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WO2015151078A4 - Hydrophilic linkers for conjugation - Google Patents

Hydrophilic linkers for conjugation Download PDF

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Publication number
WO2015151078A4
WO2015151078A4 PCT/IB2015/054521 IB2015054521W WO2015151078A4 WO 2015151078 A4 WO2015151078 A4 WO 2015151078A4 IB 2015054521 W IB2015054521 W IB 2015054521W WO 2015151078 A4 WO2015151078 A4 WO 2015151078A4
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WO
WIPO (PCT)
Prior art keywords
cell
receptor
drug
compound
inhibitors
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Application number
PCT/IB2015/054521
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French (fr)
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WO2015151078A3 (en
WO2015151078A2 (en
Inventor
Robert Yongxin Zhao
Original Assignee
Hangzhou Dac Biotech Co., Ltd
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Priority to PCT/IB2015/054521 priority Critical patent/WO2015151078A2/en
Priority to NZ737471A priority patent/NZ737471A/en
Priority to AU2015242210A priority patent/AU2015242210A1/en
Priority to CN202011053870.7A priority patent/CN112125929A/en
Priority to EP15773860.0A priority patent/EP3307749A4/en
Priority to CN201580080839.3A priority patent/CN108026123B/en
Application filed by Hangzhou Dac Biotech Co., Ltd filed Critical Hangzhou Dac Biotech Co., Ltd
Priority to CA2989269A priority patent/CA2989269C/en
Publication of WO2015151078A2 publication Critical patent/WO2015151078A2/en
Publication of WO2015151078A3 publication Critical patent/WO2015151078A3/en
Publication of WO2015151078A4 publication Critical patent/WO2015151078A4/en
Priority to AU2021201765A priority patent/AU2021201765B2/en
Priority to AU2023200925A priority patent/AU2023200925A1/en
Priority to AU2024216291A priority patent/AU2024216291A1/en

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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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Abstract

Cell binding agent-drug conjugates comprising hydrophilic linkers, and methods of using such linkers and conjugates are provided.

Claims

AMENDED CLAIMS received by the International Bureau on 26 May 2016 What is claimed is:
1. A hydrophilic linker compound of the Formula (I):
Y_R Q_R2J_LT_R3J— R4_Z
K5 K6 (J)
Wherein:
Y represents a functional group that enables reaction with a cell-binding agent. Y is preferably a thiol, a disulfide substituent, a maleimido, a haloacetyl, an alkynyl, an alkoxylamino group, carboxylic acid, or an N-hydroxysuccinimide ester.
Q and T are either -Χ!-Ρ(=0)(ΟΜ)-, or -X S(02)-, or -X!-S(O)-; or -Xi-P(=0)(OM)- X2-, or
Figure imgf000002_0001
or -X S(02)-X2-, or -X!-S(O)- x2-.
X1; X2 and X3 are independently selected from N(R7), O, or S; In addition, when Xi is either N(Pv7), or O, or S, then either X2j or X3j or another Xi that connects to -P(=0), -S(O), or - S(02) can be CH2.
m and n are integer from 0 to 5, but not 0 at the same time.
Z represents a functional group that enables linkage of a cytotoxic drug via an alkyl, alkenyl, alkynyl, aromatic, heteroalkyl, disulfide, thioether, thioester, peptide, hydrazone, ether, ester, carbamate, carbonate, amine (secondary, tertiary, or quartary), imine, cycloheteroalkyane, heteroaromatic, alkoxime or amide bond. Z is preferably a thiol, disulfide substituent, maleimido, haloacetyl, alkoxyamine, alkynyl, hydrazine group, carboxylic acid, or an N- hydroxysuccinimide ester.
Pvi, Pv2, P3, R4, Rs, P6, and R7 are the same or different and are H, linear alkyl having from 1-6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 3 to 6 carbon atoms, or 1-6 carbon atoms of esters, ether, amide, or polyethyleneoxy unit of formula (OCH2CH2)p, wherein p is an integer from 0 to about 1000, or combination thereof.
Additionally R1; R2, R3 and R4 are respectively a chain of atoms selected from C, Ν, O, S, Si, and P that covalently connects the cell-surface binding ligand, the phosphinate or sulfonyl group, the conjugated drug and among themselves (R1; R2 , R3 and R4). The atoms used in forming Ri, R2, R3 or R4 group can have a C1-C6 group of ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkox- ylamines, urethanes, amino acids, peptides, acyloxylamine s, heterocyclics, hydroxamic acids, or combination thereof.
M is H, or Na, or K, or N+RiR2R3 or a pharmaceutical salt. Ri, R2 and R3 are described above.
2. A cell-binding agent-drug conjugate compound of Formula (II):
Figure imgf000003_0001
wherein:
Cb represents a cell-binding agent/molecule.
