Claims for Patent: 10,696,699

Summary for Patent: 10,696,699

Title:	Charged linkers and their uses for conjugation
Abstract:	Cell binding agent-drug conjugates comprising phosphinate-based charged linkers and methods of using such linkers and conjugates are provided.
Inventor(s):	Zhao; Robert Yongxin (Hangzhou, CN), Li; Xing (Hangzhou, CN), Huang; Yuangyuang (Hangzhou, CN), Yang; Qingliang (Hangzhou, CN)
Assignee:	HANGZHOU DAC BIOTECH CO., LTD. (Hangzhou, CN)
Application Number:	16/228,130
Patent Claims:	1. A cell-binding agent-drug conjugate of formula (II) ##STR00030## wherein: Cb represents a cell-binding agent which is an antibody, or a fragment thereof; Drug represents a drug; n is an integer from 1 to 20; and the cell-binding agent-drug conjugate of formula (II) is formed by reacting a functional group on the drug with Z in a compound of formula (I), and reacting a functional group on the cell-binding agent with Y: ##STR00031## wherein Y is selected from the group consisting of an unsubstituted or substituted N-hydroxysuccinimide ester, hydrazide, p-nitrophenyl ester, dinitrophenyl ester, pentafluorophenyl ester, pyridyldisulfide, nitropyridyldisulfide, unsubstituted or substituted maleimido, .beta.-maleimidopropionamido, haloacetate and carboxylic acid halide; Z is a thiol, disulfide, pyridyldisulfide, --ONH.sub.2, carboxy, aldehyde, ketone, azide, unsubstituted or substituted maleimido, N-hydroxy succinimide ester, haloacetyl, halogen, hydrazine or hydroxy group; M is H, Na, K, N.sup.+R.sub.1R.sub.2R.sub.3 or a pharmaceutical salt thereof; R.sub.1 and R.sub.2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a 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; R.sub.3 is absent, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a 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 R.sub.4, and R.sub.5, are the same or different and are absent, 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 polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p-1OCH.sub.2CH.sub.3, wherein p-1 is an integer from 1 to about 1000, or a combination thereof. 2. The cell-binding agent-drug conjugate of claim 1, wherein the Drug is selected from the group consisting of 1). chemotherapeutic agents: a). alkylating agents selected from the group consisting of Nitrogen mustards selected from the group 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; benzodiazepine dimers selected from the group consisting of dimers of pyrrolobenzodiazepine, tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines; nitrosoureas selected from the group consisting of carmustine, lomustine, chlorozotocin, fotemustine, nimustine, and ranimustine; alkylsulphonates selected from the group consisting of busulfan, treosulfan, improsulfan and piposulfan; triazenes (dacarbazine); platinum containing compounds selected from the group consisting of carboplatin, cisplatin, and oxaliplatin; aziridines selected from the group consisting of benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines selected from the group consisting of altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; b). plant alkaloids selected from the group consisting of Vinca alkaloids selected from the group consisting of vincristine, vinblastine, vindesine, vinorelbine, and navelbin; Taxoids selected from the group consisting of paclitaxel, and docetaxol; maytansinoids selected from the group consisting of DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins; cryptophycins selected from the group consisting of cryptophycin 1 and cryptophycin 8; epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; and spongistatin; c). DNA topoisomerase inhibitors selected from the group consisting of Epipodophyllins selected from the group consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids (retinols), teniposide, topotecan, and 9-nitrocamptothecin; and mitomycins (mitomycin C); d). anti-metabolites selected from the group consisting of anti-folate which is selected from the group consisting of DHFR inhibitors selected from the group consisting of methotrexate, trimetrexate, denopterin, pteropterin, and aminopterin; IMP dehydrogenase inhibitors selected from the group consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR; ribonucleotide reductase inhibitors selected from the group consisting of hydroxyurea, and deferoxamine; pyrimidine compounds selected from the group consisting of uracil compounds selected from the group consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, and ratitrexed; cytosine compounds selected from the group consisting of cytarabine, cytosine arabinoside, and fludarabine; purine compounds selected from the group consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine; and folic acid replenisher (frolinic acid); e). hormonal therapies selected from the group consisting of receptor antagonists selected from the group consisting of anti-estrogen selected from the group consisting of megestrol, raloxifene, and tamoxifen; LHRH agonists