Anti-HER2 antibody-drug conjugate and application thereof
An anti-human epidermal growth factor receptor 2 (anti-HER2) antibody-drug conjugate or a pharmaceutically acceptable salt thereof, and an application of the anti-HER2 antibody-drug conjugate for preparing an antitumor 5 pharmaceutical product.
1. An antibody-drug conjugate or a pharmaceutically acceptable salt thereof, wherein the structure of the antibody-drug conjugate is as shown in formula I:
Ab -( L - D ) n I
wherein:
Ab is an antibody, wherein the antibody is pertuzumab;
L is a linker connecting the antibody and the drug; wherein L has a structure of L-1:
wherein L 21 is a linker moiety independently selected from the group consisting of Val-Cit, —(CH 2 )n-, —(CH 2 CH 2 O)n-, Ala-Ala-Asn, and a combination thereof, and the wavy line indicates the connection position with antibody
D is a small molecule drug that inhibits tumor cells, and the structure of D is as shown in formula II:
wherein in formula II, Y is O or NH, and the wavy line indicates the connection position with L,
X is CH 2 N3 or
n is an average number of coupled drugs in the antibody-drug, and n is from 1.8 to 2;
the dash marks represent bonds;
wherein the light chain constant region of the antibody comprises a EKH motif and the drug molecule is linked to a lysine (K) residue of the motif.
2. The antibody-drug conjugate of claim 1 , wherein the light chain constant region of the antibody comprises YEKHK (SEQ ID NO: 59) motif and the drug molecule is linked to the first lysine (K) site of the motif.
3. The antibody-drug conjugate of claim 1 , wherein X is
4. The antibody-drug conjugate of claim 1 , wherein n is 2.
5. The antibody-drug conjugate of claim 1 , wherein X is CH 2 N 3 .
6. The antibody-drug conjugate of claim 1 , wherein the antibody-drug conjugate is selected from the group consisting of: ZV0201, ZV0202, ZV0203, ZV0204, ZV0205, and ZV0230,
wherein,
the structure of conjugate ZV0203 is shown as follows:
the structure of conjugate ZV0230 is shown as follows:
the structure of conjugate ZV0201 is shown as follows:
the structure of conjugate ZV0202 is shown as follows:
the structure of conjugate ZV0204 is shown as follows:
the structure of conjugate ZV0205 is shown as follows:
7. The antibody-drug conjugate of claim 6 , wherein the antibody-drug conjugate is ZV0203, ZV0204, ZV0205, or ZV0230.
8. The antibody-drug conjugate of claim 6 , wherein the antibody-drug conjugate is ZV0201.
9. A pharmaceutical composition which comprises the antibody-drug conjugate of claim 1 , and a pharmaceutically acceptable carrier.
10. A preparation method for the antibody-drug conjugate of claim 1 , wherein the method comprises the following steps:
configuring a reaction system including an antibody and a free drug molecule, and then performing a coupling reaction to prepare the antibody-drug conjugate,
wherein the drug molecule includes a linker.
11. The method of claim 10 , wherein the pH of the reaction system is from 6.5 to 8.0.
12. The method of claim 11 , wherein the pH is from 6.8 to 7.8.
13. The method of claim 12 , wherein the pH is from 6.8 to 7.2.
14. A method of treating a tumor, which comprises a step of administering to a subject in need thereof the antibody-drug conjugate of claim 1 , wherein the tumor is breast cancer.