Drug represents a drug linked to the cell-binding agent via the hydrophilic linker by an al- kyl, alkylene, alkenylene, alkynylene, ether, polyoxyalkylene, ester, amine, imine, polyamine, hydrazine, hydrazone, amide, urea, semicarbazide, carbazide, alkoxyamine, urethanes, amino acid, peptide, acyloxylamine, hydroxamic acid, disulfide, thioether, thioester, carbamate, carbonate, heterocyclic ring, heteroalkyl, heteroaromatic, or alkoxime bond, or combination thereof. q is 1 - 30.
Wherein Q, T, m, n, R1; R2, R3, Rt, R5 and R5 are defined the same as in Claim 1.
3.
Figure imgf000003_0002
Wherein:
Q, T, Z, m, n, R1; R2, R3, Rt, R5 and R5 are defined the same as in Claim 1.
Cb and q are defined the same as in Claim 2.
4. A compound of Formula (IV):
Y-Rj-[-Q-R2 fT-R3-j R -Drug
R5 R6 (IV)
Wherein:
Y, Q, T, m, n, R1; R2, R3, Rt, R5 and R5 are defined the same as in Claim 1.
Drug is defined the same as in Claim 2.
5. The compound of Formula (I) of claims 1, wherein Q, or/and T is-Xi-P(=0)[Xi-Ri-Y]- X3-, thus the compound of the Formula (I) containing two or more Y groups, can be used to link to two or more sites, preferably link to a pair of sites of cell binding molecules. wherein X2 and X3 are independently selected from N(R7), O, CH2 or S; and Y, Ri and R7 are defined in Claim 1.
6. The compound of Formula (I) of claims 1, wherein Q, or/and T is -Xi-P(=0)[X2-R4-Z]- X3 -, thus the compound of the Formula (I) containing two or more Z groups can be used for linking two or more drugs, preferably two different drugs. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2 or S; and Z, R4 and R7 are defined in Claim 1.
7. The conjugate compound of Formula (II) of claims 2, wherein Q, or/and T is -Xi- P(=0)[Xi-Ri-Cb]-X3-, thus the compound of the Formula (II) containing two or more Cb groups is linked to two or more sites, preferably a pair of sites of a cell binding molecule. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2 or S; Ri and R7 are defined in Claim 1; and Cb is defined the same in Claim 2.
8. The compound of Formula (II) of claims 2, wherein Q, or/and T is
Figure imgf000004_0001
Drug] -X3-, thus the compound of the Formula (II) containing two or more "Drugs" is linked to two or more drugs, preferably two different drugs. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2j or S; Rt and R7 are defined in Claim 1; and Drug is defined the same in Claim 2.
9. The compound of Formula (III) of claims 3, wherein Q, or/and T is-Xi-P(=0)[X2-Rr Cb]-X3-, thus the compound of the Formula (III) containing two or more Cb groups is linked to two or more sites, preferably a pair of sites of a cell binding molecule. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2 or S; Ri and R7 are defined in Claim 1; and Cb is defined the same in Claim 2.
10. The compound of Formula (III) of claims 3, wherein Q, or/and T is
Figure imgf000004_0002
X3-, thus the compound of the Formula (III) containing two or more Z groups can be used for linking to two or more drugs, preferably two different drugs. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2j or S; and Z, R4 and R7 are defined in Claim 1.
11. The compound of Formula (IV) of claims 4, wherein Q, or/and T is
Figure imgf000004_0003
X3-, thus the compound of the Formula (IV) containing two or more Y groups can be used for linking to two or more sites, preferably to a pair of sites of a cell binding molecule. Wherein X^ X2 and X3 are independently selected from N(R7), O, CH2 or S; and Y, Ri and R7 are defined in Claim 1.
12. The compound of Formula (IV) of claims 4, wherein Q, or/and T is -Xi-P(=0)[X2-Pv4- Drug] -X3-, thus the compound of the Formula (IV) containing two or more "Drug" groups is linked to two or more drugs, preferably two different drugs. Wherein X^ X2 and X3 are inde- pendently selected from N(R7), O, CH2j or S; R4 and R7 are defined in Claim 1; and Drug is defined the same in Claim 2.
