JP7456930B2 - エンドセリン受容体サブタイプaに対する抗体及びその使用 - Google Patents
エンドセリン受容体サブタイプaに対する抗体及びその使用 Download PDFInfo
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- JP7456930B2 JP7456930B2 JP2020542857A JP2020542857A JP7456930B2 JP 7456930 B2 JP7456930 B2 JP 7456930B2 JP 2020542857 A JP2020542857 A JP 2020542857A JP 2020542857 A JP2020542857 A JP 2020542857A JP 7456930 B2 JP7456930 B2 JP 7456930B2
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- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
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- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-AHCXROLUSA-N ruthenium-97 Chemical compound [97Ru] KJTLSVCANCCWHF-AHCXROLUSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- 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
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-OUBTZVSYSA-N water-17o Chemical compound [17OH2] XLYOFNOQVPJJNP-OUBTZVSYSA-N 0.000 description 1
Images
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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
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57407—Specifically defined cancers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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]
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- 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
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- Proteomics, Peptides & Aminoacids (AREA)
- Hospice & Palliative Care (AREA)
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- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
i)少なくとも1つの軽鎖可変領域であって、
- CDR1Lのアミノ酸配列が以下のアミノ酸配列SQSIVYSNGKIYL (配列番号2)と少なくとも60%の同一性を有し、
- CDR2Lのアミノ酸配列が以下のアミノ酸配列KVSと少なくとも60%の同一性を有し、
- CDR3Lのアミノ酸配列が以下のアミノ酸配列FQGSHLPLT (配列番号4)と少なくとも60%の同一性を有する、軽鎖可変領域と、
ii)少なくとも1つの重鎖可変領域であって、
- CDR1Hのアミノ酸配列が以下のアミノ酸配列GFTFNIYA (配列番号6)と少なくとも60%の同一性を有し、
- CDR2Hのアミノ酸配列が以下のアミノ酸配列IRSKSNNYAT (配列番号8)と少なくとも60%の同一性を有し、
- CDR3Hのアミノ酸配列が以下のアミノ酸配列VSSYYSGSFFAY (配列番号10)と少なくとも60%の同一性を有する、重鎖可変領域と
を有する、エンドセリン受容体サブタイプAに対する抗体、この抗体の断片、又はこの抗体の誘導体に関する。
