Antibody-drug conjugates containing two or more functional small molecule compounds for enhancing treatment of refractory diseases

Abstract

The invention provides an antibody drug conjugate containing a functional small molecule side chain. The antibody drug conjugate is used for enhancing the targeted therapeutic effect of cancers and refractory diseases. The invention also relates to a preparation method of the conjugate, a pharmaceutical composition and a method for treating refractory diseases.

Description

[0001] describe

[0002] Priority information

[0003] This application claims priority to PCT / CN2023 / 096066, filed on May 24, 2023, the contents of which are incorporated herein by reference.

[0004] background

[0005] Antibody-drug conjugates (ADCs) are a class of anticancer therapeutics that utilize the targeted specificity of monoclonal antibodies (mAbs) to bind with potent cytotoxic drugs, and their development has been rapid in recent years. Currently, 15 ADCs have been approved as monotherapy or in combination therapy for the treatment of various solid tumors and hematological malignancies. Among them, nine ADCs approved in the past five years have achieved significant success in the treatment of refractory diseases. According to... https: / / www.clinicaltrials.gov According to website data, more than 200 new ADCs have entered the clinical trial stage, covering a variety of tumor types. Despite the high enthusiasm for ADC research and development, how to improve its therapeutic index (enhance efficacy and reduce toxicity) and expand its application in the treatment of various cancers remains a challenge (Dean, AQ et al., mAbs, 2021, 13(1), 1951427). More and more studies are combining ADCs with chemotherapy drugs, immunotherapy compounds, etc., to expand the range of therapeutic indications (Li, Y et al., Am J Cancer Res. 2023, 13(1): 161-17; Ceci, C. et al., Pharmacol. 2022, 236: 108106; Gerber, HP et al., Biochem Pharmacol. 2016, 102: 1-6). Because chemotherapy drugs typically have short half-lives, when used in combination with ADCs, the dosing frequency needs to be increased (compared to ADC monotherapy), thus increasing toxicity (Fuentes-Antrás, J. et al., Trends Cancer 2023, 9(4): 339-354). We have invented an ADC containing affinity small molecules (affinity peptides or cell-penetrating peptides to enhance antibody affinity), which can expand the scope of tumor treatment (PCT / CN2023 / 096066). This invention discloses an ADC that covalently links one or more functional small molecules, which enhance the targeted therapeutic effect on various cancers and refractory diseases by generating synergistic affinity with antibodies and / or broad-spectrum synergistic effects with cytotoxic drugs. The preparation method, pharmaceutical composition, screening scheme and treatment method of the conjugate are also disclosed. Summary of the Invention

[0006] This invention provides an antibody-drug conjugate (ADC) that links a chemical drug or a functional small molecule through a branched structure to enhance the targeted therapeutic effect of cancer and refractory diseases. The ADC is preferably represented by the following general formulas (I), (II), (III), and (IV):

[0007]

[0008]

[0009] in,

[0010] D1 and D2 are cytotoxic agents; mAb is an antibody, antibody-like protein, or cell-binding protein; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and these numbers may have decimals;

[0011] L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, and Ld6 are linking groups, independently selected from O, NH, S, N, NH-NH, NN, N(R3), and N(R3)N(R 3′ C(=O)N, C(=O)NH, C(=O)NN, C1-C8 alkyl (alkylene); C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, aralkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or ester, ether, amide, aminoalkylcarboxyl or oxoalkylcarboxyl with 2-8 carbon atoms; or 1-8 natural or non-natural amino acids as defined in this invention; or formula (OCH2CH2). p OR3, or (OCH2CH(CH3)) p OR3, or NH(CH2CH2O) p R3, or NH(CH2CH(CH3)O) p R3, or N[(CH2CH2O)] p R3][(CH2CH2O) p′ R 3′ ] or (OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p The polyoxyethylene unit of COOR3, wherein p and p′ are independently integers selected from 0 to about 100, or combinations thereof; wherein R3 and R 3′ Independently, it is H, C(=O)H, C(=O)CH3, C1-C8 alkyl; or a combination thereof;

[0012] E1 and E2 are linking groups that connect two reactive groups Lv1 and Lv2, wherein Lv1 and Lv2 are preferably capable of reacting with thiol, amino, phenol, ketone, aldehyde, alkynyl, hydroxyl, or carboxylic acid groups in the antibody to form Lv1′ and Lv2′, respectively. E1 and E2 are independently selected from CH, CH2, CH-CH, NH, NHNH, N(R3), N(R3)N(R 3′ N=N, NN, P, P(=O), S, Si, C2-C8 alkyl, heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; peptides containing 1 to 4 amino acid units, preferably amino acids selected from aspartic acid, glutamic acid, arginine, histidine, lysine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, tyrosine, phenylalanine, glycine, proline, tryptophan, alanine; for a more detailed structural description, please refer to the specification of this invention. Furthermore, E1 can be omitted, therefore La1 or / and La2 can be directly attached to the Lv1′ or Lv2′ group;

[0013] m1, m2, m3, m4, m5, m6, m7, m8, m9, m 10 m 11 and m 12 Independently, they are 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and these numbers can have decimals; in addition, m2, m3, m8, m9, and / or m 10 The value can be 0, therefore Ld2-A2, Ld3-A3, Ld5-A5 and / or Ld6-A6 can be omitted;

[0014] A1, A2, A3, A4, A5, and A6 are functional small molecules independently selected from affinity ligands, such as those targeting bufotenide receptors / neuropressin receptors (including neuropeptide Y receptors), cell-penetrating peptides; and / or nucleoside antimetabolites / analytes; which have synergistic effects with D1 and / or D2, or enhance affinity for mAbs. See the specification of this invention for specific structures.

[0015] Wherein, Lv1′ and Lv2′ are groups generated after Lv1 and Lv2 react with the amino acids of antibodies or cell-binding proteins, and their specific structures are detailed in the specification of this invention.

[0016] The present invention also provides an antibody-drug conjugate (ADC) comprising a monoclonal antibody or its antigen-binding fragment, a cytotoxin, and a linker, including a functional small molecule and / or an affinity ligand, such as an affinity ligand targeting the bufotenide receptor / neuropressin receptor (including the neuropeptide-Y receptor), and / or a cell-penetrating peptide, and / or an affinity peptide, such as programmed death ligand-1 (PD-L1 or CD274) expressed on tumor cells and tumor-infiltrating immune cells, thereby enhancing targeted therapy for cancer and refractory diseases. In a further embodiment, the antigen-binding protein is conjugated to a potent toxin, such as a tubulolysin analog, camptothecin (CPT) analog, PBD dimer, eribulin, auratestatin analog, docamycin analog, or anthracycline analog.

[0017] Furthermore, the present invention provides compositions comprising the aforementioned antibody-drug conjugates and pharmaceutically acceptable carriers, as well as methods for targeted therapy against various cancers and refractory diseases.

[0018] Legend

[0019] Figure 1 The synthesis of linkers containing DUPA components is shown.

[0020] Figure 2 The synthesis of conjugates of tubulysin analogs containing DUPA components is shown.

[0021] Figure 3 The synthesis of conjugates of tubulysin analogs containing DUPA components is shown.

[0022] Figure 4 The synthesis of conjugates of tubulysin analogs containing DUPA components is shown.

[0023] Figure 5 The synthesis of conjugates of tubulysin analogs containing DUPA components is shown.

[0024] Figure 6 The synthesis of conjugates of tubulysin analogs containing DUPA components is shown.

[0025] Figure 7 The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0026] Figure 8 The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0027] Figure 9The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0028] Figure 10 The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0029] Figure 11 The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0030] Figure 12 The synthesis of conjugates of tubulysin analogs containing bis-DUPA components is shown.

[0031] Figure 13 The synthesis of a linker containing three gemcitabine analogues was shown.

[0032] Figure 14 The synthesis of a CPT analog containing a coupling linker connected to three gemcitabines is shown.

[0033] Figure 15 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0034] Figure 16 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0035] Figure 17 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0036] Figure 18 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0037] Figure 19 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0038] Figure 20 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0039] Figure 21 The synthesis of a CPT analog containing a coupler linker connected to three gemcitabines is shown.

[0040] Figure 22 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0041] Figure 23 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0042] Figure 24 The synthesis of a CPT analog containing a coupler linker connected to three gemcitabines is shown.

[0043] Figure 25 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0044] Figure 26 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0045] Figure 27 The synthesis of CPT-ADC containing three gemcitabine linkers is shown.

[0046] Figure 28 The synthesis of a CPT-ADC comprising a coupling linker and a CPT load / linker complex, wherein the linker is linked with three gemcitabines, is shown.

[0047] Figure 29 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0048] Figure 30 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0049] Figure 31 The synthesis of bi-linker ADCs containing tubulysin analogues and CPT analogues, as well as bi-linker ADCs containing dual CPT loaders / linkers, is shown.

[0050] Figure 32 The synthesis of a dual-connector ADC containing dual CPT analog payloads is shown.

[0051] Figure 33 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0052] Figure 34 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0053] Figure 35 The synthesis of a linker ADC containing dual loads of tubulysin analogues and CPT analogues is shown.

[0054] Figure 36 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0055] Figure 37 The synthesis of a dual-connector ADC containing both tubulysin and CPT analogs is shown.

[0056] Figure 38 The synthesis of ADCs containing dual loads of tubulysin and CPT analogs, as well as cell-penetrating cyclic peptides and CPT-load / linker complexes, is shown.

[0057] Figure 39 The synthesis of CPT-ADC containing cell-penetrating cyclic peptide dual linkers and CPT / linker complex containing cell-penetrating cyclic peptide linkers is shown.

[0058] Figure 40 The synthesis of CPT-ADC containing a cell-penetrating cyclic peptide dual linker and a tubulysin conjugate containing a cell-penetrating cyclic peptide is shown.

[0059] Figure 41 The synthesis of a tubulysin-linker complex containing a cell-penetrating cyclic peptide is shown.

[0060] Figure 42 The synthesis of tubulysin conjugates containing cell-penetrating cyclic peptide linkers and CPT load-linker complexes containing cell-penetrating cyclic peptide linkers is shown.

[0061] Figure 43 The synthesis of CPT-coupled compounds containing cell-penetrating cyclic peptide linkers and CPT-load-linker complexes containing cell-penetrating cyclic peptides is shown.

