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Last Updated: November 30, 2020

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Claims for Patent: 9,187,561

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Summary for Patent: 9,187,561
Title:Humanized anti-HLA-DR antibodies
Abstract: The present invention concerns compositions and methods of use of humanized anti-HLA-DR antibodies. In preferred embodiments, the antibodies induce apoptosis and inhibit proliferation of lymphoma cells without inducing CDC or ADCC. In more preferred embodiments, the humanized anti-HLA-DR antibodies bind to the same epitope of HLA-DR as, or compete for binding to HLA-DR with, a murine L243 antibody. Most preferably, the humanized anti-HLA-DR antibody exhibits a higher affinity for HLA-DR than the parental murine antibody. The humanized HLA-DR antibody is of use for therapy of various diseases such as cancer, autoimmune disease or immune dysregulatory function, and is of particular use for therapy of B cell lymphomas and leukemias. In most preferred embodiments, the humanized anti-HLA-DR antibody is capable of inducing at least partial remission of lymphomas that are resistant to other B cell antibodies, such as rituximab.
Inventor(s): Goldenberg; David M. (Mendham, NJ), Hansen; Hans J. (Picayune, MS), Chang; Chien-Hsing (Downingtown, PA)
Assignee: Immunomedics, Inc. (Morris Plains, NJ)
Application Number:14/224,866
Patent Claims:1. A method of treating hematopoietic cancer comprising: a) administering to a subject with hematopoietic cancer a humanized anti-HLA-DR antibody or antigen-binding fragment thereof comprising the heavy chain complementarity determining region (CDR) sequences CDR1 (NYGMN (SEQ ID NO: 39)), CDR2 (WINTYTREPTYADDFKG (SEQ ID NO: 40)), and CDR3 (DITAVVPTGFDY (SEQ ID NO: 41)) and the light chain CDR sequences CDR1 (RASENIYSNLA (SEQ ID NO: 42)), CDR2 (AASNLAD (SEQ ID NO: 43)), and CDR3 (QHFWTTPWA (SEQ ID NO: 44)); wherein the humanized antibody is an IgG4 antibody comprising a Ser241Pro mutation, further comprising light chain murine L243 FR residues R37, K39, V48, F49, and G100 and heavy chain murine L243 FR residues F27, K38, K46, A68, and F91 and wherein the hematopoietic cancer is selected from the group consisting of indolent forms of B-cell lymphoma, aggressive forms of B-cell lymphoma, chronic lymphatic leukemia, acute lymphatic leukemia, multiple myeloma, Hodgkin lymphoma, Non-Hodgkin's lymphoma, Burkitt lymphoma, and hairy cell leukemia.

2. The method of claim 1, wherein said humanized anti-HLA-DR antibody has a higher affinity for HLA-DR than a murine L243 antibody that comprises the heavy chain CDR sequences CDR1 (NYGMN (SEQ ID NO: 39)), CDR2 (WINTYTREPTYADDFKG (SEQ ID NO: 40)), and CDR3 (DITAVVPTGFDY (SEQ ID NO: 41)) and the light chain CDR sequences CDR1 (RASENIYSNLA (SEQ ID NO: 42)), CDR2 (AASNLAD (SEQ ID NO: 43)), and CDR3 (QHFWTTPWA (SEQ ID NO: 44)).

3. The method of claim 1, wherein said humanized anti-HLA-DR antibody is a naked antibody.

4. The method of claim 3, further comprising: b) administering to said subject at least one therapeutic agent selected from the group consisting of an antibody, an antibody fragment, an immunoconjugate, an immunomodulator, a hormone, a cytotoxic agent, an enzyme, a hormone, a cytokine, an anti-angiogenic agent, a pro-apoptosis agent, a photodynamic agent, a drug and a toxin.

5. The method of claim 4, wherein the antibody, antibody fragment, or immunoconjugate binds to an antigen selected from the group consisting of A3, BrE3-antigen, CD1, CD1a, CD3, CD5, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD79a, CD80, HLA-DR, NCA95, NCA90, HCG, CEACAM-5, CEACAM-6, CSAp, EGFR, EGP-1, EGP-2, Ep-CAM, Ba 733, HER2/neu, hypoxia inducible factor (HIF), KC4-antigen, KS-1 antigen, KS1-4, Le-Y, macrophage inhibition factor (MIF), MAGE, MUC1, MUC2, MUC3, MUC4, MUC16, PAM-4-antigen, PSA, PSMA, RS5, S100, TAG-72, p53, tenascin, IL-6, IL-8, insulin growth factor-1 (IGF-1), Tn antigen, VEGF, 17-1A-antigen, ED-B fibronectin, HM1.24, VEGF, ILGF, placental growth factor and carbonic anhydrase IX.

