公开(公告)号：EP2900695A1

公开(公告)日：2015-08-05

申请号：EP13766859.6

申请日：2013-09-16

申请人： The United States Of America, As Represented By The Secretary, Department Of Health And Human Services

发明人： HO, Mitchell ,  PASTAN, Ira, H. ,  DIMITROV, Dimiter, S. ,  TANG, Zhewei ,  FENG, Mingqian ,  GAO, Wei

IPC分类号： C07K16/30 ,  A61K39/395 ,  A61P35/00

CPC分类号： C07K16/30 ,  A61K2039/505 ,  C07K2317/21 ,  C07K2317/30 ,  C07K2317/52 ,  C07K2317/56 ,  C07K2317/569 ,  C07K2317/73 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2319/00 ,  G01N33/57492 ,  G01N2333/705

摘要： Described herein is the use of phage display antibody engineering technology and synthetic peptide screening to identify SD1 and SD2, human single-domain antibodies to mesothelin. SD1 recognizes a conformational epitope at the C-terminal end (residues 539-588) of human mesothelin close to the cell surface. SD2 binds full-length mesothelin. To investigate SD1 as a potential therapeutic agent, a recombinant human Fc (SD1-hFc) fusion protein was generated. The SD1-hFc protein exhibits strong complement-dependent cytotoxicity (CDC), in addition to antibody-dependent cellular cytotoxicity (ADCC), against mesothelin-expressing tumor cells. Furthermore, the SD1-hFc protein causes significant tumor growth inhibition of tumor xenografts in nude mice. SD1 and SD2 are the first human single-domain antibodies targeting mesothelin-expressing tumors.

摘要翻译： 本文描述的是使用噬菌体展示抗体工程技术和合成肽筛选来鉴定SD1和SD2，人间皮素间接抗体。 SD1识别靠近细胞表面的人间皮素C末端（残基539-588）的构象表位。 SD2结合全长间皮素。 为了研究SD1作为潜在的治疗剂，产生了重组人Fc（SD1-hFc）融合蛋白。 除抗体依赖性细胞毒性（ADCC）外，SD1-hFc蛋白对表达间皮素的肿瘤细胞具有强的补体依赖性细胞毒性（CDC）。 此外，SD1-hFc蛋白在裸鼠中引起肿瘤异种移植物的显着肿瘤生长抑制。 SD1和SD2是靶向表达间皮素的肿瘤的第一个人单域抗体。

公开(公告)号：EP2900695B1

公开(公告)日：2018-01-17

申请号：EP13766859.6

申请日：2013-09-16

申请人： The United States Of America, As Represented By The Secretary, Department Of Health And Human Services

发明人： HO, Mitchell ,  PASTAN, Ira, H. ,  DIMITROV, Dimiter, S. ,  TANG, Zhewei ,  FENG, Mingqian ,  GAO, Wei

IPC分类号： C07K16/30 ,  A61K39/395 ,  A61P35/00 ,  G01N33/574 ,  A61K39/00

CPC分类号： C07K16/30 ,  A61K2039/505 ,  C07K2317/21 ,  C07K2317/30 ,  C07K2317/52 ,  C07K2317/56 ,  C07K2317/569 ,  C07K2317/73 ,  C07K2317/732 ,  C07K2317/734 ,  C07K2319/00 ,  G01N33/57492 ,  G01N2333/705

摘要： Described herein is the use of phage display antibody engineering technology and synthetic peptide screening to identify SD1 and SD2, human single-domain antibodies to mesothelin. SD1 recognizes a conformational epitope at the C-terminal end (residues 539-588) of human mesothelin close to the cell surface. SD2 binds full-length mesothelin. To investigate SD1 as a potential therapeutic agent, a recombinant human Fc (SD1-hFc) fusion protein was generated. The SD1-hFc protein exhibits strong complement-dependent cytotoxicity (CDC), in addition to antibody-dependent cellular cytotoxicity (ADCC), against mesothelin-expressing tumor cells. Furthermore, the SD1-hFc protein causes significant tumor growth inhibition of tumor xenografts in nude mice. SD1 and SD2 are the first human single-domain antibodies targeting mesothelin-expressing tumors.