[0062] Figure 44 The synthesis of CPT-ADC containing a cell-penetrating cyclic peptide linker and a CPT load-linker complex containing a cell-penetrating cyclic peptide is shown.

[0063] Figure 45 The synthesis of CPT load-linker couplings containing DUPA components is shown.

[0064] Figure 46 The synthesis of CPT load-linker couplings containing DUPA components is shown.

[0065] Figure 47 The synthesis of a CPT-bismaleamide linker complex containing the DUPA component is shown.

[0066] Figure 48 The synthesis of CPT-coupled compounds containing DUPA linkers is shown.

[0067] Figure 49 The synthesis of CPT-coupled compounds containing DUPA linkers is shown.

[0068] Figure 50 The synthesis of CPT-couplers containing dual DUPA linkers is shown.

[0069] Figure 51 The synthesis of CPT-coupled compounds containing DUPA linkers is shown.

[0070] Figure 52 The synthesis of CPT-coupled compounds containing DUPA linkers is shown.

[0071] Figure 53 The synthesis of CPT-coupled compounds containing DUPA linkers is shown.

[0072] Figure 54 The synthesis of CPT-couplers containing DUPA linkers and linkers containing three gemcitabines is shown.

[0073] Figure 55 The synthesis of CPT-coupled compounds containing three gemcitabine linkers is shown.

[0074] Figure 56 The synthesis of CPT-coupled compounds containing a single gemcitabine linker is shown.

[0075] Figure 57 The synthesis of CPT-coupled compounds containing three gemcitabine linkers is shown.

[0076] Figure 58 The synthesis of CPT-coupled compounds containing bisgecitabine linkers was demonstrated.

[0077] Figure 59 The synthesis of CPT-coupled compounds containing bisgecitabine linkers was demonstrated.

[0078] Figure 60 The synthesis of CPT-coupled compounds containing cell-penetrating cyclic peptide linkers is shown.

[0079] Figure 61 The synthesis of CPT-coupled compounds containing cell-penetrating cyclic peptide linkers is shown.

[0080] Figure 62Compared with PBS buffer (control), the changes in tumor volume in C4-2B prostate cancer xenograft mice after continuous single-dose (4.0 mg / kg) treatment with Steap1 ADCs (GGFG-Dxd, C025, C030, C043, C072, C082, C095, C284, C324, C358, C361, C366, and C383, DAR values ​​are shown in the figure). The figure shows that all 13 conjugates exhibited antitumor activity, with the order of antitumor activity being: Dxd < C284 < C358 < C366 < C324 < C082 < C361 < C383 < C030 < C025 < C043 < C072 < C095. It has been demonstrated that the conjugates of the payload / linker complex containing affinity ligands of the present invention can enhance in vivo antitumor activity and have better in vivo activity than the well-known GGFG-Dxd complex.

[0081] Figure 63 Compared with PBS buffer (control), the changes in tumor volume in A431 cancer cell xenograft mice after continuous single-dose (6.0 mg / Kg) administration of Muc1 / EGFR bispecific ADCs (GGFG-Dxd, C342, C467, C571a, C571c, C574c, C574d, C572d, C572i, C574q, C572q, C662 and C675, DAR as shown in the figure) were compared with those after continuous single-dose (6.0 mg / Kg) administration. The figure shows that all 13 conjugates exhibit antitumor activity, with the order of their antitumor activity being: GGFG-Dxd < C342 < C467 < C571a < C571c < C574c < C574d < C572d < C572i < C574q < C572q < C662 < C675. This also demonstrates that the small molecules added to the load / linker complex of the present invention can enhance in vivo antitumor activity. Using the same type of load, conjugates containing the small molecules in the load / linker complex of the present invention exhibit better antitumor activity than the known GGFG-Dxd conjugate.

[0082] Figure 64.Compared with PBS buffer (control), the changes in tumor volume in HCC827 cancer cell xenograft mice after continuous single-dose (3.0 mg / Kg) treatment with Trop 2 ADCs (GGFG-Dxd, C150, C141, C423, C190, C222, C433, C211, C416, C534, C578f, C578k, C578n, and C580m, DAR values ​​are shown in the figure). The figure shows that all 14 conjugates have antitumor activity, and the order of antitumor activity is: GGFG-Dxd < C150 < C141 < C423 < C190 < C222 < C433 < C211 < C416 < C534 < C578f < C578k < C578n < C580m. This also indicates that the small molecules added to the load / linker complex of the present invention can enhance in vivo antitumor activity. Using the same type of payload, conjugates containing the small molecules in the load / linker complex of the present invention have better antitumor activity than known GGFG-Dxd conjugates.

[0083] Figure 65 Compared with PBS buffer (control), the changes in tumor volume in SU86.86 cancer cell xenograft mice after continuous single-dose (2.5 mg / Kg) treatment with bispecific Her2 ADCs (GGFG-Dxd, C254, C314, C572o, C572k, C439, C534, C576c, C577c, C580c, C580e, C580g, and C658, DAR values ​​are shown in the figure). The figure shows that all 13 conjugates have antitumor activity, and the order of antitumor activity is: GGFG-Dxd < C254 < C314 < C572o < C572k < C439 < C534 < C576c < C577c < C580c < C580e < C580g < C658. This also indicates that the small molecules added to the load / linker complex of the present invention can enhance in vivo antitumor activity. Using the same type of payload, conjugates containing the small molecules in the load / linker complex of the present invention have better antitumor activity than known GGFG-Dxd conjugates. Summary of the Invention

[0085] definition

[0086] "Alkyl" refers to an aliphatic hydrocarbon group or monovalent group formed by removing one or two hydrogen atoms from an alkane. It can be straight-chain or branched, and has C1-C8 (1-8 carbon atoms) in the chain. "Branched" means that one or more low-carbon alkyl groups, such as methyl, ethyl, or propyl, are attached to a straight-chain alkyl group. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-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-methylhexyl, 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. C1-C8 alkyl groups can be unsubstituted or substituted with one or more groups, including but not limited to C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R′, -OC(O)R′, -C(O)OR′, -C(O)NH2, -C(O)NHR′, -C(O)N(R′)2, -NHC(O)R′, -SR′, -S(O)2R′, -S(O)R′, -OH, -halogen, -N3, -NH2, -NH(R′), -N(R′)2, and -CN; wherein each R′ is independently selected from C1-C8 alkyl and aryl groups. When an alkyl group is inserted into the middle of a group, for example, into the middle of a linking group, therefore, "alkyl" in this application refers to "alkylene".

[0087] "Halogen" refers to fluorine, chlorine, bromine or iodine atoms; fluorine and chlorine atoms are preferred.

[0088] "Heteroalkyl" refers to a C2-C8 alkyl group in which 1 to 4 carbon atoms are independently replaced by heteroatoms selected from O, S and N.

[0089] "Carbon ring" refers to a saturated or unsaturated monocyclic ring containing 3 to 8 carbon atoms, or a saturated or unsaturated bicyclic ring containing 7 to 13 carbon atoms. Monocyclic carbon rings have 3 to 6 ring atoms, typically 5 or 6. Bicyclic carbon rings have 7 to 12 ring atoms, forming bicyclic systems of [4, 5], [5, 5], [5, 6], or [6, 6], or have 9 or 10 ring atoms, forming bicyclic systems of [5, 6] or [6, 6]. Representative C3-C8 carbon rings 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-cycloheptanetrienyl, -cyclooctyl, and -cyclooctadienyl.

[0090] "C3-C8 carbon ring" refers to a saturated or unsaturated non-aromatic carbon ring containing 3, 4, 5, 6, 7, or 8 ring atoms. The "C3-C8 carbon ring" can be unsubstituted or substituted with one or more groups, including but not limited to C1-C8 alkyl, -O-(C1-C8 alkyl), -aryl, -C(O)R′, -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′, -OH, -halogen, -N3, -NH2, -NH(R′), -N(R′)2, and -CN; wherein each R′ is independently selected from C1-C8 alkyl and aryl groups.

[0091] "Alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group containing carbon-carbon double bonds, with 2 to 8 carbon atoms in the chain. Exemplary alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, hexenyl, heptenyl, and octenyl.

[0092] "Alynyl" refers to a straight-chain or branched aliphatic hydrocarbon group containing a carbon-carbon triple bond, with 2 to 8 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, 5-pentynyl, n-pentynyl, hexynyl, hepynyl, and octyynyl.

[0093] "Alkylene" refers to a saturated branched, straight, or cyclic hydrocarbon group containing 1-18 carbon atoms, and carrying two monovalent free radicals formed by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylenes include, but are not limited to: methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), etc.

[0094] "Alkenyl" refers to an unsaturated branched, straight-chain, or cyclic hydrocarbon group containing 2-18 carbon atoms, and carrying two monovalent free radicals generated by removing two hydrogen atoms from the same or two different carbon atoms of the parent olefin. Typical alkenyl groups include, but are not limited to: 1,2-ethylene (-CH=CH-).

[0095] "Inyynyl" refers to an unsaturated branched, straight-chain, or cyclic hydrocarbon group containing 2-18 carbon atoms, and carrying two monovalent free radicals generated by removing two hydrogen atoms from the same or two different carbon atoms of the parent yethyn. Typical nyynyl groups include, but are not limited to: acetylene, propynyl, and 4-pentynyl.

[0096] "Aryl" or "aromatic group" refers to an aromatic or heteroaromatic group consisting of one or more rings containing three to fourteen carbon atoms, preferably six to ten carbon atoms. The term "heteroaromatic group" refers to a group formed by replacing one or more carbon atoms, preferably one, two, three or four carbon atoms, of an aromatic group with oxygen (O), nitrogen (N), silicon (Si), selenium (Se), phosphorus (P) or (S), preferably with oxygen, sulfur and nitrogen. The term "aryl" or "aromatic group" also refers to an aromatic group formed by the independent substitution of one or more hydrogen atoms by -R', halogen, -OR', -SR', -NR'R", -N=NR', -N=R', -NR'R", -NO2, -S(O)R', -S(O)2R', -S(O)2OR', -OS(O)2OR', -PR'R", -P(O)R'R", -P(OR')(OR"), -P(O)(OR')(OR"), or -OP(O)(OR')(OR"), where R' and R" are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, aralkyl, carbonyl, or their pharmaceutical salts.

