Specific conjugation of an antibody

Abstract

This invention relates to a method for preparing homogeneous antibody-drug conjugates or antibody-like protein conjugates by linking cysteine ​​sites between the heavy and light chains of IgG antibodies or antibody-like proteins. The invention also relates to a method for preparing conjugates in a specific manner, including generating specific thiol groups of an antibody or antibody-like protein reagent and then reacting it with a drug / linker complex, or generating protein molecules of an antibody or antibody-like protein reagent while simultaneously reacting in a pot with a synthetically prepared linker-drug assembly to provide a conjugate with more than 75%, and in most cases more than 80% of the payload linked to specific cysteine ​​sites between the heavy and light chains of IgG antibodies or antibody-like proteins. It also relates to methods for using homogeneous conjugates in the targeted prevention or treatment of cancer, infections, and immune diseases.

Claims

1. A conjugate of formula (VII), (VII), wherein n' is 1-10; mAb is an antibody or antibody-like protein; wherein L1 and L2 are the same or different, independently selected from the group consisting of: O, NH, S, NHNH, N(R3), N(R3)N(R3'), (OCH2CH2)pOR3, (OCH2CH(CH3))pOR3, NH(CH2CH2O)pR3, or NH(CH2CH(CH3)O)pR3, N[(CH2CH2O)pR3][(CH2CH2O)p'R3'], (OCH2CH2)pCOOR3, CH2CH2(OCH2CH2)pCOOR of polyethylene glycol unit 3, wherein p and p' are independently selected from the group consisting of: integers from 0 to about 1000, C1-C8 alkyl, C2-C8 Heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, aryl-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; wherein R3 and R3' are independently H, C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, aryl-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or ester, ether, or amide with 1-8 carbon atoms; or 1-8 natural or non-natural amino acids as defined; or polyethylene glycol units with the structural formula (OCH2CH2)p or (OCH2CH(CH3))p. Where p is an integer from 0 to about 1000, or a combination of one or more of the above; or where L1 or L2 may independently contain a self-destructive or non-self-destructive component, peptide unit, hydrazone bond, disulfide, ester, oxime, amide, or thioether bond, wherein the self-destructive component is an aromatic compound selected from the group consisting of: derivatives of 2-aminoimidazolium-5-methanol, heterocyclic PAB analogs, β-glucuronic acid, and ortho- or para-aminobenzyl condensate; wherein the self-destructive component has one of the following structures: ; ; .; where (*) is an additional spacer or breakable linker unit, or a linker for cytotoxic agents, and / or cell-binding molecules (CBA); X1, Y1, Z2, and Z3 are independently NH, O, or S; Z1 is independently H, NH, O, or S; v is 0 or 1; U1 is independently H, OH, C1-C6 alkyl, (OCH2CH2)nF, Cl, Br, I, OR5, SR5, NR5R5', N=NR5, N=R5, NR5R5', NO2, SOR5R5', SO2R5, SO3R5, OSO3R5, PR5R5', POR5R5', PO2R5R5', OPO(OR5)(OR5'), or OCH2PO(OR5(OR5'), where R5 and R5' are independently H, C1-C8 straight-chain or branched alkyl, C3-C8 Aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acetoamine, or (aryl)r, r = 1-6 (amino acid or peptide having the same or