6. The method of claim 4, 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-pyrrolinodoxorubicine (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, lenalidomide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicamycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, SN-38, streptozocin, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids.

7. The method of claim 4, 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.

8. The method of claim 4, wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-P1GF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Flt-1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP-10, Gro-.beta., thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxyamidotriazole, CM101, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, roquinimex, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline.

9. The method of claim 4, wherein the immunomodulator is selected from the group consisting of erythropoietin, thrombopoietin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., 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, tumor necrosis factor-a, tumor necrosis factor-.beta., 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, kit-ligand, angiostatin, thrombospondin, endostatin, tumor necrosis factor and lymphotoxin (LT).

10. The method of claim 1, wherein said humanized anti-HLA-DR antibody is attached to at least one therapeutic agent.

11. The method of claim 10, wherein the therapeutic agent is selected from the group consisting of a drug, a toxin, an enzyme, a radionuclide, an immunomodulator, a cytokine, a hormone, an antibody or fragment thereof, an anti-angiogenic agent, a cytotoxic agent, a pro-apoptosis agent, and a photodynamic agent.

12. The method of claim 11, 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-pyrrolinodoxorubicine (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, lenalidomide, leucovorin, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, nitrosourea, plicamycin, procarbazine, paclitaxel, pentostatin, PSI-341, raloxifene, semustine, SN-38, streptozocin, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine and vinca alkaloids.

13. The method of claim 11, wherein the drug is SN-38.

14. The method of claim 11, wherein the toxin is selected from the group consisting of ricin, abrin, saporin, ribonuclease (RNase), onconase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin and Pseudomonas endotoxin.

15. The method of claim 11, wherein the anti-angiogenic agent is selected from the group consisting of angiostatin, baculostatin, canstatin, maspin, anti-VEGF antibodies, anti-P1GF peptides and antibodies, anti-vascular growth factor antibodies, anti-Flk-1 antibodies, anti-Flt-1 antibodies and peptides, anti-Kras antibodies, anti-cMET antibodies, anti-MIF (macrophage migration-inhibitory factor) antibodies, laminin peptides, fibronectin peptides, plasminogen activator inhibitors, tissue metalloproteinase inhibitors, interferons, interleukin-12, IP-10, Gro-.beta., thrombospondin, 2-methoxyoestradiol, proliferin-related protein, carboxyamidotriazole, CM101, pentosan polysulphate, angiopoietin-2, interferon-alpha, herbimycin A, PNU145156E, 16K prolactin fragment, roquinimex, thalidomide, pentoxifylline, genistein, TNP-470, endostatin, paclitaxel, accutin, angiostatin, cidofovir, vincristine, bleomycin, AGM-1470, platelet factor 4 and minocycline.

16. The method of claim 11, wherein the immunomodulator is selected from the group consisting of erythropoietin, thrombopoietin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-.alpha., interferon-.beta., interferon-.gamma., 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, tumor necrosis factor-.alpha., tumor necrosis factor-.beta., 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, kit-ligand, angiostatin, thrombospondin, endostatin, tumor necrosis factor and lymphotoxin (LT).

17. The method of claim 11, 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.161Tb, .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, .sup.225Ac, and an alpha-emitting radionuclide.

18. The method of claim 5, wherein the administration of a combination of said humanized anti-HLA-DR antibody with an anti-CD20 antibody inhibits proliferation of lymphoma cells more than either anti-HLA-DR antibody or anti-CD20 antibody alone.

19. The method of claim 1, wherein the subject is a human subject.

20. The method of claim 1, wherein the hematopoietic cancer is non-Hodgkin's lymphoma.

21. The method of claim 1 wherein the humanized anti-HLA-DR antibody or antigen-binding fragment thereof is administered intravenously, subcutaneously, or intramuscularly at a dose of between 20 and 2000 mg.

Details for Patent 9,187,561

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10   Start Trial Immunomedics, Inc. (Morris Plains, NJ) 2025-03-03 RX search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23   Start Trial Immunomedics, Inc. (Morris Plains, NJ) 2025-03-03 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Start Trial Immunomedics, Inc. (Morris Plains, NJ) 2025-03-03 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Start Trial Immunomedics, Inc. (Morris Plains, NJ) 2025-03-03 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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