Nectin-4 antibody conjugates and uses thereof
The present disclosure provides conjugates of anti-Nectin-4 antibodies or antigen binding fragments thereof to a myeloid cell agonist, compositions comprising the conjugates, and methods of treating cancer with the conjugates. The present disclosure also provides for anti-Nectin-4 antibodies or antigen binding fragments thereof and method for using the antibodies or antigen binding fragments thereof in treating cancer.
1. A myeloid cell agonist conjugate or a salt thereof, wherein the conjugate is represented by Formula (I):
wherein:
A is an anti-Nectin-4 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a CDR1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:1, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:2, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:3; and the VL comprises a CDR1 (VL-CDR1) comprising the amino acid sequence selected from any one of SEQ ID NOS:4-6, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:7, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:8;
L is a linker;
D x comprises a TLR8 agonist;
n is selected from 1 to 20; and
z is selected from 1 to 20.
2. The myeloid cell agonist conjugate of claim 1 , wherein the anti-Nectin-4 antibody or antigen-binding fragment thereof comprises:
(a) a VH comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 10, and a VL comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 14; or
(b) a VH comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 10, and a VL comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 13; or
(c) a VH comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 10, and a VL comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO: 12; or
(d) a VH comprising the amino acid sequence of SEQ ID NO: 10, and a VL comprising the amino acid sequence of SEQ ID NO: 14; or
(e) a VH comprising the amino acid sequence of SEQ ID NO: 10, and a VL comprising the amino acid sequence of SEQ ID NO: 13; or
(f) a VH comprising the amino acid sequence of SEQ ID NO: 10, and a VL comprising the amino acid sequence of SEQ ID NO: 12.
3. The myeloid cell agonist conjugate of claim 1 , wherein A is an anti-Nectin-4 antibody and the antibody comprises:
(a) a heavy chain comprising an amino acid sequence that is at least 90% identity with the amino acid sequence of SEQ ID NO:24, and a light chain comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO:28; or
(b) a heavy chain comprising an amino acid sequence that is at least 90% identity with the amino acid sequence of SEQ ID NO:24, and a light chain comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO:27; or
(c) a heavy chain comprising an amino acid sequence that is at least 90% identity with the amino acid sequence of SEQ ID NO:24, and a light chain comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO:26; or
(d) a heavy chain comprising an amino acid sequence of SEQ ID NO:24, and a light chain comprising the amino acid sequence of SEQ ID NO:28; or
(e) a heavy chain comprising an amino acid sequence of SEQ ID NO:24, and a light chain comprising the amino acid sequence of SEQ ID NO:27 or
(f) a heavy chain comprising an amino acid sequence of SEQ ID NO:24, and a light chain comprising the amino acid sequence of SEQ ID NO:26.
4. The myeloid cell agonist conjugate of claim 1 , wherein the TLR8 agonist is selected from any one of compounds 1.1-1.69 or a salt thereof.
5. The myeloid cell agonist conjugate of claim 4 , wherein the TLR8 agonist is compound 1.36, 1.50, 1.57, 1.60, or 1.64 or a salt thereof.
6. The myeloid cell agonist conjugate of claim 1 , wherein the TLR8 agonist is:
7. The myeloid cell agonist conjugate of claim 1 , wherein the linker is represented by formula (V):
wherein L 4 represents the C-terminus of the peptide and L 5 is selected from a bond, alkylene and heteroalkylene, wherein L 5 is optionally substituted with one or more groups independently selected from R 32 ; RX* comprises a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of the antibody, wherein
on RX* represents the point of attachment to the residue of the antibody and the other
represents the point of attachment to the TLR8 agonist; and R 32 is independently selected at each occurrence from halogen, —OH, —CN, —O—C 1-10 alkyl, —SH, ═O, ═S, —NH 2 , —NO 2 ; C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl, each of C 1-10 alkyl, C 2-10 alkenyl, and C 2-10 alkynyl is optionally substituted with one or more substituents independently selected from halogen, —OH, —CN, —O—C 1-10 alkyl, —SH, ═O, ═S, —NH 2 , and —NO 2 .