different amino acid sequences); wherein the non-self-destructive component is one of the following structures: Where (*) is a junction of another spacer R1 or a breakable linker unit, a cytotoxic molecule, and / or a cell-binding molecule; X1, Y1, U1, R1, R5, R5' as defined above; r is 0-100; m and n are independently 0-6; or where L1 or L2 may independently consist of one or more of the following linker components: 6-maleiminohexanoyl ("MC"), maleiminopropyl ("MP"), valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("... ala-phe (or "af"), p-aminobenzyloxycarbonyl ("PAB"), 4-thiopentayl ("SPP"), 4-(N-maleiminomethyl)cyclohexane-1-acyl ("MCC"), (4-acetylaminobenzoyl ("SIAB"), 4-thiobutyryl (SPDB), 4-thio-2-hydroxysulfonyl-butyryl (2-Sulfo-SPDB), or a natural or non-natural peptide having 1-8 natural or non-natural amino acid units; or wherein L1 and L2 are independently cleavable linkers; wherein the cleavable linker (L1 or L2) includes: . ‑(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-, ‑(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-, ‑(Aa)r-(CR5R6)m( CR7R8)n(OCH2CH2)t-, -(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-, -(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa) t(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2 )r-,-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m( CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m-(OCO)(Aa)t(CR9 R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2) r-, -(CR5R6)m-phenyl-CO(Aa)t(CR7R8)n-, -(CR5R6)m-furan-CO(Aa)t(CR7R8)n-, -(CR5R6)m-phenylazine-CO(Aa)t(CR7R8)n-, -(CR5R6)m-thiazol-CO(Aa)t(CCR7R8)n-, -(CR5R6)t-thiophene-CO(CR7R8)n-, -(CR5R6)t-imidazol-CO-(CR7R8)n-, -(CR5R6)t-nitrophos-CO(Aa) )t-(CR7R8)n-, -(CR5R6)t-piperazine-CO(Aa)t-(CR7R8)n-, -(CR5R6)tN-methylpiperazine-CO(Aa)t-(CR7R8)n-, -(CR5R)m-(Aa)tphenyl-, -(CR5R6)m-(Aa)tfuran-, -(CR5R6)m-malazol(Aa)t-, -(CR5R6)m-thiazol(Aa)t-, -(CR5R6)m-thiophene-(Aa)t-, -(CR5R6)m-imidazol(Aa)t-, -(CR5R6)m-nitrophos-(Aa)t-, -(CR5R6)m-piperazine-(Aa)t-,-(CR5R6)mN-Methylpyrazine-(Aa)t-, ‑K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-, ‑K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-, ‑K(Aa)r-(CR5R6)m(CR7R8)n(OC H2CH2)t-,‑K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,‑K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,‑K(CR5R6 )m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,‑K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,‑K(CR5R6)m(OCO)(A a)t(CR9R10)n-(OCH2CH2)r-,‑K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,‑K(CR5R6)m(CO)(Aa)t-(CR9R10)n( OCH2CH2)r-,‑K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,‑K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-, ‑K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-, ‑K-(CR5R6)m(CO) (Aa)t(CR9R10)n(OCH2CH2)r-, ‑K(CR5R6)m-phenyl‑ CO(Aa)t(CR7R8)n-, -K-(CR5R6)m-furan-CO(Aa)t-(CR7R8)n-, -K(CR5R6)m-malazol-CO(Aa)t(CR7R8)n-, -K(CR5R6)m-thiazol-CO(Aa)t-(CR7R8)n-, -K(CR5R6)t-thiophene-CO(CR7R8)n-, -K(CR5R6)timidazol-CO-(CR7R8)n-, -K(CR5R6)tmorpholine-CO(Aa)t(CR7R8)n-, -K(CR5R6)tpirazine-CO(Aa)t-(CR7R8)n-, -K(CR5R6)tN-methylpirazine-CO(Aa)t(CR7R8)n-, -K(CR5R)m(Aa)tphenyl, -K-(CR5R6)m-(Aa)tfuran-, -K(CR5R6)m-malazol(Aa)t-, -K(CR5R6)m-thiazole(Aa)t-, -K(CR5R6)m-thiophene-(Aa)t-, -K(CR5R6)m-imidazol(Aa)t-,-K(CR5R6)m-morpholine(Aa)t-, -K(CR5R6)m-piperazine-(Aa)tG, -K(CR5R6)mN-methylpiperazine(Aa)t-; wherein