selected from the group consisting of goscrclin, and leuprolide acetate; anti-androgens selected from the group consisting of bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, and trilostane; retinoids/deltoids which is selected from the group consisting of Vitamin D3 compounds selected from the group consisting of CB 1093, EB 1089 KH 1060, cholecalciferol, and ergocalciferol; photodynamic therapies selected from the group consisting of verteporfin, phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A; cytokines selected from the group consisting of Interferon-alpha, Interferon-gamma, tumor necrosis factor (TNFs), and human proteins containing a TNF domain; f). kinase inhibitors selected from the group consisting of BMW 2992 (anti-EGFR/Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, and ispinesib; g). antibiotics selected from the group consisting of enediyne antibiotics selected from the group consisting of calicheamicins, calicheamicin .gamma.1, .gamma.1, .alpha.1 and .beta.1; dynemicin selected from the group consisting of dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic 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, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; h). others selected from the group consisting of polyketides (acetogenins), bullatacin and bullatacinone; gemcitabine, epoxomicins (carfilzomib), bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, isoprenylation inhibitors (Lovastatin), dopaminergic neurotoxins (1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (staurosporine), Actinomycins selected from the group consisting of Actinomycin D and dactinomycin, Bleomycins selected from the group consisting of bleomycin A2, bleomycin B2, and peplomycin, anthracyclines selected from the group consisting of daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, and mtoxantrone, MDR inhibitors (verapamil), Ca.sup.2+ ATPase inhibitors (thapsigargin), histone deacetylase inhibitors selected from the group 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 selected from the group consisting of aminoglutethimide, mitotane, 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; PSK.RTM.; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes selected from the group consisting of T-2 toxin, verrucarin A, roridin A and anguidine; urethane, siRNA, and antisense drugs; 2). anti-autoimmune disease agents: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids selected from the group 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, tacrolimus; 3). anti-infectious disease agents: a). aminoglycosides: amikacin, astromicin, gentamicin selected from the group consisting of netilmicin, sisomicin, and isepamicin, hygromycin B, kanamycin selected from the group consisting of amikacin, arbekacin, bekanamycin, dibekacin, and tobramycin, neomycin selected from the group consisting of framycetin, paromomycin, and ribostamycin, netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin; b). amphenicols: azidamfenicol, chloramphenicol, florfenicol, thiamphenicol; c). ansamycins: geldanamycin, herbimycin; d). carbapenems: biapenem, doripenem, ertapenem, imipenem/cilastatin, meropenem, panipenem; e). cephems: carbacephem (loracarbef), 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 selected from the group consisting of cefoxitin, cefotetan, and cefmetazole, oxacephem selected from the group consisting of flomoxef, and latamoxef; f). glycopeptides: bleomycin, vancomycin selected from the group consisting of oritavancin, and telavancin, teicoplanin (dalbavancin), ramoplanin; g). glycylcyclines (tigecycline); h). .beta.-lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid); i). lincosamides: clindamycin, lincomycin; j). lipopeptides: daptomycin, A54145, calcium-dependent antibiotics; k). macrolides: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide selected from the group consisting of telithromycin, and cethromycin, midecamycin, miocamycin, oleandomycin, rifamycins selected from the group consisting of rifampicin, rifampin, rifabutin, and rifapentine, rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus, troleandomycin, telithromycin; l). monobactams: aztreonam, tigemonam; m). oxazolidinones: linezolid; n). penicillins: amoxicillin, ampicillin selected from the group consisting of pivampicillin, hetacillin, bacampicillin, metampicillin, and talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin (carindacillin), cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam (pivmecillinam), mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticillin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, ticarcillin; o). polypeptides: bacitracin, colistin, polymyxin B; p). quinolones: 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, trovafloxacin; q). streptogramins: pristinamycin, quinupristin/dalfopristin; r). sulfonamides: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (co-trimoxazole); s). steroid antibacterials (fusidic acid); t). tetracyclines: doxycycline, chlortetracycline, clomocycline, demeclocycline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracycline, tetracycline, glycylcyclines (tigecycline); u). antibiotics: annonacin, arsphenamine, bactoprenol inhibitors (Bacitracin), DADAL/AR inhibitors (cycloserine), dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, mycolactone, NAM synthesis inhibitors (fosfomycin), nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (rifampin), tazobactam tinidazole, uvaricin; 4). anti-viral drugs: a). entry/fusion inhibitors: aplaviroc, maraviroc, vicriviroc, gp41 (enfuvirtide), PRO 140, CD4 (ibalizumab); b). integrase inhibitors: raltegravir, elvitegravir, globoidnan A; c). maturation inhibitors: bevirimat, vivecon; d). neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e). nucleosides and nucleotides: abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluorouracil (5-FU), 3'-fluoro-substituted 2',3'-dideoxynucleoside analogues (3'-fluoro-2',3'-dideoxythymidine (FLT) and 3'-fluoro-2',3'-di deoxyguanosine (FLG), fomivirsen, ganciclovir, idoxuridine, lamivudine (3TC), 1-nucleosides (.beta.-1-thymidine and .beta.-1-2'-deoxycytidine), penciclovir, racivir, ribavirin, stampidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluridine valaciclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT); f). non-nucleosides: amantadine, ateviridine, capravirine, diarylpyrimidines (etravirine, rilpivirine), delavirdine, docosanol, emivirine, efavirenz, foscarnet (phosphonoformic acid), imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod (R-848), tromantadine; g). protease inhibitors: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir (VX-950), tipranavir; h). antivirus drugs: abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, foscarnet, griffithsin, taribavirin (viramidine), hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib; 5). radioactive isotopes 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; and 6). pharmaceutically acceptable salts, or acids of any of the above drugs. 3. The cell-binding agent-drug conjugate of claim 1, wherein Drug is selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 compounds, morpholinos doxorubicins, taxanes, cryptophycins, epothilones, and benzodiazepine dimers selected from the group consisting of dimers of pyrrolobenzodiazepine, tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines, siRNA or a combination thereof, and pharmaceutically acceptable salts, or acids of any of the above. 4. The cell-binding agent-drug conjugate of claim 1, wherein the Drug is selected from the group consisting of a toxin, a chemotherapeutic agent, a drug moiety, an antibiotic, a radioactive isotope, and a nucleolytic enzyme. 5. The cell-binding agent-drug conjugate of claim 1, wherein the Drug is selected from the group consisting of tubulysins, maytansinoids, taxanoids, CC-1065 compounds, daunorubicin and doxorubicin compounds, benzodiazepine dimers selected from the group consisting of dimers of pyrrolobenzodiazepine, tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines, calicheamicins and the enediyne antibiotics, actinomycin, azaserines, bleomycins, epirubicin, tamoxifen, idarubicin, dolastatins/auristatins selected from the group consisting of monomethyl auristatin E, MMAE, MMAF, auristatin PYE, auristatin TP, auristatins 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP), duocarmycins, thiotepa, vincristine, hemiasterlins, and esperamicins. 6. The cell-binding agent-drug conjugate of claim 1, wherein the cell-binding agent binds to target cells which are selected from the group consisting of tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes; cells expressing the CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD40, CD 51, CD52, CD56, CD66, CD70, CD74, CD79, CD80, CD98, CD125, CD221, CD227, CD262, CD309, CD326, CEACAM3, CEACAM5 (carcinoembryonic antigen), DLL4 (.DELTA.-like-4), EGFR, CTLA4, CXCR4 (CD184), Endoglin (CD105), EPCAM (epithelial cell adhesion molecule), ERBB2 (Epidermal Growth Factor Receptor 2), FCGR1, FOLR (folate receptor,), GD2 ganglioside, G-28 (a cell surface antigen glyvolipid), GD3 idiotype, Heat shock proteins, HER1, HER2, HLA-DR10, HLA-DRB, human chorionic gonadotropin, IGF1R (insulin-like growth factor 1 receptor), IL-2 receptor (interleukin 2 receptor), IL-6R (interleukin 6 receptor), Integrins (.alpha.v.beta.3, .alpha.5.beta.1, .alpha.6.beta.4, .alpha.11.beta.3, .alpha.5.beta.5, .alpha.v.beta.5), MAGE-1, MAGE-2, MAGE-3, MAGE 4, anti-transferrin receptor, p97, MS4A1 (membrane-spanning 4-domains subfamily A member 1), MUC1 or MUC1-KLH, MUC16 (CA125), CEA, gp100, MART1, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), Nucleolin, Neu oncogene product, P21, Paratope of anti-(N-glycolylneuraminic acid), PLAP-like testicular alkaline phosphatase, PSMA, PSA, ROBO4, TAG 72 (tumor associated glycoprotein 72), T cell transmembrane protein, Tie (CD202b), TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R.sub.1 (tumor necrosis apoprosis inducing ligand receptor 1), VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), CanAg, CALLA, and cells expressing insulin growth factor receptor, and epidermal growth factor receptor. 