[0097] "Heterocyclic" refers to a ring structure in which one to four ring carbon atoms are independently replaced by heteroatoms such as O, N, S, Se, B, Si, or P. Preferred heteroatoms are O, N, and S. A description of heterocyclic compounds can also be found on pages 225-226 of the 78th edition of the *Handbook of Chemistry and Physics* (CRC Press, Inc., 1997-1998), which is cited here for reference. Preferred non-aryl heterocyclic compounds include epoxy group, aziridinyl group, thiopropyl group, pyrrolyl group, pyrazolyl group, imidazoyl group, ethylene oxide group, tetrahydrofuranyl group, dioxaneyl group, tetrahydropyranyl group, dioxaneyl group, dioxaneyl group, dioxaneyl group, piriminyl group, morpholinyl group, pyranyl group, imidazolinyl group, pyrrololinyl group, pyrazolyl group, thiazoylyl group, tetrahydrothiaranyl group, dithiaranyl group, thiomorpholinyl group, dihydropyranyl group, tetrahydropyranyl group, dihydropyridinyl group, tetrahydropyridinyl group, dihydropyridinyl group, tetrahydropyrimidinyl group, dihydrothiaranyl group, azirheptanyl group, and fused ring systems obtained by condensation of the above groups with phenyl groups.

[0098] The term "heteroaryl" or "aryl heterocycle" refers to an aromatic heterocycle containing 3 to 14, preferably 5 to 10 atoms, and may be monocyclic, bicyclic, or polycyclic. Examples include pyrroleyl, pyridyl, pyrazolyl, thiopheneyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl, imidazolyl, thiopheneyl, thiazolyl, benzothiazolyl, furanyl, benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoquinolinyl, benzothiapheneyl, isobenzofuranyl, pyrazolyl, carbazoleyl, benzimidazolyl, isoxazolyl, pyridyl-N-oxide, and fused-ring systems obtained by condensation of the aforementioned groups with a phenyl group.

[0099] "alkyl", "cycloalkyl", "alkenyl", "alkynyl", "aryl", "heteroaryl", "heterocyclic", etc., also contain their respective "alkylene", "cycloalkylene", "alkenylene", "alkynylene", "arylene", "heteroaryl", "heterocyclic", etc., which are formed by removing two hydrogen atoms.

[0100] "Aryl group" refers to a class of noncyclic alkyl groups, one of which is associated with a carbon atom (usually terminal or sp). 3 The hydrogen atoms bonded to the carbon atom are replaced by aryl groups. Typical aryl alkyl groups include benzyl, 2-phenylethyl-1-yl, 2-phenylvinyl-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, 2-naphthylethyl-1-yl, naphthobenzyl, 2-naphthylphenyl-1-yl, etc.

[0101] "Heteroarylene" refers to a class of noncyclic alkyl groups, one of which is associated with a carbon atom (usually terminal or sp). 3 The hydrogen atom bonded to the carbon atom is replaced by a heteroaryl group. Examples of heteroaryl groups include 2-benzimidazolylmethyl and 2-furanylethyl.

[0102] Examples of “hydroxyl protecting groups” include methoxymethyl ethers, 2-methoxyethoxymethyl ethers, tetrahydropyranyl ethers, benzyl ethers, p-methoxybenzyl ethers, trimethylsilyl ethers, triethylsilyl ethers, triisopropylsilyl ethers, tert-butyldimethylsilyl ethers, triphenylmethylsilyl ethers, acetates, substituted acetates, pentyl esters, benzoates, methanesulfonates, and p-toluenesulfonates.

[0103] A “leaving group” is a functional group that can be replaced by another functional group. Such leaving groups are well known in the art, and examples include halides (e.g., chlorides, bromides, and iodides), mesylate, tosyl, trifluoromethanesulfonyl, and trifluoromethanesulfonates. Preferred leaving groups include those derived from nitrophenol; N-hydroxysuccinimide (NHS) group; phenol; dinitrophenol; pentafluorophenol; tetrafluorophenol; difluorophenol; monofluorophenol; pentachlorophenol; trifluoromethanesulfonate; imidazolium; dichlorophenol; tetrachlorophenol; 1-hydroxybenzotriazolium; toluenesulfonate; methanesulfonate; 2-ethyl-5-phenylisoxazole-3′-sulfonate, self-formed or formed with other anhydrides, such as acetic anhydride, formic anhydride; or intermediate molecules formed with condensing agents during peptide coupling or intermediate molecules from the Mitsunobu reaction.

[0104] The following abbreviations are used in this invention and are defined as follows: Boc, tert-butoxycarbonyl; BroP, bromotetradecylphosphonium hexafluorophosphate; CDI, 1,1′-carbonyldiimidazole; DCC, dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; DIAD, diisopropyl azodicarbonate; DIBAL-H, diisobutylaluminum hydride; DIPEA, diisopropylethylamine; DEPC, diethylcyanophosphate; DMA, N,N-dimethylacetamide; DMAP, 4-(N,N-dimethylamino)pyridine; DMF, N... N-Dimethylformamide; DMSO, Dimethyl sulfoxide; DTT, Dithiothreitol; EDC, 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI-MS, Electrospray ionization mass spectrometry; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethylurea hexafluorophosphate; HOBt, 1-hydroxybenzotriazole; HPLC, High-performance liquid chromatography; NHS, N-hydroxysuccinimide; MMP, 4-methylmorpholine; PAB, p-aminobenzoic acid; PBS, Phosphate buffer (pH 7.0-7.5); PEG, Polyethylene glycol; SEC, Size exclusion chromatography; TCEP, Tris(2-carboxyethyl)phosphine; TFA, Trifluoroacetic acid; THF, Tetrahydrofuran; Val, Valine.

[0105] Amino acids can be natural or non-natural, with α-amino acids being preferred. Natural amino acids can be encoded by the genetic code, and their names, structures, and single-letter or three-letter codes are well-known in university textbooks: G-glycine (Gly), P-proline (Pro), A-alanine (Ala), V-valine (Val), L-leucine (Leu), I-isoleucine (Ile), M-methionine (Met), C-cysteine ​​(Cys), F-phenylalanine (Phe), Y-tyrosine (Tyr), W-tryptophan (Trp), H-histidine (His), K-lysine (Lys), R-arginine (Arg), Q-glutamine (Gln), N-asparagine (Asn), E-glutamic acid (Glu), D-aspartic acid (Asp), S-serine (Ser), T-threonine (Thr). Non-natural amino acids are derivatives of protein amino acids, including hydroxyproline, lanethionine, 2-aminoisobutyric acid, dehydroalanine, γ-aminobutyric acid (a neurotransmitter), ornithine, citrulline, β-alanine (3-aminopropionic acid), γ-carboxyglutamic acid, selenocysteine ​​(found in many non-eukaryotic and most eukaryotic cells, but not directly encoded by DNA), pyrrolidone (found only in some archaea and one bacterium), N-formylmethionine (often the original amino acid in 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 simulants. Analogs are compounds having the same structural formula H₂N(R)CHCO₂H as natural amino acids, where R is not present in the natural amino acid. Examples of analogs include homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. More preferably, amino acid mimics are compounds that have a different chemical structure from α-amino acids but a similar mode of action. "Non-natural amino acids" are amino acids with a "D" configuration, while natural amino acids are mostly in an "L" stereoconfiguration. When using 1 to 8 amino acids in this patent application, their sequence is preferably a sequence recognizable by proteolytic enzymes.Many hydrolases recognize sequences known in the art, see: Matayoshi et al. Science 247:954 (1990); Dunn et al. Meth. Enzymol. 241:254 (1994); Seidah et al. Meth. Enzymol. 244:175 (1994); Thornberry, Meth. Enzymol. 244:615 (1994); Weber et al. Meth. Enzymol. 244:595 (1994); Smith et al. Meth. Enzymol. 244:412 (1994); and Bouvier et al. Meth. Enzymol. 248:614 (1995); which are incorporated herein by reference. Specifically, sequences selected from the following: Val-Cit, Val-Ala, Val-Gln, Val-Lys, Tyr-Arg, Phe-Arg, Tyr-Met, Leu-Gln, Met-Thr, Phe-Gln, Thr-Thr, Val-Thr, Ala-Ala, (D)Val-(D)Gln, Val-Lys(NPr2), Val-Lys(NMe2), Val-Lys(NEt2), Val-Lys(NBu2), Val-Lys(NBz2), Val-Ala-Val, Lys-L ys, Ala-Asn-Val, Ala-Val-Lys, Ala-Val-Glu, Val-Leu-Lys, Cit-Cit, Val-Lys, Ala-Ala-Asn, Gly-Gly, Gly-Gly-Gly, Ala-Ala- Ala, Ala-Ala-Ala-Glu, Ala-Val-Arg, Ala-Val-Arg-Arg, Ala-Ala-Arg, Ala-Ala-Arg-Arg, Gly-Gly-Phe-Gly, Lys, Cit, Ser and Glu. In addition to the 20 standard L- or D-amino acids, some less common amino acids are coded as follows: Gamma-aminobutyric acid (Abu), Aminoisobutyric acid (Aib), Alpha-cyclohexylalanine (Cha), Citrulline (Cit), Diaminopropionic acid (Dap), Hydroxylysine (Hyl), Hydroxyproline (Hyp), Leucine (Nle), Valine (Nva), Ornithine (O), Penicillamine (Pen), Pyroglutamic acid (Pyr), Sarcosine (Sar), and Statin (Sta).Examples of single-code modified amino acids are as follows: asparagine-EDANS (D-EDANS), cysteine-3-nitro-2-pyridinesulfonyl (C-NPys), glutamic acid-EDANS (E-EDANS), N-methylglycine (G-NMe), N-methylleucine (L-NMe), phosphorylated serine (pS), phosphorylated threonine (pT), phosphorylated tyrosine (pY), O-methylated tyrosine (Y-OMe), 3-nitrotyrosine (Y-NO2), and sulfated tyrosine (sY). 5-Carboxyfluorescein lysine (K-5-FAM), 5-Carboxytetramethylrhodamine lysine (K-5-TAMRA), acetylated lysine (K-Ac), biotinylated lysine (K-Biotin), lysine-DABCYL (K-DABCYL), lysine-dansyl (K-DANSYL), lysine-DNP (K-Dnp), lysine-MCA (K-Mca), methylated lysine (K-Me), dimethylated lysine (K-Me2), trimethylated lysine (K-Me3).

[0106] "Pharmaceutical acceptable" or "pharmaceuticalally acceptable" means that when the molecular entity and composition are administered to animals or humans as appropriate, they will not produce adverse, allergic or other adverse reactions.

