Claims for Patent: 9,139,657

Summary for Patent: 9,139,657

Title:	Class I anti-CEA antibodies and uses thereof
Abstract:	The present invention provides compositions and methods of use of humanized, chimeric or human Class I anti-CEA antibodies or fragments thereof, preferably comprising the light chain variable region CDR sequences SASSRVSYIH (SEQ ID NO:1); GTSTLAS (SEQ ID NO:2); and QQWSYNPPT (SEQ ID NO:3); and the heavy chain variable region CDR sequences DYYMS (SEQ ID NO:4); FIANKANGHTTDYSPSVKG (SEQ ID NO:5); and DMGIRWNFDV (SEQ ID NO:6). The Class I anti-CEA antibodies or fragments are useful for treating diseases, such as cancer, wherein the diseased cells express CEACAM5 and/or CEACAM6 antigens. The Class I anti-CEA antibodies or fragments are also of use for interfering with specific processes, such as metastasis, invasiveness and/or adhesion of cancer cells, or for enhancing sensitivity of cancer cells to cytotoxic agents and have favorable effects on the survival of subjects with cancer.
Inventor(s):	Hansen; Hans J. (Picayune, MS), Chang; Chien-Hsing (Downingtown, PA), Goldenberg; David M. (Mendham, NJ)
Assignee:	Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	14/576,656
Patent Claims:	1. A chimeric, humanized or human Class I anti-CEA antibody or fragment thereof, wherein the Class I anti-CEA antibody or fragment thereof comprises the light chain variable region CDR sequences SASSRVSYIH (SEQ ID NO:1); GTSTLAS (SEQ ID NO:2); and QQWSYNPPT (SEQ ID NO:3); and the heavy chain variable region CDR sequences DYYMS (SEQ ID NO:4); FIANKANGHTTDYSPSVKG (SEQ ID NO:5); and DMGIRWNFDV (SEQ ID NO:6), wherein the antibody or fragment thereof comprises human antibody IgG4 constant region sequences. 2. The antibody or fragment thereof of claim 1, wherein the antibody or fragment binds to CEACAM5, CEACAM6 and granulocytes. 3. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is a chimeric antibody or fragment thereof. 4. The antibody or fragment thereof of claim 3, wherein the chimeric antibody or fragment thereof comprises the variable region amino acid sequences of SEQ ID NO:9 and SEQ ID NO:10. 5. The antibody or fragment thereof of claim 1, wherein antibody or fragment thereof is a humanized antibody or fragment thereof. 6. The antibody or fragment thereof of claim 5, wherein the humanized antibody or fragment thereof comprises the amino acid sequences of SEQ ID NO:7 and SEQ ID NO:8. 7. The antibody or fragment thereof of claim 1, wherein the antibody or fragment is a naked antibody or fragment. 8. The antibody or fragment thereof of claim 1, wherein the antibody or fragment is conjugated to at least one diagnostic or therapeutic agent. 9. The antibody or fragment thereof of claim 8, wherein the therapeutic agent is selected from the group consisting of an antibody, an antibody fragment, a cytotoxic agent, a drug, a radionuclide, boron atoms, an immunomodulator, a photoactive therapeutic agent, an immunoconjugate, an oligonucleotide and a hormone. 10. The antibody or fragment thereof of claim 9, wherein the cytotoxic agent is a drug or toxin. 11. The antibody or fragment thereof of claim 10, wherein the drug has a pharmaceutical property selected from the group consisting of antimitotic, alkylating, antimetabolite, antiangiogenic, apoptotic, alkaloid, COX-2, and antibiotic agents. 12. The antibody or fragment thereof of claim 10, wherein the drug is selected from the group consisting of nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, triazenes, folic acid analogs, anthracyclines, taxanes, COX-2 inhibitors, pyrimidine analogs, purine analogs, antimetabolites, antibiotics, enzymes, epipodophyllotoxins, platinum coordination complexes, vinca alkaloids, substituted ureas, methyl hydrazine derivatives, adrenocortical suppressants, antagonists, endostatin, taxols, camptothecins, oxaliplatin and doxorubicins. 