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Claims for Patent: 10,265,291


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Summary for Patent: 10,265,291
Title:Disulfur bridge linkers for conjugation of a cell-binding molecule
Abstract: The present invention relates to novel disulfur bridge linkers containing hydrazine used for the specific conjugation of compounds/cytotoxic agents to a cell-binding molecule, through bridge linking a pair of thiols on the cell-binding molecule. The invention also relates to methods of making such linkers, and of using such linkers in making homogeneous conjugates, as well as of application of the conjugates in treatment of cancers, infections and autoimmune disorders.
Inventor(s): Zhao; Robert Yongxin (Lexington, MA)
Assignee: HANGZHOU DAC BIOTECH CO., LTD. (Hangzhou, CN)
Application Number:15/431,154
Patent Claims:1. A cell-binding agent-drug conjugate compound of Formula (II) ##STR00045## wherein: Cb represents an antibody; Drug.sub.1 and Drug.sub.2 are the same or different, and are selected from the group consisting of 1). chemotherapeutic agents consisting of a). alkylating agents consisting of Nitrogen mustards consisting of chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, and uracil mustard; CC-1065 and adozelesin, carzelesin and bizelesin synthetic derivatives thereof; duocarmycin and synthetic derivatives thereof; benzodiazepine dimers; Nitrosoureas consisting of carmustine, lomustine, chlorozotocin, fotemustine, nimustine, and ranimustine; alkylsulphonates consisting of busulfan, treosulfan, improsulfan and piposulfan: triazenes; platinum containing compounds consisting of carboplatin, cisplatin, and oxaliplatin; aziridines consisting of benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines consisting of altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaor-amide and trimethylolomelamine: b). plant alkaloids consisting of Vinca alkaloids consisting of vincristine, vinblastine, vindesine, vinorelbine, and navelbin; taxoids consisting of paclitaxel, docetaxol and derivatives thereof, maytansinoids consisting of DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins, and derivatives thereof, cryptophycins consisting of cryptophycin 1 and cryptophycin 8; epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; spongistatin; c). DNA topoisomerase inhibitors consisting of Epipodophyllins consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids and retinols, teniposide, topotecan, and 9-nitrocamptothecin; mitomycins; d). antimetabolites consisting of anti-folate, DHFR inhibitors consisting of methotrexate, trimetrexate, denopterin, pteropterin, aminopterin and folic acid derivatives thereof; IMP dehydrogenase inhibitors consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR; ribonucleotide reductase inhibitors consisting of hydroxyurea, and deferoxamine; pyrimidine derivatives, uracil derivatives consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-Fluorouracil, floxuridine, and ratitrexed; cytosine derivatives consisting of cytarabine, cytosine arabinoside, and fludarabine; purine derivatives consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine; frolinic acid; e). hormonal therapies consisting of receptor antagonists consisting of anti-estrogen corn consisting of prising megestrol, raloxifene, and tamoxifen; LHRH agonists consisting of goserelin, and leuprolide acetate: anti-androgens consisting of bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, and trilostane: retinoids/deltoids consisting of Vitamin D3 derivatives consisting of CB 1093, EB 1089 KH 1060, cholecalciferol, and ergocalciferol; photodynamic therapies consisting of verteporfin, phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A; cytokines consisting of Interferon-alpha, Interferon-gamma, tumor necrosis factor (TNF), and human proteins containing a TNF domain; f). kinase inhibitors consisting of anti-EGFR/Erb2, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, anti-VEGFR2, mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, and ispinesib; g). antibiotics consisting of enediyne antibiotics consisting of calicheamicin .gamma.1, .delta.1, .alpha.1 and .beta.1; dynemicin, including dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophe-nolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; h). polyketides (acetogenins) consisting of bullatacin and bullatacinone: gemcitabine, epoxomicins, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, isoprenylation inhibitors, dopaminergic neurotoxins, cell cycle inhibitors, Actinomycins consisting of Actinomycin D, and dactinomycin, Bleomycins consisting of bleomycin A2, bleomycin B2, and peplomycin, Anthracyclines consisting of daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mtoxantrone, MDR inhibitors, Ca.sup.2+ ATPase inhibitors, Histone deacetylase inhibitors consisting of Vorinostat, Romidepsin, Panobinostat, Valproic acid, Mocetinostat, Belinostat, PCI-24781, Entinostat, SB939, Resminostat, Givinostat, AR-42, CUDC-101, sulforaphane, and Trichostatin A; Thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, Disulfiram, Salinosporamide A; Anti-adrenals consisting of aminoglutethimide, mitotane, trilostane; aceglatone; aldophosphamnide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine: diaziquone; eflornithine, elfornithine; elliptinium acetate, etoglucid; gallium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM.; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2',2''-trichlorotriethylamine; trichothecenes consisting of T-2 toxin, verrucarin A, roridin A and anguidine; urethane, siRNA, and antisense drugs; 2). anti-autoimmune disease agents consisting of cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids consisting of amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone acetonide, and beclometasone dipropionate, DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, and tacrolimus; 3). anti-infectious disease agents consisting of a). aminoglycosides consisting of amikacin, astromicin, gentamicin consisting of netilmicin, sisomicin, and isepamicin, hygromycin B, kanamycin consisting of amikacin, arbekacin, bekanamycin, dibekacin, and tobramycin, neomycin consisting of framycetin, paromomycin, and ribostamycin, netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin; b). Amphenicols consisting of azidamfenicol, chloramphenicol, florfenicol, and thiamphenicol; c). ansamycins consisting of geldanamycin, and herbimycin; d). Carbapenems consisting of biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, and panipenem; e). Cephems consisting of carbacephem, cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine, cefalotin or cefalothin, cefalexin, cefaloglycin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefepime, cefminox, cefoxitin, cefprozil, cefroxadine, ceftezole, cefuroxime, cefixime, cefdinir, cefditoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamycin consisting of cefoxitin, cefotetan, and cefmetazole, oxacephem consisting of flomoxef, and latamoxef; f). glycopeptides consisting of bleomycin, vancomycin consisting of oritavancin, and telavancin, teicoplanin, and ramoplanin; g). glycylcyclines; h). .beta.-lactamase inhibitors consisting of penam consisting of sulbactam, and tazobactam, and clavam; i). Lincosamides consisting of clindamycin, and lincomycin; j). lipopeptides consisting of daptomycin, A54145, calcium-dependent antibiotics; k). macrolides consisting of azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide consisting of telithromycin, and cethromycin, midecamycin, miocamycin, oleandomycin, rifamycins consisting of rifampicin, rifampin, rifabutin, and rifapentine, rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus, troleandomycin, and telithromycin; l). monobactams consisting of aztreonam, and tigemonam; m). oxazolidinones: n). Penicillins consisting of amoxicillin, ampicillin consisting of pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam, mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, and ticarcillin; o). polypeptides consisting of bacitracin, colistin, and polymyxin B; p). quinolones consisting of alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxacin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, and trovafloxacin; q). Streptogramins consisting of ristinamycin, quinupristin and dalfopristin; r). sulfonamides consisting of mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole; s). steroid antibacterials; t). tetracyclines consisting of doxycycline, chlortetracycline, clomocycline, demeclocycline, lymnecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, and glycylcyclines; u). antibiotics consisting of annonacin, arsphenamine, bactoprenol inhibitors, DADAL/AR inhibitors, dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitors, nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin, tazobactam tinidazole, and uvaricin; 4). anti-viral drugs consisting of a). entry/fusion inhibitors consisting of aplaviroc, maraviroc, vicriviroc, enfuvirtide, PRO 140, and ibalizumab; b). integrase inhibitors consisting of raltegravir, elvitegravir, and globoidnan A; c). maturation inhibitors consisting of bevirimat, and vivecon; d). neuraminidase inhibitors consisting of oseltamivir, zanamivir, and peramivir; c). nucleosides and nucleotides consisting of abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine, elvucitabine, emtricitabine, entecavir, famciclovir, fluorouracil, 3'-fluoro-substituted 2', 3'-dideoxynucleoside derivatives consisting of 3'-fluoro-2',3'-dideoxythymidine and 3'-fluoro-2',3'-dideoxyguanosine, fomivirsen, ganciclovir, idoxuridine, lamivudine, 1-nucleosides consisting of .beta.