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Transgenic non-human animal expressing human-specific molecules and human FC gamma RECEPTOR FAMILY

A non-human animal, transgenic technology, applied in the direction of specific peptides, receptors/cell surface antigens/cell surface determinants, genetic engineering, etc., can solve the function, effectiveness and safety evaluation of pharmaceuticals in animal models, without using disease models Non-clinical test methods, problems with evaluation safety, etc., to achieve high-sensitivity results

Active Publication Date: 2018-01-02
INST OF IMMUNOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, when the above-mentioned transgenic mice expressing human antigens are used for in vivo evaluation of antibody drugs, it may be necessary to administer doses far exceeding clinical doses, which may cause problems in evaluation safety (Non-Patent Document 2 and Non-Patent Document 4 )
[0007] In summary, in the development of molecularly targeted drugs represented by antibody drugs, there is no suitable animal model that can evaluate the function, effectiveness, and safety of the drug in vivo, and there is no non-human animal model that uses a disease model. approach to clinical trials, thus requiring new methods that enable the proper evaluation of pharmaceutical agents using animal models

Method used

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  • Transgenic non-human animal expressing human-specific molecules and human FC gamma RECEPTOR FAMILY
  • Transgenic non-human animal expressing human-specific molecules and human FC gamma RECEPTOR FAMILY
  • Transgenic non-human animal expressing human-specific molecules and human FC gamma RECEPTOR FAMILY

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Example 1: Selection of BACs comprising gene clusters of the human Fcγ receptor family

[0110] Based on the cDNA sequences of human FcγRIIa, IIb, IIc, IIIa, and IIIb genes (GenBank: BC019931, BC031992, BC137397, BC017865, and BC128562), the human genome sequence was retrieved using UCSC GenomeBrowser, and the sequences containing these genes were found. BAC clones of all gene clusters of the human Fcγ receptor family. As a result, RP11-925D6 (Advanced Geno Techs Co.) with a size of 179.6 kb including the entire genomic DNA sequence of the human FcγRIIa, IIb, IIc, IIIa, and IIIb genes was identified and obtained, and it was used as the gene cluster BAC of the human Fcγ receptor family Expression vector( figure 1 ).

Embodiment 2

[0111] Example 2: Selection of BACs comprising the genomic sequences of the human CD20 and mouse CD20 genes

[0112]Based on the cDNA sequence of the mouse CD20 gene (GenBank: BC028322), the mouse genome DNA sequence was retrieved using the UCSC genome browser, and the mouse CD20 gene was found to be located in the 198.19cM region of chromosome 19. Comparison of the cDNA sequence of the mouse CD20 gene with the mouse genome sequence shows that the coding region of the mouse CD20 gene is also encoded by 7 exons in the entire 15 kb genome sequence.

[0113] Then, find the BAC clone encoding the mouse CD20 locus, identify and obtain the genomic DNA sequence of the mouse CD20 locus, the 111 kb genome sequence of the 5' upstream and the 83 kb genome sequence of the 3' downstream chromosome 19 209.9kb covered BAC clone RP23-117H19 ( figure 2 ) (Advanced Geno Techs Co.). According to the above gene information, it can be considered that the 209.9 kb BAC clone RP23-117H19 contains ...

Embodiment 3

[0115] Embodiment 3: Construction of the recombinant BAC expression vector of human CD20 gene

[0116] When constructing the recombinant BAC expression vector of the human CD20 gene, the sequence of intron 4 of the human CD20 gene of the human CD20 gene shown below, the human CD20 gene from the translation initiation codon to the termination codon of the human CD20 gene The sequences of both ends of the genomic DNA sequence, and the 3' side end and 5' side end of the mouse CD20 gene genomic DNA sequence from the translation start codon to the stop codon of the CD20 gene cloned from the mouse BAC were used as Key sequences for active homologous recombination reactions.

[0117] CD20-H1:

[0118] 5'-ATGACAACACCCAGAAATTCAGTAAATGGGACTTTCCCGGCAGAGCCAAT-3' (SEQ ID NO: 1)

[0119] CD20-H2:

[0120] 5'-CTCCCCAAGATCAGGAATCCTCACCAATAGAAAATGACAGCTCTCCTTAA-3' (SEQ ID NO: 2)

[0121] CD20-H3:

[0122] 5'-CCTAGACATTTAGACTAGATAGCAAGATGTTTTGGAAAGCAAGAGGCAGC-3' (SEQ ID NO: 3)

[0123] CD...

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Abstract

The purpose of the present invention is to provide a transgenic non-human animal with which it is possible to appropriately evaluate characteristics, pharmacological effects, and safety of molecularlytargeted substances or drugs with respect to human-specific molecules, and to provide a manufacturing method therefor. The transgenic non-human animal is subjected to transgenesis by using genes coding for human-specific molecules and genes coding for the human Fc gamma receptor family, thus expressing the genes coding for the human-specific molecules and the genes coding for the human Fc gamma receptor family.

Description

technical field [0001] The present invention relates to a transgenic non-human animal expressing human receptors, regulatory factors, antigens and other human specific molecules and human Fcγ receptor family, and using the transgenic non-human animal to utilize experimental animals (mice, rats) in vivo , rabbits, etc.) to evaluate the characteristics, safety and therapeutic effects of molecular targeting substances (such as human chimeric antibodies, humanized antibodies, etc.) that bind to specific human molecules. Background technique [0002] In recent years, genetic engineering technology and antibody engineering technology have made brilliant progress, that is, it is possible to produce targeted drugs against human molecules represented by antibody drugs. However, when non-clinical animal experiments are used to evaluate the pharmacological effects and safety of targeted drugs targeting human molecules, even non-human animals (such as mice, rats, etc.) that do not have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01K67/027C12N15/09C12Q1/68G01N33/15G01N33/50
CPCC12N15/09A01K67/0278A01K2267/03G01N33/5088A01K2217/072A01K2217/15A01K2227/105C07K14/70503C07K14/70535C07K14/71A01K2207/15A01K2217/20C12N15/8509G01N33/15A01K67/027A01K67/0271A01K67/0275A01K2207/12A01K2217/05G01N33/50C12Q1/68
Inventor 盐田明沟吕木达也守时由起
Owner INST OF IMMUNOLOGY
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