13. The antibody or fragment thereof of claim 10, wherein the drug is selected from the group consisting of 5-fluorouracil, aplidin, azaribine, anastrozole, anthracyclines, bendamustine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celecoxib, chlorambucil, cisplatinum, COX-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicin (2P-DOX), pro-2P-DOX, cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, estramustine, epipodophyllotoxin, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, gemcitabine, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, lenolidamide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicomycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, streptozocin, tamoxifen, temazolomide, transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids. 14. The antibody or fragment thereof of claim 10, wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), onconase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin and Pseudomonas endotoxin. 15. The antibody or fragment thereof of claim 9, wherein the oligonucleotide is selected from the group consisting of an RNAi and a siRNA. 16. The antibody or fragment thereof of claim 9, wherein the radionuclide is selected from the group consisting of .sup.111In, .sup.111At, .sup.177Lu, .sup.211Bi, .sup.212Bi, .sup.213Bi, .sup.211At, .sup.62Cu, .sup.67Cu, .sup.90Y, .sup.125I, .sup.131I, .sup.133I, .sup.32P, .sup.33P, .sup.47Sc, .sup.111Ag, .sup.67Ga, .sup.153Sm, .sup.161Tb, .sup.152Dy, .sup.166Dy, .sup.161Ho, .sup.166Ho, .sup.186Re, .sup.188Re, .sup.189Re, .sup.211Pb, .sup.212Pb, .sup.223Ra, .sup.225Ac, .sup.77As, .sup.89Sr, .sup.99Mo, .sup.105Rh, .sup.149Pm, .sup.169Er, .sup.194Ir, .sup.58Co, .sup.80mBr, .sup.99mTc, .sup.103mRh, .sup.109Pt, .sup.119Sb, .sup.125I, .sup.189mOs, .sup.192Ir, .sup.219Rn, .sup.215Po, .sup.221Fr, .sup.255Fm, .sup.11C, .sup.13N, .sup.15O, .sup.75Br, .sup.198Au, .sup.199Au, .sup.224Ac, .sup.77Br, .sup.113mIn, .sup.95Ru, .sup.97Ru, .sup.103Ru, .sup.105Ru, .sup.107Hg, .sup.203Hg, .sup.121mTe, .sup.122mTe, .sup.125mTe, .sup.165Tm, .sup.167Tm, .sup.168Tm, .sup.197Pt, .sup.109Pd, .sup.142Pr, .sup.143Pr, .sup.161Tb, .sup.57Co, .sup.58Co, .sup.51Cr, .sup.59Fe, .sup.75Se, .sup.201Tl, .sup.76Br, .sup.169Yb, and an alpha-particle emitting radionuclide. 17. The antibody or fragment thereof of claim 9, wherein the immunomodulator is selected from the group consisting of a cytokine, a chemokine, a stem cell growth factor, a lymphotoxin, an hematopoietic factor, a colony stimulating factor (CSF), an interferon, erythropoietin, thrombopoietin, a tumor necrosis factor (TNF), an interleukin (IL), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and a stem cell growth factor designated "S1 factor". 18. The antibody or fragment thereof of claim 17, wherein the cytokine is selected from the group consisting of 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), osteoinductive factors, interferon-.alpha., interferon-I.beta., interferon-.gamma., 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-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, tumor necrosis factor and lymphotoxin. 19. The antibody or fragment thereof of claim 17, wherein the chemokine is selected from the group consisting of RANTES, MCAF, MIP1-alpha, MIP1-beta and IP-10. 20. The antibody or fragment thereof of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, Fab', Fab, Fv, single domain antibody (VHH) and scFv. 21. The antibody or fragment thereof of claim 5, wherein the framework regions of the light and heavy chain variable regions of the humanized antibody or fragment thereof comprise at least one amino acid substitution selected from the heavy chain amino acid residues 28, 29, 30, 48 and 49 of SEQ ID NO:10 and the light chain amino acid residues 21, 47 and 60 of SEQ ID NO:9. 22. The antibody or fragment thereof of claim 8, wherein the diagnostic agent is selected from the group consisting of a radionuclide, a radiological contrast agent, a paramagnetic ion, a metal, a fluorescent label, a chemiluminescent label, an ultrasound contrast agent and a photoactive agent. 23. The antibody or fragment thereof of claim 22, wherein the radionuclide is selected from the group consisting of .sup.110In, .sup.111In, .sup.177Lu, .sup.18Fe, .sup.52Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.90Y, .sup.89Zr, .sup.94mTc, .sup.94Tc, .sup.99mTc, .sup.120I, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.154-158Gd, .sup.32P, .sup.11C, .sup.13N, .sup.15O, .sup.186Re, .sup.188Re, .sup.51Mn, .sup.52mMn, .sup.55Co, .sup.72As, .sup.75Br, .sup.76Br, .sup.82mRb and .sup.83Sr. 24. The antibody or fragment thereof of claim 22, wherein the paramagnetic ion is selected from the group consisting of chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III) and erbium (III). 