-1-thymidine and .beta.-1-2'-deoxycytidine, penciclovir, racivir, ribavirin, stampidine, stavudine, taribavirin, telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, zalcitabine, zidovudine; f). non-nucleosides consisting of amantadine, ateviridine, capravirine, diarylpyrimidines consisting of etravirine, and rilpivirine, delavirdine, docosanol, emivirine, efavirenz, foscarnet, imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod, and tromantadine; g). protease inhibitors consisting of amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir, and tipranavir; h). anti-virus drugs consisting of abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, foscarnet, griffithsin, taribavirin, hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, and seliciclib; 5). a radioisotope selected from the group consisting of .sup.3H, .sup.11C, .sup.14C, .sup.18F, .sup.32P, .sup.35S, .sup.64Cu, .sup.68Ga, .sup.86Y, .sup.99Tc, .sup.111In, .sup.123I, .sup.125I, .sup.131I, .sup.133Xe, .sup.177Lu, .sup.211At, and .sup.213Bi; 6). a chromophore molecule, which is capable of absorbing a UV light, florescent light, IR light, near IR light, or visual light; and is selected from the group consisting of xanthophores, erythrophores, iridophores, leucophores, melanophores, cyanophores, fluorophore molecules which are fluorescent chemical compounds re-emitting light upon light, visual phototransduction molecules, photophore molecules, luminescence molecules, luciferin compounds: non-protein organic fluorophores consisting of xanthene derivatives consisting of fluorescein, rhodamine, Oregon green, eosin, and Texas red: cyanine derivatives consisting of cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine; Squaraine derivatives and ring-substituted squaraines, consisting of Seta, SeTau, and Square dyes; naphthalene derivatives consisting of dansyl and prodan derivatives; coumarin derivatives; oxadiazole derivatives consisting of pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; anthracene derivatives consisting of anthraquinones; pyrene derivatives: oxazine derivatives consisting of Nile red, Nile blue, cresyl violet, and oxazine 170; acridine derivatives consisting of proflavin, acridine orange, and acridine yellow; arylmethine derivatives consisting of auramine, crystal violet, and malachite green; tetrapyrrole derivatives consisting of porphin, phthalocyanine, and bilirubin; derivatives of fluorophore compounds consisting of CF dye, DRAQ and CyTRAK probes, BODIPY, Alexa Fluor, DyLight Fluor, Atto and Tracy, FluoProbes, Abberior Dyes, DY and MegaStokes Dyes, Sulfo Cy dyes, HiLyte Fluor, Seta, SeTau and Square Dyes, Quasar and Cal Fluor dyes, SureLight Dyes consisting of APC, RPEPerCP, Phycobilisomes, APC, APCXL, RPE, BPE, Allophycocyanin, Aminocoumarin, APC-Cy7 conjugates, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Fluorescein, FluorX, Hydroxycoumarin, Lissamine Rhodamine B, Lucifer yellow, Methoxycoumarin, NBD, Pacific Blue, Pacific Orange, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP, R-Phycoerythrin, Red 613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS, Seta-680-NHS, Seta-780-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau-380-NHS, SeTau-405-Maleimide, SeTau-405-NHS, SeTau-425-NHS, SeTau-647-NHS, Texas Red, TRITC, TruRed, X-Rhodamine, 7-AAD, Acridine Orange, Chromomycin A3, CyTRAK Orange, DAPI, DRAQ5, DRAQ7, Ethidium Bromide, Hoechst33258, Hoechst33342, LDS 751, Mithramycin, Propidiumlodide, SYTOX Blue, SYTOX Green, SYTOX Orange, Thiazole Orange, TO-PRO: Cyanine Monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1, wherein the fluorophore compounds consists of DCFH, DHR, Fluo-3, Fluo-4, Indo-1, SNARF, Allophycocyanin, AmCyan1, AsRed2, Azami Green, Azurite, B-phycoerythrin, Cerulean, CyPet, DsRed monomer, DsRed2, EBFP, EBFP2, ECFP, EGFP, Emerald, EYFP, GFP, GFP, GFP, GFP, GFP, GFP, GFP, GFPuv, HcRed1, J-Red, Katusha, Kusabira Orange mCFP, mCherry, mCitrine, Midoriishi Cyan, mKate, mKeima-Red, mKO, mOrange, mPlum, mRaspberry, mRFP1, mStrawberry, mTFP1, mTurquoise2, P3, Peridinin Chlorophyll, R-phycoerythrin, T-Sapphire, TagCFP, TagGFP, TagRFP, TagYFP, tdTomato, Topaz, TurboFP602, TurboFP635, TurboGFP, TurboRFP, TurboYFP, Venus, Wild Type GFP, YPet, ZsGreen1, ZsYellow1 and derivatives thereof; and 7). a pharmaceutically acceptable salt, acid or derivative of any of the above drugs; n is 1.about.20; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different, and are absent, a linear alkyl having from 1-8