- そのCDR1Lのアミノ酸配列はSQSIVYSNGKIYL (配列番号2)であり、
- そのCDR2Lのアミノ酸配列はKVSであり、
- そのCDR3Lのアミノ酸配列はFQGSHLPLT (配列番号4)である。
と少なくとも60%の同一性を有する。
- そのCDR1Hのアミノ酸配列はGFTFNIYA (配列番号6)であり、
- そのCDR2Hのアミノ酸配列はIRSKSNNYAT (配列番号8)であり、
- そのCDR3Hのアミノ酸配列はVSSYYSGSFFAY (配列番号10)である。
と少なくとも60%の同一性を有する。
α)既に定義した抗体をコードするポリヌクレオチド、
β)ポイント(α)で定義したポリヌクレオチドに相補的なポリヌクレオチド、
γ)ポイント(α)及び(β)で定義したポリヌクレオチドに高度に厳密な条件下でハイブリダイズすることができる少なくとも18ヌクレオチドのポリヌクレオチド。
i')軽鎖可変領域をコードする少なくとも1つのヌクレオチド配列であって、
- CDR1Lをコードし、以下のヌクレオチド配列AGT CAG AGC ATT GTA TAT AGT AAT GGA AAA ATC TAT TTA (配列番号1)と少なくとも60%の同一性を有する第1の配列、
- CDR2Lをコードし、以下のヌクレオチド配列AAA GTT TCCと少なくとも60%の同一性を有する第2の配列、
- CDR3Lをコードし、以下のヌクレオチド配列TTT CAA GGT TCA CAT CTT CCG CTC ACG (配列番号3)と少なくとも60%の同一性を有する第3の配列、
を含むヌクレオチド配列と、
ii')重鎖可変領域をコードする少なくとも1つのヌクレオチド配列であって、
- CDR1Hをコードし、以下のヌクレオチド配列GGA TTC ACC TTC AAT ATC TAC GCC (配列番号5)と少なくとも60%の同一性を有する第1の配列、
- CDR2Hをコードし、以下のヌクレオチド配列ATA AGA AGT AAA AGT AAT AAT TAT GCA ACA (配列番号7)と少なくとも60%の同一性を有する第2の配列、
- CDR3Hをコードし、以下のヌクレオチド配列GTG AGT TCC TAT TAC TCC GGT AGT TTC TTT GCT TAC (配列番号9)と少なくとも60%の同一性を有する第3の配列、
を含むヌクレオチド配列と
を含む。
- そのヌクレオチド配列がAGT CAG AGC ATT GTA TAT AGT AAT GGA AAA ATC TAT TTA (配列番号1)であるCDR1Lをコードする第1の配列、
- そのヌクレオチド配列がAAA GTT TCCであるCDR2Lをコードする第2の配列、
- そのヌクレオチド配列がTTT CAA GGT TCA CAT CTT CCG CTC ACG (配列番号3)であるCDR3Lをコードする第3の配列
を含む、少なくとも1つのヌクレオチド配列を含む。
GAT GTT TTG ATG ACC CAA ACT CCA CTC TCC CTG CCT GTC AGT CTT GGA GAT CAA GCC TCC ATC TCG TGC AGA TCT AGT CAG AGC ATT GTA TAT AGT AAT GGA AAA ATC TAT TTA GAA TGG TAC CTG CAG AAA CCA GGC CAG TCT CCA AAG CTC CTA ATC TAC AAA GTT TCC AAC CGA TTT TCT GGG GTC CCA GAC AGG TTC AGT GGC AGT GGA TCA GGG ACA GAT TTC ACA CTC AAG ATC AGC AGA GTG GAG GCT GAG GAT CTG GGA GTT TAT TAC TGC TTT CAA GGT TCA CAT CTT CCG CTC ACG TTC GGT GCT GGG ACC AAG CTG GAG CTG AAA CGG (配列番号11)
と少なくとも60%の同一性を有する軽鎖可変領域をコードする少なくとも1つのヌクレオチド配列を含む。
- そのヌクレオチド配列がGGA TTC ACC TTC AAT ATC TAC GCC (配列番号5)であるCDR1Hをコードする第1の配列、
- そのヌクレオチド配列がATA AGA AGT AAA AGT AAT AAT TAT GCA ACA (配列番号7)であるCDR2Hをコードする第2の配列、
- そのヌクレオチド配列がGTG AGT TCC TAT TAC TCC GGT AGT TTC TTT GCT TAC (配列番号9)であるCDR3Lをコードする第3の配列
