとを比較する工程とを含み、
前記度合A>前記度合Bの場合に、前記候補物質はKIR2DL1のアンタゴニストであると判定し、
前記度合A<前記度合Bの場合に、前記候補物質はKIR2DL1のアゴニストであると判定することを特徴とする。
本発明の第1及び第2の観点に係るKIR2DS1に対するモノクローナル抗体又はその抗原結合領域を含むフラグメントと、被験者由来のサンプルと、を接触させる工程と、
前記モノクローナル抗体又はその抗原結合領域を含むフラグメントが、前記サンプル中のKIR2DS1に結合するか否かを判定する工程と、
を含む。
本発明の第1及び第2の観点に係るKIR2DS1に対するモノクローナル抗体又はその抗原結合領域を含むフラグメントと、被験者由来のサンプルと、を接触させて、前記サンプル中のKIR2DS1量を測定する工程と、
前記サンプル中のKIR2DL1量を測定する工程と、
を含む。
CDR1として配列番号1のアミノ酸配列を有し、CDR2として配列番号2のアミノ酸配列を有し、CDR3として配列番号3のアミノ酸配列を有するVLと、
CDR1として配列番号4又は配列番号5のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号7、配列番号8及び配列番号9からなる群より選択されるいずれか1つのアミノ酸配列を有するVHと、
を有する。
cancer − non−small cell)、非ホジキンリンパ腫(Lymphoma − Non−Hodgkin’s)、黒色腫(Melanoma)、中皮腫(Mesothelioma)、多発性骨髄腫(Multiple myeloma)、卵巣癌(Ovarian cancer)、膵臓癌(Pancreatic cancer)、前立腺癌(Prostate cancer)、胃癌(Stomach cancer)、睾丸癌(Testicular cancer)、甲状腺癌(Thyroid cancer)等の治療及び/又は予防の効果が期待される。
(a)本発明のモノクローナル抗体と、被験者由来のサンプルと、を接触させる工程と、(b)本発明のモノクローナル抗体が、被験者由来のサンプル中のKIR2DS1に結合するか否かを判定する工程と、
を含む。
本発明によるモノクローナル抗体と、被験者由来のサンプルと、を接触させて、サンプル中のKIR2DS1量を測定する工程と、
サンプル中のKIR2DL1量を測定する工程と、
を含む。
(A)本発明によるモノクローナル抗体を細胞集団に投与する工程と、
(B)細胞集団の、KIR2DL1の活性の度合Aを測定する工程と、
(C)候補物質を細胞集団に投与する工程と
(D)候補物質を細胞集団に投与した後の、KIR2DL1の活性の度合Bを測定する工程と、
(E)度合Aと度合Bとを比較する工程と、
を含む。
以下の通り、NK細胞活性化受容体のひとつであるKIR2DS1に特異的に結合するモノクローナル抗体を作製した。
抗原タンパク質として、大腸菌において組換え発現させたKIR2DS1を用いた。
Wisterラット(8週齢、雌)(三協ラボサービス)を4匹用意した。ラットに1匹あたり抗原250μgを免疫注射した。より具体的には、0.5mg/mLのKIR2DS1タンパク質の抗原液をラット1匹あたり500μL、ラットの臀部に注射した。免疫2週間後に心採血を行うとともに、腸骨リンパ節を摘出した。摘出された腸骨リンパ節をディッシュ中のRPMI 1640培地(L−グルタミン、フェノールレッド含有)(WAKO)に入れ、該培地中ですりつぶし、細胞懸濁液とした。細胞懸濁液をチューブに移して3分間静置した後、上層を別のチューブに移して遠心した(1200rpm×5分間)。細胞をRPMI 1640培地に懸濁し、さらに遠心した(1200rpm×5分間)後、細胞を2mLのRPMI 1640培地に懸濁し、腸骨リンパ節細胞液とした(合計で4×107個の腸骨リンパ節細胞を得た)。
上記にて得られたRPMI 1640培地中の腸骨リンパ節細胞4×107個と、2mLのRPMI 1640培地に懸濁されたマウスミエローマ細胞(X63/Ag8−653)4×106個と、を混合し、50mLチューブに移し、細胞混合液を遠心した(1500rpm×5分間)。RPMI培地 1640を除いた後、チューブ内の沈殿をよくほぐした。50%PEG溶液(PEG1500、ロシュディアグノスティック)1mLを添加し、チューブを回転させて1分間混合させた。RPMI 1640培地2mLとおだやかに懸濁させ、さらにRPMI 1640培地8mLとおだやかに懸濁させた。細胞混合液を遠心(1000rpm×10分間)した後、細胞を50mLのGIT−HAT培地(後述)に懸濁し、96ウェルプレート5枚に100μL/ウェルで播種した。37℃で5日間培養し、5日後に、ウェルが8割位満たされる程度に各ウェルにGIT−HAT培地を足した。培養開始12日目に、1ウェルの中でシングルクローンと確認できたコロニーが出現していたのは、233ウェルであった。
なお、GIT−HAT培地(400mL)の組成は以下の通りである。
GIT培地(日本製薬) 332mL
非働化済FBS(final 10%) 40mL
BM−condimed H1(ロシュディアグノスティック)(final 5%)
20mL
50×HAT(invitrogen) 8mL
前述の通り得られた培養上清を用いて、ELISA法による1次スクリーニングを行った。