13. The "Drug" according to claim 2, 4, 8 or 12is selected from:
1). Chemotherapeutic agents: a). Alkylating agents: Nitrogen mustards: chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pi- pobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); benzodiazepine dimers (, dimmers of pyrrolobenzodiazepine (PBD) or tomaymycin, indolinobenzodiazepines, imidazobenzothi- adiazepines, or oxazolidinobenzodiazepines); Nitrosoureas: (carmustine, lomustine, chlorozoto- cin, fotemustine, nimustine, ranimustine); Alkylsulphonates: (busulfan, treosulfan, improsulfan and piposulfan); Triazenes: (dacarbazine); Platinum containing compounds: (carboplatin, cis- platin, oxaliplatin); aziridines, benzodopa, carboquone, meturedopa, and uredopa; ethyl- enimines and methylamelamines including altretamine, triethylenemelamine, trietylenephospho- ramide, triethylenethiophosphoramide and trimethylolomelamine] ; b). Plant Alkaloids: Vinca alkaloids: (vincristine, vinblastine, vindesine, vinorelbine, navelbin); Taxoids: (paclitaxel, docetaxol) and their analogs, Maytansinoids (DM1, DM2, DM3, DM4, DM5, DM6, DM7, may- tansine and ansamitocins) and their analogs, cryptophycins (cryptophycin 1 and cryptophycin 8); epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; spongistatin; c). DNA Topoisomerase Inhibitors: [Epipodophyllins: (9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids (retinols), teniposide, topotecan, 9-nitrocamptothecin (RFS 2000)); mitomycins: (mitomycin C)]; d). Antimetabolites: {[Anti-folate: DHFR inhibitors: (methotrexate, trimetrexate, denopterin, pteropter- in, aminopterin (4-aminopteroic acid) or the other folic acid analogues); IMP dehydrogenase Inhibitors: (mycophenolic acid, tiazofurin, ribavirin, EICAR); Ribonucleotide reductase Inhibitors: (hydroxyurea, deferoxamine)]; [Pyrimidine analogs: Uracil analogs: (ancitabine, aza- citidine, 6-azauridine, capecitabine (Xeloda), carmofur, cytarabine, dideoxyuridine, doxi- fluridine, enocitabine, 5-Fluorouracil, floxuridine, ratitrexed (Tomudex)); Cytosine analogs: (cytarabine, cytosine arabinoside, fludarabine); Purine analogs: (azathioprine, fludarabine, mer- captopurine, thiamiprine, thioguanine)]; folic acid replenisher, frolinic acid}; e). Hormonal therapies: {Receptor antagonists: [Anti-estrogen: (megestrol, raloxifene, tamoxifen); LHRH agonists: (goscrclin, leuprolide acetate); Anti -androgens: (bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, tes- tolactone, trilostane and other androgens inhibitors)]; Retinoids/Deltoids: [Vitamin D3 analogs: (CB 1093, EB 1089 KH 1060, cholecalciferol, ergocalciferol); Photodynamic therapies: (ver- teporfm, phthalocyanine, photosensitizer Pc4, demethoxyhypocrellin A); Cytokines: (Interfer- on-alpha, Interferon-gamma, tumor necrosis factor (TNFs), human proteins containing a TNF domain)]}; f). Kinase inhibitors, BIBW 2992 (anti-EGFR/Erb2), imatinib, gefitinib, peg- aptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib.
vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivoza- nib, sorafenib, bevacizumab, cetuximab, Trastuzumab, Ranibizumab, Panitumumab, ispinesib; g). antibiotics, the enediyne antibiotics ( calicheamicins, especially calicheamicin .γΐ, δΐ, αΐ and βΐ; dynemicin, including dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C- 1027, maduropeptin, as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomy- cin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino- doxorubicin, cyanomoφholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic acid, nogalamy- cin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, strepto- nigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; f). Others: Polyketides (aceto- genins), especially bullatacin and bullatacinone; gemcitabine, epoxomicins ( carfilzomib), bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA- 9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, Isoprenylation inhibitors ( Lovas- tatin), Dopaminergic neurotoxins ( l-methyl-4-phenylpyridinium ion), Cell cycle inhibitors ( staurosporine), Actinomycins ( Actinomycin D, dactinomycin), Bleomycins ( bleomycin A2, bleomycin B2, peplomycin), Anthracyclines ( daunorubicin, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, mtoxantrone, MDR inhibitors ( verapamil), Ca2+ATPase inhibitors ( thapsigargin), Histone deacetylase inhibitors (Vorinostat, Romidepsin, Panobinostat, Valproic acid, Mocetinostat (MGCD0103), Belinostat, PCI-24781, Entinostat, SB939,
Resminostat, Givinostat, AR-42, CUDC-101, sulforaphane, Trichostatin A) ; Thapsigargin, Celecoxib, glitazones, epigallocatechin gallate, Disulfiram, Salinosporamide A.; Anti -adrenals, aminoglutethimide, mitotane, trilostane; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine (DFMO), elfomithine; elliptinium acetate, etoglucid; gallium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mitoxantrone; mop- idamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; tria- ziquone; 2, 2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verrucarin A, roridin A and anguidine); urethane, siR A, antisense drugs.
2) . Anti -autoimmune disease agents: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids ( amcinonide, betamethasone, budesonide, hydrocortisone, flunisolide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone acetonide, beclometasone dipropionate), DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, myco- phenylate, prednisone, sirolimus, tacrolimus.
