Human monoclonal antibodies to human interleukine-4 (hil-4)

FIELD: medicine.

SUBSTANCE: there is offered a monoclonal antibody specific to human interleukine-4 (hIL-4) containing two domains with the related CDR1-3 region. There are described versions thereof that contain specified CDR, polynucleotide coding said antibody. There are described an expression vector and a host-cell for preparing the antibody to human interleukine-4 (hIL-4). There are opened: application of the antibody for preparing a pharmaceutical agent for treating the diseases mediated by interleukine-4 and/or IgE. There is discovered the pharmaceutical composition for treating the diseases mediated by interleukine-4 and/or IgE is opened.

EFFECT: application of the invention ensured the high-affinity neutralised monoclonal antibodies to human interleukine-4.

14 cl, 1 tbl, 6 ex

 

The text descriptions are given in facsimile form.

1. Antibody to IL-4, which has a first domain containing arranged in sequence hypervariable sites CDR1, CDR2 and CDR3, and a second domain that contains arranged in sequence hypervariable sites CDR1', CDR2' and CDR3', selected from the group comprising an antibody, in which
a) CDR1 has the amino acid sequence Gly-Phe-Thr-Phe-Ser-Ser-Tyr-Ala-Met-His,
CDR2 has the amino acid sequence Phe-lle-Trp-Asp-Asp-Gly-Ser-Phe-Lys-Tyr-Tyr-Ala-Glu-Ser-Val-Lys-Gly,
CDR3 has the amino acid sequence Glu-Gly-Ser-Trp-Ser-Pro-Asp-Ile-Phe,
CDR1' has the amino acid sequence Ser-Gln-Gly-lle-Ser-Arg-Ala,
CDR2' has the amino acid sequence Asp-Ala-Ser (DAS),
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-ro-Ile,
b) CDR1 has the amino acid sequence Gly-Phe-Thr-Leu-Ser-Ser-Phe-Gly-Met-His,
CDR2 has the amino acid sequence Val-lle-Trp-Tyr-Asp-Gly-Ser-Asn-Glu-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly,
CDR3 has the amino acid sequence Glu-Gly-Ser-Trp-Ser-Pro-Asp-Ile-Phe,
CDR1' has the amino acid sequence Ser-Gln-Gly-Ile-Arg-Ser-Ala,
CDR2' has the amino acid sequence Asp-Ala-Ser,
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-Pro-Val
b) CDR1 has the amino acid sequence Gly-Phe-Thr-Leu-Ser-Ser-Tyr-Gly-Met-His,
CDR2 has the amino acid sequence Val-Ile-Trp-Tyr-Asp-Gly-Asn-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly,
CDR3 has the amino acid sequence Glu-Gly-Ser-Trp-Ser-Pro-Asp-Ile-Phe,
CDR1' has the amino acid sequence Ser-Gln-Gly-Ile-Ser-Ser-Tyr,
CDR2' has the amino acid sequence Asp-Ala-Ser,
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-Pro
d) CDR1 has the amino acid sequence Gly-Asp-Thr-Phe-Ser-Ser-Tyr-Ala-Ile-Ser,
CDR2 has the amino acid sequence Gly-Ile-Ile-Ile-Pro-Val-Ile-Gly-Thr-Val-Asn-Tyr-Glu-Glu-Arg-Phe-Gln-Asp-Arg,
CDR3 has the amino acid sequence Glu-Glu-Gly-Phe-Leu,
CDR1' has the amino acid sequence Ser-Gln-Gly-Ile-Ser-Ser-Ala,
CDR2' has the amino acid sequence Asp-Ala-Ser,
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-Pro-Leu,
d) CDR1 has the amino acid sequence Gly-Phe-Thr-Phe-Ser-Cys-Cys-Gly-Met-His,
CDR2 has the amino acid on sledovatelnot Val-Ile-Trp-Tyr-Asp-Gly-Ser-Asn-Lys-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly,
CDR3 has the amino acid sequence Asp-Ser-Ser-Gly-Ser-Phe-Tyr-Glu-Tyr-Phe,
CDR1' has the amino acid sequence Ser-Gln-Gly-Ile-Asn-Ser-Ala,
CDR2' has the amino acid sequence Asp-Ala-Ser,
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-Pro-Tyr and
e) CDR1 has the amino acid sequence Gly-Phe-Thr-Phe-Ser-Gly-Tyr-Gly-Met-His,
CDR2 has the amino acid sequence Val-Val-Trp-Tyr-Asp-Gly-
Gly-Tyr-Lys-Phe-Tyr-Ala-Asp-Ser-Val-Lys-Gly,
CDR3 has the amino acid sequence Asp-Ser-Ser-Gly-Ser-Phe-Tyr-Glu-Tyr-Leu,
CDR1' has the amino acid sequence Ser-Gln-Gly-Ile-Ser-Ser-Ala,
CDR2' has the amino acid sequence Asp-Ala-Ser,
CDR3' has the amino acid sequence Phe-Asn-Ser-Tyr-Pro-His.

