A conjugate of a cytotoxic agent to a cell binding molecule with branched linkers

Abstract

Provided is a conjugation of cytotoxic drug to a cell-binding molecule with a side-chain linker. It provides side-chain linkage methods of making a conjugate of a cytotoxic molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and immunological disorders.

Description

DEMANDE OU BREVET VOLUMINEUX LA PRÉSENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND PLUS D'UN TOME. CECI EST LE TOME 1 DE 2 CONTENANT LES PAGES 1 À 270 NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS / PATENTS THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE THAN ONE VOLUME THIS IS VOLUME 1 OF 2 CONTAINING PAGES 1 TO 270 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME : NOTE POUR LE TOME / VOLUME NOTE: 1 A CONJUGATE OF A CYTOTOXIC AGENT TO A CELL BINDING MOLECULE WITH BRANCHED LINKERS FIELD OF THE INVENTION The present invention relates to the conjugation of a cytotoxic agent to a cell-binding molecule with branch linkers for having better pharmacokinetics in delivery of the conjugate compound, resulting in much precise targeted treatment of abnormal cells. It also relates to a branch-linkage method of conjugation of a cytotoxic agent to a cell-binding ligand, as well as methods of using the conjugate in targeted prophylaxis or treatment of cancer, infection and immunological disorders. BACKGROUND OF THE INVENTION An antibody–drug conjugate (ADC) which consists of a monoclonal antibody (mAb) linked to a cytotoxic drug via a specialized linking molecule is becoming one of the major biotherapeutics for the treatment of cancers, infection, autoimmune disorder and the other drug resistant diseases (Lambert, J. M. and Berkenblit, A., Annu Rev Med. 2018, 69:191-207; Mariathasan, S. and Tan, M., Trends Mol Med. 2017, 23(2):135-149; Kern, J. C. et al. J. Am. Chem.Soc. 2016, 138, 1430–1445; Lee, H. et al, Bioconjug Chem. 2017, 28(4): 1084-1092). Because the antibody containing 100s-time larger in size structure have in general much longer half-life in blood circulation than that of the cytotoxic drug. Thus, the likelihood of systemic exposure and toxicity of the regular cytotoxic drug once linked to an antibody is greatly reduced. Moreover, ADC is able to pose more precisely a feature of delivering and releasing cytotoxic agents at the tumor site or within the target tumor cells. Therefore, the therapeutic window which is tumor to-normal tissue selectivity and specificity for the cytotoxic drug is much improved. Currently, there are five ADCs approved by the US FDA: gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, and moxetumomab pasudotox, and over 100 new promising agents are under development. Among the ADC complexes of a cytotoxic drug, a releasable linker, an antibody, and a technology to conjugate the components at the antibody site, it has been known that the linker significantly affects the potency, selectivity and the pharmacokinetics of the resulting ADC conjugate, as well as it can overcome multi-drug resistant ailment cells that overexpress effluxing transporter proteins (Zhao, R. Y. et al (2011) J. Med. Chem. 54, 3606; Acchionea, M. et al (2012) mAbs, 4, 362; Doronina, S. et al, (2006) Bioconjug Chem, 17, 114; Hamann, P. et al. (2005) Bioconjug Chem. 16, 346). Thus, the optimizing linker is of crucial importance for improving the spectrum of the therapeutic potential and safety profiles of ADCs. Because the linker for ADCs has to be degradable, the conjugated cytotoxic drugs could be potentially released in the blood circulation stream, and therefore increase systemic toxicity and decrease effectiveness. This type off-target toxicity, plus poor permeability / internalization, metabolic liabilities, and target specificity on tumor cells cause over 40 ADC drugs failed in the clinic trials during the past 4 decades. The off-target toxicity also hurdles the expansive application of the approved ADC drugs. For instance, in clinical practice Ado-trastuzumab emtansine (T-DM1, Kadcyla®) which is used stable (none-cleavable) MCC linker has shown great benefit to patients who have HER2-positive metastatic breast cancer (mBC) or who have already been treated for mBC or developed HER2 tumor recurrence within six months of adjuvant therapy (Peddi, P. and Hurvitz, S., Ther. Adv. Med. Oncol. 2014, 6(5), 202 –209; Piwko C, et al, Clin Drug Investig. 2015, 35(8), 487-93; Lambert, J. and Chari, R., J. Med. Chem. 2014, 57, 6949–64). But, T-DM1 had failed in clinic trial as first-line treatment for patients with HER2 positive unresectable locally advanced or metastatic breast cancer and as the second line treatment of HER2-positive advanced gastric cancer due to a little benefit to patients when comparison the side toxicity to the efficacy (Ellis, P. A., et al, J. Clin. Oncol. 2015, 33, (suppl; abstr 507 of 2015 ASCO Annual Meeting); Shen, K. et al, Sci Rep. 2016; 6: 23262; de Goeij, B. E. and Lambert, J. M. Curr Opin Immunol 2016, 40, 14-23; Barrios, C. H. et al, J Clin Oncol 2016, 34, (suppl; abstr 593 of 2016 ASCO Annual Meeting). To address issues of the off-target toxicity, research and development into ADC chemistry and design are now expanding the scopes of the linker-payload compartments and conjugate chemistry beyond the sole potent payloads, and especially to address activity of the linker- payload of ADCs toward targets / target diseases (Lambert, J. M. Ther Deliv 2016, 7, 279-82; Zhao, R. Y. et al, 2011, J. Med. Chem. 54, 3606-23). Nowadays many drug developers and academic institutions are highly focusing on establishing novel reliable specific conjugation linkers and methods for site-specific ADC conjugation, which seem to have longer circulation half-life, higher efficacy, potentially decreased off-target toxicity, and a narrow range of in vivo pharmacokinetic (PK) properties of ADCs as well as better batch-to-batch consistency in ADC production (Hamblett, K. J. et al, Clin. Cancer Res. 2004, 10, 7063-70; Adem, Y. T. et al, Bioconjugate Chem. 2014, 25, 656–664; Boylan, N. J. Bioconjugate Chem. 2013, 24, 1008–1016; Strop, P., et al 2013 Chem. Biol. 20, 161–67; Wakankar, A. mAbs, 2011, 3, 161–172). These specific conjugation methods reported so far include incorporation of engineered cysteines (Junutula, J. R. et al. Nat. Biotechnol. 2008, 26, 925–32; Junutula, J. R., et al 2010 Clin. Cancer Res. 16, 4769; US Patents 8,309,300; 7,855,275; 7,521,541; 7,723,485, WO2008 / 141044), selenocysteines (Hofer, T., et al. Biochemistry 2009, 48, 12047–57; Li, X., et al. Methods 2014, 65, 133–8; US Patent 8,916,159 for US National Cancer Institute), cysteine containing tag with perfluoroaromatic reagents (Zhang, C. et al. Nat. Chem. 2015, 8, 1–9), thiolfucose (Okeley, N. M., et al 2013 Bioconjugate Chem. 24, 1650), non-natural amino acids (Axup, J. Y., et al, Proc. Nat. Acad. Sci. USA. 2012, 109, 16101-6; Zimmerman, E.S., et al., 2014, Bioconjug. Chem. 25, 351–361; Wu, P., et al, 2009 Proc. Natl. Acad. Sci. 106, 3000-5; Rabuka, D., et al, Nat. Protoc. 2012, 7, 1052–67; US Patent 8,778,631 and US Pat Appl. 20100184135, WO2010 / 081110 for Sutro Biopharma; WO2006 / 069246, 2007 / 059312, US Patents 7,332,571, 7,696,312, and 7,638,299 for Ambrx; WO2007 / 130453, US patents 7,632,492 and 7,829,659 for Allozyne), conjugation to reduced intermolecular disulfides by re-bridging dibromomalemides (Jones, M. W. et al. J. Am. Chem. Soc. 2012, 134, 1847–52), bis-sulfone reagents (Badescu, G. et al. Bioconjug. Chem. 2014, 25, 1124–36; WO2013 / 190272, WO2014 / 064424 for PolyTherics Ltd). dibromopyridazinediones (Maruani, A. et al. Nat. Commun. 2015, 6, 6645), galactosyl- and sialyltransferases (Zhou, Q. et al. Bioconjug. Chem. 2014, 25, 510–520; US Pat Appl 20140294867 for Sanofi-Genzyme), formylglycine generating enzyme (FGE) (Drake, P. M. et al. Bioconj. Chem. 2014, 25, 1331–41; Carrico, I. S. et al US Pat. 7,985,783; 8,097,701; 8,349,910, and US Pat Appl 20140141025, 20100210543 for Redwood Bioscience), phosphopantetheinyl transferases (PPTases) (Grünewald, J. et al. Bioconjug. Chem. 2015, 26, 2554–62), sortase A (Beerli, R. R., et al. PLoS One 2015, 10, e0131177), genetically introduced glutamine tag with Streptoverticillium mobaraense transglutaminase (mTG) (Strop, P., Bioconj. Chem., 2014, 25, 855-62; Strop, P., et al., Chem. Biol. 2013, 20, 161-7; US Patent 8,871,908 for Rinat-Pfizer) or with microbial transglutaminase (MTGase) (Dennler, P., et al, 2014, Bioconjug. Chem. 25, 569– 78; Siegmund, V. et al. Angew. Chemie - Int. Ed. 2015, 54, 13420-4; US pat appl 20130189287 for Innate Pharma; US Pat 7,893,019 for Bio-Ker S.r.l. (IT)), an enzyme / bacterium forming an isopeptide bond-peptide bonds that form outside of the protein main chain (Kang, H. J., et al. Science 2007, 318, 1625–8; Zakeri, B. et al. Proc. Natl. Acad. Sci. USA 2012, 109, E690–7; Zakeri, B. & Howarth, M. J. Am. Chem. Soc. 2010, 132, 4526–7). We have disclosed several conjugation methods of rebridging a pair of thiols of the reduced inter chain disulfide bonds of a native antibody, such as using bromo maleimide and dibromomaleimide linkers (WO2014 / 009774), 2,3-disubstituted succinic / 2-monosubstituted / 2,3-disubstituted fumaric or maleic linkers (WO2015 / 155753, WO20160596228), acetylenedicarboxylic linkers (WO2015 / 151080, WO20160596228) or hydrazine linkers (WO2015 / 151081). The ADCs made with these linkers and methods have demonstrated better therapeutic index windows than the traditionally unselective conjugation via the cysteine or lysine residues on an antibody. Here we disclose the invention of conjugates of a cytotoxic drug containing a long side chain linker. The long side chain linker can prevent an antibody-drug conjugate from hydrolysis by a hydrolase, e.g. a proteinase or an esterase, and make the conjugate more stable during the targeted delivery and minimize exposure to non-target cells, tissues or organs in the circulation, resulting in longer half-life in the blood stream, less the off- target toxicity d and wider therapeutic windows of the conjugate. SUMMARY OF THE INVENTION The present invention provides branched-linkage of a cytotoxic agent to an antibody. It also provides a method of conjugation of a cytotoxic agent analog to an antibody with the side chain-linker. In one aspect of the present invention, a conjugate containing a side chain-linkage is represented by Formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein "—" represents a single bond; n is 1 to 30; T is a cell-binding agent / molecule, selected from the group consisting of an antibody, a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment that binds to 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, an adnectin that mimics antibody, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule (a transferrin), and a binding peptide, protein, small molecule attached on albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or a (viral) capsid; L<com:Sub>1< / com:Sub> and L<com:Sub>2< / com:Sub> are a chain of atoms selected from C, N, O, S, Si, and P, preferably having 0~500 atoms, which covalently connects to W and <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>. The atoms used in forming the <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> and L<com:Sub>2< / com:Sub> may be combined in all chemically relevant ways, such as forming alkylene, alkenylene, and alkynylene, ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or combination above thereof. Preferably L<com:Sub>1< / com:Sub> and L<com:Sub>2< / com:Sub> are, the same or different, independently selected from O, NH, N, S, P, NNH, NHNH, <com:Math><semantics>N(R3)<annotation encoding="application / x-tex">N(R_3)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R3)N(R3)<annotation encoding="application / x-tex">N(R_3)N(R_3)< / annotation>< / semantics>< / com:Math>, CH, CO, C(O)NH, C(O)O, NHC(O)NH, NHC(O)O, polyethyleneoxy unit of formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>OR<com:Sub>3< / com:Sub>, or (OCH<com:Sub>2< / com:Sub>CH-(CH<com:Sub>3< / com:Sub>))<com:Sub>p< / com:Sub>OR<com:Sub>3< / com:Sub>, or <com:Math><semantics>NH(CH2CH2O)pR3<annotation encoding="application / x-tex">NH(CH_2CH_2O)_pR_3< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>NH(CH2CH(CH3)O)pR3<annotation encoding="application / x-tex">NH(CH_2CH(CH_3)O)_pR_3< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>N[(CH2CH2O)pR3]<annotation encoding="application / x-tex">N[(CH_2CH_2O)_pR_3]< / annotation>< / semantics>< / com:Math>-[(<com:Math><semantics>CH2CH2O)pR3<annotation encoding="application / x-tex">CH_2CH_2O)_pR_3< / annotation>< / semantics>< / com:Math>], or (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>COOR<com:Sub>3< / com:Sub>, or CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>(OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>COOR<com:Sub>3< / com:Sub>, wherein p and p' are independently an integer selected from 0 to about 1000, or combination thereof; C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> of alkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or <com:Math><semantics>(Aa)r<annotation encoding="application / x-tex">(Aa)_r< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>r=1−12<annotation encoding="application / x-tex">r = 1-12< / annotation>< / semantics>< / com:Math> (one to 12 amino acid units), which is composed from natural or unnatural amino acids, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; W is a stretcher unit, normally a self-immolative spacer, a peptidyl unit, a hydrazone, a disulfide, a thioether, an ester, or an amide bond; w is 1 or 2 or 3; V<com:Sub>1< / com:Sub> and V<com:Sub>2< / com:Sub> are independently a spacer unit and selected from O, NH, S, C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl, C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> heteroalkyl, alkenyl, or alkynyl, C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl, or <com:Math><semantics>(Aa)r<annotation encoding="application / x-tex">(Aa)_r< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>r=1−12<annotation encoding="application / x-tex">r = 1-12< / annotation>< / semantics>< / com:Math> (one to 12 amino acid units), which is composed from a natural or unnatural amino acid, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; or <com:Math><semantics>(CH2CH2O)p<annotation encoding="application / x-tex">(CH_2CH_2O)_p< / annotation>< / semantics>< / com:Math>, p is 0-1000; and <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> are independently 0, 1 or 2, but <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> are 0 at the same time; when <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> is 0, it means that one of the side chain <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> fragment is absent. <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are independently represented by Formula (I-q1): [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(I−q1);<annotation encoding="application / x-tex">(I-q1);< / annotation>< / semantics>< / com:Math> wherein <com:Math><semantics>∼∼<annotation encoding="application / x-tex">\sim \sim< / annotation>< / semantics>< / com:Math> is the site linked to L<com:Sub>1< / com:Sub> or L<com:Sub>2< / com:Sub>; G<com:Sub>1< / com:Sub> and G<com:Sub>2< / com:Sub> are independently OC(O), NHC(O), C(O), CH<com:Sub>2< / com:Sub>, NH, OC(O)NH, NHC(O)NH, O, S, B, P(O)(OH), NHP(O)(OH), NHP(O)(OH)NH, <com:Math><semantics>CH2P(O)(OH)NH<annotation encoding="application / x-tex">CH_2P(O)(OH)NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OP(O)(OH)O<annotation encoding="application / x-tex">OP(O)(OH)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH2P(O)(OH)O<annotation encoding="application / x-tex">CH_2P(O)(OH)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2<annotation encoding="application / x-tex">NHS(O)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2NH<annotation encoding="application / x-tex">NHS(O)_2NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH2S(O)2NH<annotation encoding="application / x-tex">CH_2S(O)_2NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OS(O)2O<annotation encoding="application / x-tex">OS(O)_2O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH2S(O)2O<annotation encoding="application / x-tex">CH_2S(O)_2O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Ar<annotation encoding="application / x-tex">Ar< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ArCH2<annotation encoding="application / x-tex">ArCH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ArO<annotation encoding="application / x-tex">ArO< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ArNH<annotation encoding="application / x-tex">ArNH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ArS<annotation encoding="application / x-tex">ArS< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ArNR1<annotation encoding="application / x-tex">ArNR_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(Aa)r<annotation encoding="application / x-tex">(Aa)_r< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(r=1−12)<annotation encoding="application / x-tex">(r = 1-12)< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> are independently O, CH<com:Sub>2< / com:Sub>, S, NH, N(R<com:Sub>12< / com:Sub>), <com:Math><semantics>†<annotation encoding="application / x-tex">{}^{\dagger}< / annotation>< / semantics>< / com:Math>NH(R<com:Sub>12< / com:Sub>), <com:Math><semantics>†<annotation encoding="application / x-tex">{}^{\dagger}< / annotation>< / semantics>< / com:Math>N(R<com:Sub>12< / com:Sub>)(R<com:Sub>13< / com:Sub>), C(O), OC(O), OC(O)O, NHSO<com:Sub>2< / com:Sub>NH, NHP(O)(NH)<com:Sub>2< / com:Sub>, SO<com:Sub>2< / com:Sub>NH, P(O)(NH)<com:Sub>2< / com:Sub>, NHS(O)NH, NHP(O)(OH)(NH), OC(O)NH, NHC(O)NH; Y<com:Sub>2< / com:Sub> is O. NH, NR<com:Sub>1< / com:Sub>, CH<com:Sub>2< / com:Sub>. S. Ar; G<com:Sub>3< / com:Sub> is OH, SH, OR<com:Sub>1< / com:Sub>, SR<com:Sub>1< / com:Sub>, OC(O)R<com:Sub>1< / com:Sub>, NHC(O)R<com:Sub>12< / com:Sub>, <com:Math><semantics>C(O)R12<annotation encoding="application / x-tex">C(O)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH3<annotation encoding="application / x-tex">CH_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR12<annotation encoding="application / x-tex">NR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH(R12)<annotation encoding="application / x-tex">NH(R_{12})< / annotation>< / semantics>< / com:Math> <com:Math><semantics>BR12R13<annotation encoding="application / x-tex">BR_{12}R_{13}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>P(O)(OH)2<annotation encoding="application / x-tex">P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHP(O)(OH)2<annotation encoding="application / x-tex">NHP(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHP(O)(NH2)2<annotation encoding="application / x-tex">NHP(O)(NH_2)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(O)2(OH)<annotation encoding="application / x-tex">S(O)_2(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(CH2)q1C(O)OH<annotation encoding="application / x-tex">(CH_2)_{q_1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">C(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">OC(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CO(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">CO(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)O(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)O(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">OC(O)NH(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHCO(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">NHCO(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)(NH)(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)(NH)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CONH(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">CONH(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHS(O)_2(CH_2)_{q_1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CO(CH2)q1S(O)2(OH)<annotation encoding="application / x-tex">CO(CH_2)_{q_1}S(O)_2(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHS(O)_2NH(CH_2)_{q_1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OS(O)2NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">OS(O)_2NH(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHCO(CH2)q1S(O)2(OH)<annotation encoding="application / x-tex">NHCO(CH_2)_{q1}S(O)_2(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHP(O)(OH)(NH)(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHP(O)(OH)(NH)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, [Image disponible dans le document PDF, Image available in the PDF document] CH<com:Sub>2< / com:Sub>S(O)<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, OS(O)<com:Sub>2< / com:Sub>OH, OS(O)<com:Sub>2< / com:Sub>OR<com:Sub>1< / com:Sub>, CH<com:Sub>2< / com:Sub>S(O)<com:Sub>2< / com:Sub>OR<com:Sub>1< / com:Sub>, Ar, ArR<com:Sub>12< / com:Sub>, ArOH, ArNH<com:Sub>2< / com:Sub>, ArSH, ArNHR<com:Sub>12< / com:Sub>, or (Aa)<com:Sub>q1< / com:Sub>; <com:Math><semantics>p1<annotation encoding="application / x-tex">p_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>p2<annotation encoding="application / x-tex">p_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>p3<annotation encoding="application / x-tex">p_3< / annotation>< / semantics>< / com:Math> are independently 0 -100 but are not 0 at the same time; <com:Math><semantics>q1<annotation encoding="application / x-tex">q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>q2<annotation encoding="application / x-tex">q_2< / annotation>< / semantics>< / com:Math> are independently 0 -24; Preferably <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are independently, lineal or branched, a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C90<annotation encoding="application / x-tex">C_{90}< / annotation>< / semantics>< / com:Math> polycarboxylacid or a C<com:Sub>2< / com:Sub>-C<com:Sub>90< / com:Sub> polyalkylamine, a C<com:Sub>6< / com:Sub>-C<com:Sub>90< / com:Sub> oligosaachride or polysaccharide a C<com:Sub>6< / com:Sub>-C<com:Sub>90< / com:Sub> zwitterionic betaines or zwitterionic poly(sulfobetaine)) (PSB)s that consist of a quarternary ammonium cation and a sulfonate anion, biodegradable polymer (such as composed of poly (lactic / glycolic) acid (PLGA), poly(acrylates), chitosans, copolymer of N-(2- hydroxypropyl)methacrylamide, poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC), poly-L-glutamic acid, poly(lactide-co-glycolide) (PLG), poly(lactide-co-glycolide), Poly(ethylene glycol)(PEG), poly(propylene glycol)(PPG), poly(lactide-co-glycolide), poly(ethylene glycol)-modified peptides, poly(ethylene glycol)-modified lipids, poly(ethylene glycol)-modified alkylcarboxic acid, poly(ethylene glycol)-modified alkylamine, poly(lactide)- co-glycolide, polysarcosine, hyaluronic acid (HA) (glycosaminoglycan), heparin / heparan sulfate (HSGAGs), chondroitin sulfate / dermatan sulfate (CSGAGs), poly(ethylene glycol)-modified alkylsulfate, poly(ethylene glycol)-modified alkylphosphate, or poly(ethylene glycol)-modified alkyl quarternary ammonium; D is a cytotoxic agent that is independently selected from calicheamicins, camptothecins, maytansinoids, taxanes, daunorubicin / doxorubicin, vinca alkaloids, auristatins, eribulins, pyrrolobenzodiazepines (PBDs), duocarmycins, kinase inhibitors, MEK inhibitors, KSP inhibitors, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, immunotoxins, analogs or prodrugs thereof. In another aspect of the present invention, a conjugate containing a side chain-linkage is represented by Formula (II), and (III): [Image disponible dans le document PDF, Image available in the PDF document] (III), wherein D, W, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v3<annotation encoding="application / x-tex">v_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v4<annotation encoding="application / x-tex">v_4< / annotation>< / semantics>< / com:Math> are defined the same as in Formula (I); w and w'are independently 1, 2 or 3; and ---- is a single bond, double bond or absent; <com:Math><semantics>D1<annotation encoding="application / x-tex">D_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>D2<annotation encoding="application / x-tex">D_2< / annotation>< / semantics>< / com:Math> are the same or different, and they are defined the same as D. In another aspect of the present invention, the side chain-linkage compound is represented by Formula (IV), which can readily react to a cell-binding molecule T to form a conjugate of Formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (IV), wherein D, W, w, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math>, and n, are defined the same as in Formula (I); Lv1 is a function group described below. In another aspect of the present invention, the side chain-linkage compound is represented by Formula (V), and (VI) which can readily react to a pair of sites on a cell-binding molecule T to form a conjugate of Formula (II), and (III) respectively: [Image disponible dans le document PDF, Image available in the PDF document] (VI), wherein D, D<com:Sub>1< / com:Sub>, D<com:Sub>2< / com:Sub>, W, w, w', L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub>, Q<com:Sub>1< / com:Sub>, Q<com:Sub>2< / com:Sub>, V<com:Sub>1< / com:Sub>, V<com:Sub>2< / com:Sub>, v<com:Sub>1< / com:Sub>, v<com:Sub>2< / com:Sub>, ..... and n, are defined the same as above. Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> represent the same or different reacting group that can be reacted with a thiol, amine, carboxylic acid, selenol, phenol or hydroxyl group on a cell-binding molecule. Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> are independently selected from OH; F; Cl; Br; I; nitrophenol; N-hydroxysucci-nimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; mono- fluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1- hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate,anhydrides formed its self, or formed with the other anhydride, e.g. acetyl anhydride, formyl anhydride; or an intermediate molecule generated with a condensation reagent for peptide coupling reactions, or for Mitsunobu reactions. The examples of condensation reagents are: EDC (N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide), DCC (Dicyclohexyl-carbodiimide), N,N'- Diisopropylcarbodiimide (DIC), N-Cyclohexyl-N'-(2-morpholino-ethyl)carbodiimide metho-p- toluenesulfonate (CMC, or CME-CDI), 1,1'-Carbonyldiimi-dazole (CDI), TBTU (O- (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), N,N,N',N'-Tetramethyl-O- (1H-benzotriazol-1-yl)-uronium hexafluoro-phosphate (HBTU), (Benzotriazol-1- yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), (Benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), Diethyl cyanophosphonate (DEPC), Chloro-N,N,N',N'-tetramethylformamidiniumhexafluorophosphate, 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophos- phate (HATU), 1-[(Dimethylami-no)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine- 1-ium 3-oxide hexafluoro-phosphate (HDMA), 2-Chloro-1,3-dimethyl-imidazolidinium hexafluorophosphate (CIP), Chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), Fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH), N,N,N',N'-Tetramethyl-S-(1-oxido-2-pyridyl)thiuronium hexafluorophosphate, O-(2-Oxo- 1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), S-(1-Oxido-2-pyridyl)- N,N,N',N'-tetramethylthiuronium tetrafluoroborate, O-[(Ethoxycarbonyl)-cyanomethylenamino]- N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), (1-Cyano-2-ethoxy-2- oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), O-(Benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), N- Benzyl-N'-cyclohexyl-carbodiimide (with, or without polymer-bound), Dipyrrolidino(N- succinimidyl-oxy)carbenium hexafluoro-phosphate (HSPyU), Chlorodipyrrolidinocarbenium hexafluorophosphate (PyClU), 2-Chloro-1,3-dimethylimidazolidinium tetrafluoroborate(CIB), (Benzotriazol-1-yloxy)dipiperidino-carbenium hexafluorophosphate (HBPipU), O-(6- Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), Bromotris(dimethylamino)-phosphonium hexafluorophosphate (BroP), Propylphosphonic anhydride (PPACA, T3P®), 2-Morpholinoethyl isocyanide (MEI), N,N,N',N'-Tetramethyl-O-(N- succinimidyl)uronium hexafluorophosphate (HSTU), 2-Bromo-1-ethyl-pyridinium tetrafluoroborate (BEP), O-[(Ethoxycarbonyl)cyano-methylenamino]-N,N,N',N'-tetra- methyluronium tetrafluoroborate (TOTU), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholiniumchloride (MMTM, DMTMM), N,N,N',N'-Tetramethyl-O-(N- succinimidyl)uronium tetrafluoroborate (TSTU), O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)- N,N,N',N'-tetramethyluronium tetrafluoro-borate (TDBTU),1,1'-(Azodicarbonyl)-dipiperidine (ADD), Di-(4-chlorobenzyl)azodicarboxylate (DCAD), Di-tert-butyl azodicarboxylate (DBAD), Diisopropyl azodicarboxylate (DIAD), Diethyl azodicarboxylate (DEAD). In addition, Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> can be an anhydride, formed by acid themselves or formed with other <com:Math><semantics>C1∼C8<annotation encoding="application / x-tex">C_1 \sim C_8< / annotation>< / semantics>< / com:Math> acid anhydrides; The present invention further relates to a method of making a cell-binding molecule-drug conjugate of Formula (I) and Formula (II) as well the application of the conjugates of Formula (I) and Formula (II). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the synthesis of a component of a tubulysin analog containing a linker. Figure 2 shows the synthesis of a component of a linear linker. Figure 3 shows the synthesis of a tubulysin analog having side-chain linkers. Figure 4 shows the synthesis of a tubulysin analog having side-chain linkers. Figure 5 shows the synthesis of a fragment of tubulysin analog containing a side-chain linker. Figure 6 shows the synthesis of conjugates of tubulysin analogs containing side-chain linkers. Figure 7 shows the syntheses of exatecan and fragments of a side-chain linker. Figure 8 shows the synthesis of conjugates of exatecan containing side-chain linkers. Figure 9 shows the synthesis of components of a linear linker. Figure 10 shows the general synthesis of drug-linker components containing side-chain linkers. Figure 11 shows the synthesis of a conjugate of drug containing a side-chain linker and a maytansinoid-linker component having a side-chain linker. Figure 12 shows the synthesis of conjugates of a maytansinoid and an exatecan containing side-chain linkers. Figure 13 shows the synthesis of a conjugate of MMAE analog containing a side-chain linker. Figure 14 shows the synthesis of a conjugate of MMAF analog containing a side-chain linker... Figure 15 shows the synthesis of conjugatable eribulin containing side-chain linkers. Figure 16 shows the syntheses of a conjugate of eribulin containing side-chain linkers and a conjugatable CBI-dimer containing side-chain linkers. Figure 17 shows the synthesis of a conjugate of a CBI-dimer containing side-chain linkers and a conjugate of a topotecan analog containing side-chain linkers. Figure 18 shows the synthesis of a conjugate of a tubulysin analog containing side-chain linkers and a conjugate of a MMAE analog containing side-chain linkers. Figure 19 shows the synthesis of a conjugate of a tubulysin analog containing side-chain linkers. Figure 20 shows the comparison of the anti-tumor effect of conjugate compounds 49 (C- 30), 51 (C-48), C-173, C-238, C-312, 132 (C-131), 135 (C-134), C-321, and C-322, with T-DM1 using human gastric tumor N87 cell model, i.v., one injection at dosing of 6 mg / kg. Figure 21 shows an acute toxicity study on ADC conjugates 49 (C-30), 51 (C-48), C-173, C-238, C-312, 132 (C-131), 135 (C-134), C-321, and C-322, and T-DM1 through observing changes in body weight (BW) of mice in 12 days. DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS "Alkyl" refers to an aliphatic hydrocarbon group or univalent groups derived from alkane by removal of one or two hydrogen atoms from carbon atoms. It may be straight or branched having <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> (1 to 8 carbon atoms) in the chain. "Branched" means that one or more lower C numbers of alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, octyl, nonyl, decyl, cyclopentyl, cyclohexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3-methyl-hexyl, 2,2- dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2- methylheptyl, 3-methylheptyl, n-heptyl, isoheptyl, n-octyl, and isooctyl. A C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl group can be unsubstituted or substituted with one or more groups including, but not limited to, -C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl,-O-(<com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> alkyl), -aryl, -C(O)R', -OC(O)R', -C(O)OR', -C(O)NH<com:Sub>2< / com:Sub>, -C(O)NHR', - <com:Math><semantics>C(O)N(R′)2<annotation encoding="application / x-tex">C(O)N(R')_2< / annotation>< / semantics>< / com:Math>, -NHC(O)R', -SR', -S(O)<com:Sub>2< / com:Sub>R', -S(O)R', -OH, -halogen, -N<com:Sub>3< / com:Sub>, -NH<com:Sub>2< / com:Sub>, -NH(R'), -N(R')<com:Sub>2< / com:Sub> and -CN; where each R' is independently selected from -C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> alkyl and aryl. "Halogen" refers to fluorine, chlorine, bromine or iodine atom; preferably fluorine and chlorine atom. "Heteroalkyl" refers to <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> alkyl in which one to four carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N. "Carbocycle" refers to a saturated or unsaturated ring having 3 to 8 carbon atoms as a monocycle or 7 to 13 carbon atoms as a bicycle. Monocyclic carbocycles have 3 to 6 ring atoms, more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, arranged as a bicycle [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicycle [5,6] or [6,6] system. Representative <com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> carbocycles include, but are not limited to, -cyclopropyl, - cyclobutyl, -cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, - 1,4-cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl. A "C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> carbocycle" refers to a 3-, 4-, 5-, 6-, 7- or 8-membered saturated or unsaturated nonaromatic carbocyclic ring. A C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> carbocycle group can be unsubstituted or substituted with one or more groups including, but not limited to, <com:Math><semantics>−C1−C8<annotation encoding="application / x-tex">-C_1-C_8< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>−O−(C1−C8<annotation encoding="application / x-tex">-O-(C_1-C_8< / annotation>< / semantics>< / com:Math> alkyl), -aryl, <com:Math><semantics>−C(O)R′<annotation encoding="application / x-tex">-C(O)R'< / annotation>< / semantics>< / com:Math>, - <com:Math><semantics>OC(O)R′,−C(O)OR′,−C(O)NH2,−C(O)NHR′,−C(O)N(R′)2,−NHC(O)R′,−SR′,−S(O)R′,−S(O)2R′,−<annotation encoding="application / x-tex">OC(O)R', -C(O)OR', -C(O)NH_2, -C(O)NHR', -C(O)N(R')_2, -NHC(O)R', -SR', -S(O)R', -S(O)_2R', -< / annotation>< / semantics>< / com:Math> OH, -halogen, -N<com:Sub>3< / com:Sub>, -NH<com:Sub>2< / com:Sub>, -NH(R'), -N(R') <com:Sub>2< / com:Sub> and -CN; where each R' is independently selected from <com:Math><semantics>−C1−C8<annotation encoding="application / x-tex">-C_1-C_8< / annotation>< / semantics>< / com:Math> alkyl and aryl. "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond which may be straight or branched having 2 to 8 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, hexylenyl, heptenyl, octenyl. "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond which may be straight or branched having 2 to 8 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, 5- pentynyl, n-pentynyl, hexylynyl, heptynyl, and octynyl. "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH<com:Sub>2< / com:Sub>-), 1,2-ethyl (-CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-), 1,3-propyl (-CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-), 1,4-butyl (-CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-), and the like. "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to: 1,2-ethylene (-CH=CH-). "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to: acetylene, propargyl and 4-pentynyl. "Aryl" or Ar refers to an aromatic or hetero aromatic group, composed of one or several rings, comprising three to fourteen carbon atoms, preferentially six to ten carbon atoms. The term of "hetero aromatic group" refers one or several carbon on aromatic group, preferentially one, two, three or four carbon atoms are replaced by O, N, Si, Se, P or S, preferentially by O, S, and N. The term aryl or Ar also refers to an aromatic group, wherein one or several H atoms are replaced independently by -R', -halogen, -OR', or -SR', -NR'R", -N=NR', -N=R', -NR'R", NO<com:Sub>2< / com:Sub>, -S(O)R', -S(O)<com:Sub>2< / com:Sub>R', -S(O)<com:Sub>2< / com:Sub>OR', -OS(O)<com:Sub>2< / com:Sub>OR', -PR'R" -P(O)R'R"", -P(OR'')(OR"), - P(O)(OR')(OR") or -OP(O)(OR')(OR") wherein R', R" are independently H, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, arylalkyl, carbonyl, or pharmaceutical salts. "Heterocycle" refers to a ring system in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group of O, N, S, Se, B, Si and P. Preferable heteroatoms are O, N and S. Heterocycles are also described in The Handbook of Chemistry and Physics, 78th Edition, CRC Press, Inc., 1997-1998, p. 225 to 226. Preferred nonaromatic heterocyclic include epoxy, aziridinyl, thiiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxiranyl, tetrahydrofaranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyranyl, imidazolinyl, pyrrolinyl, pyrazolinyl, thiazolidinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimidinyl, dihydrothiopyranyl, azepanyl, as well as the fused systems resulting from the condensation with a phenyl group. The term "heteroaryl" or aromatic heterocycles refers to a 3 to 14, preferably 5 to 10 membered aromatic hetero, mono-, bi-, or multi-cyclic ring. Examples include pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, as well as the fused systems resulting from the condensation with a phenyl group. "Alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocyclic" and the like refer also to the corresponding "alkylene", "cycloalkylene", "alkenylene", "alkynylene", "arylene", "heteroarylene", "heterocyclene" and the likes which are formed by the removal of two hydrogen atoms. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp<com:Sup>3< / com:Sup> carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2- naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. "Heteroarylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp<com:Sup>3< / com:Sup> carbon atom, is replaced with a heteroaryl radical. Examples of heteroarylalkyl groups are 2-benzimidazolylmethyl, 2-furylethyl. Examples of a "hydroxyl protecting group" includes, methoxymethyl ether, 2- methoxyethoxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, t-butyldimethylsilyl ether, triphenylmethylsilyl ether, acetate ester, substituted acetate esters, pivaloate, benzoate, methanesulfonate and p-toluenesulfonate. "Leaving group" refers to a functional group that can be substituted by another functional group. Such leaving groups are well known in the art, and examples include, a halide (e.g., chloride, bromide, and iodide), methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), trifluoromethylsulfonyl (triflate), and trifluoromethylsulfonate. A preferred leaving group is selected from nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, anhydrides formed its self, or formed with the other anhydride, e.g. acetyl anhydride, formyl anhydride; or an intermediate molecule generated with a condensation reagent for peptide coupling reactions or for Mitsunobu reactions. The following abbreviations may be used herein and have the indicated definitions: Boc, tert-butoxy carbonyl; BroP, bromotrispyrrolidinophosphonium hexafluorophosphate; CDI, 1,1'- carbonyldiimidazole; DCC, dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; DEAD is diethylazodicarboxylate, DIAD, diisopropylazodicarboxylate; DIBAL-H, diisobutyl-aluminium hydride; DIPEA or DEA, diisopropylethylamine; DEPC, diethyl phosphorocyanidate; DMA, N,N-dimethyl acetamide; DMAP, 4-(N, N- dimethylamino)pyridine; DMF, N,N-dimethylformamide; DMSO, dimethylsulfoxide; DTPA is diethylenetriaminepentaacetic acid; DTT, dithiothreitol; EDC, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; ESI-MS, electrospray mass spectrometry; EtOAc is ethyl acetate; Fmoc is N-(9-fluorenylmethoxycarbonyl); HATU, O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, high pressure liquid chromatography; NHS, N-Hydroxysuccinimide; MeCN is acetonitrile; MeOH is methanol; MMP, 4-methylmorpholine; PAB, p-aminobenzyl; PBS, phosphate-buffered saline (pH 7.0~7.5); Ph is phenyl; phe is L-phenylalanine; PyBrop is bromo-tris-pyrrolidino- phosphonium hexafluorophosphate; PEG, polyethylene glycol; SEC, size-exclusion chromatography; TCEP, tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid; THF, tetrahydrofuran; Val, valine; TLC is thin layer chromatography; UV is ultraviolet. The "amino acid(s)" can be natural and / or unnatural amino acids, preferably alpha-amino acids. Natural amino acids are those encoded by the genetic code, which are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tyrosine. tryptophan and valine. The unnatural amino acids are derived forms of proteinogenic amino acids. Examples include hydroxyproline, lanthionine, 2-aminoisobutyric acid, dehydroalanine, gamma- aminobutyric acid (the neurotransmitter), ornithine, citrulline, beta alanine (3-aminopropanoic acid), gamma-carboxyglutamate, selenocysteine (present in many noneukaryotes as well as most eukaryotes, but not coded directly by DNA), pyrrolysine (found only in some archaea and one bacterium), N-formylmethionine (which is often the initial amino acid of proteins in bacteria, mitochondria, and chloroplasts), 5-hydroxytryptophan, L-dihydroxyphenylalanine, triiodothyronine, L-3,4-dihydroxyphenylalanine (DOPA), and O-phosphoserine. The term amino acid also includes amino acid analogs and mimetics. Analogs are compounds having the same general H<com:Sub>2< / com:Sub>N(R)CHCO<com:Sub>2< / com:Sub>H structure of a natural amino acid, except that the R group is not one found among the natural amino acids. Examples of analogs include homoserine, norleucine, methionine-sulfoxide, and methionine methyl sulfonium. Preferably, an amino acid mimetic is a compound that has a structure different from the general chemical structure of an alpha-amino acid but functions in a manner similar to one. The term "unnatural amino acid" is intended to represent the "D" stereochemical form, the natural amino acids being of the "L" form. When 1~8 amino acids are used in this patent application, amino acid sequence is then preferably a cleavage recognition sequence for a protease. Many cleavage recognition sequences are known in the art. See, e.g., Matayoshi et al. Science 247: 954 (1990); Dunn et al. Meth. Enzymol. 241: 254 (1994); Seidah et al. Meth. Enzymol. 244: 175 (1994); Thomberry, Meth. Enzymol. 244: 615 (1994); Weber et al. Meth. Enzymol. 244: 595 (1994); Smith ct al. Moth. Enzymol. 244: 412 (1994); and Bouvier et al. Meth. Enzymol. 