3) . Anti-infectious disease agents, a). Aminoglycosides: amikacin, astromicin, gentami- cin (netilmicin, sisomicin, isepamicin), hygromycin B, kanamycin (amikacin, arbekacin, bekan- amycin, dibekacin, tobramycin), neomycin (framycetin, paromomycin, ribostamycin), netilmicin, spectinomycin, streptomycin, tobramycin, verdamicin; b). Amphenicols: azidam- fenicol, chloramphenicol, florfenicol, thiamphenicol; c). Ansamycins: geldanamycin, herbimy- cin; 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, cefd- itoren, cefepime, cefetamet, cefmenoxime, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotiam, cefozopran, cephalexin, cefpimizole, cefpiramide, cefpirome, cefpodox- ime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceftibuten, ceftiolene, ceftizox- ime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamycin (cefoxitin, cefotetan, cefmetazole), oxacephem (flomoxef, latamoxef); f). Glycopeptides: bleomycin, vancomycin (oritavancin, telavancin), teicoplanin (dalbavancin), ramoplanin; g). Glycylcyclines: tigecy- cline; g). β-Lactamase inhibitors: penam (sulbactam, tazobactam), clavam (clavulanic acid); i). Lincosamides: clindamycin, lincomycin; j). Lipopeptides: daptomycin, A54145, calcium- dependent antibiotics (CD A); k). Macrolides: azithromycin, cethromycin, clarithromycin, dirith- romycin, erythromycin, flurithromycin, josamycin, ketolide (telithromycin, cethromycin), midecamycin, miocamycin, oleandomycin, rifamycins (rifampicin, rifampin, rifabutin, rifapen- tine), rokitamycin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), trolean- domycin, telithromycin; 1). Monobactams: aztreonam, tigemonam; m). Oxazolidinones: linezol- id; n). Penicillins: amoxicillin, ampicillin (pivampicillin, hetacillin, bacampicillin, metampicil- lin, talampicillin), azidocillin, azlocillin, benzylpenicillin, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin (ca- rindacillin), 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, gat- ifloxacin, gemifloxacin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, mar- bofloxacin, 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, lymecy- cline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicycline, rolitetracy- cline, tetracycline, glycylcyclines ( tigecycline); u). Other types of antibiotics: annonacin, ars- phenamine, bactoprenol inhibitors (Bacitracin), DADAL/AR inhibitors (cycloserine), dicty- ostatin, 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: osel- tamivir, zanamivir, peramivir; e). Nucleosides ^nucleotides: abacavir, aciclovir, adefovir, amdoxovir, apricitabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine (ddl), el- vucitabine, 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'-dideoxyguanosine (FLG), fomivirsen, ganciclovir, idoxuridine, lamivudine (3TC), 1-nucleosides ( ?-l-thymidine and ?-l-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, docosa- nol, 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). Other types of anti -virus drugs:
abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate (EGCG), foscarnet, griffithsin, taribavirin (viramidine), hydroxyurea, KP-1461, miltefosine, pleconaril, portmanteau inhibitors, ribavirin, seliciclib.
3 11 14 18 32 35
5) . A radioisotope that can be selected from (radionuclides) H, C, C, F, P, S, 64Cu, 68Ga, 86Y, "Tc, i nIn, 123I, 1241, 125I, 131I, 133Xe, 177Lu, 211At, or 213Bi.
6) . A chromophore molecule, which can be one that has the ability to absorb a kind of light, UV light, florescent light, IR light, near IR light, visual light; A class or subclass of xan- thophores, erythrophores, iridophores, leucophores, melanophores, cyanophores, fluorophore molecules which are fluorescent chemical compounds re-emitting light upon light, visual photo- transduction molecules, photophore molecules, luminescence molecules, luciferin compounds; Non-protein organic fluorophores, : Xanthene derivatives (fluorescein, rhodamine, Oregon green, eosin, and Texas red); Cyanine derivatives: (cyanine, indocarbocyanine, oxacarbocya- nine, thiacarbocyanine, and merocyanine); Squaraine derivatives and ring-substituted squaraines, including Seta, SeTau, and Square dyes; Naphthalene derivatives (dansyl and prodan derivatives); Coumarin derivatives; Oxadiazole derivatives (pyridyloxazole, nitroben- zoxadiazole and benzoxadiazole); Anthracene derivatives (anthraquinones, including DRAQ5, DRAQ7 and CyTRAK Orange); Pyrene derivatives (cascade blue, ); Oxazine derivatives (Nile red, Nile blue, cresyl violet, oxazine 170 ). Acridine derivatives (proflavin, acridine orange, ac- ridine yellow ). Arylmethine derivatives (auramine, crystal violet, malachite green).
