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Target-tissue-specific antigen-binding molecule

An antigen-binding molecule and specificity technology, applied in drug combination, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, etc., can solve problems such as the specificity of protease cancer

Active Publication Date: 2015-04-01
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antibody cleavage by protease is irreversible, so the antibody cleaved at the lesion site returns to normal tissue along with the bloodstream, and it is considered a problem that the antibody can also bind to the antigen in normal tissue
In addition, it is considered that such a protease has a problem in terms of cancer specificity
Therefore, there is no known technique for reversibly acting on cancerous or inflammatory sites as diseased sites without systemically acting on normal tissues or blood in order to exhibit drug effects while avoiding side effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0523] (1) Preparation of effector cells

[0524] Spleen cells were isolated in RPMI1640 medium (Invitrogen) from spleens extracted from CBA / N mice and the like. The concentration of the spleen cells washed with the same medium containing 10% fetal bovine serum (FBS, HyClone) was adjusted to 5×10 6 / mL, from which effector cells can be prepared.

[0525] (2) Preparation of complement solution

[0526] A complement solution was prepared by diluting Baby Rabbit Complement (CEDARLANE) 10-fold with a medium containing 10% FBS (Invitrogen).

[0527] (3) Preparation of target cells

[0528] Antigen-expressing cells were treated with 0.2 mCi of 51 The target cells were radiolabeled by incubating with Cr-sodium chromate (GE Healthcare Bio-Sciences) in DMEM medium containing 10% FBS at 37°C for 1 hour. After radiolabeling, wash 3 times with RPMI1640 medium containing 10% FBS, and adjust the concentration of cells to 2×10 5 / mL, thus the target cells can be obtained.

[0529] ADC...

Embodiment

[1734] [Example 1] The concept of an antibody that binds to an antigen by using a low molecule present in a high concentration in the target tissue as a switch

[1735] In order to exhibit drug efficacy while avoiding side effects, it is necessary to develop a drug that does not act systemically in normal tissues or blood, but acts on cancerous or inflammatory sites as diseased sites. Antibody molecules that can bind to antigens expressed on cancer cells but not to antigens expressed in normal tissues after administration can exert potent anti-cancer cells while avoiding side effects caused by cytotoxic effects on normal tissues Toxic effects. For example, the antigen-binding molecule obtained by changing the aforementioned EGFR-BiTE (Non-Patent Document 9) is a molecule that does not bind to EGFR expressed in normal tissues but can bind to EGFR expressed on cancer cells, which can avoid side effects Play a strong anti-tumor effect. In addition, BiTE recruits and activates T...

Embodiment 2

[1740] [Example 2] Obtaining an antibody that binds to human IL-6 in the presence of low molecular weight from a human antibody library using phage display technology

[1741] (2-1) Preparation of natural human antibody phage display library

[1742] Using poly A RNA prepared from human PBMC or commercially available human poly A RNA as a template, human antibodies consisting of a plurality of phages displaying Fab domains of human antibody sequences different from each other can be constructed according to methods known to those skilled in the art Phage display library.

[1743] (2-2) Obtained from the library by bead panning in the presence of low molecular weight and human IL - 6 Conjugated Antibodies

[1744] From the natural human antibody phage display library constructed in (2-1), screening was performed for antibodies exhibiting antigen-binding activity in the presence of low molecules. That is, phages displaying antibodies exhibiting binding activity to antige...

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Abstract

The inventors of the present invention have invented an antigen-binding molecule, which contains an antigen-binding domain in which binding activity with respect to antigens changes depending on the concentration of a target-tissue-specific compound. Using the present antigen-binding molecule enables various diseases stemming from target tissues to be treated in a target-tissue-specific manner.

Description

technical field [0001] The present invention provides an antigen-binding molecule comprising an antigen-binding domain whose antigen-binding activity varies depending on the concentration of a target tissue-specific compound, methods for producing and screening the antigen-binding molecule, and pharmaceutical compositions comprising the antigen-binding molecule. Background technique [0002] Antibodies are highly stable in plasma and have few side effects, so they are attracting attention as pharmaceuticals. Among them, various IgG-type antibody drugs have been marketed, and many antibody drugs are currently under development (Non-Patent Document 1 and Non-Patent Document 2). [0003] Rituximab (Rituxan) targeting the CD20 antigen, cetuximab (cetuximab) targeting the EGFR antigen, and Herceptin (herceptin) targeting the HER2 antigen have so far been used as cancer therapeutics using antibody drugs. recognized (Non-Patent Document 3). These antibody molecules bind to antige...

Claims

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Application Information

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IPC IPC(8): C07K16/32A61K39/395A61P29/00A61P35/00C07K16/28C07K16/46G01N33/15G01N33/50G01N33/531C12N15/09
CPCC07K16/00C07K16/005C07K16/18C07K16/248C07K16/2866C07K16/30C07K16/44G01N33/6845G01N33/6869A61K2039/505C07K2317/21C07K2317/55C07K2317/34C07K2317/92C07K2317/732G01N2500/00G01N2500/20G01N2333/5412A61P29/00A61P35/00A61P43/00C07K2317/76G01N33/563G01N33/57484
Inventor 井川智之丹波茂郎辰巳加奈子清水骏门野正次郎
Owner CHUGAI PHARMA CO LTD
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