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Generated: August 23, 2019

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Claims for Patent: 8,987,421

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Summary for Patent: 8,987,421
Title:Chimeric and humanized anti-histone antibodies
Abstract: The present invention concerns chimeric or humanized antibodies or antigen-binding fragments thereof that comprise specific CDR sequences, disclosed herein. Preferably, the antibodies or fragments comprise specific heavy and light chain variable region sequences disclosed herein. More preferably, the antibodies or fragments also comprise specific constant region sequences, such as those associated with the nG1m1,2 or Km3 allotypes. The antibodies or fragments may bind to a human histone protein, such as H2B, H3 or H4. The antibodies or fragments are of use to treat a variety of diseases that may be associated with histones, such as autoimmune disease (e.g., SLE), atherosclerosis, arthritis, rheumatoid arthritis, edema, sepsis, septic shock, hyperinflammatory disorder, infectious disease, inflammatory disease, immune dysregulatory disorder, GVHD, transplant rejection, atherosclerosis, asthma, a coagulopathy, myocardial ischemia, thrombosis, nephritis, inflammatory liver injury, acute pancreatitis, ischemia-reperfusion injury, stroke, cardiovascular disease, and burn.
Inventor(s): Chang; Chien-Hsing (Downingtown, PA), Hansen; Hans J. (Picayune, MS), Goldenberg; David M. (Mendham, NJ)
Assignee: Immunomedics, Inc. (Morris Plains, NJ)
Application Number:14/180,646
Patent Claims:1. A chimeric or humanized anti-histone H4 antibody or antigen-binding fragment thereof, comprising the heavy chain complementarity-determining region (CDR) sequences CDR1 (DDYLH, SEQ ID NO:90), CDR2 (WIGWIDPENGDTEYASKFQG, SEQ ID NO:91) and CDR3 (PLVHLRTFAY, SEQ ID NO:92) and the light chain CDR sequences CDR1 (RASESVDSYDNSLH, SEQ ID NO:93), CDR2 (LASNLES, SEQ ID NO:94) and CDR3 (QQNNEDPWT, SEQ ID NO:95).

2. The chimeric antibody or fragment thereof of claim 1, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:98 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:99.

3. The humanized antibody or fragment thereof of claim 1, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:96 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:97.

4. A chimeric or humanized anti-histone H3 antibody or antigen-binding fragment thereof, comprising the heavy chain CDR sequences CDR1 (SYWMH, SEQ ID NO:100), CDR2 (NIDPSDSETHYNQKFKD, SEQ ID NO:101) and CDR3 (EKITDDYNYFDY, SEQ ID NO:102) and the light chain CDR sequences CDR1 (RASESVDSYGNSFMH, SEQ ID NO:103), CDR2 (HASNLES, SEQ ID NO:104) and CDR3 (QQNNEDPLT, SEQ ID NO:105).

5. The chimeric antibody or fragment thereof of claim 4, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:108 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:109.

6. The humanized antibody or fragment thereof of claim 4, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:106 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:107.

7. A chimeric or humanized anti-histone H2B antibody or antigen-binding fragment thereof, comprising the heavy chain CDR sequences CDR1 (SYVMY, SEQ ID NO:110), CDR2 (YINPYNDGTKYNEKFKG, SEQ ID NO:111) and CDR3(PGDGYPFDY, SEQ ID NO:112) and the light chain CDR sequences CDR1(RSSQSIVHSNGNTYLE, SEQ ID NO:113), CDR2 (KVSNRFS, SEQ ID NO:114) and CDR3 (FQGSHVPYT, SEQ ID NO:115).

8. The chimeric antibody or fragment thereof of claim 7, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:118 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:119.

9. The humanized antibody or fragment thereof of claim 7, wherein the amino acid sequence of the heavy chain variable region sequence is SEQ ID NO:116 and the amino acid sequence of the light chain variable region sequence is SEQ ID NO:117.

10. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is not conjugated to a therapeutic agent.

11. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is conjugated to at least one therapeutic agent.

12. The chimeric or humanized antibody or fragment thereof of claim 11, wherein the therapeutic agent is selected from the group consisting of a second antibody, a second antibody fragment, a radionuclide, an immunomodulator, an anti-angiogenic agent, a pro-apoptotic agent, a cytokine, a chemokine, a drug, a toxin, a hormone, an siRNA and an enzyme.

13. The chimeric or humanized antibody or fragment thereof 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, 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 (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vinorelbine, vinblastine, vincristine, a vinca alkaloid, a tyrophostin, 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.

14. The chimeric or humanized antibody or fragment thereof of claim 11, wherein the toxin is selected from the group consisting of ricin, abrin, alpha toxin, saporin, ribonuclease (RNase), ranpirnase, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.

15. The chimeric or humanized antibody or fragment thereof of claim 11, 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), 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., TGF-.alpha., TGF-.beta., interleukin-1 (IL-1), IL-la.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.

16. The chimeric or humanized antibody or fragment thereof of claim 15, 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-.beta., interferon-.gamma., macrophage-CSF (M-CSF), IL-1, IL-la.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.

17. The chimeric or humanized antibody or fragment thereof of claim 11, 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.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 .sup.227Th.

18. The chimeric or humanized antibody fragment of claim 1, wherein the antibody fragment is selected from the group consisting of F(ab').sub.2, Fab', Fab, Fv and scFv.

19. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody or fragment thereof is conjugated to at least one diagnostic agent.

20. The chimeric or humanized antibody or fragment thereof of claim 19, 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.

21. The chimeric or humanized antibody or fragment thereof of claim 20, wherein the radionuclide is selected from the group consisting of .sup.110In, .sup.111In, .sup.177Lu, .sup.18F, .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.

22. The chimeric or humanized antibody or fragment thereof of claim 20, 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).

23. The chimeric or humanized antibody or fragment thereof of claim 20, 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 amino, 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.

24. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody has a nG1m1,2 heavy chain null allotype.

25. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody has a Km3 light chain allotype.

26. The chimeric or humanized antibody or fragment thereof of claim 1, wherein the antibody comprises heavy chain constant region amino acid residues arginine-214, glutamic acid-356, methionine-358 and alanine-431.

27. A fusion protein comprising a chimeric or humanized antibody or fragment thereof of claim 1.

28. A therapeutic composition comprising a chimeric or humanized antibody or fragment thereof of claim 1.

Details for Patent 8,987,421

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   Try a Free Trial Immunomedics, Inc. (Morris Plains, NJ) 2033-02-15 RX search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 001 2015-01-23   Try a Free Trial Immunomedics, Inc. (Morris Plains, NJ) 2033-02-15 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 002 2015-01-23   Try a Free Trial Immunomedics, Inc. (Morris Plains, NJ) 2033-02-15 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 003 2015-01-23   Try a Free Trial Immunomedics, Inc. (Morris Plains, NJ) 2033-02-15 RX Orphan search
Nps Pharms Inc NATPARA parathyroid hormone INJECTABLE;INJECTION 125511 004 2015-01-23   Try a Free Trial Immunomedics, Inc. (Morris Plains, NJ) 2033-02-15 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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International Patent Family for US Patent 8,987,421

Country Patent Number Publication Date
World Intellectual Property Organization (WIPO) 2014127200 Aug 21, 2014
United States of America 10040848 Aug 07, 2018
United States of America 10160801 Dec 25, 2018
United States of America 2014234209 Aug 21, 2014
United States of America 2015150969 Jun 04, 2015
United States of America 2016130333 May 12, 2016
United States of America 2017218059 Aug 03, 2017
>Country >Patent Number >Publication Date

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