Antigen-binding molecule containing modified antibody variable region

Inactive Publication Date: 2016-09-29
CHUGAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new type of antagonist molecule that has the ability to bind to three different antigens. This molecule has been designed to have improved activity and to avoid cross-linking between different cells that can cause adverse reactions when used as a drug. Overall, this invention provides a more effective and safer way to target multiple antigens.

Problems solved by technology

As a result, strong adverse reactions are induced.
The trifunctional antibodies are very difficult to administer systemically due to serious cytokine storm-like adverse reactions (Cancer Immunol Immunother.
Even such an antibody, however, fails to act on two immunoreceptors, i.e., CD3ε and FcγR, while binding to the cancer antigen, in view of its molecular structure.

Method used

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  • Antigen-binding molecule containing modified antibody variable region
  • Antigen-binding molecule containing modified antibody variable region
  • Antigen-binding molecule containing modified antibody variable region

Examples

Experimental program
Comparison scheme
Effect test

example 1

Concept of Altered Immunoglobulin Variable (Fab) Region that Binds CD3 (First Antigen) and Another Antigen (Second Antigen), but does not Bind to CD3 (First Antigen) and Another Antigen (Second Antigen) on Different Cells at Same Time

[0272]The binding of an immunoglobulin to two or more molecules of activating FcγR at the same time or to activating FcγR and another antigen at the same time causes the cross-linking reaction of the activating FcγR, which may in turn transduces FcγR ITAM signals, resulting in the possible activation of immunocytes. One molecule of an IgG-type antibody is capable of binding to only one FcγR molecule, as described above. Therefore, two or more molecules of activating FcγR are cross-linked only in the presence of an antigen to activate immunocytes.

[0273]When an IgG-type antibody binds to an antigen through its variable region (Fab), this antibody is also capable of binding to one molecule of FcγR through its Fc region at the same time therewith. This caus...

example 2

Preparation of Anti-Human and Anti-Cynomolgus Monkey CD3ε Antibody CE115

[0286](2-1) Preparation of Hybridoma Using Rat Immunized with Cell Expressing Human CD3 and Cell Expressing Cynomolgus Monkey CD3

[0287]Each SD rat (female, 6 weeks old at the start of immunization, Charles River Laboratories Japan, Inc.) was immunized with Ba / F3 cells expressing human CD3εγ or cynomolgus monkey CD3εγ as follows: at day 0 (the priming date was defined as day 0), 5×107 Ba / F3 cells expressing human CD3εγ were intraperitoneally administered together with a Freund complete adjuvant (Difco Laboratories, Inc.) to the rat. At day 14, 5×107 Ba / F3 cells expressing cynomolgus monkey CD3εγ were intraperitoneally administered thereto together with a Freund incomplete adjuvant (Difco Laboratories, Inc.). Then, 5×107 Ba / F3 cells expressing human CD3εγ and Ba / F3 cells expressing cynomolgus monkey CD3εγ were intraperitoneally administered thereto a total of four times every other week in an alternate manner. One...

example 3

Preparation of Antibody that Binds to CD3 and Human Integrin αvβ3, but does not Bind to these Antigens at Same Time

[0309]As shown in FIGS. 1 to 6, the dual binding Fab is a molecule that binds to CD3 (first antigen) and the antigen of interest (second antigen) through its variable (Fab) region, but does not bind to CD3 (first antigen) and the antigen of interest (second antigen) at the same time. In the case of introducing amino acid alteration for binding to the second antigen to a CD3 (first antigen)-binding antibody Fab region, the amino acid alteration is usually introduced to both of two H chains or L chains. As a result of introducing the alteration to both of the H chains or the L chains, the two antibody Fabs become capable of binding to two antigens, respectively. Thus, these two Fabs might bind to CD3 (first antigen) and the antigen of interest (second antigen) at the same time to cross-link them. Thus, one Fab of the antibody is prepared as Fab binding to a third antigen ...

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Abstract

The present inventors have successfully prepared an antigen-binding molecule comprising an antibody variable region that has binding activity against a molecule expressed on the surface of a T cell and a molecule expressed on the surface of any other immunocyte, but does not bind to these molecules at the same time. The present invention allows the preparation of an antigen-binding molecule capable of circumventing adverse reactions that may be caused by the cross-linking of T cells to other immunocytes, and provides an antigen-binding molecule suitable as a drug.

Description

TECHNICAL FIELD[0001]The present invention provides an antigen-binding molecule comprising: an antibody variable region that is capable of binding to two different antigens (first antigen and second antigen), but does not bind to these antigens at the same time; and an antibody variable region binding to a third antigen different from these antigens, a pharmaceutical composition comprising the antigen-binding molecule, and a method for producing the antigen-binding molecule.BACKGROUND ART[0002]Antibodies have received attention as drugs because of having high stability in plasma and producing few adverse reactions (Nat. Biotechnol. (2005) 23, 1073-1078 (Non Patent Literature 1) and Eur J Pharm Biopharm. (2005) 59 (3), 389-396 (Non Patent Literature 2)). The antibodies not only have an antigen-binding effect and an agonist or antagonist effect, but induce cytotoxic activity mediated by effector cells (also referred to as effector functions), such as ADCC (antibody dependent cytotoxic...

Claims

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Application Information

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IPC IPC(8): C07K16/28C07K16/42
CPCC07K16/2809C07K16/2848C07K16/2896C07K16/2866C07K16/4283C07K2317/565C07K2317/31C07K2317/76C07K2317/55C07K2317/24C07K2317/526C07K16/2875C07K16/30C07K16/2863C07K2319/00C07K2319/70A61P35/00C07K2317/56A61K2039/505
InventorIGAWA, TOMOYUKIKADONO, SHOJIROHIRONIWA, NAOKASAKURAI, MIKA
OwnerCHUGAI PHARMA CO LTD