Anti-transthyretin humanized antibody
A humanized antibody which comprises a complementarity determining region of an H chain consisting of the amino acid sequence as shown in SEQ ID NOs: 1 to 3 and a complementarity determining region of an L chain consisting of the amino acid sequence as shown in SEQ ID NOs: 4 to 6. The humanized antibody of the present invention has the activity to specifically bind to transthyretin (TTR) with structural change and the activity to inhibit fibrillization of TTR and is a humanized antibody suitable for application to human body.
1. A humanized antibody having the activity to inhibit fibrillization of transthyretin (TTR) which binds to TTR amyloid derived from two or more kinds of variant TTRs and wherein the variant TTR is TTR having a mutation selected from the group consisting of D18G, V30M, E54K, L55P, Y114C, Y116S and V122I, the antibody comprising a complementarity determining region (CDR) of a heavy chain comprising the polypeptide of (a) or (b) below and a CDR of a light chain comprising the polypeptide of (c) or (d) below:
(a) a polypeptide comprising the complementarity determining regions (CDRs) of SEQ ID NOs: 1 to 3;
(b) a polypeptide comprising SEQ ID NO: 7;
(c) a polypeptide comprising the CDRs of SEQ ID NOs: 4 to 6;
(d) a polypeptide comprising SEQ ID NO: 8.
2. The humanized antibody of claim 1 which specifically recognizes TTRs with structural change.
3. The humanized antibody of claim 1 which specifically binds to TTR amyloid.
4. The humanized antibody of claim 1 which promotes removal of TTR amyloid.
5. The humanized antibody of claim 1 which promotes the phagocytic ability of macrophages to TTR amyloid.
6. The humanized antibody of claim 1 wherein an epitope is a sequence comprising position 118 to position 122 of TTR.
7. The humanized antibody of claim 6 wherein an epitope is position 118 to position 122 of TTR.
8. The humanized antibody of claim 1 which has a therapeutic effect to TTR amyloidosis.
9. The humanized antibody of claim 8 wherein the TTR amyloidosis is Familial Amyloidotic Polyneuropathy (FAP).
10. The humanized antibody of claim 8 wherein the TTR amyloidosis is Senile Systemic Amyloidosis (SSA).
11. The humanized antibody of claim 1 , which is formed by linking a human-derived constant region to:
(1) a heavy chain variable region fragment comprising a complementarity determining region of a heavy chain comprising the CDRs of SEQ ID NOs: 1 to 3;
or
(2) a heavy chain variable region fragment comprising a complementarity determining region of an H chain comprising SEQ ID NO: 7;
and
(3) a light chain variable region fragment comprising a complementarity determining region of a light chain comprising the CDRs of SEQ ID NOs: 4 to 6;
or
(4) a light chain variable region fragment comprising a complementarity determining region of a light chain comprising SEQ ID NO: 8.
12. A TTR-fibrillization inhibitor comprising the antibody or a fragment thereof of claim 1 .
13. A pharmaceutical composition for the treatment of TTR amyloidosis comprising the antibody or a fragment thereof of claim 1 .
14. The pharmaceutical composition of claim 13 wherein the TTR amyloidosis is Familial Amyloidotic Polyneuropathy (FAP).
15. The pharmaceutical composition of claim 13 wherein the TTR amyloidosis is Senile Systemic Amyloidosis (SSA).
16. A single-chain variable region fragment of an antibody to TTR, which is formed by linking:
a) a heavy chain variable region fragment comprising the complementarity determining regions (CDRs) comprising SEQ ID NOs: 1 to 3,
or
b) a heavy chain variable region fragment comprising the CDRs comprising SEQ ID NO: 7,
and
c) a light chain variable region fragment comprising the CDRs of SEQ ID NOs: 4 to 6,
or
d) a light chain variable region fragment comprising the CDRs comprising SEQ ID NO: 8.