を含む、少なくとも1つのヌクレオチド配列を含む。
GAG GTG CAG CTT GTT GAG TCT GGT GGA GGA TTG GTG CAG CCT AAA GGG TCA TTG AAA CTC TCA TGT GCA GCC TCT GGA TTC ACC TTC AAT ATC TAC GCC ATG AAC TGG ATC CGC CAG GCT CCA GGA AAG GGT TTG GAA TGG ATT GCT CGC ATA AGA AGT AAA AGT AAT AAT TAT GCA ACA TAT TAT GCC GAT TCA GTG AAA GAC AGG TTC ACC ATC TCC AGA GAT GAT TCA CAG AAT ATG GTC TAT CTG CAA ATG AAC AAC TTG AAA ACT GAG GAC ACA GCC ATG TAT TAC TGT GTG AGT TCC TAT TAC TCC GGT AGT TTC TTT GCT TAC TGG GGC CAA GGG ACT CTG GTC ACT GTC TCT GCA (配列番号13)
と少なくとも60%の同一性を有する重鎖可変領域をコードする少なくとも1つのヌクレオチド配列を含む。
a) 本発明による宿主生命体、特に単細胞宿主生命体を培地中、適切な条件下で培養する工程、
b) 前記培養された宿主生命体の培地から、又は前記培養された宿主生命体から前記抗体を回収する工程
を含む。
a) 生物学的試料を本発明による化合物と接触させる工程、
b) 前記化合物と前記エンドセリン受容体サブタイプAとの複合体を検出する工程
を含む、エンドセリン受容体サブタイプAの発現又は過剰発現をインビボ又はインビトロで検出し定量するための方法に関する。
a1') 対象の生物学的試料を本発明による化合物と接触させる工程、
b1') 易検出基によって放射されるシグナルを検出する工程、及び
c1') 工程(b1')で検出され、任意選択で対照シグナルと比較したシグナルに基づいて前記対象におけるがんの存在又は非存在を決定する工程
を含む。
本発明において用いた免疫及びハイブリドーマの選択の戦略は、国際出願WO第2012/045776号[14]及びWO第2017/220739号[15]において用いられたものと同一である。
Rendomab-A63をプロテインA-PropSep高容量(Millipore社)で精製した後に、その生化学的特性の特徴解析を行った。
i) ETA-Rを発現していないCHO(「チャイニーズハムスター卵巣」の略)細胞株(CHO-WT)で、
ii) 安定な様式でトランスフェクトしてETA-Rの強い発現を可能にしたCHO-ETAR株、CHO細胞で、及び
iii) 患者の膠芽腫の切除の後の生検からJean-Philippe Hugnot博士によって確立された膠芽腫細胞株Gli-7の株で、
生成した。
III.1. 序言
膠芽腫腫瘍細胞は、図3に提示するGliovis社の公衆ベース(http://gliovis.bioinfo.cnio.es/)のトランスクリプトデータによって示されるように、ET-1[20]及びエンドセリンタイプA受容体(ETAR)を過剰発現していることが公知である。これらのデータは、患者の膠芽腫細胞におけるEDNRAトランスクリプトの過剰発現を明らかに示している。
図4は、以下の操作条件:
- 1μMのET1-FAM(Phoenix Pharmaceuticals社FG-023-01A)の存在下(図4A)、
- 30nMのRendomab-A63の存在下(図4B)、及び
- 30nMの対照抗体(NC)の存在下で同じ二次抗体を400倍に希釈(図4C)
における膠芽腫Gli-7細胞株の免疫蛍光の結果を提示する。
本発明によるRA63抗体を産生することができた免疫プロセスにおいて、複数のモノクローナル抗体が得られた。
図7に、Gli-7細胞を同じ位置に異種移植した前臨床ヌードマウスモデルにおけるインビボ蛍光イメージングの結果を提示する。
Rendomab-A63の重鎖及び軽鎖をコードする核トランスクリプトのクローニングを、キット「GenElute/Total RNA」(Sigma-Aldrich社)及び「RACE-PCR」(Invitrogen社)を用いて実施した。
Claims (19)
- i)少なくとも1つの軽鎖可変領域であって、
- CDR1Lのアミノ酸配列がSQSIVYSNGKIYL (配列番号2)であり、
- CDR2Lのアミノ酸配列がKVSであり、
- CDR3Lのアミノ酸配列がFQGSHLPLT (配列番号4) である、軽鎖可変領域と、