[0107] "Pharmaceutically acceptable solvate" or "solvent" means a combination of one or more solvent molecules with a compound disclosed in this invention. Examples of solvents that form a pharmaceutically acceptable solvate include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0108] "Pharmaceutically acceptable excipients" include any carrier, diluent, adjuvant, or other agent such as preservatives or antioxidants, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of these media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent, unless incompatible with the active ingredient, may also be considered for use in therapeutic compositions. Supplemental active ingredients may also be incorporated into the composition to create a suitable therapeutic combination.

[0109] In this patent application, "pharmaceutical salt" refers to a derivative of the disclosed compound, obtained by preparing an acid salt or base salt of the parent compound. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts formed from a non-toxic inorganic acid or organic acid and the parent compound. For example, said conventional non-toxic salts include salts derived from inorganic acids (e.g., hydrochloric acid, hydrobromide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.); and salts prepared from organic acids (e.g., acetic acid, propionic acid, succinic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, glucuronic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, and lactic acid, etc.). Other addition salts include ammonium salts, such as salts of trimethylamine, meglumine, glycerol, etc., and metal salts, such as sodium, potassium, calcium, zinc, or magnesium salts.

[0110] The pharmaceutical salts of this invention can be synthesized from a parent compound containing a basic or acidic moiety using conventional chemical methods. Generally, these salts can be prepared by adding an equimolar amount of a suitable base or acid to the parent compound in water or an organic solvent, or a mixture of both. Generally, diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred non-aqueous media. A list of suitable salts is available in Remington's Pharmaceutical Sciences, published by Mack Publishing in 1985, the disclosure of which is incorporated herein by reference.

[0111] "Administration" or "dosage" means the transfer, delivery, introduction, or transport of a drug or other pharmaceutical agent to a subject by any means. These means include oral administration, local contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal, subcutaneous, or intrathecal administration. The present invention also contemplates the use of devices or instruments for administering pharmaceutical agents. Such devices may be active or passive delivery methods and may be sustained-release or rapid-release delivery devices.

[0112] The abbreviations and chemical names of biological buffer solutions are as follows:

[0113] A buffer system of ACES (N-(2-acetamido)-2-aminoethanesulfonic acid), pH 6.1-7.5 (pKa = 6.88).

[0114] A buffer system of ADA (N-(2-acetamido)iminodiacetic acid, N-(carbamoylmethyl)iminodiacetic acid), pH 6.0-7.2 (pKa = 6.65).

[0115] AMPD (2-amino-2-methyl-1,3-propanediol), a buffer system with pH 7.8-9.7.

[0116] AMPSO (N-(1,1-dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid).

[0117] BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid).

[0118] A buffer system of Bicine (bis(N,N-bis(2-hydroxyethyl)glycine), bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane), pH 5.8-7.2 (pKa = 8.35).

[0119] BisTris (bis-(2-hydroxyethyl)amino-tris(hydroxymethyl)methane).

[0120] BisTris propane (1,3-bis[tris(hydroxymethyl)methylamino]propane).

[0121] A buffer system of DIPSO (N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid), pH 7.0-8.2.

[0122] A buffer system of Gly-Gly (diglycine, glycyl-glycine) with a pH of 7.5-8.9 (pKa = 8.30).

[0123] HEBPS (N-(2-hydroxyethyl)piperazine-N′-(4-butyric acid)) is a homologue of HEPES and EPPS, with a high pKa (pKa = 8.30) and a buffer system with a pH of 7.6-9.0.

[0124] HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid, 2-morpholinoethanesulfonic acid, 2-(4-morpholino)ethanesulfonic acid, 2-(N-morpholino)ethanesulfonic acid, morpholino-4-ethanesulfonic acid hydrate), pH 6.8-8.2 buffer system; pKa 7.45-7.65 at 20℃)

[0125] A buffer system of HEPPS or EPPS (3-[4-(2-hydroxyethyl)-1-piperazinyl]propanesulfonic acid hydrate, 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate), pH 7.3-8.7 (pKa=8.00 / piperazine ring).

[0126] HEPPSO (4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate).

[0127] A buffer system of MES (2-(N-morpholino)ethanesulfonic acid monohydrate), pH 5.2-7.1 (pKa 6.16).

[0128] MOBS (4-morpholinobutanesulfonic acid, hemisodium 3-(N-morpholino)butanesulfonic acid) is a homologue of MES and MOPS with a high pKa and is a buffer system with a pH of 6.9-8.3 (pKa 7.6).

[0129] MOPS (sodium 4-morpholinopropanesulfonate).

[0130] MOPSO (β-hydroxy-4-morpholinopropanesulfonic acid, 3-morpholino-2-hydroxypropanesulfonic acid).

[0131] PIPES (piperazine-1,4-bis(2-ethanesulfonic acid), pH 6.1-7.5 (pKa = 6.80) buffer system.

[0132] POPSO (piperazine-1,4-bis(2-hydroxypropanesulfonic acid) dihydrate).

[0133] TAPS ([(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid).

[0134] TAPSO (2-hydroxy-3-[tris(hydroxymethyl)methylamino]-1-propanesulfonic acid).

[0135] TES (2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid).

[0136] Tricine (piperazine-N,N'-bis[2-hydroxypropanesulfonic acid]), pH 7.4-8.8 (pKa 8.16) buffer system.

[0137] The term "antibody" is used in the broadest sense in this patent application to encompass a wide range of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (provided they possess the desired antigen-binding activity), antibody-containing fusion proteins, and any other conformationally modified immunoglobulin molecules containing antigen recognition sites. Antibodies include any type of antibody, such as IgG, IgA, or IgM (or its subclasses), and the antibody need not be of any particular kind. Immunoglobulins can be classified into different types based on the amino acid sequence of the antibody heavy chain constant region. There are five main types of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known. The subunit structures and three-dimensional conformations of different types of immunoglobulins are well known. "Antibody fragment" refers to a molecule that is different from the intact antibody, contains a portion of the intact antibody, and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab′, Fab′-SH, F(ab′)2; bispecific antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. "Humanized" antibody refers to a chimeric antibody containing amino acid residues from a non-human HVR and amino acid residues from a human FR. In some embodiments, the humanized antibody will contain substantially all, at least one, typically two variable domains, wherein all or substantially all of the HVR (e.g., CDR) are derived from the non-human antibody HVR, and all or substantially all of the FR are derived from the FR of the human antibody. Optionally, the humanized antibody may contain at least a portion of an antibody constant region derived from the human antibody. The "humanized form" of an antibody, such as a non-human antibody, refers to a humanized antibody. The terms "variable region" or "variable domain" refer to a domain of the antibody heavy or light chain involved in antigen binding. The heavy and light chain variable domains (VH and VL, respectively) of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Antibodies binding to a specific antigen can be obtained by screening a complementary VL or VH display library using the VH or VL of any antibody binding to that antigen.(See, for example, Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991)).

[0138] In this patent application, "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous group of antibodies, meaning that the individual antibodies constituting the group are identical, except for the possible small number of naturally occurring mutations. Monoclonal antibodies are highly specific, targeting a single antigenic site. Furthermore, unlike polyclonal antibody products, they typically contain different types of antibodies targeting different determinants (epitopes), with each monoclonal antibody targeting only a single determinant on the antigen. The modifier "monoclonal" indicates that the antibody is characterized by being obtained from a substantially homogeneous group of antibodies and should not be construed as requiring preparation by any particular method. For example, the monoclonal antibody used according to the invention can be prepared by the hybridoma method first described by Kohler and Milstein in Nature 256:495, 1975, or by a recombinant DNA method, such as the recombinant DNA method described in U.S. Patent 4,816,567. Alternatively, the monoclonal antibody can also be isolated from a phage library using the technique described by McCafferty et al. in Nature 348:552-554, 1990.

[0139] In this patent application, a "humanized" antibody refers to a non-human (e.g., mouse) antibody that is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (e.g., Fv, Fab, Fab′, F(ab′)2, or antigen-binding sequence of another antibody), containing a minimum of sequences derived from non-human immunoglobulins. Preferably, the humanized antibody is a human immunoglobulin (receptor antibody) in which residues of the receptor complementarity-determining region (CDR) are replaced by residues of a CDR derived from a non-human species (donor antibody), such as mouse, rat, or rabbit, and possessing the desired specificity, affinity, and function. In some cases, residues of the Fv framework region (FR) of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the residues introduced into the humanized antibody are neither in the receptor antibody nor in the introduced CDR or framework sequence, with the aim of further improving and optimizing antibody performance. Generally, the humanized antibody will contain substantially all, at least one, typically two variable domains, wherein all or substantially all of the CDR regions correspond to the CDR regions of the non-human immunoglobulin, and all or substantially all of the FR regions are regions of the human immunoglobulin common sequence. Preferred humanized antibodies also contain at least a portion of the immunoglobulin constant region or domain (Fc), typically derived from human immunoglobulins. Antibodies having an Fc region modified as described in WO 99 / 58572 are preferred. Other forms of humanized antibodies, having one or more CDRs (CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, or CDRH3) altered relative to the original antibody, are also referred to as "derived" one or more CDRs from the original antibody.

[0140] In this patent application, "human antibody" means an antibody containing an amino acid sequence corresponding to the amino acid sequence of an antibody produced by humans and / or prepared by any technique known to those skilled in the art or disclosed in this patent application for preparing human antibodies. Human antibodies include antibodies containing at least one human heavy chain polypeptide or at least one human light chain polypeptide. One example is an antibody composed of mouse light chain and human heavy chain polypeptides. Human antibodies can be prepared using various techniques known in the art. In one embodiment, the human antibody is selected from a phage library expressing a human antibody (Vaughan et al., Nature Biotechnology, 14: 309-314, 1996; Sheets et al., Proc. Natl. Acad. Sci. (USA) 95: 6157-6162, 1998; Hoogenboom and Winter, J. Mol. Biol., 227: 381, 1991; Marks et al., J. Mol. Biol., 222: 581, 1991). Human antibodies can also be prepared by immunizing animals by partially or completely inactivating the endogenous immunoglobulin genes of animals, such as mice, and then transferring the human immunoglobulin genes into the animal's endogenous gene locus. This method is described in U.S. Patents 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016. Alternatively, human antibodies can be prepared by immortalizing human B lymphocytes that produce antibodies targeting the target antigen (these B lymphocytes can be recovered from an individual or a single-cell clone of cDNA, or can be immunized in vitro). See Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77, 1985; Boerner et al., J. Immunol., 147(1): 86-95, 1991; and U.S. Patent 5,750,373.

