JP2020520230A - Paufタンパク質に特異的に結合する抗体及びその用途 - Google Patents
Paufタンパク質に特異的に結合する抗体及びその用途 Download PDFInfo
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- G01N2500/00—Screening for compounds of potential therapeutic value
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Abstract
Description
具体的には、配列番号1の重鎖CDR1;配列番号2の重鎖CDR2;及び配列番号3の重鎖CDR3を含む重鎖可変領域及び配列番号5の軽鎖CDR1;配列番号6の軽鎖CDR2;及び配列番号7の軽鎖CDR3を含む軽鎖可変領域を含むか、
具体的には、配列番号1の重鎖CDR1;配列番号2の重鎖CDR2;及び配列番号30の重鎖CDR3を含む重鎖可変領域及び配列番号5の軽鎖CDR1;配列番号6の軽鎖CDR2;及び配列番号31の軽鎖CDR3を含む軽鎖可変領域を含むか、または
実施例1−1.2H2及び20C5の発掘
PAUFタンパク質を標的とする抗体を開発するために、まずPUAFタンパク質に結合するマウスモノクローナル抗体を用いた。
前記実施例1−1で発掘した2H2、4E6、11G6及び20C5の4種の抗体中、PUAFタンパク質に親和度が最も高い抗体を発掘するために、次のような方法を行った。
前記実施例1−1で発掘した2H2または20C5のエピトープを確認するために、まず、韓国登録特許公報第10−1098186号(特許文献1)に公知となったPAUF特異的なヒトモノクローナル抗体である8F3、即ち、PMAb83と同一なエピトープを有するかを確認した。
実施例2−1.cPMAb22またはcPMAb205の製造
前記実施例1で発掘した2H2または20C5マウス抗体の拒否反応を最小限に抑えるために、前記抗体の可変領域は維持し、不変領域のみヒト由来のタンパク質に変えたキメラ抗体を製造した。
前記実施例2−1で製造したcPMAb22またはcPMAb205のPUAFタンパク質に対する特異度を確認するために、次のような方法を行った。
前記実施例2−1で製造したcPMAb22またはcPMAb205のPUAFタンパク質に対する親和度を確認するために、次のような方法を行った。
前記実施例2−1で製造したキメラ抗体cPMAb22の癌に対する治療効果を確認するために、膵臓癌細胞株BxPC−3に対する増殖抑制効果を確認した。
前記実施例2−1で製造したキメラ抗体cPMAb22の癌に対する治療効果を確認するために、膵臓癌細胞株CFPAC−1及び膵臓癌の患者に由来する膵臓癌細胞AMCPAC04の移動抑制効果を確認した。
前記実施例2−1で製造したキメラ抗体cPMAb22の癌に対する治療効果を確認するために、膵臓癌細胞株CFPAC−1及び膵臓癌患者に由来する膵臓癌細胞であるAMCPAC04に対する浸潤抑制効果を確認した。
実施例3−1.hPMAb22の製造
前記実施例1で発掘した2H2マウス抗体及び前記実施例2で製造したcPMAb22キメラ抗体の拒否反応を最小限に抑えるために、2H2及びcPMAb22のCDR(マウス由来)は維持し、CDRを除いた可変領域及び不変領域はヒト由来のタンパク質に変えたヒト化抗体を製造した。
前記実施例3−1で製造したヒト化抗体hPMAb22のPUAFタンパク質に対する特異度を確認するために、前記実施例2−2による方法を行った。
前記実施例3−1で製造したヒト化抗体hPMAb22のPUAFタンパク質に対する親和度を確認するために、次のような方法を行った。
前記実施例3−1で製造したhPMAb22のエピトープを確認するために、まず既存の抗PAUFヒト抗体であるPMAb83とエピトープが同一かを前記実施例1〜3に基づいて確認した。
前記実施例3−1で製造したヒト化抗体hPMAb22の癌に対する治療効果を確認するために、膵臓癌細胞株CFPAC−1に対する増殖抑制効果を、前記実施例2−4に係る方法で確認した。
