Claims for Patent: 10,328,157

Summary for Patent: 10,328,157

Title:	Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule
Abstract:	Cell binding agent-drug conjugates comprising bridge linkers, and methods of using such linkers and conjugates are provided.
Inventor(s):	Zhao; Robert Yongxin (Lexington, MA)
Assignee:	HANGZHOU DAC BIOTECH CO., LTD. (Hangzhou, CN)
Application Number:	15/423,695
Patent Claims:	1. A cell-binding agent-drug conjugate compound of Formula (II) ##STR00077## wherein: Cb represents a cell-binding agent; Drug.sub.1 and Drug.sub.2 are the same or different and represent cytotoxic agents; n is 1.about.20; R.sub.1 and R.sub.2 are the same or different, and are absent, a linear alkyl having from 1 to 6 carbon atoms; branched or cyclic alkyl having from 3 to 6 carbon atoms; linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms; ester, ether, or amide having from 2 to 6 carbon atoms; or polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is an integer from 1 to about 1000, or a combination thereof; and X.sub.1 and X.sub.2 are independently NH, N(R.sub.3), O, S or CH.sub.2; R.sub.3 is H, a linear alkyl having from 1 to 6 carbon atoms; branched or cyclic alkyl having from 3 to 6 carbon atoms; linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms; or esters, ether, amide having from 2 to 6 carbon atoms; or polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is an integer from 0 to about 1000, or a combination thereof, wherein the cell-binding agent is selected from the group consisting of an antibody, a protein, a vitamin, a peptide, a polymeric micelle, a liposome, a lipoprotein-based drug carrier, a nano-particle drug carrier, and a dendrimer, each of which optionally is coated with a cell-binding ligand, and a combination thereof, and wherein the cytotoxic agents 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 compounds thereof; duocarmycin compounds, KW-2189 and CBI-TMI; benzodiazepine dimers consisting of dimers of pyrrolobenzodiazepine or tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines; 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, Maytansinoids consisting of DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins, cryptophycins consisting of cryptophycin 1 and cryptophycin 8; epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, and cephalostatins; pancratistatin; sarcodictyin; and spongistatin; c). DNA topoisomerase inhibitors consisting of: epipodophyllins consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids, teniposide, topotecan, and 9-nitrocamptothecin; mitomycins; d). antimetabolites consisting of: anti-folate: DHFR inhibitors consisting of methotrexate, trimetrexate, denopterin, pteropterin, and aminopterin; IMP dehydrogenase inhibitors consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR; ribonucleotide reductase inhibitors consisting of hydroxyurea, and deferoxamine; pyrimidine compounds consisting of uracil compounds consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, and ratitrexed; cytosine compounds consisting of cytarabine, cytosine arabinoside, and fludarabine; Purine compounds consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine; folic acid replenisher; e). hormonal therapies consisting of: receptor antagonists consisting of anti-estrogen consisting of: megestrol, raloxifene, and tamoxifen; LHRH agonists consisting of goscrclin, 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 compounds 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, and human proteins containing a TNF domain; f). kinase inhibitors consisting of BIMW 2992, imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080, 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 calicheamicins consisting of calicheamicin .gamma.1, .delta.1, .alpha.1 and .beta.1; dynemicin consisting of dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, and neocarzinostatin chromophore, 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, and trilostane; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine, elfomithine; elliptinium acetate, etoglucid; gallium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; protein-bound polysaccharide; 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, and 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). monobac-tams 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 pristinamycin, 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, lymecycline, 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 (rifampin), tazobactam tinidazole, and uvaricin; 4). anti-viral drugs consisting of: a). entry/fusion inhibitors consisting of aplaviroc, maraviroc, vicriviroc, gp41, PRO 140, and CD4; 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; e). 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 compounds, 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, and zidovudine; f). non-nucleosides consisting of amantadine, ateviridine, capravirine, diarylpyrimidines, 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.124I, .