1次スクリーニングで得られた16の陽性クローンを用いて、ELISA法による2次スクリーニングを行った。
of larvae and pupae of silkworm by Bombyx mori nuclear polyhedrosis virus bacmid system.Motohashi T, Shimojima T,Fukagawa T,Maenaka K,Park EY.Biochem Biophys Res Commun.2005 Jan 21;326(3):564−9.で既報のBmNPVのバクミドをDH10Bに導入したもの)にトランスポジションし、テトラサイクリン及びゲンタマイシン含有培地中で培養し、その後、寒天培地上に撒き、37℃で培養した。コロニーを釣菌し、コロニーPCRを行った。PCR溶液を以下の通り調製し、プライマーとして、Forwardプライマー(5’−gttttcccagtcacgac−3’、配列番号23)及びReverseプライマー(5’−caggaaacagctatgac−3’、配列番号24)を用いた。
Go Taq DNAポリメラーゼ(プロメガ) 4μL
Forwardプライマー 1μL
Reverseプライマー 1μL
Milli Q 2μL
PCRの条件は、95℃5分間、95℃30秒間−50℃30秒間−72℃3分30秒間×25サイクル、72℃10分間、4℃×∞であった。陽性のコロニーをカナマイシン及びゲンタマイシン含有培地に植え、37℃で一晩培養した。培養した菌を集菌し、バクミドを、Plasmid Midi Kit(QIAGEN)を用いて精製した。精製したバクミド1μg(Milli Q 50μL中)に、DMRIE−C(Invitrogen)3μLを加え、5齢のカイコ(愛媛蚕種株式会社)に接種した。接種6日後、カイコを解剖して体液及び脂肪体を回収し、Ni Sepharose 6 Fast Flow(GE Healthcare)を用いてHis−tagタンパク質精製を行い、タンパク液(KIR2DL1)を得た。抗原液のタンパク質濃度は、50ng/50μLであった。
前述の通り得られた陽性クローンをスケールアップし、限界希釈を繰り返して、単クローン化した。
前述の通り得られた22クローンを各々精製した。
実施例1にて単クローン化したハイブリドーマ産生モノクローナル抗体(22クローン)について、ELISA及び表面プラズモン共鳴(SPR)法により、細胞外ドメインの相同性が高いKIRファミリータンパク質KIR2DS1、KIR2DL1、KIR2DS2、KIR2DL2及びKIR2DL3に対する結合特異性を検証した。
抗原:50ng/50μL(/well)
1次抗体:精製抗体(1/100)50μL/well
positive control−1:ラット抗血清(×1000、2000、5000)
control:精製前抗体(2B7C2‐B3)(培養上清(GIT)、精製時のFlow Through)
negative control:0.1M Glycine−HCl
(抗体精製時にelution bufferとして使用、中和済み)
2次抗体:anti−rat IgG−HRP(×3000)50μL/well
検出系:ABTS(415nm)
抗原:50ng/50μL(/well)
1次抗体:精製抗体(原液)50μL/well
positive control−1:ラット抗血清(×1000、2000、5000)
positive control−2:精製抗体(1C7B8−E1)(×100)
negative control:0.1M Glycine−HCl(抗体精製時にelution bufferとして使用、中和済み)
2次抗体:anti−rat IgG−HRP(×3000)50μL/well
検出系:ABTS(415nm)
BP−01854が付与されている(2015年7月29日付けで受託証発行)。
実施例2で得られたモノクローナル抗体8クローンのVL、VHのクローニングを行い、VH、VLのCDR配列を決定した。
テンプレート(1/10希釈) 1.0μL
10×Ex Taq buffer 5.0μL
dNTP(2.5mM each) 4.0μL
Forwardプライマー mixture 1.5μL
Reverseプライマー mixture 1.0+1.0μL
Ex Taq 0.25μL
水 37.65μL
計 50.0μL
PCRを、95℃2分間、95℃30秒間−45℃30秒間−68℃1分間×35サイクル、68℃1分間、4℃×∞で行った。その後、pGEM−T Easy system I(プロメガ社)を用いてTA cloningを行った。colony PCRによってインサートを確認した後、ミニプレップによりプラスミドDNAを抽出し、シークエンスに供した。
Claims (19)
- CDR1として配列番号1のアミノ酸配列を有し、CDR2として配列番号2のアミノ酸配列を有し、CDR3として配列番号3のアミノ酸配列を有するVLと、
CDR1として配列番号4若しくは配列番号5のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号7、配列番号8及び配列番号9からなる群より選択されるいずれか1つのアミノ酸配列を有するVHと、