Tetrapyrrole derivatives (porphin, phthalocyanine, bilirubin); Any analogs and derivatives of the following fluorophore compounds: CF dye (Biotium), DRAQ and CyTRAK probes (BioSta- tus), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Atto and Tracy (Sigma Aldrich), FluoProbes (Interchim), Abberior Dyes (Abberior), DY and MegaStokes Dyes (Dyomics), Sulfo Cy dyes (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau and Square Dyes (SETA BioMedicals), Quasar and Cal Fluor dyes (Biosearch Technologies), SureLight Dyes (APC, RPEPerCP, Phycobilisomes)(Columbia Biosciences), APC, APCXL, RPE, BPE (Phyco-Biotech), Allophycocyanin (APC), 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(PE), 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 (7-aminoactinomycin D, CG-selective), Acridine Orange, Chromomycin A3, CyTRAK Orange (Biostatus, red excitation dark), DAPI, DRAQ5, DRAQ7, Ethidium Bromide, Hoechst33258, Hoechst33342, LDS 751, Mithramycin, Propidi- umlodide (PI), SYTOX Blue, SYTOX Green, SYTOX Orange, Thiazole Orange, TO-PRO: Cy- anine Monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1. The fluoro- phore compounds that can be linked to the linkers of the invention for study cells are selected from the following compounds or their derivatives: DCFH (2'7'Dichorodihydro-fluorescein, oxidized form), DHR (Dihydrorhodamine 123, oxidized form, light catalyzes oxidation), Fluo-3 (AM ester. pH > 6), Fluo-4 (AM ester. pH 7.2), Indo-1 (AM ester, low/high calcium (Ca2+)), SNARF(pH 6/9), Allophycocyanin(APC), AmCyanl (tetramer, Clontech), AsRed2 (tetramer, Clontech), Azami Green (monomer, MBL), Azurite, B-phycoerythrin(BPE), Cerulean, CyPet, DsRed monomer (Clontech), DsRed2 ("RFP", Clontech), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), Emerald (weak dimer, Invitrogen), EYFP (weak dimer, Clontech), GFP (S65A mutation), GFP (S65C mutation), GFP (S65L mutation), GFP (S65T mutation), GFP (Y66F mutation), GFP (Y66H mutation), GFP (Y66W mutation), GFPuv, HcRedl, J-Red, Ka- tusha, Kusabira Orange (monomer, MBL), mCFP, mCherry, mCitrine, Midoriishi Cyan (dimer, MBL), mKate (TagFP635, monomer, Evrogen), mKeima-Red (monomer, MBL), mKO, mOrange, mPlum, mRaspberry, mRFP 1 (monomer, Tsien lab), mStrawberry, mTFPl, mTur- quoise2, P3 (phycobilisome complex), Peridinin Chlorophyll (PerCP), R-phycoerythrin(RPE), T-Sapphire, TagCFP (dimer, Evrogen), TagGFP (dimer, Evrogen), TagRFP (dimer, Evrogen), TagYFP (dimer, Evrogen), tdTomato (tandem dimer), Topaz, TurboFP602 (dimer, Evrogen), TurboFP635 (dimer, Evrogen), TurboGFP (dimer, Evrogen), TurboRFP (dimer, Evrogen), Tur- boYFP (dimer, Evrogen), Venus, Wild Type GFP, YPet, ZsGreenl (tetramer, Clontech), ZsYel- lowl (tetramer, Clontech).
7). The pharmaceutically acceptable salts, acids or derivatives of any of the above drugs.
14. The compound of claim 2, 4, 8 or 12, wherein a "Drug" is a chromophore molecule, can be used for detection, monitoring, or study the interactions and/or functions of the cell binding molecule, and/or the conjugate with a target, preferably, a targeted cell.
15. The "Drug" according to of claim 2, 4, 8 or 12 is preferably selected from tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 analogs, morpholino doxorubicins, tax- anes, cryptophycins, epothilones, and benzodiazepine dimers (dimmers of pyrrolobenzo- diazepines (PBD) or tomaymycins), indolinobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinobenzodiazepines), siRNA or a combination thereof, and/or pharmaceutically acceptable salts, acids or derivatives of any one of the above molecules.
16. The cell binding agent/molecule according to any one of claim 2, 3, 7, or 9 is selected from an antibody, a protein, a vitamin ( folate), peptides, a polymeric micelle, a liposome, a lipoprotein-based drug carrier, a nano-particle drug carrier, a dendrimer, and a combination of any one above thereof.
17. The cell-binding molecule/agent according to any one of claim 2, 3, 7, 9 or 16 is preferred 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, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, or a nutrient-transport molecule.
18. The cell-binding molecule/agent according to any one of claim 2, 3, 7, 9 or 16 can be any agent that is able to target 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.
