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Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly

An antigen-binding molecule, binding domain technology, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, combinatorial chemistry, etc.

Inactive Publication Date: 2013-09-25
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, until now, in order to achieve the effect of repeatedly binding to the antigen of the pH-dependent antigen-binding antibody and the effect of promoting the elimination of the antigen from plasma, it is only known that the difference between the pH in the plasma and the endosome is used to bind the antigen to the antibody. A method for conferring pH dependence on a reaction

Method used

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  • Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly
  • Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly
  • Antigen-binding molecule capable of binding to plurality of antigen molecules repeatedly

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0662] [Example 1] Concept of Accelerating Antigen Elimination Effect of Calcium-Dependent Antigen-Binding Antibody

[0663] (1-1) Antigen elimination acceleration effect of antigen-binding antibody based on pH-dependent binding antibody

[0664] H54 / L28-IgG1 described in WO 2009 / 125825 is a humanized anti-IL-6 receptor antibody, and Fv4-IgG1 binds to soluble human IL-6 receptor in a pH-dependent manner to H54 / L28-IgG1 A humanized anti-IL-6 receptor antibody made of the characteristics (binding under neutral conditions and dissociation under acidic conditions). In the mouse in vivo test described in WO 2009 / 125825, compared with the group administered with a mixture of H54 / L28-IgG1 and antigen-soluble human IL-6 receptor, Fv4-IgG1 and antigen-soluble human IL-6 receptor were administered It was shown in the group of mixtures of IL-6 receptors that the elimination of soluble human IL-6 receptors can be greatly accelerated.

[0665] The soluble human IL-6 receptor bound to t...

Embodiment 2

[0672] [Example 2] Obtaining a Ca-dependent binding antibody from a human antibody library using phage display technology

[0673] (2-1) Preparation of naive human antibody phage display library

[0674] Multiple human antibodies displaying Fab domains containing human antibody sequences were constructed according to (Methods Mol Biol. 2002;178:87-100.) using polyA RNA prepared from human PBMC or commercially available human polyA RNA as a template Phage display library.

[0675] (2-2) Obtaining Ca-dependent binding antibody fragments from a library by bead panning

[0676] Initial selection from the constructed human antibody phage display library was carried out by enriching only antibody fragments capable of binding to the antigen or by enriching them using Ca-dependent binding ability as an index. When concentrating antibody fragments having Ca-dependent binding ability, phages are eluted by chelating Ca ions with EDTA after binding to antigens in the presence of Ca ...

Embodiment 4

[0710] [Example 4] Calcium ion binding evaluation of the obtained antibody

[0711] Next, in order to evaluate the calcium ion binding of the antibody, the intermediate temperature of thermal denaturation (Tm value) was evaluated by differential scanning calorimetry (DSC) (MicroCal VP-Capillary DSC, manufactured by MicroCal). The intermediate temperature of thermal denaturation (Tm value) is an indicator of stability. When calcium ions are bound to stabilize the protein, the intermediate temperature of thermal denaturation (Tm value) is higher than when calcium ions are not bound (J Bio Chem. 2008 Sep 12 ; Vol.283 ; No. 37:pp 25140 - 25149), using this principle, the calcium ion binding of antibodies was evaluated. Dilute the purified antibody against 20 mM Tris-HCl, 150 mM NaCl, 2 mM CaCl 2 , pH7.4, or 20 mM Tris-HCl, 150 mM NaCl, 3 μM CaCl 2 , pH7.4 solution was dialyzed (EasySEP, TOMY). The protein solution was prepared at 0.1 mg / mL from the solution used for dialysis, a...

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Abstract

The present invention addresses the problem of providing a method for promoting the uptake of an antigen into a cell by an antigen-binding molecule; a method for increasing the frequency of binding to an antigen by one antigen-binding molecule; a method for promoting a reduction in plasma antigen concentration by the administration of an antigen-binding molecule; a method for improving the retention of an antigen-binding molecule in plasma; an antigen-binding molecule which promotes the uptake of an antigen into a cell; an antigen-binding molecule such that the frequency with which the molecule binds to an antigen is increased; an antigen-binding molecule capable of promoting, by the administration thereof, a reduction in plasma antigen concentration; an antigen-binding molecule which has improved retention in plasma; pharmaceutical compositions comprising such antigen-binding molecules; and methods for producing the foregoing. The inventors discovered that the problem can be solved by using an antigen-binding molecule having a calcium-dependent antigen-antibody reaction.

Description

Background technique [0001] Antibodies have high stability in plasma and few side effects, and thus have attracted attention as pharmaceuticals. Among them, a large number of IgG-type antibody medicines are on the market, and a large number of antibody medicines are currently being developed (Non-Patent Document 1, Non-Patent Document 2). On the other hand, as technologies applicable to second-generation antibody medicines, various technologies have been developed, and technologies for improving effector functions, antigen-binding ability, pharmacokinetics, and stability, or for reducing the risk of immunogenicity have been reported. Reduced technology, etc. (Non-Patent Document 3). Usually, the dosage of antibody medicines is very high, so it is difficult to prepare preparations for subcutaneous administration, and the production cost is high. As a method of reducing the dosage of antibody medicines, a method of improving the pharmacokinetics of the antibody and a method of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61K39/395C07K16/18C07K16/46C12P21/08G01N33/15G01N33/50
CPCC07K16/248C07K16/2866C07K16/4291C07K2317/565G01N33/53C07K16/18C07K16/303C07K16/22C07K16/241C07K16/28C07K16/2812C07K16/2863C07K16/3007C07K16/40C07K16/4208C07K16/468C12N15/1037C12N15/62C40B40/02A61K39/395C12N15/09G01N33/5375
Inventor 井川智之石井慎也舩木美步广庭奈绪香前田敦彦根津淳一类家庆直马场威清水骏
Owner CHUGAI PHARMA CO LTD