US-12617869-B2 - Anti-ADAMTS13 antibody and use thereof

US12617869B2US 12617869 B2US12617869 B2US 12617869B2US-12617869-B2

Abstract

A preparation of an antibody or an antibody derivative that can prevent or treat acquired von Willebrand syndrome (AVWS) accompanied by a disease in need of mechanical assisted circulation. The antibody or an antibody derivative has specific binding activity against ADAMTS13, von Willebrand factor (VWF) cleaving protease, which is a causative factor of the acquired von Willebrand syndrome (AVWS) in humans, and can reduce the excessive cleavage of VWF by ADAMTS13.

Inventors

Masanori Matsumoto
Masaki Hayakawa
Teruhito YASUI
Takeharu Minamitani

Assignees

NARA MEDICAL UNIVERSITY
NATIONAL INSTITUTES OF BIOMEDICAL INNOVATION, HEALTH AND NUTRITION
ALFRESA PHARMA CORPORATION

Dates

Publication Date: 20260505
Application Date: 20220303
Priority Date: 20210305

Claims (15)

1 . An antibody or an antibody derivative thereof capable of binding to ADAMTS13 and having an inhibitory effect on von Willebrand factor (VWF) cleaving activity, comprising heavy chain and light chain complementarity determining regions selected from the group consisting of: (1) heavy chain complementarity determining regions CDR1 (GYSFTGYT, SEQ ID NO: 1), CDR2 (INPYNGGT, SEQ ID NO: 2), and CDR3 (ARTSGYLFAY, SEQ ID NO: 3), and light chain complementarity determining regions CDR1 (EDIYNR, SEQ ID NO: 4), CDR2 (GAT), and CDR3 (QQYWSSPLT, SEQ ID NO: 6); (2) heavy chain complementarity determining regions CDR1 (GFSLPRYG, SEQ ID NO: 7), CDR2 (IWAGGST, SEQ ID NO: 8), and CDR3 (ARAGGSQPFDY, SEQ ID NO: 9), and light chain complementarity determining regions CDR1 (RDINTY, SEQ ID NO: 10), CDR2 (RAN), and CDR3 (LQYDEFPWT, SEQ ID NO: 12); (3) heavy chain complementarity determining regions CDR1 (GFSLTRYG, SEQ ID NO: 13), CDR2 (IWAGGST, SEQ ID NO: 14), and CDR3 (ARAGGSSSFDY, SEQ ID NO: 15), and light chain complementarity determining regions CDR1 (QDINTY, SEQ ID NO: 16), CDR2 (RAN), and CDR3 (LQYDEFPWT, SEQ ID NO: 18); and (4) heavy chain complementarity determining regions CDR1 (GFSLTGYG, SEQ ID NO: 19), CDR2 (IWADGTT, SEQ ID NO: 20), and CDR3 (ARAGGSQPFDY, SEQ ID NO: 21), and light chain complementarity determining regions CDR1 (QDINSY, SEQ ID NO: 22), CDR2 (RAN), and CDR3 (LQYDEFPWT, SEQ ID NO: 24).
2 . The antibody or the antibody derivative according to claim 1 , wherein the antibody or the antibody derivative is a recombinant type.
3 . The antibody or the antibody derivative according to claim 1 , wherein the antibody derivative is selected from the group consisting of an engineered antibody, a humanized antibody, a chimeric antibody, a single-chain antibody, a multivalent antibody, a multispecific antibody, and a functional fragment thereof.
4 . The antibody or the antibody derivative according to claim 1 , wherein an amino acid sequence of a heavy chain variable region VH domain of the antibody or the antibody derivative is selected from the group consisting of: (1-1) the amino acid sequence of SEQ ID NO: 25, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 25, (1-2) the amino acid sequence of SEQ ID NO: 27, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 27, (1-3) the amino acid sequence of SEQ ID NO: 29, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 29, (2) the amino acid sequence of SEQ ID NO: 31, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 7), CDR2 (SEQ ID NO: 8), and CDR3 (SEQ ID NO: 9) in the amino acid sequence of SEQ ID NO: 31, (3) the amino acid sequence of SEQ ID NO: 33, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 13), CDR2 (SEQ ID NO: 14), and CDR3 (SEQ ID NO: 15) in the amino acid sequence of SEQ ID NO: 33, and (4) the amino acid sequence of SEQ ID NO: 35, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 19), CDR2 (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 21) in the amino acid sequence of SEQ ID NO: 35.
5 . The antibody or the antibody derivative according to claim 1 , wherein an amino acid sequence of a light chain variable region VL domain of the antibody or the antibody derivative is selected from the group consisting of: (1-1) the amino acid sequence of SEQ ID NO: 26, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 26, (1-2) the amino acid sequence of SEQ ID NO: 28, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 28, (1-3) the amino acid sequence of SEQ ID NO: 30, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 30, (2) the amino acid sequence of SEQ ID NO: 32, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 10), CDR2 (RAN), and CDR3 (SEQ ID NO: 12) in the amino acid sequence of SEQ ID NO: 32, (3) the amino acid sequence of SEQ ID NO: 34, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 16), CDR2 (RAN), and CDR3 (SEQ ID NO: 18) in the amino acid sequence of SEQ ID NO: 34, and (4) the amino acid sequence of SEQ ID NO: 36, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 22), CDR2 (RAN), and CDR3 (SEQ ID NO: 24) in the amino acid sequence of SEQ ID NO: 36.
6 . The antibody or the antibody derivative according to claim 1 , wherein the antibody or the antibody derivative is selected from the group consisting of: (1-1) an antibody or an antibody derivative comprising the amino acid sequence of SEQ ID NO: 37, or an amino acid sequence having a substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 37 and the amino acid sequence of SEQ ID NO: 38, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 38; (1-2) the amino acid sequence of SEQ ID NO: 39, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 39 and the amino acid sequence of SEQ ID NO: 40, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 40); (1-3) the amino acid sequence of SEQ ID NO: 41, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 1), CDR2 (SEQ ID NO: 2), and CDR3 (SEQ ID NO: 3) in the amino acid sequence of SEQ ID NO: 41 and the amino acid sequence of SEQ ID NO: 42, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 4), CDR2 (GAT), and CDR3 (SEQ ID NO: 6) in the amino acid sequence of SEQ ID NO: 42; (2) an antibody or an antibody derivative comprising the amino acid sequence of SEQ ID NO: 43, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 7), CDR2 (SEQ ID NO: 8), and CDR3 (SEQ ID NO: 9) in the amino acid sequence of SEQ ID NO: 43 and the amino acid sequence of SEQ ID NO: 44, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 10), CDR2 (SEQ ID NO: 11 RAN), and CDR3 (SEQ ID NO: 12) in the amino acid sequence of SEQ ID NO: 44; (3) an antibody or an antibody derivative comprising the amino acid sequence of SEQ ID NO: 45, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 13), CDR2 (SEQ ID NO: 14), and CDR3 (SEQ ID NO: 15) in the amino acid sequence of SEQ ID NO: 45 and the amino acid sequence of SEQ ID NO: 46, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 16), CDR2 (RAN), and CDR3 (SEQ ID NO: 18) in the amino acid sequence of SEQ ID NO: 46; and (4) the amino acid sequence of SEQ ID NO: 47, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 19), CDR2 (SEQ ID NO: 20), and CDR3 (SEQ ID NO: 21) in the amino acid sequence of SEQ ID NO: 47 and the amino acid sequence of SEQ ID NO: 48, or an amino acid sequence having the substitution, insertion, or deletion of one or several amino acids at a moiety except for CDR1 (SEQ ID NO: 22), CDR2 (RAN), and CDR3 (SEQ ID NO: 24) in the amino acid sequence of SEQ ID NO: 48.
7 . A pharmaceutical composition for treating bleeding caused by the excessive cleavage of VWF, comprising the antibody or the antibody derivative according to any claim 1 .
8 . The pharmaceutical composition according to claim 7 , wherein the bleeding caused by the excessive cleavage of VWF is bleeding associated with mechanical assisted circulation.
9 . The pharmaceutical composition according to claim 7 , wherein the pharmaceutical composition inhibits the cleaving activity of ADAMTS13 against VWF.
10 . The pharmaceutical composition according to claim 7 , wherein the bleeding associated with mechanical assisted circulation is acquired von Willebrand syndrome (AVWS).
11 . The pharmaceutical composition according to claim 7 , wherein the mechanical assisted circulation is selected from the group consisting of extracorporeal membrane oxygenation (ECMO), implantable left ventricular assist device (LVAD), and percutaneous cardiopulmonary support (PCPS).
12 . A method for detecting and/or measuring the presence or an amount of ADAMTS13 in a biological sample, comprising: contacting the biological sample collected from a test subject with the antibody or the antibody derivative according to claim 1 in vitro; and detecting and/or measuring ADAMTS13 in the sample bound with the antibody or the antibody derivative.
13 . A kit for detecting and/or measuring the presence or an amount of ADAMTS13 in the body of a test subject, comprising the antibody or the antibody derivative according to claim 1 .
14 . A method for detecting and/or measuring the VWF cleaving activity of ADAMTS13 in a biological sample, comprising: adding varying concentrations of the antibody or the antibody derivative according to claim 1 to the biological sample collected from a test subject, followed by incubation; and detecting and/or measuring an intact VWF multimer, an intact VWF monomer, or a cleaved VWF fragment in the sample.
15 . A kit for detecting and/or measuring an intact VWF multimer, an intact VWF monomer, or a cleaved VWF fragment in the body of a test subject, comprising the antibody or the antibody derivative according to claim 1 .