8. The myeloid cell agonist conjugate of claim 7 , wherein the peptide of the linker is Val-Cit or Val-Ala.
9. The myeloid cell agonist conjugate of claim 7 , wherein the linker is a cleavable linker.
10. The myeloid cell agonist conjugate of claim 1 , wherein L-D x has a structure selected from any one of:
and a salt of any one thereof,
wherein the RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of the antibody, and
wherein
on RX* represents the point of attachment to the residue of the antibody.
11. The myeloid cell agonist conjugate of claim 10 , wherein:
n is an integer from 1 to about 10, or from 1 to about 5, or is 1 or 2, or is 1; and
z ranges from 1 to about 10, or from 1 to about 9, or from 1 to about 8, or 2 to about 6, or about 3 to about 5, or about 4.
12. The myeloid cell agonist conjugate or a salt thereof of claim 1 , wherein:
A is an anti-Nectin-4 antibody comprising: (a) a heavy chain comprising an amino acid sequence that is at least 90% identity with the amino acid sequence of SEQ ID NO:24, and a light chain comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO:28; or (b) a heavy chain comprising an amino acid sequence that is at least 90% identity with the amino acid sequence of SEQ ID NO:24, and a light chain comprising an amino acid sequence that has at least 90% identity with the amino acid sequence of SEQ ID NO:27;
L-D x has a structure selected from any one of:
wherein RX* is a bond, a succinimide moiety, or a hydrolyzed succinimide moiety bound to a residue of the antibody, wherein
on RX* represents the point of attachment to a cysteine residue of the antibody;
n is 1; and
z ranges from 2 to about 6.
13. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising an amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:28, and L-D x has a structure of:
14. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:27, and L-D x has a structure of:
15. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:28, and L-D x has a structure of:
16. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:27, and L-D x has a structure of:
17. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:28, and L-D x has a structure of:
18. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:27, and L-D x has a structure of:
19. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:28, and L-D x has a structure of:
20. The myeloid cell agonist conjugate or a salt thereof of claim 12 , wherein A is an anti-Nectin-4 antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:24 and a light chain comprising the amino acid sequence of SEQ ID NO:27, and L-D x has a structure of:
21. A pharmaceutical composition comprising the myeloid cell agonist conjugate of claim 1 and a pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 21 , wherein the average TLR8 agonist-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5.
23. A pharmaceutical composition comprising the myeloid cell agonist conjugate of claim 12 and a pharmaceutically acceptable excipient.
24. The pharmaceutical composition of claim 23 , wherein the average TLR8 agonist-to-antibody ratio of the conjugate ranges from about 2 to about 8, about 3 to about 8, about 3 to about 7, or about 3 to about 5.
25. A method of treating a Nectin-4 expressing cancer, comprising administering to a subject in need thereof an effective amount of a myeloid cell agonist conjugate of the pharmaceutical composition of claim 23 .
26. The method of claim 25 , wherein the cancer is one or more of bladder cancer, breast cancer, lung cancer, head and neck cancer, cervical cancer, and pancreatic cancer.
27. The method of claim 26 , wherein the bladder cancer is urothelial cancer; the breast cancer is triple-negative breast cancer; the lung cancer is non-small cell lung cancer, squamous cell carcinoma, or lung adenocarcinoma; the head and neck cancer is head and neck squamous cell carcinoma; the cervical cancer is cervical squamous cell carcinoma or endocervical adenocarcinoma; and the pancreatic cancer is pancreatic adenocarcinoma.
28. The method of claim 25 , wherein the method comprises administering an additional therapeutic agent selected from a small molecule inhibitor, a CAR-T cell, a chemotherapeutic, a therapeutic antibody, and an antibody-drug conjugate.
29. The method of claim 28 , wherein the additional therapeutic agent is an anti-TIGIT antibody or an adenosine receptor antagonist.
30. The method of claim 25 , wherein the method further comprises administering an anti-PD-1 or anti-PD-L1 antibody.