[0141] The term "chimeric antibody" refers to an antibody whose variable region sequence is derived from one species and whose constant region sequence is derived from another species, such as an antibody whose variable region sequence is derived from a mouse antibody and whose constant region sequence is derived from a human antibody.

[0142] The terms “polypeptide,” “oligopeptide,” “peptide,” and “protein” are used interchangeably herein to refer to an amino acid chain of any length, preferably relatively short (e.g., 10-100 amino acids). This chain may be linear or branched, may contain modified amino acids, and / or may be separated by non-amino acid segments. The term also includes amino acid chains that are native or modified through intervention; for example, disulfide bond formation, glycosylation, esterification, acetylation, phosphorylation, or any other manipulation or modification, such as coupling with a labeled component. This definition also includes, for example, polypeptides containing one or more amino acid analogs (including, for example, non-natural amino acids) and other modifications known in the art. It should be understood that polypeptides can exist as single chains or associated chains.

[0143] Each molecule of a "monovalent antibody" contains one antigen-binding site (e.g., IgG or Fab). In some cases, a monovalent antibody may have multiple antigen-binding sites, but these sites should originate from different antigens.

[0144] Each molecule of a "monospecific antibody" contains two identical antigen-binding sites (e.g., IgG), and these two sites bind to the same epitope on the antigen. Therefore, they compete to bind to the same antigen molecule. Most antibodies found in nature are monospecific. In some cases, monospecific antibodies can also be monovalent antibodies (e.g., Fab).

[0145] Each molecule of a "bivalent antibody" contains two antigen-binding sites (e.g., IgG). In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody may be bispecific.

[0146] Bispecific antibodies are hybrid antibodies that have two different antigen-binding sites. The two antigen-binding sites of a bispecific antibody bind to two different epitopes, which may be located on the same or different protein targets.

[0147] A "bifunctional" antibody is one that has the same antigen-binding site (i.e., the same amino acid sequence) on both arms, but each binding site can recognize two different antigens.

[0148] A "heteropolymer," "heteropolymer complex," or "heteropolymer polypeptide" is a molecule comprising at least a first polypeptide and a second polypeptide, wherein the second polypeptide differs from the first polypeptide by at least one amino acid residue. A heteropolymer may comprise a "heterodimer" formed by the first and second polypeptides, or a higher-order tertiary structure formed when polypeptides other than the first and second polypeptides are present.

[0149] A "heterodimer", "heterodimeric protein", "heterodimeric complex" or "heteropolymeric polypeptide" is a molecule composed of a first polypeptide and a second polypeptide, wherein the amino acid sequence of the second polypeptide differs from that of the first polypeptide by at least one amino acid residue.

[0150] In this patent application, the meanings of "hinge region," "hinge sequence," and other variations are well known in the art and have been described in works such as Janeway et al., ImmunoBiology: the immune system in health and disease (Elsevier Science Ltd., NY) (4th ed., 1999); Bloom et al., Protein Science (1997), 6: 407-415; and Humphreys et al., J. Immunol. Methods (1997), 209: 193-202.

[0151] In this patent application, "immunoglobulin-like hinge region," "immunoglobulin-like hinge sequence," and variations thereof refer to the hinge region and hinge sequence of an immunoglobulin-like or antibody-like molecule (e.g., immunoadhesin). In some embodiments, the immunoglobulin-like hinge region may be derived from or derived from any IgG1, IgG2, IgG3, or IgG4 subtype, or from IgA, IgE, IgD, or IgM, including its chimeric forms, such as a chimeric IgG1 / 2 hinge region.

[0152] Because different IgG antibody types have different disulfide bonds, the drug / antibody ratio (DAR) of thiol-ether coupling (e.g., via a Michael addition reaction between maleimide in the drug / linker complex and cysteine ​​in the antibody) may also differ. For example, for IgG2, IgG3, or IgG4 type ADCs, the DAR (referred to as "n" in this application) can be as high as 30.

[0153] The term "immune effector cell" or "effector cell" in this patent application refers to cells within the natural cell pool of the human immune system that can be activated to influence the viability of target cells. The viability of target cells may include the ability of cells to survive, proliferate, and / or interact with other cells.

[0154] The antibodies in this invention can be prepared using techniques known in the art, such as recombinant techniques, phage display techniques, synthetic techniques or combinations of such techniques, or other existing techniques in the art (see, for example, Jayaseena S.D., Clin. Chem., 45: 1628-50, 1999 and Fellouse FA, et al., J. Mol. Biol., 373(4): 924-40, 2007).

[0155] In this patent application, the term "cytotoxic agent" refers to a substance capable of inhibiting or preventing cellular function and / or causing cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, I131, I125, Y90, In111, Re186, Re188, Sm153, Bi212, P32, Pb212, Zr89, F18, and radioactive isotopes of Lu, such as Lu177); chemotherapeutic agents or drugs (e.g., tubulysin, maytansine, aurestatin, DNA minor groove binding agents (e.g., PBD dimer), ducamycin, topoisomerase inhibitors). RNA polymerase inhibitors, DNA alkylating agents, methotrexate, adelamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and their fragments, such as lysozymes; antibiotics; toxins, such as small molecule toxins, enzymatically active toxins derived from bacteria, fungi, plants or animals, including fragments and / or variants thereof; and various antitumor or anticancer agents disclosed in this patent application.

[0156] A linker is a chemical structural fragment, a covalent bond or atomic chain, that covalently links an antibody to a drug moiety. In various embodiments, the linker comprises divalent groups such as alkyldiyl, aryldiyl, heteroaryldiyl, fragments such as repeating units of alkoxy groups (e.g., polyoxyethylene, PEG, polymethoxy), and alkylamino groups (e.g., polyvinylamino); and esters and amides, including succinates, succinamides, diglycolates, malonates, and hexamethyleneamides. In various embodiments, the linker may contain one or more amino acid residues, such as valine, phenylalanine, lysine, and ornithine.

[0157] In this specification and claims, the terms "comprise," "comprising," "including," and "includes" are used to describe the presence of the stated features, integers, components, or steps, but do not exclude the presence or coexistence of one or more other features, integers, components, steps, or components thereof. The novel conjugates disclosed in this invention are antibody conjugates targeting tumor antigens or other tumor-specific antigens. The novel conjugates disclosed in this application use bridging linkers. Examples of some conjugates and their synthesis are described in Examples 1-482 of the specification.

[0158] The antibody-drug conjugate of the present invention.

[0159] This invention provides an antibody-drug conjugate (ADC) with enhanced tumor cell killing activity. The ADC contains a branched linker, with a set of affinity small molecules, affinity peptides and / or cell-penetrating peptides, or small molecule chemotherapeutic drugs attached to its terminal end. It exhibits a synergistic effect in terms of cytotoxicity and antibody affinity, thereby enhancing the therapeutic effect against tumors and refractory diseases. The molecular formula of the ADC of this invention is represented as follows:

[0160]

[0161] in,

[0162] D1 and D2 are cytotoxic agents; mAb is an antibody or antibody-like protein; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and these numbers can be decimals;

[0163] L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, and Ld6 are linker components, independently selected from O, NH, S, N, NH-NH, NN, N(R3), N(R3)N(R 3’ C(=O)N, C(=O)NH, C(=O)NN, C1-C8 alkyl; heteroalkyl, alkylcycloalkyl, C2-C8 heterocycloalkyl; C3-C8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or esters, ethers, ureas, carbamates, carbonates, thioureas, thioethers, thioureas, amides, aminoalkylcarboxylic acids or oxyalkylcarboxylic acids having 1 to 8 carbon atoms; or 1 to 8 natural or non-natural amino acids as described in the definition; or as in the general formula (OCH2CH2). p OR3、C(O)(CH2CH2O) p R3、(OCH2CH(CH3)) p OR3, or NH(CH2CH2O) p R3, or NH(CH2CH(CH3)O) p R3, or N[(CH2CH2O)] p R3][(CH2CH2O) p’ R3'] or (OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p The polyethoxyl unit of COOR3, wherein p and p' are independently integers selected from 0 to about 100, or combinations thereof; wherein R3 and R3' are independently H, C(=O)H, C(=O)CH3, C1-C8 alkyl; or combinations thereof;

[0164] In a further embodiment, L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, and Ld6 are 1 to 4 natural or non-natural amino acids, C1-C8 γ-aminoalkyl, aminoalkylcarboxyl, thioalkylcarboxyl, or oxoalkylcarboxyl groups, or C3-C 18 The γ-aminobenzyl group or aromatic ester, ether, urea, carbamate, carbonate, thiourea, thioether, or amide, wherein the aromatic group is selected from phenyl, phenolic, benzyloxy, benzylamino, phenylcarboxyl, oxyphenylcarboxyl, aminophenylcarboxyl, benzyloxycarbonyl, benzylaminocarbonyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, and thiazolyl. Furthermore, lysine and / or glutamic acid from natural or non-natural amino acids can be linked to polyoxyethylene units having the following structural formula via an amino or carboxyl group: C(O)(CH2CH2O). p R3 or NH(CH2CH2O) p R3, where p and R3 are as described above;

[0165] E1 and E2 are linking groups selected from the following groups: CH, CH2, CH-CH, NH, NHNH, N(R3), N(R3)N(R3′), N=N, NN, P, P(=O), S, Si, C2-C8 alkyl, heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; containing 1 to 4 amino acid units, preferably selected from aspartic acid, glutamic acid, arginine, histidine, lysine, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, tyrosine, phenylalanine, glycine, proline, tryptophan, alanine; or one of the following structures:

[0166] in This is the connection site; X1, X2, X3, X4, X5, or X6 are independently selected from NH; NHNH; N(R3); N(R3)N(R3'); O; S; C1-C6 alkyl; R3 and R3' are H, C1-C6 alkyl; In addition, E1 can be omitted, so La1 or / and La2 can be directly connected to Lv1' or Lv2';

[0167] m1, m2, m3, m4, m5, m6, m7, m8, m9, m 10 m 11 and m 12 The numbers are independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and these numbers may have decimals; additionally, m2, m3, m8, m9 and / or m10 It can be 0, so Ld2-A2, Ld3-A3, Ld5-A5, and / or Ld6-A6 can be omitted;

[0168] Lv1' and Lv2' have the following structure, either independently or jointly:

[0169]

[0170]

[0171]

[0172]

[0173] in R1 and R2 are the sites for drug linkage or linker L1 or L2 linkage sites; "#" is the linkage site for mercapto (S), phenol (O), amino (NH), aldehyde (CHO), carbonyl (C(=O)), amide (C(O)(NH)), and the carboxyl (C(O)(OH)) group of the antibody; R1 and R2 are hydrogen, C1-C6 alkyl, or a peptide containing 1 to 4 amino acid units; X1', X2', and X are the linkages between two atoms of O, NH, S, and CH2. This means it can connect to either of two atoms; Ar is an aromatic group.