ii)少なくとも1つの重鎖可変領域であって、
- CDR1Hのアミノ酸配列がGFTFNIYA (配列番号6) であり、
- CDR2Hのアミノ酸配列がIRSKSNNYAT (配列番号8) であり、
- CDR3Hのアミノ酸配列がVSSYYSGSFFAY (配列番号10) である、重鎖可変領域と
を有する、エンドセリン受容体サブタイプAに対する抗体、その断片又は誘導体であって、前記断片が、少なくとも一つの抗原結合部位を有し、且つ、エンドセリン受容体サブタイプAに結合する活性を有し、前記誘導体が、一本鎖Fv(scFv)又は単一ドメイン抗体(dAb)である、抗体、その断片又は誘導体。 - 少なくとも1つの軽鎖可変領域を含み、アミノ酸配列が以下の配列
と少なくとも60%の同一性を有することを特徴とする、請求項1に記載の抗体。 - 少なくとも1つの重鎖可変領域を含み、アミノ酸配列が以下の配列
と少なくとも60%の同一性を有することを特徴とする、請求項1又は2に記載の抗体。 - IgG2b/カッパ型の免疫グロブリンであることを特徴とする、請求項1から3のいずれか一項に記載の抗体。
- モノクローナルであることを特徴とする、請求項1から4のいずれか一項に記載の抗体。
- 2017年10月18日にCNCMにCNCM番号I-5250として登録されたハイブリドーマから得られたモノクローナルマウス抗体であることを特徴とする、請求項1から5のいずれか一項に記載の抗体。
- キメラ化抗体であることを特徴とする、請求項1から6のいずれか一項に記載の抗体。
- ヒト化抗体であることを特徴とする、請求項1から7のいずれか一項に記載の抗体。
- 2017年10月18日にCNCM番号I-5250としてCNCMに登録したハイブリドーマ。
- 以下の種々のポリヌクレオチド:
α)請求項1から8のいずれか一項に記載の抗体をコードするポリヌクレオチド、
β)ポイント(α)に規定のポリヌクレオチドに相補的なポリヌクレオチド
から選ばれる単離されたポリヌクレオチド。 - 請求項10に記載のポリヌクレオチドを少なくとも1つ含むクローニング及び/又は発現のためのベクター。
- 請求項10に記載のポリヌクレオチド又は請求項11に記載のベクターによってトランスフォームされた、又はこれらを含む、ヒトを除く宿主生命体。
- 細胞毒性基、易検出基、又はエフェクター基からなる群から選ばれる要素とコンジュゲートした請求項1から8のいずれか一項に記載の抗体を含む化合物。
- 薬物としての使用のための、請求項1から8のいずれか一項に記載の抗体、請求項10に記載のポリヌクレオチド、又は請求項13に記載の化合物。
- 活性成分として請求項1から8のいずれか一項に記載の抗体、請求項10に記載のポリヌクレオチド、又は請求項13に記載の化合物、及び薬学的に許容されるビヒクルを含む医薬組成物。
- エンドセリン及び少なくとも1つのエンドセリン受容体を含む軸の、直接の又は別の生理学的経路を伴う機能不全が関与する病気又は病変の治療及び/又は予防における使用のための、請求項1から8のいずれか一項に記載の抗体、請求項10に記載のポリヌクレオチド、請求項13に記載の化合物、又は請求項15に記載の医薬組成物。
- エンドセリン及びエンドセリン受容体サブタイプAを含む軸の、直接の又は別の生理学的経路を伴う機能不全が関与する病気又は病変の治療及び/又は予防における使用のための、請求項1から8のいずれか一項に記載の抗体、請求項10に記載のポリヌクレオチド、請求項13に記載の化合物、又は請求項15に記載の医薬組成物。
- 前記病気又は前記病変ががんであることを特徴とする、請求項16又は17に規定の使用のための請求項1から8のいずれか一項に記載の抗体、請求項10に記載のポリヌクレオチド、請求項13に記載の化合物、又は請求項15に記載の医薬組成物。
- 膠芽腫等のがんをインビトロで検出するための方法であって、
a1') 対象の生物学的試料を請求項13に記載の化合物と接触させる工程、
b1') 易検出基によって放射されるシグナルを検出する工程、
c1') 工程(b1')で検出され、対照シグナルと比較したシグナルに基づいて前記対象におけるがんの存在又は非存在を決定する工程
を含む方法。
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Biochem. Biophys. Res. Commun.,1992年,vol.187, p.1241-l248 |
Peptides,2015年,vol.66, p.19-25 |
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