248: 614 (1995). In particular, the sequence is selected from the group consisting of Val-Cit, Ala-Val, Ala-Ala, Val-Val, Val-Ala-Val, Lys-Lys, Ala-Asn-Val, Val-Leu-Lys, Cit-Cit, Val-Lys, Ala-Ala-Asn, Asp-Lys, Asp-Glu, Glu-Lys, Lys, Cit, Ser, and Glu. The "glycoside" is a molecule in which a sugar group is bonded through its anomeric carbon to another group via a glycosidic bond. Glycosides can be linked by an O- (an O-glycoside), N- (a glycosylamine), S-(a thioglycoside), or C- (a C-glycoside) glycosidic bond. Its core the empirical formula is <com:Math><semantics>Cm(H2O)n<annotation encoding="application / x-tex">C_m(H_2O)_n< / annotation>< / semantics>< / com:Math> (where m could be different from n, and m and n are < 36), Glycoside herein includes glucose (dextrose), fructose (levulose) allose, altrose, mannose, gulose, iodose, galactose, talose, galactosamine, glucosamine, sialic acid, N-acetylglucosamine, sulfoquinovose (6-deoxy-6-sulfo-D-glucopyranose), ribose, arabinose, xylose, lyxose, sorbitol, mannitol, sucrose, lactose, maltose, trehalose, maltodextrins, raffinose, Glucuronic acid (glucuronide), and stachyose. It can be in D form or L form, 5 atoms cyclic furanose forms, 6 atoms cyclic pyranose forms, or acyclic form, a-isomer (the -OH of the anomeric carbon below the plane of the carbon atoms of Haworth projection), or <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-isomer (the -OH of the anomeric carbon above the plane of Haworth projection). It is used herein as a monosaccharide, disaccharide, polyols, or oligosaccharides containing 3-6 sugar units. The term "antibody," as used herein, refers to a full-length immunoglobulin molecule or an immunologically active portion of a full-length immunoglobulin molecule, i.e., a molecule that contains an antigen binding site that immunospecifically binds an antigen of a target of interest or part thereof, such targets including but not limited to, cancer cell or cells that produce auto- immune antibodies associated with an autoimmune disease. The immunoglobulin disclosed herein can be of any type (e.g. IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. The immunoglobulins can be derived from any species. Preferably, however, the immunoglobulin is of human, murine, or rabbit origin. Antibodies useful in the invention are preferably monoclonal, and include, but are not limited to, polyclonal, monoclonal; bispecific, human, humanized or chimeric antibodies, single chain antibodies, Fv, Fab fragments, F(ab') fragments, F(ab')<com:Sub>2< / com:Sub> fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR's, and epitope- binding fragments of any of the above which immunospecifically bind to cancer cell antigens, viral antigens or microbial antigens. An "enantiomer", also known as an "optical isomer", is one of two stereoisomers that are mirror images of each other that are non-superposable (not identical), much as one's left and right hands are the same except for being reversed along one axis (the hands cannot be made to appear identical simply by reorientation). A single chiral atom or similar structural feature in a compound causes that compound to have two possible structures which are non-superposable, each a mirror image of the other. The presence of multiple chiral features in a given compound increases the number of geometric forms possible, though there may be some perfect-mirror- image pairs. Enantiopure compounds refer to samples having, within the limits of detection, molecules of only one chirality. When present in a symmetric environment, enantiomers have identical chemical and physical properties except for their ability to rotate plane-polarized light (+ / -) by equal amounts but in opposite directions (although the polarized light can be considered an asymmetric medium). They are sometimes called optical isomers for this reason. A mixture of equal parts of an optically active isomer and its enantiomer is termed racemic and has zero net rotation of plane-polarized light because the positive rotation of each (+) form is exactly counteracted by the negative rotation of a (-) one. Enantiomer members often have different chemical reactions with other enantiomer substances. Since many biological molecules are enantiomers, there is sometimes a marked difference in the effects of two enantiomers on biological organisms. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even productive of adverse effects. Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to enhance the pharmacological efficacy and sometimes eliminate some side effects. Isotopes are variants of a particular chemical element which differs in neutron number. All isotopes of a given element have the same number of protons in each atom. Each atomic number identifies a specific element, but not the isotope; an atom of a given element may have a wide range in its number of neutrons. The number of nucleons (both protons and neutrons) in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. For example, carbon-12, carbon-13 and carbon-14 are three isotopes of the element carbon with mass numbers 12, 13 and 14 respectively. The atomic number of carbon is 6, which means that every carbon atom has 6 protons, so that the neutron numbers of these isotopes are 6, 7 and 8 respectively. Hydrogen atom has three isotopes of protium (<com:Sup>1< / com:Sup>H), deuterium (<com:Sup>2< / com:Sup>H), and tritium (<com:Sup>3< / com:Sup>H), which deuterium has twice the mass of protium and tritium has three times the mass of protium. Isotopic substitution can be used to determine the mechanism of a chemical reaction and via the kinetic isotope effect. Isotopic substitution can be used to study how the body affects a specific xenobiotic / chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug. This study is called pharmacokinetics (PK). Isotopic substitution can be used to study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for example, infection). This study is called pharmacodynamics (PD). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for example, infection). Both together influence dosing, benefit, and adverse effects of the drug, isotopes can contain a stable (non-radioactive) or an unstable element. Isotopic substitution of a drug may have a different thrapeutical efficacy of the original drug. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. "Pharmaceutically acceptable solvate" or "solvate" refer to an association of one or more solvent molecules and a disclosed compound. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. "Pharmaceutically acceptable excipient" includes any carriers, diluents, adjuvants, or vehicles, such as preserving or antioxidant agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions as suitable therapeutic combinations. As used herein, "pharmaceutical salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, tartaric, citric, methanesulfonic, benzenesulfonic, glucuronic, glutamic, benzoic, salicylic, toluenesulfonic, oxalic, fumaric, maleic, lactic and the like. Further addition salts include ammonium salts such as tromethamine, meulumine, epolamine, etc., metal salts such as sodium, potassium, calcium, zinc or magnesium. The pharmaceutical salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared via reaction the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17<com:Sup>th< / com:Sup> cd., Mack Publishing Company, Easton, PA, 1985, p. 1418. "Administering" or "administration" refers to any mode of transferring, delivering, introducing or transporting a pharmaceutical drug or other agent to a subject. Such modes include oral administration, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous or intrathecal administration. Also contemplated by the present invention is utilization of a device or instrument in administering an agent. Such device may utilize active or passive transport and may be slow-release or fast-release delivery device. In the context of cancer, the term "treating" includes any or all of: preventing growth of tumor cells or cancer cells, preventing replication of tumor cells or cancer cells, lessening of overall tumor burden and ameliorating one or more symptoms associated with the disease. In the context of an autoimmune disease, the term "treating" includes any or all of: preventing replication of cells associated with an autoimmune disease state including, but not limited to, cells capable of producing an autoimmune antibody, lessening the autoimmune-antibody burden and ameliorating one or more symptoms of an autoimmune disease. In the context of an infectious disease, the term "treating" includes any or all of: preventing the growth, multiplication or replication of the pathogen that causes the infectious disease and ameliorating one or more symptoms of an infectious disease. Examples of a "mammal" or "animal" include, but are not limited to, a human, rat, mouse, guinea pig, monkey, pig, goat, cow, horse, dog, cat, bird and fowl. The novel conjugates disclosed herein use the bridge linkers. Examples of some suitable linkers and their synthesis are shown in Figures 1 to 26. A CONJUGATE OF A CELL-BINDING AGENT-A CYTOTOXIC MOLECULE VIA THE SIDE CHAIN-LINKAGE In one aspect of the present invention, a conjugate containing a side chain-linkage is represented by Formula (I), (II), and (III): [Image disponible dans le document PDF, Image available in the PDF document] wherein "——" represents a single bond; —— is a single bond, double bond or absent; n is 1 to 30; w and w'are independently 1, 2 or 3; and. T is a cell-binding agent / molecule, selected from the group consisting of an antibody, a single chain antibody, an antibody fragment that binds to a target cell, a monoclonal antibody, a single chain monoclonal antibody, a monoclonal antibody fragment that binds to 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, an adnectin that mimics antibody, DARPins, a lymphokine, a hormone, a vitamin, a growth factor, a colony stimulating factor, a nutrient-transport molecule (a transferrin), and / or a cell-binding peptide, protein, or small molecule attached on albumin, a polymer, a dendrimer, a liposome, a nanoparticle, a vesicle, or on a (viral) capsid; L<com:Sub>1< / com:Sub> and L<com:Sub>2< / com:Sub> are a chain of atoms selected from C, N, O, S, Si, and P, preferably having 0~500 atoms, which covalently connects to W and <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>. The atoms used in forming the <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> and L<com:Sub>2< / com:Sub> may be combined in all chemically relevant ways, such as forming alkylene, alkenylene, and alkynylene, ethers, polyoxyalkylene, esters, amines, imines, polyamines, hydrazines, hydrazones, amides, ureas, semicarbazides, carbazides, alkoxyamines, alkoxylamines, urethanes, amino acids, peptides, acyloxylamines, hydroxamic acids, or combination above thereof. Preferably L<com:Sub>1< / com:Sub> and L<com:Sub>2< / com:Sub> are, the same or different, independently selected from O, NH, N, S, P, NNH, NHNH, N(R<com:Sub>3< / com:Sub>), N(R<com:Sub>3< / com:Sub>)N(R<com:Sub>3< / com:Sub>,), CH, CO, C(O)NH, C(O)O, NHC(O)NH, NHC(O)O, polyethyleneoxy unit of formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>OR<com:Sub>3< / com:Sub>, or (OCH<com:Sub>2< / com:Sub>CH-(CH<com:Sub>3< / com:Sub>))<com:Sub>p< / com:Sub>OR<com:Sub>3< / com:Sub>, or <com:Math><semantics>NH(CH2CH2O)pR3<annotation encoding="application / x-tex">NH(CH_2CH_2O)_pR_3< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>NH(CH2CH(CH3)O)pR3<annotation encoding="application / x-tex">NH(CH_2CH(CH_3)O)_pR_3< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>N[(CH2CH2O)pR3]−[(CH2CH2O)pR3]<annotation encoding="application / x-tex">N[(CH_2CH_2O)_pR_3]-[(CH_2CH_2O)_pR_3]< / annotation>< / semantics>< / com:Math>, or (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>COOR<com:Sub>3< / com:Sub>, or CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>(OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>COOR<com:Sub>3< / com:Sub>, wherein p and p' are independently an integer selected from 0 to about 1000, or combination thereof; C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> of alkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or <com:Math><semantics>(Aa)r<annotation encoding="application / x-tex">(Aa)_r< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>r=1−12<annotation encoding="application / x-tex">r = 1-12< / annotation>< / semantics>< / com:Math> (one to 12 amino acid units), which is composed from natural or unnatural amino acids, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; W is a stretcher unit having <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math>, normally a self-immolative spacer, a peptidyl unit, a hydrazone, a disulfide, a thioether, an ester, or an amide bond; <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> are independently a spacer unit and selected from O, NH, S, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> heteroalkyl, alkenyl, or alkynyl, C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl, or <com:Math><semantics>(Aa)r<annotation encoding="application / x-tex">(Aa)_r< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>r=1−12<annotation encoding="application / x-tex">r = 1-12< / annotation>< / semantics>< / com:Math> (one to 12 amino acid units), which is composed from a natural or unnatural amino acid, or the same or different sequences of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; or <com:Math><semantics>(CH2CH2O)p<annotation encoding="application / x-tex">(CH_2CH_2O)_p< / annotation>< / semantics>< / com:Math>, p is 0-1000; and <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> are independently 0, 1 or 2, but <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> are 0 at the same time; when <com:Math><semantics>v1<annotation encoding="application / x-tex">v_1< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>v2<annotation encoding="application / x-tex">v_2< / annotation>< / semantics>< / com:Math> is 0, it means one of the side chain Q1 or Q2 fragment is absent. <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are independently represented by Formula (I-q1): [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>∼∼<annotation encoding="application / x-tex">\sim \sim< / annotation>< / semantics>< / com:Math> is the site linked to L<com:Sub>1< / com:Sub> or L<com:Sub>2< / com:Sub>; G<com:Sub>1< / com:Sub> and G<com:Sub>2< / com:Sub> are independently OC(0), NHC(0), C(O), CH<com:Sub>2< / com:Sub>, NH, OC(O)NH, NHC(O)NH, O, S, B, P(O)(OH), NHP(O)(OH), NHP(O)(OH)NH, <com:Math><semantics>CH2P(O)(OH)NH<annotation encoding="application / x-tex">CH_2P(O)(OH)NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OP(O)(OH)O<annotation encoding="application / x-tex">OP(O)(OH)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH2P(O)(OH)O<annotation encoding="application / x-tex">CH_2P(O)(OH)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2<annotation encoding="application / x-tex">NHS(O)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2NH<annotation encoding="application / x-tex">NHS(O)_2NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH2S(O)2NH<annotation encoding="application / x-tex">CH_2S(O)_2NH< / annotation>< / semantics>< / com:Math>, OS(O)<com:Sub>2< / com:Sub>O, CH<com:Sub>2< / com:Sub>S(O)<com:Sub>2< / com:Sub>O, Ar, ArCH<com:Sub>2< / com:Sub>, ArO, ArNH, ArS, ArNR<com:Sub>1< / com:Sub>, or (Aa)<com:Sub>a1< / com:Sub>; G<com:Sub>3< / com:Sub> is OH, SH, OR<com:Sub>12< / com:Sub>, <com:Math><semantics>SR12<annotation encoding="application / x-tex">SR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)R12<annotation encoding="application / x-tex">OC(O)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)R12<annotation encoding="application / x-tex">NHC(O)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)R12<annotation encoding="application / x-tex">C(O)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH3<annotation encoding="application / x-tex">CH_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NH2<annotation encoding="application / x-tex">NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR12<annotation encoding="application / x-tex">NR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>+NH(R12)<annotation encoding="application / x-tex">^+NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>+N(R12)(R12)<annotation encoding="application / x-tex">^+N(R_{12})(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)OH<annotation encoding="application / x-tex">C(O)OH< / annotation>< / semantics>< / com:Math>, C(O)NH<com:Sub>2< / com:Sub>, NHC(O)NH<com:Sub>2< / com:Sub>, BH<com:Sub>2< / com:Sub>, BR<com:Sub>12< / com:Sub>R<com:Sub>12< / com:Sub>, P(O)(OH)<com:Sub>2< / com:Sub>, NHP(O)(OH)<com:Sub>2< / com:Sub>, NHP(O)(NH<com:Sub>2< / com:Sub>)<com:Sub>2< / com:Sub>, S(O)<com:Sub>2< / com:Sub>(OH), <com:Math><semantics>(CH2)q1C(O)OH<annotation encoding="application / x-tex">(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">C(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">OC(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CO(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">CO(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)O(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)O(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">OC(O)NH(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHCO(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">NHCO(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)(NH)(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHC(O)(NH)(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CONH(CH2)q1P(O)(OH)2<annotation encoding="application / x-tex">CONH(CH_2)_{q1}P(O)(OH)_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHS(O)_2(CH_2)_{q1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CO(CH2)q1S(O)2(OH)<annotation encoding="application / x-tex">CO(CH_2)_{q1}S(O)_2(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHS(O)2NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">NHS(O)_2NH(CH_2)_{q_1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OS(O)2NH(CH2)q1C(O)OH<annotation encoding="application / x-tex">OS(O)_2NH(CH_2)_{q_1}C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHCO(CH2)q1S(O)2(OH)<annotation encoding="application / x-tex">NHCO(CH_2)_{q_1}S(O)_2(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHP(O)(OH)(NH)(CH2)q1C(O)OH,CONH(CH2)q1S(O)(OH),OP(O)(OH)2,(CH2)q1P(O)(NH)2,<annotation encoding="application / x-tex">NHP(O)(OH)(NH)(CH_2)_{q_1}C(O)OH, CONH(CH_2)_{q_1}S(O)(OH), OP(O)(OH)_2, (CH_2)_{q_1}P(O)(NH)_2,< / annotation>< / semantics>< / com:Math> NHS(O)<com:Sub>2< / com:Sub>(OH), NHS(O)<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, CH<com:Sub>2< / com:Sub>S(O)<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, OS(O)<com:Sub>2< / com:Sub>OH, OS(O)<com:Sub>2< / com:Sub>OR<com:Sub>1< / com:Sub>, CH<com:Sub>2< / com:Sub>S(O)<com:Sub>2< / com:Sub>OR<com:Sub>12< / com:Sub>, Ar, ArR<com:Sub>12< / com:Sub>, ArOH, ArNH<com:Sub>2< / com:Sub>, ArSH, ArNHR<com:Sub>12< / com:Sub>, or (Aa)<com:Sub>q1< / com:Sub>; (Aa)<com:Sub>q1< / com:Sub> is a peptide containing the same or different sequence of natural or unnatural amino acids; <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> are independently O, <com:Math><semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics>< / com:Math>, S, <com:Math><semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>< / com:Math>, NHNH, NH, <com:Math><semantics>N(R12)<annotation encoding="application / x-tex">N(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>+NH(R12)<annotation encoding="application / x-tex">{}^{+}NH(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>+N(R12)(R12)<annotation encoding="application / x-tex">{}^{+}N(R_{12})(R_{12})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)<annotation encoding="application / x-tex">OC(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)<annotation encoding="application / x-tex">OC(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)<annotation encoding="application / x-tex">OC(O)< / annotation>< / semantics>< / com:Math>NH, NHC(O)NH; Y<com:Sub>2< / com:Sub> is O. NH, NR<com:Sub>12< / com:Sub>, CH<com:Sub>2< / com:Sub>. S, NHNH, Ar; p<com:Sub>1< / com:Sub>, p<com:Sub>2< / com:Sub> and p<com:Sub>3< / com:Sub> are independently 0 -100 but are not 0 at the same time; <com:Math><semantics>q1<annotation encoding="application / x-tex">q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>q2<annotation encoding="application / x-tex">q_2< / annotation>< / semantics>< / com:Math> are independently 0 -24; <com:Math><semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>< / com:Math>, are independently H, C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> alkyl; C<com:Sub>2< / com:Sub>~C<com:Sub>8< / com:Sub> heteroalkyl, or heterocyclic; C<com:Sub>3< / com:Sub>~C<com:Sub>8< / com:Sub> aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; Preferably <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are independently a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C100<annotation encoding="application / x-tex">C_{100}< / annotation>< / semantics>< / com:Math> polycarboxylacid, a <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C90<annotation encoding="application / x-tex">C_{90}< / annotation>< / semantics>< / com:Math> polyalkylamine, a C<com:Sub>6< / com:Sub>-C<com:Sub>90< / com:Sub> oligosaachride or polysaccharide a C<com:Sub>6< / com:Sub>-C<com:Sub>100< / com:Sub> zwitterionic betaines or zwitterionic poly(sulfobetaine)) (PSB)s that consist of a quarternary ammonium cation and / or a sulfonate anion, a C<com:Sub>6< / com:Sub>-C<com:Sub>100< / com:Sub> biodegradable polymer, such as composed of poly (lactic / glycolic acid) (PLGA), poly(acrylates), chitosans, copolymer of N-(2-hydroxypropyl)methacrylamide, poly[2- (methacryloyloxy)ethyl phosphorylcholine] (PMPC), poly-L-glutamic acid, poly(lactide-co- glycolide) (PLG), poly(lactide-co-glycolide), Poly(ethylene glycol)(PEG), poly(propylene glycol)(PPG), poly(lactide-co-glycolide), poly(ethylene glycol)-modified peptides, poly(ethylene glycol)-containing an amino acid or peptides, poly(ethylene glycol)-modified lipids, poly-glycine, poly-N-methyl-glycine, poly(ethylene glycol)-modified alkylcarboxic acid, poly(ethylene glycol)-modified alkylamine, poly(lactide-co-glycolide, hyaluronic acid (HA) (glycosaminoglycan), heparin / heparan sulfate (HSGAGs), chondroitin sulfate / dermatan sulfate (CSGAGs), poly(ethylene glycol)-modified alkylsulfate, poly(ethylene glycol)-modified alkylphosphate, or poly(ethylene glycol)-modified alkyl quarternary ammonium; Example structures of <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are shown below: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] A . wherein R<com:Sub>25< / com:Sub> and R<com:Sub>25< / com:Sub>, are independently selected from H; HC(O), CH<com:Sub>3< / com:Sub>C(O), CH<com:Sub>3< / com:Sub>C(NH), NHCH<com:Sub>3< / com:Sub>, COOH, CONH<com:Sub>2< / com:Sub>, CONHCH<com:Sub>3< / com:Sub>, C<com:Sub>1< / com:Sub>-C<com:Sub>18< / com:Sub> alkyl, C<com:Sub>1< / com:Sub>-C<com:Sub>18< / com:Sub> alkyl, alkyl-Y<com:Sub>1< / com:Sub>-SO<com:Sub>3< / com:Sub>H, C<com:Sub>1< / com:Sub>-C<com:Sub>18< / com:Sub> alkyl-Y<com:Sub>1< / com:Sub>-PO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math> alkyl-<com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CO2<annotation encoding="application / x-tex">CO_2< / annotation>< / semantics>< / com:Math>H, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math> alkyl-<com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>N†R12R13R13<annotation encoding="application / x-tex">N^{\dagger}R_{12}R_{13}R_{13}< / annotation>< / semantics>< / com:Math>'<com:Math><semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math> alkyl-<com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>CONH2<annotation encoding="application / x-tex">CONH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math> alkylene, C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> ester, C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> ether, C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> amine, C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> alkyl carboxylamide, C<com:Sub>3< / com:Sub>-C<com:Sub>18< / com:Sub> Aryl, C<com:Sub>3< / com:Sub>- C<com:Sub>18< / com:Sub> cyclic alkyl, C<com:Sub>3< / com:Sub>-C<com:Sub>18< / com:Sub> hyterocyclic, 1~24 amino acids; C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> lipid, a C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> fatty acid or a C<com:Sub>2< / com:Sub>- <com:Math><semantics>C18<annotation encoding="application / x-tex">C_{18}< / annotation>< / semantics>< / com:Math> fatty ammonium lipid; <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math> are independently selected from NH, <com:Math><semantics>N(R12)<annotation encoding="application / x-tex">N(R_{12})< / annotation>< / semantics>< / com:Math>, O, CH<com:Sub>2< / com:Sub>, S, <com:Math><semantics>C(O)<annotation encoding="application / x-tex">C(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(O)<annotation encoding="application / x-tex">S(O)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>S(O2)<annotation encoding="application / x-tex">S(O_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>P(O)(OH)<annotation encoding="application / x-tex">P(O)(OH)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHNH<annotation encoding="application / x-tex">NHNH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH=CH<annotation encoding="application / x-tex">CH=CH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Ar<annotation encoding="application / x-tex">Ar< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>(Aa)q1<annotation encoding="application / x-tex">(Aa)q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>q1=0<annotation encoding="application / x-tex">q_1=0< / annotation>< / semantics>< / com:Math> - 24 (0-24 amino acids, <com:Math><semantics>q1=0<annotation encoding="application / x-tex">q_1=0< / annotation>< / semantics>< / com:Math> means absent); <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Y2<annotation encoding="application / x-tex">Y_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y3<annotation encoding="application / x-tex">Y_3< / annotation>< / semantics>< / com:Math> are independently selected from NH, <com:Math><semantics>N(R12)<annotation encoding="application / x-tex">N(R_{12})< / annotation>< / semantics>< / com:Math>, O, C(O), CH<com:Sub>2< / com:Sub>, S, S(O), NHNH, C(O), OC(O), OC(O)O, OC(O)NH, NHC(O)NH, Ar or Ar or <com:Math><semantics>(Aa)q1,X1,X2,X3,X4,Y1,Y2<annotation encoding="application / x-tex">(Aa)q_1, X_1, X_2, X_3, X_4, Y_1, Y_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Y3<annotation encoding="application / x-tex">Y_3< / annotation>< / semantics>< / com:Math> can be independently absent; <com:Math><semantics>p1,p2<annotation encoding="application / x-tex">p_1, p_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>p3<annotation encoding="application / x-tex">p_3< / annotation>< / semantics>< / com:Math> are independently 0 -100 but are not 0 at the same time; <com:Math><semantics>q1<annotation encoding="application / x-tex">q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>q2<annotation encoding="application / x-tex">q_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>q3<annotation encoding="application / x-tex">q_3< / annotation>< / semantics>< / com:Math> are independently 0 -24; <com:Math><semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R14<annotation encoding="application / x-tex">R_{14}< / annotation>< / semantics>< / com:Math>' are independently selected from H and <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> alkyl; Aa is natural or unnatural amino acid; Ar or <com:Math><semantics>(Aa)q1<annotation encoding="application / x-tex">(Aa)q_1< / annotation>< / semantics>< / com:Math>, is the same or different sequence of peptides; <com:Math><semantics>q1=0<annotation encoding="application / x-tex">q_1=0< / annotation>< / semantics>< / com:Math> means <com:Math><semantics>(Aa)q1<annotation encoding="application / x-tex">(Aa)q_1< / annotation>< / semantics>< / com:Math> absent; D is a cytotoxic agent that is independently selected from calicheamicins, maytansinoids, camptothecins, taxanes, anthracyclines (daunorubicin / doxorubicin), vinca alkaloids, auristatins, eribulins, (pyrrolo)benzodiazepines (PBDs), CC-106 / duocarmycins, tubulysins, amatoxins (such as amanitins), protein kinase inhibitors, MEK inhibitors, KSP inhibitors, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, immunotoxins, analogs or prodrugs of these compounds above thereof; <com:Math><semantics>D1<annotation encoding="application / x-tex">D_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>D2<annotation encoding="application / x-tex">D_2< / annotation>< / semantics>< / com:Math> are the same or different, and they are defined the same as D; Calicheamicins and their related enediyne antibiotics that are described in: Nicolaou, K. C. et al, Science 1992, 256, 1172-1178; Proc. Natl. Acad. Sci USA. 1993, 90, 5881-8), U.S. Patent Nos. 4,970,198; 5,053,394; 5,108,912; 5,264,586; 5,384,412; 5,606,040; 5,712,374; 5,714,586; 5,739,116; 5,770,701; 5,770,710; 5,773,001; 5,877,296; 6,015,562; 6,124,310; 8,153,768. The structure of calicheamicins is preferred the following formula: [Image disponible dans le document PDF, Image available in the PDF document] (Ia), or a isotope of a chemical element, or a pharmaceutically acceptable salt, hydrates, or hydrated salt; or a polymorphic crystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof, wherein <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> is the site linked to W; Maytansinoids, including maytansinol and its analogues are described in U.S. Patent Nos. 4,256,746, 4,361,650, 4,307,016, 4,294,757, 4,294,757, 4,371,533, 4,424,219, 4,331,598, 4,450,254, 4,364,866, 4,313,946, 4,315,929 4,362,663, 4,322,348,4,371,533,4,424,219, 5,208,020, 5,416,064, 5,208,020; 5,416,064; 6,333.410; 6,441,163; 6,716,821, 7,276,497, 7,301,019,7,303,749, 7,368,565, 7,411,063, 7,851,432, and 8,163,888. The structure of maytansinoids is preferred the following formula: [Image disponible dans le document PDF, Image available in the PDF document] (Ib), wherein <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> is the site linked to W. A camptothecin (CPTs) and its derivatives, which are topoisomerase inhibitors to prevent DNA re-ligation and therefore to causes DNA damage resulting in apoptosis, are described in: Shang, X. F. et al, Med Res Rev. 2018, 38(3):775-828; Botella, P. and Rivero-Buceta, E. J. Control Release. 2017, 247: 28-54; Martino, E. et al, Bioorg Med Chem Lett. 2017, 27(4):701- 707; Lu, A., et al, Acta Pharmacol Sin 2007, 28(2): 307–314. It includes SN-38, Topotecan, Irinotecan (CPT-11), Silatecan (DB-67, AR-67), Cositecan (BNP-1350), Etirinotecan, Exatecan, Lurtotecan, Gimatecan (ST1481), Belotecan (CKD-602), Rubitecan and several others (Shang, X. F. et al, Med Res Rev. 2018, 38(3):775-828). So far three CPT analogues, topotecan, irinotecan, and belotecan have been approved and are used in cancer chemotherapy (Palakurthi, S., Expert Opin Drug Deliv. 2015;12(12):1911-21; Shang, X. F. et al, Med Res Rev. 2018, 38(3):775-828) and both SN-38 and Exatecan have been successfully used as payloads for ADC conjugates in the clinical trials (Ocean, A. J. et al, Cancer. 2017, 123(19): 3843-3854; Starodub, A. N., et al, Clin Cancer Res. 2015, 21(17): 3870-8; Cardillo, T. M., et al, Bioconjug Chem. 2015, 26(5): 919-31; Ogitani, Y. et al, Bioorg Med Chem Lett. 2016, 26(20): 5069-5072; Takegawa, N. et al, Int J Cancer. 2017 Oct 15;141(8):1682-1689. US patents 7,591,994; 7,999,083, 8,080,250, 8,268,317; US patent applications 20130090458, 20140099258, 20150297748, 20160279259). The structure of Camptothecin (CPT) is illustrated below formula: [Image disponible dans le document PDF, Image available in the PDF document] (Ic) or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math> are independently selected from H, F, Cl, Br, CN, NO<com:Sub>2< / com:Sub>, C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> alkyl; O-C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> alkyl; NH-C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> alkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or 2-8 carbon atoms of esters, ether, amide, carbonate, urea, or carbamate; R<com:Sub>3< / com:Sub> is H, OH, NH<com:Sub>2< / com:Sub>, C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> alkyl; <com:Math><semantics>O−C1∼C8<annotation encoding="application / x-tex">O-C_1\sim C_8< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>NH−C1∼C8<annotation encoding="application / x-tex">NH-C_1\sim C_8< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>C2−C8<annotation encoding="application / x-tex">C_2-C_8< / annotation>< / semantics>< / com:Math> of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; or 2-8 carbon atoms of esters, ether, amide, carbonate, urea, or carbamate; or R<com:Sub>1< / com:Sub>R<com:Sub>2< / com:Sub>, R<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub> and R<com:Sub>3< / com:Sub>R<com:Sub>4< / com:Sub> independently form a 5~7 membered carbocyclic, heterocycloalkyl, aromatic or heteroaromatic ring system. The structures of camptothecins are preferred the following formula: [Image disponible dans le document PDF, Image available in the PDF document] 5 log, [Image disponible dans le document PDF, Image available in the PDF document] log, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-14), Belotecan, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-15), Rubitecan or IDEC-132 analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-16), BN-80927 analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-17), BN-80927 analog, or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> is the site linked to W; <com:Math><semantics>P1<annotation encoding="application / x-tex">P^1< / annotation>< / semantics>< / com:Math> is H, OH, NH<com:Sub>2< / com:Sub>, COOH, C(O)NH<com:Sub>2< / com:Sub>, OCH<com:Sub>2< / com:Sub>OP(O)(OR<com:Sup>18< / com:Sup>)<com:Sub>2< / com:Sub>, OC(O)OP(O)(OR<com:Sup>18< / com:Sup>)<com:Sub>2< / com:Sub>, <com:Math><semantics>OPO(OR18)2<annotation encoding="application / x-tex">OPO(OR^{18})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHPO(OR18)2<annotation encoding="application / x-tex">NHPO(OR^{18})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)R18<annotation encoding="application / x-tex">OC(O)R^{18}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OP(O)(OR18)OP(O)(OR18)2<annotation encoding="application / x-tex">OP(O)(OR^{18})OP(O)(OR^{18})_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NHR18<annotation encoding="application / x-tex">OC(O)NHR^{18}< / annotation>< / semantics>< / com:Math>, OC(O)N(C<com:Sub>2< / com:Sub>H<com:Sub>4< / com:Sub>)<com:Sub>2< / com:Sub>NCH<com:Sub>3< / com:Sub>, OSO<com:Sub>2< / com:Sub>(OR<com:Sup>18< / com:Sup>), O-(C<com:Sub>4< / com:Sub>-C<com:Sub>12< / com:Sub>-glycoside), OC(O)N(C<com:Sub>2< / com:Sub>H<com:Sub>4< / com:Sub>)<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>N(C<com:Sub>2< / com:Sub>H<com:Sub>4< / com:Sub>)<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> of linear or branched alkyl or heteroalkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR<com:Sup>17< / com:Sup>), carbamate (-C(O)NR<com:Sup>17< / com:Sup>R<com:Sup>18< / com:Sup>); R<com:Sup>17< / com:Sup>and R<com:Sup>18< / com:Sup> are independently H, linear or branched alkyl or heteroalkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of linear or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> linear or branched of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR<com:Sup>17< / com:Sup>), carbamate (-C(O)NR<com:Sup>17< / com:Sup>R<com:Sup>18< / com:Sup>). Taxanes, which includes Paclitaxel (Taxol), a cytotoxic natural product, and docetaxel (Taxotere), a semi-synthetic derivative, and their analogs which are preferred for conjugation are exampled in: K.C. Nicolaou et al., J. Am. Chem. Soc. 117, 2409-20, (1995); Ojima et al, J. Med. Chem. 39:3889-3896 (1996); 40:267-78 (1997); 45, 5620-3 (2002); Ojima et al., Proc. Natl. Acad. Sci., 96:4256-61 (1999); Kim et al., Bull. Korean Chem. Soc., 20, 1389-90 (1999); Miller, et al. J. Med. Chem., 47, 4802-5 (2004); U.S. Patent No. 5,475,011 5,728,849, 5,811,452; 6,340,701; 6,372,738; 6,391,913, 6.436,931; 6,589,979; 6,596,757; 6,706,708; 7,008,942; 7,186,851; 7,217,819; 7,276,499; 7,598,290; and 7,667,054. The structures of taxanes are preferred the following formula: [Image disponible dans le document PDF, Image available in the PDF document] d-01), . . [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(Id−04),<annotation encoding="application / x-tex">(Id-04),< / annotation>< / semantics>< / com:Math> wherein \simes is the site linked to W; Ar and Ar' are independently aryl or heteroaryl. Anthracyclines are mammalian DNA topoisomerases II inhibitors that are able to stabilize enzyme-DNA complexes wherein DNA strands are cut and covalently linked to the protein. These anticancer agents maintain a prominent role in treating many forms of solid tumors and acute leukemias during the last several decades. However, anthracyclines cause cardiovascular morbidity and mortality (Sagi, J. C., et al, Pharmacogenomics. 2016, 17(9), 1075-87; McGowan, J. V., et al, Cardiovasc Drugs Ther. 2017, 31(1), 63-75). Thus, to enhance specific activity of such molecules while reducing the cardiotoxicity, reasearchers actively are using the conjugation of anthracyclines to a cell-binding molecule as a general approach for improving the therapeutic index of these drugs, (Mollaev, M. et al, Int J Pharm. 2018 Dec 29. pii: S0378- 5173(18) 30991-8; Rossin, R., et al, Bioconjug Chem. 2016, 27(7):1697-706; Dal Corso, A., et al, J Control Release. 2017, 264:211-218). The structures of anthracyclines are preferred the following formula: [Image disponible dans le document PDF, Image available in the PDF document] (Ie-01), Daunorubicin analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ie-02), Daunorubicin analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ie-03), Doxorubicin analog, Ie-04), Epirubicin analog, e-05), Idarubicin analog, [Image disponible dans le document PDF, Image available in the PDF document] , Mitoxantrone analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ie-07), Pixantrone analog, (Ie-08), Losoxantrone analog, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (Ie-09), analog, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 10), (Ie-11), [Image disponible dans le document PDF, Image available in the PDF document] (Ie-12), (Ie-13), Amrubicin analog. wherein <com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math> is the site. Vinca alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents that work by inhibiting the ability of cancer cells to divide. Vinca alkaloids include vinblastine, vincristine, vindesine, leurosine, vinorelbine, catharanthine, vindoline, vincaminol, vineridine, minovincine, methoxyminovincine, minovincinine, vincadifformine, desoxyvincaminol, vincamajine, vincamine, vinpocetine, and vinburnine. The structures of vinca alkaloids are preferred vinblastine, vincristine having the following formula: [Image disponible dans le document PDF, Image available in the PDF document] (If-01), vincristine (leurocristine), [Image disponible dans le document PDF, Image available in the PDF document] +<com:Br / >+ Auristatin or dolastatin analogs are preferred in conjugation containing the bis-linkers of this patent. The auristatins (e.g. auristatin E (AE) auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin E (MMAE), Monomethylauristatin (MMAF), Auristatin F phenylene diamine (AFP) and a phenylalanine variant of MMAE) which are synthetic analogs of dolastatins, are described in Int. J. Oncol. 15: 367-72 (1999); Molecular Cancer Therapeutics, vol. 3, No. 8, pp. 921-32 (2004); U.S. Application Nos. 11134826, 20060074008, 2006022925. U.S. Patent Nos. 4414205, 4753894, 4764368, 4816444, 4879278, 4943628, 4978744, 5122368, 5165923, 5169774, 5286637, 5410024, 5521284, 5530097, 5554725, 5585089, 5599902, 5629197, 5635483, 5654399, 5663149, 5665860, 5708146, 5714586, 5741892, 5767236, 5767237, 5780588, 5821337, 5840699, 5965537, 6004934, 6033876, 6034065, 6048720, 6054297, 6054561, 6124431, 6143721, 6162930, 6214345, 6239104, 6323315, 6342219, 6342221, 6407213, 6569834, 6620911, 6639055, 6884869, 6913748, 7090843, 7091186, 7097840, 7098305, 7098308, 7498298, 7375078, 7462352, 7553816, 7659241, 7662387, 7745394, 7754681, 7829531, 7837980, 7837995, 7902338, 7964566, 7964567, 7851437, 7994135. The structures of auristatin analogs are preferred the following formula (Ih-01), (Ih-02), (Ih-03), (Ih- 04), (Ih-05), (Ih-06), and (Ih-07): [Image disponible dans le document PDF, Image available in the PDF document] 12), 13), [Image disponible dans le document PDF, Image available in the PDF document] 06), Ih-07), or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein R<com:Sup>1< / com:Sup>, R<com:Sup>2< / com:Sup>, R<com:Sup>3< / com:Sup>, R<com:Sup>4< / com:Sup> and R<com:Sup>5< / com:Sup> are independently H; C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> lineal or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amines, heterocycloalkyl, or acyloxylamines; or peptides containing 1-8 aminoacids, or polyethyleneoxy unit having formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub> or (OCH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>))<com:Sub>p< / com:Sub>, wherein p is an integer from 1 to about 5000. The two Rs: R<com:Sup>1< / com:Sup>R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>R<com:Sup>3< / com:Sup>, R<com:Sup>1< / com:Sup>R<com:Sup>3< / com:Sup> or R<com:Sup>3< / com:Sup>R<com:Sup>4< / com:Sup> can form 3~8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group; X<com:Sub>3< / com:Sub> is H, CH<com:Sub>3< / com:Sub> or X<com:Sub>1< / com:Sub>'R<com:Sub>1< / com:Sub>', wherein <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>' is NH, N(CH<com:Sub>3< / com:Sub>), NHNH, O, or S, and <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>' is H or <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C8<annotation encoding="application / x-tex">C_8< / annotation>< / semantics>< / com:Math> lineal or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxylamines; R<com:Sub>3< / com:Sub>' is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> lineal or branched alkyl; Z<com:Sub>3< / com:Sub>' is H, COOR<com:Sub>1< / com:Sub>, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, OR<com:Sub>1< / com:Sub>, CONHR<com:Sub>1< / com:Sub>,NHCOR<com:Sub>1< / com:Sub>, OCOR<com:Sub>1< / com:Sub>, OP(O)(OM<com:Sub>1< / com:Sub>)(OM<com:Sub>2< / com:Sub>), OCH<com:Sub>2< / com:Sub>OP(O)(OM<com:Sub>1< / com:Sub>)(OM<com:Sub>2< / com:Sub>), OSO<com:Sub>3< / com:Sub>M<com:Sub>1< / com:Sub>, R<com:Sub>1< / com:Sub>, or O-glycoside (glucoside, galactoside, mannoside, glucuronoside / glucuronide, alloside, fructoside, etc.), NH-glycoside, S-glycoside or CH<com:Sub>2< / com:Sub>- glycoside; M<com:Sub>1< / com:Sub> and M<com:Sub>2< / com:Sub> are independently H, Na, K, Ca, Mg, NH<com:Sub>4< / com:Sub>, NR<com:Sub>1< / com:Sub>R<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>; Y<com:Sub>1< / com:Sub> and Y<com:Sub>2< / com:Sub> are independently O, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(<com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>), N(<com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>)C(O)N(<com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>), C(O)NHNHC(O) and C(O)NR<com:Sub>1< / com:Sub> when linked to the connecting site "\"; or OH, NH<com:Sub>2< / com:Sub>, NHNH<com:Sub>2< / com:Sub>, NHR<com:Sub>5< / com:Sub>, SH, C(O)OH, C(O)NH<com:Sub>2< / com:Sub>, OC(O)NH<com:Sub>2< / com:Sub>, <com:Math><semantics>OC(O)OH<annotation encoding="application / x-tex">OC(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)NH2<annotation encoding="application / x-tex">NHC(O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)SH<annotation encoding="application / x-tex">NHC(O)SH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NH(R1)<annotation encoding="application / x-tex">OC(O)NH(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R1)C(O)NH(R2)<annotation encoding="application / x-tex">N(R_1)C(O)NH(R_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NHNHC(O)OH<annotation encoding="application / x-tex">C(O)NHNHC(O)OH< / annotation>< / semantics>< / com:Math> and C(O)NHR<com:Sub>1< / com:Sub> when not linked to the connecting site "\\"; R<com:Sub>12< / com:Sub> is OH, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, NHNH<com:Sub>2< / com:Sub>, NHNHCOOH, O-R<com:Sub>1< / com:Sub>-COOH, NH-R<com:Sub>1< / com:Sub>-COOH, NH-(Aa)<com:Sub>n< / com:Sub>COOH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NR<com:Sub>1< / com:Sub>R<com:Sub>1< / com:Sub>', NHOH, NHOR<com:Sub>1< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH-Ar-COOH, NH-Ar-NH<com:Sub>2< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH-SO<com:Sub>3< / com:Sub>H, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHSO<com:Sub>3< / com:Sub>H, R<com:Sub>1< / com:Sub>-NHSO<com:Sub>3< / com:Sub>H, NH-R<com:Sub>1< / com:Sub>- NHSO<com:Sub>3< / com:Sub>H, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, OR<com:Sub>1< / com:Sub>, R<com:Sub>1< / com:Sub>- NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, R<com:Sub>1< / com:Sub>-OPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, OR<com:Sub>1< / com:Sub>-NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, NH-R<com:Sub>1< / com:Sub>-NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>S)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>S)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>-CH<com:Sub>2< / com:Sub>OH, NH-R<com:Sub>1< / com:Sub>-NH<com:Sub>2< / com:Sub>, or NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, wherein Aa is 1-8 the same or different aminoacids; p is 1-5000; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Z2<annotation encoding="application / x-tex">Z_2< / annotation>< / semantics>< / com:Math>, and n are defined the same above. Eribulin which is binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules has both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxic effects are related to its antimitotic activities, wherein apoptosis of cancer cells is induced following prolonged and irreversible mitotic blockade (Kuznetsov, G. et al, Cancer Research. 