Aa is 1-8 identical or different amino acids; m, n, R3 and R5 are defined as described above; t and r are independently 0-100; R6, R7, and R8 are independently selected from H, halides, C1-C8 alkyl, aryl, alkenyl, alkynyl, ether, ester, amine or amide, optionally substituted by one or more halides, CN, NR1R2, CF3, OR1, aryl, heterocyclic, S(O)R1, SO2R1, -CO2H, -SO3H, -OR1, -CO2R1, -CONR1, -PO2R1R2, -PO3H or P(O)R1R2R3; K It is NR1, -SS-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, S, Se, B or C3-C6 heteroaryl; or wherein the structure of the components of the linkers L1 and L2 is: , (containing MC, 6-maleiminohexacryl), , (MP, maleiminopropyl), , , (PAB, p-para-aminobenzyloxyamino), , , , , , (containing valine-citrulline (VC)), , (MCC, 4-(N-maleiminomethyl)cyclohexane-1-carboxylic acid ester), , ((4-acetylated)aminobenzoate), , (4-Thio-2-hydroxysulfonylbutyrate, 2-sulfo-SPDB), 4-thiovalerate (SPP), 4-thiobutyryl (SPDB), 4-(N-maleiminomethyl)cyclohexane-1-acyl (MCC), maleiminoethylamino (ME), 4-thio-2-hydroxysulfonylbutyryl (2-Sulfo-SPDB), aryl mercaptoether (PhSS), (4-acetylated)aminobenzoyl (SIAB). , oxybenzyl thioether group, aminobenzyl thioether group, dioxybenzyl thioether group, diaminobenzyl thioether group, aminooxybenzyl thioether group, alkoxyamino group (AOA), ethyleneoxy group (EO), disulfide, 4-methyl-4-dithiovaleric acid (MPDP), triazole, alkylsulfonyl, alkylsulfonamide, urethanedisulfonamide, phosphodiamide, alkylphosphodiamide, phosphonic acid, N-methylalkylphosphodiamide, N,N'-dimethylphosphodiamide, N,N'-alkylphosphodiamide, ... gly-gly-gly, gly-gly, gly-gly-gly-gly, Lys-gly, gly-gly-phe-gly, ala-ala,glu-gly, glu-lys, (VC), ..., ..., ..., ... (ala-phe), ..., ... (lys-phe), or a combination of two or more; Wherein are the linking sites; X2, X3, X4, X5, or X6 are independently selected from the following groups of composition: NH, NHNH, N(R12), N(R12)N(R12'), O, S, C1-C6 alkyl, C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, CH2OR12, CH2SR12, CH2NHR12 and 1-8 amino acids; wherein R12 and R12' are independently H, C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or C1-C8 ester, ether, or amide; or have the structural formula (OCH2CH2)p Or (OCH2CH(CH3))p polyethylene glycol unit, where p is an integer from 0 to about 1000, or a combination of two or more; or where L1, L2, X1, X2, X3, X1', X2' and X3' may be omitted independently; where E1 is a linking group connecting two mercapto reactive groups Lv1' and Lv2', and E1 is selected from the group consisting of: CH, CH2, NH, NHNH, N(R3), N(R3)N(R3'), N=N, NN, P, P(=O), S, Si, C2-C8 alkyl, heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, peptide containing 1 to 4 amino acid residues, and one of the following structures: , where D1 and D2 are cytotoxic drugs or therapeutic drugs, immunotherapeutic short antibody proteins, functional molecules used to enhance or stabilize cell-binding antibody protein reagents, cell surface receptor binders, antibody fragments, siRNA or DNA molecules, and selected from the following: 1) Chemotherapy drugs: a) Alkylating agents: Nitrogen mustard: chlorpheniramine, chlorpromazine, cyclophosphamide, dacarbazine, estradiol nitrogen mustard, ifosfamide, nitrogen mustard, dimethoxyamine hydrochloride, dioxane, amlodipine hydrochloride, mycophenolic acid, eugenol, guanopromethane, neonitrogen mustard, benzyl mustard cholesterol, pine oxybenzyl mustard, thiotetracycline, trefophos, uracil, CC-1065, docalamycin, benzodiazepine dimer, nitrosourea, alkyl sulfonates, triazine, platinum-containing compounds, acridine derivatives, benzodihydropyranone, carboxone, methotrexate and uredopa, ethyleneimine and methyl melamine;b) Plant alkaloids: Vinca minor, Taxol, Maytansine, Cryptopycin, Epothilone, Soft coral alcohol, Dimodilide, Bryophyllactone, Sea hare toxin, Oprestatin, Microtubule toxin, Cephalostatin, Pancratistatin, Sarcodictyin, Spongistatin; c) DNA topoisomerase inhibitors: Etoposidetinib, Mitomycin; d) Antimetabolites: Antifolate agents, DHFR inhibitors, IMP dehydrogenase inhibitors, Ribonucleotide reductase inhibitors, Pyrimidine analogs, Uracil analogs, Cytosine analogs, Purine analogs, Folic acid supplements, Floradic acid; e) Hormone therapy agents: Receptor antagonists, Retinoids / Deltoids; f) Kinase inhibitors: BIBW 2992 (anti-EGFR / Erb2), Imatinib, Gefitinib, Guagatanib, Sorafenib, Dasatinib, Sunitinib, Erlotinib, Nilotinib, Lapatinib, Axitinib, Pazopanib, Vandetanib, E7080 (anti-VEGFR2), Mubritinib, Ponatinib (AP24534), Bafetinib (INNO-406), Bosutinib (SKI-606), Cabozantinib, Vemoderil, Iniparib, Russoritinib, CYT387, Axitinib, Vivozanib, Sorafenib, Bevacizumab, Cetuximab, Trastuzumab, Ranibizumab, Panitumab, Ispins; g) Antibiotics, aclacinomysins, actinomycins, atrazomycin, diazoserine, bleomycin, carnomycin, kanamycin, erythromycin, carcinogens, chromomycin, dachlormycin, daunorubicin, dedaunorubicin, 6-diazo-5-sideoxy-L-demethylleucine, doxorubicin, morpholine-doxorubicin, cyanomorpholine-doxorubicin, 2-pyrrolidone-doxorubicin and deoxydaunorubicin, epirubicin, arubicin, idarubicin, macromycin, nitomycin, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramycin, rodolmycin, streptomycin, streptozotocin, tuberculin, ubenmexicin, fenestrated statin, zorubicin;h) Polyketides (anthocyanins): bullatacin, bullatacinone, gemcitabine, cyclooxygenase, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allolovectin-7, Xegeva, Provenge, Yervoy, isoprenoidation inhibitors, dopaminergic neurotoxins, cell cycle inhibitors, actinomycin, bleomycin, anthracycline antibiotics, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone, MDR inhibitors, Ca2+ ATPase inhibitors, histone deacetase inhibitors, celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A. Antiadrenergic drugs, amylglutathione, mitotane, tralostertan, glucuronolactone, aldoxime, aminoacetylpropionic acid, acridine, arabinoside, bestrabucil, bisacodyl, edatraxate, defofamine, mecosine, diazinon, efornithine (DFMO), elfomithine, elifonitrile, etoglutarate, gallium nitrate, cytosine, hydroxyl Urea, ibandronate, lentinan, chlordamine, mitoxantrone, mitoxantrone, mogudaol, diamine nitrazepam, pentostatin, methamidophos, pirarubicin, podophyllotoxin, 2-ethylhydrazine, methylbenzylhydrazine, pirazine dione propane, rhizomycin, cizol, spirocyclic germanium, sigmazoic acid, triamine, 