前記実施例3−1で製造したヒト化抗体hPMAb22の癌に対する治療効果を確認するために、膵臓癌患者に由来する膵臓癌細胞AMCPAC06及び卵巣癌細胞株OVCAR−5に対する移動抑制効果を、前記実施例2−5による方法で確認した。
前記実施例3−1で製造したヒト化抗体hPMAb22の癌に対する治療効果を確認するために、膵臓癌患者に由来する膵臓癌細胞AMCPAC04またはAMCPAC06及び卵巣癌細胞株OVCAR−5に対する浸潤抑制効果を、実施例2−6による方法で確認した。
前記実施例3−5〜3−7を通じてPAUFタンパク質に特異的なヒト化抗体hPMAb22は試験管内(in vitro)で癌細胞の増殖、移動及び浸潤を抑制することを確認することにより、生体内(in vivo)でも同一な抗癌効果を示すかを確認した。
具体的には、配列番号1の重鎖CDR1;配列番号2または39の重鎖CDR2;及び配列番号3の重鎖CDR3を含む重鎖可変領域及び配列番号5の軽鎖CDR1;配列番号6の軽鎖CDR2;及び配列番号7の軽鎖CDR3を含む軽鎖可変領域を含むか、
具体的には、配列番号1の重鎖CDR1;配列番号2または39の重鎖CDR2;及び配列番号30の重鎖CDR3を含む重鎖可変領域及び配列番号5の軽鎖CDR1;配列番号6の軽鎖CDR2;及び配列番号31の軽鎖CDR3を含む軽鎖可変領域を含むか、または
Claims (14)
- 配列番号1の重鎖CDR1;配列番号2の重鎖CDR2;及び配列番号3、4または30の重鎖CDR3を含む重鎖可変領域及び
配列番号5の軽鎖CDR1;配列番号6の軽鎖CDR2;及び配列番号7または31の軽鎖CDR3を含む軽鎖可変領域を含む、PAUF(Pancreatic adenocarcinoma upregulated factor)タンパク質に結合する抗体。 - 前記抗体の重鎖可変領域は、配列番号8、19、または32の重鎖FR1;配列番号9または20の重鎖FR2;配列番号10、21、または33の重鎖FR3;及び配列番号11、12、22、23、または34の重鎖FR4を含み、
前記抗体の軽鎖可変領域は、配列番号13、24、または35の軽鎖FR1;配列番号14または25の軽鎖FR2;配列番号15または26の軽鎖FR3;及び配列番号16、27または36の軽鎖FR4を含む、請求項1に記載の抗体。 - 前記重鎖可変領域は、配列番号17、28、または37のアミノ酸配列からなり;
前記軽鎖可変領域は、配列番号18、29、または38のアミノ酸配列からなるものである、請求項1に記載の抗体。 - 請求項1〜3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。
- 請求項4に記載のポリヌクレオチドを含む発現ベクター。
- 請求項5に記載の発現ベクターが導入された形質転換体。
- 請求項1〜3のいずれか一項に記載の抗体を含む、癌の予防または治療用医薬組成物。
- 請求項1〜3のいずれか一項に記載の抗体を個体に投与する段階を含む、癌の予防または治療方法。
- 請求項1〜3のいずれか一項に記載の抗体を個体に投与する段階を含む、癌細胞の増殖、移動、または浸潤を抑制する方法。
- 請求項1〜3のいずれか一項に記載の抗体に薬物が結合された、抗体−薬物結合体。
- 請求項1〜3のいずれか一項に記載の抗体を含む、癌診断用組成物。
- 請求項11に記載の組成物を含む、癌診断用キット。
- 請求項1〜3のいずれか一項に記載の抗体を用いて、癌が疑われる個体の分離された生物学的試料からPAUF(Pancreatic adenocarcinoma upregulated factor)タンパク質を抗原抗体反応を通じて検出する段階を含む、癌の診断方法。
- (a)癌細胞に癌の予防または治療候補物質を処理する段階;
(b)前記候補物質が処理された癌細胞において、請求項1〜3のいずれか一項に記載の抗体を用いて、PAUF(Pancreatic adenocarcinoma upregulated factor)タンパク質のレベルを測定する段階;及び
(c)前記段階(b)のPAUFタンパク質のレベルが候補物質を処理していない癌細胞のものより減少する場合、前記(a)段階で処理した候補物質を癌の予防または治療物質と判断する段階を含む、癌の予防または治療物質のスクリーニング方法。
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