Common light chain mouse

A mouse and light chain technology, applied in the direction of medical preparations containing active ingredients, peptides, anti-animal/human immunoglobulins, etc., can solve problems and other problems

Active Publication Date: 2012-11-21
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, producing bispecific antibodies with suitable light chain components capable of satisfactorily associating with each heavy chain of the bispecific antibody has proven problematic

Method used

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preparation example Construction

[0084] Previous efforts to generate useful multispecific epitope-binding proteins (e.g., bispecific antibodies) have been hampered by multiple problems that often share a common paradigm: in vitro selection or manipulation of sequences for rational engineering, or by trying-and- - Errors (forms suitable for paired heterodimeric bispecific human immunoglobulins) were engineered. Unfortunately, most, if not all, in vitro engineering methods primarily provide for immediate localization of individual molecules, if any. On the other hand, in vitro methods employing complex organisms to select appropriate pairs capable of producing human therapeutics have not been achieved.

[0085] In general, naive mouse sequences are often not a good source of human therapeutic sequences. For at least this reason, generation of mouse heavy chain immunoglobulin variable regions paired with consensus human light chains is of limited practical utility. More in vitro engineering efforts will be spe...

Embodiment 1

[0111] Example 1. Identification of Human Heavy Chain Variable Regions Associated with Selected Human Light Chain Variable Regions

[0112] An in vitro expression system was constructed to determine whether a single rearranged human germline light chain could be co-expressed with a human heavy chain from an antigen-specific human antibody.

[0113] Methods for producing human antibodies in genetically modified mice are known (see, e.g., US 6,596,541, Regeneron Pharmaceuticals, ). The technique involves producing a genetically modified mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse responds to an antigen Stimulation produces antibodies comprising human variable regions and mouse constant regions. encoded by The DNA of the variable regions of the heavy and light chains of antibodies produced by mice is entirely human. Initially, high affinity chimeric antibodies with...

Embodiment 2

[0122] Example 2. Generation of rearranged human germline light chain loci

[0123] use technology (see, e.g., U.S. Pat. No. 6,586,251 and Valenzuela et al. (2003) High-throughput engineering of the mouse genome coupled with high-resolution expression analysis, Nature Biotech.21(6):652-659) prepared a variety of A row of human germline light chain targeting vectors was used to modify the mouse genome bacterial artificial chromosome (BAC) clones 302g12 and 254m04 (Invitrogen). Using these two BAC clones, a genomic construct was engineered to contain a single rearranged human germline light chain region and inserted into the endogenous kappa light chain locus preceded by Modified to delete endogenous kappa variable and linker gene segments.

[0124] A. Construction of rearranged human germline light chain targeting vectors

[0125] Three different rearranged human germline light chain regions were prepared using standard molecular biology techniques recognized in the art. T...

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Abstract

A genetically modified mouse is provided, wherein the mouse is incapable of rearranging and expressing an endogenous mouse immunoglobulin light chain variable sequence, wherein the mouse expresses only one or two human light chain variable domains encoded by human immunoglobulin sequences operably linked to the mouse kappa (K) constant gene at the endogenous mouse K locus, wherein the mouse expresses a reverse chimeric antibody having a light chain variable domain derived from one of only two human light chain variable region gene segments and a mouse K constant domain,. and a human heavy chain variable domain and a mouse heavy chain constant domain, from an endogenous mouse heavy chain locus. Bispecific epitope-binding proteins that are fully human are provided, comprising two different heavy chains that associate with an identical light chain that comprises a variable domain derived from one of two different human light chain variable region gene segments.

Description

field of invention [0001] Genetically modified mice are provided that express antibodies with a common human variable / mouse constant light chain associated with multiple human variable / mouse constant heavy chains. Provided are methods for preparing human bispecific antibodies from human variable region gene sequences of mouse B cells. Background technique [0002] Antibodies typically comprise homodimeric heavy chain components, wherein each heavy chain monomer is associated with the same light chain. Antibodies with heterodimeric heavy chain components (eg, bispecific antibodies) are desired as therapeutic antibodies. However, preparing bispecific antibodies with suitable light chain components capable of satisfactorily associating with each heavy chain of the bispecific antibody has proven problematic. [0003] In one approach, light chains can be selected by surveying the usage statistics of all light chain variable domains, identifying the most commonly employed light ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/85A01K67/027C07K16/46
CPCC12N15/8509A01K2267/01A01K2217/15A01K2227/105A01K67/0278C07K16/22A01K2217/072C12N2800/204C07K2319/30A01K2207/15C07K16/00C07K2317/21C07K2317/24C07K2317/515C07K2317/565C07K2317/567C07K2317/76C07K2317/92A61K38/17A61K38/18A61K39/395C07K14/435C07K14/475C07K14/54C07K16/18C07K16/24C07K16/28C07K16/46C12N15/09A01K67/0276C12N5/0606C12N5/10C07K16/462
Inventor J·麦克沃克L·麦克唐纳S·史蒂文斯S·戴维斯A·J·莫菲D·R·巴克勒
Owner REGENERON PHARM INC
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