2004, 64 (16): 5760–6.; Towle, M. J., et al., Cancer Research. 2010, 71 (2): 496–505). In addition to its cytotoxic, antimitotic-based mechanisms, preclinical studies in human breast cancer models have shown that eribulin also exerts complex effects on the biology of surviving cancer cells and residual tumors that appear unrelated to its antimitotic effects. Eribulin has been approved by US FDA for the treatment of metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline- and taxane- based chemotherapies, as well as for the treatment of liposarcoma (a specific type of soft tissue sarcoma) that cannot be removed by surgery (unresectable) or is advanced (metastatic). Eribulin has been used as payload for ADC conjugates (US20170252458). The structure of Eribulin is preferred the following formula, Eb01: [Image disponible dans le document PDF, Image available in the PDF document] Eb01, An Inhibitor of nicotinamide phosphoribosyltransferases (NAMPT) can be an interesting ADC payload due to their unique mechanisms of high potent activity (Sampath D, et al, Pharmacol Ther 2015; 151, 16-31). NAMPT regulates nicotinamide adenine dinucleotide (NAD) levels in cells wherein NAD plays as an essential redox cofactor to support energy and anabolic metabolism. NAD has several essential roles in metabolism. It acts as a coenzyme in redox reactions, as a donor of ADP-ribose moieties in ADP-ribosylation reactions, as a precursor of the second messenger molecule cyclic ADP-ribose, as well as acting as a substrate for bacterial DNA ligases and a group of enzymes called sirtuins that use NAD<com:Sup>+< / com:Sup> to remove acetyl groups from proteins. In addition to these metabolic functions, NAD<com:Sup>+< / com:Sup> emerges as an adenine nucleotide that can be released from cells spontaneously and by regulated mechanisms (Smyth L. M, et al, J. Biol. Chem. 2004, 279 (47), 48893–903; Billington R. A, et al, Mol Med. 2006, 12, 324–7), and can therefore have important extracellular roles (Billington R. A, et al, Mol Med. 2006, 12, 324–7). When inhibitors of NAMPT present, NAD levels decline below the level needed for metabolism resulting in energy crisis and therefore cell death. So far, clinical NAMPT inhibitor candidates FK-866, CHS-828, and GMX-1777 advanced to clinical trials but each encountered dose-limiting toxicities prior to any objective responses (Holen K., et al, Invest New Drugs 2008, 26, 45-51; Hovstadius, P., et al, Clin Cancer Res 2002, 8, 2843-50; Pishvaian, M. J., et al, J Clin Oncol 2009, 27, 3581). Thus using ADCs for targeting delivery of NAMPT inhibitors might circumvent the systemic toxicities to achieve much broader therapeutic index. The structures of NAMPT inhibitors are preferred the following formula, NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, and NP09: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein "<com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math>" is the same above; <com:Math><semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics>< / com:Math> is F, Cl, Br, I, OH, OR<com:Sub>1< / com:Sub>, R<com:Sub>1< / com:Sub>, OPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, OSO<com:Sub>3< / com:Sub>H, NHR<com:Sub>1< / com:Sub>, OCOR<com:Sub>1< / com:Sub>, NHCOR<com:Sub>1< / com:Sub>. A benzodiazepine dimer and its analog: (e. g. a dimer of pyrrolobenzodiazepine (PBD) or (tomaymycin), indolinobenzodiazepine, imidazobenzothiadiazepine, or oxazolidinobenzodiazepines) which is preferred cytotoxic agent according to the present invention is exampled in: US Patent Nos. 8,163,736; 8,153,627; 8,034,808; 7,834,005; 7,741,319; 7,704,924; 7,691,848; 7,678,787; 7,612,062; 7,608,615; 7,557,099; 7,528,128; 7,528,126; 7,511,032; 7,429,658; 7,407,951; 7,326,700; 7,312,210; 7,265,105; 7,202,239; 7,189,710; 7,173,026; 7,109,193; 7,067,511; 7,064,120; 7,056,913; 7,049,311; 7,022,699; 7,015,215; 6,979,684; 6,951,853; 6,884,799; 6,800,622; 6,747,144; 6,660,856; 6,608,192; 6,562,806; 6,977,254; 6,951,853; 6,909,006; 6,344,451; 5,880,122; 4,935,362; 4,764,616; 4,761,412; 4,723,007; 4,723,003; 4,683,230; 4,663,453; 4,508,647; 4,464,467; 4,427,587; 4,000,304; US patent appl. 20100203007, 20100316656, 20030195196. Examples of the structures of the conjugate of the antibody-benzodiazepine dimers via the present linker are illustrated below PB01, PB02, PB03, PB04, PB05, PB06, PB07, PB08, PB09, PB10, PB11, PB12, PB13, PB14, PB15, and PB16. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 7, [Image disponible dans le document PDF, Image available in the PDF document] - 5 [Image disponible dans le document PDF, Image available in the PDF document] PB16, or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein <com:Math><semantics>X1,X2,Y1,Y2,R4,R5,R5<annotation encoding="application / x-tex">X_1, X_2, Y_1, Y_2, R_4, R_5, R_5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Z1<annotation encoding="application / x-tex">Z_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ℤ2<annotation encoding="application / x-tex">\mathbb{Z}_2< / annotation>< / semantics>< / com:Math>, and n are defined the same above; Preferabably <com:Math><semantics>𝕏1<annotation encoding="application / x-tex">\mathbb{X}_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>𝕏2<annotation encoding="application / x-tex">\mathbb{X}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>𝕐1<annotation encoding="application / x-tex">\mathbb{Y}_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>𝕐2<annotation encoding="application / x-tex">\mathbb{Y}_2< / annotation>< / semantics>< / com:Math> are independently O, N, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R<com:Sub>1< / com:Sub>), <com:Math><semantics>N(R1)C(O)N(R1)<annotation encoding="application / x-tex">N(R_1)C(O)N(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH1C(O)NHNHC(O)<annotation encoding="application / x-tex">CH_1C(O)NHNHC(O)< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C(O)NR1<annotation encoding="application / x-tex">C(O)NR_1< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1′<annotation encoding="application / x-tex">R^{1'}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2′<annotation encoding="application / x-tex">R^{2'}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R3′<annotation encoding="application / x-tex">R^{3'}< / annotation>< / semantics>< / com:Math> are independently H; F; Cl; <com:Math><semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics>< / com:Math>O; <com:Math><semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics>< / com:Math>S; OH; SH; C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> lineal or branched alkyl, aryl, alkenyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester (COOR<com:Sub>5< / com:Sub> or <com:Math><semantics>−OC(O)R5<annotation encoding="application / x-tex">-OC(O)R_5< / annotation>< / semantics>< / com:Math>), ether (OR<com:Sub>5< / com:Sub>), amide (CONR<com:Sub>5< / com:Sub>), carbamate (OCONR<com:Sub>5< / com:Sub>), amines (NHR<com:Sub>5< / com:Sub>, NR<com:Sub>5< / com:Sub>R<com:Sub>5< / com:Sub>'), heterocycloalkyl, or acyloxylamines (- C(O)NHOH, -ONHC(O)R<com:Sub>5< / com:Sub>); or peptides containing 1-20 natural or unnatural aminoacids, or polyethyleneoxy unit of formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub> or (OCH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>))<com:Sub>p< / com:Sub>, wherein p is an integer from 1 to about 5000. The two Rs: R<com:Sup>1< / com:Sup>R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>R<com:Sup>3< / com:Sup>, R<com:Sup>1< / com:Sup>R<com:Sup>3< / com:Sup>, R<com:Sup>1< / com:Sup>'R<com:Sup>2< / com:Sup>, R<com:Sup>2< / com:Sup>'R<com:Sup>3< / com:Sup>, or R<com:Sup>1< / com:Sup>'R<com:Sup>3< / com:Sup> can independently form 3~8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group; X<com:Sub>3< / com:Sub> and Y<com:Sub>3< / com:Sub> are independently N, NH, CH<com:Sub>2< / com:Sub> or CR<com:Sub>5< / com:Sub>, wherein R<com:Sub>4< / com:Sub>, R<com:Sub>5< / com:Sub>, R<com:Sub>6< / com:Sub>, R<com:Sub>12< / com:Sub> and R<com:Sub>12< / com:Sub>' are independently H, OH, NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>3< / com:Sub>), NHNH<com:Sub>2< / com:Sub>, COOH, SH, OZ<com:Sub>3< / com:Sub>, SZ<com:Sub>3< / com:Sub>, F, Cl, or C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> lineal or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxylamines; <com:Math><semantics>Z3<annotation encoding="application / x-tex">Z_3< / annotation>< / semantics>< / com:Math> is H, <com:Math><semantics>OP(O)(OM1)(OM2)<annotation encoding="application / x-tex">OP(O)(OM_1)(OM_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OCH2OP(O)(OM1)(OM2)<annotation encoding="application / x-tex">OCH_2OP(O)(OM_1)(OM_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OSO3M1<annotation encoding="application / x-tex">OSO_3M_1< / annotation>< / semantics>< / com:Math>, or O-glycoside (glucoside, galactoside, mannoside, glucuronoside / glucuronide, alloside, fructoside, etc.), NH-glycoside, S-glycoside or CH<com:Sub>2< / com:Sub>- glycoside; M<com:Sub>1< / com:Sub> and M<com:Sub>2< / com:Sub> are independently H, Na, K, Ca, Mg, NH<com:Sub>4< / com:Sub>, NR<com:Sub>1< / com:Sub>R<com:Sub>2< / com:Sub>R<com:Sub>3< / com:Sub>. An CC-1065 analog and doucarmycin analogs are also preferred to be used for a conjugate containing bis-bridge linkage of the present patent. The examples of the CC-1065 analogues and doucarmycin analogs as well as their synthesis are described in: e.g. Warpehoski, et al, J. Med. Chem. 31:590-603 (1988); D. Boger et al., J. Org. Chem; 66; 6654-61, 2001; U. S. Patent Nos: 4169888, 4391904, 4671958, 4816567, 4912227, 4923990, 4952394, 4975278, 4978757, 4994578, 5037993, 5070092, 5084468, 5101038, 5117006, 5137877, 5138059, 5147786, 5187186, 5223409, 5225539, 5288514, 5324483, 5332740, 5332837, 5334528, 5403484, 5427908, 5475092, 5495009, 5530101, 5545806, 5547667, 5569825, 5571698, 5573922, 5580717, 5585089, 5585499, 5587161, 5595499, 5606017, 5622929, 5625126, 5629430, 5633425, 5641780, 5660829, 5661016, 5686237, 5693762, 5703080, 5712374, 5714586, 5739116, 5739350, 5770429, 5773001, 5773435, 5786377 5786486, 5789650, 5814318, 5846545, 5874299, 5877296, 5877397, 5885793, 5939598, 5962216, 5969108, 5985908, 6060608, 6066742, 6075181, 6103236, 6114598, 6130237, 6132722, 6143901, 6150584, 6162963, 6172197, 6180370, 6194612, 6214345, 6262271, 6281354, 6310209, 6329497, 6342480, 6486326, 6512101, 6521404, 6534660, 6544731, 6548530, 6555313, 6555693, 6566336, 6,586,618, 6593081, 6630579, 6,756,397, 6759509, 6762179, 6884869, 6897034, 6946455, 7,049,316, 7087600, 7091186, 7115573, 7129261, 7214663, 7223837, 7304032, 7329507, 7,329,760, 7,388,026, 7,655,660, 7,655,661, 7,906,545, and 8,012,978. Examples of the structures of the conjugate of the antibody-CC-1065 analogs via the linker of the patent are illustrated below CC01, CC02, CC03, CC04, CC05, CC06 and CC07: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] CC06, [Image disponible dans le document PDF, Image available in the PDF document] CC07, wherein X<com:Sub>1< / com:Sub>, X<com:Sub>2< / com:Sub>, Y<com:Sub>1< / com:Sub> and Y<com:Sub>2< / com:Sub> are independently O, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, <com:Math><semantics>OC(O)NH<annotation encoding="application / x-tex">OC(O)NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)O<annotation encoding="application / x-tex">OC(O)O< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)NH<annotation encoding="application / x-tex">NHC(O)NH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)S<annotation encoding="application / x-tex">NHC(O)S< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)N(R1)<annotation encoding="application / x-tex">OC(O)N(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R1)C(O)N(R2)<annotation encoding="application / x-tex">N(R_1)C(O)N(R_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NHNHC(O)<annotation encoding="application / x-tex">C(O)NHNHC(O)< / annotation>< / semantics>< / com:Math> and C(O)NR<com:Sub>1< / com:Sub> when linked to the connecting site "\square\"; or OH, NH<com:Sub>2< / com:Sub>, NHNH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, SH, <com:Math><semantics>C(O)OH<annotation encoding="application / x-tex">C(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NH2<annotation encoding="application / x-tex">C(O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NH2<annotation encoding="application / x-tex">OC(O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)OH<annotation encoding="application / x-tex">OC(O)OH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)NH2<annotation encoding="application / x-tex">NHC(O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NHC(O)SH<annotation encoding="application / x-tex">NHC(O)SH< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OC(O)NH(R1)<annotation encoding="application / x-tex">OC(O)NH(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R1)C(O)NH(R2)<annotation encoding="application / x-tex">N(R_1)C(O)NH(R_2)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>C(O)NHNHC(O)OH<annotation encoding="application / x-tex">C(O)NHNHC(O)OH< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C(O)NHR1<annotation encoding="application / x-tex">C(O)NHR_1< / annotation>< / semantics>< / com:Math> when not linked to the connecting site "<com:Math><semantics>∼<annotation encoding="application / x-tex">\sim< / annotation>< / semantics>< / com:Math>"; Z<com:Sub>3< / com:Sub> is H, PO(OM<com:Sub>1< / com:Sub>)(OM<com:Sub>2< / com:Sub>), SO<com:Sub>3< / com:Sub>M<com:Sub>1< / com:Sub>, CH<com:Sub>2< / com:Sub>PO(OM<com:Sub>1< / com:Sub>)(OM<com:Sub>2< / com:Sub>), CH<com:Sub>3< / com:Sub>N(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>2< / com:Sub>NC(O)-, <com:Math><semantics>O(CH2CH2)2NC(O)<annotation encoding="application / x-tex">O(CH_2CH_2)_2NC(O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, or glycoside; wherein <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>M1<annotation encoding="application / x-tex">M_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>M2<annotation encoding="application / x-tex">M_2< / annotation>< / semantics>< / com:Math>, and n are defined the same above; A tubulysin and its analogs that are preferred for conjugation in the present invention are well known in the art and can be isolated from natural sources according to known methods or prepared synthetically according to known methods (e. g. Balasubramanian, R., et al. J. Med. Chem., 2009, 52, 238–40; Pando, O., et al. J. Am. Chem. Soc., 2011, 133, 7692–5; Reddy, J. A., et al. Mol. Pharmaceutics, 2009, 6, 1518–25; Raghavan, B., et al. J. Med. Chem., 2008, 51, 1530–33; Patterson, A. W., et al. J. Org. Chem., 2008, 73, 4362–9; Pando, O., et al. Org. Lett., 2009, 11 (24), 5567–9; Wipf, P., et al. Org. Lett., 2007, 9 (8), 1605–7; Peltier, H. M., et al. J. Am. Chem. Soc., 2006, 128, 16018–9; Chandrasekhar, S., et al J. Org. Chem., 2009, 74, 9531–4; Liu, Y., et al. Mol. Pharmaceutics, 2012, 9, 168–75; Friestad, G. K., et al. Org. Lett., 2009, 11, 1095–8; Kubicek, K., et al., Angew Chem Int Ed Engl, 2010.49: 4809-12; Chai, Y., et al., Chem Biol, 2010, 17: 296-309; Ullrich, A., et al., Angew Chem Int Ed Engl, 2009, 48, 4422-5; Sani, M., et al. Angew Chem Int Ed Engl, 2007, 46, 3526-9; Domling, A., et al., Angew Chem Int Ed Engl, 2006, 45, 7235-9; Patent applications: Zanda, M., et al, Can. Pat. Appl. 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The preferred structures of tubulysins for conjugation of cell binding molecules are described in the patent application of PCT / IB2012 / 053554. Examples of the structures of the conjugates of the antibody-tubulysin analogs via the linker are Tb01, Tb02, Tb03, Tb04, Tb05, Tb06 Tb07, Tb08, Tb09, and T10 illustrated below: [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] ر or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are independently O, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R<com:Sub>1< / com:Sub>), <com:Math><semantics>N(R1)C(O)N(R1)<annotation encoding="application / x-tex">N(R_1)C(O)N(R_1)< / annotation>< / semantics>< / com:Math>, CH, C(O)NHNHC(O) and C(O)NR<com:Sub>1< / com:Sub>; mAb is antibody, preferably monoclonal antibody; R<com:Sub>12< / com:Sub> is OH, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, NHNH<com:Sub>2< / com:Sub>, NHNHCOOH, O-R<com:Sub>1< / com:Sub>-COOH, NH-R<com:Sub>1< / com:Sub>-COOH, NH- (Aa)<com:Sub>n< / com:Sub>COOH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NR<com:Sub>1< / com:Sub>R<com:Sub>1< / com:Sub>', NHOH, NHOR<com:Sub>1< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH-Ar-COOH, NH-Ar-NH<com:Sub>2< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHSO<com:Sub>3< / com:Sub>H, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHSO<com:Sub>3< / com:Sub>H, R<com:Sub>1< / com:Sub>-NHSO<com:Sub>3< / com:Sub>H, NH-R<com:Sub>1< / com:Sub>-NHSO<com:Sub>3< / com:Sub>H, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, OR<com:Sub>1< / com:Sub>, R<com:Sub>1< / com:Sub>-NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, R<com:Sub>1< / com:Sub>- <com:Math><semantics>OPO3H2<annotation encoding="application / x-tex">OPO_3H_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>O(CH2CH2O)pCH2CH2OPO3H2<annotation encoding="application / x-tex">O(CH_2CH_2O)_pCH_2CH_2OPO_3H_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>OR1<annotation encoding="application / x-tex">OR_1< / annotation>< / semantics>< / com:Math>-NHPO<com:Math><semantics>3H2<annotation encoding="application / x-tex">_3H_2< / annotation>< / semantics>< / com:Math>, NH-R<com:Math><semantics>1<annotation encoding="application / x-tex">_1< / annotation>< / semantics>< / com:Math>-NHPO<com:Math><semantics>3H2<annotation encoding="application / x-tex">_3H_2< / annotation>< / semantics>< / com:Math>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>S)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>S)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, NH-R<com:Sub>1< / com:Sub>-NH<com:Sub>2< / com:Sub>, or NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, wherein Aa is 1- 8 aminoacids; n and m<com:Sub>1< / com:Sub> are independently 1-20; p is 1-5000; Preferably R<com:Sub>1< / com:Sub>, R<com:Sub>1< / com:Sub>, R<com:Sub>2< / com:Sub>, R<com:Sub>3< / com:Sub>, and R<com:Sub>4< / com:Sub> are independently H, C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> lineal or branced alkyl, amide, or amines; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> aryl, alkenyl, alkynyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, heterocycloalkyl, or acyloxylamines; or peptides containing 1-8 aminoacids, or polyethyleneoxy unit having formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub> or <com:Math><semantics>(OCH2CH(CH3))p<annotation encoding="application / x-tex">(OCH_2CH(CH_3))_p< / annotation>< / semantics>< / com:Math>, wherein p is an integer from 1 to about 5000; The two Rs: <com:Math><semantics>R1R2<annotation encoding="application / x-tex">R_1R_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2R3<annotation encoding="application / x-tex">R_2R_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1R3<annotation encoding="application / x-tex">R_1R_3< / annotation>< / semantics>< / com:Math> or R<com:Sub>3< / com:Sub>R<com:Sub>4< / com:Sub> can form 3~8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group; X<com:Sub>3< / com:Sub> is H, CH<com:Sub>3< / com:Sub>, CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>, C<com:Sub>3< / com:Sub>H<com:Sub>7< / com:Sub>, or X<com:Sub>1< / com:Sub>'R<com:Sub>1< / com:Sub>', wherein X<com:Sub>1< / com:Sub>' is NH, N(CH<com:Sub>3< / com:Sub>), NHNH, O, or S; R<com:Sub>1< / com:Sub>' is H or C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> lineal or branced alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, or acyloxylamines; R<com:Sub>3< / com:Sub>' is H or C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> lineal or branced alkyl; Z<com:Sub>3< / com:Sub> is H, COOR<com:Sub>1< / com:Sub>, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, OR<com:Sub>1< / com:Sub>, <com:Math><semantics>CONHR1,NHCOR1,OCOR1,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1,R1,O−100<annotation encoding="application / x-tex">CONHR_1, NHCOR_1, OCOR_1, OP(O)(OM_1)(OM_2), OCH_2OP(O)(OM_1)(OM_2), OSO_3M_1, R_1, O-100< / annotation>< / semantics>< / com:Math> glycoside (glucoside, galactoside, mannoside, glucuronoside / glucuronide, alloside, fructoside, etc), NH-glycoside, S-glycoside or CH<com:Sub>2< / com:Sub>-glycoside; M<com:Sub>1< / com:Sub> and M<com:Sub>2< / com:Sub> are independently H, Na, K, Ca, Mg, <com:Math><semantics>NH4<annotation encoding="application / x-tex">NH_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>NR1R2R3<annotation encoding="application / x-tex">NR_1R_2R_3< / annotation>< / semantics>< / com:Math>; An amatoxin and its analogs which are a subgroup of at least ten toxic compounds originally found in several genera of poisonous mushrooms, most notably Amanita phalloides and several other mushroom species, are also preferred for conjugation of the present patent. These ten amatoxins, named <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>-Amanitin, <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-Amanitin, <com:Math><semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>< / com:Math>-Amanitin, <com:Math><semantics>ϵ<annotation encoding="application / x-tex">\epsilon< / annotation>< / semantics>< / com:Math>-Amanitin, Amanullinic acid, Amaninamide, Amanin, Proamanullin, are rigid bicyclic peptides that are synthesized as 35- amino-acid proproteins, from which the final eight amino acids are cleaved by a prolyl oligopeptidase (Litten, W. 1975 Scientific American232 (3): 90–101; H. E. Hallen, et al. 2007 Proc. Nat. Aca. Sci. USA 104, 19097–101; K. Baumann, et al, 1993 Biochemistry 32 (15): 4043– 50; Karlson-Stiber C, Persson H. 2003, Toxicon 42 (4): 339–49; Horgen, P. A. et al. 1978 Arch. Microbio. 118 (3): 317–9). Amatoxins kill cells by inhibiting RNA polymerase II (Pol II), shutting down gene transcription and protein biosynthesis (Brodner, O. G. and Wieland, T. 1976) Biochemistry, 15(16): 3480–4; Fiume, L., Curr Probl Clin Biochem, 1977, 7: 23-8; Karlson-Stiber C, Persson H. 2003, Toxicon 42(4): 339–49; Chafin, D. R., Guo, H. & Price, D. H. 1995 J. Biol. Chem. 270 (32): 19114–19; Wieland (1983) Int. J. Pept. Protein Res. 22(3): 257-76.). Amatoxins can be produced from collected Amanita phalloides mushrooms (Yocum, R. R. 1978 Biochemistry) 17(18): 3786-9; Zhang, P. et al, 2005, FEMS Microbiol. Lett. 252(2), 223-8), or from fermentation using a basidiomycete (Muraoka, S. and Shinozawa T., 2000 J. Biosci. Bioeng. 89(1): 73-6) or from fermentation using A. fissa (Guo, X. W., et al, 2006 Wei Sheng Wu Xue Bao 46(3): 373-8), or from culturing Galerina fasciculata or Galerina helvoliceps, a strain belonging to the genus (WO / 1990 / 009799, JP11137291). However the yields from these isolation and fermentation were quite low (less than 5 mg / L culture). Several preparations of amatoxins and their analogs have been reported in the past three decades (W. E. Savige, A. Fontana, Chem. Commun. 1976, 600–1; Zanotti, G., et al, Int J Pept Protein Res, 1981. 18(2): 162-8; Wieland, T., et al, Eur. J. Biochem. 1981, 117, 161–4; P. A. Bartlett, et al, Tetrahedron Lett. 1982, 23, 619–22; Zanotti, G., et al., Biochim Biophys Acta, 1986. 870(3): 454-62; Zanotti, G., et al., Int. J. Peptide Protein Res. 1987, 30, 323–9; Zanotti, G., et al., Int. J. Peptide Protein Res. 1987, 30, 450–9; Zanotti, G., et al., Int J. Pept Protein Res, 1988. 32(1): 9-20; G. Zanotti, T. et al, Int. J. Peptide Protein Res. 1989, 34, 222–8; Zanotti, G., et al., Int J Pept Protein Res, 1990. 35(3): 263-70; Mullersman, J. E. and J. F. Preston, 3rd, Int J Pept Protein Res, 1991. 37(6): 544-51; Mullersman, J.E., et al, Int J Pept Protein Res, 1991. 38(5): 409-16; Zanotti, G., et al, Int J Pept Protein Res, 1992. 40(6): 551-8; Schmitt, W. et al, J. Am. Chem. Soc. 1996, 118, 4380–7; Anderson, M.O., et al, J. Org. Chem., 2005, 70(12): 4578-84; J. P. May, et al., J. Org. Chem. 2005, 70, 8424-30; F. Brueckner, P. Cramer, Nat. Struct. Mol. Biol. 2008, 15, 811–8; J. P. May, D. M. Perrin, Chem. Eur. J. 2008, 14, 3404–9; J. P. May, et al, Chem. Eur. J. 2008, 14, 3410–17; Q. Wang, et al, Eur. J. Org. Chem. 2002, 834– 9; May, J. P. and D. M. Perrin, Biopolymers, 2007. 88(5): 714-24; May, J. P., et al., Chemistry, 2008. 14(11): 3410-7; S. De Lamo Marin, et al, Eur. J. Org. Chem. 2010, 3985-9; Pousse, G., et al., Org Lett, 2010. 12(16): 3582-5; Luo, H., et al., Chem Biol, 2014. 21(12): 1610-7; Zhao, L., et al., Chembiochem, 2015. 16(10): 1420-5) and most of these preparations were by partial synthesis. Because of their extreme potency and unique mechanism of cytotoxicity, amatoxins have been used as payloads for conjugations (Fiume, L., Lancet, 1969. 2 (7625): 853-4; Barbanti-Brodano, G. and L. Fiume, Nat New Biol, 1973. 243(130): 281-3; Bonetti, E., M. et al, Arch Toxicol, 1976. 35(1): p. 69-73; Davis, M. T., Preston, J. F. Science 1981, 213, 1385–1388; Preston, J.F., et al, Arch Biochem Biophys, 1981. 209(1): 63-71; H. Faulstich, et al, Biochemistry 1981, 20, 6498– 504; Barak, L.S., et al., Proc Natl Acad Sci U S A, 1981. 78(5): 3034-8; Faulstich, H. and L. Fiume, Methods Enzymol, 1985. 112: 225-37; Zhelev, Z., A. et al, Toxicon, 1987. 25(9): 981-7; Khalacheva, K., et al, Eksp Med Morfol, 1990. 29(3): 26-30; U. Bermbach, H. Faulstich, Biochemistry 1990, 29, 6839–45; Mullersman, J. E. and J. F. Preston, Int. J. Peptide Protein Res. 1991, 37, 544–51; Mullersman, J.E. and J.F. Preston, Biochem Cell Biol, 1991. 69(7): 418-27; J. Anderl, H. Echner, H. Faulstich, Beilstein J. Org. Chem. 2012, 8, 2072–84; Moldenhauer, G., et al, J. Natl. Cancer Inst. 2012, 104, 622–34; A. Moshnikova, et al; Biochemistry 2013, 52, 1171–8; Zhao, L., et al., Chembiochem, 2015. 16(10): 1420-5; Zhou, B., et al., Biosens Bioelectron, 2015. 68: 189-96; WO2014 / 043403, US20150218220, EP 1661584). We have been working on the conjugation of amatoxins for a while. Examples of the structures of the conjugate of the antibody- amatoxins via the linker are preferred the following structures of Am01, Am02, and Am03: [Image disponible dans le document PDF, Image available in the PDF document] Am01, Am02, Am03, or an isotope of one or more chemical elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y_1< / annotation>< / semantics>< / com:Math> are independently <com:Math><semantics>O<annotation encoding="application / x-tex">O< / annotation>< / semantics>< / com:Math>, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, <com:Math><semantics>OC(O)N(R1)<annotation encoding="application / x-tex">OC(O)N(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>N(R1)C(O)N(R1)<annotation encoding="application / x-tex">N(R_1)C(O)N(R_1)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>CH1C(O)NHNHC(O)<annotation encoding="application / x-tex">CH_1C(O)NHNHC(O)< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C(O)NR1<annotation encoding="application / x-tex">C(O)NR_1< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics>< / com:Math> are independently H, OH, OR<com:Sub>1< / com:Sub>, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, C<com:Sub>1< / com:Sub>-C<com:Sub>6< / com:Sub> alkyl, or absent; Y<com:Sub>2< / com:Sub> is O, O<com:Sub>2< / com:Sub>, NR<com:Sub>1< / com:Sub>, NH, or absent; R<com:Sub>10< / com:Sub> is CH<com:Sub>2< / com:Sub>, O, NH, NR<com:Sub>1< / com:Sub>, NHC(O), NHC(O)NH, NHC(O)O, OC(O)O, C(O), OC(O), OC(O)(NR<com:Sub>1< / com:Sub>), (NR<com:Sub>1< / com:Sub>)C(O)(NR<com:Sub>1< / com:Sub>), C(O)R<com:Sub>1< / com:Sub> or absent; R<com:Sub>11< / com:Sub> is OH, NH<com:Sub>2< / com:Sub>, NHR<com:Sub>1< / com:Sub>, NHNH<com:Sub>2< / com:Sub>, NHNHCOOH, O-R<com:Sub>1< / com:Sub>- COOH, NH-R<com:Sub>1< / com:Sub>-COOH, NH-(Aa)<com:Sub>r< / com:Sub>COOH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OH, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NH<com:Sub>2< / com:Sub>, NR<com:Sub>1< / com:Sub>R<com:Sub>1< / com:Sub>', O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>COOH, NH-Ar-COOH, NH-Ar-NH<com:Sub>2< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHSO<com:Sub>3< / com:Sub>H, NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHSO<com:Sub>3< / com:Sub>H, R<com:Sub>1< / com:Sub>-NHSO<com:Sub>3< / com:Sub>H, NH-R<com:Sub>1< / com:Sub>- [Image disponible dans le document PDF, Image available in the PDF document] NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, R<com:Sub>1< / com:Sub>-OPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, O(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>OPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>. OR<com:Sub>1< / com:Sub>-NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>. NH-R<com:Sub>1< / com:Sub>-NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, or NH(CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>NHPO<com:Sub>3< / com:Sub>H<com:Sub>2< / com:Sub>, wherein (Aa)<com:Sub>r< / com:Sub> is 1-8 aminoacids; n and m<com:Sub>1< / com:Sub> are independently 1-20; p is 1-5000; <com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Ar<annotation encoding="application / x-tex">Ar< / annotation>< / semantics>< / com:Math>, are the same defined in Formula (I). Protein kinase inhibitors that block the action of an enzyme to add a phosphate (PO<com:Sub>4< / com:Sub>) group to serine, threonine, or tyrosine amino acids on a protein, and can modulate the protein function. The protein kinase inhibitors can be used to treat diseases due to hyperactive protein kinases (including mutant or overexpressed kinases) in cancer or to modulate cell functions to overcome other disease drivers. The structures of protein kinase inhibitors are preferred to selected from Adavosertib, Afatinib, Axitinib, Bafetinib, Bosutinib, Cobimetinib, Crizotinib, Cabozantinib, Dasatinib, Entrectinib, Erdafitinib, Erlotinib, Fostamatinib, Gefitinib, Ibrutinib, Imatinib, Lapatinib, Lenvatinib, Mubritinib, Nilotinib, Pazopanib, Pegaptanib, Ponatinib, Rebastinib, Regorafenib, Ruxolitinib, Sorafenib, Sunitinib, SU6656, Tofacitinib, Vandetanib, and Vemurafenib, having the following formula, PK01 ~ PK29: [Image disponible dans le document PDF, Image available in the PDF document] N-NH <com:Math><semantics>⊕<annotation encoding="application / x-tex">\oplus< / annotation>< / semantics>< / com:Math> O H PK02, Axitinib, [Image disponible dans le document PDF, Image available in the PDF document] PK03, Bafetinib 49 [Image disponible dans le document PDF, Image available in the PDF document] b, 5 '9 [Image disponible dans le document PDF, Image available in the PDF document] matinib, matinib, [Image disponible dans le document PDF, Image available in the PDF document] > inib, [Image disponible dans le document PDF, Image available in the PDF document] 5 ib; tinib; A MEK inhibitor inhibits the mitogen-activated protein kinases MEK1 and / or MEK2 which is often overactive in some cancers. MEK inhibitors are especially used for treatment of BRAF- mutated melanoma, and KRAS / BRAF mutated colorectal cancer, breast cancer, and non-small cell lung cancer (NSCLC). MEK inhibitors are selected from PD0325901, selumetinib (AZD6244), cobimetinib (XL518), refametinib, trametinib (GSK1120212), pimasertib, Binimetinib (MEK162), AZD8330, RO4987655, RO5126766, WX-554, E6201, GDC-0623, PD-325901 and TAK-733. The preferred MEK inhibitors are selected from Trametinib (GSK1120212), Cobimetinib (XL518), Binimetinib (MEK162), selumetinib having the following formula: [Image disponible dans le document PDF, Image available in the PDF document] ub, wherein Z<com:Sub>5< / com:Sub> is selected from O, NH, NHNH, NR<com:Sub>5< / com:Sub>, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(<com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>), N(<com:Math><semantics>R1<annotation encoding="application / x-tex">R_1< / annotation>< / semantics>< / com:Math>)C(O)N(<com:Math><semantics>R2<annotation encoding="application / x-tex">R_2< / annotation>< / semantics>< / com:Math>), C(O)NHNHC(O) and <com:Math><semantics>C(0)NR1<annotation encoding="application / x-tex">C(0)NR_{1}< / annotation>< / semantics>< / com:Math> A proteinase inhibitor that are used as a payload is preferably selected from: Carfilzomib, Clindamycin, Retapamulin, Indibulin, as shown in the following structures: [Image disponible dans le document PDF, Image available in the PDF document] PI01, Carfilzomib, [Image disponible dans le document PDF, Image available in the PDF document] PI02, Clindamycin, [Image disponible dans le document PDF, Image available in the PDF document] PI03, Carmaphycin analog, An immunotoxin herein is a macromolecular drug which is usually a cytotoxic protein derived from a bacterial or plant protein, such as Diphtheria toxin (DT), Cholera toxin (CT), Trichosanthin (TCS), Dianthin, Pseudomonas exotoxin A (ETA'), Erythrogenic toxins, Diphtheria toxin, AB toxins, Type III exotoxins, etc. It also can be a highly toxic bacterial pore-forming protoxin that requires proteolytic processing for activation. An example of this protoxin is proaerolysin and its genetically modified form, topsalysin. Topsalysin is a modified recombinant protein that has been engineered to be selectively activated by an enzyme in the prostate, leading to localized cell death and tissue disruption without damaging neighboring tissue and nerves; An immunotoxin herein is preferably conjugated via the side-chain linker of the application through an amino acid having free amino, thiol or carboxyl acid group; and more preferably through N- terminal amino acid. Additionally W, L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub>, V<com:Sub>1< / com:Sub>, and V<com:Sub>2< / com:Sub>, may independently be composed of one or more linker components of 6-maleimidocaproyl ("MC"), maleimidopropanoyl ("MP"), valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("ala-phe" or "af"), p-aminobenzyloxy-carbonyl ("PAB"), 4-thiopentanoate ("SPP"), 4-(N-maleimidomethyl)cyclohexane-1 carboxylate 55 ("MCC"), (4-acetyl)amino-benzoate ("SIAB"), 4-thio-butyrate (SPDB), 4-thio-2- hydroxysulfonyl-butyrate (2-Sulfo-SPDB), as the structures shown below or natural or unnatural peptides having 1~12 natural or unnatural amino acid unites. The natural amino acid is preferably selected from aspartic acid, glutamic acid, arginine, histidine, lysine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, tyrosine, phenylalanine, glycine, proline, tryptophan, and alanine; 6-maleimidocaproyl (MC) H O Ħ <com:Math><semantics>N∼NH2<annotation encoding="application / x-tex">N \sim NH_2< / annotation>< / semantics>< / com:Math> maleimido propanoyl (MP), O valine-citrulline (val-cit), NH<com:Sub>2< / com:Sub> () ö alanine-phenylalanine (ala-phe), lysine- HN, <com:Math><semantics>ONH−S<annotation encoding="application / x-tex">O_{NH}-S< / annotation>< / semantics>< / com:Math> phenylalanine (lys-phe), p-aminobenzyloxycarbonyl (PAB), 4-thio-pentanoate (SPP), 4-thio-butyrate (SPDB), 4-(N-maleimidomethyl)cyclo-hexane-1-carboxylate (MCC), H v maleimidoethyl (ME), v 4-thio-2-hydroxysulfonyl- butyrate (2-Sulfo-SPDB), aryl-thiol (PySS), (4- acetyl)aminobenzoate (SIAB), oxylbenzylthio, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] H, 30 , 30 , and L- or D-, natural or unnatural peptides containing 1-20 amino acids; wherein <com:Math><semantics>52<annotation encoding="application / x-tex">\frac{5}{2}< / annotation>< / semantics>< / com:Math> is the site of linkage; Preferably <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>X6<annotation encoding="application / x-tex">X_6< / annotation>< / semantics>< / com:Math>, are independently selected from NH; NHNH; <com:Math><semantics>N(R12)<annotation encoding="application / x-tex">N(R_{12})< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>N(R12)N(R12′)<annotation encoding="application / x-tex">N(R_{12})N(R_{12'})< / annotation>< / semantics>< / com:Math>; O; S; <com:Math><semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> of alkyl; <com:Math><semantics>C2<annotation encoding="application / x-tex">C_2< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>< / com:Math> of heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; CH<com:Sub>2< / com:Sub>OR<com:Sub>12< / com:Sub>, CH<com:Sub>2< / com:Sub>SR<com:Sub>12< / com:Sub>, CH<com:Sub>2< / com:Sub>NHR<com:Sub>12< / com:Sub>, or 1~8 amino acids; wherein R<com:Sub>12< / com:Sub> and R<com:Sub>12< / com:Sub> are independently H;C<com:Sub>1< / com:Sub>-C<com:Sub>8< / com:Sub> of alkyl; C<com:Sub>2< / com:Sub>-C<com:Sub>8< / com:Sub> of hetero-alkyl, alkylcycloalkyl, heterocycloalkyl; C<com:Sub>3< / com:Sub>-C<com:Sub>8< / com:Sub> of aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or 1-8 carbon atoms of esters, ether, or amide; or polyethyleneoxy unit of formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub> or (OCH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>))<com:Sub>p< / com:Sub>, wherein p is an integer from 0 to about 1000, or combination above thereof; W, L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub> V<com:Sub>1< / com:Sub>, and V<com:Sub>2< / com:Sub> may also independently contain a self-immolative or a non-self- immolative component, peptidic units, a hydrazone bond, a disulfide, an ester, an oxime, an amide, or a thioether bond. The self-immolative unit includes, but is not limited to, aromatic compounds that are electronically similar to the para-aminobenzylcarbamoyl (PAB) groups such as 2-aminoimidazol-5-methanol derivatives, heterocyclic PAB analogs, beta-glucuronide, and ortho or para-aminobenzylacetals; Preferably, the self-immolative linker component has one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] wherein the (*) atom is the point of attachment of additional spacer or releasable linker units, or the cytotoxic agent, and / or the binding molecule (CBA); X<com:Sup>1< / com:Sup>, Y<com:Sup>1< / com:Sup>, Z<com:Sup>2< / com:Sup> and Z<com:Sup>3< / com:Sup> are independently NH, O, or S; Z<com:Sup>1< / com:Sup> is independently H, NHR<com:Sub>1< / com:Sub>, OR<com:Sub>1< / com:Sub>, SR<com:Sub>1< / com:Sub>, COX<com:Sub>1< / com:Sub>R<com:Sub>1< / com:Sub>, wherein X<com:Sub>1< / com:Sub> and R<com:Sub>1< / com:Sub> are defined above; v is 0 or 1; U<com:Sup>1< / com:Sup> is independently H, OH, C<com:Sub>1< / com:Sub>~C<com:Sub>6< / com:Sub> alkyl, (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>n< / com:Sub>, F, Cl, Br, I, OR<com:Sup>5< / com:Sup>, SR<com:Sup>5< / com:Sup>, NR<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, N=NR<com:Sub>5< / com:Sub>, N=R<com:Sub>5< / com:Sub>, NR<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, NO<com:Sub>2< / com:Sub>, SOR<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, SO<com:Sub>2< / com:Sub>R<com:Sup>5< / com:Sup>, SO<com:Sub>3< / com:Sub>R<com:Sup>5< / com:Sup>, OSO<com:Sub>3< / com:Sub>R<com:Sup>5< / com:Sup>, PR<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, POR<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, PO<com:Sub>2< / com:Sub>R<com:Sup>5< / com:Sup>R<com:Sup>5< / com:Sup>, OPO(OR<com:Sup>5< / com:Sup>)(OR<com:Sup>5< / com:Sup>), or OCH<com:Sub>2< / com:Sub>PO(OR<com:Sup>5< / com:Sup>(OR<com:Sup>5< / com:Sup>), wherein R<com:Sup>5< / com:Sup> and R<com:Sup>5< / com:Sup> are independently selected from H, C<com:Sub>1< / com:Sub>~C<com:Sub>8< / com:Sub> of alkyl; C<com:Sub>2< / com:Sub>~C<com:Sub>8< / com:Sub> of alkenyl, alkynyl, heteroalkyl, or amino acid; C<com:Sub>3< / com:Sub>~C<com:Sub>8< / com:Sub> of aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl, or glycoside; or pharmaceutical cation salts; W, L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub> V<com:Sub>1< / com:Sub>, and V<com:Sub>2< / com:Sub> may also independently contain non-self-immolative linker component having one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 , wherein the (*) atom is the point of attachment of additional spacer or releasable linkers, the cytotoxic agents, and / or the binding molecules; <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Y1<annotation encoding="application / x-tex">Y^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>U1<annotation encoding="application / x-tex">U^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math> are defined as above; r is <com:Math><semantics>0∼100<annotation encoding="application / x-tex">0\sim100< / annotation>< / semantics>< / com:Math>; m