2,2',2''-trichlorotriethylamine, trichothecene, polyurethane, siRNA, antisense drugs, and nucleases; 2) Drugs for autoimmune diseases are selected from the following groups: cyclosporine, cyclosporine A, aminocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, corticosteroids, DHEA, etanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mycophenolate mofetil, prednisone, sirolimus, and tacrolimus; 3) Anti-infective drugs: a) Aminoglycosides: amikacin, asmicin, gentamicin, hygromycin B, kanamycin, neomycin, spectinomycin, streptomycin, tobramycin, methylphenidate; b) Acidulosins: chloramphenicol, chloramphenicol, florfenicol, methylphenidate; c) Ansarmycin: gerdemycin, atrazine; d) Carbapenems: Biapenem, Doripenem, Ertapenem, Imipenem / Cilastatin, Meropenem, Panipenem; e) Cephalosporins: Carbapenem (Loracarbi), Cefaclor, Chloramphenicol, Cefradine, Cefadroxil, Cefalothin, Cefotaxime, Cefalothin or Cefadroxil, Cefalexin, Cefalecin, Cefamandole, Cefaspirin, Hydroxylamine Cephalosporin, Fluoxetine Cephalosporin, Folicazone, Zoclopyralid Cephalosporin, Cefadroxil, Cefacarpine, Cefotaxime, Cefpyridamole, Cefixime, Cefoxitin, Cefrazolium, Cefoxitin, Cefoxitin, Cefoxitin, Cefotaxime, Cefotiam, Cefotaxime, Cefotiam Pyridine, Cefotaxime, Cefotaxime, Cefodizine, Cefonicid, Cefovirdione, Cefradine, Cefotaxime, Thiamethoxazole Cephalosporin, Cefazolin, Cefaclor, Cefoperazone, Cefimazole, Cefpirome, Cefpirome, Cefpodoxime, Cefrozil, Cefquinoline, Cefsulfuron-methyl, Ceftazidime, Cefterenol, Cefbutane, Cefotaxime, Cefazolin, Cefpyripril, Ceftriaxone, Cefuroxime, Cefazolin, Cephalosporins (Cefoxidin, Cefotetan, Cefcyanazol), Oxycephalosporins (Fluoxaclor, Latamoxaclor); f) Glycopeptides: Bleomycin, Vancomycin (Olivancin, Tervavancin), Teicoplanin (Dabavancin), Ramolane; g) Glycinecycline; h) β-lactamase inhibitors: Penicillane (Sulbactam, Tazobactam), Oxypenicillane (Clavulanic acid); i) Lincosamides: Clindamycin, Lincomycin; j) Lipopeptides: Daptomycin, A54145, Calcium-dependent antibiotics (CDA); k) Macrolides: Azithromycin, Clostridium, Clarithromycin, Dierythromycin, Erythromycin, Fluremycin, Josamycin, Ketolactone, Midecamycin, Micardicin, Pyruvicin, Rifamycin, Ropimycin, Roxithromycin, Spectinomycin, Spiramycin, Tacrolimus (FK506), Pyruvicin, Telithromycin; l) Monocyclic amines: Amintramum, Tegamonan; m) Oxazolidinones: Linezolid;n) Penicillins: Amoxicillin, Ampicillin, Azoxycillin, Aloxicillin, Benzylpenicillin, Benzylpenicillin, Benzylpenicillin, Phenoxymethylpenicillin, Clocillin, Procaine penicillin (Meticillin), Meticillin, Nafcillin, Oxazolidin, Acetylpenicillin, Penicillin, Fennecillin, Phenoxymethylpenicillin, Guaricillin, Ampicillin, Sulfobencillin, Temoxicillin, Tekexilin; o) Polypeptides: Bacitracin, Colistin, Polymyxin B; p) Quinolones: Aratrofloxacin, Barofloxacin, Ciprofloxacin, Clindamycin, Daflonxacin, Difloxacin, Enrofloxacin, Enrofloxacin, Garefloxacin, Gatifloxacin, Gemifloxacin, Gaptafloxacin, Carnotrovafloxacin, Levofloxacin, Lomefloxacin, Mebofloxacin, Moxifloxacin, Naflufloxacin, Norfloxacin, Obibixin, Ofloxacin, Pefloxacin, Travafloxacin, Gaptafloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Toxacin, Travafloxacin; q) Streptocins: Punamycin, Quinupordin / Dalfopristin; r) Sulfonamides: Ampicillin, Azosulfan, Sulfadiazine, Sulfamethoxazole, Sulfamethoxazole, Sulfapyridine, Sulfamethoxazole, Trimethoprim, Sulfamethoxazole (Combined Sulfamethoxazole); s) Steroid antibiotics; t) Tetracyclines: Doxycycline, Chlortetracycline, Clomicycline, Demeclocycline, Ramoxil, Methionine, Methacycline, Minocycline, Oxytetracycline, Panmeclocycline, Pyrrolidine Methyltetracycline, Tetracycline, Glycinecycline; u) Other types of antibiotics: Anthocyanin, Arsphenamine, Bacterial Terpene Inhibitors (Bacitracin), DANAL / AR Inhibitors (Cycloserine), Dictyostatin, Spongiform Cocos, Coralol, Epothilone, Ethambutol, Etoposide, Faropenem, Fusidic Acid, Furazolidone, Isoniazid, Laulimalide, Metronidazole, Mupirocin, NAM Synthesis Inhibitors, Nitrofurantoin, Paclitaxel, Pramipexole, Pyrazinamide, Quinupordin / Dalfopristin, Rifampin, Tazobactam, Tinidazole, Chrysanthemin; 4) Antiviral drugs: a) Invasion / fusion inhibitors: apavirol, maraviro, vicriviroc, gp41 (enfuvirtide), PRO 140, CD4 (elbalizumab); b) Integrase inhibitors: retegvir, elvitegravir, globoidnan A; c) Maturation inhibitors: bevirimat, vivecon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir;e) Nucleosides and nucleotides: Abacavir, Abciximvir, Adefovir, Amoxivir, Abciximab, Bivudine, Sidofovir, Clavudine, Dexamethasone, Doxorubicin (ddI), Elvucitabine, Emtricitabine (FTC), Entecavir, Famciclovir, Fluracillin (5-FU), 3'-Fluorosubstituted 2',3'-Deoxynucleoside analogs, Penciclovir, Racivir, Ribavirin, Ditidine, Stavudine (d4T), Taribavirin (viramidine), Telbivudine, Tenofovir, Trifluorouridine valacyclovir, Valganciclovir, Zacitabine (ddC), Zidovudine (AZT); f) Non-nucleoside analogues: Amantadine, Atepiridine, Capvirine, Diarylpyrimidine (Etravirine, Rilpivirine), Delavedine, Docosanol, Emivirine, Efaviren, Phosphoric acid, Imiquimod, Pegylated interferon, Loviramide, Lodeadenosine, Meinthiazone, Nevirapine, NOV-205, Long-acting Interferon Alpha, Podophyllotoxin, Rifampin, Amantadine, Requimod (R-848), Amantadine acetaminophen; g) Protease inhibitors: Ampravir, Atazanavir, Boceprevir, Darunavir, Fosanavir, Indinavir, Lopinavir, Nefernavir, Procannavir, Ritonavir, Saquinavir, Telaprevir (VX-950), Telanavir; h) Antiviral drugs: Anti-enzymes, Arbidol, Calanolide a) Ceragenin, Cyanavirin-n, Diarylpyrimidine, Epigallocatechin Gallate (EGCG), Phosphoric Acid, Griffithin, Taribavirin (Viramidine), Hydroxyurea, KP-1461, Mitefocin, Precocinone, Hybrid Inhibitors, Ribavirin, Seliciclib; 5) Radioisotopes (radionucleases): 3H, 11C, 14C, 18F, 32P, 35S, 64Cu, 68Ga, 86Y, 99Tc, 111In, 123I, 124I, 125I, 131I, 133Xe, 177Lu, 211At, and 213Bi; 6) Pharmaceutically acceptable salts, acids, or derivatives of any of the above drugs; wherein Lv1' and Lv2' independently have one of the following structures: , ; 2. The coupling of claim 1, wherein in formula (VII), the moiety is independently selected from the group consisting of: , ...

3. The conjugate of claim 1 or 2 has in vitro, in vivo or ex vivo cell-killing activity.

4. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 3, and a pharmaceutically acceptable salt, carrier, diluent, or excipient thereof, or a combination of two or more conjugates, for the treatment or prevention of cancer, autoimmune diseases, or infectious diseases.

