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Antibody having enhanced activity, and method for modifying same

a technology of enhanced activity and antibodies, which is applied in the field of enhanced activity of antibodies, can solve the problem that the bleeding cannot be sufficiently stopped by the bypassing agen

Inactive Publication Date: 2020-08-27
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 creating better antibodies that can mimic FVIII, a protein that helps with blood clotting. The invention also includes methods for improving the FVIII mimic activity using certain mutations. Overall, this technology can help develop better treatments for hemophilia.

Problems solved by technology

Therefore, in some cases, bypassing agents cannot sufficiently stop the bleeding.

Method used

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  • Antibody having enhanced activity, and method for modifying same
  • Antibody having enhanced activity, and method for modifying same
  • Antibody having enhanced activity, and method for modifying same

Examples

Experimental program
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Effect test

example 1

[0087]ACE910 which is an anti-FIXa / FX bispecific antibody is an antibody having the human IgG4 isotype (J Thromb Haemost. 2014 February; 12(2):206-213). ACE910 (hereinafter, also described as ACE910-A) comprises four chains composed of three types of chains. The anti-FIXa heavy chain is called Q chain, the anti-FX heavy chain is called J chain, and the common light chain is called L chain. ACE910-A (Q, J, and L: SEQ ID NOs: 1, 2, and 3) (WO 2012 / 067176) was used as the control antibody.

[0088]The knobs-into-holes technology (Nat Biotechnol. 1998 July; 16(7):677-81) was used to prepare ACE910 of human IgG1, 2, and 4 types. That is, ACE910-B-IgG1 (Q, J, and L: SEQ ID NOs: 4, 5, and 3), ACE910-B-IgG2 (Q, J, and L: SEQ ID NOs: 6, 7, and 3), and ACE910-B-IgG4 (Q, J, and L: SEQ ID NOs: 8, 9, and 3) were prepared, and effects of the human IgG isotypes on the FVIII mimetic activity were evaluated.

[0089]ACE910 is an anti-FIXa / FX bispecific antibody that uses the common L chain (prepared by re...

example 2

[0094]Various ACE910 variants were produced by introducing mutations by methods known to those skilled in the art such as total gene synthesis or PCR, into the human IgG4 bispecific antibody ACE910-B-IgG4 (Q, J, and L: SEQ ID NOs: 8, 9, and 3) and ACE910-C(Q, J, and L: SEQ ID NOs: 10, 11, and 3) (prepared by referring to WO2015 / 046467), which have the same variable region sequence as ACE910-A (Q, J, and L: SEQ ID NOs: 1, 2, and 3). Antibody expression and purification were performed according to the method of Example 1. The introduced mutations are summarized in Table 1 (mutations introduced into regions other than the hinge region) and Table 2 (mutations introduced into the hinge region) below.

TABLE 1Antibody nameMutations introduced into the heavy chainT01P387R, E388R, Q311RT03P387R, D399R, S400R, E345R, H285RT06E345R, E430G, S440YT08N434YT09N434WT56E345RT57S440KQH0001 / / G26E (Q chain only)JH0000QCH0001 / / A162K(Q chain only), N208D (J chain only)JCH0001T63C-terminal sequence of the ...

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Abstract

As a result of producing ACE910 variants in which various sites of the constant regions were modified, the inventors discovered bispecific antibodies having FVIII mimetic activity higher than that of ACE910. The inventors also identified mutation positions that elevate the FVIII mimetic activity and discovered methods for elevating the FVIII mimetic activity by using the mutations.

Description

TECHNICAL FIELD[0001]The present invention relates to antibodies having enhanced activity, pharmaceutical compositions comprising such antibodies as active ingredients, methods for producing them, and methods for enhancing antibody activity. More specifically, the present invention relates to bispecific antibodies having blood coagulation factor VIII (FVIII) mimetic activity higher than that of ACE910.BACKGROUND ART[0002]Antibodies are drawing attention as pharmaceuticals as they are highly stable in plasma and have few adverse effects. Of them, a number of IgG-type antibody pharmaceuticals are available on the market and many antibody pharmaceuticals are currently under development (Non-patent Documents 1, 2 and 3).[0003]Hemophilia A is a bleeding abnormality caused by a hereditary decrease or deficiency of FVIII function. Hemophilia A patients are generally administered with an FVIII formulation for bleeding (on-demand administration). In recent years, FVIII formulations are also ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/36
CPCC07K16/36C07K2317/53C07K2317/526C07K2317/31C07K2317/90C07K2317/75C07K2317/52
Inventor IGAWA, TOMOYUKITERANISHI, YURI
Owner CHUGAI PHARMA CO LTD
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