and n are <com:Math><semantics>0∼20<annotation encoding="application / x-tex">0\sim20< / annotation>< / semantics>< / com:Math> independently; Further preferably, W, L<com:Sub>1< / com:Sub>, L<com:Sub>2< / com:Sub> V<com:Sub>1< / com:Sub>, and V<com:Sub>2< / com:Sub> may independently be a releasable linker component. The term releasable refers to a linker that includes at least one bond that can be broken under physiological conditions, such as a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically labile, biochemically labile or enzyme-labile bond. It is appreciated that such physiological conditions resulting in bond breaking do not necessarily include a biological or metabolic process, and instead may include a standard chemical reaction, such as a hydrolysis or substitution reaction, for example, an endosome having a lower pH than cytosolic pH, and / or disulfide bond exchange reaction with a intracellular thiol, such as a millimolar range of abundant of glutathione inside the malignant cells; Examples of the releasable components of W, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> independently include, but not limited: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>(OCH2CH2)r−<annotation encoding="application / x-tex">(OCH_2CH_2)_{r^-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−K(CR15R16)m−(OCO)(Aa)t(CR19R20)n(OCH2CH2)r−<annotation encoding="application / x-tex">-K(CR_{15}R_{16})_{m^-}(OCO)(Aa)_t(CR_{19}R_{20})_n(OCH_2CH_2)_{r^-}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−K(CR15R16)m(OCNR17)(Aa)t−<annotation encoding="application / x-tex">-K(CR_{15}R_{16})_m(OCNR_{17})(Aa)_{t^-}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(CR19R20)n(OCH2CH2)r<annotation encoding="application / x-tex">(CR_{19}R_{20})_n(OCH_2CH_2)_r< / annotation>< / semantics>< / com:Math>-, -K-<com:Math><semantics>(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r<annotation encoding="application / x-tex">(CR_{15}R_{16})_m(CO)(Aa)_t(CR_{19}R_{20})_n(OCH_2CH_2)_r< / annotation>< / semantics>< / com:Math>-, -K<com:Math><semantics>(CR15R16)m<annotation encoding="application / x-tex">(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>- phenyl-CO(Aa)<com:Sub>t< / com:Sub>(CR<com:Sub>17< / com:Sub>R<com:Sub>18< / com:Sub>)<com:Sub>n< / com:Sub>-, -K-(CR<com:Sub>15< / com:Sub>R<com:Sub>16< / com:Sub>)<com:Sub>m< / com:Sub>-furyl-CO(Aa)<com:Sub>t< / com:Sub>(CR<com:Sub>17< / com:Sub>R<com:Sub>18< / com:Sub>)<com:Sub>n< / com:Sub>-, -K(CR<com:Sub>15< / com:Sub>R<com:Sub>16< / com:Sub>)<com:Sub>m< / com:Sub>-oxazolyl- <com:Math><semantics>CO(Aa)t(CR17R18)n<annotation encoding="application / x-tex">CO(Aa)_t(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, -<com:Math><semantics>K(CR15R16)m<annotation encoding="application / x-tex">K(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>-thiazolyl-<com:Math><semantics>CO(Aa)t<annotation encoding="application / x-tex">CO(Aa)_t< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CR17R18)n<annotation encoding="application / x-tex">(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, -<com:Math><semantics>K(CR15R16)t<annotation encoding="application / x-tex">K(CR_{15}R_{16})_t< / annotation>< / semantics>< / com:Math>-thienyl- <com:Math><semantics>CO(CR17R18)n<annotation encoding="application / x-tex">CO(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, -<com:Math><semantics>K(CR15R16)t<annotation encoding="application / x-tex">K(CR_{15}R_{16})_t< / annotation>< / semantics>< / com:Math>imidazolyl-<com:Math><semantics>CO<annotation encoding="application / x-tex">CO< / annotation>< / semantics>< / com:Math>-(<com:Math><semantics>CR17R18)n<annotation encoding="application / x-tex">CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, -<com:Math><semantics>K(CR5R6)t<annotation encoding="application / x-tex">K(CR_5R_6)_t< / annotation>< / semantics>< / com:Math>morpholino-<com:Math><semantics>CO(Aa)t<annotation encoding="application / x-tex">CO(Aa)_t< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>(CR17R18)n<annotation encoding="application / x-tex">(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−K(CR15R16)t<annotation encoding="application / x-tex">-K(CR_{15}R_{16})_t< / annotation>< / semantics>< / com:Math>-piperazino-<com:Math><semantics>CO(Aa)t<annotation encoding="application / x-tex">CO(Aa)_t< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>(CR17R18)n<annotation encoding="application / x-tex">(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−K(CR15R16)t<annotation encoding="application / x-tex">-K(CR_{15}R_{16})_t< / annotation>< / semantics>< / com:Math>-N-methylpiperazin- <com:Math><semantics>CO(Aa)t(CR17R18)n<annotation encoding="application / x-tex">CO(Aa)_t(CR_{17}R_{18})_n< / annotation>< / semantics>< / com:Math>-, -<com:Math><semantics>K(CR15R16)m<annotation encoding="application / x-tex">K(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>-(Aa)<com:Sub>t< / com:Sub>phenyl, -<com:Math><semantics>K<annotation encoding="application / x-tex">K< / annotation>< / semantics>< / com:Math>-(CR<com:Sub>15< / com:Sub>R<com:Sub>16< / com:Sub>)<com:Sub>m< / com:Sub>-(Aa)<com:Sub>t< / com:Sub>furyl-, -<com:Math><semantics>K(CR15R16)m<annotation encoding="application / x-tex">K(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>- oxazolyl-<com:Math><semantics>(Aa)t−<annotation encoding="application / x-tex">(Aa)_{t-}< / annotation>< / semantics>< / com:Math>, -K<com:Math><semantics>(CR15R16)m<annotation encoding="application / x-tex">(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>-thiazolyl<com:Math><semantics>(Aa)t−<annotation encoding="application / x-tex">(Aa)_{t-}< / annotation>< / semantics>< / com:Math>, -K<com:Math><semantics>(CR15R16)m<annotation encoding="application / x-tex">(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>-thienyl-<com:Math><semantics>(Aa)t−<annotation encoding="application / x-tex">(Aa)_{t-}< / annotation>< / semantics>< / com:Math>, -K<com:Math><semantics>(CR15R16)m<annotation encoding="application / x-tex">(CR_{15}R_{16})_m< / annotation>< / semantics>< / com:Math>- imidazolyl(Aa)<com:Sub>t< / com:Sub>-, -K(CR<com:Sub>15< / com:Sub>R<com:Sub>16< / com:Sub>)<com:Sub>m< / com:Sub>-morpholino(Aa)<com:Sub>t< / com:Sub>-, -K(CR<com:Sub>15< / com:Sub>R<com:Sub>16< / com:Sub>)<com:Sub>m< / com:Sub>piperazino(Aa)<com:Sub>t< / com:Sub>G, -K(CR<com:Sub>5< / com:Sub>R<com:Sub>6< / com:Sub>)<com:Sub>m< / com:Sub> -N-methylpiperazino(Aa)<com:Sub>t< / com:Sub>-; wherein m, Aa, m, n, R<com:Sub>13< / com:Sub>, R<com:Sub>14< / com:Sub>, and R<com:Sub>15< / com:Sub> are described above; t and r here are <com:Math><semantics>0−100<annotation encoding="application / x-tex">0 - 100< / annotation>< / semantics>< / com:Math> independently; <com:Math><semantics>R16<annotation encoding="application / x-tex">R_{16}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R17<annotation encoding="application / x-tex">R_{17}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R18<annotation encoding="application / x-tex">R_{18}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R19<annotation encoding="application / x-tex">R_{19}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R20<annotation encoding="application / x-tex">R_{20}< / annotation>< / semantics>< / com:Math> are independently chosen from H; halide; <com:Math><semantics>C1∼C8<annotation encoding="application / x-tex">C_1 \sim C_8< / annotation>< / semantics>< / com:Math> of alkyl or heteroalkkyl, <com:Math><semantics>C2∼C8<annotation encoding="application / x-tex">C_2 \sim C_8< / annotation>< / semantics>< / com:Math> of aryl, alkenyl, alkynyl, ether, ester, amine or amide, C<com:Sub>3< / com:Sub>~C<com:Sub>8< / com:Sub> of aryl, which optionally substituted by one or more halide, CN, NR<com:Sub>12< / com:Sub>R<com:Sub>12< / com:Sub>, CF<com:Sub>3< / com:Sub>, <com:Math><semantics>OR12<annotation encoding="application / x-tex">OR_{12}< / annotation>< / semantics>< / com:Math>, Aryl, heterocycle, <com:Math><semantics>S(O)R12<annotation encoding="application / x-tex">S(O)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SO2R12<annotation encoding="application / x-tex">SO_2R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CO2H<annotation encoding="application / x-tex">-CO_2H< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SO3H<annotation encoding="application / x-tex">-SO_3H< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR12<annotation encoding="application / x-tex">-OR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CO2R12<annotation encoding="application / x-tex">-CO_2R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−CONR12<annotation encoding="application / x-tex">-CONR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>PO2R12R13<annotation encoding="application / x-tex">PO_2R_{12}R_{13}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−PO3H<annotation encoding="application / x-tex">-PO_3H< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>P(O)R12R12<annotation encoding="application / x-tex">P(O)R_{12}R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R13<annotation encoding="application / x-tex">R_{13}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>K<annotation encoding="application / x-tex">K< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>NR12<annotation encoding="application / x-tex">NR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SS<annotation encoding="application / x-tex">-SS< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)<annotation encoding="application / x-tex">-C(=O)< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)NH<annotation encoding="application / x-tex">-C(=O)NH< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, <com:Math><semantics>−C(=O)O<annotation encoding="application / x-tex">-C(=O)O< / annotation>< / semantics>< / com:Math>-, C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, S, Se, B, Het (heterocyclic or heteroaromatic ring having <com:Math><semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>C12<annotation encoding="application / x-tex">C_{12}< / annotation>< / semantics>< / com:Math>); or peptides containing the same or different 1- 20 amino acids More preferably, components of W, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> are independently linear alkyl having from 1-6 carbon atoms, or polyethyleneoxy unit of formula (OCH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>)<com:Sub>p< / com:Sub>, <com:Math><semantics>p=1∼5000<annotation encoding="application / x-tex">p = 1 \sim 5000< / annotation>< / semantics>< / com:Math>, or a peptide containing 1~4 units of amino acids (L or D form), or combination above. Alternatively, any one or more of W, <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, can be independently absent but <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are not absent at the same time. Generally stated, in another aspect, when <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> linked to the cell-binding molecule, T, or when <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math> and / or <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math> directly linked to T (wherein <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> are absent), the conjugation linkage could have one or more of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] > [Image disponible dans le document PDF, Image available in the PDF document] 7 5 wherein <com:Math><semantics>R20<annotation encoding="application / x-tex">R^{20}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R21<annotation encoding="application / x-tex">R^{21}< / annotation>< / semantics>< / com:Math> are independently <com:Math><semantics>C1∼C8<annotation encoding="application / x-tex">C_1 \sim C_8< / annotation>< / semantics>< / com:Math> alkyl; <com:Math><semantics>C2∼C8<annotation encoding="application / x-tex">C_2 \sim C_8< / annotation>< / semantics>< / com:Math> heteroalkyl, or heterocyclic; <com:Math><semantics>C3∼C8<annotation encoding="application / x-tex">C_3 \sim C_8< / annotation>< / semantics>< / com:Math> aryl, Ar-alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic, or alkylcarbonyl; or C<com:Sub>2< / com:Sub>-C<com:Sub>100< / com:Sub> polyethylene glycol having formula of (CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>O)<com:Sub>p,< / com:Sub> p is defined above; or absent. In another further aspect, <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math> are preferably selected from a polyglycine or a polyalkylene glycol containing a C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> lipid, or a C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> fatty acid, or a C<com:Sub>2< / com:Sub>-C<com:Sub>18< / com:Sub> fatty ammonium lipid. The polyalkylene glycol chain not only helps the conjugate more hydrophilic during the production, but also prevents the conjugate linker from hydrolysis by a hydrolase, e.g. a proteinase or an esterase. The lipid can help the conjugate to bind to an albumin in mammal bloods and then leads to the conjugate slowly dissociation from this complex during the blood circulation. Thus the side chain linker of the present patent application makes the conjugate more stable in the circulation. Polyalkylene glycols here include, but are not limited to, poly(ethylene glycols) (PEGs), poly(propylene glycol) and copolymers of ethylene oxide and propylene oxide; particularly preferred are PEGs, and more particularly preferred are monofunctionally activated hydroxyPEGs (e.g., hydroxyl PEGs activated at a single terminus, including reactive esters of hydroxyPEG-monocarboxylic acids, hydroxyPEG-monoaldehydes, hydroxyPEG-monoamines, hydroxyPEG-monohydrazides, hydroxyPEG-monocarbazates, hydroxyl PEG-monoiodo- acetamides, hydroxyl PEG-monomaleimides, hydroxyl PEG-monoorthopyridyl disulfides, hydroxyPEG-monooximes, hydroxyPEG-monophenyl carbonates, hydroxyl PEG-monophenyl glyoxals, hydroxyl PEG-monothiazolidine-2-thiones, hydroxyl PEG-monothioesters, hydroxyl PEG-monothiols, hydroxyl PEG-monotriazines and hydroxyl PEG-monovinylsulfones). The polyalkylene glycol has a molecular weight of from about 10 Daltons to about 200 kDa, preferably about 88 Da to about 40 kDa; two branch chains each with a molecular weight of about 88 Da to about 40 kDa; and more preferably two branches, each of about 88 Da to about 20 kDa. In one particular embodiment, the polyalkylene glycol is poly(ethylene) glycol and has a molecular weight of about 10 kDa; about 20 kDa, or about 40 kDa. In specific embodiments, the PEG is a PEG 10 kDa (linear or branched), a PEG 20 kDa (linear or branched), or a PEG 40 kDa (linear or branched). A number of US patents have disclosed the preparation of linear or branched "non-antigenic" PEG polymers and derivatives or conjugates thereof, e.g., U.S. Pat. Nos. 5,428,128; 5,621,039; 5,622,986; 5,643,575; 5,728,560; 5,730,990; 5,738,846; 5,811,076; 5,824,701; 5,840,900; 5,880,131; 5,900,402; 5,902,588; 5,919,455; 5,951,974; 5,965,119; 5,965,566; 5,969,040; 5,981,709; 6,011,042; 6,042,822; 6,113,906; 6,127,355; 6,132,713; 6,177,087, and 6,180,095. A cell-binding agent / molecule, T, can be any kind presently known, or that become known, of a molecule that binds to, complexes with, or reacts with a moiety of a cell population sought to be therapeutically or otherwise biologically modified. Preferably the cell-binding agent / molecule is an immunotherapeutic protein, 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; adnectins that mimic antibodies; DARPins; a lymphokine; a hormone; a vitamin; a growth factor; a colony stimulating factor; or a nutrient-transport molecule (a transferrin); a binding peptides having over four amino acids, or protein, or antibody, or small cell-binding molecule or ligand attached on albumin, polymers, dendrimers, liposomes, nanoparticles, vesicles, or (viral) capsids; Examples of Formula (I), (II), and (III) are illustrated below: [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] ) a009, 67 [Image disponible dans le document PDF, Image available in the PDF document] 5 7 a014, 68 [Image disponible dans le document PDF, Image available in the PDF document] a015, [Image disponible dans le document PDF, Image available in the PDF document] a016, [Image disponible dans le document PDF, Image available in the PDF document] 5 a017, [Image disponible dans le document PDF, Image available in the PDF document] . [Image disponible dans le document PDF, Image available in the PDF document] ), 5 a023, 70 [Image disponible dans le document PDF, Image available in the PDF document] 5 a028, [Image disponible dans le document PDF, Image available in the PDF document] n a032, 72 [Image disponible dans le document PDF, Image available in the PDF document] 5 a037, 73 [Image disponible dans le document PDF, Image available in the PDF document] 5 0, a042, 74 [Image disponible dans le document PDF, Image available in the PDF document] ١, a046, 75 [Image disponible dans le document PDF, Image available in the PDF document] 5 0, ~~ a051, 76 [Image disponible dans le document PDF, Image available in the PDF document] a056, [Image disponible dans le document PDF, Image available in the PDF document] F a061, [Image disponible dans le document PDF, Image available in the PDF document] ---- a062, [Image disponible dans le document PDF, Image available in the PDF document] a063, _ [Image disponible dans le document PDF, Image available in the PDF document] a064, [Image disponible dans le document PDF, Image available in the PDF document] a065, [Image disponible dans le document PDF, Image available in the PDF document] -- a066, [Image disponible dans le document PDF, Image available in the PDF document] a067, [Image disponible dans le document PDF, Image available in the PDF document] 5 a068, [Image disponible dans le document PDF, Image available in the PDF document] a069, [Image disponible dans le document PDF, Image available in the PDF document] a070, [Image disponible dans le document PDF, Image available in the PDF document] 5 avit, [Image disponible dans le document PDF, Image available in the PDF document] a075, [Image disponible dans le document PDF, Image available in the PDF document] a076, [Image disponible dans le document PDF, Image available in the PDF document] a077, [Image disponible dans le document PDF, Image available in the PDF document] a078, [Image disponible dans le document PDF, Image available in the PDF document] a079, [Image disponible dans le document PDF, Image available in the PDF document] a080, [Image disponible dans le document PDF, Image available in the PDF document] a081, [Image disponible dans le document PDF, Image available in the PDF document] a082, [Image disponible dans le document PDF, Image available in the PDF document] a083, [Image disponible dans le document PDF, Image available in the PDF document] • 5 ----- a088, [Image disponible dans le document PDF, Image available in the PDF document] 5 a093, [Image disponible dans le document PDF, Image available in the PDF document] a094, [Image disponible dans le document PDF, Image available in the PDF document] a095, [Image disponible dans le document PDF, Image available in the PDF document] a096, [Image disponible dans le document PDF, Image available in the PDF document] a097, [Image disponible dans le document PDF, Image available in the PDF document] a098, [Image disponible dans le document PDF, Image available in the PDF document] a099, [Image disponible dans le document PDF, Image available in the PDF document] a100, [Image disponible dans le document PDF, Image available in the PDF document] 5 a101, [Image disponible dans le document PDF, Image available in the PDF document] a102, [Image disponible dans le document PDF, Image available in the PDF document] a103, [Image disponible dans le document PDF, Image available in the PDF document] 5 1 .m. m. 10 a108, 88 [Image disponible dans le document PDF, Image available in the PDF document] __ • 5 __ a113, [Image disponible dans le document PDF, Image available in the PDF document] a114, [Image disponible dans le document PDF, Image available in the PDF document] a114, [Image disponible dans le document PDF, Image available in the PDF document] 5 al 15, [Image disponible dans le document PDF, Image available in the PDF document] a116, [Image disponible dans le document PDF, Image available in the PDF document] al17, [Image disponible dans le document PDF, Image available in the PDF document] _ al18, [Image disponible dans le document PDF, Image available in the PDF document] a119, [Image disponible dans le document PDF, Image available in the PDF document] a120, [Image disponible dans le document PDF, Image available in the PDF document] ~ a121, [Image disponible dans le document PDF, Image available in the PDF document] ~ a122, [Image disponible dans le document PDF, Image available in the PDF document] 5 a123, [Image disponible dans le document PDF, Image available in the PDF document] a124, 92 [Image disponible dans le document PDF, Image available in the PDF document] a125, [Image disponible dans le document PDF, Image available in the PDF document] a126, [Image disponible dans le document PDF, Image available in the PDF document] 5 a127, [Image disponible dans le document PDF, Image available in the PDF document] . .... • - a128, 93 [Image disponible dans le document PDF, Image available in the PDF document] a129, [Image disponible dans le document PDF, Image available in the PDF document] a130, [Image disponible dans le document PDF, Image available in the PDF document] 5 a131, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] a133, [Image disponible dans le document PDF, Image available in the PDF document] a134, [Image disponible dans le document PDF, Image available in the PDF document] 5 a135, [Image disponible dans le document PDF, Image available in the PDF document] a136, 95 [Image disponible dans le document PDF, Image available in the PDF document] a137, [Image disponible dans le document PDF, Image available in the PDF document] a138, [Image disponible dans le document PDF, Image available in the PDF document] 5 a139, [Image disponible dans le document PDF, Image available in the PDF document] a140, [Image disponible dans le document PDF, Image available in the PDF document] a141, [Image disponible dans le document PDF, Image available in the PDF document] a142, [Image disponible dans le document PDF, Image available in the PDF document] 5 a143, [Image disponible dans le document PDF, Image available in the PDF document] a144, [Image disponible dans le document PDF, Image available in the PDF document] a145, [Image disponible dans le document PDF, Image available in the PDF document] a146, [Image disponible dans le document PDF, Image available in the PDF document] - a147, [Image disponible dans le document PDF, Image available in the PDF document] - ) 5 [Image disponible dans le document PDF, Image available in the PDF document] a153, [Image disponible dans le document PDF, Image available in the PDF document] a154, [Image disponible dans le document PDF, Image available in the PDF document] 5 a155, [Image disponible dans le document PDF, Image available in the PDF document] a156, [Image disponible dans le document PDF, Image available in the PDF document] ___ a157, [Image disponible dans le document PDF, Image available in the PDF document] a158, [Image disponible dans le document PDF, Image available in the PDF document] 5 a159, [Image disponible dans le document PDF, Image available in the PDF document] a160, [Image disponible dans le document PDF, Image available in the PDF document] a161, [Image disponible dans le document PDF, Image available in the PDF document] a162, [Image disponible dans le document PDF, Image available in the PDF document] 5 a163, [Image disponible dans le document PDF, Image available in the PDF document] ~~~................................... a164, [Image disponible dans le document PDF, Image available in the PDF document] a165, [Image disponible dans le document PDF, Image available in the PDF document] a166, [Image disponible dans le document PDF, Image available in the PDF document] 5 a167, [Image disponible dans le document PDF, Image available in the PDF document] a168, [Image disponible dans le document PDF, Image available in the PDF document] a169, [Image disponible dans le document PDF, Image available in the PDF document] 5 a170, [Image disponible dans le document PDF, Image available in the PDF document] a171, [Image disponible dans le document PDF, Image available in the PDF document] a172, [Image disponible dans le document PDF, Image available in the PDF document] a173, [Image disponible dans le document PDF, Image available in the PDF document] a174, [Image disponible dans le document PDF, Image available in the PDF document] 5 _ ------- al75, [Image disponible dans le document PDF, Image available in the PDF document] a176, [Image disponible dans le document PDF, Image available in the PDF document] • a177, [Image disponible dans le document PDF, Image available in the PDF document] 5 a178, [Image disponible dans le document PDF, Image available in the PDF document] a179, [Image disponible dans le document PDF, Image available in the PDF document] a180, [Image disponible dans le document PDF, Image available in the PDF document] a181, [Image disponible dans le document PDF, Image available in the PDF document] 5 · · [Image disponible dans le document PDF, Image available in the PDF document] - a185, [Image disponible dans le document PDF, Image available in the PDF document] a186, [Image disponible dans le document PDF, Image available in the PDF document] 5 a187, [Image disponible dans le document PDF, Image available in the PDF document] a188, [Image disponible dans le document PDF, Image available in the PDF document] a189, [Image disponible dans le document PDF, Image available in the PDF document] a190, [Image disponible dans le document PDF, Image available in the PDF document] a191, [Image disponible dans le document PDF, Image available in the PDF document] a192, (\( \frac{1}{25} \) <Formule mathématique disponible dans le document PDF, Math available in the PDF document display="block">\begin{array}{cccccccccccccccccccccccccccccccccccc O O HN -NH 'p<com:Sub>2< / com:Sub> FO ≈0≥ M. O. O Ö ĤΝ, H LLN. >_s. N O O OH OH OH OH OH OH OH OH OH OH OH OH OH NH NH H O H <com:Math><semantics>M1−8<annotation encoding="application / x-tex">M_{1-8}< / annotation>< / semantics>< / com:Math> mAb Miles H<com:Br / >H O. HN- O. ŅН <com:Math><semantics>−NH<annotation encoding="application / x-tex">-NH< / annotation>< / semantics>< / com:Math> <com:Math><semantics>HN−<annotation encoding="application / x-tex">HN-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>R25−<annotation encoding="application / x-tex">R_{25}-< / annotation>< / semantics>< / com:Math> o'pi o n H<com:Sub>O< / com:Sub> R<com:Sub>25< / com:Sub>' m a193, [Image disponible dans le document PDF, Image available in the PDF document] a194, [Image disponible dans le document PDF, Image available in the PDF document] a195, [Image disponible dans le document PDF, Image available in the PDF document] 5 a196, [Image disponible dans le document PDF, Image available in the PDF document] a197, [Image disponible dans le document PDF, Image available in the PDF document] a198, or one or more isotope of chemical elements, pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein X<com:Sub>8< / com:Sub> is O, S, NH, NHNH, NHR<com:Sub>12< / com:Sub>, <com:Math><semantics>SR12<annotation encoding="application / x-tex">SR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSR12<annotation encoding="application / x-tex">SSR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSCH(CH3)R12<annotation encoding="application / x-tex">SSCH(CH_3)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSC(CH3)2R12<annotation encoding="application / x-tex">SSC(CH_3)_2R_{12}< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X1,X2,X3,X4,X5,X6,Y1,Y2,Y3,Y5,R12,R12,R13,R13,R25,R25,p1,p2,q1,q2,m,m1,n,and<annotation encoding="application / x-tex">X_1, X_2, X_3, X_4, X_5, X_6, Y_1, Y_2, Y_3, Y_5, R_{12}, R_{12}, R_{13}, R_{13}, R_{25}, R_{25}, p_1, p_2, q_1, q_2, m, m_1, n, and< / annotation>< / semantics>< / com:Math> mAb are described the same above; Aa is natural or unnatural amino acid; r is 0-12; (Aa)r is a peptide containing the same or different sequence of amino acids when <com:Math><semantics>r>2<annotation encoding="application / x-tex">r > 2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>r=0<annotation encoding="application / x-tex">r = 0< / annotation>< / semantics>< / com:Math> means (Aa)r absent. In another aspect of the present invention, the side chain-linkage compound is represented by Formula (IV), (V) and (VI) which can readily react to a cell-binding molecule T, or to a modified cell-binding molecule T to form a conjugate of Formula (I), (II) and (III) respectively: [Image disponible dans le document PDF, Image available in the PDF document] wherein <com:Math><semantics>D<annotation encoding="application / x-tex">D< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>D1<annotation encoding="application / x-tex">D_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>D2<annotation encoding="application / x-tex">D_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>W<annotation encoding="application / x-tex">W< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>w<annotation encoding="application / x-tex">w< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>w<annotation encoding="application / x-tex">w< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L1<annotation encoding="application / x-tex">L_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>L2<annotation encoding="application / x-tex">L_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q1<annotation encoding="application / x-tex">Q_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>Q2<annotation encoding="application / x-tex">Q_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V1<annotation encoding="application / x-tex">V_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>V2<annotation encoding="application / x-tex">V_2< / annotation>< / semantics>< / com:Math> same as in Formula (I) above; Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> are independently a reacting group that can be reacted with a thiol, amine, carboxylic acid, selenol, phenol or hydroxyl group on a cell-binding molecule. Such reacting groups are, but are not limited to, a halide (e.g., fluoride, chloride, bromide, and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethyl-sulfonyl (triflate), trifluoro- methylsulfonate, nitrophenoxyl, N-succinimidyloxyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluoro- phenoxyl, pentachloro-phenoxyl, 1H-imidazole-1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl)oxyl, 2-ethyl-5-phenylisoxazolium- 3'-sulfonyl, phenyloxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazolium-yl, phenyloxadiazol-yl (ODA), oxadiazol-yl, unsaturated carbon (a double or a triple bond between carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphrus, sulfur-nitrogen, phosphrus- nitrogen, oxygen-nitrogen, or carbon-oxygen), or an intermediate molecule generated with a condensation reagent for Mitsunobu reactions. The examples of condensation reagents are: EDC (N-(3-Dimethyl-aminopropyl)-N'-ethylcarbodiimide), DCC (Dicyclohexyl-carbodiimide), N,N'- Diisopropyl-carbodiimide (DIC), N-Cyclohexyl-N'-(2-morpholino-ethyl)carbodiimide metho-p- toluenesulfonate (CMC, or CME-CDI), 1,1'-Carbonyldiimi-dazole (CDI), TBTU (O- (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), N,N,N',N'-Tetramethyl-O- (1H-benzotriazol-1-yl)-uronium hexafluorophosphate (HBTU), (Benzotriazol-1-yloxy)tris- (dimethylamino)-phosphonium hexafluorophosphate (BOP), (Benzotriazol-1-yloxy)tripyrroli- dinophosphonium hexafluorophosphate (PyBOP), Diethyl cyanophosphonate (DEPC), Chloro- N,N,N',N'-tetramethylformamidiniumhexafluorophosphate, 1-[Bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophos-phate (HATU), 1-[(Dimethylami- no)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3-oxide hexafluoro- phosphate (HDMA), 2-Chloro-1,3-dimethyl-imidazolidinium hexafluorophosphate (CIP), Chlorotripyrrolidinophosphonium hexafluorophosphate (PvCloP). Fluoro-N.N,N',N'- bis(tetramethylene)formamidinium hexafluorophosphate (BTFFH), N,N,N',N'-Tetramethyl-S-(1- oxido-2-pyridyl)thiuronium hexafluorophosphate, O-(2-Oxo-1(2H)pyridyl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TPTU), S-(1-Oxido-2-pyridyl)-N,N,N',N'- tetramethylthiuronium tetrafluoroborate, O-[(Ethoxycarbonyl)-cyanomethylenamino]-N,N,N',N'- tetramethyluronium hexafluorophosphate (HOTU), (1-Cyano-2-ethoxy-2-oxoethylidenamino- oxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), O-(Benzotriazol-1- yl)-N,N',N'-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), N-Benzyl-N'- cyclohexyl-carbodiimide (with, or without polymer-bound), Dipyrrolidino(N-succinimidyl- oxy)carbenium hexafluoro-phosphate (HSPyU), Chlorodipyrrolidinocarbenium hexafluoro- phosphate (PyClU), 2-Chloro-1,3-dimethylimidazolidinium tetrafluoroborate(CIB), (Benzotriazol-1-yloxy)dipiperidino-carbenium hexafluorophosphate (HBPipU), O-(6- Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU), Bromotris(dimethylamino)-phosphonium hexafluorophosphate (BroP), Propylphosphonic anhydride (PPACA, T3P<com:Sup>®< / com:Sup>), 2-Morpholinoethyl isocyanide (MEI), N,N,N',N'-Tetramethyl-O-(N- succinimidyl)uronium hexafluorophosphate (HSTU), 2-Bromo-1-ethyl-pyridinium tetrafluoro- borate (BEP), O-[(Ethoxycarbonyl)cyano-methylenamino]-N,N,N',N'-tetra-methyluronium tetrafluoroborate (TOTU), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride (MMTM, DMTMM), N,N,N',N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoro-borate (TDBTU), 1, 1'-(Azodicarbonyl)-dipiperidine (ADD), Di-(4-chlorobenzyl)- azodicarboxylate (DCAD), Di-tert-butyl azodicarboxylate (DBAD), Diisopropyl azodicarboxylate (DIAD), Diethyl azodicarboxylate (DEAD). In addition, Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> can be an anhydride, formed by acid themselves or formed with other <com:Math><semantics>C1∼C8<annotation encoding="application / x-tex">C_1 \sim C_8< / annotation>< / semantics>< / com:Math> acid anhydrides; Preferably Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> are independently selected from, a halide (e.g., fluoride, chloride, bromide, and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethyl-sulfonyl (triflate), trifluoromethylsulfonate, nitrophenoxyl, N-succinimidyloxyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluoro-phenoxyl, pentachlorophenoxyl, 1H-imidazole-1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl)oxyl, 2-ethyl-5- phenylisoxazolium-3'-sulfonyl, phenyloxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5- phenylisoxazolium-yl, phenyloxadiazol-yl (ODA), oxadiazol-yl, unsaturated carbon (a double or a triple bond between carbon-carbon, carbon-nitrogen, carbon-sulfur, carbon-phosphrus, sulfur- nitrogen, phosphrus-nitrogen, oxygen-nitrogen, or carbon-oxygen), or one of the following structure: [Image disponible dans le document PDF, Image available in the PDF document] H<com:Sub>2< / com:Sub>N-O-s<com:Sup>s< / com:Sup> alkyloxyamino; N<com:Sub>3< / com:Sub> -s<com:Sup>s< / com:Sup> azido, R<com:Sub>3< / com:Sub> -s<com:Sup>s< / com:Sup> alkynyl, or H<com:Sub>2< / com:Sub>NHN -s<com:Sup>s< / com:Sup> hydrazide; wherein <com:Math><semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics>< / com:Math>' is F, Cl, Br, I or Lv<com:Sub>3< / com:Sub>; <com:Math><semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics>< / com:Math>' is O, NH, N(R<com:Sub>1< / com:Sub>), or CH<com:Sub>2< / com:Sub>; R<com:Sub>3< / com:Sub> is independently H, aromatic, heteroaromatic, or aromatic group wherein one or several H atoms are replaced independently by <com:Math><semantics>−R1<annotation encoding="application / x-tex">-R_1< / annotation>< / semantics>< / com:Math>, -halogen, <com:Math><semantics>−OR1<annotation encoding="application / x-tex">-OR_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−SR1<annotation encoding="application / x-tex">-SR_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR1R2<annotation encoding="application / x-tex">-NR_1R_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NO2<annotation encoding="application / x-tex">-NO_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)R1<annotation encoding="application / x-tex">-S(O)R_1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(O)2R1<annotation encoding="application / x-tex">-S(O)_2R_1< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−COOR1<annotation encoding="application / x-tex">-COOR_1< / annotation>< / semantics>< / com:Math>; Lv<com:Sub>3< / com:Sub> is a leaving group selected from F, Cl, Br, I, nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol; tetrachlorophenol; 1- hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenylisoxazolium-3'-sulfonate, anhydrides formed its self, or formed with the other anhydride, e.g. acetyl anhydride, formyl anhydride; or an intermediate molecule generated with a condensation reagent for peptide coupling reactions or for Mitsunobu reactions. Examples of Formula (IV), (V) and (VI) are shown below: [Image disponible dans le document PDF, Image available in the PDF document] b001, [Image disponible dans le document PDF, Image available in the PDF document] b002, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5 0041, [Image disponible dans le document PDF, Image available in the PDF document] 5 " [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] - ) 5 b038, [Image disponible dans le document PDF, Image available in the PDF document] ~ , b042, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] -8, b050, [Image disponible dans le document PDF, Image available in the PDF document] 5 r, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] b061, [Image disponible dans le document PDF, Image available in the PDF document] b062, [Image disponible dans le document PDF, Image available in the PDF document] 5 b063, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 , [Image disponible dans le document PDF, Image available in the PDF document] b070. [Image disponible dans le document PDF, Image available in the PDF document] b071, [Image disponible dans le document PDF, Image available in the PDF document] 5 b072, [Image disponible dans le document PDF, Image available in the PDF document] b073, [Image disponible dans le document PDF, Image available in the PDF document] , and [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] > 5 * [Image disponible dans le document PDF, Image available in the PDF document] 5 , [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 3, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , 5 b124, [Image disponible dans le document PDF, Image available in the PDF document] 28, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] 5, 137, [Image disponible dans le document PDF, Image available in the PDF document] 39, 148 [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 5 , [Image disponible dans le document PDF, Image available in the PDF document] b154, [Image disponible dans le document PDF, Image available in the PDF document] b155, [Image disponible dans le document PDF, Image available in the PDF document] 5 b156, [Image disponible dans le document PDF, Image available in the PDF document] 152 [Image disponible dans le document PDF, Image available in the PDF document] • ÷ [Image disponible dans le document PDF, Image available in the PDF document] 154 [Image disponible dans le document PDF, Image available in the PDF document] HN 7<com:Sub>12< / com:Sub> OH - ő N<com:Br / >H LN TO HO U H H mAb NH Ħ n HO OH b170, <com:Math><semantics>0∼H1<annotation encoding="application / x-tex">0 \stackrel{\mathrm{H}}{\sim} 1< / annotation>< / semantics>< / com:Math> NH- HN O H H O H O H O * ### OH OH N ő Ĥ <Formule mathématique disponible dans le document PDF, Math available in the PDF document display="block">\begin{array}{cccccccccccccccccccccccccccccccccccc H О Н О Н О Н О Н О Н О В В Г О Н О Н О Н О Н О Н О Н О Н О Н О Н О O H O H O H O H O H O H O H O H O H O H b172, HN O H O O N O O O O O O O O O O O O O O HO H NH H H () 5 OH b173, H O H O H O H O H O H O H O H O H O H O он b174, <Formule mathématique disponible dans le document PDF, Math available in the PDF document display="block"> \begin{array}{cccccccccccccccccccccccccccccccccccc 0 йн нг ЙH 0 HO <com:Math><semantics>=<annotation encoding="application / x-tex">=< / annotation>< / semantics>< / com:Math> H<com:Math><semantics>y<annotation encoding="application / x-tex">_{y}< / annotation>< / semantics>< / com:Math> H 'p<com:Sub>2< / com:Sub> H 0 H NH HN- ЙH 0 HO) HN. mR<com:Sub>25< / com:Sub>' b175, [Image disponible dans le document PDF, Image available in the PDF document] 157 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] --- --- b186, [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>−−<annotation encoding="application / x-tex">--< / annotation>< / semantics>< / com:Math> b187, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b192, [Image disponible dans le document PDF, Image available in the PDF document] b193, [Image disponible dans le document PDF, Image available in the PDF document] 5 [Image disponible dans le document PDF, Image available in the PDF document] T. b197, or one or more isotope of chemical elements, pharmaceutically acceptable salts, hydrates, or hydrated salts; or the polymorphic crystalline structures of these compounds; or the optical isomers, racemates, diastereomers or enantiomers; wherein X<com:Sub>8< / com:Sub> is O, S, NH, NHNH, NHR<com:Sub>12< / com:Sub>, <com:Math><semantics>SR12<annotation encoding="application / x-tex">SR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSR12<annotation encoding="application / x-tex">SSR_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSCH(CH3)R12<annotation encoding="application / x-tex">SSCH(CH_3)R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>SSC(CH3)2R12<annotation encoding="application / x-tex">SSC(CH_3)_2R_{12}< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>R12<annotation encoding="application / x-tex">R_{12}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R^5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R_4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5<annotation encoding="application / x-tex">R_5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R7<annotation encoding="application / x-tex">R_7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R8<annotation encoding="application / x-tex">R_8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9<annotation encoding="application / x-tex">R_9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R10<annotation encoding="application / x-tex">R_{10}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X1,X2,X3,X4,X5,X6,Y1,Y2,Y3,Y5,R12,R12,R13,R13,R25,R25,Z2,Z3,p.p1,p2,p3,q1,q2,q3,q4,q5,q5,q5,q6,q6,q6,q6,q6,q6,q6,q6<annotation encoding="application / x-tex">X_1, X_2, X_3, X_4, X_5, X_6, Y_1, Y_2, Y_3, Y_5, R_{12}, R_{12}, R_{13}, R_{13}, R_{25}, R_{25}, Z_2, Z_3, p. p_1, p_2, p_3, q_1, q_2, q_3, q_4, q_5, q_5, q_5, q_6, q_6, q_6, q_6, q_6, q_6, q_6, q_6< / annotation>< / semantics>< / com:Math> Lv<com:Sub>1< / com:Sub>, Lv<com:Sub>2< / com:Sub>, Lv<com:Sub>3< / com:Sub>, Lv<com:Sub>3< / com:Sub>, m, m<com:Sub>1< / com:Sub>, n, and mAb are described the same above; Aa is natural or unnatural