19. The cell-binding molecule/agent according to any one of claim 2, 3, 7, 9 or 16 can be any agent/molecule that is able to against any one of the following antigens or receptors: CD3, CD4, CD5, CD6, CD7, CD8, CD9, CD10, CDl la, CDl lb, CDl lc, CD12w, CD14, CD15, CD16, CDwl7, 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, CDwl86, CD194, CD195, CD200, CD200a, CD200b, CD209, CD221, CD227, CD235a, CD240, CD262, CD271, CD274, CD276 (B7-H3), CD303, CD304, CD309, CD326, 4- IBB, 5AC, 5T4 (Trophoblast glycoprotein, TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF 1), 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 Al, Anthrax toxin protective antigen, Anti-transferrin receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracis anthrax, BAFF (B- cell activating factor), B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242 antigen, CA125 (carbohydrate antigen 125, MUC16), CA-IX (or CAIX, carbonic anhydrase 9), CALLA, CanAg, Canis lupus familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, CCL11(C-C motif chem- okine 11), CCR4 (C-C chemokine receptor type 4, CD194), CCR5, CD3E (epsilon), CEA (Carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (Factor D), Ch4D5, Cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), Clumping factor A, CRIPTO, FCSF1R (Colony stimulating factor 1 receptor, CD115), CSF2 (colony stimulating factor 2, Granulocyte-macrophage colony-stimulating factor (GM-CSF)), CTLA4 (cytotoxic T- lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4 (CD184), C-X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin Bl, CYPIBI, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL4 (delta-like-ligand 4), DPP4 (Dipeptidyl- peptidase 4), DR5 (Death receptor 5), E. coli shiga toxin type- 1, E. coli shiga toxin type-2, ED- B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRvIII, Endoglin (CD 105), Endothelin B receptor, Endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, Episialin, ERBB2 (Epidermal Growth Factor Receptor 2), ERBB3, ERG (TMPRSS2 ETS fusion gene), Escherichia coli, ETV6-AML, FAP (Fibroblast activation protein alpha), FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR (folate receptor), Folate receptor alpha, Folate hydrolase, Fos-related antigen l .F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28 (a cell surface antigen glyvolipid), GD3 idiotype, GloboH, Glypican 3, N-glycolylneuraminic acid, GM3, GMCSF receptor a-chain, Growth differentiation factor 8, GP100, GPNMB (Transmembrane glycoprotein NMB), GUCY2C (Guanylate cyclase 2C, guanylyl cyclase C(GC-C), intestinal Guanylate cyclase, Guanylate cyclase-C receptor, Heat-stable enterotoxin receptor (hSTAR)), Heat shock proteins, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, HER1 (human epidermal growth factor receptor 1), HER2, HER2/neu, HER3 (ERBB-3), IgG4, HGF/SF (Hepato- cyte growth factor/scatter factor), HHGFR, HIV-1, Histone complex, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB , HMWMAA, Human chorionic gonadotropin, HNGF, Human scatter factor receptor kinase, HPV E6/E7, Hsp90, hTERT, ICAM-1 (Intercellular Adhesion Molecule 1), Idiotype, IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN- γ, Influenza hemagglutinin, IgE, IgE Fc region, IGHE, IL-1, IL-2 receptor (interleukin 2 receptor), IL-4, IL-5, IL-6, IL-6R (interleukin 6 receptor), IL-9, IL-10, IL-12, IL-13, IL-17, IL-17A, IL-20, IL-22, IL-23, IL31RA, ILGF2 (Insulin-like growth factor 2), Integrins (α4, ο¾,β3, ανβ3, α4β7ι α5β1, α6β4, α7β7, α11β3, α5β5, ανβ5), Interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, LCK, Le, Legumain, Lewis-Y antigen, LFA-1 (Lymphocyte function-associated antigen
1, CD 11a), LHRH, LINGO- 1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-
2, MAGE-1, MAGE-2, MAGE-3, MAGE Al, MAGE A3, MAGE 4, MARTI, MCP-1, MIF (Macrophage migration inhibitory factor, or glycosylation-inhibiting factor (GIF)), MS4A 1 (membrane -spanning 4-domains subfamily A member 1), MSLN (mesothelin), MUCl(Mucin 1, cell surface associated (MUCl) or polymorphic epithelial mucin (PEM)), MUCl-KLH, MUCl 6 (CA125), MCPl(monocyte chemotactic protein 1), MelanA/MART 1 , ML-IAP, MPG, MS4A1 (membrane -spanning 4-domains subfamily A), MYCN, Myelin-associated glycoprotein, Myostatic NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), NGF, Neural apoptosis-regulated proteinase 1, NOGO-A, Notch receptor, Nucleolin, Neu oncogene product, NY-BR-1, NY-ESO-1, OX-40, OxLDL (Oxidized low-density lipoprotein), OY-TES1, P21, p53 nonmutant, P97, Page4, PAP, Paratope of anti-(N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PDCD1 (PD-1, Programmed cell death protein 1,CD279), PDGF-Ra (Alpha-type platelet-derived growth factor receptor ), PDGFR-β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, Platelet-derived growth factor receptor beta, Phosphate-sodium co-transporter, PMEL 17, Polysialic acid, Proteinase3 (PR1), Prostatic carcinoma, PS (Phosphatidylserine), Prostatic carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI), CD240), Rhesus factor, RANKL, RhoC, Ras mutant, RGS5, ROB04, Respiratory syncytial virus, RON, Sarcoma translocation breakpoints, SART3, Sclerostin, SLAMF7 (SLAM family member 7), Selectin P, SDC1 (Syndecan 1), sLe(a), Somatomedin C, SIP (Sphingosine-1 -phosphate), Somatostatin, Sperm protein 17, SSX2, STEAP1 (six-transmembrane epithelial antigen of the prostate 1), STEAP2, STn, TAG-72 (tumor associated glycoprotein 72), Survivin, T-cell receptor, T cell transmembrane protein, TEM1 (Tumor endothelial marker 1), TENB2, Tenascin C (TN-C), TGF-a, TGF-β (Transforming growth factor beta), TGF-βΙ, TGF^2 (Transforming growth factor-beta 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-a, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor super- family member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-Rl (Tumor necrosis apoprosis Inducing ligand Receptor 1), TRAILR2 (Death receptor 5 (DR5)), tumor-associated calcium signal transducer 2, tumor specific glycosylation of MUCl, TWEAK receptor, TYRPl (glycoprotein 75), TRP-2, Tyrosinase, VCAM-1 (CD106), VEGF, VEGF-A, VEGF-2 (CD309), VEGFR-1, VEGFR2, or vimentin, WT1, XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptors.