7. The cell-binding agent-drug conjugate of claim 6, wherein the tumor cells are 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, testicular cancer cells, or any cells that grow and divide at an unregulated, quickened pace to cause cancers. 8. The cell-binding agent-drug conjugate of claim 1, wherein the cell-binding agent is an antibody, a single chain antibody, an antibody fragment that binds to the 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. 9. The cell-binding agent-drug conjugate of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L comprises one or more linker components of 6-maleimidocaproyl, maleimidopropanoyl, valine-citrulline, alanine-phenylalanine, p-aminobenzyloxycarbonyl, 4-thio-pentanoate, 4-(N-maleimidomethyl)cyclohexane-1-carboxylate, 4-thio-butyrate, maleimidoethyl containing compounds, 4-thio-2-hydroxysulfonyl-butyrate and (4-acetyl)aminobenzoate. 10. The cell-binding agent-drug conjugate of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L comprises a peptides 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 an alkoxime unit. 11. The cell-binding agent-drug conjugate of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L is cleavable by a protease. 12. The cell-binding agent-drug conjugate of claim 1, wherein R.sub.1 and R.sub.2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms. 13. The cell-binding agent-drug conjugate of claim 1, wherein R.sub.3, R.sub.4 and R.sub.5 are absent. 14. The cell-binding agent-drug conjugate of claim 1, wherein R.sub.3 is a polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.p, wherein p is an integer from 1 to about 1000, and R.sub.4 and R.sub.5 are absent. 15. The cell-binding agent-drug conjugate of claim 14, wherein p is an integer from 1 to 24. 16. The cell-binding agent-drug conjugate of claim 1, wherein M is H. 17. The cell-binding agent-drug conjugate of claim 1, having in vitro, in vivo or ex vivo cell killing activity. 18. A cell-binding agent-drug conjugate having one of following formulae: ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## wherein mAb represents a monoclonal antibody, and Ab represents an antibody. 19. The cell-binding agent-drug conjugate of claim 1, having following formula: ##STR00040## wherein Ab is an antibody. 20. A pharmaceutical composition comprising a therapeutically effective amount of the cell-binding agent-drug conjugate of claim 1, and a pharmaceutically acceptable salt, carrier, diluent, or excipient therefore, or a combination therefore. 21. A pharmaceutical composition comprising a therapeutically effective amount of the cell-binding agent-drug conjugate of claim 1, and a therapeutic agent selected from the group consisting of a chemotherapeutic agent, a radiation therapy, an immunotherapy agent, an autoimmune disorder agent, and an anti-infectious agent. 22. The compound of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L comprises a single bond, or a disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, secondary, tertiary or quaternary amine, imine, cycloheteroalkyane, heteroaromatic, oxime or amide linker, which directly connects to the Drug. 23. The compound of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L comprises ##STR00041## R.sub.1 being H, Me, Et or Ph, ##STR00042## R'' being H, Me, Et, Pr, Bu or Ph, ##STR00043## which directly connects to the Drug. 24. The compound of claim 1, having a formula Cb-(-L-Drug).sub.n, wherein L comprises --O--, --(CO)--O--, --(CO)--NH--, --(CO)--S--, --S--S--, ##STR00044## or --S--CH.sub.2--(CO)--O-- which directly connects to the cell-binding agent. 25. The compound of claim 1, wherein the cell binding agent is selected from the group consisting of polyconal antibodies, monoclonal antibodies, dimers, multimers, multispecific antibodies; single chain antibodies; fragments of antibodies selected from the group consisting of Fab, Fab', F(ab')2, Fv, fragments produced by a Fab expression library, anti-idiotypic antibodies, CDR's, and epitope-binding fragments thereof.

Details for Patent 10,696,699

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	January 15, 1974	10,696,699	2038-12-20
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	December 27, 1984	10,696,699	2038-12-20
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 15, 1985	10,696,699	2038-12-20
Ferring Pharmaceuticals Inc.	NOVAREL	chorionic gonadotropin	For Injection	017016	February 16, 1990	10,696,699	2038-12-20
Bel-mar Laboratories, Inc.	CHORIONIC GONADOTROPIN	chorionic gonadotropin	Injection	017054	March 26, 1974	10,696,699	2038-12-20
Ferring Pharmaceuticals Inc.	A.P.L.	chorionic gonadotropin	For Injection	017055	December 13, 1974	10,696,699	2038-12-20
Fresenius Kabi Usa, Llc	CHORIONIC GONADOTROPIN	chorionic gonadotropin	For Injection	017067	March 05, 1973	10,696,699	2038-12-20