Claims for Patent: 9,089,618

Summary for Patent: 9,089,618

Title:	Anti-mucin antibodies for early detection and treatment of pancreatic cancer
Abstract:	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 antibodies show novel and useful diagnostic 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. Preferably, the antibodies bind to pancreatic cancer mucins such as MUC1 or MUC5ac and are of use for the detection and diagnosis of early stage pancreatic cancer. In more preferred embodiments, the anti-pancreatic cancer antibodies can be used for immunoassay of serum samples, wherein the immunoassay detects a marker for early stage pancreatic cancer in serum. Most preferably, the serum is extracted with an organic phase, such as butanol, before immunoassay. Alternatively, immunoassay with PAM4 and anti-CA19.9 antibodies may be utilized to improve sensitivity for pancreatic cancer.
Inventor(s):	Gold; David V. (Metuchen, NJ), Goldenberg; David M. (Mendham, NJ)
Assignee:	Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	14/312,873
Patent Claims:	1. A method of treating a cancer that expresses MUC5ac comprising administering to a human subject with a cancer that expresses MUC5ac a humanized anti-MUC5ac monoclonal antibody or antigen-binding fragment thereof that binds to the same epitope as or competes for binding to MUC5ac with an antibody that comprises the light chain variable region CDR sequences CDR1 (SASSSVSSSYLY, SEQ ID NO:1); CDR2 (STSNLAS, SEQ ID NO:2); and CDR3 (HQWNRYPYT, SEQ ID NO:3); and the heavy chain variable region CDR sequences CDR1 (SYVLH, SEQ ID NO:4); CDR2 (YINPYNDGTQYNEKFKG, SEQ ID NO:5) and CDR3 (GFGGSYGFAY, SEQ ID NO:6), wherein the anti-MUC5ac antibody is conjugated to at least one therapeutic agent. 2. The method of claim 1, wherein the cancer is selected from the group consisting of gastric, colorectal, lung, biliary and pancreatic adenocarcinoma. 3. The method of claim 1, wherein the cancer is pancreatic adenocarcinoma. 4. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of a radionuclide, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an anti-sense oligonucleotide, siRNA, an enzyme inhibitor, a photoactive therapeutic agent, a cytotoxic agent, a drug, a toxin, an angiogenesis inhibitor and a pro-apoptotic agent. 5. The method of claim 4, wherein the radionuclide is selected from the group consisting of .sup.14C, .sup.13N, .sup.15O, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo, .sup.99mTc, .sup.103mRh, .sup.103Ru, .sup.105Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.113mIn, .sup.119Sb, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.161Ho, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166Ho, .sup.167Tm, .sup.168Tm, .sup.169Er, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189mOs, .sup.189Re, .sup.192Ir, .sup.194Ir, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.211Bi, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.215Po, .sup.217At, .sup.219Rn, .sup.221Fr, .sup.223Ra, .sup.224Ac, .sup.225Ac, .sup.255Fm and Th.sup.227. 6. The method of claim 5, wherein the radionuclide is .sup.90Y. 7. The method of claim 4, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecpxob, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2PDOX), pro-2PDOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839. 8. The method of claim 4, wherein the toxin is elected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin. 9. The method of claim 4, wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., interferon-.lamda., human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-.alpha., tumor necrosis factor-.beta., mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), NGF-.beta., platelet-growth factor, TGF-.alpha., TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), macrophage-CSF (M-CSF), IL-1, IL-1.alpha., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-23, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, and lymphotoxin. 10. The method of claim 4, wherein the tyrosine kinase inhibitor is selected from the group consisting of canertinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, leflunomide, nilotinib, pazopanib, semaxinib, sorafenib, sunitinib, sutent, vatalanib, PCI-32765 (ibrutinib), PCI-45292, GDC-0834, LFM-A13 and RN486. 11. The method of claim 1, further comprising administering at least one other therapeutic agent to the human subject, wherein the at least one other therapeutic agent is selected from the group consisting of a second antibody, a second antigen-binding antibody fragment, an immunoconjugate, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an anti-sense oligonucleotide, siRNA, an enzyme inhibitor, a photoactive therapeutic agent, a cytotoxic agent, a drug, a toxin, an angiogenesis inhibitor and a pro-apoptotic agent. 12. The method of claim 11, wherein the second antibody, second antigen-binding antibody fragment, or immunoconjugate binds to an antigen selected from the group consisting of CA19.9, DUPAN2, SPAN1, Nd2, B72.3, CC49, Le.sup.a, Le(y), CEACAM5, CEACAM6, CSAp, MUC1, MUC2, MUC3, MUC4, MUC5ac, MUC16, MUC17, HLA-DR, CD40, CD74, CD138, HER2/neu, EGFR, EGP-1, EGP-2, VEGF, P1GF, insulin-like growth factor, tenascin, platelet-derived growth factor, IL-6, bcl-2, K-ras, p53 and cMET. 13. The method of claim 11, wherein the second antibody, second antigen-binding antibody fragment, or immunoconjugate is selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-MUC5ac), hIMMU-31 (anti-AFP), hLL1 (anti-CD74), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hL243 IgG4P (anti-HLA-DR), hMN-14 (anti-CEACAM5), hMN-15 (anti-CEACAM6), hRS7 (anti-EGP-1 or anti-TROP-2), hMN-3 (anti-CEACAM6), Ab124 (anti-CXCR4) and Ab125 (anti-CXCR4). 