5. The pharmaceutical composition of claim 4, which is a liquid formulation or a formulated lyophilized solid / powder, comprises, by weight: 0.01%-99% of one or more coupling agents; 0.0%-20.0% of one or more polyols; 0.0%-2.0% of one or more surfactants; 0.0%-5.0% of one or more preservatives; 0.0%-30% of one or more amino acids; 0.0%-5.0% of one or more antioxidants; 0.0%-0.3% of one or more metal chelating agents; 0.0%-30.0% of one or more buffer salts for adjusting the pH of the composition to pH 4.5-7.5; and 0.0%-30%.One or more isotonic agents of 0% are used to adjust the osmotic pressure to about 250-350 mOsm when reconstituted for administration to a patient; wherein the polyol is selected from the group consisting of fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, glucose, sucrose, trehalose, sorbitol, loose sugar, raffinose, mannitol, xylitol, erythritol, maltitol, lactitol, threitol, sorbitol, glycerol, and L-gluconate and their metal salts; The surfactant is selected from the group consisting of: polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81, or polysorbate 85, poloxamer, poly(ethylene oxide)-poly(propylene oxide), polypropylene glycol-propylene glycol, Triton, sodium lauryl sulfate (SDS), sodium lauryl sulfate, sodium octyl glycoside, dodecyl, myristyl, linoleic or stearyl sulfobetaine, dodecyl, myristyl, linoleic or stearyl sarcosinate, linoleic acid, myristyl or Hexadecyl betaine, laurylaminopropyl, cocamidopropyl, linoleic acid propyl, myristylpropyl, palmitoylpropyl or isostearylaminopropyl-betaine (laurylaminopropyl), myristylaminopropyl, palmitoylpropyl or isostearylaminopropyl-dimethylamine, sodium methylcocoyl or disodium methyl taurate, dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine and cocoamphoteric glycine, isostearyl ethyliminomonyl ethyl sulfate, polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol; The preservative is selected from the group consisting of: benzyl alcohol, octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride and benzyl chloride, phenol, butanol and benzyl alcohol, alkyl p-hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol and m-cresol; the amino acid is selected from the group consisting of: arginine, cystine, glycine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine, glutamine and aspartic acid; the antioxidant is selected from the group consisting of: ascorbic acid, glutathione, cystine or methionine; and the chelating agent is EDTA. The buffer salt is selected from the group consisting of: sodium, potassium, ammonium, or trihydroxyethylamino salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; glycerol hydrochloride; phosphates or sulfates; arginine; glycine; glycine; or histidine acetates, chlorides, phosphates, sulfates, and succinates; The isotonic agent is selected from the group consisting of: mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, and sodium chloride.

6. The pharmaceutical composition of claim 4 or 5, which is contained in a vial, bottle, prefilled syringe or prefilled auto-injector in liquid or lyophilized solid form.

7. Use of a pharmaceutical composition as claimed in claim 4 or 5 for the preparation of a medicament for the synergistic treatment or prevention of cancer, autoimmune diseases, or infectious diseases, wherein the medicament is administered together with a synergist of a chemotherapeutic agent, a radiotherapy agent, an immunotherapy agent, an autoimmune dysregulator, an anti-infective agent, or another conjugate.