[0174] A1, A2, A3, A4, A5, and A6 are independently affinity ligands of affinity peptides and cell-penetrating peptides (CPP), ligands of dermalin receptors / neurotensin receptors (including neuropeptide-Y receptors), and / or nucleoside antimetabolites / analytes that synergize with D1 or D2 or enhance antibody affinity.

[0175] In some implementations, the affinity ligand / peptide (including cell-penetrating peptides) has an EC50 of <100 nM with the receptor. CPP is a linear or cyclic peptide containing fewer than 50 amino acids, including one, two, or several arginine or lysine residues, capable of internalizing (transporting) more than 40% of the ligand bound to the cell, or assisting in the internalization of 40% of the ADC bound to the cell, and crossing the cell membrane within 2 hours.

[0176] In some implementations, the affinity ligand / peptide, including cell-penetrating peptides (CPPs), is independently selected from:

[0177]

[0178]

[0179]

[0180] LyP-1 peptide:

[0181] iRGD:

[0182] K237 peptide (binds to VEGFR-2):

[0183] RVG peptide:

[0184]

[0185] mUNO (CD206):

[0186] GALA peptide:

[0187]

[0188] IL4R-binding peptide:

[0189] L17E endocytosis peptide:

[0190]

[0191] C16K-protoporphyrin IX:

[0192] E-selectin targeting peptide:

[0193] (KLAKLAK)2:

[0194] CD44v6 - Combination:

[0195] Her-2 binding:

[0196] Targeted therapy for prostate tumors:

[0197] Targeted therapy for bladder tumors:

[0198] Defense peptide 1:

[0199] Antimicrobial peptide B:

[0200] Magainin:

[0201] Dermaseptin:

[0202] lactoferrin 5 derivatives:

[0203] eMTD peptide:

[0204]

[0205] H3 peptide:

[0206]

[0207] Octreotide:

[0208] RP527 peptide:

[0209] Minigastrin:

[0210] Nectin-4:

[0211] in dC = D-cysteine;

[0212] TIM-3-binding peptide:

[0213] LAG-3-binding peptide:

[0214] TIGIT-binding peptide:

[0215] CM7 peptide (cMet):

[0216] HB10:

[0217] HB10(sHB-EGF):

[0218] A8 peptide (Hsp72):

[0219] Somatostatin:

[0220] KRpep-2d peptide:

[0221] KS36 peptide: Among them, Dap is (S)-2,3-diaminopropionic acid, Nle is L-ortholeucine, Anon is (S)-2-aminononanoic acid, and Cha is L-cyclohexylalanine. The others are all natural amino acids.

[0222] KS58 peptide: Where βAla is β-alanine, Nle is L-leucine, Anon is (S)-2-aminononanoic acid, 4fF is 4-fluoro-1-phenylalanine, and dCys is D-cysteine;

[0223] Goserelin: Its analogues are shown below:

[0224]

[0225] Angiopep-2:

[0226] CBX-12:

[0227] SG3299:

[0228]

[0229] TH1902:

[0230]

[0231]

[0232]

[0233]

[0234] Angiopep-2:Thr-Phe-Phe-Tyr-Gly-Gly-Ser-Arg-Gly-Lys-Arg-Asn-Asn-Phe-Lys-Thr-Glu-Glu-Tyr-Cys

[0235]

[0236] Transportan:Gly-Trp - Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Lys-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu(GWTLNSAGYLLGKlNLKALAALAKKIL):

[0237]

[0238] TfR-T12:Thr-His-Arg-Pro-Pro-Met-Trp-Ser-Pro-Val-Trp-Pro(THRPPMWSPVWP):

[0239]

[0240]

[0241] Glutathione:γ-L-Glutamyl-L-cysteinylglycine:

[0242]

[0243] RVG29:(YTIWMPENPRPGTPCDIFTNSRGKRASNG),Tyr-Thr-Ile-Trp - Met-Pro-Glu-Asn-Pro-Arg - Pro-Gly - Thr-Pro-Cys-Asp -I le-Phe-Thr-Asn-Ser-Arg - Gly - Lys-Arg-Ala-Ser-Asn-Gly-Cys:

[0244]

[0245]

[0246] K-FGF:Ala-Ala-Val-Leu-Leu-Pro-Val-Leu-Leu-Ala-Ala-Pro(AAVLLPVLLAAP):

[0247] NF-κB: Val-Gln-Arg - Lys-Arg-Gln-Lys-Leu-Met-Pro(VQRKRQKLMP):

[0248] β1-tail:Tyr-Lys-Ser-Ala-Val-Thr-Thr-Val-Val-Asn-Pro-Lys-Tyr-Glu-Gly-Lys(YKSAVTTVVNPKYEGK):

[0249]

[0250] BIP:Val-Pro-Met-Leu-Lys-Glu(VPMLK(E)):

[0251]

[0252] C105Y:Cys-Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile(CSIPPEVKFNK)PFVYLI:

[0253]

[0254]

[0255] MAPl2:Leu-Lys-Thr-Leu-Thr-Glu-Thr-Leu-Lys-Glu-Leu-Thr-Lys-Thr-Leu-Thr-Glu-Leu(LKTLTETLKELTKTLTEL):

[0256]

[0257] GALA:Trp-Glu-Ala-Ala-Leu-Ala-Glu-Ala-Leu-Ala-Glu-Ala-Leu-Ala-Glu-His-Leu-Ala-Glu-Ala-Leu-Ala-Glu-Ala-Leu-Glu-Ala-Leu-Ala-Ala(WEAALAEAALAEALAEHLAEALAEALEALAA):

[0258]

[0259] PTD4:Tyr-Ala-Arg-Ala-Ala-Ala-Arg - Gln-Ala-Arg-Ala(YARAAARQARA):

[0260] PreS2:Pro-Leu-Ser-Ser-Ile-Phe-Ser-Arg-Ile-Gly-Asp-Pro(PLSSIFSRIGDP):

[0261]

[0262] AIP6:Arg - Leu-Arg-Trp-Arg(RLRWR):

[0263]

[0264] EB-1:Leu-Ile-Arg - Leu-Trp-Ser-His-Leu-Ile-His-Ile-Trp - Phe-Gln-Asn-Arg-Arg-Leu-Lys-Trp-Lys-Lys-Lys(LIRLWSHLIHIWFQNRRLKWKKK):

[0265]

[0266]

[0267] DPV6:Gly-Arg-Pro-Arg-Glu-Ser-Gly-Lys-Lys-Arg-Lys-Arg-Lys-Arg - Leu-Lys-Pro(GRPRESGKKRKRKRLKP):

[0268]

[0269] THRre:Pro-Trp-Val-Pro-Ser-Trp-Met-Pro-Pro-Arg-His-Thr(PWVPSWMPPRHT):

[0270]

[0271] TGN: Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly (TGNYKALHPHNG):

[0272]

[0273] THR: Thr-His-Arg-Pro-Pro-Met-Trp-Ser-Pro-Val-Trp-Pro (THRPPMWSPVWP):

[0274]

[0275] K16APoE: His-Ala-Tyr-Glu-Asp (HAYED):

[0276]

[0277] Neuroleptin-1-targeting peptide: Arg-Gly-Glu-Arg-Pro-Arg-Arg (RGERPRR):

[0278]

[0279] pPAC: Cys-Asn-Ala-Phe-Thr-Pro-Asp (CNAFTPD):

[0280]

[0281] R9F2C: Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Phe-Phe-Cys (RRRRRRRRFFC):

[0282]

[0283]

[0284] Mini-penetratin: Arg-Arg-Met-Lys-Trp-Lys-Lys (RRMKWKK):

[0285]

[0286] IRS-tag: Arg-Tyr-Ile-Arg-Ser (RYIRS):

[0287]

[0288] CPPP-2: Lys-Leu-Pro-Val-Met (KLPVM):

[0289]

[0290] Apamin: Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-Ala-Arg-Arg-Cys-Gln-Gln-His (disulfide bonds: Cys1-Cys11; Cys3-Cys15) (CNCKAPETALCARRCQQH-NH2):

[0291]

[0292] hApoE: Leu-Arg-Lys-Leu-Arg-Lys-Arg-Leu-Leu (LRKLRKRLL):

[0293]

[0294] PepH3: Ala-Gly-Ile-Leu-Lys-Arg-Trp (AGILKRW):

[0295]

[0296]

[0297] B6 peptide: Cys-Gly-His-Lys-Ala-Lys-Gly-Pro-Arg-Lys (CGHKAKGPRK):

[0298]

[0299] HIV-Tat: Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg (YGRKKRRQRR):

[0300]

[0301] Pep-7: Ser-Asp-Leu-Trp-Glu-Met-Met-Met-Val-Ser-Leu-Ala-Cys-Gln-Tyr (SDLWEMMMVSLACQY):

[0302]

[0303] YTA4:Ile-Ala-Trp-Val-Lys-Ala-Phe-Ile-Arg-Lys-Leu-Arg-Lys-Gly-Pro-Leu-Gly(IAWVKAFIRKLRKGPLG):

[0304]

[0305] RGD:Arg-Gly-Asp:

[0306]

[0307] TAT:Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg(YGRKKRRQRRR):

[0308]

[0309] R9:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg(RRRRRRRR):

[0310]

[0311] R4:Arg-Arg-Arg-Arg(RRRR):

[0312]

[0313] R6:Arg-Arg-Arg-Arg-Arg-Arg(RRRRRR):

[0314]

[0315] R3:Arg-Arg-Arg(RRR):

[0316]

[0317] Cyclo(His-Pro):