14. A method of treating a cancer that expresses MUC5ac comprising: a. administering to a subject with a cancer that expresses MUC5ac a bispecific antibody comprising (i) a humanized anti-MUC5ac monoclonal antibody or antigen-binding fragment thereof that binds to the same epitope as or competes for binding to MUC5ac with an antibody that comprises the light chain variable region CDR sequences CDR1 (SASSSVSSSYLY, SEQ ID NO:1); CDR2 (STSNLAS, SEQ ID NO:2); and CDR3 (HQWNRYPYT, SEQ ID NO:3); and the heavy chain variable region CDR sequences CDR1 (SYVLH, SEQ ID NO:4); CDR2 (YINPYNDGTQYNEKFKG, SEQ ID NO:5) and CDR3 (GFGGSYGFAY, SEQ ID NO:6), and (ii) an anti-hapten antibody or antigen-binding fragment thereof; and b. administering to the individual a targetable construct comprising at least one copy of the hapten, wherein the targetable construct is conjugated to at least one therapeutic agent. 15. The method of claim 14, wherein the hapten is HSG or In-DTPA. 16. The method of claim 14, wherein the cancer is selected from the group consisting of gastric, colorectal, lung, biliary and pancreatic adenocarcinoma. 17. The method of claim 14, wherein the cancer is pancreatic adenocarcinoma. 18. The method of claim 14, wherein the therapeutic agent is selected from the group consisting of a radionuclide, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an anti-sense oligonucleotide, siRNA, an enzyme inhibitor, a photoactive therapeutic agent, a cytotoxic agent, a drug, a toxin, an angiogenesis inhibitor and a pro-apoptotic agent. 19. The method of claim 18, wherein the radionuclide is selected from the group consisting of .sup.14C, .sup.13N, .sup.15O, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Co, .sup.58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo, .sup.99mTc, .sup.103mRh, .sup.103Ru, .sup.105Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.113mIn, .sup.119Sb, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.161Ho, .sup.161Tb, .sup.165Tm, .sup.166Dy, .sup.166Ho, .sup.167Tm, .sup.168Tm, .sup.169Er, .sup.169Yb, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189mOs, .sup.189Re, .sup.192Ir, .sup.194Ir, .sup.197Pt, .sup.198Au, .sup.199Au, .sup.199Au, .sup.201Tl, .sup.203Hg, .sup.211At, .sup.211Bi, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.215Po, .sup.217At, .sup.219Rn, .sup.221Fr, .sup.223Ra, .sup.224Ac, .sup.225Ac, .sup.255Fm and Th.sup.227. 20. The method of claim 18, wherein the radionuclide is .sup.90Y. 21. The method of claim 18, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-29 1, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecpxob, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2PDOX), pro-2PDOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839. 22. The method of claim 18, wherein the toxin is elected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin. 23. The method of claim 18, wherein the immunomodulator is selected from the group consisting of a cytokine, a stem cell growth factor, a lymphotoxin, a hematopoietic factor, a colony stimulating factor (CSF), an interferon (IFN), erythropoietin, thrombopoietin tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., interferon-.lamda., human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, tumor necrosis factor-.alpha., tumor necrosis factor-.beta., mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, thrombopoietin (TPO), NGF-.beta., platelet-growth factor, TGF-.alpha., TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, erythropoietin (EPO), macrophage-CSF (M-CSF), IL-1, IL-1.alpha., IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-23, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, and lymphotoxin. 24. The method of claim 18, wherein the tyrosine kinase inhibitor is selected from the group consisting of canertinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, leflunomide, nilotinib, pazopanib, semaxinib, sorafenib, sunitinib, sutent, vatalanib, PCI-32765 (ibrutinib), PCI-45292, GDC-0834, LFM-A13 and RN486. 25. The method of claim 14, further comprising administering at least one other therapeutic agent to the individual, wherein the at least one other therapeutic agent is selected from the group consisting of a second antibody, a second antigen-binding antibody fragment, an immunoconjugate, an immunomodulator, a hormone, a hormone antagonist, an enzyme, an anti-sense oligonucleotide, siRNA, an enzyme inhibitor, a photoactive therapeutic agent, a cytotoxic agent, a drug, a toxin, an angiogenesis inhibitor and a pro-apoptotic agent. 26. The method of claim 25, wherein the second antibody, second antigen-binding antibody fragment, or immunoconjugate binds to an antigen selected from the group consisting of CA19.9, DUPAN2, SPAN1, Nd2, B72.3, CC49, Le.sup.a, Le(y), CEACAMS, CEACAM6, CSAp, MUC1, MUC2, MUC3, MUC4, MUCSac, MUC16, MUC17, HLA-DR, CD40, CD74, CD138, HER2/neu, EGFR, EGP-1, EGP-2, VEGF, P1GF, insulin-like growth factor, tenascin, platelet-derived growth factor, IL-6, bc1-2, K-ras, p53 and cMET. 27. The method of claim 25, wherein the second antibody, second antigen-binding antibody fragment, or immunoconjugate is selected from the group consisting of hR1 (anti-IGF-1R), hPAM4 (anti-MUC5ac), hIMMU-31 (anti-AFP), hLL1 (anti-CD74), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hL243 IgG4P (anti-HLA-DR), hMN-14 (anti-CEACAMS), hMN-15 (anti-CEACAM6), hRS7 (anti-EGP-1 or anti-TROP-2), hMN-3 (anti-CEACAM6), Ab124 (anti-CXCR4) and Ab125 (anti-CXCR4). 28. The method of claim 14, wherein the subject is a human subject.

Details for Patent 9,089,618

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2022-06-14
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2022-06-14