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In vivo ADCC model

An antibody, endogenous technology, applied in the field of transgenic non-human animals at the FcgR) locus, can solve the problem of increasing the overall level of FcgR

Inactive Publication Date: 2014-07-02
ROCHE GLYCART AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in BAC transgenic mice, human and endogenous mouse FcgRs are expressed, resulting in abnormally elevated global FcgR levels

Method used

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Embodiment Construction

[0038] The entire locus containing two murine low-affinity receptor genes (Fcgr4, Fcgr3) was replaced with four human genes (FCGR2A, FCGR3A, FCGR2C, FCGR3B) via recombinase-mediated gene replacement (RMGR). Using this technique, the 54 kb mouse genome, including Fcgr4, Fcgr3 and adjacent non-coding DNA regions, is first flanked by two incompatible Lox elements via sequential homologous gene targeting in mouse ES cells (LoxP and Lox511). In parallel, a BAC construct was prepared containing 160 kb of human genomic DNA including the genes FCGR2A, FCGR3A, FCGR2C, FCGR3B and adjacent noncoding regions, also flanked by LoxP and Lox511. Using the latter DNA construct, Cre-recombinase-mediated exchange of the mouse region with human DNA yields mutant ES cells bearing four human low-affinity FcgR genes that replace the two mouse counterparts. and located at the natural position of said counterpart in the mouse genome (see Figure 1-3 ). Chimeric mice were generated by microinjecting...

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Abstract

The present invention relates to a non-human animal comprising a humanized low affinity FcgR locus. Also provided herein is the use of said non-human animal for determining in vivo efficacy of antibodies, and methods for determining in vivo efficacy of antibodies.

Description

technical field [0001] The field of the invention is transgenic non-human animals comprising a humanized low affinity Fc-gamma receptor (FcgR) locus, including transgenes comprising replacement of the endogenous low affinity FcgR gene with a human low affinity FcgR gene Non-human animals include non-human animals capable of expressing four functional human low-affinity FcgR genes, and non-human animals that do not express endogenous low-affinity FcgR genes. Background technique [0002] Therapeutic antibodies (TherAbs) have proven to be highly effective in the treatment of human diseases such as neoplastic diseases or autoimmune inflammatory afflictions. Often, the therapeutic action of TherAbs is based on the cytotoxic clearance of tumor cells, making the effector function characterization of these antibody preparations a critical issue. TherAbs of murine origin often lead to immune responses (anti-drug antibody (ADA) responses) in treated patients. Although purely human ...

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Application Information

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IPC IPC(8): C12N15/85A01K67/027C07K16/28C07K14/705
CPCA01K67/0278C12N2800/204A01K2227/105A01K2217/072A01K2267/03C07K14/70535C12N15/8509C12N2800/30A01K2207/15A01K2227/10A01K2267/0331A61K49/0008G01N33/5011
Inventor D·布罗伊斯泰特C·格德斯A·伊格莱希亚斯P·乌马纳
Owner ROCHE GLYCART AG
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