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ANTICORPS BISPÉCIFIQUE ANTI-WT1/HLA
专利权人:
MEMORIAL SLOAN-KETTERING CANCER CENTER;EUREKA THERAPEUTICS, INC.
发明人:
SCHEINBERG, David,XIANG, Jingyi,DAO, Tao,YAN, Su,LIU, Cheng
申请号:
USUS2014/064621
公开号:
WO2015/070061A1
申请日:
2014.11.07
申请国别(地区):
US
年份:
2015
代理人:
摘要:
Disclosed herein is a bi-specific form of a T cell receptor mimic (TCRm) mAb with reactivity to human immune effector cell antigen and a WT1 peptide/HLA-A epitope. This antibody selectively bound to leukemias and solid tumor cells expressing WT1 and HLA-A as well as activated resting human T cells to release interferon- (IFN-γ) and to kill the target cancer cells in vitro. Importantly, the antibody mediated autologous T cell proliferation and directed potent cytotoxicity against fresh ovarian cancer cells. Therapeutic activity in vivo of the antibody was demonstrated in NOD SCID SCID Yc* (NSG) mice with three different human cancers expressing WT1 /HLA-A2 including disseminated Ph+ acute lymphocytic leukemia (ALL), disseminated acute myeloid leukemia, and peritoneal mesothelioma. In both of the leukemia xenograft models, mice that received the antibody and T cells also showed longer survival and delayed limb paralysis. Also provided are methods for stimulating a primary T cell response comprising stimulating cytotoxic T cells against a first tumor antigen and a secondary T cell response comprising stimulating effector T cells and/or memory T cells against a first tumor antigen and/or against a second tumor antigen using the bi-specific antibodies described herein.La présente invention concerne une forme bispécifique d'un anticorps monoclonal d'un analogue des récepteurs des lymphocytes T présentant une réactivité contre un antigène des cellules effectrices humaines de l'immunité et un peptide WT1/épitope HLA-A. Ledit anticorps se lie de façon sélective aux cellules leucémiques et tumorales solides exprimant WT1 et HLA-A, ainsi qu'aux lymphocytes T humains au repos activés afin de libérer de l'interféron (IFN-γ) et de tuer les cellules cancéreuses cibles in vitro. Il est important de noter que l'anticorps a été un médiateur de la prolifération des lymphocytes T autologues et a été à l'origine d'une forte cytotoxicité à l'encontre de cellules du cancer de l'ovaire fra
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