carbon atoms, branched or cyclic alkyl having from 3 to 8 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 8 carbon atoms, an ester, ether or amide having 2 to 8 carbon atoms, or a polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is an integer from 1 to about 1000, 6-maleimidocaproyl, carbonyl, sulfonyl, thioether, azide, amine, imine, polyamine, hydrazine, hydrazone, urea, semicarbazide, carbazide, alkoxylamine, urethane, amino acid, peptide having 1 to 20 natural or unnatural amino acids, acyloxylamine, hydroxamic acid, or combination thereof, or a combination thereof with a disulfide, hydrozone, triazole, or alkoxime unit.

2. The cell-binding agent-drug conjugate compound of Formula (II) of claim 1, wherein Drug.sub.1 and Drug.sub.2 are the chromophore molecule, which is capable of absorbing a UV light, florescent light, IR light, near IR light, or visual light.

3. The cell-binding agent-drug conjugate compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 derivatives, daunorubicin and doxorubicin compounds, taxanoids, cryptophycins, epothilones, benzodiazepine dimers consisting of dimmers of pyrrolobenzodiazepine, tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiaze-pines, calicheamicins and the enediyne antibiotics, actinomycin, azaserines, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatins/auristatins consisting of monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, Auristatins 2-AQ, 6-AQ, EB, and EFP, duocarmycins, thiotepa, vincristine, hemiasterlins, nazumamides, microginins, radiosumins, alterobactins, microsclerodermins, theonellamides, esperamicins, siRNA, nucleolytic enzymes, and pharmaceutically acceptable salts, acids, and derivatives of any of the above molecules.

4. The cell-binding agent-drug conjugate molecule of claim 1, wherein the cell-binding agent is capable of targeting against a tumor cell, a virus infected cell, a microorganism infected cell, a parasite infected cell, an autoimmune disease cell, an activated tumor cells, a myeloid cell, an activated T-cell, an affecting B cell, or a melanocyte.

