Claims for Patent: 8,367,037

Summary for Patent: 8,367,037

Title:	Anti-CD74 immunoconjugates and methods of use
Abstract:	Disclosed are compositions that include anti-CD74 immunoconjugates and optionally a therapeutic and/or diagnostic agent. In preferred embodiments, the immunoconjugates comprise one or more anti-CD74 antibodies or antigen-binding fragments thereof, conjugated to a liposome or micelle. Also disclosed are methods for preparing the immunoconjugates and using the immunoconjugates in diagnostic and therapeutic procedures. In certain preferred embodiments, the therapeutic methods comprise administering to a subject with a CD74-expressing disease an anti-CD74 immunoconjugate and thereby inducing apoptosis of CD74-expressing cells. In more preferred embodiments, the CD74 immunoconjugate is capable of inducing cell death in the absence of any other therapeutic agent, although such agents may be optionally administered prior to, together with or subsequent to administration of the anti-CD74 immunoconjugate. The compositions may be part of a kit for administering the anti-CD74 immunoconjugates or compositions.
Inventor(s):	Byrd; John C. (Columbus, OH), Goldenberg; David M. (Mendham, NJ), Hansen; Hans J. (Picayune, MS)
Assignee:	Immunomedics, Inc. (Morris Plains, NJ)
Application Number:	13/347,934
Patent Claims:	1. A therapeutic composition comprising: a) an immunoconjugate comprising at least one anti-CD74 antibody or antigen-binding fragment thereof; and b) a liposome attached to the at least one anti-CD74 antibody or antigen-binding fragment thereof; wherein exposing cells expressing CD74 to the composition results in cross-linking of CD74 on the surface of CD74-expressing cells and induces apoptosis of the CD74 expressing cells. 2. The composition of claim 1, wherein the anti-CD74 antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody, an antigen-binding fragment of a monoclonal antibody, a bispecific antibody, a multispecific antibody and an antibody fusion protein. 3. The composition of claim 1, wherein the composition further comprises at least one therapeutic or diagnostic agent. 4. The composition of claim 1, wherein the anti-CD74 antibody is milatuzumab. 5. The composition of claim 1, wherein the anti-CD74 antibody comprises the light chain variable region complementarity-determining region (CDR) sequences CDR1 (RSSQSLVHRNGNTYLH; SEQ ID NO:1), CDR2 (TVSNRFS; SEQ ID NO:2), and CDR3 (SQSSHVPPT; SEQ ID NO:3) and the heavy chain variable region CDR sequences CDR1 (NYGVN; SEQ ID NO:4), CDR2 (WINPNTGEPTFDDDFKG; SEQ ID NO:5), and CDR3 (SRGKNEAWFAY; SEQ ID NO:6). 6. The composition of claim 1, wherein the anti-CD74 antibody is a chimeric, humanized or human antibody. 7. The composition of claim 1, wherein the anti-CD74 antibody or fragment thereof is a naked anti-CD74 antibody or fragment thereof. 8. The composition of claim 1, wherein the anti-CD74 antibody or fragment thereof is conjugated to at least one therapeutic or diagnostic agent. 9. The composition of claim 1, wherein the one or more anti-CD74 antibody or antigen-binding fragment thereof is conjugated to the liposome by a linkage selected from the group consisting of a sulfide linkage, a hydrazone linkage, a hydrazine linkage, an ester linkage, an amido linkage, an amino linkage, an imino linkage, a thiosemicarbazone linkage, a semicarbazone linkage, an oxime linkage, a carbon-carbon linkage, or a combination thereof. 10. The composition of claim 3, wherein the therapeutic or diagnostic agent is selected from the group consisting of a drug, a prodrug, a toxin, an enzyme, a radionuclide, an immunomodulator, a cytokine, a hormone, a second antibody or antigen-binding fragment thereof, an antisense oligonucleotide, an RNAi, an anti-angiogenic agent, a pro-apoptosis agent, a dye, a fluorescent agent, a contrast agent, a paramagnetic ion and a photodynamic agent. 11. The composition of claim 10, wherein the second antibody or antigen-binding fragment thereof binds to an antigen selected from the group consisting of carbonic anhydrase IX, CCCL19, CCCL21, 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, CEACAM-6, 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-.gamma., IFN-.alpha., IFN-.beta., 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. 12. The composition of claim 10, wherein the therapeutic agent is selected from the group consisting of aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin. 13. The composition of claim 10, wherein the therapeutic agent comprises FUdR, FUdR-dO, or mixtures thereof. 14. The composition of claim 1, further comprising one or more hard acid chelators or soft acid chelators. 15. The composition of claim 14, further comprising one or more cations selected from Group II, Group III, Group IV, Group V, transition, lanthanide or actinide metal cations, or mixtures thereof, wherein said cation is attached to the one or more hard or soft acid chelators. 16. The composition of claim 15, wherein the cation is selected from the group consisting of Tc, Re, Bi, Cu, As, Ag, Au, At and Pb. 17. The composition of claim 14, wherein said chelator is selected from the group consisting of NOTA, DOTA, DTPA, TETA, Tscg-Cys and Tsca-Cys. 18. The composition of claim 10, wherein the radionuclide is selected from the group consisting of .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.77As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, .sup.105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.153Sm, .sup.154-158Gd, .sup.161.sub.Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb, .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra; and .sup.225Ac. 19. The composition of claim 10, wherein the enzyme is selected from the group consisting of carboxylesterase, glucuronidase, carboxypeptidase, beta-lactamase and phosphatase. 20. The composition of claim 10, 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 interleukin (IL) and an interferon (IFN). 21. The composition of claim 10, wherein the immunomodulator is selected from the group consisting of erythropoietin, thrombopoietin tumor necrosis factor-.alpha. (TNF), TNF-.beta., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., stem cell growth factor designated "S1 factor", 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, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-.beta., platelet-growth factor, TGF-.alpha., TGF-.beta., insulin-like growth factor-I, insulin-like growth factor-II, 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 and endostatin. 22. The composition of claim 10, wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, endostatin, basculostatin, canstatin, maspin, anti-VEGF antibody or antigen-binding fragment thereof, anti-placental growth factor antibody or antigen-binding fragment thereof and anti-vascular growth factor antibody or antigen-binding fragment thereof. 23. The composition of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, F(ab).sub.2, Fab, Fab' and scFv fragments. 24. The composition of claim 6, wherein the human, chimeric, or humanized anti-CD74 antibody or fragment thereof further comprises human constant regions selected from the group consisting of IgG1, IgG2a, IgG3 and IgG4. 25. The composition of claim 10, wherein the photodynamic agent is selected from the group consisting of benzoporphyrin monoacid ring A (BDP-MA), tin etiopurpurin (SnET2), sulfonated aluminum phthalocyanine (AISPc) and lutetium texaphyrin. 26. The composition of claim 10, wherein the diagnostic agent is a radionuclide selected from the group consisting of .sup.18F, .sup.52Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.89Zr, .sup.94Tc, .sup.94mTc, .sup.99mTc, .sup.111I, .sup.123I, .sup.124I, .sup.125I and .sup.131I. 27. The composition of claim 10, wherein the diagnostic agent is a contrast agent selected from the group consisting of gadolinium ions, lanthanum ions, manganese ions, iron, chromium, copper, cobalt, nickel, fluorine, dysprosium, rhenium, europium, terbium, holmium, neodymium, barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexyl, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosemetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone and thallous chloride.

Details for Patent 8,367,037

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2019-05-10
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2019-05-10