25. The antibody or fragment thereof of claim 22, wherein the fluorescent label is selected from the group consisting of Alexa 350, Alexa 430, AMCA, aminoacridine, BODIPY 630/650, BODIPY 650/665, BODIPY-FL, BODIPY-R6G, BODIPY-TMR, BODIPY-TRX, 5-carboxy-4', 5'-dichloro-2',7'-dimethoxy fluorescein, 5-carboxy-2',4',5',7'-tetrachlorofluorescein, 5-carboxyfluorescein, 5-carboxyrhodamine, 6-carboxyrhodamine, 6-carboxytetramethyl rhodamine, Cascade Blue, Cy2, Cy3, Cy5,6-FAM, dansyl chloride, Fluorescein, HEX, 6-JOE, NBD (7-nitrobenz-2-oxa-1,3-diazole), Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, phthalic acid, terephthalic acid, isophthalic acid, cresyl fast violet, cresyl blue violet, brilliant cresyl blue, para-aminobenzoic acid, erythrosine, phthalocyanines, azomethines, cyanines, xanthines, succinylfluoresceins, rare earth metal cryptates, europium trisbipyridine diamine, a europium cryptate or chelate, diamine, dicyanins, La Jolla blue dye, allopycocyanin, allococyanin B, phycocyanin C, phycocyanin R, thiamine, phycoerythrocyanin, phycoerythrin R, REG, Rhodamine Green, rhodamine isothiocyanate, Rhodamine Red, ROX, TAMRA, TET, TRIT (tetramethyl rhodamine isothiol), Tetramethylrhodamine, and Texas Red. 26. The antibody or fragment thereof of claim 1, wherein the antibody comprises a Ser241Pro point mutation in the hinge region of the antibody or fragment. 27. The antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is a bispecific antibody. 28. The bispecific antibody of claim 27, wherein the bispecific antibody comprises a first chimeric, humanized or human Class I anti-CEA antibody or fragment thereof and a second antibody or fragment thereof. 29. The bispecific antibody of claim 27, wherein the bispecific antibody is a fusion protein. 30. The bispecific antibody of claim 28, wherein the second antibody or fragment thereof binds to a tumor-associated antigen (TAA) or a hapten on a targetable construct. 31. The bispecific antibody of claim 30, wherein the TAA is selected from the group consisting of carbonic anhydrase IX, CCL19, CCL21, CSAp, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, IGF-1R, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, AFP, PSMA, CEACAM5, CEACAM6, B7, ED-B of fibronectin, Factor H, FHL-1, Flt-3, folate receptor, GROB, HMGB-1, hypoxia inducible factor (HIF), HM1.24, insulin-like growth factor-1 (ILGF-1), IFN-13, IL-2, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, PAM4 antigen, NCA-95, NCA-90, Ia, HM1.24, EGP-1, EGP-2, HLA-DR, tenascin, Le(y), RANTES, T101, TAC, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, TNF-.alpha., TRAIL receptor (R1 and R2), VEGFR, EGFR, P1GF, complement factors C3, C3a, C3b, C5a, C5 and an oncogene product. 32. The bispecific antibody of claim 30, wherein the second antibody is selected from the group consisting of hPAM4, hA20, hA19, hIMMU31, hLL1, hLL2, hMu-9, hL243, hMN-14, hMN-3, hR1, h679 and 734. 33. A fusion protein comprising comprising a chimeric, humanized or human Class I anti-CEA antibody or fragment thereof according to claim 1. 34. The fusion protein of claim 33, further comprising a DDD (dimerization and docking domain) moiety or an AD (anchor domain) moiety, wherein said DDD moiety has a peptide sequence from a dimerization and docking domain of protein kinase A and said AD moiety has a peptide sequence from an anchoring domain of an AKAP (A-kinase anchoring protein). 35. The fusion protein of claim 34, wherein the DDD moiety as an amino acid sequence selected from the group consisting of DDD1 (SEQ ID NO:11) and DDD2 (SEQ ID NO:12). 36. The fusion protein of claim 34, wherein the AD moiety as an amino acid sequence selected from the group consisting of AD1 (SEQ ID NO:13) and AD2 (SEQ ID NO:14).

Details for Patent 9,139,657

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2029-09-16
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2029-09-16