Immunoglobulin-like molecules directed against fibronectin-EDA
The present invention is concerned with immunoglobulin (Ig)-like molecules or fragments thereof for use in treatment, prevention, or prevention of progression of adverse cardiac remodelling and conditions resulting from or relating to myocardial infarction and pressure-overload, such as heart failure, aneurysm formation and remote myocardial fibrosis and for use in improving angiogenesis, preferably after ischemic injury. The invention also provides nucleic acid molecules encoding said Ig-like molecules, vectors comprising same, and host cells comprising same.
1. An antibody or antigen-binding fragment thereof that binds the EDA domain of fibronectin-EDA, comprising
a heavy chain variable region comprising
a CDR1 having the amino acid sequence GYSIX 1 SGYSWH, wherein X 1 is selected from T and A (SEQ ID NO: 21);
a CDR2 having the amino acid sequence YIHX 2 SGX 3 ANYNPSLKS, wherein X 2 is selected from Y and F, and wherein X 3 is selected from S and I (SEQ ID NO: 22); and
a CDR3 having the amino acid sequence EX 4 X 5 GX 6 FDY, wherein X 4 is selected from K and A, X 5 is selected from T and R, and X 6 is selected from F and Y (SEQ ID NO: 23);
and a light chain variable region comprising:
a CDR1 having the amino acid sequence RSSQSX 7 VX 8 SNGNTYLX 9 , wherein X 7 is selected from L and I, X 8 is selected from H and R, and X 9 is selected from H and T (SEQ ID NO: 24);
a CDR2 having the amino acid sequence KVSNRFS (SEQ ID NO: 25); and
a CDR3 having the amino acid sequence X 10 QX 11 X 12 HVPPT, wherein X 10 is selected from S and F, X 11 is selected from S and G, and X 12 is selected from A and S (SEQ ID NO: 26).
2. The antibody, antibody or antigen-binding fragment thereof according to claim 1 comprising
a heavy chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:9;
a CDR2 having the amino acid sequence shown in SEQ ID NO:10; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:11;
and a light chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:12;
a CDR2 having the amino acid sequence shown in SEQ ID NO:13; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:14.
3. The antibody, antibody or antigen-binding fragment thereof according to claim 1 comprising
a heavy chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:3;
a CDR2 having the amino acid sequence shown in SEQ ID NO:4; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:5;
and a light chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:6;
a CDR2 having the amino acid sequence shown in SEQ ID NO:7; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:8.
4. The antibody, antibody or antigen-binding fragment thereof according to claim 1 comprising
a heavy chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:15;
a CDR2 having the amino acid sequence shown in SEQ ID NO:16; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:17;
and a light chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:18;
a CDR2 having the amino acid sequence shown in SEQ ID NO:19; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:20.
5. An antibody or antigen-binding fragment thereof that binds the EDA domain of fibronectin-EDA, comprising
a heavy chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:29;
a CDR2 having the amino acid sequence shown in SEQ ID NO:30; and
a CDR3 having the amino acid sequence SHY;
and/or a light chain variable region comprising:
a CDR1 having the amino acid sequence shown in SEQ ID NO:31;
a CDR2 having the amino acid sequence shown in SEQ ID NO:32; and
a CDR3 having the amino acid sequence shown in SEQ ID NO:33.
6. The antibody or antigen-binding fragment thereof according to claim 1 , comprising a heavy chain and a light chain, wherein said heavy chain has an amino acid sequence as shown in SEQ ID NO:34 and said light chain has an amino acid sequence as shown in SEQ ID NO:35.
7. The antibody or antigen-binding fragment thereof according to claim 1 , which is an antibody.
8. The antibody or antigen-binding fragment thereof according to claim 1 , which is monoclonal.
9. The antibody or antigen-binding fragment thereof according to claim 1 , which is of murine origin or which is derived from a mouse.
10. The antibody or antigen-binding fragment thereof according to claim 1 , which is chimeric.
11. The antibody or antigen-binding fragment thereof according to claim 1 , which is human or humanized.