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Humanized rodents for testing therapeutic agents

A rodent and human antibody technology, applied in compound screening/testing, chemical instruments and methods, polypeptides containing positioning/targeting motifs, etc., can solve problems such as limiting safety and usefulness, and reducing usefulness

Active Publication Date: 2020-12-18
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the therapeutics often exhibit vastly different pharmacokinetic properties when administered to rodents compared to when they are administered to humans, limiting rodent models for the safety of complex therapeutics in humans Usefulness of Predictors of Sexuality, Efficacy, and Optimal Dosing
This in turn makes the animal model less useful in preclinical testing

Method used

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  • Humanized rodents for testing therapeutic agents
  • Humanized rodents for testing therapeutic agents
  • Humanized rodents for testing therapeutic agents

Examples

Experimental program
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Embodiment 1

[1048] Example 1: Genetic Engineering of Mice Containing Humanized Immunoglobulin Constant Regions

[1049] This example illustrates an exemplary method for constructing a series of targeting vectors for insertion into the genome of a non-human animal such as a rodent (eg, mouse). The methods described in this Example demonstrate the generation of non-human animals whose genomes comprise engineered immunoglobulin heavy chain constant regions and / or engineered immunoglobulin light chain (kappa or lambda) constant regions. In particular, this example demonstrates the construction of targeting vectors for engineering immunoglobulin heavy constant regions to allow non-human animals to express and / or produce antibodies comprising immunoglobulin heavy chains Having a human variable domain and a constant domain that is fully or partially human (eg, comprising a human portion and a rodent portion). It also demonstrates the construction of targeting vectors for engineering immunoglobu...

Embodiment 11

[1053] Example 1.1: Genetic Engineering of Mice Comprising Human Heavy Chain Variable Regions and Chimeric or Fully Human Heavy Chain Constant Regions

[1054] To generate rodents that can be used in human antibody testing (eg, pharmacokinetic and dosing studies of therapeutic antibodies), several methods have been implemented. In the first approach, a human heavy chain variable region and a chimeric (human C H 1-H-C H 2-C H 3 coding sequence and mouse M1-M2 coding sequence) or fully human (C H 1-H-C H 2-C H 3-M1-M2 coding sequence) heavy chain constant region mouse of the heavy chain constant region gene segment. Such mice can be used, for example, to test the relationship with immunoglobulin constant domains encoded by modified gene segments (i.e., the C of the constant domains). H 1-H-C H 2-C H Part 3) Isotype-matched therapeutic antibodies (eg, testing IgG1 antibodies in mice containing genetically engineered IgG1 constant domains).

[1055] In one example, a chim...

Embodiment 12

[1083] Example 1.2: Genetic Engineering of Mice Comprising Mouse Heavy Chain Variable Regions and Human Heavy Chain Constant Regions

[1084] To generate constructs for targeting mouse ES cells comprising a mouse heavy-chain variable region and a human heavy-chain constant region, an intronic enhancer (Eμ) and a 3' regulatory region (3' RR) deletion constructs of the entire mouse IgH constant region (IgM, IgD, IgG3, IgGl, IgG2b, IgG2a, IgE and IgA).

[1085] Briefly, a 5.2 kb 5' mouse homology arm was amplified from BAC clone BMQ-451A16 (The Sanger Centre) by PCR and cloned into a plasmid with the R6K origin of replication and the lox2372-ub-neo cassette using isothermal assembly middle. The resulting plasmid contains from 5' to 3': 392bp R6K origin, unique I-CeuI site, 5.2kb region of the mouse IgH locus including DQ52, JH1-4 and Eμ, unique NotI site, lox2372-ub-neo box and a unique AscI site. This plasmid was digested and the I-CeuI-AscI fragment of the plasmid ligated in...

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Abstract

Provided herein are methods and compositions related to the in vivo testing of therapeutic agents comprising a human Fc in genetically modified rodents (e.g., the testing of the pharmacokinetic and / orpharmacodynamic properties of such a therapeutic agent in genetically modified rodents). In some embodiments the genetically modified rodents express antibodies comprising a human Fc (e.g., a human IgG1 Fc, a human IgG4 Fc). In some embodiments, the rodents express fully human antibodies (i.e., antibodies having human heavy chains and human light (gamma or kappa) chains). In certain embodiments the genetically modified rodents comprise one or more Fc receptors with a human extracellular domain (e.g., a Neonatal Fc Receptor (FcRn), a beta-2-microglobulin polypeptide (beta 2Mu), a Fc epsilon receptor 1 alpha (Fc[epsilon]R1[alpha]), a Fc gamma receptor 1 alpha (Fc[gamma]R1a), a Fc gamma receptor 2a (Fc[gamma]R2a), a Fc gamma receptor 2b (Fc[gamma]R2b), a Fc gamma receptor 3a (Fc[gamma]R3a),a Fc gamma receptor 3b (Fc[gamma]R3b), a Fc gamma receptor 2c (Fc[gamma]R2c)). The transmembrane and cytoplasmic domain of such receptors can be human or non-human (e.g., rodent).

Description

[0001] related application [0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 648,197, filed March 26, 2018, and U.S. Provisional Patent Application Serial No. 62 / 689,628, filed June 25, 2018, in which Each of is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy was created on March 20, 2019, named RPB-01925_(28744-01925)_SL.txt, and is 12,008 bytes in size. Background technique [0005] The safety, efficacy, and pharmacokinetic properties of therapeutic agents are typically tested in animal models prior to administration of the drug to humans. The use of large animals such as non-human primates in such preclinical studies is expensive, and suitable disease models are often not available, limiting the usefulness of s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01K67/027
CPCA01K67/0278A61K49/0008C07K16/00A01K2207/15A01K2217/072A01K2217/15A01K2227/105A01K2267/03C07K2319/03
Inventor V·沃罗宁那C·莫蒙特J·麦克维尔特N·图L·麦克唐纳A·J·莫菲
Owner REGENERON PHARM INC
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