[0318] gHoPe2:Asn-His-Gln-Gln-Gln-Asn-Pro-His-Gln-Pro-Pro-Met(NHQQQNPHQPPM):

[0319]

[0320]

[0321] Phage-derived peptide: Cys-Asn-Ser-Arg-Leu-His-Leu-Arg-Cys (CNSRLHLRC):

[0322]

[0323] SynB3: Arg-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe (RRLSYSRRRF):

[0324]

[0325] SV40 nuclear transport signal peptide analog: Cys-Gly-Tyr-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val-Gly-Gly (CGYGPKKKRKVGG):

[0326]

[0327] TAT2-4: Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly (YGRKKRRQRRRGYGRKKRRQRRRG):

[0328]

[0329]

[0330] pVEC: Leu-Leu-Ile-Ile-Leu-Arg-Arg-Arg-Ile-Arg-Lys-Gln-Ala-His-Ala-his-Ser-Lys (LLIILRRRIRKQAHAHSK):

[0331]

[0332] Pep-1: Cya-Lys-Glu-Thr-Trp-Trp-Glu-Thr-Trp-Trp-Thr-Glu-Trp-Ser-Gln-Pro-Lys-Lys-Lys-Arg-Lys-Val (Cya-KETWWETWWTEWSQPKKKRKV):

[0333]

[0334] MAP: Lys-Leu-Ala-Leu-Lys-Leu-Ala-Leu-Lys-Ala-Leu-Lys-Ala-Ala-Leu-Lys-Leu-Ala (KLALKLALKALKAALKLA):

[0335]

[0336]

[0337] Calcitonin(9-32) (free acid): Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro (LGTYTQDFNKTHTFPQTAIGVGAP):

[0338]

[0339] PTD-5: Arg-Arg-Gln-Arg-Arg-Thr-Ser-Lys-Leu-Met-Lys-Arg (RRQRRTSKLMKR):

[0340]

[0341] SynB1: Arg-Gly-Gly-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe-Ser-Thr-Ser-Thr-Gly-Arg-Ala (RGGRLSYSRRRFSTSTGRA):

[0342]

[0343] Penetratin: Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Gly-Gly (RQIKIWFQNRRMKWKKGG):

[0344]

[0345] Activatable CPPs\ACPP: Glu-Glu-Glu-Glu-Glu-Glu-Glu-Gly-Ala-Leu-Gly-Leu-Pro-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Lys-Lys-Arg(EEEEEEEGALGLPRRRRRRRRKKR):

[0346]

[0347] M918: Met-Val-Thr-Val-Leu-Phe-Arg-Arg-Leu-Arg-Ile-Arg-Arg-Ala-Cys-Gly-Pro-Pro-Arg-Val-Arg-Val(MVTVLFRRLRIRRACGPPRVRV):

[0348]

[0349] Hel 13-5: Lys-Leu-Leu-Lys-Leu-Leu-Leu-Lys-Leu-Trp-Leu-Lys-Leu-Leu-Lys-Leu-Leu-Leu(KLLKLLLKLWLKLLKLLL):

[0350]

[0351]

[0352] POD: Gly-Gly-Gly-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala(GGGARKKAAKAARKKAAKAARKKAAKAARKKAAKA):

[0353]

[0354] (iRGD): LyP-1 peptide: where is the linking site with Ld1, Ld2, Ld3, Ld4, Ld5, or Ld6, and Ra is Ar, which is preferably selected from Rb is OH, COOH, COOCH3, CH3OH, CH3NH2, CONH2;

[0355] In other embodiments, A1, A2, A3, A4, A5, and A6 are nucleoside analogs that have a synergistic effect with D1 and / or D2.

[0356] Nucleoside analogs: These are molecules that act as nucleosides in DNA synthesis. They comprise a range of antiviral products used to prevent viral replication in infected cells. Nucleoside analogs can be used against hepatitis B virus, hepatitis C virus, herpes simplex virus, and HIV. Once phosphorylated, they can function as antimetabolites because they are similar enough to nucleotides to be incorporated into growing DNA chains. Less selective nucleoside analogs are used as chemotherapeutic agents to treat cancer, such as gemcitabine and 5-FU. Antimetabolites are chemicals that inhibit the use of metabolites, which are other chemicals that are normally metabolized. These substances often have structures similar to the metabolites they interfere with, such as antifolate agents that interfere with folic acid use. The presence of antimetabolites can have toxic effects on cells, such as inhibiting cell growth and division; therefore, these compounds are used as chemotherapeutic agents for cancer. The following illustrates some conjugable nucleoside analog structures from this patent application:

[0357]

[0358]

[0359] Antibody

[0360] The antibody (mAb) used in the coupling process is preferably a cell-binding antibody or antibody-like protein molecule that binds, complexes, or reacts to a portion of the cell population being treated or biomodified.

[0361] For convenience in this section and elsewhere, "antibody" should be understood to include "antibody-like proteins and peptides" unless the context requires otherwise. Suitable antibody-like proteins that may be present in the conjugates of this invention include, for example, peptides, polypeptides, antibodies, antibody fragments, enzymes, cytokines, chemokines, receptors, blood factors, peptide hormones, toxins, transcriptional antibody-like proteins, or multimeric antibody-like proteins that have interchain disulfide bonds in their structure. Enzymes include carbohydrate-specific enzymes, proteolytic enzymes, etc., such as the oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases disclosed in US Patent No. 4,179,337. Relevant specific enzymes include asparaginase, arginase, adenosine deaminase, superoxide dismutase, catalase, chymotrypsin, lipase, uricase, bilirubin oxidase, glucose oxidase, glucuronidase, galactosidase, glucosidase, and glutaminase.

[0362] Blood antibody-like proteins include albumin, transferrin, factor VII, factor VIII or factor IX, von Willebrand factor, insulin, ACTH, glucagon, somatostatin, growth hormone, thymosin, parathyroid hormone, pigment hormone, growth hormone, erythropoietin, luteinizing hormone, hypothalamic releasing factor, antidiuretic hormone, prolactin, interleukins, interferons such as IFN-α or IFN-β, colony-stimulating factor, hemoglobin, cytokines, antibodies, antibody fragments, human chorionic gonadotropin, follicle-stimulating hormone, thyroid-stimulating hormone, and tissue plasminogen activator.

[0363] Other relevant antibody-like proteins include allergen antibody-like proteins disclosed by Dreborg et al. in Crit. Rev. Therap. Drug Carrier Syst. (1990) 6315-365. These proteins exhibit reduced allergenicity when bound to polymers such as poly(epoxides), making them suitable as tolerance inducers. The disclosed allergens include Ragweed antigen E, bee venom, and dust mite allergens.

[0364] This also includes glycopeptides such as immunoglobulins, ovalbumin, lipases, glucocerebrosidase, lectins, tissue plasminogen activator, and glycosylated interleukins, interferons, and colony-stimulating factors, as well as immunoglobulins such as IgG, IgE, IgM, IgA, IgD, and their fragments. Of particular interest are receptor- and ligand-binding antibody-like proteins and antibodies, as well as antibody fragments, which are used in clinical medicine for diagnosis and treatment.

[0365] The preferred antibody in this article (A) is an antibody, an antibody-like protein molecule, a masking antibody, a nanobody, a peptide, an antibody on a polymer micelle, an antibody liposome, a lipoprotein-based drug carrier, an antibody on a nanoparticle, an antibody dendritic macromolecule, and the above-mentioned particles coated or linked with an antibody-like protein (antibody), or a combination thereof.

[0366] (B): Antibodies, full-length antibodies (polyclonal antibodies, monoclonal antibodies, dimers, multimers, multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies, or tetraspecific antibodies); single-chain antibodies; antibody fragments that bind to target cells, monoclonal antibodies, single-chain monoclonal antibodies, monoclonal antibody fragments that bind to target cells, chimeric antibodies, chimeric antibody fragments that bind to target cells, domain antibodies, domain antibody fragments that bind to target cells, surface-remodeled antibodies, surface-remodeled single-chain antibodies or antibodies that bind to target cells, humanized antibodies or surface-remodeled antibodies, tetrasomes, microantibodies, masking antibodies, masking antibody fragments, small immune antibody-like proteins (SIPs), lymphokine antibody-like proteins, hormone-like antibodies, growth factor antibody-like proteins, colony-stimulating factor-like antibody-like proteins, nutrient transport antibody-like proteins, high molecular weight antibody-like proteins, fusion antibody-like proteins, kinase inhibitor antibody-like proteins, gene-targeting antibody-like proteins, antibody-like proteins or high molecular weight antibody-like proteins encapsulated on nanoparticles or polymers;

[0367] Antibody fragments include Fab, Fab', F(ab')2, Fv, [Parham, J. Immunol. 13182895-902 (1983)], fragments generated from Fab expression libraries, and any of the above epitope-binding fragments generated by immune-specific binding to cancer cell antigens, viral antigens, or microbial antigens, or antibody-like proteins generated by the immune system that can recognize, bind to specific antigens or exhibit the desired biological activity (Miller et al. (2003) J. of Immunology 170: 4854-61); interferons (such as type I, II, and III); peptides; lymphokines such as IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, GM-CSF, and interferon-γ (IFN-γ);

[0368] Hormones, such as insulin, TRH (thyrotropin-releasing hormone), 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 factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor (TGF), such as TGFα, TGFβ, insulin and insulin-like growth factor (IGF-I, IGF-II), G-CSF, M-CSF and GM-CSF [Burgess, Immunology Today, 5155-8 (1984)]; vaccinia growth factor; fibroblast growth factor; small antibody-like proteins, polypeptides, peptides and peptide hormones, such as scutellarin, gastrin, gastrin-releasing peptide; platelet-derived growth factor; interleukins and cytokines, such as interleukin-2 (IL-2), interleukin-6 (IL-6), leukemia inhibitory factor, granulocyte-macrophage colony-stimulating factor (GM-CSF); vitamins, such as folic acid; apolipoproteins and glycoproteins, such as transferrin [O'Keefe [ et al., 260 J. Biol. Chem. 932-7 (1985)]; glycoproteins or lipoproteins, such as lectins; cellular nutrient transport molecules; and small molecule inhibitors, such as prostate-specific membrane antigen (PSMA) inhibitors and small molecule tyrosine kinase inhibitors (TKIs), non-peptides or any other cell-binding molecules or substances, such as bioactive polymers (Dhar et al., Proc. Natl. Acad. Sci. 2008 105 17356-61); bioactive dendritic macromolecules (Lee et al., Nat. Biotechnol. 2005, 2315 17-26; Almutairi et al., Proc. Natl. Acad. Sci. 2009 106685-90); nanoparticles (Liong et al., ACS Nano, 2008, 21309-12; Medarova et al., Nat. Med. 2007, 13372-7; Javier et al., Bioconjugate Chem. 2008, 191309-12); liposomes (Medinai, et al, Curr. Phar. Des. 2004, 10, 2981-9); viral capsids (Flenniken, et al, Viruses Nanotechnol. 2009, 327, 71-93).