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 which 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 compounds consisting of fluorescein, rhodamine, Oregon green, eosin, and Texas red; cyanine compounds consisting of cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, and merocyanine; squaraine compounds and ring-substituted squaraines consisting of Seta, SeTau, and Square dyes; naphthalene compounds consisting of dansyl and prodan compounds; coumarin compounds; oxadiazole compounds consisting of pyridyloxazole, nitrobenzoxadiazole and benzoxadiazole; anthracene compounds consisting of anthraquinones consisting of DRAQ5, DRAQ7 and CyTRAK Orange; pyrene compounds; oxazine compounds consisting of Nile red, Nile blue, cresyl violet, oxazine 170; acridine compounds consisting of proflavin, acridine orange, and acridine yellow; arylmethine compounds consisting of auramine, crystal violet, and malachite green; tetrapyrrole compounds consisting of porphin, phthalocyanine, and bilirubin; 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, 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; and 7). a pharmaceutically acceptable salt or acid of any of the above drugs. 2. The cell-binding agent-drug conjugate compound according to claim 1, wherein the cell-binding agent is an antibody. 3. The cell-binding agent-drug conjugate compound according to claim 1, wherein the fluorophores are selected from the group consisting 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, and ZsYellow1. 4. The cell-binding agent-drug conjugate compound according to claim 1, wherein Drug.sub.1 and Drug.sub.2 are a chromophore molecule. 5. The cell-binding agent-drug conjugate compound according to claim 1, wherein Drug.sub.1 and Drug.sub.2 are selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 and adozelesin, carzelesin and bizelesin compounds thereof, daunorubicin and doxorubicin compounds, taxanoids, cryptophycins, epothilones, benzodiazepine dimers consisting of dimers of pyrrolobenzodiazepine, tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines, 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 and acids of any of the above molecules. 6. The cell-binding agent-drug conjugate compound according to claim 1, wherein the cell-binding agent is selected from the group consisting of full-length antibodies consisting of polyclonal antibodies, monoclonal antibodies, dimers, multimers, and multispecific antibodies; a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, or a monoclonal antibody fragment that binds the target cell, a chimeric antibody, a chimeric antibody fragment that binds to the target cell, a domain antibody, a domain antibody fragment that binds to the target cell, a resurfaced antibody, a resurfaced single chain antibody, or a resurfaced antibody fragment that binds to the target cell, a humanized antibody or a resurfaced antibody, a humanized single chain antibody, or a humanized antibody fragment that binds to the target cell, anti-idiotypic antibodies, CDR's, diabody, triabody, miniantibody, small immune proteins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule, and large molecular weight proteins. 7. The cell-binding agent-drug conjugate compound according to 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. 8. The cell-binding agent-drug conjugate compound according to claim 1, wherein the cell-binding agent is capable of targeting against any one of following antigens and receptors: 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, CD103, 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, CDw186, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276, 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, FCSF1R, CSF2, CTLA4, CTAA16.88 tumor antigen, CXCR4, C-X-C chemokine receptor type4, cyclic ADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL3, DPP4, DR5, E. coli shiga toxin type-1, E. coli shiga toxin type-2, ED-B, EGFL7, EGFR, EGFRII, EGFRvIII, Endoglin, 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 a-chain, growth differentiation factor 8, GP100, GPNMB, GUCY2C, 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, 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, MUC 16, MCP1, Mel anA/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, 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, or vimentin, WT1, XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptors. 9. The cell-binding agent-drug conjugate compound according to claim 7, 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. 10. The cell-binding agent-drug conjugate compound according to claim 1, wherein R.sub.1 or R.sub.2 is 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, peptides, and (4-acetyl)aminobenzoate. 11. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of structures of T01, T02, T03, T04, T05, T06 and T07 as following: ##STR00078## ##STR00079## ##STR00080## ##STR00081## wherein mAb is an antibody; Z.sub.3 and Z'.sub.3 are independently H, OP(O)(OM.sub.1)(OM.sub.2), OCH.sub.2OP(O)(OM.sub.1)(OM.sub.2), OSO.sub.3M.sub.1, R.sub.1, or O-glycoside comprising 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, NR.sub.1R.sub.2R.sub.3; n is 1.about.20. 12. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) has a structure of C01 as following: ##STR00082## wherein mAb is an antibody; n is 1.about.20. 13. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) has a structure of M01 as following: ##STR00083## wherein mAb is an antibody; n is 1.about.20. 14. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of structures of Tx01, Tx02 and Tx03 as following: ##STR00084## ##STR00085## wherein mAb is an antibody; n is 1.about.20. 15. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of structures of CC01, CC02, and CC03 as following: ##STR00086## wherein mAb is an antibody; n is 1.about.20; Z.sub.4 and Z'.sub.4 are independently H, PO(OM.sub.1)(OM.sub.2), CH.sub.2PO(OM.sub.1)(OM.sub.2), SO.sub.3M.sub.1, CH.sub.3N(CH.sub.2CH.sub.2).sub.2NC(O)--, O(CH.sub.2CH.sub.2).sub.2NC(O)--, R.sub.1, or glycoside; X.sub.3 and X'.sub.3 are independently O, NH, NHC(O), OC(O), --C(O)O, R.sub.1, or absent. 16. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of structures of Da01, Da02, Da03 and Da04 as following: ##STR00087## ##STR00088## wherein mAb is an antibody; n is 1.about.20; X.sub.3 and X'.sub.3 are independently H, O, NH, NHC(O), NHC(O)NH, C(O), R.sub.1, or OC(O). 17. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of structures of Au01, Au02, Au03, Au04, and Au05 as following: ##STR00089## ##STR00090## wherein mAb is an antibody; n is 1.about.20; X.sub.3 and X'.sub.3 are independently CH.sub.2, O, NH, NHC(O), NHC(O)NH, C(O), OC(O) R.sub.1, or absent; X.sub.4 and X'.sub.4 are independently CH.sub.2, C(O), C(O)NH, C(O)N(R.sub.1), R.sub.1, NHR.sub.1, NR.sub.1, C(O)R.sub.1 or C(O)O; Z.sub.3 and Z'.sub.3 are independently H, R.sub.1, OP(O)(OM.sub.1)(OM.sub.2), NHR.sub.1, 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. 18. The cell-binding agent-drug conjugate compound of claim 1, wherein the conjugate compound of Formula (II) is selected from the group consisting of PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, PB09, PB10 and PB11 as following: ##STR00091## ##STR00092## ##STR00093## ##STR00094## wherein mAb is an antibody; n is 1.about.20; X.sub.3 and X'.sub.3 are independently CH.sub.2, O, NH, NHC(O), NHC(O)NH, C(O), OC(O), OC(O)(NR.sub.3), R.sub.1, NHR.sub.1, NR.sub.1 C(O)R.sub.1 or absent; X.sub.4 and X'.sub.4 are independently CH.sub.2, C(O), C(O)NH, C(O)N(R.sub.1), R.sub.1, NHR.sub.1, NR.sub.1, C(O)R.sub.1 or C(O)O. 19. The cell-binding agent-drug conjugate compound of claim 1, having in vitro, in vivo or ex vivo cell killing activity. 20. The cell-binding agent-drug conjugate compound of claim 1, wherein R.sub.1 or R.sub.2 comprises a peptide of 1.about.20 units of natural or unnatural amino acids, a p-aminobenzyl unit, a 6-maleimidocaproyl unit, a disulfide unit, a thioether unit, a hydrozone unit, a triazole unit, or an alkoxime unit. 21. The cell-binding agent-drug conjugate compound of claim 1, wherein R.sub.1 or R.sub.2 is cleavable by a protease. 22. 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 therefor. 23. A method of treating gastric cancer, ovarian cancer, or leukemia comprising administering to a patient in need thereof the pharmaceutical composition of claim 22. 24. The method of claim 23, further comprising administering concurrently to the patient a synergistically effective amount of a therapeutic agent of a chemotherapeutic agent, radiation therapy, immunotherapy agent, autoimmune disorder agent, or anti-infectious agent. 25. The method according to claim 24, wherein the therapeutic agent comprises abatacept, abiraterone acetate, acetaminophen /hydrocodone, adalimumab, afatinib dimaleate, alemtuzumab, alitretinoin, ado-trastuzumab emtansine, amphetamine mixed salts or amphetamine/dextroamphetamine, 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 la, interferon beta lb, 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 ester, 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, or a pharmaceutically acceptable salt thereof. 26. A method for detecting, monitoring, or studying interactions or functions of a cell-binding agent-drug conjugate compound with a targeted cell comprising utilizing the cell-binding agent-drug conjugate compound of claim 4. 27. The pharmaceutical composition of claim 22, further comprising a synergistically effective amount of a therapeutic agent of a chemotherapeutic agent, radiation therapy, immunotherapy agent, autoimmune disorder agent, or anti-infectious agent.

Details for Patent 10,328,157

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	01/15/1974		2035-07-15
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	12/27/1984		2035-07-15
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/15/1985		2035-07-15
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	02/16/1990		2035-07-15