Modified antibody constant region

An antibody and domain technology, applied in the direction of antibodies, antibody medical components, antibody mimetics/scaffolds, etc., can solve the problem of difficult identification

Inactive Publication Date: 2019-08-09
威隆股份公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This makes the identification of target mutations more difficult since it is not possible to extrapolate results obtained on one species to another

Method used

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  • Modified antibody constant region
  • Modified antibody constant region
  • Modified antibody constant region

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1: Preparation of Mutant Canine IgG Fc Domains

[0128] gene synthesis

[0129] Anti-HIV-1 gp120 neutralizing antibody (Zhou T et al.: "Structural definition of a conserved neutralization epitope on HIV-1 gp120" ( "Structural definition of a conserved neutralizing epitope on HIV-1 gp120"), Nature.2007 Feb 15;445(7129):732-7([10])) for the design of codon-optimized DNA for mammalian expression sequence. For both heavy and light chains, a unique NotI restriction site followed by a consensus Kozak sequence (GCCGCCACC) followed by a signal peptide (MGVPTQLGLLLWLTDARC (SEQ ID NO: 5) for the light chain and DNA of strand MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 6)), B12 variable regions (VH and VL) and unique restriction sites (NheI for VH and BsiWI for VL). The VH and VL constructs delivered in the shuttle vector were digested with restriction enzymes (Not I and NheI for VH; NotI and BsiWI for VL) and ligated into which canine IgG2 (isotype B = Chain B) CH1+hinge+CH2+CH...

Embodiment 2

[0141] Example 2: Measurement of canine mAb-FcRn interaction in vitro

[0142] Canine IgG Fc mutant YTE, comprising substitution of amino acid 15.1 of the CH2 domain with tyrosine, substitution of amino acid 16 of the CH2 domain with threonine, and substitution of amino acid 18 of the CH2 domain with glutamic acid (“YTE variant body"), prepared as in Example 1 above.

[0143] In addition, mutant N114A, which corresponds to the canine IgG Fc domain, whose amino acid sequence comprises substitution of amino acid 114 of the CH3 domain with alanine ("NA mutation"), and mutant N90A N40A N114A, which corresponds to canine An IgG Fc domain of a family whose amino acid sequence comprises a substitution of amino acid 90 of the CH2 domain with alanine, substitution of amino acid 40 of the CH3 domain with alanine, and substitution of amino acid 114 of the CH3 domain with alanine ("AAA" mutation), prepared as in Example 1.

[0144] In the first case the interaction between canine IgG2...

Embodiment 3

[0156] Example 3: Determination of Canine WT in Dogs Following Intravenous Administration at a Dose of 0.2 mg / kg b12-IgGB and canine Pharmacokinetic Parameters of YTE-b12-igGB Variants in Animals

[0157] The aim of this study was to verify that the elimination half-life of immunoglobulin (Ig) containing a modified Fc fragment is greater than that of wild-type Ig in the family Canidae.

[0158] For this purpose, the plasma pharmacokinetic parameters of these 2 canine IgGs were compared in dogs following intravenous administration at a dose of 0.2 mg / kg:

[0159] Immunoglobulin A: wild type

[0160] Immunoglobulin B: YTE variant

[0161] animal

[0162] Nine male and / or female Beagle dogs weighing 8.0 kg to 17.5 kg at baseline participated in the study. Breed, body weight, sex, date of birth and source of animal are listed in Table 1 below

[0163] Table 1: Characteristics of the animals used in the study

[0164]

[0165] Measurement conditions

[0166] Immu...

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Abstract

The present invention relates to a canine IgG Fc domain, the amino acid sequence of which comprising at least one mutation selected among: the substitution of amino acid 15.1 of CH2 domain according to the IMGT numbering system for C-domain with tyrosine; the substitution of amino acid 16 of CH2 domain according to the IMGT numbering system for C-domain with threonine; and the substitution of amino acid 18 of CH2 domain according to the IMGT numbering system for C-domain with glutamic acid. The present invention also relates to an Fc-fusion protein, comprising the canine IgG Fc domain, that isgenetically linked to a peptide or a protein or an engineered ligand-binding proteins or a VHH domain, and to an antibody comprising the canine IgG Fc domain.

Description

technical field [0001] The present invention relates to a canine IgG Fc domain, the amino acid sequence of which contains at least one mutation, antibodies and Fc fusion proteins containing the canine IgG Fc domain, especially for use as a medicine. [0002] Accordingly, the present invention has utility in the fields of medicine and pharmacy, especially veterinary medicine. Background technique [0003] Monoclonal antibodies are used as therapeutic agents for the treatment of a variety of conditions, including cancer, autoimmune disease, chronic inflammatory disease, transplant rejection, infectious disease, and cardiovascular disease. Currently, they are more than 60 monoclonal antibody or monoclonal antibody fragment products approved on the market, and hundreds more are in clinical development. Despite such promises and expectations, there remains a significant need to optimize the structural and functional properties of antibodies. [0004] One of the key issues with ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/00A61K39/00
CPCC07K16/00A61K2039/505A61K2039/54A61K2039/545C07K2317/52C07K2317/524C07K2317/526C07K2317/94C07K16/283C07K2317/20C07K2317/92C07K2319/30C12N15/62
Inventor 奥利维耶·勒格尔帕斯卡莱·里亚兰理查德·莫尔斯
Owner 威隆股份公司
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