5. The cell-binding agent-drug conjugate molecule of claim 1, wherein the cell-binding agent is capable of targeting against any one of antigens or receptors comprising CD3, CD4, CD5, CD6, CD7, CD8, CD9, CD10, CD11a, CD11b, CD11c, CD12w, CD14, CD15, CD16, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD51, CD52, CD53, CD54, CD55, CD56, CD58, CD59, CD61, CD62E, CD62L, CD62P, CD63, CD66, CD68, CD69, CD70, CD72, CD74, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD86, CD87, CD88, CD89, CD90, CD91, CD95, CD96, CD98, CD100, CD1003, CD105, CD106, CD109, CD117, CD120, CD125, CD126, CD127, CD133, CD134, CD135, CD138, CD141, CD142, CD143, CD144, CD147, CD151, CD147, CD152, CD154, CD156, CD158, CD163, CD166, CD168, CD174, CD180, CD184, CD186, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276 (B7-H3), CD303, CD304, CD309, CD326, 4-1BB, 5AC, 5T4, Adenocarcinoma antigen, AGS-5, AGS-22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, Alpha intergrin, Alpha v beta6, Amino-peptidase N, Amyloid beta, Androgen receptor, Angiopoietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin protective antigen, Anti-transferrin receptor, AOC3, B7-H3, Bacillus anthracis anthrax, BAFF, B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242 antigen, CA125, CA-IX, CALLA, CanAg, Canis lupus familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11, CCR4, CCR5, CD3E, CEA, CEACAM3, CEACAM5, CFD, Ch4D5, Cholecystokinin 2, CLDN18, Clumping factor A, CRIPTO, FCSFIR, CSF2, CTLA4, CTAA16.88 tumor antigen, CXCR4, C-X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL4, DPP4, DR5, E. coli shiga toxin type-1, E. coli shiga toxin type-2, ED-B, EGFL7, EGFR, EGFRII, EGFRvIII, Endoglin (CD105), Endothelin B receptor, Endotoxin, EpCAM, EphA2, Episialin, ERBB2, ERBB3, ERG, Escherichia coli, ETV6-AML, FAP, FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR, Folate receptor alpha, Folate hydrolase, Fos-related antigen 1.F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28, GD3 idiotype, GloboH, Glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor .alpha.-chain, Growth differentiation factor 8, GP100, GPNMB, GUCY2C comprising Guanylate cyclase 2C, guanylyl cyclase C(GC-C), intestinal Guanylate cyclase, Guanylate cyclase-C receptor, and Heat-stable enterotoxin receptor, Heat shock proteins, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, HER1, HER2, HER2/neu, HER3, IgG4, HGF/SF, HHGFR, HIV-1, Histone complex, HLA-DR, HLA-DR10, HLA-DRB, HMWMAA, Human chorionic gonadotropin, HNGF, Human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1, Idiotype, IGF1R, IGHE, IFN-.gamma., Influenza hemagglutinin, IgE, IgE Fc region, IGHE, IL-1, IL-2 receptor, IL-4, IL-5, IL-6, IL-6R, IL-9, IL-10, IL-12, IL-13, IL-17, IL-17A, IL-20, IL-22, IL-23, IL31RA, ILGF2, Integrins comprising .alpha.4, .alpha..sub.IIb.beta..sub.3, .alpha.v.beta.3, .alpha..sub.4.beta..sub.7, .alpha.5.beta.1, .alpha.6.beta.4, .alpha.7.beta.7, .alpha.5.beta.5, and .alpha.v.beta.5, Interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, LCK, Le, Legumain, Lewis-Y antigen, LFA-1, LHRH, LINGO-1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF, MS4A1, MSLN, MUC1, MUC1-KLH, MUC16, MCP1, MelanA/MART1, ML-IAP, MPG, MS4A1, MYCN, Myelin-associated glycoprotein, Myostatin, NA17, NARP-1, NCA-90, Nectin-4, NGF, Neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL, OY-TES1, P21, p53 nonmutant, P97, Page4, PAP, Paratope of anti-(N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1, PDGF-R.alpha., PDGFR-.beta., PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, Platelet-derived growth factor receptor beta, Phosphate-sodium co-transporter, PMEL 17, Polysialic acid, Proteinase3, Prostatic carcinoma, PS, Prostatic carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD, Rhesus factor, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory syncytial virus, RON, Sarcoma translocation breakpoints, SART3, Sclerostin, SLAMF7, Selectin P, SDC1, sLe(a), Somatomedin C, SIP, Somatostatin, Sperm protein 17, SSX2, STEAP1, STEAP2, STn, TAG-72, Survivin, T-cell receptor, T cell transmembrane protein, TEM1, TENB2, Tenascin C, TGF-.alpha., TGF-.beta., TGF-.beta.1, TGF-.beta.2, Tie, Tie2, TIM-1, Tn, TNF, TNF-.alpha., TNFRSF8, TNFRSF10B, TNFRSF13B, TPBG, TRAIL-R1, TRAILR2, tumor-associated calcium signal transducer 2, tumor specific glycosylation of MUC1, TWEAK receptor, TYRP1, TRP-2, Tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR2, vimentin, WT1, XAGE 1, and cells expressing an insulin growth factor receptor, or an epidermal growth factor receptor.

