Anti-pancreatic cancer antibodies
Described herein are compositions and methods of use of anti-pancreatic cancer antibodies or fragments thereof, such as murine, chimeric, humanized or human PAM4 antibodies. The subject antibodies show a number of novel and useful therapeutic characteristics, such as binding with high specificity to pancreatic and other cancers, but not to normal or benign pancreatic tissues and binding to a high percentage of early stage pancreatic cancers. In preferred embodiments, the antibodies bind to pancreatic cancer mucins. The antibodies and fragments are of use for the detection, diagnosis and/or treatment of cancer, such as pancreatic cancer. The antibodies, such as PAM4 antibodies, bind to a PAM4 antigen that shows unique cell and tissue distributions compared with other known antibodies such as CA19.9, DUPAN2, SPAN1, Nd2, B72.3, and Le a and Le(y) antibodies that bind to the Lewis antigens.
1. An antibody construct comprising at least one humanized or human anti-pancreatic cancer antibody or antigen-binding fragment thereof that binds to pancreatic cancer cells and does not bind to normal pancreatic tissue or pancreatitis or benign pancreatic tissue, wherein the anti-pancreatic cancer antibody or fragment thereof can bind to a linear peptide comprising the amino acid sequence WTWNITKAYPLP (SEQ ID NO:29) or to a cyclic peptide comprising the amino acid sequence ACPEWWGTTC (SEQ ID NO:30).
2. The antibody construct of claim 1 , wherein the anti-pancreatic cancer antibody binds to PanIN-1A, PanIN-1B, PanIN-2, invasive pancreatic adenocarcinoma, pancreatic carcinoma, mucinous cyst neoplasms (MCN), intrapancreatic mucinous neoplasms (IPMN) and intraductal papillary mucinous neoplasia.
3. An antibody construct comprising at least one humanized or human anti-pancreatic cancer antibody or antigen-binding fragment thereof that binds to pancreatic cancer cells and does not bind to normal pancreatic tissue or pancreatitis or benign pancreatic tissue, wherein the anti-pancreatic cancer antibody or fragment thereof can bind to a linear peptide comprising the amino acid sequence WTWNITKAYPLP (SEQ ID NO:29) or to a cyclic peptide comprising the amino acid sequence ACPEWWGTTC (SEQ ID NO:30), wherein the construct is a trimeric DNL (dock and lock) construct comprising two copies of a PAM4 antibody fragment moiety attached to one copy of a second antibody fragment moiety.
4. The antibody construct of claim 3 , wherein each PAM4 antibody fragment moiety comprises a PAM4 Fab fragment attached to a DDD2 (SEQ ID NO:34) sequence and the second antibody fragment moiety comprises a Fab fragment attached to an AD2 (SEQ ID NO:36) sequence and a dimer of the DDD2 sequence binds to the AD2 sequence to form the trimeric construct.
5. The antibody construct of claim 4 , wherein the PAM4 antibody fragment is an hPAM4 Fab fragment and the second antibody fragment binds to a tumor associated antigen (TAA) or a hapten.
6. The antibody construct of claim 1 , wherein the anti-pancreatic cancer antibody or fragment thereof binds to the PAM4 antigen.
7. The antibody construct of claim 5 , wherein the hapten is HSG and the second antibody is a 679 antibody.
8. The antibody construct of claim 5 , wherein the second antibody binds to a TAA selected from the group consisting of a Lewis antigen, Le(y), carcinoembryonic antigen (CEACAM5), CEACAM6, colon-specific antigen-p (CSAp), MUC-1, MUC-2, MUC-3, MUC-4, MUC-5ac, MUC-16, MUC-17, HLA-DR, CD40, CD74, CD-80, CD138, HER2/neu, EGFR, EGP-1, EGP-2, an angiogenesis factor, VEGF, PlGF, insulin-like growth factor, carbonic anhydrase IX, tenascin, platelet-derived growth factor, IL-6, an oncogene product, bcl-2, Kras, p53, cMET and a tumor necrosis factor.
9. The antibody construct of claim 5 , wherein the second antibody is selected from the group consisting of hA20, hA19, hIMMU31, hLL1, hLL2, hMu-9, hL243, hMN-14, hRS7, hMN-3, hR1, CA19.9, DUPAN2, SPAN1, Nd2, B72.3 and CC49.