Plasmin-cleavable anti-insoluble fibrin antibody-drug conjugate
View Patent ↗The present invention relates to an antibody-drug conjugate (ADC) and a composition containing the conjugate for use in treating cancer. According to the present invention, provided are an ADC of an antibody specific to insoluble fibrin and a drug in which a linker linking the antibody and the drug has a plasmin cleavage sequence, and a pharmaceutical composition containing the ADC for use in treating cancer.
1. An antibody-drug conjugate (ADC), wherein
the antibody is an antibody that binds to fibrin and has affinity to insoluble fibrin higher than that to fibrinogen,
the drug is a cytotoxic agent, and
the antibody and the drug are linked to each other through a linker having a plasmin cleavage site that allows cleavage by plasmin, wherein the antibody has
(i) a heavy chain variable region having CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and a light chain variable region having CDR1 set forth in SEQ ID NO: 5, CDR2 set forth in SEQ ID NO: 6, and CDR3 set forth in SEQ ID NO: 7;
(ii) a heavy chain variable region having CDR1 set forth in SEQ ID NO: 9, CDR2 set forth in SEQ ID NO: 10, and CDR3 set forth in SEQ ID NO: 11, and a light chain variable region having CDR1 set forth in SEQ ID NO: 13, CDR2 set forth in SEQ ID NO: 14, and CDR3 set forth in SEQ ID NO: 15; or
(iii) a heavy chain variable region having CDR1 set forth in SEQ ID NO: 17, CDR2 set forth in SEQ ID NO: 18, and CDR3 set forth in SEQ ID NO: 19, and a light chain variable region having CDR1 set forth in SEQ ID NO: 21, CDR2 set forth in SEQ ID NO: 22, and CDR3 set forth in SEQ ID NO: 23.
2. The ADC according to claim 1 , wherein the linker has a valine-leucine-lysine peptide sequence as the plasmin cleavage site.
3. A pharmaceutical composition comprising the ADC according to claim 1 and a pharmaceutically acceptable excipient.
4. An antibody that binds to fibrin, wherein the antibody has
a heavy chain variable region having CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and
a light chain variable region having CDR1 set forth in SEQ ID NO: 5, CDR2 set forth in SEQ ID NO: 6, and CDR3 set forth in SEQ ID NO: 7.
5. The antibody according to claim 4 , wherein the antibody has
a heavy chain variable region set forth in SEQ ID NO: 4 and a light chain variable region set forth in SEQ ID NO: 8; or
an antigen-binding fragment thereof.
6. An antibody that binds to fibrin, wherein the antibody has
a heavy chain variable region having CDR1 set forth in SEQ ID NO: 9, CDR2 set forth in SEQ ID NO: 10, and CDR3 set forth in SEQ ID NO: 11, and
a light chain variable region having CDR1 set forth in SEQ ID NO: 13, CDR2 set forth in SEQ ID NO: 14, and CDR3 set forth in SEQ ID NO: 15.
7. The antibody according to claim 6 , wherein the antibody has
a heavy chain variable region set forth in SEQ ID NO: 12 and a light chain variable region set forth in SEQ ID NO: 16; or
an antigen-binding fragment thereof.
8. The ADC according to claim 1 , wherein the antibody has
a heavy chain variable region having CDR1 set forth in SEQ ID NO: 1, CDR2 set forth in SEQ ID NO: 2, and CDR3 set forth in SEQ ID NO: 3, and
a light chain variable region having CDR1 set forth in SEQ ID NO: 5, CDR2 set forth in SEQ ID NO: 6, and CDR3 set forth in SEQ ID NO: 7
or an antigen-binding fragment thereof.
9. A pharmaceutical composition comprising the ADC according to claim 8 and a pharmaceutically acceptable excipient.
10. The ADC according to claim 1 , wherein the antibody has
a heavy chain variable region having CDR1 set forth in SEQ ID NO: 9, CDR2 set forth in SEQ ID NO: 10, and CDR3 set forth in SEQ ID NO: 11, and
a light chain variable region having CDR1 set forth in SEQ ID NO: 13, CDR2 set forth in SEQ ID NO: 14, and CDR3 set forth in SEQ ID NO: 15.
11. A pharmaceutical composition comprising the ADC according to claim 10 and a pharmaceutically acceptable excipient.