Allergotropines for treatment of allergy caused by house dust mites

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of medicine, namely to immunology and allergology, and can be used for the treatment of allergy to house dust mites. For this purpose an allergotropine is obtained by a method of chemical conjugation of an allergoid and synthetic highly molecular immunomodulator Polyoxidonium. The allergotropine contains 1000±200 PNU of the allergoid of house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae and 6.25±1.25 mg of Polyoxidonium.

EFFECT: obtaining the allergotropines, based on the allergoid forms of allergens of house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae, possessing more expressed immunogenic and hyposensitising properties in comparison with the native allergen, makes it possible to carry out the effective treatment of allergy by ASIT method.

2 ex, 2 tbl, 2 dwg

 

The invention relates to medicine, namely to immunology, and relates to the treatment of Allergy to house dust mites.

Currently allergenspecific immunotherapy (ASIT), such as hay fever, is carried out as the method of subcutaneous injection (posit) and sublingual (classic). For injectable formulations using water-salt extracts (LFI) allergens, modified allergens (allergodil) and deposited allergens and Allergology. For classic use of water-salt extracts of allergens and Allergology.

Known water-salt extracts of allergens and allergodil for posit presented in the pharmaceutical market of domestic drugs: "Allergen from house dust for diagnosis and treatment", registration number 94/161/20, (Biomed. I. I. Mechnikov, Russia); "Allergen of the mite Dermatophagoides pteronissimus for diagnosis and treatment", registration number 89/686/16, (Biomed. I. I. Mechnikov, Russia); "the mite Allergen from Dermatophagoides farinae in diagnosis and treatment", registration died 92/203/19 (Biomed. I. I. Mechnikov, Russia); "Allergoids from house dust for the treatment of" registration number R N 001536/01 from 05.03.2009 G. ("Microgen" FGUP NPO, Stavropol).

The LFI allergens in their relative cheapness and availability on the market of pharmaceuticals are not safety and convenience�Ohm applications. The main drawback of the LFI is a high content of ballast substances, which are potential allergens, which creates in the treatment of risk - getting reactions anaphylactic type.

Allergodil ("NPO Microgen") is relatively cheap and available in the market of pharmaceutical preparations, characterized by reduced allergenicity compared to the LFI allergens and, consequently, greater efficiency and lower risk, treatment takes less time. However, the holding posit allergoids ensures even the drug enters the patient's body, besides the current time these allergodil often not stable enough.

Known deposited allergovaktsiny for posit presented the drug "Alustar" "Allergen mites", registration number PL-001047, registration date: 21.10.2011 G., (AO Stillorgan, France). "Alustar" represents adsorbed on the suspension of aluminum hydroxide the LFI allergens. With such benefits of the drug "Alustar" how prolonged action of injection allergovaktsiny, not to mention the main drawback caused by the presence of the LFI of the allergen in the composition allergovaktsiny - the risk of anaphylactic reactions type. In addition, the deposited drugs cause the formation of painful lumps in IU�those injections.

Well-known oral formulations of Allergology on the basis of the LFI allergens presented drugs as solutions: "Staloral" "Allergen mites", registration number LSR-008340/10-180810 (AO Stillorgan, France) and "N-Al" "Mixture ticks" ("Sevapharma", Czech Republic), registration number LSR-003619/09 from 14.05.2009. Oral formulations of Allergology based allergoids (in pill form) submitted by the drug lais Dermatophagoides", registration number PL-001303 of 29.11.2011 (Lofarma Spa, Italy). Preparations for classic easy to use, but expensive and not always readily available in the pharmaceutical market. Method clasic easy to use, but does not provide uniform drug enters the patient's body. In addition, it is impossible not to note the high allergenicity of drugs based on the LFI allergens.

Based on the foregoing, it is clear that the main objective to be solved by the present invention is the improvement of allergovaktsiny, namely: reduction of allergenicity, while maintaining immunogenicity, improved stability allergovaktsiny, creating prolonged dosage forms.

A method of producing allergoids by modifying allergens formaldehyde (V. A. Fradkin "Diagnostic and therapeutic allergens", Moscow, Medicine, 1990 ).

Thus, an immediate�logs to destination not found.