amino acid; r is 0-12; (Aa)r is a peptide containing the same or different sequence of amino acids when <com:Math><semantics>r>2<annotation encoding="application / x-tex">r > 2< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>r=0<annotation encoding="application / x-tex">r = 0< / annotation>< / semantics>< / com:Math> means (Aa)r absent. Preferably Lv<com:Sub>1< / com:Sub>, Lv<com:Sub>2< / com:Sub>, Lv<com:Sub>3< / com:Sub> and Lv<com:Sub>3< / com:Sub>, react to thiols of a cell-binding agent / molecule. The thiols are more preferably pairs of sulfur atoms reduced from the inter chain disulfide bonds of the cell- binding agent by a reducing agent selected from dithiothreitol (DTT), dithioerythritol (DTE), L- glutathione (GSH), tris (2-carboxyethyl) phosphine (TCEP), 2-mercaptoethylamine (β-MEA), or / and beta mercaptoethanol (β-ME, 2-ME). The thiol of a cell-binding agent / molecule can also be generated through Traut's reagent or a thiolactone, wherein the Traut's reagent or a thiolactone react to an amine of the cell-binding agent / molecule to form a thiol, following by simultaneously or sequentially react to Lv<com:Sub>1< / com:Sub>, Lv<com:Sub>2< / com:Sub>, Lv<com:Sub>3< / com:Sub> or Lv<com:Sub>3< / com:Sub>. [Image disponible dans le document PDF, Image available in the PDF document] The present invention further relates to a method of making a cell-binding molecule- amatoxin analog conjugate of Formula (I), (II) and (III) as well the application of the conjugates of Formula (I), (II) and (III). THE PREPARATION OF A CONJUGATE OF A DRUG TO A CELL BINDING MOLECULE VIA A SIDE CHAIN-LINKAGE The preparation of the conjugates of an amatoxin analog to a cell binding molecules of the present invention and the synthetic routes to produce the conjugates via side chain-linkage are shown in Figures 1~19 and in the experimental section. The conjugates of Formula (I), (II) and (III) can be prepared through the intermediate compounds of Formula (IV), (V) and (VI) respectively. In general, the compounds of Formula (IV), (V) and (VI) are synthesized to have the function groups of maleimido, Lv1 and Lv2 that can be readily reacted to a cell-binding molecule or to a modified cell-binding molecule. The synthesis of the compounds of Formula (IV), (V) and (VI) and some of preparations of Formula (I), (II) and (III) are structurally shown in the Figures <com:Math><semantics>1∼19<annotation encoding="application / x-tex">1\sim19< / annotation>< / semantics>< / com:Math>. To synthesize the conjugate of Formula (I), in general, a function group <com:Math><semantics>Lv1<annotation encoding="application / x-tex">Lv_1< / annotation>< / semantics>< / com:Math> on Formula (IV) reacts one, two or more residues of a cell binding molecule at <com:Math><semantics>0−60∘<annotation encoding="application / x-tex">0 - 60^{\circ}< / annotation>< / semantics>< / com:Math>C, pH <com:Math><semantics>5∼9<annotation encoding="application / x-tex">5 \sim 9< / annotation>< / semantics>< / com:Math> aqueous media with or without addition of <com:Math><semantics>0∼30%<annotation encoding="application / x-tex">0\sim30\%< / annotation>< / semantics>< / com:Math> of water mixable (miscible) organic solvents, such as DMA, DMF, ethanol, methanol, acetone, acetonitrile, THF, isopropanol, dioxane, propylene glycol, or ethylene diol, following by dialysis or chromatographic purification to form a conjugate compound of Formula (I). Some of the residue (reacting group for conjugation) of the cell-binding molecule can be obtained through protein engineering. The conjugates of the Formula (II) and (III) can also be obtained through the reaction of the function group Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> of linkers of the Formula (V) and (VI) to two or more residues of a cell binding molecule, preferably a pair of free thiols generated through reduction of disulfide bonds of the cell-binding molecule at <com:Math><semantics>0−60∘<annotation encoding="application / x-tex">0-60^{\circ}< / annotation>< / semantics>< / com:Math>C, pH <com:Math><semantics>5∼9<annotation encoding="application / x-tex">5\sim9< / annotation>< / semantics>< / com:Math> aqueous media with or without addition of 0~30% of water mixable (miscible) organic solvents, to form the conjugate molecule. The pairs of thiols are preferred pairs of disulfide bonds reduced from the inter chain disulfide bonds of the cell-binding agent by a reducing agent which can selected from dithiothreitol (DTT), dithioerythritol (DTE), L-glutathione (GSH), tris (2-carboxyethyl) phosphine (TCEP), 2- mercaptoethylamine (<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-MEA), or / and beta mercaptoethanol (<com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-ME, 2-ME) at pH 4 ~ 9 aqueous media with or without addition of <com:Math><semantics>0∼30%<annotation encoding="application / x-tex">0\sim30\%< / annotation>< / semantics>< / com:Math> of water mixable (miscible) organic solvents. The reactive groups of Lv<com:Sub>1< / com:Sub>, and Lv<com:Sub>2< / com:Sub> on Formula (IV) (V) and (VI), which can be independently disulfide, thiol, thioester, maleimido, halogen substituted maleimidoes, haloacetyl, azide, 1-yne, ketone, aldehyde, alkoxyamino, triflate, carbonylimidazole, tosylate, mesylate, 2- ethyl-5-phenylisoxazolium-3'-sulfonate, or carboxyl acid esters of nitrophenol, N- hydroxysuccinimide (NHS), phenol; dinitrophenol, pentafluorophenol, tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, dichlorophenol, tetrachlorophenol, 1- hydroxybenzotriazole, anhydrides, or hydrazide groups, or other acid ester derivatives, can react to one, two or more groups on a cell-binding molecule / agent, simultaneously or sequentially at 0- 60°C, pH 4~9.5 aqueous media with or without addition of 0~30% of water mixable (miscible) organic solvents, to yield a conjugate of the Formula (I), (II) and (III), after column purification or dialysis. The reactive groups of <com:Math><semantics>Lv1<annotation encoding="application / x-tex">Lv_1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Lv2<annotation encoding="application / x-tex">Lv_2< / annotation>< / semantics>< / com:Math> on Formula (IV), (V) and Formula (VI) react to the modified cell-binding molecule in different ways accordingly. For example, a linkage containing disulfide bonds in a cell-binding agent-amatoxin analog conjugate of Formula (I) is achieved by a disulfide exchange between the disulfide bond in the modified cell-binding agent and Lv<com:Sub>1< / com:Sub> and Lv<com:Sub>2< / com:Sub> having a free thiol group, or by a disulfide exchange between a free thiol group in the modified cell-binding agent and a disulfide bond on Lv<com:Sub>1< / com:Sub> and / or Lv<com:Sub>2< / com:Sub>. In order to swift the disulfide exchange reaction, the disulfide group normally are a group of disulfanylpyridine, disulfanyl-nitropyridine, disulfanyl-nitrobenzene, disulfanyl-nitrobenzoic acid, or disulfanyl- dinitrobenzene, etc. A linkage containing thioether bonds in the conjugates of Formula (I) (II) and (III) is achieved by reaction of the maleimido or haloacetyl or ethylsulfonyl either on a modified cell-binding agent or a compound of Formula (IV), (V) and (VI) to a free thiol group on a compound of Formula (IV), (V) and Formula (VI) or on a modified cell-binding agent respectively; A linkage containing a bond of an acid labile hydrazone in the conjugates can be achieved by reaction of a carbonyl group of the drug of Formula (IV), (V) and (VI) or of cell- binding molecule with the hydrazide moiety on a modified cell-binding molecule or on the drug of Formula (IV), (V) and (VI) accordingly, by methods known in the art (see, for example, P. Hamann et al., Cancer Res. 53, 3336-34, 1993; B. Laguzza et al., J. Med. Chem., 32; 548-55, 1959; P. Trail et al., Cancer Res., 57; 100-5, 1997); A linkage containing a bond of triazole in the conjugates can be achieved by reaction of a 1-yne group of the drug of Formula (IV), (V) and (VI) or of cell-binding molecule with the azido moiety on the other counter part accordingly, through the click chemistry (Huisgen cycloaddition) (Lutz, J-F. et al, 2008, Adv. Drug Del. Rev.60, 958-70; Sletten, E. M. et al. 2011, AccChem. Research 44, 666-76). A linkage containing a bond of oxime in the conjugates linked via oxime is achieved by reaction of a group of a ketone or aldehyde group of the drug of Formula (IV), (V) and (VI) or of a cell-binding molecule with a group of oxyamine on the other counter part respectively. A thiol-containing cell-binding molecule can react with the drug molecule linker of of Formula (IV), (V) and (VI) bearing a maleimido, or a haloacetyl, or an ethylsulfonyl substituent at pH 5.5~9.0 in aqueous buffer to give a thioether linkage conjugate of Formula (I), (II) and (III). A thiol-containing cell- binding molecule can undergo disulfide exchange with a drug linker of Formula (IV), (V) and (VI) bearing a pyridyldithio moiety to give a conjugate having a disulfide bond linkage. A cell- binding molecule bearing a hydroxyl group or a thiol group can be reacted with a drug linker of Formula (IV), (V) and (VI) bearing a halogen, particularly the alpha halide of carboxylates, in the presence of a mild base, e.g. pH 8.0~9.5, to give a modified drug bearing an ether or thiol ether linkage. A hydroxyl or an amino group on a cell-binding molecule can be condensed with a cross drug linker of Formula (IV), (V) and (VI) bearing a carboxyl group, in the presence of a dehydrating agent, such as EDC or DCC, to give ester linkage. A cell-binding molecule containing an amino group can condensate with a group of carboxyl ester of NHS, imidazole, nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; dichlorophenol;tetrachlorophenol;1-hydroxyben-zotriazole; tosylate; mesylate; or 2-ethyl-5- phenylisoxazolium-3'-sulfonate on the drug-linker of Formula (IV), (V) and (VI) to give a conjugate via amide bond linkage. The synthetic conjugate may be purified by standard biochemical means, such as gel filtration on a Sephadex G25 or Sephacryl S300 column, adsorption chromatography, and ion exchange or by dialysis. In some cases, a small molecule as a cell-binding agent (e.g. folic acid, melanocyte stimulating hormone, EGF etc) conjugated with a small molecular drugs can be purified by chromatography such as by HPLC, medium pressure column chromatography or ion exchange chromatography. In order to achieve a higher yield of conjugation reaction for the Formula (I), (II) or (III) with a pair of free thiols on the cell-binding molecule, preferably on an antibody, a small percentage of water miscible organic solvents, or phase transfer agents, may be required to add to the reaction mixture. To cross-linking reagent (linker) of Formula (IV), (V) or (VI) can be first dissolved in a polar organic solvent that is miscible with water, for example in different alcohols, such as methanol, ethanol, and propanol, acetone, acetonitrile, tetrahydrofuran (THF), 1,4- dioxane, dimethyl formamide (DMF), dimethyl acetamide (DMA), or dimethylsulfoxide (DMSO) at a high concentration, for example 1-800 mM. Meanwhile, the cell-binding molecule, such as antibody dissolved in an aqueous buffer pH <com:Math><semantics>4.0∼9.5<annotation encoding="application / x-tex">4.0 \sim 9.5< / annotation>< / semantics>< / com:Math>, preferably pH <com:Math><semantics>6.0∼8.5<annotation encoding="application / x-tex">6.0 \sim 8.5< / annotation>< / semantics>< / com:Math>, at <com:Math><semantics>1∼50<annotation encoding="application / x-tex">1 \sim 50< / annotation>< / semantics>< / com:Math> mg / ml concentration was treated with 0.5~20 equivalent of TCEP or DTT for 20 min to 48 hour. After the reduction, DTT can be removed by SEC chromatographic purification. TCEP can be optionally removed by SEC chromatography too, or staying in the reaction mixture for the next step reaction without further purification, but preferably TCEP is neutralized with azide compounds, such as 4-azidobenzoic acid, 4-(azidomethyl)benzoic acid, or azido-polyethelene glycoyl (e. g. 2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethox antibodies or the other cell-binding agents with TCEP can be performed along with existing a drug-linker molecule of Formula (IV), (V) or (VI), for which the cross-linking conjugation of the cell-binding molecules can be achieved simultaneously along with the TCEP reduction. The aqueous solutions for the modification of cell-binding agents are buffered between pH 4 and 9, preferably between 6.0 and 8.0 and can contain any non-nucleophilic buffer salts useful for these pH ranges. Typical buffers include phosphate, acetate, triethanolamine HCl, HEPES, and MOPS buffers, which can contain additional components, such as cyclodextrins, hydroxypropyl-β-cyclodextrin, polyethylene glycols, sucrose and salts, for examples, NaCl and KCl. After the addition of the drug-linker of Formula (IV), (V) or (VI) into the solution containing the reduced cell-binding molecules, the reaction mixture is incubated at a temperature of from 0 °C to 50 °C, preferably at 15°C – 37.5 °C. The progress of the reaction can be monitored by measuring the decrease in the absorption at a certain UV wavelength, such as at 252 nm, or increase in the absorption at a certain UV wavelength, such as 280 nm, or the other appropriate wavelength. After the reaction is complete, isolation of the modified cell-binding agent can be performed in a routine way, using for example a gel filtration chromatography, an ion exchange chromatography, an adsorptive chromatography or column chromatography over silica gel or alumina, crystallization, preparatory thin layer chromatography, ion exchange chromatography, or HPLC. The extent of modification can be assessed by measuring the absorbance of the nitropyridine thione, dinitropyridine dithione, pyridine thione, carboxylamidopyridine dithione and dicarboxyl-amidopyridine dithione group released via UV spectra. For the conjugation without a chromophore group, the modification or conjugation reaction can be monitored by LC- MS, preferably by HPLC-MS / MS, UPLC-QTOF mass spectrometry, or Capilary electrophoresis—mass spectrometry (CE-MS). The side chain cross-linkers described herein have diverse functional groups that can react with any cell-binding molecules, particularly a modified cell-binding molecule that possess a suitable substituent. For examples, the modified cell-binding molecules bearing an amino or hydroxyl substituent can react with drugs bearing an N-hydroxysuccinimide (NHS) ester, the modified cell-binding molecules bearing a thiol substituent can react with drugs bearing a maleimido or haloacetyl group. Additionally, the modified cell-binding molecules bearing a carbonyl (ketone or aldehyde) substituent either through protein engineering, enzymatical reaction or chemical modification can react with drugs bearing a hydrazide or an alkoxyamine. One skilled in the art can readily determine which modified drug-linker to be used based on the known reactivity of the available functional group on the modified cell-binding molecules. CELL-BINDING AGENTS The cell-binding molecule, T or Cb or mAb, that comprises the conjugates and the modified cell-binding agents of the present invention may be of any kind presently known, or that become known, molecule that binds to, complexes with, or reacts with a moiety of a cell population sought to be therapeutically or otherwise biologically modified. The cell binding molecules / agents include, but are not limited to, large molecular weight proteins such as, for example, antibody, an antibody-like protein, full-length antibodies (polyclonal antibodies, monoclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies); single chain antibodies; fragments of antibodies such as Fab, Fab', F(ab')<com:Sub>2< / com:Sub>, F<com:Sub>v.< / com:Sub> [Parham, J. Immunol. 131, 2895-902 (1983)], fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, CDR's, diabody, triabody, tetrabody, miniantibody, small immune proteins (SIP), and epitope-binding fragments of any of the above which immuno- specifically bind to cancer cell antigens, viral antigens, microbial antigens or a protein generated by the immune system that is capable of recognizing, binding to a specific antigen or exhibiting the desired biological activity (Miller et al (2003) J. of Immunology 170: 4854-61); interferons (such as type I, II, III); peptides; lymphokines such as IL-2, IL-3, IL-4, IL-5, IL-6, IL-6R, IL-10, IL-11, IL-16, IL-17, GM-CSF, interferon-gamma (IFN-γ); hormones such as insulin, TRH (thyrotropin releasing hormones), MSH (melanocyte-stimulating hormone), steroid hormones, such as androgens and estrogens, melanocyte-stimulating hormone (MSH); growth factors and colony-stimulating factors such as epidermal growth factors (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factors (TGF), such as TGFa, TGFI3, insulin and insulin like growth factors (IGF-I, IGF-II) G-CSF, M-CSF and GM-CSF [Burgess, Immunology Today, 5, 155-8 (1984)]; vaccinia growth factors (VGF); fibroblast growth factors (FGFs); smaller molecular weight proteins, poly-peptide, peptides and peptide hormones, such as bombesin, gastrin, gastrin-releasing peptide; platelet-derived growth factors; interleukin and cytokines, such as interleukin-2 (IL-2), interleukin-6 (IL-6), leukemia inhibitory factors, granulocyte-macrophage colony-stimulating factor (GM-CSF); vitamins, such as folate; apoproteins and glycoproteins, such as transferrin [O'Keefe et al, 260 J. Biol. Chem. 932-7 (1985)]; sugar-binding proteins or lipoproteins, such as lectins; cell nutrient-transport molecules; and small molecular inhibitors, such as prostate-specific membrane antigen (PSMA) inhibitors and small molecular tyrosine kinase inhibitors (TKI), non-peptides or any other cell binding molecule or substance, such as bioactive polymers (Dhar, et al, Proc. Natl. Acad. Sci. 2008, 105, 17356-61); fusion proteins; kinase inhibitors; gene-targeting agents; bioactive dendrimers (Lee, et al, Nat. Biotechnol. 2005, 23, 1517-26; Almutairi, et al; Proc. Natl. Acad. Sci. 2009, 106, 685- 90); nanoparticles (Liong, et al, ACS Nano, 2008, 2, 1309-12; Medarova, et al, Nat. Med. 2007, 13, 372-7; Javier, et al, Bioconjugate Chem. 2008, 19, 1309-12); liposomes (Medinai, et al, Curr. Phar. Des. 2004, 10, 2981-9); viral capsides (Flenniken, et al, Viruses Nanotechnol. 2009, 327, 71-93). In general, a monoclonal antibody is preferred as a cell-surface binding agent if an appropriate one is available. And the antibody may be murine, human, humanized, chimeric, or derived from other species. Production of antibodies used in the present invention involves in vivo or in vitro procedures or combinations thereof. Methods for producing polyclonal anti-receptor peptide antibodies are well-known in the art, such as in U.S. Pat. No. 4,493,795 (to Nestor et al). A monoclonal antibody is typically made by fusing myeloma cells with the spleen cells from a mouse that has been immunized with the desired antigen (Köhler, G.; Milstein, C. (1975). Nature 256: 495-7). The detailed procedures are described in "Antibodies--A Laboratory Manual", Harlow and Lane, eds., Cold Spring Harbor Laboratory Press, New York (1988). Particularly monoclonal antibodies are produced by immunizing mice, rats, hamsters or any other mammal with the antigen of interest such as the intact target cell, antigens isolated from the target cell, whole virus, attenuated whole virus, and viral proteins. Splenocytes are typically fused with myeloma cells using polyethylene glycol (PEG) 6000. Fused hybrids are selected by their sensitivity to HAT (hypoxanthine-aminopterin- thymine). Hybridomas producing a monoclonal antibody useful in practicing this invention are identified by their ability to immunoreact specified receptors or inhibit receptor activity on target cells. A monoclonal antibody used in the present invention can be produced by initiating a monoclonal hybridoma culture comprising a nutrient medium containing a hybridoma that secretes antibody molecules of the appropriate antigen specificity. The culture is maintained under conditions and for a time period sufficient for the hybridoma to secrete the antibody molecules into the medium. The antibody-containing medium is then collected. The antibody molecules can then be further isolated by well-known techniques, such as using protein-A affinity chromatography; anion, cation, hydrophobic, or size exclusive chromatographies (particularly by affinity for the specific antigen after protein A, and sizing column chromatography); centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Media useful for the preparation of these compositions are both well-known in the art and commercially available and include synthetic culture media. An exemplary synthetic medium is Dulbecco's minimal essential medium (DMEM; Dulbecco et al., Virol. 8, 396 (1959)) supplemented with 4.5 gm / l glucose, 0~20 mM glutamine, 0~20% fetal calf serum, several ppm amount of heavy metals, such as Cu, Mn, Fe, or Zn, etc, or / and the other heavy metals added in their salt forms, and with an anti-foaming agent, such as polyoxyethylene-polyoxypropylene block copolymer. In addition, antibody-producing cell lines can also be created by techniques other than fusion, such as direct transformation of B lymphocytes with oncogenic DNA, or transfection with an oncovirus, such as Epstein-Barr virus (EBV, also called human herpesvirus 4 (HHV-4)) or Kaposi's sarcoma-associated herpesvirus (KSHV). See, U.S. Pat. Nos. 4,341,761; 4,399,121; 4,427,783; 4,444,887; 4,451,570; 4,466,917; 4,472,500; 4,491,632; 4,493,890. A monoclonal antibody may also be produced via an anti-receptor peptide or peptides containing the carboxyl terminal as described well-known in the art. See Niman et al., Proc. Natl. Acad. Sci. USA, 80: 4949-53 (1983); Geysen et al., Proc. Natl. Acad. Sci. USA, 82: 178-82 (1985); Lei et al. Biochemistry 34(20): 6675-88, (1995). Typically, the anti-receptor peptide or a peptide analog is used either alone or conjugated to an immunogenic carrier, as the immunogen for producing anti- receptor peptide monoclonal antibodies. There are also a number of other well-known techniques for making monoclonal antibodies as binding molecules in this invention. Particularly useful are methods of making fully human antibodies. One method is phage display technology which can be used to select a range of human antibodies binding specifically to the antigen using methods of affinity enrichment. Phage display has been thoroughly described in the literature and the construction and screening of phage display libraries are well known in the art, see, e.g., Dente et al, Gene. 148(1):7-13 (1994); Little et al, Biotechnol Adv. 12(3): 539-55 (1994); Clackson et al., Nature 352: 264-8 (1991); Huse et al., Science 246: 1275-81 (1989). Monoclonal antibodies derived by hybridoma technique from another species than human, such as mouse, can be humanized to avoid human anti-mouse antibodies when infused into humans. Among the more common methods of humanization of antibodies are complementarity- determining region grafting and resurfacing. These methods have been extensively described, sec e.g. U.S. Pat. Nos. 5,859,205 and 6,797,492; Liu et al, Immunol Rev. 222: 9-27 (2008); Almagro et al, Front Biosci. 13: 1619-33 (2008); Lazar et al, Mol Immunol. 44(8): 1986-98 (2007); Li et al, Proc. Natl. Acad. Sci. U S A. 103(10): 3557-62 (2006). Fully human antibodies can also be prepared by immunizing transgenic mice, rabbits, monkeys, or other mammals, carrying large portions of the human immunoglobulin heavy and light chains, with an immunogen. Examples of such mice are: the Xenomouse. (Abgenix / Amgen), the HuMAb-Mouse (Medarex / BMS), the VelociMouse (Regeneron), see also U.S. Pat. Nos. 6,596,541, 6,207,418, 6,150,584, 6,111,166, 6,075,181, 5,922,545, 5,661,016, 5,545,806, 5,436,149 and 5,569,825. In human therapy, murine variable regions and human constant regions can also be fused to construct called "chimeric antibodies" that are considerably less immunogenic in man than murine mAbs (Kipriyanov et al, Mol Biotechnol. 26: 39-60 (2004); Houdebine, Curr Opin Biotechnol. 13: 625-9 (2002). In addition, site-directed mutagenesis in the variable region of an antibody can result in an antibody with higher affinity and specificity for its antigen (Brannigan et al, Nat Rev Mol Cell Biol. 3: 964-70, (2002)); Adams et al, J Immunol Methods. 231: 249-60 (1999)) and exchanging constant regions of a mAb can improve its ability to mediate effector functions of binding and cytotoxicity. Antibodies immunospecific for a malignant cell antigen can also be obtained commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques. The nucleotide sequence encoding antibodies immune- specific for a malignant cell antigen can be obtained commercially, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing. Apart from an antibody, a peptide or protein that bind / block / target or in some other way interact with the epitopes or corresponding receptors on a targeted cell can be used as a binding molecule. These peptides or proteins could be any random peptide or proteins that have an affinity for the epitopes or corresponding receptors and they don't necessarily have to be of the immune-globulin family. These peptides can be isolated by similar techniques as for phage display antibodies (Szardenings, J Recept Signal Transduct Res. 2003, 23(4): 307-49). The use of peptides from such random peptide libraries can be similar to antibodies and antibody fragments. The binding molecules of peptides or proteins may be conjugated on or linked to a large molecules or materials, such as, but is not limited, an albumin, a polymer, a liposome, a nano particle, a dendrimer, as long as such attachment permits the peptide or protein to retain its antigen binding specificity. Examples of antibodies used for conjugation of drugs via the linkers of this prevention for treating cancer, autoimmune disease, and / or infectious disease include, but are not limited to, 3F8 (anti-GD2), Abagovomab (anti CA-125), Abciximab (anti CD41 (integrin alpha-IIb), Adalimumab (anti-TNF-α), Adecatumumab (anti-EpCAM, CD326), Afelimomab (anti-TNF-α); Afutuzumab (anti-CD20), Alacizumab pegol (anti-VEGFR2), ALD518 (anti-IL-6), Alemtuzumab (Campath, MabCampath, anti-CD52), Altumomab (anti-CEA), Anatumomab (anti-TAG-72), Anrukinzumab (IMA-638, anti-IL-13), Apolizumab (anti-HLA-DR), Arcitumomab (anti-CEA), Aselizumab (anti-L-selectin (CD62L), Atlizumab (tocilizumab, Actemra, RoActemra, anti-IL-6 receptor), Atorolimumab (anti-Rhesus factor), Bapineuzumab (anti-beta amyloid), Basiliximab (Simulect, antiCD25 (α chain of IL-2 receptor), Bavituximab (anti-phosphatidylserine), Bectumomab (LymphoScan, anti-CD22), Belimumab (Benlysta, LymphoStat-B, anti-BAFF), Benralizumab (anti-CD125), Bertilimumab (anti-CCL11 (eotaxin- 1)), Besilesomab (Scintimun, anti-CEA-related antigen), Bevacizumab (Avastin, anti-VEGF-A), Biciromab (FibriScint, anti-fibrin II beta chain), Bivatuzumab (anti-CD44 v6), Blinatumomab (BiTE, anti-CD19), Brentuximab (cAC10, anti-CD30 TNFRSF8), Briakinumab (anti-IL-12, IL- 23) Canakinumab (Ilaris, anti-IL-1), Cantuzumab (C242, anti-CanAg), Capromab, Catumaxomab (Removab, anti-EpCAM, anti-CD3), CC49 (anti-TAG-72), Cedelizumab (anti- CD4), Certolizumab pegol (Cimzia anti-TNF-α), Cetuximab (Erbitux, IMC-C225, anti-EGFR), Citatuzumab bogatox (anti-EpCAM), Cixutumumab (anti-IGF-1), Clenoliximab (anti-CD4), Clivatuzumab (anti-MUC1), Conatumumab (anti-TRAIL-R2), CR6261 (anti-Influenza A hemagglutinin), Dacetuzumab (anti-CD40), Daclizumab (Zenapax, anti-CD25 (α chain of IL-2 receptor)), Daratumumab (anti-CD38 (cyclic ADP ribose hydrolase), Denosumab (Prolia, anti- RANKL), Detumomab (anti-B-lymphoma cell), Dorlimomab, Dorlixizumab, Ecromeximab (anti-GD3 ganglioside), Eculizumab (Soliris, anti-C5), Edobacomab (anti-endotoxin), Edrecolomab (Panorex, MAb17-1A, anti-EpCAM), Efalizumab (Raptiva, anti-LFA-1 (CD11a), Efungumab (Mycograb, anti-Hsp90), Elotuzumab (anti-SLAMF7), Elsilimomab (anti-IL-6), Enlimomab pegol (anti-ICAM-1 (CD54)), Epitumomab (anti-episialin), Epratuzumab (anti- CD22), Erlizumab (anti-ITGB2 (CD18)), Ertumaxomab (Rexomun, anti-HER2 / neu, CD3), Etaracizumab (Abegrin, anti-integrin <com:Math><semantics>αvβ3<annotation encoding="application / x-tex">\alpha_v\beta_3< / annotation>< / semantics>< / com:Math>), Exbivirumab (anti-hepatitis B surface antigen), Fanolesomab (NeutroSpec, anti-CD15), Faralimomab (anti-interferon receptor), Farletuzumab (anti-folate receptor 1), Felvizumab (anti-respiratory syncytial virus), Fezakinumab (anti-IL-22), Figitumumab (anti-IGF-1 receptor), Fontolizumab (anti-IFN-γ), Foravirumab (anti-rabies virus glycoprotein), Fresolimumab (anti-TGF-β), Galiximab (anti-CD80), Gantenerumab (anti-beta amyloid), Gavilimomab (anti-CD147 (basigin)), Gemtuzumab (anti-CD33), Girentuximab (anti- carbonic anhydrase 9), Glembatumumab (CR011, anti-GPNMB), Golimumab (Simponi, anti- TNF-α), Gomiliximab (anti-CD23 (IgE receptor)), Ibalizumab (anti-CD4), Ibritumomab (anti- CD20), Igovomab (Indimacis-125, anti-CA-125), Imciromab (Myoscint, anti-cardiac myosin), Infliximab (Remicade, anti-TNF-α), Intetumumab (anti-CD51), Inolimomab (anti-CD25 (α chain of IL-2 receptor)), Inotuzumab (anti-CD22), Ipilimumab (anti-CD152), Iratumumab (anti-CD30) (TNFRSF8)), Keliximab (anti-CD4), Labetuzumab (CEA-Cide, anti-CEA), Lebrikizumab (anti- IL-13), Lemalesomab (anti-NCA-90 (granulocyte antigen)), Lerdelimumab (anti-TGF beta 2), Lexatumumab (anti-TRAIL-R2), Libivirumab (anti-hepatitis B surface antigen), Lintuzumab (anti-CD33), Lucatumumab (anti-CD40), Lumiliximab (anti-CD23 (IgE receptor), Mapatumumab (anti-TRAIL-R1), Maslimomab (anti-T-cell receptor), Matuzumab (anti-EGFR), Mepolizumab (Bosatria, anti-IL-5), Metelimumab (anti-TGF beta 1), Milatuzumab (anti-CD74), Minretumomab (anti-TAG-72), Mitumomab (BEC-2, anti-GD3 ganglioside), Morolimumab (anti-Rhesus factor), Motavizumab (Numax, anti-respiratory syncytial virus), Muromonab-CD3 (Orthoclone OKT3, anti-CD3), Nacolomab (anti-C242), Naptumomab (anti-5T4), Natalizumab (Tysabri, anti-integrin <com:Math><semantics>α4<annotation encoding="application / x-tex">\alpha_4< / annotation>< / semantics>< / com:Math>) Nebacumab (anti-endotoxin), Necitumumab (anti-EGFR), Nerelimomab (anti-TNF-α), Nimotuzumab (Theracim, Theraloc, anti-EGFR), Nofetumomab, Ocrelizumab (anti-CD20), Odulimomab (Afolimomab, anti-LFA-1 (CD11a)), Ofatumumab (Arzerra, anti-CD20), Olaratumab (anti-PDGF-R α), Omalizumab (Xolair, anti-IgE Fc region), Oportuzumab (anti-EpCAM), Oregovomab (OvaRex, anti-CA-125), Otelixizumab (anti-CD3), Pagibaximab (anti-lipoteichoic acid), Palivizumab (Synagis, Abbosynagis, anti-respiratory syncytial virus), Panitumumab (Vectibix, ABX-EGF, anti-EGFR), Panobacumab (anti- Pseudomonas aeruginosa), Pascolizumab (anti-IL-4), Pemtumomab (Theragyn, anti-MUC1), Pertuzumab (Omnitarg, 2C4, anti-HER2 / neu), Pexelizumab (anti-C5), Pintumomab (anti- adenocarcinoma antigen), Priliximab (anti-CD4), Pritumumab (anti-vimentin), PRO 140 (anti- CCR5), Racotumomab (1E10, anti-(N-glycolylneuraminic acid (NeuGc, NGNA)-gangliosides GM3)), Rafivirumab (anti-rabies virus glycoprotein), Ramucirumab (anti-VEGFR2), Ranibizumab (Lucentis, anti-VEGF-A), Raxibacumab (anti-anthrax toxin, protective antigen), Regavirumab (anti-cytomegalovirus glycoprotein B), Reslizumab (anti-IL-5), Rilotumumab (anti-HGF), Rituximab (MabThera, Rituxanmab, anti-CD20), Robatumumab (anti-IGF-1 receptor), Rontalizumab (anti-IFN-α), Rovelizumab (LeukArrest, anti-CD11, CD18), Ruplizumab (Antova, anti-CD154 (CD40L)), Satumomab (anti-TAG-72), Sevirumab (anti- cytomegalovirus), Sibrotuzumab (anti-FAP), Sifalimumab (anti-IFN-α), Siltuximab (anti-IL-6), Siplizumab (anti-CD2), (Smart) MI95 (anti-CD33), Solanezumab (anti-beta amyloid), Sonepcizumab (anti-sphingosine-1-phosphate), Sontuzumab (anti-episialin), Stamulumab (anti- myostatin), Sulesomab (LeukoScan, (anti-NCA-90 (granulocyte antigen), Tacatuzumab (anti- alpha-fetoprotein), Tadocizumab (anti-integrin <com:Math><semantics>αIIbβ3<annotation encoding="application / x-tex">\alpha_{\text{IIb}}\beta_3< / annotation>< / semantics>< / com:Math>), Talizumab (anti-IgE), Tanezumab (anti- NGF), Taplitumomab (anti-CD19), Tefibazumab (Aurexis, (anti-clumping factor A), Telimomab, Tenatumomab (anti-tenascin C), Teneliximab (anti-CD40), Teplizumab (anti-CD3), TGN1412 (anti-CD28), Ticilimumab (Tremelimumab, (anti-CTLA-4), Tigatuzumab (anti- TRAIL-R2), TNX-650 (anti-IL-13), Tocilizumab (Atlizumab, Actemra, RoActemra, (anti-IL-6) receptor), Toralizumab (anti-CD154 (CD40L)), Tositumomab (anti-CD20), Trastuzumab (Herceptin, (anti-HER2 / neu), Tremelimumab (anti-CTLA-4), Tucotuzumab celmoleukin (anti- EpCAM), Tuvirumab (anti-hepatitis B virus), Urtoxazumab (anti- Escherichia coli), Ustekinumab (Stelara, anti-IL-12, IL-23), Vapaliximab (anti-AOC3 (VAP-1)), Vedolizumab, (anti-integrin <com:Math><semantics>α4β7<annotation encoding="application / x-tex">\alpha_4\beta_7< / annotation>< / semantics>< / com:Math>), Veltuzumab (anti-CD20), Vepalimomab (anti-AOC3 (VAP-1), Visilizumab (Nuvion, anti-CD3), Vitaxin (anti-vascular integrin avb3), Volociximab (anti-integrin <com:Math><semantics>α5β1<annotation encoding="application / x-tex">\alpha_5\beta_1< / annotation>< / semantics>< / com:Math>), Votumumab (HumaSPECT, anti-tumor antigen CTAA16.88), Zalutumumab (HuMax-EGFr, (anti-EGFR), Zanolimumab (HuMax-CD4, anti-CD4), Ziralimumab (anti-CD147 (basigin)), Zolimomab (anti-CD5), Etanercept (Enbrel®), Alefacept (Amevive®), Abatacept (Orencia®), Rilonacept (Arcalyst), 14F7 [anti-IRP-2 (Iron Regulatory Protein 2)], 14G2a (anti-GD2) ganglioside, from Nat. Cancer Inst. for melanoma and solid tumors), J591 (anti-PSMA, Weill Cornell Medical School for prostate cancers), 225.28S [anti-HMW-MAA (High molecular weight-melanoma-associated antigen), Sorin Radiofarmaci S.R.L. (Milan, Italy) for melanoma], COL-1 (anti-CEACAM3, CGM1, from Nat. Cancer Inst. USA for colorectal and gastric cancers), CYT-356 (Oncoltad®, for prostate cancers), HNK20 (OraVax Inc. for respiratory syncytial virus), ImmuRAIT (from Immunomedics for NHL), Lym-1 (anti-HLA-DR10, Peregrine Pharm. for Cancers), MAK-195F [anti-TNF (tumor necrosis factor; TNFA, TNF- alpha; TNFSF2), from Abbott / Knoll for Sepsis toxic shock], MEDI-500 [T10B9, anti-CD3, TRαβ (T cell receptor alpha / beta), complex, from MedImmune Inc for Graft-versus-host disease], RING SCAN [ anti-TAG 72 (tumour associated glycoprotein 72), from Neoprobe Corp. for Breast, Colon and Rectal cancers], Avicidin (anti-EPCAM (epithelial cell adhesion molecule), anti-TACSTD1 (Tumor-associated calcium signal transducer 1), anti-GA733-2 (gastrointestinal tumor-associated protein 2), anti-EGP-2 (epithelial glycoprotein 2); anti-KSA; KS1 / 4 antigen; M4S; tumor antigen 17-1A; CD326, from NeoRx Corp. for Colon, Ovarian, Prostate cancers and NHL]; LymphoCide (Immunomedics, NJ), Smart ID10 (Protein Design Labs), Oncolym (Techniclone Inc, CA), Allomune (BioTransplant, CA), anti-VEGF (Genentech, CA); CEAcide (Immunomedics, NJ), IMC-1C11 (ImClone, NJ) and Cetuximab (ImClone, NJ). Other antibodies as cell binding molecules / ligands include, but are not limited to, are antibodies against the following antigens: Aminopeptidase N (CD13), Annexin A1, B7-H3 (CD276, various cancers), CA125 (ovarian), CA15-3 (carcinomas), CA19-9 (carcinomas), L6 (carcinomas), Lewis Y (carcinomas), Lewis X (carcinomas), alpha fetoprotein (carcinomas), CA242 (colorectal), placental alkaline phosphatase (carcinomas), prostate specific antigen (prostate), prostatic acid phosphatase (prostate), epidermal growth factor (carcinomas), CD2 (Hodgkin's disease, NHL lymphoma, multiple myeloma), CD3 epsilon (T cell lymphoma, lung, breast, gastric, ovarian cancers, autoimmune diseases, malignant ascites), CD19 (B cell malignancies), CD20 (non-Hodgkin's lymphoma), CD22 (leukemia, lymphoma, multiple myeloma, SLE), CD30 (Hodgkin's lymphoma), CD33 (leukemia, autoimmune diseases), CD38 (multiple myeloma), CD40 (lymphoma, multiple myeloma, leukemia (CLL)), CD51 (Metastatic melanoma, sarcoma), CD52 (leukemia), CD56 (small cell lung cancers, ovarian cancer, Merkel cell carcinoma, and the liquid tumor, multiple myeloma), CD66e (cancers), CD70 (metastatic renal cell carcinoma and non-Hodgkin lymphoma), CD74 (multiple myeloma), CD80 (lymphoma), CD98 (cancers), mucin (carcinomas), CD221 (solid tumors), CD227 (breast, ovarian cancers), CD262 (NSCLC and other cancers), CD309 (ovarian cancers), CD326 (solid tumors), CEACAM3 (colorectal, gastric cancers), CEACAM5 (carcinoembryonic antigen; CEA, CD66e) (breast, colorectal and lung cancers), DLL3 (delta-like-3), DLL4 (delta-like-4), EGFR (Epidermal Growth Factor Receptor, various cancers), CTLA4 (melanoma), CXCR4 (CD184, Heme-oncology, solid tumors), Endoglin (CD105, solid tumors), EPCAM (epithelial cell adhesion molecule, bladder, head, neck, colon, NHL prostate, and ovarian cancers), ERBB2 (Epidermal Growth Factor Receptor 2; lung, breast, prostate cancers), FCGR1 (autoimmune diseases), FOLR (folate receptor, ovarian cancers), GD2 ganglioside (cancers), G-28 (a cell surface antigen glyvolipid, melanoma), GD3 idiotype (cancers), Heat shock proteins (cancers), HER1 (lung, stomach cancers), HER2 (breast, lung and ovarian cancers), HLA-DR10 (NHL), HLA-DRB (NHL, B cell leukemia), human chorionic gonadotropin (carcinoma), IGF1R (insulin-like growth factor 1 receptor, solid tumors, blood cancers), IL-2 receptor (interleukin 2 receptor, T-cell leukemia and lymphomas), IL-6R (interleukin 6 receptor, multiple myeloma, RA, Castleman's disease, IL6 dependent tumors), Integrins (<com:Math><semantics>ανβ3<annotation encoding="application / x-tex">\alpha \nu \beta 3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>α5β1<annotation encoding="application / x-tex">\alpha 5\beta 1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>α6β4<annotation encoding="application / x-tex">\alpha 6\beta 4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>α11β3<annotation encoding="application / x-tex">\alpha 11\beta 3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>α5β5<annotation encoding="application / x-tex">\alpha 5\beta 5< / annotation>< / semantics>< / com:Math>, ανβ5, for various cancers), MAGE-1 (carcinomas), MAGE-2 (carcinomas), MAGE-3 (carcinomas), MAGE 4 (carcinomas), anti-transferrin receptor (carcinomas), p97 (melanoma), MS4A1 (membrane-spanning 4-domains subfamily A member 1, Non-Hodgkin's B cell lymphoma, leukemia), MUC1 or MUC1-KLH (breast, ovarian, cervix, bronchus and gastrointestinal cancer), MUC16 (CA125) (Ovarian cancers), CEA (colorectal), gp100 (melanoma), MART1 (melanoma), MPG (melanoma), MS4A1 (membrane-spanning 4-domains subfamily A, small cell lung cancers, NHL), Nucleolin, Neu oncogene product (carcinomas), P21 (carcinomas), Paratope of anti-(N-glycolylneuraminic acid, Breast, Melanoma cancers), PLAP-like testicular alkaline phosphatase (ovarian, testicular cancers), PSMA (prostate tumors), PSA (prostate), ROBO4, TAG 72 (tumour associated glycoprotein 72, AML, gastric, colorectal, ovarian cancers), T cell transmembrane protein (cancers), Tie (CD202b), TNFRSF10B (tumor necrosis factor receptor superfamily member 10B, cancers), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B, multiple myeloma, NHL, other cancers, RA and SLE), TPBG (trophoblast glycoprotein, Renal cell carcinoma), TRAIL-R1 (Tumor necrosis apoprosis Inducing ligand Receptor 1, lymphoma, NHL, colorectal, lung cancers), VCAM-1 (CD106, Melanoma), VEGF, VEGF-A, VEGF-2 (CD309) (various cancers). Some other tumor associated antigens recognized by antibodies have been reviewed (Gerber, et al, mAbs 1:3, 247- 53 (2009); Novellino et al, Cancer Immunol Immunother. 54(3), 187-207 (2005). Franke, et al, Cancer Biother Radiopharm. 2000, 15, 459-76). The cell-binding agents, more preferred antibodies, can be any agents that are able to against tumor cells, virus infected cells, microorganism infected cells, parasite infected cells, autoimmune cells, activated cells, myeloid cells, activated T-cells, B cells, or melanocytes. More specifically the cell binding agents can be any agent / molecule that is able to against any one of the following antigens or receptors: CD1, CD1a, CD1b, CD1c, CD1d, CD1e, CD2, CD3, CD3d, CD3e, CD3g, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, CD10, CD11a, CD11b, CD11c, CD11d, CD12w, CD14, CD15, CD16, CD16a, CD16b, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD49c, CD49d, CD49f, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, CD85a, CD85b, CD85c, CD85d, CD85e, CD85f, CD85g, CD85g, CD85i, CD85j, [Image disponible dans le document PDF, Image available in the PDF document] (Trophoblast glycoprotein, TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF1), Adenocarcinomaantigen, AGS-5, AGS-22M6, Activin receptor-like kinase 1, AFP, AKAP-4, ALK, Alpha intergrin, Alpha v beta6, Amino-peptidase N, Amyloid beta, Androgen receptor, Angiopoietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin-protective antigen, Anti-transferrin receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracisanthrax, 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 chemokine 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 B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glycoprotein B, Dabigatran, DLL3 (delta-like-ligand 3), DLL4 (delta-like-ligand 4), DPP4 (Dipeptidyl-peptidase 4), DR5 (Death receptor 5), E. coli shiga toxintype-1, E. coli shiga toxintype-2, ED-B, EGFL7 (EGF-like domain-containing protein 7), EGFR, EGFRII, EGFRVIII, Endoglin (CD105), 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 proteinalpha), FCGR1, alpha- Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, FOLR (folate receptor), Folate receptor alpha, Folate hydrolase, Fos-related antigen 1, 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 α-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 (Hepatocyte 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, Influeza hemag-glutinin, 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-16, IL-17, IL-17A, IL-20, IL-22, IL-23, IL31RA, ILGF2 (Insulin-like growth factor 2), Integrins (<com:Math><semantics>α4<annotation encoding="application / x-tex">\alpha 4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>αIIbβ3<annotation encoding="application / x-tex">\alpha_{IIb}\beta_{3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>ανβ3<annotation encoding="application / x-tex">\alpha \nu \beta_{3}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>α4β7<annotation encoding="application / x-tex">\alpha_{4}\beta_{7}< / annotation>< / semantics>< / com:Math>. α5β1, α6β4, α7β7,αllβ3, α5β5, ανβ5), Interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, LCK, Le, Legumain, Lewis-Y antigen, LFA-1(Lymphocyte function-associated antigen 1, CD11a), LHRH, LINGO-1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF (Macrophage migration inhibitory factor, or glycosylation-inhibiting factor (GIF)), MS4A1 (membrane-spanning 4-domains subfamily A member 1), MSLN (meso-thelin), MUC1(Mucin 1, cell surfaceassociated (MUC1) orpolymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1(monocyte chemotactic protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1 (membrane-spanning 4-domains subfamily A), MYCN, Myelin-associated glycoprotein, Myostatin, 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-Rα (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 (Phos- phatidylserine), Prostatic carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD (...

