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Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly

a technology of antigen-binding molecules and antigen-binding peptides, which is applied in the direction of immunological disorders, drug compositions, peptides, etc., can solve the problems of high production cost, difficult subcutaneous formulation production, and inability to completely neutralize antigens with less antibodies than the amount of antigens, so as to achieve superior in vivo effects and improve the pharmacokinetics of antigen-binding molecules

Inactive Publication Date: 2013-01-10
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0020]The present invention provides methods for making single antigen-binding molecules to repeatedly bind to multiple antigen molecules. When an antigen-binding molecule binds to multiple antigen molecules, the pharmacokinetics of the antigen-binding molecule can be improved and such molecule can exert more superior in vivo effects than those of ordinary antigen-binding molecules.

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 is impossible to completely neutralize antigen with the smaller amount of antibody than the amount of antigen.
With the improvement of antibody pharmacokinetics or affinity maturation technology alone described above, there is thus a limitation in the reduction of the required antibody dose.
However, there have been no reports of catalytic antibodies having sufficient catalytic activity as a pharmaceutical agent.

Method used

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  • Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
  • Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly
  • Antigen-binding molecule capable of binding to two or more antigen molecules repeatedly

Examples

Experimental program
Comparison scheme
Effect test

example 1

Production of Modified Humanized PM1 Antibody

Preparation of Recombinant Soluble Human IL-6 Receptor (SR344)

[0324]A recombinant human IL-6 receptor of the human IL-6 receptor, which served an antigen, was prepared as described below. A CHO cell line that constantly expresses a soluble human IL-6 receptor (hereinafter referred to as SR344) (Yamasaki, et al., Science 1988; 241: 825-828 (GenBank #X12830)) consisting of the amino acid sequence from the 1st amino acid to the 344th amino acid on the N-terminal side as reported in J. Biochem., 108, 673-676 (1990), was produced.

[0325]SR344 was purified from culture supernatant obtained from the SR344-expressing CHO cells using three column chromatographies: Blue Sepharose 6 FF column chromatography, affinity chromatography using a column in which an antibody specific to SR344 is immobilized, and gel filtration column chromatography. The fraction that eluted as the main peak was used as the final purified product.

Preparation of Recombinant Cy...

example 2

Production of pH-Dependently-Binding Antibody H3pI / L73

Method for Creating Antibody Capable of Neutralizing Antigen Multiple Times

[0333]Since IgG molecules are divalent, a single IgG molecule can neutralize up to two antigen molecules when the two sites bind to the antigens; however, it cannot neutralize three or more antigen molecules. Therefore, to maintain the neutralizing effect of a neutralizing antibody over a certain period, it is necessary to administer an amount of the antibody equal to or greater than the amount of antigen produced during the period. Thus, there is a limitation on the extent to which the required dose of antibody can be reduced by improving the pharmacokinetics or affinity of antibody. Therefore, if it were possible to neutralize two or more antigen molecules with a single IgG molecule, the same dose could improve the duration of neutralizing effect, or alternatively the dose of antibody required to achieve the same duration could be reduced.

[0334]For neutr...

example 3

Conferring pH-Dependent Antigen Binding Ability by His Modification of CDR Using Phage Display Technology

[0346]Production of scFv Molecule of Humanized PM1 Antibody

[0347]The humanized PM1 antibody, which is a humanized anti-IL-6R antibody (Cancer Res. 1993 Feb. 15; 53(4): 851-6), was converted into scFv. The VH and VL regions were amplified by PCR, and humanized PM1 HL scFv having the linker sequence GGGGSGGGGSGGGGS (SEQ ID NO. 15) between VH and VL was produced.

Selection of Histidine-Introducible Positions by Histidine Scanning

[0348]PCR was performed using the produced humanized PM1 HL scFv DNA as a template to produce a histidine library in which any one of the CDR amino acids is replaced with histidine. The library portions were constructed by PCR using primers in which the codon of an amino acid desired to be mutated for the library was replaced with CAT, a codon corresponding to histidine, and other portions were constructed by normal PCR. These portions were then linked by ass...

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Abstract

The present inventors discovered that antibodies having weaker antigen-binding activity at the early endosomal pH in comparison with that at the pH of plasma are capable of binding to multiple antigen molecules with a single antibody molecule, have long half-lives in plasma, and have improved durations of time in which they can bind to antigen.

Description

TECHNICAL FIELD[0001]The present invention relates to methods for improving the pharmacokinetics of antigen-binding molecules and methods for increasing the number of times of antigen-binding of antigen-binding molecules, as well as antigen-binding molecules having improved pharmacokinetics, antigen-binding molecules having increased number of times of antigen-binding, and methods for producing such molecules.BACKGROUND ART[0002]Antibodies are drawing attention as pharmaceuticals as they are highly stable in plasma and have few adverse effects. At present, a number of IgG-type antibody pharmaceuticals are available on the market and many more antibody pharmaceuticals are currently under development (Non-Patent Documents 1 and 2). Meanwhile, various technologies applicable to second-generation antibody pharmaceuticals have been developed, including those that enhance effector function, antigen-binding ability, pharmacokinetics, and stability, and those that reduce the risk of immunog...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/53
CPCA61K2039/505C07K16/244C07K16/248C07K16/2866C07K2316/96C07K2317/24C12N15/1037C07K2317/565C07K2317/622C07K2317/77C07K2317/92G01N33/6854G01N2500/00C07K2317/56C07K2317/76A61K39/12A61K39/145A61K2039/544A61K2039/545A61K2039/552C12N2760/16111C12N2760/16134C12N2770/20071A61P37/00A61P43/00C07K16/00C07K2317/90
Inventor IGAWA, TOMOYUKIISHII, SHINYAMAEDA, ATSUHIKONAKAI, TAKASHI
Owner CHUGAI PHARMA CO LTD
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