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Last Updated: March 28, 2024

Claims for Patent: 8,349,332


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Summary for Patent: 8,349,332
Title:Multiple signaling pathways induced by hexavalent, monospecific and bispecific antibodies for enhanced toxicity to B-cell lymphomas and other diseases
Abstract: Disclosed herein are compositions and methods of use comprising hexavalent DNL complexes. Preferably, the complexes comprise anti-CD20 and/or anti-CD22 antibodies or fragments thereof. More preferably, the anti-CD20 antibody is veltuzumab and the anti-CD22 antibody is epratuzumab. Administration of the subject hexavalent DNL complexes induces apoptosis and cell death of target cells in diseases such as B-cell lymphomas or leukemias, autoimmune disease or immune dysfunction disease. In most preferred embodiments, the DNL complexes increase levels of phosphorylated p38 and PTEN, decrease levels of phosphorylated Lyn, Akt, ERK, IKK.alpha./.beta. and I.kappa.B.alpha., increase expression of RKIP and Bax and decrease expression of Mcl-1, Bcl-xL, Bcl-2, and phospho-BAD in target cells. The subject DNL complexes show EC.sub.50 values for inhibiting tumor cell growth in the low nanomolar or even sub-nanomolar concentration range.
Inventor(s): Chang; Chien-Hsing (Dowingtown, PA), Goldenberg; David M. (Mendham, NJ), Rossi; Edmund A. (Woodland Park, NJ)
Assignee: IBC Pharmaceuticals, Inc. (Morris Plains, NJ)
Application Number:13/086,786
Patent Claims:1. A method of killing CD20.sup.+ and/or CD22.sup.+ cells, comprising exposing the cells to a hexavalent DNL complex comprising: a. a first fusion protein comprising an AD moiety from the N-terminus of an AKAP protein consisting of SEQ ID NO: 16 attached to the C-terminal end of an IgG antibody, and b. four copies of a second fusion protein comprising a DDD sequence from human protein kinase A (PKA) RI.alpha., RI.beta., RII.alpha. or RII.beta. consisting of SEQ ID NO: 14 attached to the C-terminal end of a Fab antibody; wherein pairs of the DDD sequence form dimers that bind to the AD moiety to form the DNL complex; and wherein the IgG antibody and the Fab antibody fragment bind to one or more antigens selected from the group consisting of CD20 and CD22.

2. The method of claim 1, wherein the IgG antibody is an anti-CD20 or an anti-CD22 antibody.

3. The method of claim 2, wherein the Fab antibody fragment is a Fab fragment of an anti-CD20 or an anti-CD22 antibody.

4. The method of claim 1, wherein the anti-CD20 antibody is hA20 and the anti-CD22 antibody is hLL2.

5. The method of claim 1, wherein the anti-CD20 or anti-CD22 antibody or naked Fab fragment thereof is a naked antibody or fragment thereof.

6. The method of claim 5, further comprising exposing the cell to at least one therapeutic agent selected from the group consisting of a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, and a hormone.

7. The method of claim 1, wherein the anti-CD20 or anti-CD22 antibody or Fab fragment thereof is further conjugated to at least one therapeutic agent selected from the group consisting of a radionuclide, a cytotoxin, a chemotherapeutic agent, a drug, a pro-drug, a toxin, an enzyme, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, and a hormone.

8. The method of claim 6, 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, celecoxib, chlorambucil, cisplatinum, 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, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, ranpirnase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.

9. The method of claim 6, wherein the therapeutic agent is bortezomib.

10. The method of claim 7, wherein the therapeutic agent is a radionuclide selected from the group consisting of .sup.103mRh, .sup.103Ru, .sup.105Rh, .sup.105Ru, .sup.107Hg, .sup.109Pd, .sup.109Pt, .sup.111Ag, .sup.111In, .sup.113mIn, .sup.119Sb, .sup.11C, .sup.121mTe, .sup.122mTe, .sup.125I, .sup.125mTe, .sup.126I, .sup.131I, .sup.133I, .sup.13N, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.152Dy, .sup.153Sm, .sup.15O, .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.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.225Fm, .sup.32P, .sup.33P, .sup.47Sc, .sup.51Cr, .sup.57Cr, .sup.57Co, 58Co, .sup.59Fe, .sup.62Cu, .sup.67Cu, .sup.67Ga, .sup.75Br, .sup.75Se, .sup.76Br, .sup.77As, .sup.77Br, .sup.80mBr, .sup.89Sr, .sup.90Y, .sup.95Ru, .sup.97Ru, .sup.99Mo and .sup.99mTc.

11. The method of claim 6, wherein the therapeutic agent is an enzyme selected from the group consisting of malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase.

12. The method of claim 6, wherein the therapeutic agent is an immunomodulator 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, LIF, FLT-3, angiostatin, thrombospondin, endostatin and lymphotoxin lymphotoxin (LT).

Details for Patent 8,349,332

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Recordati Rare Diseases, Inc. ELSPAR asparaginase For Injection 101063 01/10/1978 ⤷  Try a Trial 2025-04-06
Nps Pharmaceuticals, Inc. NATPARA parathyroid hormone For Injection 125511 01/23/2015 ⤷  Try a Trial 2025-04-06
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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