Known allergotropin (patent RF №2205661 "Allergotropin for the treatment of hay fever and a method for the treatment of hay fever"). This allergotropin is characterized in that it contains the pollen allergoids allergenic plants (birch, Timothy grass or sage) and the associated synthetic immunomodulator Polyoxidonium. This allergotropin is intended for the treatment of hay fever caused by pollen of Timothy grass, birch or mugwort and, accordingly, is not an analogue of the invention for the intended purpose. However, the structure is known allergotropina can be called an analogue of the claimed invention.

Allergotropiny are conjugate allergoids prepared from purified allergen-specific freeze-dried water extract of the allergen, and synthetic high molecular weight immunomodulator - Polyoxidonium. Polyoxidonium (copolymer of N-oxide-1,4-ethyleneimine and N-carboxyethyl-1,4-ethyleneimine bromide), registration number 96/302/9, patent RF N 2073031, FEF 42-0501460703, soluble in water, non-toxic, will destroy and completely eliminated from the body.

The allergoids is a chemically modified allergen, and has advantages over the latter, since the chemical modification decreased the allergenicity and the risk of anaphylactic shock guidance. The transformation and�of lerena in the allergoids by chemical modification in the presence of formaldehyde, resulting in the interaction of high - and low-molecular components, contributes to the preservation of the properties of allergoids to induce the synthesis of antibodies. This action increases and due to the rigid and stable structure of the molecule allergoids, resistant to the effects of denaturant unlike the original allergen, and also contributes to prolongation of the action of allergoids, since the destruction of his body, the patient will be slower.

Reduction of allergenicity in the polymerized allergens is connected, on the one hand, with the decrease in the number of antigenic determinants as a result of their reaction with aldehyde groups, on the other hand - unavailability for reagin other determinants, hidden inside high-molecular compounds. Positive impact on the immunogenicity has the increase in molecular weight and creating a more rigid intramolecular bonds.

Active principles of allergotropinov - allergoids with a reduced allergenic activity compared with the original allergen), and immunomodulator Polyoxidonium. The drug should contain specific active antigen and have the ability to interact with specific to it IgG-antibody positive control serum of patients with hypersensitivity to the allergen.

Based on the research� installed, what allergotropiny retain their medico-biological and physico-chemical properties for 3 years.

Using a combination of allergoids and immunomodulator reduces the course of treatment (up to 32 injections in conducting posit the LFI of the allergen to 15), which reduces the possibility of complications (anaphylactic reactions) when the course of treatment.

Thus, high efficiency, safety and low cost of allergotropinov makes them extremely promising and competitive in the market antiallergic drugs.

The object of this invention is the improvement of allergovaktsiny, and the technical result is the creation of medicines for specific immunotherapy of Allergy to house dust mites.

This problem is solved and the technical result is achieved due to the fact that the developed allergotropin for the treatment of allergies caused by house dust mites, characterized by the fact that it is obtained by chemical conjugation allergoids and synthetic high molecular weight immunomodulator - Polyoxidonium, and containing 1000±200 PNU allergoids house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae and 6.25±1.25 mg Polyoxidonium.

Thus, to solve this problem have been developed allergotropiny "Parpol" - for allergies to CR�cabbage soup Dermatophagoides pteronyssinus and Farol" - for the treatment of Allergy to dust mites Dermatophagoides farinae. Drugs obtained by chemical conjugation allergoids and Polyoxidonium.

Allergotropiny "Parpol" and "Parpol" contain 1000±200 PNU allergoids house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae and 6.25±1.25 mg Polyoxidonium.

Claimed in the invention of drugs allergotropinov have a number of obvious advantages, namely: regarding the LFI allergen - reduced allergenic activity, enhanced immune response, prolonged action; relative allergoids - enhanced immune response, prolonged action; with respect to the deposited forms the LFI allergen - reduced allergenic activity, enhanced immune response, lack of painful compression at the injection site due to the basis of water-soluble polymeric carrier.

The present invention is illustrated by the following graphic materials: table 1 presents the results of determination of immunogenicity allergotropina "Parpol", table 2 presents the results of determination of immunogenicity allergotropina "Parpol", Fig. 1 shows a graph of OD values in ELISA by neutralizing IgE antibodies to allergens, allergoids and allergotropina "Parpol", Fig. 2 shows a graph of OD values in ELISA by neutralizing IgE antibodies to the allergen�on, allergoids and allergotropina "Parpol".

