公开(公告)号：EP3066131A1

公开(公告)日：2016-09-14

申请号：EP14810051.4

申请日：2014-11-07

申请人： Memorial Sloan-Kettering Cancer Center ,  Eureka Therapeutics, Inc. ,  Novartis AG

发明人： SCHEINBERG, David ,  VEOMETT, Nicholas ,  LIU, Hong ,  XIANG, Jingyi ,  LIU, Cheng ,  DAO, Tao ,  HUET, Heather, Adkins

IPC分类号： C07K16/32 ,  A61K39/395 ,  A61P35/00 ,  A61P35/02 ,  A01K67/027

CPC分类号： C07K16/32 ,  A01K2227/105 ,  A01K2267/0387 ,  A61K2039/505 ,  C07K2317/21 ,  C07K2317/41 ,  C07K2317/72 ,  C07K2317/732 ,  C07K2317/92 ,  C07K2317/94

摘要： The present disclosure relates to an anti-WT-1/HLA/A2 antibody with enhanced antibody dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. The antibody, which has reduced fucose and/or galactose, was compared to its normally glycosylated counterpart in binding assays,
in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. The antibody with normal glycosylation mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/ml, but the reduced fucosylated antibody was about 5-10 fold more potent
in vitro against multiple cancer cell lines, was more potent
in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9
vs 6.5 days), but an identical biodistribution pattern in C57BL6/J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A2.1 + transgenic mice compared to the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage.