Bispecific antibody substituting for functional proteins
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsKunihiro Hattori, Tetsuo Kojima, Taro Miyazaki, Tetsuhiro Soeda
Life of this patent
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Abstract
The present inventors succeeded in constructing bispecific antibodies, which bind to both the blood coagulation factor IX/activated blood coagulation factor IX and blood coagulation factor X, and functionally substitute for blood coagulation factor VIII/activated blood coagulation factor VIII which enhances the enzymatic reaction.
Claims33
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein said antibody comprises complementarity determining regions (CDRs) comprising
- (A) the amino acid sequences of anti-blood coagulation factor IX/IXa antibody H chain CDRs of the following (a1) or (a2) and L chain CDRs of the following (b1) or (b2);
- and
- (B) the amino acid sequences of anti-blood coagulation factor X antibody H chain CDRs of any one of the following (c1) to (c9) and L chain CDRs of the following (d1) or (d2):
- (a1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively;
- (a2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 18, 19, and 20, respectively;
- (b1) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- (b2) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (c1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively;
- (c2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 26, 27, and 28, respectively;
- (c3) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 30, 31, and 32, respectively;
- (c4) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 34, 35, and 36, respectively;
- (c5) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 38, 39, and 40, respectively;
- (c6) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 42, 43, and 44, respectively;
- (c7) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 46, 47, and 48, respectively;
- (c8) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 50, 51, and 52, respectively;
- (c9) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 54, 55, and 56, respectively;
- (d1) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively;
- (d2) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (A) binds the same epitope of blood coagulation factor IX/IXa as an antibody having the H chain CDRs of (a1) or (a2) below and the L chain CDRs of (b1 or (b2) below, and
- (B) binds the same epitope of blood coagulation factor X as an antibody having the H chain CDRs of any one of (c1) to (c9) below and the L chain CDRs of (d1) or (d2) below:
- (a1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively;
- (a2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 18, 19, and 20, respectively;
- (b1) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- (b2) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (c1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively;
- (c2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 26, 27, and 28, respectively;
- (c3) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 30, 31, and 32, respectively;
- (c4) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 34, 35, and 36, respectively;
- (c5) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 38, 39, and 40, respectively;
- (c6) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 42, 43, and 44, respectively;
- (c7) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 46, 47, and 48, respectively;
- (c8) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 50, 51, and 52, respectively;
- (c9) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 54, 55, and 56, respectively;
- (d1) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively;
- (d2) L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising:
- (a) an anti-blood coagulation factor IX/IXa antibody variable region comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213;
- and
- (b) an anti-blood coagulation factor X antibody variable region comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising anti-blood coagulation factor IX/IXa H and L variable domains comprising a set of six CDR sequences selected from (a1) and (a2) below and anti-blood coagulation factor X H and L variable domains comprising a set of six CDR sequences selected from (b1) and (b2) below:
- (a1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (a2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- (b1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively;
- (b2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising
- (A) anti-blood coagulation factor IX/IXa antibody H and L variable domains comprising a set of six CDR sequences selected from (i) and (ii):
- (i) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (ii) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- and
- (B) an anti-blood coagulation factor X antibody variable domain comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising
- (A) an anti-blood coagulation factor IX/IXa antibody variable domains comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213;
- and
- (B) anti-blood coagulation factor X antibody H and L variable domains comprising a set of six CDR sequences selected from (i) and (ii):
- (i) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively;
- (ii) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising an anti-blood coagulation factor IX/IXa antibody variable domain comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213, wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising anti-blood coagulation factor IX/IXa antibody H and L variable domains comprising a set of six CDR sequences selected from (a) and (b):
- (a) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (b) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising an anti-blood coagulation factor X antibody variable region comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217, wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, the antibody comprising anti-blood coagulation factor X antibody H and L variable domains comprising a set of six CDR sequences selected from (a) and (b):
- (a) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively;
- (b) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (a) binds the same epitope of blood coagulation factor IX/IXa as an antibody having a variable region comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213, and
- (b) binds the same epitope of blood coagulation factor X as an antibody having variable region comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (A) binds the same epitope of blood coagulation factor IX/IXa as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (a1) and (a2) below, and
- (B) binds the same epitope of blood coagulation factor X as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (b1) and (b2) below,
- (a1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (a2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- (b1) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively;
- (b2) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively;
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (A) binds the same epitope of blood coagulation factor IX/IXa as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (i) and (ii):
- (i) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (ii) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively;
- and (B) binds the same epitope of blood coagulation factor X as an antibody having variable domain comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (A) binds the same epitope of blood coagulation factor IX/IXa as an antibody having variable domains comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213;
- and
- (B) binds the same epitope of blood coagulation factor X as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (i) and (ii):
- (i) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:218,219, and 220, respectively;
- (ii) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 210, 211, and 212, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody binds the same epitope of blood coagulation factor IX/IXa as an antibody having variable domain comprising the amino acid sequence of SEQ ID NO:
- 13, 17, 85, 205, or 213, wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody binds the same epitope of blood coagulation factor IX/IXa as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (a) and (b):
- (a) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 14, 15, and 16, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 214, 215, and 216, respectively;
- (b) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 86, 87, and 88, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 206, 207, and 208, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody binds the same epitope of blood coagulation factor X as an antibody having variable region comprising the amino acid sequence of SEQ ID NO:
- 21, 25, 29, 33, 37, 41, 45, 49, 53, 161, 209, or 217, wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
A bispecific antibody that recognizes blood coagulation factor IX and/or activated blood coagulation factor IX and blood coagulation factor X, wherein the antibody
- (A) binds the same epitope of blood coagulation factor X as an antibody having H and L variable domains comprising a set of six CDR sequences selected from (a) and (b):
- (a) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 22, 23, and 24, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 218, 219, and 220, respectively;
- (b) H chain CDR 1, 2, and 3 amino acid sequences described in SEQ ID NOs:
- 162, 163, and 164, respectively, and L chain CDR 1, 2, and 3 amino acid sequences described in SEQ 1D NOs:
- 210, 211, and 212, respectively,
- wherein the antibody functionally substitutes for blood coagulation factor VIII and/or activated blood coagulation factor VIII.
Dependencies are inferred from the claim text.