Description

This application is the U.S. National Phase under 35 U.S.C. § 371 of International Application PCT/JP2022/009106, filed Mar. 3, 2022, designating the U.S., and published in Japanese as WO 2022/186331 on Sep. 9, 2022, which claims priority to Japanese Patent Application No. 2021-035392, filed on Mar. 5, 2021, the entire content of which is incorporated herein by reference. SEQUENCE LISTING STATEMENT The present application contains a Sequence Listing, which is being submitted via Patent Center on even date herewith. The Sequence Listing is submitted in a file entitled “2024-02-14_Sequence_Listing_UIPS004_001APC.txt” which was created on Feb. 14, 2024, and is approximately 57, 344 bytes in size. This Sequence Listing is hereby incorporated by reference. TECHNICAL FIELD The present invention relates to an antibody having an inhibitory function against the activity of ADAMTS13, which is von Willebrand factor (VWF) cleaving protease, having activity of cleaving VWF, and pharmaceutical use of such an antibody. BACKGROUND ART Von Willebrand factor (VWF) is a high-molecular plasma glycoprotein having effects of initial platelet adhesion, platelet aggregation, and coagulation factor VIII stabilization at a vascular injury site. VWF is produced by vascular endothelial cells or megakaryocytes, secreted as a multimer, and cleaved into a size appropriate for a hemostatic function by ADAMTS13, VWF cleaving protease. However, the excessive cleavage of VWF by ADAMTS13 develops von Willebrand disease (VWD) which is a congenital coagulopathy causing bleeding. The inventors of the present invention have prepared a monoclonal antibody having specific affinity for ADAMTS13 for the purpose of treating VMD (Patent Literature 1). The inventors have showed that the obtained antibody was used to exhibit localization of human ADAMTS13 in satellite cells of the liver (Non Patent Literature 1). In recent years, the occurrence of bleeding complications after implantation of left ventricular assist device (LVAD) has become a large problem. An important factor thereof is a loss of a high-molecular-weight multimer of VWF in patients after mechanical assisted circulation (Non Patent Literature 2). In short, unlike VMD, the congenital genetic disease, this disorder is acquired von Willebrand syndrome (AVWS) which is characterized by having bleeding diathesis neither in a previous medical history nor in a family history. In the present situation, AVWS is gaining attention with increase in the number of diseases in need of mechanical assisted circulation. However, a method for preventing or treating AVWS has not yet been established. Therefore it is an urgent issue to establish such method. CITATION LIST Patent Literature Patent Literature 1: Japanese Patent No. 4533995 Non Patent Literature Non Patent Literature 1: Uemura M, et al., Blood, 106, 922-924, 2005Non Patent Literature 2: Meyer A L, et al., JACC Heart Fail 2141-145, 2014 SUMMARY OF INVENTION Technical Problem An object of the present invention is to provide a preparation of an antibody or an antibody derivative that can prevent or treat AVWS accompanied by a disease in need of mechanical assisted circulation. Solution to Problem The present invention has achieved the object by providing an antibody or an antibody derivative that has specific binding activity against ADAMTS13, VWF cleaving protease which is considered as a causative factor of the human AVWS, and can reduce the excessive cleavage of VWF by ADAMTS13. More specifically, the application of this case provides the following aspects in order to attain the object mentioned above: [1] an antibody or an antibody derivative thereof having a binding property to ADAMTS13 and having an inhibitory effect on von Willebrand factor (VWF) cleaving activity, comprising any heavy chain and light chain complementarity determining regions selected from the group consisting of (1) heavy chain complementarity determining regions CDR1 (GYSFTGYT, SEQ ID NO: 1), CDR2 (INPYNGGT, SEQ ID NO: 2), and CDR3 (ARTSGYLFAY, SEQ ID NO: 3), andlight chain complementarity determining regions CDR1 (EDIYNR, SEQ ID NO: 4), CDR2 (GAT, SEQ ID NO: 5), and CDR3 (QQYWSSPLT, SEQ ID NO: 6);(2) heavy chain complementarity determining regions CDR1 (GFSLPRYG, SEQ ID NO: 7), CDR2 (IWAGGST, SEQ ID NO: 8), and CDR3 (ARAGGSOPFDY, SEQ ID NO: 9), andlight chain complementarity determining regions CDR1 (RDINTY, SEQ ID NO: 10), CDR2 (RAN, SEQ ID NO: 11), and CDR3 (LOYDEFPWT, SEQ ID NO: 12);(3) heavy chain complementarity determining regions CDR1 (GFSLTRYG, SEQ ID NO: 13), CDR2 (IWAGGST, SEQ ID NO: 14), and CDR3 (ARAGGSSSFDY, SEQ ID NO: 15), andlight chain complementarity determining regions CDR1 (QDINTY, SEQ ID NO: 16), CDR2 (RAN, SEQ ID NO: 17), and CDR3 (LOYDEFPWT, SEQ ID NO: 18); and(4) heavy chain complementarity determining regions CDR1 (GFSLTGYG, SEQ ID NO: 19), CDR2 (IWADGTT, SEQ ID NO: 20), and CDR3 (ARAGGSQPFDY, SEQ ID NO: 21), andlight chain complementarity determinin