Claims

1. A side chain-linked conjugate compound of the Formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) wherein "—" represents a single bond; n is 1 to 30; T is a cell-binding agent or molecule comprising an antibody; L 1 L_1 and L 2 L_2 are, the same or different and are independently N, N ( R 12 ) N(R_{12}) , N ( R 12 ) N ( R 12 ) N(R_{12})N(R_{12}) , CH, CO, C(O)NH, C(O)O, NHC(O)NH, NHC(O)O, or (Aa) r , r=1 (one amino acid unit), which is an amino acid; W is a stretcher unit having C 1 C_1 - C 18 C_{18} , comprising a self-immolative spacer, a peptidyl unit, a hydrazone, a disulfide, a thioether, an ester, or an amide bond; w is 1 or 2 or 3; V 1 and V 2 are independently a spacer unit comprising O, NH, S, C 1 -C 8 alkyl, C 2 -C 8 heteroalkyl, (Aa) r , r=1-12 (one to 12 amino acid units); or (CH 2 CH 2 O) p , p is 0-100; and v 1 and v 2 v_2 are independently 0, 1 or 2, but v 1 v_1 and v 2 v_2 are not 0 at the same time; when v 1 v_1 or v 2 v_2 is 0, it means one of the side chain Q1 or Q2 fragment is absent; Q 1 and Q 2 are independently represented by Formula (I-q1): [Image disponible dans le document PDF, Image available in the PDF document] ( I − q 1 ) ; (I-q1); wherein ∼ \sim is the site linked to L 1 or L 2 ; G 1 and G 2 are independently OC(O), N H C ( O ) NHC(O) , C ( O ) C(O) , C H 2 CH_2 , N H NH , O C ( O ) N H OC(O)NH , N H C ( O ) N H NHC(O)NH , O O , S S , N H P ( O ) ( O H ) NHP(O)(OH) , N H P ( O ) ( O H ) N H NHP(O)(OH)NH , O P ( O ) ( O H ) O OP(O)(OH)O , N H S ( O ) 2 NHS(O)_2 , N H S ( O ) 2 N H NHS(O)_2NH , A r Ar , or ( A a ) q 1 (Aa)_{q1} ; G 3 G_3 is O R 12 OR_{12} , S R 12 SR_{12} , O C ( O ) R 12 OC(O)R_{12} , N H C ( O ) R 12 NHC(O)R_{12} , C ( O ) R 12 C(O)R_{12} , C H 3 CH_3 , N R 12 NR_{12} , + N H ( R 12 ) {}^{+}NH(R_{12}) , + N ( R 12 ) ( R 12 ) ^{+}N(R_{12})(R_{12}) , C(O)OH, C(O)NH 2 , NHC(O)NH 2 , P(O)(OH) 2 , NHP(O)(OH) 2 , S(O) 2 (OH), ( C H 2 ) q 1 C ( O ) O H , C ( O ) ( C H 2 ) q 1 C ( O ) O H , O C ( O ) ( C H 2 ) q 1 C ( O ) O H , N H C ( O ) ( C H 2 ) q 1 C ( O ) O H , (CH_2)_{q1}C(O)OH, C(O)(CH_2)_{q1}C(O)OH, OC(O)(CH_2)_{q1}C(O)OH, NHC(O)(CH_2)_{q1}C(O)OH, or ( A a ) q 1 (Aa)_{q1} ; [Image disponible dans le document PDF, Image available in the PDF document] + N(R 12 )(R 12 , C(O), OC(O), OC(O)O, OC(O)NH, or NHC(O)NH; R 12 , R 12 , R 13 and R 13 are independently H, or C 1 ∼ C 8 C_1 \sim C_8 alkyl; Y 2 is O, NH, NR 1 , CH 2 , S, NHNH, or Ar; p 1 p_1 , p 2 p_2 and p 3 p_3 are independently 0 -100 but are not 0 at the same time; q 1 q_1 and q 2 q_2 are independently 0 -24; alternatively Q 1 and Q 2 are independently a C 6 -C 100 poly(ethylene glycol) (PEG) or poly(ethylene glycol)-containing an amino acid or peptides; alternatively, any one or more of W, Q 1 , Q 2 , L 1 , L 2 , V 1 , or V 2 , can be independently ab- sent but Q 1 Q_1 , and Q 2 Q_2 are not absent at the same time; D is a cytotoxic agent comprising a calicheamicin, a maytansinoid, a camptothecin, a taxane, an anthracycline, daunorubicin, doxorubicin, a vinca alkaloid, an auristatin, an eribu- lin, a (pyrrolo)benzodiazepine (PBD), a CC-106 / duocarmycin, a tubulysin, a protein kinase inhibitor, a MEK inhibitor, a KSP inhibitor, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, or an immunotoxin.

