Tissue factor-targeted antibody-drug conjugate
A tissue factor (TF)-targeted antibody-drug conjugate (ADC) and a method for preparing the ADC. The ADC is capable of binding to TF antigen with high specificity, and has high affinity, low immunogenicity, high cytotoxicity, and significant anti-tumor activity.
1. An antibody-drug conjugate, wherein the antibody-drug conjugate comprises:
(a) an antibody moiety; and
(b) a conjugation moiety conjugated to the antibody moiety, wherein the conjugation moiety is selected from the group consisting of:
(i) Maytansine derivatives (DM1, DM4), auristatin and dolastatin; and
(ii) Monomethyl auristatin E (MMAE), Monomethyl auristatin F (MMAF), Monomethyl Dolastatin 10 (MMAD) derivatives or a combination thereof;
wherein the heavy chain variable region of the antibody comprises the following three complementary determining regions (CDRs):
(H1) CDR1 as set forth in SEQ ID NO: 1,
(H2) CDR2 as set forth in SEQ ID NO: 2, and
(H3) CDR3 as set forth in SEQ ID NO: 3; and
the light chain variable region of the antibody comprises the following three complementary determining regions (CDRs):
(L1) CDR1′ as set forth in SEQ ID NO: 4,
(L2) CDR2′ as set forth in SEQ ID NO: 5, and
(L3) CDR3′ as set forth in SEQ ID NO: 6.
2. The antibody-drug conjugate according to claim 1 , wherein the antibody-drug conjugate (ADC) has a formula as follows:
Ab LU-D) p
wherein:
Ab is an anti-TF antibody,
LU is a linker;
D is the conjugate moiety;
and the subscript p is a value selected from 1-10.
3. The antibody-drug conjugate according to claim 2 , wherein D is Monomethyl auristatin E (MMAE).
4. The antibody-drug conjugate according to claim 1 , wherein the antibody is selected from: an animal-derived antibody, a chimeric antibody, a humanized antibody, or a combination thereof.
5. The antibody-drug conjugate according to claim 1 , wherein the sequence of the heavy chain variable region of the antibody is selected from the group consisting of: SEQ ID NO: 7, 9, 10, 11, 12, or 13; and/or
the sequence of the light chain variable region of the antibody is selected from the group consisting of: SEQ ID NO: 8, 14, 15, 16, or 17.
6. The antibody-drug conjugate according to claim 1 , wherein the antibody is selected from the group consisting of: TF-mAb-SC1, TF-mAb-Ch, TF-mAb-H29, TF-mAb-H30, TF-mAb-H31, TF-mAb-H32, TF-mAb-H33, TF-mAb-H34, TF-mAb-H35, TF-mAb-H36, TF-mAb-H37, TF-mAb-H38, TF-mAb-H39, TF-mAb-H40, TF-mAb-H41, TF-mAb-H42, TF-mAb-H43, TF-mAb-H44, TF-mAb-H45, TF-mAb-H46, TF-mAb-H47, and TF-mAb-H48.
7. A pharmaceutical composition, comprising:
(i) an active ingredient, which is the antibody-drug conjugate according to claim 1 or a combination thereof; and
(ii) a pharmaceutically acceptable carrier.
8. The antibody-drug conjugate according to claim 1 , wherein the antibody is TF-mAb-H39 or TF-mAb-H44.
9. A method for treating a TF-related disease, comprising administering a therapeutically effective amount of the antibody-drug conjugate according to claim 1 to a subject in need thereof, wherein the TF-related disease is selected from the group consisting of tumorigenesis, tumor growth, and tumor metastasis, and wherein the tumor is a tumor with high TF expression.
10. The method according to claim 9 , wherein the antibody is TF-mAb-H39 or TF-mAb-H44.