Allergotropin for the treatment of allergies caused by house dust mites, was obtained by chemical conjugation allergoids and synthetic high molecular weight immunomodulator - Polyoxidonium. The allergotropina contained 1000±200 PNU allergoids house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae and 6.25±1.25 mg Polyoxidonium.

The implementation of the invention is illustrated by examples.

Example 1.

Allergotropin "Parpol" is a conjugate allergoids from house dust mites Dermatophagoides pteronyssinus prepared from highly purified lyophilized water-salt extract, and synthetic high molecular weight immunomodulator Polyoxidonium.

One vial contains 1000+200 PNU allergoids from house dust mites and 6.25+1.25 mg Polyoxidonium.

Allergotropin presented in the form of a lyophilizate for solution preparation for subcutaneous administration. Dilution of the extract is carried out using a dilution fluid for noncommunicable allergens (FAK 42-0010-2041-01).

Allergotropin used for specific immunotherapy (SIT) hay fever patients with sensitization to house dust mites D. pteronysinus.

Allergotropin assign with history and clinical disease with such manifestations as rhinoconjunctivitis and and�opetceska bronchial asthma IA 1; and when the diagnosis of Allergy, confirmed provocative nasal test and skin tests with commercial allergen house dust mites D. pterony sinus.

Allergotropin stored in a dry, dark place at a temperature of from 4 to 8°C. shelf Life 3 years.

Since the medication is intended for the treatment of Allergy, the conjugation with Polyoxidonium must not alter the allergenic properties of the drug in comparison with the original allergoids.

Compared the immunogenicity and residual allergenicity. Moreover, immunogenicity may not be lower, and the residual allergenicity is not higher than the corresponding values for the original allergoids.

Determination of immunogenicity and residual allergenicity of the preparation was carried out in immunoassay analysis (ELISA). On the polystyrene plates were applied, respectively:

- allergoids made of allergen house dust mites Dermatophagoides pteronyssinus obtained in fsbi "Institute of immunology" FMBA Russia;

- allergotropin "Parpol" received in fsbi "Institute of immunology" FMBA of Russia.

Immunogenicity of the drug is determined by the ability to interact with specific to it IgG from sera of patients. As a positive control was used pulirovaniya serum with a high content of SPE�specific IgG antibodies. Serum for her, containing not less than 10 mgA/1, were selected using a commercial fluoroimmunoassay sets the instrument ImmunoCAP (Pharmacia biotech). The results of the determination of immunogenicity of allergotropinov presented in table 1.

It is seen that the optical density of the obtained preparations and controls are very close, the difference is unreliable (p > 0,05). Thus, it is shown that the immunogenicity manufactured by us allergotropina "Parpol" has not changed compared with the original allergoids.

Like the original allergoids, manufactured drug should have a reduced specific activity compared to purified allergen from which the prepared drug - allergic activity of the allergen source to exceed the allergenic activity allergoids or allergotropina not less than 40%.

The assay was performed by the method of inhibition ELISA. As a positive control was used pulirovaniya serum with a high content of specific IgE antibodies. Serum for her, containing not less than 85 kUA/1, were selected using a commercial fluoroimmunoassay sets the instrument ImmunoCAP (Pharmacia biotech).

The results are presented in Fig. 1. The results of the reaction were evaluated on the chart by the difference OP compared samples at two points of the linear section of the calibration curves, the difference Dol�on at least 40%. From Fig. 1 shows that the binding of allergen with specific IgE control serum above, because the OD values in ELISA by neutralizing antibody significantly lower than for the corresponding concentrations allergoids and the drug that best shows the binding of specific IgE control serum. In two points of the linear section of the calibration curve the difference OP for allergen and allergoids, along with produced on the basis of the drug exceeded 40%. Thus, allergotropin "Parpol" as the original allergoids has a lower allergenicity compared with the allergen house dust mite Dermatophagoides pteronyssinus.

Example 2.

Allergotropin "Farol" is a conjugate allergoids from house dust mites Dermatophagoides farinae prepared from highly purified lyophilized water-salt extract, and synthetic high molecular weight immunomodulator Polyoxidonium.

