Antibodies to centrin-1, methods of making, and uses thereof
Provided herein are antibodies that specifically bind Centrin-1 and methods of making the same, for use the treatment, prevention, detection, imaging, and diagnosis of cancers including pancreatic and prostate cancer.
1. An antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
(a) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 42; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10, or SEQ ID NO: 46 or SEQ ID NO: 47, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 48, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 49;
(b) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 42; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 50 or SEQ ID NO: 51; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 52; and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 53;
(c) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 40, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO: 41, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO: 42; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 or SEQ ID NO: 54, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 55, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 or SEQ ID NO: 56;
(d) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO: 43, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 45; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10, or SEQ ID NO: 46 or SEQ ID NO: 47, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11 or SEQ ID NO: 48, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12 or SEQ ID NO: 49;
(e) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO: 43, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 45; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14, SEQ ID NO: 50 or SEQ ID NO: 51; a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 52; and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 or SEQ ID NO: 53; or
(f) the VH comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO: 43, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO: 44, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO: 45; and the VL comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 or SEQ ID NO: 54, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 or SEQ ID NO: 55, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 or SEQ ID NO: 56.
2. The antibody of claim 1 , wherein the antibody comprises:
(a) a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising the amino acid sequence of SEQ ID NO: 9;
(b) a VH comprising the amino acid sequence of SEQ ID NO: 5; and a VL comprising the amino acid sequence of SEQ ID NO: 9;
(c) a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising the amino acid sequence of SEQ ID NO: 13;
(d) a VH comprising the amino acid sequence of SEQ ID NO: 5; and a VL comprising the amino acid sequence of SEQ ID NO: 13;
(e) a VH comprising the amino acid sequence of SEQ ID NO: 1; and a VL comprising the amino acid sequence of SEQ ID NO: 17; or
(f) a VH comprising the amino acid sequence of SEQ ID NO: 5; and a VL comprising the amino acid sequence of SEQ ID NO:17.
3. The antibody of claim 1 , wherein the antibody is an antigen-binding fragment thereof.
4. The antibody of claim 1 , wherein the antibody is a full-length antibody.
5. The antibody of claim 1 , wherein the antibody is conjugated to a radionuclide.
6. The antibody of claim 5 , wherein the radionuclide is an α-emitting or a β-emitting radioisotope.
7. The antibody of claim 5 , wherein the radionuclide comprises 213-Bismuth, 177-Lutetium, 212-Lead, 225 Actinium, 227-Thorium, 186-Rhenium, or 188-Rhenium.
8. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxin.
9. The antibody of claim 1 , wherein the antibody is bispecific, wherein the antibody comprises a first specificity to Centrin-1 and a second specificity to an immune checkpoint inhibitor.
10. The antibody of claim 1 , wherein the antibody is humanized.
11. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable excipient.
12. A method of treating pancreatic cancer or prostate cancer in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of the antibody of claim 1 .
13. The method of claim 12 , wherein the cancer is pancreatic cancer.
14. The method of claim 13 , wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).
15. The method of claim 12 , wherein the cancer is prostate cancer.
16. The method of claim 15 , wherein the prostate cancer is adenocarcinoma of the prostate.
17. The method of claim 12 , wherein the administration is systemic, regional, local, or intracavity administration.
18. A method of determining that a subject has, or is at risk for developing pancreatic cancer or prostate cancer comprising contacting a biological sample from the subject with the antibody of claim 1 , and determining that the subject has, or is at risk for developing, pancreatic cancer or prostate cancer if the relative level of Centrin-1 is higher than a control value.
19. The method of claim 18 , comprising administering a treatment to the subject.
20. A nucleic acid molecule encoding the antibody of claim 1 .