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New recombinant diamine oxidase and its use for the treatment of diseases characterized by excess histamine

A diamine oxidase, special technology, applied in allergic diseases, oxidoreductase, recombinant DNA technology, etc., can solve problems such as unmet needs

Pending Publication Date: 2021-12-10
VETERINARMEDIZINISCHE UNIV WIEN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Therefore, there is a high and unmet need for improved treatment of conditions associated with excess histamine

Method used

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  • New recombinant diamine oxidase and its use for the treatment of diseases characterized by excess histamine
  • New recombinant diamine oxidase and its use for the treatment of diseases characterized by excess histamine
  • New recombinant diamine oxidase and its use for the treatment of diseases characterized by excess histamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0254] DAOs with modified GAG binding domains:

[0255] Overview: Amino acid mutations in the GAG-binding (heparin / heparan sulfate-binding domain) of DAO. Following mutations in the heparin-binding domain of DAO, animal studies were performed with these mutants. In rats, the short alpha half-life can be nearly eliminated and the beta half-life increased to 6 hours. Alpha half-life refers to the rate of decrease in plasma concentration due to the process of drug redistribution from the central compartment to the peripheral compartment, and β half-life refers to the rate of decrease due to the process of drug elimination by metabolism or excretion. The area under the curve (AUC) increased more than 20-fold. The half-life of 6 hours in rats is extrapolated to 24 to 48 hours in humans, and this is certainly sufficient for the treatment of acute and subacute conditions with excess histamine. For example, anaphylaxis or MCAS events last from a few hours to 1 to 2 days, and in 1...

Embodiment 2

[0328] Fc-DAO with modified GAG binding domain:

[0329] Fc-DAO fusion variants were also tested with further improvements in heparin binding mutations and PK parameters with beta half-life of 9 hours and increased AUC. Amino acids involved in high-affinity interaction with Fc_γ receptors were removed, and amino acids involved in interaction with FcRN were not changed.

[0330] Intravenous injection of Fc-DAO_WT and Fc-DAO-Hepmut4 into rats

[0331] Below are the results using linear and log scales from 6 and 4 rats following iv injection of 1 mg / kg Fc-DAO wild type and Fc-Hepmut4 protein. We only use Fc-DAO wild type to measure 4 hours. Nevertheless, the derived exponential function can be used to extrapolate to 1680 minutes, as measured with the Fc-Hepmut4 variant (see below). Similar to the DAO wild-type protein, the Fc-DAO fusion protein exhibits a very rapid alpha distribution half-life. Most fusion variants were removed from plasma within 20 minutes. Afterwards, u...

Embodiment 3

[0349] DAO with modified GAG binding domain and modified cys123:

[0350] Cysteine ​​123 and 633 are not involved in the disulfide bond formation of the DAO dimer.

[0351] The relative accessible surface area or relative solvent accessibility (RSA) of protein residues is a measure of the solvent exposure of the residues. It can be calculated from the following formula: RSA=ASA / MaxASA, where ASA is the solvent-accessible surface area and MaxASA is the surface area of ​​the largest possible solvent-accessible residue. Both ASA and MaxASA usually start with Measurement.

[0352] RSA Cys123

[0353] reachable / (monomer B)

[0354] reachable / (Monomer A), average = 62.4%

[0355] RSA Cys633

[0356]Cys633 = 34.62 accessible / 148 = 23.4% (monomer B)

[0357] Cys633 = 33.49 accessible / 148 = 22.6% (monomer A), average = 23%

[0358] Cys123 is on the surface, and this is unusual. The cysteine ​​amino acid is the rarest and "least and highest" conserved amino acid in...

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Abstract

The invention refers to a recombinant human diamine oxidase (DAO) with decreased glycosaminoglycan binding affinity, wherein said DAO comprises at least one amino acid modification in the glycosaminoglycan (GAG) binding domain. The present invention also refers to the use of the DAO in the treatment of a condition associated with excess histamine, specifically in the treatment of chronic allergic diseases, more specifically in the treatment of anaphylaxis, anaphylactic shock, chronic urticaria, acute urticaria, asthma, hay fever, allergic rhinitis, allergic conjunctivitis, histamine intoxication, headache, atopic dermatitis inflammatory diseases, mastocytosis, mast cell activation syndrome (MCAS), pre-eclampsia, hyperemesis gravidarum, pre-term labor, peptic ulcers, acid reflux, pruritus, and sepsis.

Description

technical field [0001] The present invention relates to a recombinant diamine oxidase (DAO) with reduced glycosaminoglycan binding affinity, wherein said DAO comprises at least one amino acid modification in the glycosaminoglycan (GAG) binding domain. [0002] The invention also relates to the use of said DAO in the treatment of conditions associated with excess histamine, in particular in the treatment of chronic allergic diseases and / or in the treatment of high-risk pregnancy, more in particular in the treatment of anaphylaxis, anaphylactic shock, Chronic urticaria, acute urticaria, asthma, hay fever, allergic rhinitis, allergic conjunctivitis, histamine poisoning, headache, atopic dermatitis inflammatory disease, mastocytosis, mast cell activation syndrome (MCAS ), preeclampsia, hyperemesis gravidarum, premature labor, peptic ulcer, acid reflux, pruritus and sepsis. Background technique [0003] Histamine (2-(1H-imidazol-4-yl)ethylamine) is an organic nitrogen-containing...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/06A61K38/44C12N15/53
CPCC07K2319/30C07K2319/31A61K38/00C12N9/0022C12Y104/03022A61K38/44A61P37/08C07K16/40G16B30/20G16B35/10C07K14/765C12N15/85
Inventor T·伯姆B·伊尔马N·博特E·格卢多瓦茨
Owner VETERINARMEDIZINISCHE UNIV WIEN
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