One vial contains 1000+200 PNU allergoids from house dust mites Dermatophagoides farinae and 6.25+1.25 mg Polyoxidonium.

Allergotropin presented in the form of a lyophilizate for solution preparation for subcutaneous administration. Dilution of the extract is carried out using a dilution fluid for noncommunicable allergens (FAK 42-0010-2041-01).

Allergotropin used for specific immunotherapy (�it) hay fever patients with sensitization to house dust mites Dermatophagoides farinae.

Allergotropin assign with history and clinical disease with such manifestations as rhinoconjunctivitis and atopic bronchial asthma IA 1; and when the diagnosis of Allergy, confirmed provocative nasal test and skin tests with commercial allergen house dust mites Dermatophagoides farinae.

Allergotropin stored in a dry, dark place at a temperature of from 4 to 8°C. shelf Life 3 years.

Since the medication is intended for the treatment of Allergy, the conjugation with Polyoxidonium must not alter the allergenic properties of the drug in comparison with the original allergoids.

Compared the immunogenicity and residual allergenicity. Moreover, immunogenicity may not be lower, and the residual allergenicity is not higher than the corresponding values for the original allergoids.

Determination of immunogenicity and residual allergenicity of the preparation was carried out in immunoassay analysis (ELISA). On the polystyrene plates were applied, respectively:

- allergoids made of allergen house dust mites Dermatophagoides farinae obtained in fsbi "Institute of immunology" FMBA Russia;

- Allergotropin "Parpol" received in fsbi "Institute of immunology" FMBA of Russia.

Immunogenicity of the drug is determined by the ability interfaced as�VAT with specific to it IgG from sera of patients. As a positive control was used pulirovaniya serum with a high content of specific IgG antibodies. Serum for her, containing not less than 10 mgA/1, were selected using a commercial fluoroimmunoassay sets the instrument ImmunoCAP (Pharmacia biotech). The results of the determination of immunogenicity of allergotropinov presented in table 2.

It is seen that the optical density of the obtained preparations and controls are very close, the difference is unreliable (p > 0,05). Thus, it is shown that the immunogenicity manufactured by us allergotropina "Parpol" has not changed compared with the original allergoids.

Like the original allergoids, manufactured drug should have a reduced specific activity compared to purified allergen from which the prepared drug allergic activity of the allergen source to exceed the allergenic activity allergoids or allergotropina not less than 40%.

The assay was performed by the method of inhibition ELISA. As a positive control was used pulirovaniya serum with a high content of specific IgE antibodies. Serum for her, containing not less than 85 kUA/1, were selected using a commercial fluoroimmunoassay sets the instrument ImmunoCAP (Pharmacia biotech).

The results are presented in Fig. 2. The results of response assessment�Wali on the chart by the difference OP compared samples in two points of the linear section of the calibration curves, the difference must be at least 40%. From Fig. 2 shows that the binding of allergen with specific IgE control serum above, because the OD values in ELISA by neutralizing antibody significantly lower than for the corresponding concentrations allergoids and the drug that best shows the binding of specific IgE control serum. In two points of the linear section of the calibration curve the difference OP for allergen and allergoids, together with made on its basis, the drug exceeded 40%. Thus, allergotropin "Parpol" as the original allergoids has a lower allergenicity compared with allergens house dust mites Dermatophagoides farinae.

Table 1
Determination of immunogenicity allergotropina "Parpol"
Form of the drug isManufacturerIgG-antibodies (optical density) M±mThe number of experiments
The allergoidsInstitute of immunology1,322±0,1375
"Parpol" Institute of immunology1,418±0,1645

Table 2
Determination of immunogenicity allergotropina "Parpol"
Form of the drug isManufacturerIgG-antibodies (optical density) M±mThe number of experiments
The allergoidsInstitute of immunology1,291±was 0.1385
"Parpol"Institute of immunology1,309±0,1435