6. The cell-binding agent-drug conjugate molecule of claim 5, wherein the tumor cell is selected from the group consisting of lymphoma cells, myeloma cells, renal cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cancer cells, small-cell lung cancer cells, none small-cell lung cancer cells, testicular cancer cells, and cells that grow and divide at an unregulated, quickened pace to cause cancers.

7. The cell-binding agent-drug conjugate molecule of claim 1, wherein R.sub.1 R.sub.2, R.sub.3 or R.sub.4 is one or more selected from the group consisting of 6-maleimidocaproyl, maleimido propanoyl, valine-citrulline, alanine-phenylalanine, lysine-phenylalanine, p-aminobenzyloxycarbonyl, 4-thio-pentanoate, 4-(N-maleimidomethyl)cyclo-hexane-1-carboxylate, 4-thio-butyrate, maleimidoethyl, 4-thio-2-hydroxysulfonyl-butyrate, pyridinyl-dithiol, alkoxy amino, ethyleneoxy, 4-methyl-4-dithio-pentanoic, azido, alkynyl, dithio, and (4-acetyl)aminobenzoate.

8. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures of T01, T02, T03, T04, T05, T06 and T07 as following: ##STR00046## ##STR00047## ##STR00048## wherein mAb is an antibody; Z.sub.3 is H, R.sub.1, OP(O)(OM.sub.1)(OM.sub.2), OCH.sub.2OP(O)(OM.sub.1)(OM.sub.2), OSO.sub.3M.sub.1, or O-glycoside selected from the group consisting of glucoside, galactoside, mannoside, glucuronoside, alloside, and fructoside, NH-glycoside, S-glycoside, or CH.sub.2-glycoside; M.sub.1 and M.sub.2 are independently H, Na, K, Ca, Mg, NH.sub.4, or NR.sub.1R.sub.2R.sub.3R.sub.4; n is 1.about.20; and R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same defined in claim 1.

9. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is structure C01 as following: ##STR00049## wherein mAb is an antibody; n is 1.about.20; and R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same defined in claim 1.

10. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is structure M01 as following: ##STR00050## wherein mAb is an antibody; n is 1.about.20; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same defined in claim 1.

11. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures of Tx01, Tx02 and Tx03 as following: ##STR00051## wherein mAb is an antibody; n is 1.about.20; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same defined in claim 1.

12. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures of CC01, CC02, and CC03 as following: ##STR00052## wherein mAb is an antibody; n is 1.about.20; Z.sub.4 is H, PO(OM.sub.1)(OM.sub.2), SO.sub.3M.sub.1, CH.sub.2PO(OM.sub.1)(OM.sub.2), CH.sub.3N(CH.sub.2CH.sub.2).sub.2NC(O)--, O(CH.sub.2CH.sub.2).sub.2NC(O)--, or glycoside; X.sub.3 is O, NH, NR.sub.1, NHC(O), OC(O), CO, R.sub.1, or absent; M.sub.1 and M.sub.2 is independently Na, K, H, NH.sub.4, NR.sub.1R.sub.2R.sub.3R.sub.4; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same defined in claim 1.

13. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures Da01, Da02, Da03 and Da04 as following: ##STR00053## ##STR00054## wherein mAb is an antibody; n is 1.about.20; X.sub.3 is O, NH, NR.sub.1, NHC(O), OC(O), CO, R.sub.1, or absent; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same defined in claim 1.

14. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures Au01, Au02, Au03, Au04, and Au05 as following: ##STR00055## ##STR00056## wherein mAb is an antibody; n is 1.about.20; X.sub.3 is CH.sub.2, O, NH, NR.sub.1, NHC(O), NHC(O)NH, C(O), OC(O), R.sub.1, or absent; X.sub.4 is CH.sub.2, C(O), C(O)NH, C(O)N(R.sub.1), R.sub.1, or C(O)O; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same defined in claim 1.

15. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is one of structures of PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08 and PB09 as following: ##STR00057## ##STR00058## ##STR00059## wherein mAb is an antibody; n is 1.about.20; X.sub.3 is CH.sub.2, O, NH, NR.sub.1, NHC(O), NHC(O)NH, C(O), OC(O), R.sub.1, or absent; X.sub.4 is CH.sub.2, C(O), C(O)NH, C(O)N(R.sub.1), C(O)O, R.sub.1, or absent; R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are the same defined in claim 1.

16. The cell-binding agent-drug conjugate compound of claim 1, having in vitro, in vivo or ex vivo cell killing activity.

17. The cell-binding agent-drug conjugate compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is a peptide of 1.about.20 units of natural or unnatural amino acids, or a p-aminobenzyl unit, or a 6-maleimidocaproyl unit, or a disulfide unit, or a thioether unit, or a hydrozone unit, or a triazole unit, or an alkoxime unit.

18. The cell-binding agent-drug conjugate compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is cleaveable by a protease.

19. A pharmaceutical composition comprising a therapeutically effective amount of the cell-binding agent-drug conjugate compound of claim 1, and a pharmaceutically acceptable salt, carrier, diluent, or excipient therefore.

20. A method for preparing the cell-binding agent-drug conjugate compound of claim 1, comprising: reducing a cell-binding molecule containing a disulfide bond with TCEP or DTT, to generate a molecule having a pair of free thoils, and reacting the molecule having a pair of free thoils with a linker-drug molecule.

21. A method for synergistically effective treatment of a cancer, an autoimmune disease, or an infectious disease comprising administering, to a subject in need thereof, the pharmaceutical composition of claim 19, concurrently with a synergistically effective amount of a therapeutic agent selected from the group consisting of chemotherapeutic agents, radiation therapies, immunotherapy agents, autoimmune disorder agents, and anti-infectious agents.

22. The method of claim 21, wherein the therapeutic agent is selected from the group consisting of Abatacept, Abiraterone acetate, Acetaminophen/hydrocodone, Adalimumab, afatinib dimaleate, alemtuzumab, Alitretinoin, ado-trastuzumab emtansine, Amphetamine mixed salts, anastrozole, Aripiprazole, Atazanavir, Atezolizumab, Atorvastatin, axitinib, belinostat, Bevacizumab, Cabazitaxel, Cabozantinib, bexarotene, blinatumomab, Bortezomib, bosutinib, brentuximab vedotin, Budesonide, Budesonide/formoterol, Buprenorphine, Capecitabine, carfilzomib, Celecoxib, ceritinib, Cetuximab, Ciclosporin, Cinacalcet, crizotinib, Dabigatran, dabrafenib, Darbepoetin alfa, Darunavir, imatinib mesylate, dasatinib, denileukin diftitox, Denosumab, Depakote, Dexlansoprazole, Dexmethylphenidate, Dinutuximab, Doxycycline, Duloxetine, Emtricitabine/Rilpivirine/Tenofovir disoproxil fumarate, Emtricitabine/tenofovir/efavirenz, Enoxaparin, Enzalutamide, Epoetin alfa, erlotinib, Esomeprazole, Eszopiclone, Etanercept, Everolimus, exemestane, everolimus, Ezetimibe, Ezetimibe/simvastatin, Fenofibrate, Filgrastim, fingolimod, Fluticasone propionate, Fluticasone/salmeterol, fulvestrant, gefitinib, Glatiramer, Goserelin acetate, Imatinib, Ibritumomab tiuxetan, ibrutinib, idelalisib, Infliximab, Insulin aspart, Insulin detemir, Insulin glargine, Insulin lispro, Interferon beta 1a, Interferon beta 1b, lapatinib, Ipilimumab, Ipratropium bromide/salbutamol, Lanreotide acetate, lenaliomide, lenvatinib mesylate, letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, MEDI4736, Memantine, Methylphenidate, Metoprolol, Modafinil, Mometasone, Nilotinib, Nivolumab, ofatumumab, obinutuzumab, olaparib, Olmesartan, Olmesartan/hydrochlorothiazide, Omalizumab, Omega-3 fatty acid ethyl esters, Oseltamivir, Oxycodone, palbociclib, Palivizumab, panitumumab, panobinostat, pazopanib, pembrolizumab, Pemetrexed, pertuzumab, Pneumococcal conjugate vaccine, pomalidomide, Pregabalin, Quetiapine, Rabeprazole, radium 223 chloride, Raloxifene, Raltegravir, ramucirumab, Ranibizumab, regorafenib, Rituximab, Rivaroxaban, romidepsin, Rosuvastatin, ruxolitinib phosphate, Salbutamol, Sevelamer, Sildenafil, siltuximab, Sitagliptin, Sitagliptin/metformin, Solifenacin, Sorafenib, Sunitinib, Tadalafil, tamoxifen, Telaprevir, temsirolimus, Tenofovir/emtricitabine, Testosterone gel, Thalidomide, Tiotropium bromide, toremifene, trametinib, Trastuzumab, Tretinoin, Ustekinumab, Valsartan, vandetanib, vemurafenib, vorinostat, ziv-aflibercept, Zostavax, and derivatives, pharmaceutically acceptable salts, carriers, diluents, or excipients therefore, or a combination thereof.