8. As claimed in claim 7, wherein the synergist is selected from one or more of the following groups: abatacept, abecipiride, abiraterone acetate, abraxane, acetaminophen / hydrocodone, acalabrutinib, aducanumab, adalimumab, ADXS31-142, ADXS-HER2, afatinib dimaleate, aldesleukin alectinib, alemtuzumab, alitretinoin, ado-trastuzumab emtansine, amphetamine / dextroamphetamine, anastrozole, aripiprazole, anthracyclines, aripiprazole, atazanavir, atazolizumab, atorvastatin, avirapumab, axibuxitine, brentuximab vedotin, brigatinib, budesonide, budesonide Formoterol, Buprenorphine, Cabazitaxel, Cabozantinib, Capmatinib, Capecitabine, carfilzomib, chimeric antigen receptor engineered T (CAR-T) cells, Celecoxib, Ceritinib, Cetuximab, Chidamide, Ciclosporin Cinacalcet, Crizotinib, Cobimetinib, Cosentyx, Crizotinib, CTL019, Dabigatran, Dabrafenib, Dacarbazine, Dacizumab, Dacotinib, Daptomycin, Dalatazumab, Dabiposi alpha, Darunavir, Dasatinib, Diniprofen, Denoxin, Depakote, Lansoprazole, Dexamethasone, Dinutuximab, Doxycycline, Duloxetine, Duvelisib, Durvalumab, Elotizumab, / Elotizumab / Emerovir, Elotizumab Norhexaparin, Ensartinib, Enzalutamide, Epoxetine Alpha, Erlotinib, Esomeprazole, Ezopiclone, Enalapril, Everolimus, Exemestane, Everolimus, Exenatide ER, Ezetimibe, Ezetimibe / Simvastatin, Fenofibrate, Feglastin, Fingolimod, Fluticasone Propionate, Fluticasone / Sameterol, Fulvestrant, Gazyva, Gefitinib, Glatiramer, Gosperidone Acetate, Icotinib, Imatinib, Ibrutinib, Idlib, Ifosfamide, Infliximab, Imiquimod, ImmuCyst, ImmunoBCG, Inipari, Aspartate Insulin, Dexamir Insulin, Glargine Insulin, Lispro Insulin, Alpha-Interferon, Alpha-1b Interferon, Alpha-2a Interferon, Alpha-2b Interferon, Beta-Interferon, Beta-1a Interferon, Beta-1b Interferon, Gamma-1a Interferon, Lapatini, Ipulimab, Ipratropium Bromide / Salbutamol, Isozolol MIB, Kanuma, Lanoletide Acetate, Linedolmine, Linenamide, Linetinib Mesylate, Letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Lira Lutide, Ridesamethasone, LN-144 Loratadine, Memantine, Methylpiperidone, Metoprolol, Mekinist, Mecitabine / Ripavirin / Tenofovir, Modafinil, Mometasone, Mycidac-C, Nicetumab, Neratinib, Nilotinib, Niraparib, Niraparib, Nikolaimab, Ofatumumab, Obituzumab, Olaparib, Olmesartan, Olmesartan / Hydrochlorothiazide, Omalizumab, Omega-3 Fatty Acid Ethyl Ester, Oncorine, Oseltamiv ir, Osimertinib, Oxycodone, Palbociclib, Palolizumab, Panitumumab, Panobinostat, Pazopanib, Pembrolizumab, PD-1 antibody, PD-L1 antibody, Pemetrexed, Pertuzumab, Pneumococcal conjugate vaccine, Pomalidomide, Pregabalin, ProscaVax, Propranolol, Quetiapine, Rabeprazole, Propaxin 223 radium chloride, Raloxifene, Raloxifene, Ramoximumab, Ranibizumab, Regorafenib, Rituximab Rivaroxaban, Romidisin, Rosuvastatin, Russotetinib phosphate, Salbutamol, Savolidinib, Semaglutide, Sevelamer, Sildenafil, Siltuximab, Sipuleucel-T, Sitagliptin, Sitagliptin / Metformin, Solifenacin, Solanezumab, Sonidegib, Sorafenib, Sunitinib, Tacrolimus, Tacrimus, Tapasilafil, Tacrimus tataparal, Tazopanib, Temozolomide, Tessilolimus, Tenofovir / Emtricitabine, Tenofovir Disoproxil Fumarate, Testosterone Gel, Thalidomide, TICE BCG, Iotropium bromide, Tessagiline, Toremifene, Trametinib, Trastuzumab, Trabestin (Ecteinascidin)743), trametinib, trametumab, triflupyridine / tiprazine, retinoic acid, Uro-BCG, Ustekinumab, Valsartan, Veliparib, Vandetanib, Vemurafenib, Venetoclax, Voronostat, Ziv-aflibercept, Zostavax, pharmaceutically acceptable salts, carriers, diluents or excipients, and combinations of two or more compounds.

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