を有する、KIR2DS1に対するモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - VHは、CDR1として配列番号4のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号7のアミノ酸配列を有する、
ことを特徴とする請求項1に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - VHは、CDR1として配列番号5のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号8のアミノ酸配列を有する、
ことを特徴とする請求項1に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - VHは、CDR1として配列番号5のアミノ酸配列を有し、CDR2として配列番号6のアミノ酸配列を有し、CDR3として配列番号9のアミノ酸配列を有する、
ことを特徴とする請求項1に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - 受託番号がNITE BP−01853であるハイブリドーマ、受託番号がNITE BP−01855であるハイブリドーマ及び受託番号がNITE BP−01854であるハイブリドーマからなる群より選択される少なくとも1つのハイブリドーマにより産生される、KIR2DS1に対するモノクローナル抗体又はその抗原結合領域を含むフラグメント。
- キメラ抗体又はヒト化抗体である、
ことを特徴とする請求項1乃至5のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - 請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントをコードする塩基配列を含む核酸。
- 請求項7に記載の核酸を含む発現ベクター。
- 請求項7に記載の核酸又は請求項8に記載の発現ベクターを含み、請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントを産生する形質転換体。
- 請求項9に記載の形質転換体を培養し、培養物から抗体又はその抗原結合領域を含むフラグメントを回収する工程を含む、請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントの産生方法。
- 請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントを産生する細胞。
- 受託番号がNITE BP−01853であるハイブリドーマ、受託番号がNITE BP−01855であるハイブリドーマ及び受託番号がNITE BP−01854であるハイブリドーマからなる群より選択される少なくとも1つのハイブリドーマである、
ことを特徴とする請求項11に記載の細胞。 - 請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントを含む医薬組成物。
- KIR2DS1のアゴニストとして作用する、
ことを特徴とする請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - KIR2DS1のアンタゴニストとして作用する、
ことを特徴とする請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - KIR2DS1のアゴニストとして作用せず、かつ、KIR2DS1のアンタゴニストとして作用しない、
ことを特徴とする請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメント。 - 請求項16に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントをKIR2DS1およびKIR2DL1を発現している培養細胞集団に投与する工程と、
前記細胞集団の、KIR2DL1の活性の度合Aを測定する工程と、
候補物質を更に前記細胞集団に投与する工程と、
前記候補物質を前記細胞集団に投与した後の、KIR2DL1の活性の度合Bを測定する工程と、
前記度合Aと前記度合Bとを比較する工程とを含み、
前記度合A>前記度合Bの場合に、前記候補物質はKIR2DL1のアンタゴニストであると判定し、
前記度合A<前記度合Bの場合に、前記候補物質はKIR2DL1のアゴニストであると判定することを特徴とする、KIR2DL1に結合する物質をスクリーニングするための方法。 - 請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントと、被験者由来のサンプルと、を接触させる工程と、
前記モノクローナル抗体又はその抗原結合領域を含むフラグメントが、前記サンプル中のKIR2DS1に結合するか否かを判定する工程と、
を含む、サンプル中のKIR2DS1を検出するための方法。 - 請求項1乃至6のいずれか1項に記載のモノクローナル抗体又はその抗原結合領域を含むフラグメントと、被験者由来のサンプルと、を接触させて、前記サンプル中のKIR2DS1量を測定する工程と、
前記サンプル中のKIR2DL1量を測定する工程と、
を含む、サンプル中のKIR2DS1とKIR2DL1とのポピュレーションを測定するための方法。
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