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

Inactive Publication Date: 2014-08-21
CHUGAI PHARMA CO LTD
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  • Abstract
  • Description
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  • Application Information

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Benefits of technology

[0072]The present invention provides methods for promoting antigen uptake into cells by antigen-binding molecules, methods for increasing the number of times of antigen binding by one antigen-binding molecule, methods for promoting the reduction of plasma antigen concentration by administering antigen-binding molecules, and methods for improving the plasma retention of an antigen-binding molecule. Promotion of antigen uptake into ce

Problems solved by technology

This in turn has led to problems such as high production cost, as well as the difficulty in producing subcutaneous formulations.
However, the stoichiometric neutralization of one antibody against one antigen (one divalent antibody against two antigens) is the limit of pre-existing methods, and thus it was impossible to completely neutralize antigen with an amount of

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

example 1

The Concept of Antigen Elimination-Accelerating Effect of Calcium-Dependent Antigen-Binding Antibodies

[0385](1-1) Effect of pH-Dependent Antigen-Binding Antibodies to Accelerate Antigen Elimination

[0386]H54 / L28-IgG1 described in WO 2009 / 125825 is a humanized anti-IL-6 receptor antibody. Fv-4-IgG1 is a humanized anti-IL-6 receptor antibody that results from conferring H54 / L28-IgG1 with the property to bind to soluble human IL-6 receptor in a pH-dependent manner (which binds under neutral condition but is dissociated under acidic condition). The in vivo test described in WO 2009 / 125825 using mice demonstrated that the elimination of soluble human IL-6 receptor could be greatly accelerated in a group administered with a mixture of Fv-4-IgG1 and soluble human IL-6 receptor as antigen as compared to a group administered with a mixture of H54 / L28-IgG1 and soluble human IL-6 receptor as antigen.

[0387]Soluble human IL-6 receptor bound to a general antibody that binds to soluble human IL-6 r...

example 2

Isolation of Ca-Dependent Binding Antibodies from Human Antibody Library Using Phage-Display Technique

(2-1) Preparation of Phage-Display Library of Naive Human Antibodies

[0393]Several human antibody phage-display libraries that present Fab domains comprising a human antibody sequence were constructed using as a template polyA-RNA prepared from human PBMC, human polyA RNA available on the market, or the like, according to Methods Mol. Biol. 2002, 178: 87-100.

(2-2) Isolation of Ca-Dependent Binding Antibody Fragments from Libraries by Bead Panning

[0394]The first selection from constructed human antibody phage-display libraries was achieved by enriching antibody fragments having antibody-binding ability or by enriching using the Ca-dependent binding ability as an indicator. Antibody fragments with a Ca-dependent binding ability were enriched by eluting phages via EDTA chelation of Ca ion after antibody fragments were bound to an antigen in the presence of Ca ion. Biotinylated human IL-...

example 3

Assessment of the Prepared Antibodies for their Ca-Dependent Binding Activity to Human IL-6 Receptor

[0401]Antibodies 6RL#9-IgG1 (heavy chain SEQ ID NO: 1; light chain SEQ ID NO: 2), 6RK#12-IgG1 (heavy chain SEQ ID NO: 66; light chain SEQ ID NO: 67), and FH4-IgG1 (heavy chain SEQ ID NO: 3; light chain SEQ ID NO: 4) prepared in Example 2 were assessed for their binding activity to human interleukin 6 receptor (hIL6R) at pH 7.4 using Biacore T100 (GE Healthcare). The assay was carried out using as a running buffer 0.05% Surfactant P20, 10 mmol / l ACES, 150 mmol / l NaCl (pH 7.4 or 6.0) containing 3 μM or 2 mM CaCl2.

[0402]After immobilizing an adequate amount of recombinant Protein A (Thermo Scientific) onto Sensor chip CM4 (GE Healthcare) by an amino coupling method, antibodies were allowed to bind onto the sensor chip. An appropriate concentration of hIL-6R was injected as an analyte to interact with antibodies on the sensor chip. Then, 10 mmol / l glycine-HCl (pH 1.5) was injected to rege...

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Abstract

An objective of the present invention is to provide methods for promoting antigen uptake into cells by antigen-binding molecules, methods for increasing the number of times of antigen binding by one antigen-binding molecule, methods for promoting reduction of the antigen concentration in plasma by administering antigen-binding molecules, and methods for improving the plasma retention of an antigen-binding molecule, as well as antigen-binding molecules that allow enhanced antigen uptake into cells, antigen-binding molecules having an increased number of times of antigen binding, antigen-binding molecules that can promote reduction of the antigen concentration in plasma when administered, antigen-binding molecules with improved plasma retention, pharmaceutical compositions comprising the above antigen-binding molecules, and methods for producing them. The present inventors revealed that the above objective can be achieved by using antigen-binding molecules that show calcium-dependent antigen-antibody reaction.

Description

BACKGROUND ART[0001]Antibodies are drawing attention as pharmaceuticals as they are highly stable in plasma and have few side effects. At present, 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). Meanwhile, various technologies applicable to second-generation antibody pharmaceuticals have been reported, including those that enhance effector function, antigen-binding ability, pharmacokinetics, and stability, and those that reduce the risk of immunogenicity (Non-patent Document 3). In general, the requisite dose of an antibody pharmaceutical is very high. This in turn has led to problems such as high production cost, as well as the difficulty in producing subcutaneous formulations. In theory, the dose of an antibody pharmaceutical may be reduced by improving antibody pharmacokinetics or improving the affinity between antibodies and antigens.[0002]The literature ha...

Claims

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Application Information

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IPC IPC(8): C07K16/18
CPCC07K16/18C07K16/248C07K16/2866C07K16/4291C07K2317/565G01N33/53C07K16/303C07K16/22C07K16/241C07K16/28C07K16/2812C07K16/2863C07K16/3007C07K16/40C07K16/4208C07K16/468C12N15/1037C12N15/62C40B40/02A61K39/395C12N15/09G01N33/5375
Inventor IGAWA, TOMOYUKIISHII, SHINYAFUNAKI, MIHOHIRONIWA, NAOKAMAEDA, ATSUHIKONEZU, JUNICHIRUIKE, YOSHINAOBABA, TAKESHISHIMIZU, SHUN
Owner CHUGAI PHARMA CO LTD
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