2. A side chain-linked conjugate compound of Formula (II) or (III): [Image disponible dans le document PDF, Image available in the PDF document] (III), wherein D, W, L 1 L_1 , L 2 L_2 , Q 1 Q_1 , Q 2 Q_2 , V 1 V_1 , V 2 V_2 , v 1 v_1 , v 2 v_2 , v 1 v_1 , v 2 v_2 , v 3 v_3 , v 4 v_4 are as defined in claim 1; w and w'are independently 1, 2 or 3; is a single bond, double bond or absent, and D 1 D_1 and D 2 D_2 are the same or different, and have the same definition as D as defined in claim 1.

3. A side chain-linked compound of Formula (IV) which can readily react to a cell- binding molecule T to form a conjugate of Formula (I) as defined in claim 1: [Image disponible dans le document PDF, Image available in the PDF document] (IV) wherein D, W, w, L 1 L_1 , L 2 L_2 , Q 1 Q_1 , Q 2 Q_2 , V 1 V_1 , V 2 V_2 , v 1 v_1 , v 2 v_2 , and n are as defined in claim 1; Lv 1 is a reacting group that can be reacted with a thiol, amine, carboxylic acid, selenol, phenol or hydroxyl group on a cell-binding molecule, wherein Lv 1 is OH; F; Cl; Br; I; nitro- phenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetrafluor- ophenol; difluorophenol; mono-fluorophenol; pentachlorophenol; triflate; imidazole; dichlo- rophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phenyli- soxazolium-3'-sulfonate, an anhydride formed with itself, or formed with acetyl anhydride, formyl anhydride; [Image disponible dans le document PDF, Image available in the PDF document] (fluorophenoxy)-acetyl; -(difluorophenoxy)-acetyl; 2-(((trifluoromethyl)-sulfonyl)oxy)acetyl; phenyl ke- tone or aldehyde, 2-(pentafluorophenoxy)acetyl; N − N N-N [Image disponible dans le document PDF, Image available in the PDF document] MeO 2 S methylsulfonephenyloxadiazole (ODA); [Image disponible dans le document PDF, Image available in the PDF document] acid anhydride, H 2 N -0 alkyloxyamino; N 3 azido, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] alkynyl, or hydrazide; wherein X 1 X_1 ' is F, Cl, Br, I or Lv 3 ; X 2 X_2 ' is O, NH, N(R 1 ), or CH 2 ; R 3 is independently H, aromatic, heteroaromatic, or aromatic group wherein one or several H atoms are replaced independently by -R 1 , -halogen, -OR 1 , -SR 1 , - N R 1 R 2 NR_1R_2 , - N O 2 NO_2 , - S ( O ) R 1 S(O)R_1 ,- S ( O ) 2 R 1 S(O)_2R_1 , or - C O O R 1 COOR_1 ; Lv 3 is a leaving group comprising F, Cl, Br, I, nitrophenol; N-hydroxysuccinimide (NHS); phenol; dinitrophenol; pentafluorophenol; tetra- fluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; triflate; imidazole; di- chlorophenol; tetrachlorophenol; 1-hydroxybenzotriazole; tosylate; mesylate; 2-ethyl-5-phe- nylisoxazolium-3'-sulfonate, an anhydride formed with itself, or formed with acetyl anhy- dride or formyl anhydride.

4. A side chain-linked compound of Formula (V) and (VI), which can readily react to a cell-binding molecule T to form a conjugate of Formula (II) and (III) respectively as defined in claim 2: [Image disponible dans le document PDF, Image available in the PDF document] wherein D D , D 1 D_1 , D 2 D_2 , W W , w w , L 1 L_1 , L 2 L_2 , Q 1 Q_1 , Q 2 Q_2 , V 1 V_1 , V 2 V_2 , V 1 V_1 , V 2 V_2 , V 2 V_2 , V 2 V_2 , and V 2 V_2 , are as defined in claim 1; wherein Lv 1 is as defined in claim 3, and Lv 2 independently has the same definition as L v 1 Lv_1 as defined in claim 3.

5. A side chain-linked compound according to any one of claims 1 to 4, wherein the side chains Q 1 and Q 2 are independently one of Iq-01 to Iq-37 below: [Image disponible dans le document PDF, Image available in the PDF document] 10, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein R 25 and R 25 , are independently H; HC(O), CH 3 C(O), CH 3 C(NH), NHCH 3 , COOH, CONH 2 , CONHCH 3 , C 1 -C 18 alkyl, alkyl-Y 1 -SO 3 H, C 1 -C 18 alkyl-Y 1 -PO 3 H 2 , C 1 -C 18 alkyl-Y 1 -CO 2 H, C 1 -C 18 alkyl-Y 1 -N + R 12 R 13 R 13 'R 14 , C 1 -C 18 alkyl-Y 1 -CONH 2 , C 2 -C 18 al- kylene, a peptide of 1~24 amino acids; C 2 -C 18 lipid, a C 2 -C 18 fatty acid or a C 2 -C 18 fatty am- monium lipid; X 1 and X 2 are independently NH, N(R 12 '), O, CH 2 , S, C(O), S(O 2 ), P(O)(OH), NHNH, CH=CH, Ar or ( A a ) q 1 , q 1 = 0 − 24 ; (Aa)q_1, q_1 = 0-24; X 3 , X 4 , Y 1 , Y 2 and Y 3 are independently NH, N(R 12 '), O, C(O), CH 2 , S, NHNH, C(O), O C ( O ) OC(O) , O C ( O ) O OC(O)O , O C ( O ) N H OC(O)NH , N H C ( O ) N H NHC(O)NH , A r Ar or ( A a ) q 1 (Aa)q_1 , wherein X 1 X_1 , X 2 X_2 , X 3 X_3 , X 4 X_4 , Y 1 Y_1 , Y 2 Y_2 and Y 3 Y_3 can be independently absent; p 1 p_1 , p 2 p_2 and p 3 p_3 are independently 0 -100 but are not 0 at the same time; q 1 , q 2 and q 3 are independently 0-24; R 12 , R 13 , R 13 ' and R 14 ' are independently H or C 1 - C 6 alkyl; Aa is an amino acid; Ar or ( A a ) q 1 (Aa)q_1 , is the same or different sequence of peptides; q 1 = 0 q_1=0 means ( A a ) q 1 (Aa)q_1 absent. 6 . A s i d e c h a i n − l i n k e d c o m p o u n d a c c o r d i n g t o a n y o n e o f c l a i m s 1 t o 4 , w h e r e i n D , D 1 6. \ A \ side \ chain-linked \ compound \ according \ to \ any \ one \ of \ claims \ 1 \ to \ 4, \ wherein \ D, \ D_1 and D 2 D_2 are each independently: (A) a Calicheamicin analog: [Image disponible dans le document PDF, Image available in the PDF document] (Ia); wherein ∼ ∼ \sim \sim is the connecting site; (B) a Maytansinoid: [Image disponible dans le document PDF, Image available in the PDF document] (Ib), wherein ∼ \sim is the connecting site; (C) a Camptothecin: [Image disponible dans le document PDF, Image available in the PDF document] nalog, - - [Image disponible dans le document PDF, Image available in the PDF document] 06), Irinotecan ana- log, [Image disponible dans le document PDF, Image available in the PDF document] . 19 C-132 analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-16), BN-80927 analog, [Image disponible dans le document PDF, Image available in the PDF document] (Ic-17), BN-80927 analog, wherein ∼ ∼ \sim \sim is the connecting site; wherein R 1 , R 2 and R 4 are independently H, F, Cl, Br, CN, NO 2 , C 1 ~C 8 alkyl; O-C 1 ~C 8 alkyl; NH-C 1 ~C 8 alkyl; C 2 -C 8 heteroalkyl, heterocycloalkyl; or C 2 -C 8 esters, ether, amide, carbonate, urea, or carbamate; R 3 is H, OH, NH 2 , C 1 ∼ C 8 C_1 \sim C_8 alkyl; O- C 1 ∼ C 8 C_1 \sim C_8 alkyl; NH- C 1 ∼ C 8 C_1 \sim C_8 alkyl; C 2 - C 8 C_8 heteroalkyl, heterocycloalkyl; or C 2 -C 8 ether or amide; or R 1 R 2 and R 3 R 4 independently form a 5~7 membered carbocyclic, heterocyclic or het- erocycloalkyl ring system; P 1 P^{1} is H, OH, NH 2 , COOH, C(O)NH 2 , OCH 2 OP(O)(OR 18 ) 2 , O C ( O ) O P ( O ) ( O R 18 ) 2 OC(O)OP(O)(OR^{18})_2 , O P O ( O R 18 ) 2 OPO(OR^{18})_2 , N H P O ( O R 18 ) 2 NHPO(OR^{18})_2 , O C ( O ) R 18 OC(O)R^{18} , OP(O)(OR 18 )OP(O)(OR 18 ) 2 , OC(O)NHR 18 , OC(O)N(C 2 H 4 ) 2 NCH 3 , OSO 2 (OR 18 ), O-(C 4 - C 12 C_{12} -glycoside), O C ( O ) N ( C 2 H 4 ) 2 C H 2 N ( C 2 H 4 ) 2 C H 3 OC(O)N(C_2H_4)_2CH_2N(C_2H_4)_2CH_3 , C 1 C_1 - C 8 C_8 alkyl or heteroalkyl; R 17 R^{17} and R 18 R^{18} are independently H, C 1 C_1 - C 8 C_8 alkyl or heteroalkyl; (D) a Taxane or one of the following analogs: [Image disponible dans le document PDF, Image available in the PDF document] , wherein ∼ \sim is the connecting site; Ar and Ar' are independently aryl or heteroaryl; (E) an Anthracycline or one of the following analogs: [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ( I e − 12 ) , (Ie-12), [Image disponible dans le document PDF, Image available in the PDF document] (Ie-13) Amrubicin analog, wherein ∼ \sim is the con- necting site; (F) A Vinca alkaloid: [Image disponible dans le document PDF, Image available in the PDF document] (If-01), vincristine (leurocristine), (If-02), vincristine (leurocristine), [Image disponible dans le document PDF, Image available in the PDF document] , f-05), Rifabutin analog, [Image disponible dans le document PDF, Image available in the PDF document] (G) an Auristatin or dolastatin analog: [Image disponible dans le document PDF, Image available in the PDF document] ), ), [Image disponible dans le document PDF, Image available in the PDF document] wherein R 1 , R 2 , R 3 , R 4 and R 5 are independently H; C 1 -C 8 lineal or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, or peptides containing 1-8 amino acids; the two Rs: R 1 R 2 , R 2 R 3 , R 1 R 3 or R 3 R 4 can form 3~8 member cyclic ring alkyl, heteroal- kyl, or alkylcycloalkyl group; X 3 is H, CH 3 or X 1 'R 1 ', wherein X 1 ' is NH, N(CH 3 ), NHNH, O, or S, R 1 R_1 ' is H or C 1 C_1 - C 8 C_8 lineal or branched alkyl; R 3 R_3 ' is H or C 1 C_1 - C 6 C_6 lineal or branched alkyl; Z 3 ' is H, COOR 1 , NH 2 , NHR 1 , OR 1 , CONHR 1 ,NHCOR 1 , OCOR 1 , OP(O)(OM 1 )(OM 2 ), OCH 2 OP(O)(OM 1 )(OM 2 ), OSO 3 M 1 , R 1 , or O-glycoside, NH-glycoside, S-glycoside or CH 2 - glycoside; M 1 and M 2 are independently H, Na, K, Ca, Mg, NH 4 ; Y 1 and Y 2 are independently O, NH, NHNH, NR 5 , S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, C(O)NHNHC(O) and C(O)NR 1 when linked to the connecting site " "; or OH, NH 2 , NHNH 2 , NHR 5 , SH, C(O)OH, C(O)NH 2 , OC(O)NH 2 , OC(O)OH, N H C ( O ) N H 2 NHC(O)NH_2 , N H C ( O ) S H NHC(O)SH , O C ( O ) N H ( R 1 ) OC(O)NH(R_1) , N ( R 1 ) C ( O ) N H ( R 2 ) N(R_1)C(O)NH(R_2) , C ( O ) N H N H C ( O ) O H C(O)NHNHC(O)OH and C ( O ) N H R 1 C(O)NHR_1 when not linked to the connecting site " ∼ \sim "; [Image disponible dans le document PDF, Image available in the PDF document] wherein Aa is 1-8 the same or different amino acids; p is 1 -5000; R 1 , R 2 , R 3 , R 4 , R 5 , and R 5 ' are independently H or C 1 -C 8 alkyl; (H) An Eribulin: [Image disponible dans le document PDF, Image available in the PDF document] (I) An Inhibitor of nicotinamide phosphoribosyltransferases (NAMPT): [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - wherein " ∼ \sim " and X 1 X_1 are as defined in claim 5; X 5 X_5 is F, Cl, Br, I, OH, OR 1 , R 1 , OPO 3 H 2 , OSO 3 H, NHR 1 , OCOR 1 , NHCOR 1 ; (J) a benzodiazepine dimer or one of the following analogs: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] i, wherein X 1 , X 2 , Y 1 and Y 2 are independently O, N, NH, NHNH, NR 5 , S, C(O)O, C ( O ) N H C(O)NH , O C ( O ) N H OC(O)NH , O C ( O ) O OC(O)O , N H C ( O ) N H NHC(O)NH , C H CH , or C ( O ) N H N H C ( O ) C(O)NHNHC(O) ; R 1 R^1 , R 2 R^2 , R 3 R^3 , R 1 ′ R^{1'} , R 2 ′ R^{2'} , and R 3 ′ R^{3'} are independently H; F; Cl; =O; =S; OH; SH; C 1 -C 8 alkyl, aryl, alkenyl, ester (COOR 5 or − O C ( O ) R 5 -OC(O)R_5 ); the two Rs: R 1 R 2 , R 2 R 3 , R 1 R 3 , R 1 'R 2 ', R 2 'R 3 ', or R 1 'R 3 ' can independently form 3~8 member cyclic ring of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl group; X 3 and Y 3 are independently N, NH, or CH 2 , wherein R 4 , R 5 , R 6 , R 12 and R 12 ' are independently H, OH, NH 2 , NH(CH 3 ), NHNH 2 , COOH, F, Cl, or C 1 -C 8 alkyl, heteroaryl, heteroalkyl; Z 3 is H, OP(O)(OM 1 )(OM 2 ), OCH 2 OP(O)(OM 1 )(OM 2 ), OSO 3 M 1 , O-glycoside, or NH- glycoside; M 1 and M 2 are independently H, Na, K, Ca, Mg, or NH 4 ; (K) an CC-1065 analog or doucarmycin analog: [Image disponible dans le document PDF, Image available in the PDF document] - 9 5, [Image disponible dans le document PDF, Image available in the PDF document] Э, [Image disponible dans le document PDF, Image available in the PDF document] CC07, wherein X 1 , X 2 , Y 1 and Y 2 are independently O, NH, NHNH, NR 5 , S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, OC(O)N(R 1 ), C(O)NHNHC(O) and C(O)NR 1 when linked to the connecting site "\sim "; or OH, NH 2 , NHNH 2 , NHR 1 , C(O)OH, C(O)NH 2 , O C ( O ) N H 2 OC(O)NH_2 , O C ( O ) O H OC(O)OH , N H C ( O ) N H 2 NHC(O)NH_2 , O C ( O ) N H ( R 1 ) OC(O)NH(R_1) , N ( R 1 ) C ( O ) N H ( R 2 ) N(R_1)C(O)NH(R_2) , C ( O ) N H N H C ( O ) O H C(O)NHNHC(O)OH and C ( O ) N H R 1 C(O)NHR_1 when not linked to the connecting site " ∼ \sim "; Z 3 Z_3 is H, PO(OM 1 )(OM 2 ), SO 3 M 1 , CH 2 PO(OM 1 )(OM 2 ), CH 3 N(CH 2 CH 2 ) 2 NC(O)-, O ( C H 2 C H 2 ) 2 N C ( O ) O(CH_2CH_2)_2NC(O) -, or glycoside; wherein R 1 , R 2 , and R 3 are independently H or C 1 -C 8 alkyl; M 1 and M 2 , are inde- pendently H, Na, K, Ca, Mg, or NH 4 ; (L) a Tubulysin or one of the following analogs: [Image disponible dans le document PDF, Image available in the PDF document] Tb01, [Image disponible dans le document PDF, Image available in the PDF document] , 315 [Image disponible dans le document PDF, Image available in the PDF document] wherein X 1 ,and Y 1 are independently O, NH, NHNH, NR 5 , C(O)O, C(O)NH, O C ( O ) N H OC(O)NH , O C ( O ) O OC(O)O , N H C ( O ) N H NHC(O)NH , O C ( O ) N ( R 1 ) OC(O)N(R_1) , N ( R 1 ) C ( O ) N ( R 1 ) N(R_1)C(O)N(R_1) , C H CH , C ( O ) N H N H C ( O ) C(O)NHNHC(O) or C ( O ) N R 1 ; C(O)NR_1; R 12 is OH, NH 2 , NHR 1 , NHNH 2 , NHNHCOOH, O-R 1 -COOH, NH-R 1 -COOH, NH- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein Aa is 1-8 amino acids; n and m 1 m_1 are independently 1-20; p is 1-5000; R 1 , R 1 ', R 2 , R 3 , and R 4 are independently H, C 1 -C 8 alkyl, or C 2 -C 8 heteroalkyl or hetero- cycloalkyl; the two Rs: R 1 R 2 , R 2 R 3 , R 1 R 3 or R 3 R 4 can form 3~8 member cyclic ring alkyl, het- eroaryl, heteroalkyl, or alkylcycloalkyl group; X 3 is H, CH 3 , CH 2 CH 3 , C 3 H 7 , or X 1 'R 1 ', wherein X 1 ' is NH, N(CH 3 ), NHNH, or O; R 1 ' is H or C 1 C_1 - C 8 C_8 alkyl; R 3 R_3 ' is H or C 1 C_1 - C 6 C_6 alkyl; Z 3 is H, COOR 1 , NH 2 , NHR 1 , OR 1 , CONHR 1 ,NHCOR 1 , OCOR 1 , OP(O)(OM 1 )(OM 2 ), [Image disponible dans le document PDF, Image available in the PDF document] M 1 and M 2 are independently H, Na, K, Ca, Mg, or NH 4 ; (N) a Protein kinase inhibitor: [Image disponible dans le document PDF, Image available in the PDF document] etinib [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] nib, [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] wherein Z 5 is O, NH, NHNH, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)O, N H C ( O ) N H , N H C ( O ) S , O C ( O ) N ( R 1 ) , N ( R 1 ) C ( O ) N ( R 2 ) , C ( O ) N H N H C ( O ) o r C ( O ) N R 1 ; R 1 a n d NHC(O)NH,\ NHC(O)S,\ OC(O)N(R_1),\ N(R_1)C(O)N(R_2),\ C(O)NHNHC(O)\ or\ C(O)NR_1;\ R_1\ and R 2 R_2 are independently is H or C 1 C_1 - C 6 C_6 alkyl; (P) a proteinase inhibitor: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] PI03, Carmaphycin analog, (Q) an immunotoxin that is a macromolecular drug which is a cytotoxic protein derived from a bacterial or plant protein comprising Diphtheria toxin (DT), Cholera toxin (CT), Tri- chosanthin (TCS), Dianthin, Pseudomonas exotoxin A (ETA'), an Erythrogenic toxin, Diph- theria toxin, an AB toxin, a Type III exotoxin, proaerolysin, topsalysin or conjugates via the side-chain linker through its amino acid having an amine, thiol or carboxylic acid group.

7. The side chain-linked compound according to any one of claims 1 to 4, wherein W, L 1 , L 2 , V 1 , and V 2 independently contain one or more linker components of the following structures: SNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN 6-maleimidocaproyl (MC), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] maleimido propanoyl (MP), valine-citrulline (val-cit), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] la- [Image disponible dans le document PDF, Image available in the PDF document] L- or D-, natural peptides containing 1-20 same or different amino acids; wherein 5 ^{5} is the site of linkage; X 2 , X 3 , X 4 , X 5 , or X 6 , are independently NH; NHNH; N(R 12 ); N(R 12 ), O; S; C 1 -C 6 alkyl; C 2 -C 6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C 3 -C 8 cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; CH 2 OR 12 , CH 2 SR 12 , CH 2 NHR 12 , or 1~8 amino acids; wherein R 12 and R 12 , are independently H;C 1 -C 8 alkyl; or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 0 to 1000, or combination above thereof.

8. The side chain-linked compound according to any one of claims 1 to 4, wherein W, L 1 L_1 , L 2 L_2 , V 1 V_1 , and V 2 V_2 independently comprise: (A) a self-immolative component, a peptidic unit, a hydrazone bond, a disulfide, an es- ter, an oxime, an amide, or a thioether bond; wherein the self-immolative unit comprises one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] of at- tachment of another component; X 1 , Y 1 , Z 2 and Z 3 are independently NH, O, or S; Z 1 is inde- pendently H, NHR 1 , OR 1 , SR 1 , COX 1 R 1 , wherein X 1 and R 1 are defined above; v is 0 or 1; U 1 is independently H, OH, C 1 ~C 6 alkyl, (OCH 2 CH 2 ) n , F, Cl, Br, I, OR 5 , SR 5 , NR 5 R 5 ', N=NR 5 , N=R 5 , NR 5 R 5 ', NO 2 , OSO 3 R 5 , OPO(OR 5 )(OR 5 '), or OCH 2 PO(OR 5 (OR 5 '), wherein R 5 and R 5 R_5 ' are independently H, C 1 ∼ C 8 C_1 \sim C_8 alkyl; or pharmaceutical cation salts; (B) a non-self-immolative linker component containing one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , wherein the (*) atom is the point of attachment of additional spacer or releasable link- ers, the cytotoxic agents, and / or the binding molecules; X 1 , Y 1 , U 1 , R 5 , R 5 are defined as above; r is 0 ∼ 100 0\sim100 ; m and n are 0 ∼ 20 0\sim20 independently; (C): a releasable component that has at least one bond that can be broken under physio- logical conditions: a pH-labile, acid-labile, base-labile, oxidatively labile, metabolically la- bile, biochemically labile or enzyme-labile bond, having one of the following structures: [Image disponible dans le document PDF, Image available in the PDF document] 1- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , − K ( C R 15 R 16 ) m -K(CR_{15}R_{16})_m -imidazolyl(Aa) t -, − K ( C R 15 R 16 ) m -K(CR_{15}R_{16})_m -morpholino(Aa) t -, − K ( C R 15 R 16 ) m -K(CR_{15}R_{16})_m -pipera- zino(Aa) t G, -K(CR 15 R 16 ) m -N-methyl-piperazino(Aa) t -; wherein m, Aa, m, n, R 13 , R 14 , and R 15 are as defined in claim 1; t and r here are 0 − 100 0 - 100 independently; R 16 R_{16} , R 17 R_{17} , R 18 R_{18} , R 19 R_{19} , and R 20 R_{20} are independently chosen from H; halide; C 1 ∼ C 8 C_1 \sim C_8 alkyl or heteroalkkyl, K is NR 12 , -SS-, -C(=O)-, - C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, or a heterocyclic or het- eroaromatic ring having 3 to 12 carbon atoms; or peptides containing the same or different 1- 20 amino acids.

9. The side chain-linked conjugate compound according to claim 1 or 2 having one of the following structures of a001 to a198, 49 (C-30), 50 (C-40), 51 (C-48), 78, 125, 141, 149, 163, 171, 174 (C-173), 179, 187, C-238, C-247, C-255, C-271, C-279, C-312, C-313, 132 (C-131), 135 (C-134), C-321, and C-322 illustrated below: [Image disponible dans le document PDF, Image available in the PDF document] a001, [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] a009, [Image disponible dans le document PDF, Image available in the PDF document] í ί a013, [Image disponible dans le document PDF, Image available in the PDF document] a016, [Image disponible dans le document PDF, Image available in the PDF document] • - a019, [Image disponible dans le document PDF, Image available in the PDF document] a023, [Image disponible dans le document PDF, Image available in the PDF document] a027, [Image disponible dans le document PDF, Image available in the PDF document] 1 a031, [Image disponible dans le document PDF, Image available in the PDF document] ξ 8 8 a035, [Image disponible dans le document PDF, Image available in the PDF document] uvvv [Image disponible dans le document PDF, Image available in the PDF document] a043, [Image disponible dans le document PDF, Image available in the PDF document] a04 a04 a046, [Image disponible dans le document PDF, Image available in the PDF document] ť ť a050, [Image disponible dans le document PDF, Image available in the PDF document] a054, [Image disponible dans le document PDF, Image available in the PDF document] 1 - a058, [Image disponible dans le document PDF, Image available in the PDF document] a0. a0 a062, [Image disponible dans le document PDF, Image available in the PDF document] l a066, [Image disponible dans le document PDF, Image available in the PDF document] a069 a070, [Image disponible dans le document PDF, Image available in the PDF document] _ a( a( a( a074, [Image disponible dans le document PDF, Image available in the PDF document] n a0 a0 a077, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] u002, [Image disponible dans le document PDF, Image available in the PDF document] ) a( a( a( a089, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] ) a097, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] a109, [Image disponible dans le document PDF, Image available in the PDF document] a113, [Image disponible dans le document PDF, Image available in the PDF document] n [Image disponible dans le document PDF, Image available in the PDF document] 1 a117 a118, [Image disponible dans le document PDF, Image available in the PDF document] l a121, [Image disponible dans le document PDF, Image available in the PDF document] n a124, [Image disponible dans le document PDF, Image available in the PDF document] a127, [Image disponible dans le document PDF, Image available in the PDF document] a130, [Image disponible dans le document PDF, Image available in the PDF document] ) a134, [Image disponible dans le document PDF, Image available in the PDF document] a137, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b a143, [Image disponible dans le document PDF, Image available in the PDF document] a144 a145 a146, [Image disponible dans le document PDF, Image available in the PDF document] a147, [Image disponible dans le document PDF, Image available in the PDF document] a148, [Image disponible dans le document PDF, Image available in the PDF document] a149, [Image disponible dans le document PDF, Image available in the PDF document] a153, [Image disponible dans le document PDF, Image available in the PDF document] a154 ) a155 a156, [Image disponible dans le document PDF, Image available in the PDF document] a157, [Image disponible dans le document PDF, Image available in the PDF document] a158, [Image disponible dans le document PDF, Image available in the PDF document] a159, [Image disponible dans le document PDF, Image available in the PDF document] a160, [Image disponible dans le document PDF, Image available in the PDF document] a161, [Image disponible dans le document PDF, Image available in the PDF document] a162, [Image disponible dans le document PDF, Image available in the PDF document] a165, [Image disponible dans le document PDF, Image available in the PDF document] a166 __ _ - a168, [Image disponible dans le document PDF, Image available in the PDF document] a16 a170, [Image disponible dans le document PDF, Image available in the PDF document] a173, [Image disponible dans le document PDF, Image available in the PDF document] a176, [Image disponible dans le document PDF, Image available in the PDF document] a177 a178, [Image disponible dans le document PDF, Image available in the PDF document] a ) a [Image disponible dans le document PDF, Image available in the PDF document] b a181 a182, [Image disponible dans le document PDF, Image available in the PDF document] a183 a184, [Image disponible dans le document PDF, Image available in the PDF document] a185 a186, [Image disponible dans le document PDF, Image available in the PDF document] a187 - 1 a188, [Image disponible dans le document PDF, Image available in the PDF document] a189, [Image disponible dans le document PDF, Image available in the PDF document] a190, [Image disponible dans le document PDF, Image available in the PDF document] a191 a192, [Image disponible dans le document PDF, Image available in the PDF document] a194, [Image disponible dans le document PDF, Image available in the PDF document] a a196, [Image disponible dans le document PDF, Image available in the PDF document] ) a198 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] U J#1 [Image disponible dans le document PDF, Image available in the PDF document] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 8 , Y 1 , Y 2 , Y 3 , Y 5 Y_5 , R 12 R_{12} , R 12 R_{12} , R 13 R_{13} , R 13 R_{13} , R 25 R_{25} , R 25 R_{25} , p 1 p_1 , p 2 p_2 , q 1 q_1 , q 2 q_2 , m m , m 1 m_1 , n n , and m A b mAb are as defined in claim 1, 2, 3, or 6; Aa is natural or unnatural amino acid; r is 0-12; (Aa)r is a peptide containing the same or different sequence of amino acids when r > 2 r > 2 ; r = 0 r = 0 means (Aa)r absent.

10. The compound according to Claim 3 or 4 having one of the following structures from b001 to b197, 30, 40, 48, 77, 124, 140, 148, 162, 170, 173, 178, 186, 202, 238, 247, 255, 271, 279, 312, 313, 131, 134, 321, and 322 illustrated below: [Image disponible dans le document PDF, Image available in the PDF document] b b b003, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b00 b00' b010, [Image disponible dans le document PDF, Image available in the PDF document] b013, [Image disponible dans le document PDF, Image available in the PDF document] b016, [Image disponible dans le document PDF, Image available in the PDF document] . . b019, [Image disponible dans le document PDF, Image available in the PDF document] b022, [Image disponible dans le document PDF, Image available in the PDF document] 1 b02 b02 b025, [Image disponible dans le document PDF, Image available in the PDF document] b02 b02 b028, [Image disponible dans le document PDF, Image available in the PDF document] b b b031, [Image disponible dans le document PDF, Image available in the PDF document] ) b032 b033 b034, [Image disponible dans le document PDF, Image available in the PDF document] b0 b0 b037, [Image disponible dans le document PDF, Image available in the PDF document] 1 b040, [Image disponible dans le document PDF, Image available in the PDF document] b 0 2 b0^2 b 0 2 b0^2 b043, [Image disponible dans le document PDF, Image available in the PDF document] b046, [Image disponible dans le document PDF, Image available in the PDF document] b04 b04 - - b049, [Image disponible dans le document PDF, Image available in the PDF document] b0 b0 b052, [Image disponible dans le document PDF, Image available in the PDF document] b0: b0: b055, [Image disponible dans le document PDF, Image available in the PDF document] b059, [Image disponible dans le document PDF, Image available in the PDF document] DUOZ, [Image disponible dans le document PDF, Image available in the PDF document] b066, [Image disponible dans le document PDF, Image available in the PDF document] DU / U, [Image disponible dans le document PDF, Image available in the PDF document] b073, [Image disponible dans le document PDF, Image available in the PDF document] b077, [Image disponible dans le document PDF, Image available in the PDF document] b081, [Image disponible dans le document PDF, Image available in the PDF document] b085, [Image disponible dans le document PDF, Image available in the PDF document] b089, [Image disponible dans le document PDF, Image available in the PDF document] b093, [Image disponible dans le document PDF, Image available in the PDF document] b097, [Image disponible dans le document PDF, Image available in the PDF document] b101, [Image disponible dans le document PDF, Image available in the PDF document] • ___ b105, [Image disponible dans le document PDF, Image available in the PDF document] b109, [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] b115, [Image disponible dans le document PDF, Image available in the PDF document] b118, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b127, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b134, [Image disponible dans le document PDF, Image available in the PDF document] . . b137, [Image disponible dans le document PDF, Image available in the PDF document] b138, [Image disponible dans le document PDF, Image available in the PDF document] b139, [Image disponible dans le document PDF, Image available in the PDF document] b142, [Image disponible dans le document PDF, Image available in the PDF document] . b1 b1 b145, [Image disponible dans le document PDF, Image available in the PDF document] · · [Image disponible dans le document PDF, Image available in the PDF document] b152, [Image disponible dans le document PDF, Image available in the PDF document] [ b155, [Image disponible dans le document PDF, Image available in the PDF document] b158, [Image disponible dans le document PDF, Image available in the PDF document] b161, [Image disponible dans le document PDF, Image available in the PDF document] 1 . b164, [Image disponible dans le document PDF, Image available in the PDF document] b167, [Image disponible dans le document PDF, Image available in the PDF document] b b b170, [Image disponible dans le document PDF, Image available in the PDF document] b173, [Image disponible dans le document PDF, Image available in the PDF document] b174 b175, [Image disponible dans le document PDF, Image available in the PDF document] b176, [Image disponible dans le document PDF, Image available in the PDF document] b177, [Image disponible dans le document PDF, Image available in the PDF document] [ b178 b179, [Image disponible dans le document PDF, Image available in the PDF document] ) b180, b181, [Image disponible dans le document PDF, Image available in the PDF document] b182 b183, [Image disponible dans le document PDF, Image available in the PDF document] b184, [Image disponible dans le document PDF, Image available in the PDF document] b185, [Image disponible dans le document PDF, Image available in the PDF document] b186, [Image disponible dans le document PDF, Image available in the PDF document] b187, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] b192, [Image disponible dans le document PDF, Image available in the PDF document] b193, [Image disponible dans le document PDF, Image available in the PDF document] b194, [Image disponible dans le document PDF, Image available in the PDF document] b195, [Image disponible dans le document PDF, Image available in the PDF document] b196, [Image disponible dans le document PDF, Image available in the PDF document] 1 [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 312 [Image disponible dans le document PDF, Image available in the PDF document] 0 wherein R 1 R^1 , R 2 R^2 , R 3 R^3 , R 4 R^4 , R 5 R^5 , R 4 R_4 , R 5 R_5 , R 7 R_7 , R 8 R_8 , R 9 R_9 , R 10 R_{10} , X 1 X_1 , X 2 X_2 , X 3 X_3 , X 4 X_4 , X 5 X_5 , X 6 X_6 , X 8 X_8 , Y 1 Y_1 , Y 2 Y_2 , Y 3 Y_3 , Y 5 Y_5 , R 12 R_{12} , R 12 R_{12} , R 13 R_{13} , R 13 R_{13} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , R 25 R_{25} , <Formule mathématique disponible dans le document PDF, Math available in the PDF document>R_{ mAb are as defined in claim 3 or 6; Aa is amino acid; r is 0-12; (Aa)r is a peptide containing the same or different sequence of amino acids when r > 2 r > 2 ; r = 0 r = 0 means (Aa)r absent.