Allergotropin for the treatment of allergies caused by house dust mites, characterized by the fact that it is obtained by chemical conjugation allergoids and synthetic high molecular weight immunomodulator - Polyoxidonium, and containing 1000±200 PNU allergoids house dust mites Dermatophagoides pteronyssinus or Dermatophagoides farinae and 6.25±1.25 mg Polyoxidonium.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to antibodies including human antibodies and their antigen-binding portions, which specifically bind to CCR2, in particular to human CCR2, and can act as CCR2 inhibitors. Anti-CCR2 antibodies are those binding to first and/or second extra-cellular CCR2 loops. The present invention also refers to human anti-CCR2 antibodies and to their antigen-binding portions. The present invention refers to the recovered heavy and light chains of immunoglobulin initiated from human anti-CCR2 antibodies, and to nucleic acid molecules coding such immunoglobulins. The present invention also refers to methods for preparing human anti-CCR2 antibodies and their antigen-binding portions, to compositions containing such antibodies or their antigen-binding portions, and to methods for using antibodies and their antigen-binding portions, and compositions for diagnosing and treating.

EFFECT: invention refers to methods for gene therapy with the use of nucleic acid molecules coding molecules of heavy and light chains of immunoglobulin, wherein the above molecules contain anti-CCR2 antibodies and their antigen-binding portions.

25 cl, 24 dwg, 8 tbl, 17 ex

Csf-1r antibody // 2547586

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented an antibody and its antigen-binding fragment specifically binding human colony-stimulating factor-1 receptor (CSF-1R) characterised by sequences of complementary-determining regions (CDR). There are also disclosed a nucleic acid coding the antibody according to the invention or its antigen-binding fragment, a vector providing the expression of the antibody and its antigen-binding fragment, and a pharmaceutical composition applicable in treating the diseases associated with an inflammation or an autoimmunity, or cancer.

EFFECT: invention can find further application in diagnosing and therapy of the CSF-1 associated diseases.

23 cl, 18 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically to a monoclonal antibody (mAb), and can be used in medicine. The above antibody binds to the fibroblast growth factor receptor 2-IIIb (FGFR2IIIb) and contains three CDRs of the light chain and three CDR of the heavy chain presented in Fig.13A and 13B, respectively. The engineered antibody or its humanised analogue is used as an ingredient of a pharmaceutical composition for treating a malignant disease.

EFFECT: invention enables producing the anti-FGFR2IIIb antibody promoting the most effective and complete inhibition of the human tumour heterograft growth in mice.

12 cl, 16 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to an immunostimulatory composition containing a) an adjuvant component containing or consisting of at least one (m)RNA combined with a polycationic peptide or a protein, and b) at least one free mRNA coding at least one antigen with immunostimulatory composition being able to induce or improve the innate or optionally adaptive immune response in a mammal. The molar ration of (m)RNA of the adjuvant component a) to at least one free mRNA of the second component b) of the immunostimulatory composition falls within the range of approximately 0.001:1 to approximately 1:0.001. The immunostimulatory composition according to the present invention can be both a pharmaceutical composition, and a vaccine. The group of inventions also refers to a method for preparing the immunostimulatory composition and using it for treating various diseases.

EFFECT: group of inventions is effective in inducing and improving the immune response in the mammal, as well as in preventing and treating the diseases and disorders specified in a group consisting of tumour, autoimmune, infectious and allergic diseases.

22 cl, 2 tbl, 14 dwg, 11 ex

FIELD: medicine.

SUBSTANCE: treating moderate house atopic bronchial asthma in the patients with immune deficiency suffering from frequent acute respiratory infections is ensured by administering Grippferon intranasally 5 days a week with a leech therapy accompanied by a subcutaneous allergen-specific immune therapy with causally relevant allergens. The leech therapy is performed by applying one medical leech on the skin in a projection of the thymus twice a day for the period of time with no ARI episodes recorded over the last 3 months. The allergens are administered endolymphatically in the proximal direction from a cuff applied on a forehand, and pressure is maintained at 40 mm Hg for 60 minutes with an underlying basic therapy with the Symbicort preparation.

EFFECT: using the method enables providing the higher clinical effectiveness in anti-recurrent therapy of the frequent ARI episodes in the patients suffering from the moderate form of bronchial asthma, reducing the number and length of the ARI episodes, preserving control over the asthmatic symptoms with reducing a dose and a frequency of the preparations of the bronchial asthma therapy.

1 ex

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