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Antibody molecules that bind to il-6 receptor

a technology of il-6 receptor and antibody, which is applied in the field of pharmaceutical compositions comprising antiil6 receptor antibodies, can solve the problems of high production cost associated with the administration of extremely large quantities of protein, no report to date on the improvement of the plasma half-life of il-6 receptor antibodies through alteration, etc., to achieve prolong the therapeutic effect, improve the pharmacokinetics, and improve the effect of efficacy

Inactive Publication Date: 2012-10-04
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0071]The humanized anti-IL-6 receptor IgG antibodies obtained according to the present invention have enhanced efficacy and improved pharmacokinetics; thus, they can exert a prolonged therapeutic effect with a less administration frequency.

Problems solved by technology

However, there is no report describing a human, humanized, or chimeric antibody having an affinity greater than 0.05 nM.
A problem encountered with current antibody pharmaceuticals is the high production cost associated with the administration of extremely large quantities of protein.
However, there is no report to date on the improvement of the plasma half-life of IL-6 receptor antibodies through alteration of the variable region.
Another important problem encountered in the development of biopharmaceuticals is immunogenicity.
Furthermore, the CDR sequence of TOCILIZUMAB is a mouse sequence, and thus, like Adalimumab, it may have T-cell epitopes in the CDR, which may have a potential immunogenicity risk.
However, there has been no report on reducing the immunogenicity risk of TOCILIZUMAB by amino acid substitution.
The binding to Fcγ receptor may even be unfavorable from the viewpoint of adverse effects.
It is not easy and would be more costly to manufacture them as pharmaceutical in large-scale while maintaining the objective substances / related substances related heterogeneity derived from disulfide bonds between productions.
However, there is no previous report on constant region sequences for antibodies with the IgG2-isotype constant region that have reduced heterogeneity, high stability, and superior plasma half-life than antibodies with the IgG1 isotype constant region.

Method used

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  • Antibody molecules that bind to il-6 receptor
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  • Antibody molecules that bind to il-6 receptor

Examples

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Effect test

example 1

Identification of Mutation Sites in the Variable Regions for Enhancing the Affinity of TOCILIZUMAB for IL-6 Receptor

[0211]A library of CDR sequences into which mutations have been introduced was constructed and assayed to improve the affinity of TOCILIZUMAB (H chain WT-IgG1 / SEQ ID NO: 53; L chain WT-kappa / SEQ ID NO: 54) for IL-6 receptor. Screening of a library of CDR mutations revealed mutations that improve the affinity for IL-6 receptor. The mutations are shown in FIG. 1. A combination of these mutations yielded high-affinity TOCILIZUMAB such as RDC-23 (H chain RDC23H-IgG1 / SEQ ID NO: 55; L chain RDC-23L-kappa / SEQ ID NO: 56). The affinity for soluble IL-6 receptor and biological activity determined using BaF / gp130 were compared between RDC-23 and TOCILIZUMAB (see Reference Examples for the method).

[0212]The result of affinity measurement is shown in Table 1. The result of biological activity determination using BaF / gp130 (the final concentration of IL-6 was 30 ng / ml) is shown in F...

example 2

Identification of Mutations for Improving the Pharmacokinetics of TOCILIZUMAB Via Reduction of its Isoelectric Point

[0213]To improve the pharmacokinetics of TOCILIZUMAB, investigation was carried out to identify mutation sites that would decrease the isoelectric point of the variable regions without significantly reducing the binding to the IL-6 receptor. Screening of mutation sites in the variable regions, which were predicted based on a three-dimensional structure model of TOCILIZUMAB, revealed mutation sites that would decrease the isoelectric point of the variable regions without significantly reducing its binding to the IL-6 receptor. These are shown in FIG. 3. A combination of these mutations yielded TOCILIZUMAB with reduced isoelectric point including, for example, H53 / L28 (H chain H53-IgG1 / SEQ ID NO: 57; L chain L28-kappa / SEQ ID NO: 58). The affinity for soluble IL-6 receptor, isoelectric point, pharmacokinetics in mice, and biological activity determined using BaF / gp130 wer...

