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Anti-cd137 antigen-binding molecule and utilization thereof

An antigen-binding molecule, CD137 technology, applied in applications, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody medical components, etc., can solve problems such as damage to normal cells

Pending Publication Date: 2021-05-25
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in many cases, the same antigens are also expressed in non-lesional sites, i.e. normal tissues, which may be responsible for undesirable side effects from a therapeutic point of view
For example, although antibodies against tumor antigens can exhibit cytotoxic activity against tumor cells through ADCC, etc., they may also damage normal cells if the same antigen is expressed in normal cells

Method used

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  • Anti-cd137 antigen-binding molecule and utilization thereof
  • Anti-cd137 antigen-binding molecule and utilization thereof
  • Anti-cd137 antigen-binding molecule and utilization thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1130] Example 1: Antigen Preparation

[1131] (1-1) Preparation of human CD137 extracellular domain

[1132] The extracellular domain of human CD137 (also known as hCD137) was prepared using methods known to those skilled in the art. Specifically, downstream of the gene fragment encoding the extracellular region of human CD137, a gene fragment encoding a histidine tag and a gene fragment encoding a biotin-added specific sequence (AviTag sequence, SEQ ID NO: 86) were connected. A gene fragment encoding a protein (human CD137 or hCD137-HisBAP, SEQ ID NO: 87) in which the extracellular region of human CD137, histidine tag and Avitag are linked was incorporated into an animal cell expression vector. The constructed plasmid vector was transfected into FreeStyle293 cells (Invitrogen) using 293-fectin (Invitrogen). At this time, a plasmid vector containing a gene expressing EBNA1 (SEQ ID NO: 88) was simultaneously transfected. Place the cells transfected with the gene accordi...

Embodiment 2

[1147] Example 2: Obtaining ATP-dependent CD137 antibody

[1148] (2-1) Using ATP to obtain antibodies with small molecule-dependent antigen-binding activity through rationally designed libraries (Small Molecule Conversion Antibody)(1)

[1149] (2-1-1) Panning

[1150] Antibodies exhibiting binding activity to antigen in the presence of adenosine triphosphate (adenosine 5'-triphosphate; ATP) were obtained from a rationally designed antibody phage display library constructed in previous patent WO2015 / 083764. Note that an antibody with small molecule-dependent antigen (eg, CD137) binding activity may be referred to as a "switch antibody" or "small molecule switch antibody", and an antibody with ATP-dependent antigen (eg, CD137) binding activity is referred to as "Converted antibody" or "ATP-converted antibody". To obtain, phages presenting antibodies that exhibited binding activity to antigen captured on beads in the presence of ATP were harvested. Subsequently, phage...

Embodiment 3

[1217] Example 3: Enhancement of Antigen Binding Antibodies in the Presence of Small Molecules Using Rationally Designed Light and Heavy Chain Libraries binding activity

[1218] (3-1) Construction of a library for enhancing binding activity using a rationally designed light chain library

[1219] For the antibody library containing a large number of antibodies having ATP-dependent antigen-binding activity harvested in Example 2-2-1, the binding activity was enhanced by reconstituting the antibody light chain library.

[1220] The light chain and heavy chain regions of a rationally designed antibody phage display library constructed in the existing patent WO2015 / 083764 were used to construct an antibody light chain library and an antibody heavy chain library to enhance binding activity. They were introduced into the light chain or heavy chain regions of the above-mentioned light chain library or the phagemid vector library harvested in Example 2-2-1, and introduced into ...

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Abstract

The purpose of the present disclosure is to provide anti-CD137 antigen-binding molecules that have an effect of activating immunocytes, a cytotoxic activity or an antitumor activity and yet scarcely affect non-tumor tissues such as normal tissues and have few side effects, and a method for using these molecules. By finding a CD137 antigen-binding molecule that shows a change in CD137-binding activity depending on various substances (for example, a low molecular compound) in a target tissue and producing the molecule, provided is an anti-CD137 antigen-binding molecule that has an effect of activating immunocytes, a cytotoxic activity or an antitumor activity and yet scarcely affects non-tumor tissues such as normal tissues and has few side effects. Also provided are a method for using the anti-CD137 antigen-binding molecule, a pharmaceutical formulation, etc. The present disclosure also provides an antigen-binding molecule showing a change in antigen-binding activity depending on a low molecular compound, a method for producing the molecule and utilization of the same.

Description

technical field [0001] The present disclosure relates to anti-CD137 antigen binding molecules and methods of their use. Background technique [0002] Cancer is a deadly disease and, with some exceptions, it is difficult to completely cure it. Chemotherapy drugs, which are the main treatment method, are not very effective. It has been suggested that not only the heterogeneity of cancer cells themselves but also the tumor microenvironment plays an important role as a factor making cancer therapy difficult (Non-Patent Document 1). Recently, it has been shown that unresectable malignant melanoma and the like may be cured with an anti-CTLA-4 antibody that inhibits the immunosuppressive function of CTLA-4, thereby promoting activation of T cells (Non-Patent Document 2). In 2011, an anti-human CTLA-4 monoclonal antibody (ipilimumab) was approved by the US Food and Drug Administration (FDA) as the world's first immune-activating antibody drug. In addition, inhibitory antibodies a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395A61K47/64A61K47/68A61P35/00C12N1/15C12N1/19C12N1/21C12N5/10C12N15/13C12N15/63C12P21/08
CPCA61P35/00C12N15/1037C07K16/2878C07K2317/524C07K2317/526C07K2317/33C07K2317/75C07K2317/92C07K2317/567C07K2317/73A61K2039/505A61K2039/545C07K16/2818C07K16/2866C07K2317/76C07K16/2809A01K67/0278A01K2227/105A01K2267/0393A61K39/395A61K47/64A61K47/68C07K16/28C12N5/10C12N15/63A61K47/6849C07K2317/52C07K2317/56
Inventor 井川智之樱井实香清水骏堀裕次广庭奈绪香濑堀那沙成田义规上川雄之宫崎太郎门野正次郎长谷川雅巳辰巳加奈子早坂昭河合武扬味元风太河内宏树上村将树
Owner CHUGAI PHARMA CO LTD
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