11. The compound according to claim 1, 2, or 9, wherein the cell binding agent or mole- cule comprises: (A) an antibody, a protein, probody, nanobody,; (B) an antibody-like protein, a full-length antibody, a polyclonal antibody, a monoclonal antibody, an antibody dimer, an antibody multimer, a multispecific antibody comprising a bispecific antibody, a trispecific antibody, or tetraspecific antibody; a single chain antibody, an antibody fragment that binds to the target cell, a monoclonal antibody, a single chain mon- oclonal antibody, a monoclonal antibody fragment that binds the target cell, a chimeric anti- body, 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 frag- ment that binds to the target cell, anti-idiotypic (anti-Id) antibodies, CDR's, diabody, triabody, tetrabody, miniantibody, a probody, a probody fragment, small immune proteins (SIP),; (C) a cell-binding ligand or receptor agonist comprising folate; glutamic acid urea; soma- tostatin, octreotide (Sandostatin), lanreotide (Somatuline); an aromatic sulfonamide; a pitui- tary adenylate cyclase activating peptide; a vasoactive intestinal peptide; a melanocyte-stimu- lating hormone ( α \alpha -MSH); a cholecystokinins (CCK) / gastrin receptor agonist; a bombesins comprising Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 ) / gastrin- releasing peptide (GRP); a neurotensin receptor ligand (NTR1, NTR2, NTR3); a substance P (NK1 receptor) ligand; a Neuropeptide Y (Y1–Y6); a homing peptides comprising RGD (Arg-Gly-Asp) or NGR (Asn-Gly-Arg), a dimeric and multimeric cyclic RGD peptide com- prising cRGDfV, TAASGVRSMH or LTLRWVGLMS (Chondroitin sulfate proteoglycan NG2 receptor ligands) or F3 peptides; a cell penetrating peptide (CPP); a peptide hormones comprising a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, or a gon- adotropin-releasing hormone (GnRH) agonist which acts by targeting follicle stimulating hor- mone (FSH) or luteinizing hormone (LH), as well as testosterone production, comprising buserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), Gonadorelin (Pyr-His- Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ), Goserelin (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu- Arg-Pro-AzGly-NH 2 ), Histrelin (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), leuprolide (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser- Tyr-2Nal-Leu-Arg-Pro-Gly-NH 2 ), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly- NH 2 ), Nafarelin, Deslorelin, Abarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N- Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH 2 ), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D- 3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH 2 ), Degarelix (Ac-D-2Nal-D-4-chlo- roPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu- isopropylLys-Pro-D-Ala-NH 2 ), and Ganirelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3- pyridyl)Ala-Ser-Tyr-D-(N9, N10-diethyl)-homoArg-Leu-(N9, N10-diethyl)-homoArg-Pro-D- Ala-NH 2 ); a pattern recognition receptor (PRR) comprising a Toll-like receptor (TLR) ligand, a C-type lectin or nodlike receptor (NLR) ligand; a calcitonin receptor agonist; an integrin re- ceptor or their receptor subtype comprising α V β 1 \alpha_V\beta_1 , α V β 3 \alpha_V\beta_3 , α V β 5 \alpha_V\beta_5 , α V β 6 \alpha_V\beta_6 , α 6 β 4 \alpha_6\beta_4 , α 7 β 1 \alpha_7\beta_1 , α L β 2 \alpha_L\beta_2 , α I I b β 3 \alpha_{IIb}\beta_3 agonist comprising GRGDSPK, cyclo(RGDfV) (L1), cyclo(-N(Me)R-GDfV), cyclo(R-Sar-DfV), cy- clo(RG-N(Me)D-fV), cyclo(RGD-N(Me)f-V), cyclo(RGDf-N(Me)V-) or cilengitide; a nanobody (VHH (camelid Ig); a domain antibody; a bispecific T cell Engager (BiTE, a bispecific diabody); a Dual Affinity ReTargeting (DART, a bispecific diabody); a Tetravalent tandem antibody (TandAb, a dimerized bispecific diabody); Anticalin; an adnectin (10th FN3 (Fibronectin)); a Designed Ankyrin Repeat Protein (DARPin); an Avimer; an EGF receptor, or a VEGF receptor agonist; (D) a small molecule of cell-binding molecule or ligand or a cell receptor agonist com- prising LB01 (Folate), LB02 (PMSA ligand), LB03 (PMSA ligand), LB04 (PMSA ligand), LB05 (Somatostatin), LB06 (Somatostatin), LB07 (Octreotide), LB08 (Lanreotide), LB09 (Vapreotide (Sanvar)), LB10 (CAIX ligand), LB11 (CAIX ligand), LB12 (Gastrin releasing peptide receptor (GRPr), MBA), LB13 (luteinizing hormone-releasing hormone (LH-RH) lig- and or GnRH), LB14 (luteinizing hormone-releasing hormone (LH-RH) and GnRH ligand), LB15 (GnRH antagonist, Abarelix), LB16, LB17, LB18 (for α v β 3 integrin receptor, cyclic RGD pentapeptide), LB19 (hetero-bivalent peptide ligand for VEGF receptor), LB20 (Neu- romedin B), LB21 (bombesin for a G-protein coupled receptor), LB22 (TLR 2 for a Toll-like receptor,), LB23 (for an androgen receptor), LB24 (Cilengitide / cyclo(-RGDfV-) for an α v in- tegrin receptor, LB23 (Fludrocortisone), LB25, LB26, LB27, LB28 (Fludrocortisone), LB29 (Dexamethasone), LB30 (fluticasone propionate), LB31 (Beclometasone dipropionate), LB32 (Triamcinolone acetonide), LB33 (Prednisone), LB34 (Prednisolone), LB35 (Methylpredniso- lone), LB36 (Betamethasone), LB37, LB38, LB39, LB40, LB41, LB42, LB43, LB44, LB45, LB46, LB47, LB48, LB49, LB50, LB51, LB52, LB53 or LB54 which are shown in the fol- lowing structures: HN Ĥ LB01 (Folate conjugate), [Image disponible dans le document PDF, Image available in the PDF document] ١, [Image disponible dans le document PDF, Image available in the PDF document] a LB12 (Gastrin releasing peptide receptor (GRPr), MBA), [Image disponible dans le document PDF, Image available in the PDF document] , OH, CN; LB16, [Image disponible dans le document PDF, Image available in the PDF document] R 19 is 5'deoxyadenosyl, Me, OH, CN; LB17, [Image disponible dans le document PDF, Image available in the PDF document] LB18 (for α v β 3 \alpha_v\beta_3 integrin receptor, cyclic RGD pentapeptide), [Image disponible dans le document PDF, Image available in the PDF document] LB19 (hetero-bivalent peptide ligand conjugate for VEGF receptor), [Image disponible dans le document PDF, Image available in the PDF document] LB20 (Neuromedin B), Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met- N H \stackrel{H}{N} — ∼ ξ \stackrel{\xi}{\sim} LB21 (bombesin conjugate for a G-protein coupled receptor), [Image disponible dans le document PDF, Image available in the PDF document] LB22 (TLR 2 conjugate for a Toll-like receptor), [Image disponible dans le document PDF, Image available in the PDF document] LB24 (Cilengitide / cyclo(-RGDfV-) conjugate for an α v integrin receptor) [Image disponible dans le document PDF, Image available in the PDF document] 6, [Image disponible dans le document PDF, Image available in the PDF document] ipropionate), . [Image disponible dans le document PDF, Image available in the PDF document] ;), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (E) one, two or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA), and PIWI interacting RNAs (piRNA): [Image disponible dans le document PDF, Image available in the PDF document] (F) an immunotoxin comprising Diphtheria toxin (DT), Cholera toxin (CT), Trichosan- thin (TCS), Dianthin, Pseudomonas exotoxin A (ETA'), Erythrogenic toxins, Diphtheria toxin, an AB toxin, or a Type III exotoxin; wherein "\sigma\sigma\" is the site to link the side chain linker of the present patent; is single or double strands of DNA, RNA, mRNA, siRNA, miRNA, or piRNA; X 4 ,and Y 1 are independently O, NH, NHNH, NR 1 , S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N( R 1 R_1 ), N( R 1 R_1 )C(O)N( R 1 R_1 ), CH 2 , C(O)NHNHC(O) or C(O)NR 1 ; X 1 is H, CH 2 , OH, O, C(O), C(O)NH, C(O)N(R 1 ), R 1 , NHR 1 , NR 1 , C(O)R 1 or C(O)O; X 5 is H, CH 3 , F, or Cl; M 1 and M 2 are independently H, Na, K, Ca, Mg, NH 4 .

12. The compound according to claim 1, 2 or 11, when cell-binding molecule, T or mAb, linking to V 1 and / or V 2 , of Formula (I), (II) or (III), or when cell-binding molecule, T directly linking to L 1 and / or L 2 of Formula (I), (II) or (III), wherein V 1 , and / or V 2 , are ab- sent, the conjugate compound having one or more of the following the linkage structures: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , [Image disponible dans le document PDF, Image available in the PDF document] independently C 1 ~C 8 alkyl; C 2 ~C 8 heteroalkyl, or heterocyclic; C 3 ~C 8 aryl, Ar-alkyl, cycloal- kyl, alkylcycloalkyl, heterocycloalkyl, or alkylcarbonyl; or C 2 -C 100 polyethylene glycol hav- ing formula of ( C H 2 C H 2 O ) p (CH_2CH_2O)_p wherein p is 2-100.

13. The compound according to claim 1, 2, 9, or 11, wherein the cell binding agent / mole- cule targets a tumor cell, a virus infected cell, a microorganism infected cell, a parasite in- fected cell, an autoimmune disease cell, an activated tumor cells, a myeloid cell, an activated T-cell, an affecting B cell, or a melanocyte, or any cells expressing any one of the following antigens or receptors: CD1, CD1a, CD1b, CD1c, CD1d, CD1e, CD2, CD3, CD3d, CD3e, CD3g, CD4, CD5, CD6, CD7, CD8, CD8a, CD8b, CD9, CD10, CD11a, CD11b, CD11c, CD11d, CD12w, CD14, CD15, CD16, CD16a, CD16b, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD49c, CD49d, CD49f, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, CD66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD81, CD82 , CD83, CD84, CD85, CD85a, CD85b, CD85c, CD85d, CD85e, CD85f, CD85g, CD85g, CD85i, CD85j, CD85k, CD85m, CD86, CD87, CD88, CD89, CD90, CD91, CD92, CD93, CD94, CD95, CD96, CD97, CD98, CD99, CD100, CD101, CD102, CD103, CD104, CD105, CD106, CD107, CD107a, CD107b, CD108, CD109, CD110, CD111, CD112, CD113, CD114, CD115, CD116, CD117, CD118, CD119, CD120, CD120a, CD120b, CD121, CD121a, CD121b, CD122, CD123, CD123a, CD124, CD125, CD126, CD127, CD128, CD129, CD130, CD131, CD132, CD133, CD134, CD135, CD136, CD137, CD138, CD139, CD140, CD140a, CD140b, CD141, CD142, CD143, CD144, CD145, CDw145, CD146, CD147, CD148, CD149, CD150, CD151, CD152, CD153, CD154, CD155, CD156, CD156a, CD156b, CD156c, CD156d, CD157, CD158, CD158a , CD158b1, CD158b2, CD158c, CD158d, CD158e1, CD158e2, CD158f2, CD158g , CD158h, CD158i, CD158j, CD158k, CD159, CD159a, CD159b, CD159c, CD160, CD161, CD162, CD163, CD164, CD165, CD166, CD167, CD167a, CD167b, CD168, CD169, CD170, CD171, CD172, CD172a, CD172b, CD172g, CD173, CD174 , CD175, CD175s, CD176, CD177, CD178, CD179, CD179a, CD179b, CD180, CD181, CD182, CD183, CD184, CD185, CD186, CDw186, CD187, CD188, CD189 , CD190, CD191, CD192, CD193, CD194, CD195, CD196, CD197, CD198, CD199 , CDw198, CDw199, CD200, CD201, CD202, CD202 (a, b), CD203, CD203c, CD204, CD205, CD206, CD207, CD208, CD209, CD210, CDw210a, CDw210b, [Image disponible dans le document PDF, Image available in the PDF document] Androgen receptor, Angiopoietin 2, Angiopoietin 3, Annexin A1, Anthrax toxin protective an- tigen, Anti-transferrin receptor, AOC3, VAP-1, B7-H3, Bacillus anthracis anthrax, B-cell acti- vating factor, BCMA, B-lymphoma cell, bcr-abl, Bombesin, BORIS, C5, C242 antigen, car- bohydrate antigen 125, MUC16, CA-IX, carbonic anhydrase 9, CALLA, CanAg, Canis lupus familiaris IL31, Carbonic anhydrase IX, Cardiac myosin, C-C motif chemokine 11, C-C chemokine receptor type 4, CCR5, CD3E, Carcinoembryonic antigen, CEACAM3, CEA- CAM5, CFD, Factor D, Ch4D5, Cholecystokinin 2, CCK2R, CLDN18, Claudin-18, Clumping factor A, cMet, CRIPTO, FCSF1R, Colony stimulating factor 1 receptor, colony stimulating factor 2, Granulocyte-macrophage colony-stimulating factor, CSP4, cytotoxic T-lymphocyte- associated protein 4, CTAA16.88 tumor antigen, CXCR4, C-X-C chemokine receptor type 4, cyclic ADP ribose hydrolase, Cyclin B1, CYP1B1, Cytomegalovirus, Cytomegalovirus glyco- protein B, Dabigatran, delta-like-ligand 3, delta-like-ligand 4, Dipeptidyl-peptidase 4, Death receptor 5, E. coli shiga toxin type-1, E. coli shiga toxin type-2, ED-B, EGF-like domain-con- taining protein 7, EGFR, EGFRII, EGFRVIII, Endoglin, Endothelin B receptor, Endotoxin, epithelial cell adhesion molecule, EphA2, Episialin, ERBB2, Epidermal Growth Factor Re- ceptor 2, ERBB3, ERG, TMPRSS2 ETS fusion gene, Escherichia coli, ETV6-AML, FAP, Fi- broblast activation protein alpha, FCGR1, alpha-Fetoprotein, Fibrin II, beta chain, Fibronectin extra domain-B, folate receptor, Folate receptor alpha, Folate hydrolase, Fos-related antigen 1F protein of respiratory syncytial virus, Frizzled receptor, Fucosyl GM1, GD2 ganglioside, G-28 cell surface antigen glyvolipid, GD3 idiotype, GloboH, Glypican 3, N-glycolylneu- raminic acid, GM3, GMCSF receptor α \alpha -chain, Growth differentiation factor 8, GP100, GPNMB, Trans-membrane glycoprotein NMB, Guanylate cyclase 2C, guanylyl cyclase C, in- testinal Guanylate cyclase, Guanylate cyclase-C receptor, Heat-stable enterotoxin receptor, Heat shock protein, Hemagglutinin, Hepatitis B surface antigen, Hepatitis B virus, human epidermal growth factor receptor 1, HER2, HER2 / neu, HER3, ERBB-3, IgG4, Hepatocyte growth factor / scatter factor, HHGFR, HIV-1, Histone complex, HLA-DR, human leukocyte antigen, HLA-DR10, HLA-DRB, HMWMAA, Human chorionic gonadotropin, HNGF, Hu- man scatter factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, Intercellular Adhesion Mole- cule 1, Idiotype, IGF-1, insulin-like growth factor 1 receptor, IGHE, IFN-γ, Influenza hemag- glutinin, IgE, IgE Fc region, IGHE, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-6R, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-17, IL-17A, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-27, IL-28, IL31RA, Insulin-like growth factor 2, Integrin α4, α IIb β 3 , ανβ3, α 4 β 7 , α5β1, α6β4, α7β7, αllβ3, α5β5, or ανβ5, Interferon gamma-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, LCK, Le, Legumain, Lewis-Y antigen, LFA-1, Lymphocyte function-asso- ciated antigen 1, LHRH, LINGO-1, Lipoteichoic acid, LIV1A, LMP2, LTA, MAD-CT-1, MAD-CT-2, MAGE-1, MAGE-2, MAGE-3, MAGE A1, MAGE A3, MAGE 4, MART1, MCP-1, MIF, Macrophage migration inhibitory factor, glycosylation-inhibiting factor, mem- brane-spanning 4-domains subfamily A member 1, mesothelin, Mucin 1, cell surface associ- ated MUC1 or polymorphic epithelial mucin, MUC1-KLH, MUC16, CA125, monocyte chem- otactic protein 1, MelanA / MART1, ML-IAP, MPG, MS4A1, membrane-spanning 4-domains subfamily A, MYCN, Myelin-associated glycoprotein, Myostatin, 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, Oxidized low-density lipoprotein, OY-TES1, P21, p53 nonmutant, P97, PAP, Paratope of anti-(N-glycolylneuraminic acid), PAX3, PAX5, PCSK9, PD-1, Programmed cell death pro- tein 1, PDGF-Rα, 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, Phosphatidylserine, Prostatic carcinoma cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, Rabies virus glycoprotein, RHD, Rh polypeptide 1, Rhesus factor, RANKL, RhoC, Ras mutant, RGS5, ROBO4, Respiratory syncytial virus, RON, ROR1, Sarcoma trans- location breakpoints, SART3, Sclerostin, SLAM family member 7, Selectin P, SDC1 Syndecan 1, sLe(a), Somatomedin C, Sphingosine-1-phosphate, Somatostatin, Sperm protein 17, SSX2, six-transmembrane epithelial antigen of the prostate 1, STEAP2, STn, tumor asso- ciated glycoprotein 72, Survivin, T-cell receptor, T cell transmembrane protein, Tumor endo- thelial marker 1, TENB2, Tenascin C, TGF-α, Transforming growth factor beta, TGF-β1, TGF-β2, Tie, CD202b, Tie2, TIM-1, CDX-014, Tn, TNF, TNF-α, TNFRSF8, tumor necrosis factor receptor superfamily member 10B, tumor necrosis factor receptor superfamily member 13B, trophoblast glycoprotein, Tumor necrosis apoptosis Inducing ligand Receptor 1, TRAILR2, Death receptor 5, tumor-associated calcium signal transducer 2, tumor specific glycosylation of MUC1, TWEAK receptor, TYRP1, glycoprotein 75, Trop2, Tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR2, vimentin, WT1, or XAGE 1, or cells expressing any insulin growth factor receptors, or any epidermal growth factor receptors.

14. The compound according to claim 13, wherein the tumor cell is a lymphoma cell, myeloma cell, renal cell, breast cancer cell, prostate cancer cell, ovarian cancer cell, colorectal cancer cell, gastric cancer cell, squamous cancer cell, small-cell lung cancer cell, non-small- cell lung cancer cell, testicular cancer cell, or malignant cell.

15. A pharmaceutical composition comprising the conjugate compounds of claim 1, 2, or 9, or a pharmaceutically acceptable salt thereof, or a combination of the conjugates thereof, together with a carrier, diluent, or excipient, for the treatment or prevention of a cancer, or an autoimmune disease, or an infectious disease.

16. The pharmaceutical composition according to claim 15, comprising by weight of:

17. A kit comprising the pharmaceutical composition according to claim 15 or 16 packed in a vial, bottle, pre-filled syringe, or pre-filled auto-injector syringe, wherein the pharmaceu- tical composition is in a form of a liquid or lyophilized solid.

18. The conjugate of claim 1, 2, or 9, or the pharmaceutical composition of claim 15 or 16, having in vitro, in vivo or ex vivo cell killing activity.

19. Use of the pharmaceutical composition according to claim 15 or 16, which is formu- lated for administration concurrently with a chemotherapeutic agent, a radiation therapy, an immunotherapy agent, an autoimmune disorder agent, an anti-infectious agent, or a conjugate for synergistic treatment or prevention of a cancer, an autoimmune disease, or an infectious disease.

20. The use according to claim 19, wherein the chemotherapeutic agent, radiation therapy, immunotherapy agent, autoimmune disorder agent, anti-infectious agent, or conju- gate for synergistic treatment or prevention of a cancer, an autoimmune disease, or an infec- tious disease comprises: (1) a) an alkylating agent: comprising a nitrogen mustard: chlorambucil, chlornaphaz- ine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlor- ethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobro- man, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, uracil mustard; CC- 1065 or adozelesin, carzelesin, bizelesin; duocarmycin, KW-2189, CBI-TMI, or CBI dimers; benzodiazepine dimers or pyrrolobenzodiazepine dimers, tomaymycin dimers, indolinobenzo- diazepine dimers, imidazobenzothiadiazepine dimers, or oxazolidinobenzodiazepine dimers; a nitrosourea: comprising carmustine, lomustine, chlorozotocin, fotemustine, nimustine, or rani- mustine; an alkylsulphonate: comprising busulfan, treosulfan, improsulfan or piposulfan; a tri- azenes or dacarbazine; a platinum containing compound: comprising carboplatin, cisplatin, or oxaliplatin; an aziridine, benzodopa, carboquone, meturedopa, or uredopa; an ethylenimine or methylamelamine comprising altretamine, triethylenemelamine, trietylenephosphoramide, tri- ethylenethiophosphoramide or trimethylolomelamine; b) a plant alkaloid comprising a vinca alkaloid: comprising vincristine, vinblastine, vindesine, vinorelbine, or navelbin; a taxoid: comprising paclitaxel, docetaxol, a maytansinoid comprising DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine, ansamitocin, cryptophy- cin; an epothilone, eleutherobin, discodermolide, bryostatin, dolostatin, auristatin, tubulysin, cephalostatin; or pancratistatin; a sarcodictyin; or spongistatin; c) a DNA topoisomerase inhibitor comprising an epipodophyllin: comprising 9-ami- nocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, iri- notecan, mitoxantrone, novantrone, retinoic acid, retinol, teniposide, topotecan, 9-nitrocamp- tothecin or RFS 2000; or mitomycin; d) an antimetabolite comprising an anti-folate: comprising a DHFR inhibitor: comprising methotrexate, trimetrexate, denopterin, pteropterin, aminopterin (4-aminopteroic acid) or folic acid); an IMP dehydrogenase inhibitor: comprising mycophenolic acid, tiazofurin, ribavirin, or EICAR; a ribonucleotide reductase inhibitors: comprising hydroxyurea, or deferoxamine; pyrimidine, uracil, ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, or ratitrexed; cytosine, cytarabine, cytosine arabinoside, fludarabine; Purine, azathioprine, fludarabine, mercaptopu- rine, thiamiprine, or thioguanine; a folic acid replenisher, or frolinic acid; e) a hormonal therapy comprising a receptor antagonist: comprising an anti-estrogen: comprising megestrol, raloxifene, or tamoxifen; an LHRH agonist: comprising goscrclin, or leuprolide acetate; an anti-androgen: comprising bicalutamide, flutamide, calusterone, dromo- stanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolac- tone, or trilostane; a retinoid / deltoid: comprising Vitamin D3, CB 1093, EB 1089 KH 1060, cholecalciferol, or ergocalciferol; a photodynamic therapy: comprising verteporfin, phthalocyanine, photosensitizer Pc4, or demethoxyhypocrellin A; a cytokine: comprising in- terferon-alpha, interferon-gamma, tumor necrosis factor, or a human protein containing a TNF domain; f) a kinase inhibitor comprising BIBW 2992, anti-EGFR / Erb2, imatinib, gefitinib, peg- aptanib, 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, cetux- imab, trastuzumab, ranibizumab, panitumumab, or ispinesib; g) a poly (ADP-ribose) polymerase (PARP) inhibitor comprising olaparib, niraparib, iniparib, talazoparib, veliparib, CEP 9722, E7016, BGB-290, or 3-aminobenzamide; h) an antibiotic comprising an enediyne antibiotic comprising calicheamicin, calicheami- cin γ 1 \gamma 1 , δ 1 \delta 1 , α 1 \alpha 1 or β 1 \beta 1 ; dynemicin, dynemicin A, deoxydynemicin; esperamicin, kedarcidin, C- 1027, maduropeptin, or neocarzinostatin chromophore or a related chromoprotein enediyne antibiotic chromomophore, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycin, dactinomycin, dauno- rubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cy- anomorpholino-doxorubicin, 2-pyrrolino-doxorubicin or deoxydoxorubicin, epirubicin, eribu- lin, esorubicin, idarubicin, marcellomycin, nitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, or zorubicin; i) a polyketide, acetogenin, bullatacin or bullatacinone; gemcitabine, epoxomicin, carfil- zomib, bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovectin-7, Xegeva, Provenge TM , Yervoy TM , an isoprenyla- tion inhibitor or lovastatin, a dopaminergic neurotoxin or 1-methyl-4-phenylpyridinium ion, a cell cycle inhibitor comprising staurosporine, an actinomycin comprising actinomycin D or dactinomycin, amanitin, a bleomycin comprising bleomycin A2, bleomycin B2, or peplomy- cin, an anthracycline comprising daunorubicin, doxorubicin, adriamycin, idarubicin, epirubi- cin, pirarubicin, zorubicin, mtoxantrone, MDR inhibitors or verapamil, a Ca 2+ ATPase inhibi- tor or thapsigargin, a histone deacetylase inhibitor comprising vorinostat, romidepsin, pano- binostat, valproic acid, mocetinostat, MGCD0103, belinostat, PCI-24781, entinostat, SB939, resminostat, givinostat, AR-42, CUDC-101, sulforaphane, or trichostatin A; thapsigargin, celecoxib, glitazone, epigallocatechin gallate, disulfiram, salinosporamide A; an anti-adrenal comprising aminoglutethimide, mitotane, trilostane; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; arabinoside, bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; eflornithine, DFMO, elfomithine; elliptinium acetate, etoglucid; gal- lium nitrate; gacytosine, hydroxyurea; ibandronate, lentinan; lonidamine; mitoguazone; mito- xantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK ® ; razoxane; rhizoxin; sizofiran; spirogermanium; tenua- zonic acid; triaziquone; 2, 2',2"-trichlorotriethylamine; a trichothecene comprising T-2 toxin, verrucarin A, roridin A or anguidine; urethane, siRNA, or an antisense drug; (2) an anti-autoimmune disease agent comprising cyclosporine, cyclosporine A, ami- nocaproic acid, azathioprine, bromocriptine, chlorambucil, chloroquine, cyclophosphamide, a corticosteroid comprising amcinonide, betamethasone, budesonide, hydrocortisone, fluni- solide, fluticasone propionate, fluocortolone danazol, dexamethasone, Triamcinolone ace- tonide, or beclometasone dipropionate, DHEA, enanercept, hydroxychloroquine, infliximab, meloxicam, methotrexate, mofetil, mycophenylate, prednisone, sirolimus, or tacrolimus; (3) an anti-infectious disease agent comprising: a) an aminoglycoside comprising: amikacin, astromicin, gentamicin, netilmicin, siso- micin, isepamicin, hygromycin B, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, neomycin, framycetin, paromomycin, ribostamycin, netilmicin, spectinomycin, streptomycin, tobramycin, or verdamicin; b) an amphenical comprising: azidamfenical, chloramphenical, florfenical, or thiam- phenicol; c) an ansamycin comprising: geldanamycin or herbimycin; d) a carbapenem comprising: biapenem, doripenem, ertapenem, imipenem, cilastatin, meropenem, or orpanipenem; e) a cephem comprising: carbacephem, loracarbef, cefacetrile, cefaclor, cefradine, cefadroxil, cefalonium, cefaloridine, cefalotin or cefalothin, cefalexin, cefaloglycin, cefaman- dole, 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, cefpira- mide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefsulodin, ceftazidime, cefteram, ceft- ibuten, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, cephamy- cin, cefoxitin, cefotetan, cefmetazole, oxacephem, flomoxef or latamoxef; f) a glycopeptide comprising: bleomycin, vancomycin, oritavancin, telavancin, teicoplanin, dalbavancin, or ramoplanin; g) a glycylcycline comprising: tigecycline; h) a β-lactamase inhibitor comprising: penam, sulbactam, tazobactam, clavam or clavulanic acid; i) a lincosamide comprising: clindamycin or lincomycin; j) a lipopeptide comprising: daptomycin, A54145, or a calcium-dependent antibiotic; k) a macrolide comprising: azithromycin, cethromycin, clarithromycin, dirithromycin, erythromycin, flurithromycin, josamycin, ketolide, telithromycin, cethromycin, midecamycin, miocamycin, oleandomycin, rifamycin, rifampicin, rifampin, rifabutin, rifapentine, rokitamy- cin, roxithromycin, spectinomycin, spiramycin, tacrolimus (FK506), troleandomycin, or teli- thromycin; 1) a monobactam comprising: aztreonam or tigemonam; m) an oxazolidinone comprising: linezolid; n) a penicillin comprising: amoxicillin, ampicillin, pivampicillin, hetacillin, bacampicil- lin, metampicillin, talampicillin, azidocillin, azlocillin, benzylpenicillin, benzathine ben- zylpenicillin, benzathine phenoxymethylpenicillin, clometocillin, procaine benzylpenicillin, carbenicillin, carindacillin, cloxacillin, dicloxacillin, epicillin, flucloxacillin, mecillinam, pivmecillinam, mezlocillin, meticillin, nafcillin, oxacillin, penamecillin, penicillin, pheneticil- lin, phenoxymethylpenicillin, piperacillin, propicillin, sulbenicillin, temocillin, or ticarcillin; o) a polypeptide comprising: bacitracin, colistin, or polymyxin B; p) a quinolone comprising: alatrofloxacin, balofloxacin, ciprofloxacin, clinafloxacin, da- nofloxacin, difloxacin, enoxacin, enrofloxacin, floxin, garenoxacin, gatifloxacin, gemifloxa- cin, grepafloxacin, kano trovafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxa- cin, nadifloxacin, norfloxacin, orbifloxacin, ofloxacin, pefloxacin, trovafloxacin, grepafloxa- cin, sitafloxacin, sparfloxacin, temafloxacin, tosufloxacin, or trovafloxacin; q) a streptogramin comprising: pristinamycin, or quinupristin / dalfopristin; r) a sulfonamide comprising: mafenide, prontosil, sulfacetamide, sulfamethizole, sulfan- ilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole or co-tri- moxazole; s) a steroid antibacterial comprising fusidic acid; t) a tetracycline comprising: doxycycline, chlortetracycline, clomocycline, demeclocy- cline, lymecycline, meclocycline, metacycline, minocycline, oxytetracycline, penimepicy- cline, rolitetracycline, tetracycline, a glycylcycline, or tigecycline; u) an antibiotic comprising annonacin, arsphenamine, a bactoprenol inhibitor, bacitracin, a DADAL / AR inhibitor, cycloserine, dictyostatin, discodermolide, eleutherobin, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metroni- dazole, mupirocin, mycolactone, a NAM synthesis inhibitor, fosfomycin, nitrofurantoin, paclitaxel, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin, rifampin, tazo- bactam tinidazole, or uvaricin; (4) an anti-viral drug comprising: a) an entry / fusion inhibitor comprising: aplaviroc, maraviroc, vicriviroc, gp41, enfuvir- tide, PRO 140, CD4 or ibalizumab; b) an integrase inhibitor comprising: raltegravir, elvitegravir, or globoidnan A; c) a maturation inhibitor comprising: bevirimat, or vivecon; d) a neuraminidase inhibitor comprising: oseltamivir, zanamivir, or peramivir; e) a nucleoside or nucleotide comprising: abacavir, aciclovir, adefovir, amdoxovir, apri- citabine, brivudine, cidofovir, clevudine, dexelvucitabine, didanosine, ddI, elvucitabine, emtricitabine, FTC, entecavir, famciclovir, fluorouracil, 5-FU, 3'-fluoro-2',3'-dideoxythymi- dine, FLT, 3'-fluoro-2',3'-dideoxyguanosine, FLG, fomivirsen, ganciclovir, idoxuridine, lamivudine, 3TC, a l-nucleoside comprising β \beta -l-thymidine or β \beta -l-2'-deoxycytidine, penciclo- vir, racivir, ribavirin, stampidine, stavudine, d4T, taribavirin, viramidine, telbivudine, tenofo- vir, trifluridine valaciclovir, valganciclovir, zalcitabine, ddC, zidovudine or AZT; f) a non-nucleoside comprising: amantadine, ateviridine, capravirine, diarylpyrimidine, etravirine, rilpivirine, delavirdine, docosanol, emivirine, efavirenz, foscarnet, phosphonofor- mic acid, imiquimod, interferon alfa, loviride, lodenosine, methisazone, nevirapine, NOV-205, peginterferon alfa, podophyllotoxin, rifampicin, rimantadine, resiquimod, R-848, or troman- tadine; g) a protease inhibitor comprising: amprenavir, atazanavir, boceprevir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, pleconaril, ritonavir, saquinavir, telaprevir, VX-950, or tipranavir; h) an anti-virus drug comprising: abzyme, arbidol, calanolide a, ceragenin, cyanovirin-n, diarylpyrimidines, epigallocatechin gallate, foscarnet, griffithsin, taribavirin, viramidine, hydroxyurea, KP-1461, miltefosine, pleconaril, a portmanteau inhibitor, ribavirin, or seliciclib; (5) a pharmaceutically acceptable salt, acid, hydrate or hydrated salt; or a crystalline structure; or an optical isomer, racemate, diastereomer or enantiomer of any of the above drugs.

21. The use according to claim 19, wherein the chemotherapeutic agent, radiation ther- apy, immunotherapy agent, autoimmune disorder agent, anti-infectious agent, or conjugate for synergistic treatment or prevention of a cancer, an autoimmune disease, or an infectious dis- ease comprises Abatacept, abemaciclib, Abiraterone acetate, Abraxane, Acetaminophen / hy- drocodone, Acalabrutinib, aducanumab, Adalimumab, ADXS31-142, ADXS-HER2, afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, Alitretinoin, ado-trastuzumab emtansine, Am- phetamine / dextroamphetamine, anastrozole, Aripiprazole, anthracyclines, Aripiprazole, Atazanavir, Atezolizumab, Atorvastatin, Avelumab, Axicabtagene ciloleucel, axitinib, belinostat, BCG Live, Bevacizumab, bexarotene, blinatumomab, Bortezomib, bosutinib, bren- tuximab vedotin, brigatinib, Budesonide, Budesonide / formoterol, Buprenorphine, Caba- zitaxel, Cabozantinib, capmatinib, Capecitabine, carfilzomib, chimeric antigen receptor-engi- neered T (CAR-T) cells, Celecoxib, ceritinib, Cetuximab, Chidamide, Ciclosporin, Cinacalcet, crizotinib, Cobimetinib, Cosentyx, crizotinib, CTL019, Dabigatran, dabrafenib, dacarbazine, daclizumab, dacomotinib, daptomycin, Daratumumab, Darbepoetin alfa, Darunavir, dasatinib, denileukin diftitox, Denosumab, Depakote, Dexlansoprazole, Dexmethylphenidate, Dexame- thasone, DigniCap Cooling System, Dinutuximab, Doxycycline, Duloxetine, Duvelisib, dur- valumab, elotuzumab, Emtricibine / Rilpivirine / Tenofovir, disoproxil fumarate, Emtricit- bine / tenofovir / efavirenz, Enoxaparin, ensartinib, Enzalutamide, Epoetin alfa, erlotinib, Esomeprazole, Eszopiclone, Etanercept, Everolimus, exemestane, everolimus, exenatide ER, Ezetimibe, Ezetimibe / simvastatin, Fenofibrate, Filgrastim, fingolimod, Fluticasone propio- nate, Fluticasone / salmeterol, fulvestrant, gazyva, gefitinib, Glatiramer, Goserelin acetate, Ico- tinib, Imatinib, Ibritumomab tiuxetan, ibrutinib, idelalisib, ifosfamide, Infliximab, imiquimod, ImmuCyst, Immuno BCG, iniparib, Insulin aspart, Insulin detemir, Insulin glargine, Insulin lispro, Interferon alfa, Interferon alfa-1b, Interferon alfa-2a, Interferon alfa-2b, Interferon beta, Interferon beta 1a, Interferon beta 1b, Interferon gamma-1a, lapatinib, Ipilimumab, Ipratro- pium bromide / salbutamol, Ixazomib, Kanuma, Lanreotide acetate, lenalidomide, lenalio- mide, lenvatinib mesylate, letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Li- raglutide, Lisdexamfetamine, LN-144, Iorlatinib, Memantine, Methylphenidate, Metoprolol, Mekinist, mericitabine / Rilpivirine / Tenofovir, Modafinil, Mometasone, Mycidac-C, Neci- tumumab, neratinib, Nilotinib, niraparib, Nivolumab, ofatumumab, obinutuzumab, olaparib, Olmesartan, Olmesartan / hydrochlorothiazide, Omalizumab, Omega-3 fatty acid ethyl esters, Oncorine, Oseltamivir, Osimertinib, Oxycodone, palbociclib, Palivizumab, panitumumab, panobinostat, pazopanib, pembrolizumab, PD-1 antibody, PD-L1 antibody, Pemetrexed, per- tuzumab, Pneumococcal conjugate vaccine, pomalidomide, Pregabalin, ProscaVax, Proprano- lol, Quetiapine, Rabeprazole, radium 223 chloride, Raloxifene, Raltegravir, ramucirumab, Ranibizumab, regorafenib, ribociclib, Rituximab, Rivaroxaban, romidepsin, Rosuvastatin, ruxolitinib phosphate, Salbutamol, savolitinib, semaglutide, Sevelamer, Sildenafil, siltuximab, Sipuleucel-T, Sitagliptin, Sitagliptin / metformin, Solifenacin, solanezumab, Sonidegib, Soraf- enib, Sunitinib, tacrolimus, tacrimus, Tadalafil, tamoxifen, Tafinlar, Talimogene la- herparepvec, talazoparib, Telaprevir, talazoparib, Temozolomide, temsirolimus, Tenofo- vir / emtricitabine, tenofovir disoproxil fumarate, Testosterone gel, Thalidomide, TICE BCG, Tiotropium bromide, Tisagenlecleucel, toremifene, trametinib, Trastuzumab, Trabectedin, tra- metinib, tremelimumab, Trifluridine / tipiracil, Tretinoin, Uro-BCG, Ustekinumab, Valsartan, veliparib, vandetanib, vemurafenib, venetoclax, vorinostat, ziv-aflibercept, or Zostavax, or a pharmaceutically acceptable salt thereof, or any combination thereof.