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Anti-c-met antibody showing enhanced stability or antigen-binding fragments thereof

A technology of hepatocyte growth factor and binding fragment, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, specific peptide, drug combination, etc., can solve problems such as structural instability, and achieve production cost reduction , the effect of reducing immunogenicity and improving stability

Active Publication Date: 2021-07-23
HELIXMITH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, 1E4 (WO2016 / 021864A1; WO2017 / 135791A1), which is an IgG1-based anti-c-hepatocyte growth factor receptor antibody, developed by the present inventors has high affinity for c-hepatocyte growth factor receptor, but not during production, showing structural instability

Method used

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  • Anti-c-met antibody showing enhanced stability or antigen-binding fragments thereof
  • Anti-c-met antibody showing enhanced stability or antigen-binding fragments thereof
  • Anti-c-met antibody showing enhanced stability or antigen-binding fragments thereof

Examples

Experimental program
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Effect test

Embodiment

[0167] Throughout this specification, unless otherwise mentioned, "%" used to express the concentration of a specific substance is (weight / weight)% in solid / solid, (weight / volume) in solid / liquid % and (v / v)% in liquid / liquid.

[0168] Example 1. Constant region substitution and biological activity confirmation of 1E4 antibody

[0169] In order to maintain the characteristics of the anti-c-hepatocyte growth factor receptor antibody in 1E4, which is an IgG1-based anti-c-hepatocyte growth factor receptor antibody disclosed in conventional patents WO2016 / 021864A1 and WO2017 / 135791A1 To improve the structural stability, the present inventors utilized a complementarity-determining region grafting method in which the complementarity-determining region of a conventional antibody is grafted to a framework region that is more stable than that of a conventional antibody. Before implementing the complementarity-determining region transplantation method, ABZENA Company of the United King...

Embodiment 2

[0172] Example 2. Searching for the optimal framework (framework) for CDR transplantation

[0173] In relation to 1E4, which is an IgG1-based anti-c-hepatocyte growth factor receptor antibody disclosed in previous patents WO2016 / 021864A1 and WO2017 / 135791A1, the present inventors intend to maintain the anti-c-hepatocyte growth factor receptor antibody characteristics while improving structural stability. For this reason, the present inventors utilized a complementarity-determining region grafting method in which the complementarity-determining region of a conventional antibody is grafted to a framework region that is more stable than that of a conventional antibody.

[0174]First, in order to screen the optimal framework region, the heavy chain variable domain (hereinafter referred to as "VH") and the light chain variable domain (hereinafter referred to as "Vk") The amino acid sequence of the site was compared with a database of human germline variable (V) and junction (J) fr...

Embodiment 3

[0202] Example 3. Establishment of final candidate heavy chain variable region and light chain variable region sequences evaluated by In silico immunogenicity

[0203] The complementarity determining region of the 1E4 antibody was grafted to the backbone screened in Example 2, and the amino acid residues confirmed to be important for maintaining the antigen-antibody binding force were back-mutated (back-mutated) using iTope from ABZENA, UK. TM and TCED TM (Perry et al. 2008; Bryson et al. 2010) Analytical techniques to evaluate in silico immunogenicity.

[0204] Specifically, among the peptides (peptides) of the backbone candidate sequences screened in Example 2, 9 peptides were added as one amino acid unit and scanning analysis was performed. According to this analysis technique, the amino acid residues of antibody variable region sequences are numbered using the Kabat numbering system, in "iTope TM The " column indicates regions containing potentially immunogenic peptides....

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Abstract

The present invention relates to an anti-c-Met antibody showing enhanced stability or antigen-binding fragments thereof, and the use thereof. Compared to 1E4 which is a parent antibody, the anti-c-Met antibody showing enhanced stability or antigen-binding fragments thereof according to the present invention exhibits excellent productivity and biological activity, enhanced stability and reduced immunogenicity. Therefore, the anti-c-Met antibody or antigen-binding fragments thereof according to the present invention exhibits, in anti-c-Met antibody development, excellent properties such as reduced production cost, inhibition of reduced efficacy, reduced side effects and the like.

Description

technical field [0001] The present invention is completed by the project number HI17C1693 under the support of the Ministry of Health and Welfare of Korea. The research and management agency of the above-mentioned project is the Korean Health Industry Promotion Institute. )-Met Antibody Kidney Disease Biopharmaceuticals Non-clinical R&D and Mechanism Research", the competent institution is Boramae Hospital in Seoul Special City, and the research time is from April 10, 2017 to December 31, 2019. [0002] This patent application claims priority from Korean Patent Application No. 10-2018-0140196 filed on November 14, 2018, the entire contents of which are incorporated herein by reference. Background technique [0003] The c-hepatocyte growth factor receptor (Mesenchymal-epithelial transition factor) expressed on the cell surface is a receptor tyrosine kinase encoded by the hepatocyte growth factor receptor proto-oncogene (proto-oncogene). Structurally, c-hepatocyte growth fact...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28
CPCC07K16/2863C07K2317/52C07K2317/70C07K2317/56C07K2317/24C07K2317/92C07K2317/94A61P9/10A61P17/02A61P9/00A61P13/12A61P25/28C07K2317/75C07K2317/565C07K2317/567
Inventor 郑在均李政勳权桑浩
Owner HELIXMITH CO LTD
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