2. The antibody according to claim 1, containing
a) the polypeptide sequence of which is presented in SEQ ID NO:l, and the polypeptide sequence of which is presented in SEQ ID NO:2, or
b) the polypeptide sequence of which is presented in SEQ ID NO:9, and the polypeptide sequence of which is presented in SEQ ID NO:10, or
C) the polypeptide sequence of which is presented in SEQ ID NO:17, and the polypeptide sequence of which is presented in SEQ ID NO:18, or
g) the polypeptide sequence of which is presented in SEQ ID NO:25, and the polypeptide sequence of which is presented in SEQ ID NO:26, or
d) a polypeptide the sequence of which is presented in SQ ID NO:33, and the polypeptide sequence of which is presented in SEQ ID NO:34, or e) a polypeptide the sequence of which is presented in SEQ ID NO:41, and the polypeptide sequence of which is presented in SEQ ID NO:42.

3. The antibody according to claim 1 or 2, containing
a) the polypeptide sequence of which is presented in SEQ ID NO:3 and a polypeptide, the sequence of which is presented in SEQ ID NO:4, or
b) the polypeptide sequence of which is presented in SEQ ID NO:11, and the polypeptide sequence of which is presented in SEQ ID NO: 12, or
C) the polypeptide sequence of which is presented in SEQ ID NO:19, and the polypeptide sequence of which is presented in SEQ ID NO:20, or
g) the polypeptide sequence of which is presented in SEQ ID NO:27, and the polypeptide sequence of which is presented in SEQ ID NO:28, or
d) a polypeptide the sequence of which is presented in SEQ ID NO:35, and the polypeptide sequence of which is presented in SEQ ID NO:36, or e) a polypeptide the sequence of which is presented in SEQ ID NO:43, and the polypeptide sequence of which is presented in SEQ ID NO:44.

4. The antibody according to any one of claims 1 to 3, which is selected from the group comprising human-specific IL-4 monoclonal antibody, fragment and its counterpart.

5. Selected polynucleotide encoding the antibody according to any one of claims 1 to 3.

6. Pauline is looted according to claim 5, contains
a) polynucleotide, the sequence of which is presented in SEQ ID NO:5, and polynucleotide, the sequence of which is presented in SEQ ID NO:6, or
b) polynucleotide, the sequence of which is presented in SEQ ID NO:13, and polynucleotide, the sequence of which is presented in SEQ ID NO:14, or
C) polynucleotide, the sequence of which is presented in SEQ ID NO:21, and polynucleotide, the sequence of which is presented in SEQ ID NO:22, or
d) polynucleotide, the sequence of which is presented in SEQ ID NO:29, and polynucleotide, the sequence of which is presented in SEQ ID NO:30, or
e) polynucleotide, the sequence of which is presented in SEQ ID NO:37,
and polynucleotide, the sequence of which is presented in SEQ ID NO:38, or
(e) polynucleotide, the sequence of which is presented in SEQ ID NO: 45, and polynucleotide, the sequence of which is presented in SEQ ID NO:46.

7. Polynucleotide on any of pp.5 and 6, encoding
a) the polypeptide SEQ ID NO:7 and SEQ ID NO:8, or
b) the polypeptide SEQ ID NO:15 and SEQ ID NO:16, or
C) the polypeptide SEQ ID NO:23 SEQ ID NO:24, or
g) the polypeptide SEQ ID NO:31 and SEQ ID NO:32, or
d) a polypeptide SEQ ID NO:39 and SEQ ID NO:40, or
e) the polypeptide SEQ ID NO:47 and SEQ ID NO:48.

8. The expression vector containing polynucleotide on any of pp.5-7.

9. Selected a host cell containing the expression system of claim 8.

10. The application is the development of antibodies according to any one of claims 1 to 4 as pharmaceutical agents for the treatment of diseases, mediated IL-4 and/or IgE.

11. The use of antibodies according to any one of claims 1 to 4 to obtain a pharmaceutical for the treatment of diseases mediated by IL-4 and/or IgE.

12. The application of claim 11, in which the disease is selected from the group including atopic dermatitis, allergic asthma and allergic renit.

13. The use according to any one of p-12, in which the antibody is selected from the group comprising human-specific IL-4 monoclonal antibody, fragment and its counterpart.

14. Pharmaceutical composition for the treatment of diseases mediated by IL-4 and/or IgE containing the antibody according to any one of claims 1 to 4 in combination with at least one pharmaceutically acceptable excipient.



 

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