Anti-mesothelin antibody and antibody drug conjugate thereof
The present invention discloses an antibody drug conjugate that targets MSLN. The present invention also disclosed a method of making the antibody drug conjugate (ADC). The present invention further discloses a novel MSLN antibody or a functional fragment thereof comprising engineered heavy and light chains.
1. An antibody drug conjugate, which has the formula of Ab-(L-D) n , wherein:
(a) Ab is an antibody or a functional fragment thereof that specifically binds to mesothelin (MSLN);
(b) L is a linker or does not exist;
(c) D is a therapeutic agent; and
(d) n is 1, 2, 3, 4, 5, 6, 7, or 8;
wherein the antibody or the functional fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical to SEQ ID NO: 7 and a light chain variable region having an amino acid sequence that is at least 95% identical to SEQ ID NO: 8, and wherein:
(i) the heavy chain variable region comprises VH CDR1, VH CDR2, and VH CDR3 having an amino acid sequence as set forth in SEQ ID NO: 1, 2, and 3, respectively; and
(ii) the light chain variable region comprises VL CDR1, VL CDR2, and VL CDR3 having an amino acid sequence as set forth in SEQ ID NO: 4, 5, and 6, respectively.
2. The antibody drug conjugate according to claim 1 , wherein
(i) the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 7; and
(ii) the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 8.
3. The antibody drug conjugate according to claim 1 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a single chain antibody (scFv) or a bispecific antibody.
4. The antibody drug conjugate according to claim 1 , wherein the therapeutic agent is a dolastatin peptide.
5. The antibody drug conjugate according to claim 1 , wherein the linker and the antibody are linked by a thiol group on the antibody.
6. The antibody drug conjugate according to claim 1 , wherein the linker has a structure as shown by the following formula:
or the linker has a structure as shown by the following formula:
7. The antibody drug conjugate according to claim 1 , which has a structure as shown in any one of the following formulas:
8. An antibody or a functional fragment thereof capable of specifically binding to mesothelin,
wherein the antibody or the functional fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 95% identical to SEQ ID NO: 7 and a light chain variable region having an amino acid sequence that is at least 95% identical to SEQ ID NO: 8, and wherein:
(i) the heavy chain variable region comprises VH CDR1, VH CDR2, and VH CDR3 having an amino acid sequence as set forth in SEQ ID NO: 1, 2, and 3, respectively; and
(ii) the light chain variable region comprises VL CDR1, VL CDR2, and VL CDR3 having an amino acid sequence as set forth in SEQ ID NO: 4, 5, and 6, respectively.
9. The antibody or functional fragment thereof according to claim 8 , wherein
(i) the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 7; and
(ii) the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 8.
10. The antibody or functional fragment thereof according to claim 8 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a single chain antibody (scFv) or a bispecific antibody.
11. An isolated polynucleotide, which encodes the antibody or functional fragment thereof according to claim 8 .
12. An expression vector or a combination of expression vectors, which comprises the polynucleotide according to claim 11 , the polynucleotide being operably linked to a regulatory sequence allowing the expression of a polypeptide encoded thereby in a host cell or a cell-free expression system.
13. A pharmaceutical composition, which comprises the conjugate according to claim 1 , and a pharmaceutically acceptable carrier.
14. A method for treatment of a mesothelin-positive cancer, comprising administering a therapeutically effective amount of the conjugate according to claim 1 to a subject in need thereof.
15. A method for treatment of a mesothelin-positive cancer, comprising administering a therapeutically effective amount of the antibody or functional fragment thereof according to claim 8 to a subject in need thereof.
16. A method for treatment of a mesothelin-positive cancer, comprising administering a therapeutically effective amount of the polynucleotide according to claim 11 to a subject in need thereof.
17. A method for treatment of a mesothelin-positive cancer, comprising administering a therapeutically effective amount of the expression vector according to claim 12 to a subject in need thereof.
18. A method for treatment of a mesothelin-positive cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 13 to a subject in need thereof.
19. A pharmaceutical composition, which comprises the antibody or functional fragment thereof according to claim 8 and a pharmaceutically acceptable carrier.
20. The antibody drug conjugate according to claim 1 , wherein the therapeutic agent is MMAD, MMAE or MMAF.