example 3

Identification of Mutation Sites that Reduce the Immunogenicity of TOCILIZUMAB Identification of Mutations that Reduce the Immunogenicity Risk of T-Cell Epitopes Present in the Variable Regions

[0217]T-cell epitopes present in the variable-region sequence of TOCILIZUMAB were analyzed using TEPITOPE (Methods. 2004 December; 34(4):468-75). As a result, the L-chain CDR2 was predicted to have many T-cell epitopes that would bind to HLA (i.e. to have a sequence with a high immunogenicity risk). Thus, TEPITOPE analysis was carried out to examine amino acid substitutions that would reduce the immunogenicity risk of the L-chain CDR2 without decreasing the stability, binding activity, or neutralizing activity.

[0218]As described below, the screening result demonstrated that the immunogenicity risk can be reduced without decreasing the stability, binding activity, or neutralizing activity by substituting the threonine at L51 (Kabat's numbering; Kabat E A et al., (1991) Sequences of Proteins of ...

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Abstract

The present invention provides pharmaceutical compositions comprising second-generation molecules that are superior than TOCILIZUMAB, by altering the amino acid sequences of the variable and constant regions of TOCILIZUMAB, which is a humanized anti-IL-6 receptor IgG1 antibody, to enhance the antigen-neutralizing ability and increase the pharmacokinetics, so that the therapeutic effect is exerted with a less frequency of administration, and the immunogenicity, safety and physicochemical properties (stability and homogeneity) are improved. The present invention also provides methods for producing these pharmaceutical compositions. The present inventors have successfully generated second-generation molecules that are superior to TOCILIZUMAB by appropriately combining amino acid sequence alterations in the CDR domains, variable regions, and constant regions.

Description

TECHNICAL FIELD[0001]The present invention relates to pharmaceutical compositions comprising an anti-IL-6 receptor antibody as an active ingredient, methods for producing the compositions, and such.BACKGROUND ART[0002]Antibodies are drawing attention as pharmaceuticals as they are highly stable in plasma and have few adverse effects. Among them, a number of IgG-type antibody pharmaceuticals are available on the market and many antibody pharmaceuticals are currently under development (Non-Patent Documents 1 and 2). IL-6 is a cytokine involved in various autoimmune diseases, inflammatory diseases, malignant tumors, and so on (Non-Patent Document 3). TOCILIZUMAB, a humanized anti-IL-6 receptor IgG1 antibody, specifically binds to the IL-6 receptor. It is thought that TOCILIZUMAB can be used as a therapeutic agent for IL-6-associated diseases such as rheumatoid arthritis, since it neutralizes the biological activity of IL-6 (Patent Documents 1 to 3, and Non-Patent Document 4). TOCILIZUM...

Claims

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Application Information

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IPC IPC(8): C07K16/00C12N15/63C12N1/19C12N1/21C12N5/10C12N15/13C12P21/02
CPCA61K2039/505C07K2317/76C07K2317/24C07K16/2866A61P1/00A61P1/04A61P1/16A61P11/00A61P11/06A61P13/00A61P13/12A61P15/00A61P15/08A61P17/00A61P17/02A61P17/06A61P19/00A61P19/02A61P19/10A61P21/00A61P25/00A61P27/02A61P27/04A61P29/00A61P3/00A61P35/00A61P37/00A61P37/02A61P37/06A61P37/08A61P43/00A61P5/14A61P7/00A61P7/02A61P7/06A61P9/00A61P9/10A61P9/14A61P3/10A61K39/00A61K39/395C07K16/28C07K16/461C07K2317/41C07K2317/92
Inventor IGAWA, TOMOYUKIISHII, SHINYAMAEDA, ATSUHIKOSAKURAI, MIKAKOJIMA, TETSUOTACHIBANA, TATSUHIKOSHIRAIWA, HIROTAKETSUNODA, HIROYUKIHIGUCHI, YOSHINOBU
Owner CHUGAI PHARMA CO LTD
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