20. The tumor cell according to claim 18 is selected from 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, or any cells that grow and divide at an unregulated, quickened pace to cause cancers.
21. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate compounds of claim 2 and/or 8, and a pharmaceutically acceptable salt, carrier, diluent, or excipient therefore, or a combination therefore, for the treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.
22. The "Drug" according to any one of claim 2, 4, 8 or 12, is selected from a toxin, a chemo- therapeutic agent, a drug moiety, an antibiotic, a radioactive isotope, a nucleolytic enzyme and/or a chromophore molecule.
23. The linkage components according to any one of claim 1, 5 or 6 can be composed of one or more components of: 6-maleimidocaproyl (MC), maleimido propanoyl (MP), valine- citrulline (val-cit), alanine -phenylalanine (ala-phe), lysine-phenylalanine (lys-phe), p- aminobenzyloxycarbonyl (PAB), 4-thio-pentanoate (SPP), 4-(N-maleimidomethyl)- cyclohexane-l-carboxylate (MCC), 4-thio-butyrate (SPDB), maleimidoethyl (ME), 4-thio-2- hydroxysulfonyl-butyrate (2-Sulfo-SPDB), pyridinyl-dithiol (PySS), alkoxy amino (AO A), eth- yleneoxy (EO), 4-methyl-4-dithio-pentanoic (MPDP), azido (N3), alkynyl, dithio, peptide, and/or (4-acetyl)aminobenzoate (SIAB).
24. The "Drug" according to any one of claim 2, 8 or 22, is preferably selected from tubulysins, maytansinoids, taxanoids (taxanes), CC-1065 analogs, daunorubicin and doxorubicin compounds, benzodiazepine dimers (dimers of pyrrolobenzodiazepine (PBD), tomaymycin, anthramycin, indolinobenzodiazepines, imidazobenzothiadiazepines, or oxazolidinobenzodiaze- pines), calicheamicins and the enediyne antibiotics, actinomycin, azaserines, bleomycins, epiru- bicin, tamoxifen, idarubicin, dolastatins/auri statins (monomethyl auristatin E, MMAE , MMAF, auristatin PYE, auristatin TP, Auristatins 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP)), duocar- mycins, thiotepa, vincristine, hemiasterlins, nazumamides, microginins, radiosumins, alterobac- tins, microsclerodermins, theonellamides, esperamicins, and their analogues and derivatives thereof.
25. A compound according to claim 1 or 4 containing a functional group that enables reaction with a cell-binding agent comprises the formula of 5, 9, 16, 19, 27, 29, 30, 35, 40, 47, 50, 51, 53, 62, 63, 65, 68, 69, 74, 75, 77, 84, 85, 88, 89, 94, 95, 99, 100, 108, 109, 114, 115, 121, 123, 124, 135, 136, 141, 142, 144, 147a, 147b, 147c, 147d, 153, 158, 172, 173, 174, 182, 183, 193, 194,
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
17
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000019_0001
Wherein m1; m2 and m3 are 0-24 independently, Ri and Drug are defined the same as in claim 1, 2, 13, or 14.
26. The compound according to claims 2 and 3 comprises the formula of 6, 17, 10, 12, 20, 22, 28, 31, 34, 36, 37, 41, 48, 52, 54, 64, 66, 70, 71, 76, 78, 86, 87, 90, 96, 97, 101, 102, 110, 116, 125, 126, 127, 137, 143, 145, 148a, 148b, 148c, 148d, 159, 184, 185, 194, 197, 205, 210, which are illustrated below:
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
21
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000023_0001
Wherein m1; m2 and m3 are 0-24 independently, Ri q and Drug are defined the same as in claim 1, 2, 13, or 14.
27. The conjugate of any one of claim 2, 7, or 8, having in vitro, in vivo or ex vivo cell killing activity.
28. The conjugate compound of any one of claim 2, 7, and/or 8, can comprise either a peptides of 1-20 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.
29. The conjugate compound of any one of claim 2, 7 or 8, wherein the linkage components of this invention can be cleavable by a protease.
30. A pharmaceutical composition comprising a therapeutically effective amount of the conjugate compound of claim 2, 7 or/and 8, administered concurrently with the other therapeutic agents of the chemotherapeutic agent, the radiation therapy, immunotherapy agents, autoimmune disorder agents, anti-infectious agents or the other conjugates for synergistically effective treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.