23. The compound of claim 1, wherein the antibody is a monoclonal antibody.

24. The compound of claim 1, wherein R.sub.1, R.sub.2, R.sub.3 or R.sub.4 is absent, or contains a linear alkyl having from 1 to 8 carbon atoms, branched or cyclic alkyl having from 3 to 8 carbon atoms, amide having 2 to 8 carbon atoms, (OCH.sub.2CH.sub.2).sub.1-100, 6-maleimidocaproyl, CO, SO.sub.2, or S.

25. The compound of claim 1, wherein R.sub.1 and R.sub.2 are the same and represent --CO-alkyl-, --SO.sub.2-alkyl-, --CO-alkyl-S--, ##STR00060## wherein alkyl is --(CH.sub.2).sub.1-4-.

26. The compound of claim 1, wherein R.sub.3 and R.sub.4 are the same and represent -alkyl-, -alkyl-(CH.sub.2OCH.sub.2).sub.m-alkyl-, --CO-alkyl-, -alkyl-CONH-CH(-alkyl-Ph)-CONH-CH(-alkyl-NH.sub.2)--, -alkyl-CONH-alkyl-(CH.sub.2OCH.sub.2).sub.m-alkyl-, -alkyl-CON[-alkyl-(CH.sub.2OCH.sub.2).sub.m-alkyl].sub.2, --CH(-alkyl-NH.sub.2)--, or -alkyl-CO--, wherein m is 1 to 100, and alkyl is --(CH.sub.2).sub.1-4-.

27. The compound of claim 1, wherein Drug.sub.1 and Drug.sub.2 are the same and are a tubulysin, calicheamicin, maytansinoid, taxane, CC-1065, doucarmycin, daunorubicin, doxorubicin, auristatin, dolastatin, benzodiazepine dimer, or a derivative thereof.

28. The compound of claim 1, wherein the compound is ##STR00061## ##STR00062## ##STR00063## wherein Drug is the same as Drug.sub.1 or Drug.sub.2 as defined in claim 1, m is 0.about.100, n is 1.about.20, and mAb is the antibody.

29. The compound of claim 1, wherein the compound is ##STR00064## ##STR00065## ##STR00066## ##STR00067## wherein n is 1-20, and mAb is the antibody.

Details for Patent 10,265,291

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 January 15, 1974 10,265,291 2035-07-15
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 December 27, 1984 10,265,291 2035-07-15
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 February 15, 1985 10,265,291 2035-07-15
Ferring Pharmaceuticals Inc. NOVAREL chorionic gonadotropin For Injection 017016 February 16, 1990 10,265,291 2035-07-15
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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