31. The synergistic agents according to claim 30 are preferably selected from one or several of the following drugs: Abatacept (Orencia), Abiraterone acetate (Zytiga®), Acetaminophen /hydrocodone, Adalimumab, afatinib dimaleate (Gilotrif®), alemtuzumab (Campath®), Alitret- inoin (Panretin®), ado-trastuzumab emtansine (Kadcyla™), Amphetamine mixed salts (Am- phetamine/dextroamphetamine, or Adderall XR), anastrozole (Arimidex®), Aripiprazole, Atazanavir, Atezolizumab (MPDL3280A), Atorvastatin, axitinib (Inlyta®), belinostat (Bele- odaq™), Bevacizumab (Avastin®), Cabazitaxel (Jevtana®), Cabozantinib (Cometriq™), bexar- otene (Targretin®), blinatumomab (Blincyto™), Bortezomib (Velcade®), bosutinib (Bo- sulif®), brentuximab vedotin (Adcetris®), Budesonide, Budesonide/formoterol, Buprenorphine, Capecitabine, carfilzomib (Kyprolis®), Celecoxib, ceritinib (LDK378/ Zykadia), Cetuximab (Erbitux®), Cyclosporin, Cinacalcet, crizotinib (Xalkori®), Dabigatran, dabrafenib (Taf- inlar®), Darbepoetin alfa, Darunavir, imatinib mesylate (Gleevec®), dasatinib (Sprycel®), de- nileukin diftitox (Ontak®), Denosumab (Xgeva®), Depakote, Dexlansoprazole, Dexme- thylphenidate, Dinutuximab (Unituxin™), Doxycycline, Duloxetine, Emtricitabine/ Rilpi- virine/Tenofovir disoproxil fumarate, Emtricitabine/tenofovir/efavirenz, Enoxaparin, Enzalu- tamide (Xtandi®), Epoetin alfa, erlotinib (Tarceva®), Esomeprazole, Eszopiclone, Etanercept, Everolimus (Afinitor®), exemestane (Aromasin®), everolimus (Afinitor®), Ezetimibe, Ezetimibe/simvastatin, Fenofibrate, Filgrastim, fingolimod, Fluticasone propionate,
Fluticasone/salmeterol, fulvestrant (Faslodex®), gefitinib (Iressa®), Glatiramer,
Goserelin acetate (Zoladex), Imatinib (Gleevec), Ibritumomab tiuxetan (Zevalin®), ibrutinib (Imbruvica™), idelalisib (Zydelig®), Infliximab, Insulin aspart, Insulin detemir, Insulin glargine, Insulin lispro, Interferon beta la, Interferon beta lb, lapatinib (Tykerb®), Ipilimumab (Y ervoy®), Ipratropium bromide/salbutamol, Lanreotide acetate (Somatuline® Depot), lenali- omide (Revlimid®), lenvatinib mesylate (Lenvima™), letrozole (Femara®), Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Liraglutide, Lisdexamfetamine, MEDI4736 (AstraZeneca, Celgene), Memantine, Methylphenidate, Metoprolol, Modafinil, Mometasone, Nilotinib (Ta- signa®), Nivolumab (Opdivo®), ofatumumab (Arzerra®), obinutuzumab (Gazyva™), olaparib (Lynparza™), Olmesartan, Olmesartan/hydrochlorothiazide, Omalizumab, Omega-3 fatty acid ethyl esters, Oseltamivir, Oxycodone, palbociclib (Ibrance®), Palivizumab, panitumumab (Vec- tibix®), panobinostat (Farydak®), pazopanib (Votrient®), pembrolizumab (Keytru- da®), Pemetrexed (Alimta), pertuzumab (Perjeta™), Pneumococcal conjugate vaccine, poma- lidomide (Pomalyst®), Pregabalin, Quetiapine, Rabeprazole, radium 223 chloride (Xofigo®), Raloxifene, Raltegravir, ramucirumab (Cyramza®), Ranibizumab, regorafenib (Stivar- ga®), Rituximab (Rituxan®), Rivaroxaban, romidepsin (Istodax®), Rosuvastatin, ruxolitinib phosphate (Jakafi™), Salbutamol, Sevelamer, Sildenafil, siltuximab (Sylvant™), Sitagliptin, Sitagliptin/metformin, Solifenacin, Sorafenib (Nexavar®), Sunitinib (Sutent®),Tadalafil, tamoxifen, Telaprevir, temsirolimus (Torisel®), Tenofovir/emtricitabine, Testosterone gel, Thalidomide (Immunoprin, Talidex), Tiotropium bromide, toremifene (Fareston®), trametinib (Mekinist®), Trastuzumab, Tretinoin (Vesanoid®), Ustekinumab, Valsartan, vandetanib (Caprelsa®), vemurafenib (Zelboraf®), vorinostat (Zolinza®), ziv-aflibercept (Zaltrap®), Zos- tavax., and their analogs, derivatives, pharmaceutically acceptable salts, carriers, diluents, or excipients therefore, or a combination above therefore,
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