[0369] Generally, monoclonal antibodies are better suited as cell surface binding agents if suitable ones are available. These antibodies can be murine, human, humanized, chimeric, or derived from other species.

[0370] The production of the antibodies used in this 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, for example, U.S. Patent No. 4,493,795 (Nestor et al.). Monoclonal antibodies are typically prepared by fusing myeloma cells with mouse spleen cells immunized with the desired antigen. G.; Milstein, C. (1975). Nature 256: 495-7. Detailed operating procedures are described in *Antibodies: A Laboratory Manual* (Harlow and Lane, eds., ColdSpring Harbor Laboratory Press, New York (1988)), which is incorporated herein by reference. Specifically, monoclonal antibodies are prepared by immunizing mice, rats, hamsters, or other mammals with target antigens (such as intact target cells, antigens isolated from target cells, intact viruses, attenuated intact viruses, and viral proteins). Spleen cells are typically fused with myeloma cells using polyethylene glycol (PEG) 6000, and the fusion hybridomas are screened using HAT (hypoxanthine-aminopterin-thymidine) sensitivity. Hybridomas suitable for the present invention can be screened by detecting whether the hybridomas can immunely respond to specific receptors or inhibit target cell receptor activity.

[0371] The monoclonal antibodies used in this invention can be prepared by culturing monoclonal hybridomas: culture is initiated in a nutrient medium containing hybridomas secreting antibodies specific to a particular antigen; under suitable conditions, the hybridomas are maintained for a sufficient time to secrete antibodies into the medium; subsequently, the antibody-containing medium is collected. The antibody molecules can be further purified using known techniques, such as protein A affinity chromatography; anionic, cationic, hydrophobic, or size exclusion chromatography (especially affinity for specific antigens after protein A purification and size exclusion chromatography); centrifugation; differential solubility analysis; or other standard protein purification techniques.

[0372] The culture media used to prepare these compositions are well known in the art and are commercially available, including synthetic media. An exemplary synthetic media is Durbecco modified Eagle medium (DMEM; Durbecco et al., Virol. 8, 396 (1959)), supplemented with 4.5 g / L glucose, 0–20 mM glutamine, 0–20% fetal bovine serum, trace heavy metals (such as copper, manganese, iron, zinc, etc., or other heavy metals added in the form of their salts), and antifoaming agents (such as polyoxyethylene-polyoxypropylene block copolymers).

[0373] In addition to fusion technology, antibody-generating cell lines can also be established through other methods, such as direct transformation of B lymphocytes using oncogenic DNA, or transfection with oncogenic viruses (such as Epstein-Barr virus (EBV, also known as human herpesvirus type 4, HHV-4) or Kaposi's sarcoma-associated herpesvirus (KSHV)). See U.S. Patent 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; and 4,493,890 for details. Monoclonal antibodies can also be prepared using methods well-known in the art, from antireceptor peptides or carboxyl-terminated polypeptides (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)). Antireceptor peptides or their analogues are typically used as immunogens, either alone or conjugated with an immunogenic vector, to produce antireceptor peptide monoclonal antibodies.

[0374] There are also many other mature technologies in the field for preparing monoclonal antibodies that serve as binding molecules in this invention. Among them, the method for preparing fully human antibodies is particularly important, such as screening human antibodies that specifically bind to antigens using phage display technology. This technology has been described in detail in the literature, and the construction and screening methods of phage display libraries are well known in the field (see 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)).

[0375] For monoclonal antibodies prepared by non-human (e.g., mouse) hybridoma technology, humanization can be used to avoid the generation of anti-mouse antibody reactions when introduced into the human body. Commonly used humanization methods include complementarity-determining region transplantation and surface remodeling techniques (see US Patent 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. US A. 103(10): 3557-62 (2006), all of which are incorporated herein by reference). Fully human antibodies can also be prepared by immunizing transgenic mice, rabbits, monkeys or other mammals carrying a large number of human immunoglobulin heavy and light chain genes (e.g., Xenomouse (Abgenix / Amgen), HuMAb-Mouse (Medx / BMS), VelociMouse (Regeneron), related technologies can be found in US patents 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 treatment, chimeric antibodies can be constructed by fusing murine variable regions with human constant regions, exhibiting significantly lower immunogenicity than murine monoclonal antibodies (see Kipriyanov et al., Mol Biotechnol. 26: 39-60 (2004); Houdebine, Curr Opin Biotechnol. 13: 625-9 (2002), both incorporated herein by reference). Furthermore, site-directed mutations in the antibody variable region can enhance the antibody's affinity and specificity for antigens (Brannigan et al., NatRev MolCell Biol. 3: 964-70, (2002); Adams et al., J Immunol Methods. 231: 249-60 (1999)), while replacing the monoclonal antibody constant region can enhance its effector functions in mediating binding and cytotoxicity.

[0376] Specific antibodies against malignant cell antigens can be obtained commercially or prepared using any method known to those skilled in the art (such as chemical synthesis or recombinant expression techniques). The nucleotide sequence encoding the specific antibody can be obtained from commercial databases (such as GenBank and similar databases), literature publications, or conventional cloning and sequencing techniques.

[0377] Besides antibodies, any antibody-like peptides or proteins that can bind to / block / target or otherwise interact with target cell epitopes or corresponding receptors can be used as binding molecules. These antibody-like peptides or proteins can be any random peptides or proteins with affinity for epitopes or corresponding receptors, and do not necessarily belong to the immunoglobulin family. Such peptides can be screened using techniques similar to phage display of antibodies (Szardenings, J Recept Signal Transduct Res. 2003, 23(4): 307-49). The use of peptides in random peptide libraries can be similar to that of antibodies and antibody fragments. Antibody-like peptide or protein binding molecules can be coupled or linked to macromolecules or materials (including but not limited to albumin, polymers, liposomes, nanoparticles, dendritic polymers, etc.), as long as the link can maintain its antigen-binding specificity.

[0378] Examples of antibodies conjugated to drugs used for the prevention and treatment of this cancer, autoimmune disease, and / or infectious disease include, but are not limited to: 3F8 (anti-GD2), abavoxib (anti-CA-125), abcixib (anti-CD41 (integrin α-IIb)), adalimumab (anti-TNF-α), adecalimumab (anti-EpCAM, CD326), afimomab (anti-TNF-α); agituzumab (anti-CD20), and arazumab (anti-V). EGFR2), ALD518 (anti-IL-6), alemtuzumab (Campath, MabCampath, anti-CD52), atormumab (anti-CEA), atormumab (anti-TAG-72), anrutumab (IMA-638, anti-IL-13), apocizumab (anti-HLA-DR), acetomumab (anti-CEA), asceticumab (anti-L-selectin (CD62L)), atormumab (tocilizumab, Actemra, RoActemra, anti-IL-6 receptor), Atolizumab (anti-rhesus monkey factor), Bavizumab (anti-β-amyloid), Baliximab (Simulect, anti-CD25 (IL-2 receptor α chain)), Bavitumab (anti-phosphatidylserine), Betumab (LymphoScan, anti-CD22), Benlysta (LymphoStat-B, anti-BAFF), Benalizumab (anti-CD125), Betemumab (anti-CCL11 (eosinophil activation chemokine-1)), Besimumab (Scintimun, anti-CEA-associated antigen), Bevacizumab (Avastin, anti-VEGF-A), Bisimomab (FibriScint, anti-fibrin II β chain), Bivastatin (anti-CD44) v6), bonnetumab (BiTE, anti-CD19), bentoximab (cAC10, anti-CD30 TNFRSF8), brigiximab (anti-IL-12, IL-23), canatumab (Ilaris, anti-IL-1β), cantuzumab (C242, anti-CanAg), capromumab, captuxomab (Removab, anti-EpCAM, anti-CD3), CC49 (anti-TAG-72), celizumab (anti-CD4), pecelizumab (Cimzia, anti-TNF-α), cetuximab (Erbitux, IMC-C 225 (anti-EGFR), cetuzumab (anti-EpCAM), cetuzumab (anti-IGF-1), clenbuterol (anti-CD4), cetuzumab (anti-MUC1), daratumab (anti-TRAIL-R2), CR6261 (anti-influenza A virus hemagglutinin), daratumab (anti-CD40), dacrolimus (Zenapax, anti-CD25 (IL-2 receptor α chain)), daratumab (anti-CD38 (cyclic ADP ribohydrolase)).Denosumab (Prolia, anti-RANKL), Detomumab (anti-B lymphoma cells), Dolimumab, Dolizumab, Ecrolimus (anti-GD3 gangliosides), Iculizumab (Soliris, anti-C5), Edopamab (anti-endotoxin), Panorex (MAb17-1A, anti-EpCAM), Raptiva (Raptiva, anti-LFA-1 (CD11a)), Mycograb (Mycograb, anti-Hsp90), Erlotuzumab (anti-SLAMF7), Esimozumab (anti-IL-6), Enmumab (anti-ICAM-1 (CD54)), Ipimumab (anti-epithelial sialic acid protein), Ipatizumab Monoclonal antibodies (anti-CD22), ilelizumab (anti-ITGB2 (CD18)), ertuxomab (Rexomun, anti-HER2 / neu, CD3), edazolizumab (Abegrin, anti-integrin αvβ3), exemivomb (anti-hepatitis B surface antigen), fanomomumab (NeutroSpec, anti-CD15), falamomumab (anti-interferon receptor), famucinumab (anti-folate receptor 1), felizumab (anti-respiratory syncytial virus), fezanumab (anti-IL-22), fegemetuzumab (anti-IGF-1 receptor), fenstuzumab (anti-IFN-γ), fovizumab (anti-rabies virus glycoprotein), fexomumab (anti-TGF-β), galiliximab ( Anti-CD80), Ganteizumab (anti-β-amyloid), Garvicumab (anti-CD147 (basal protein)), Gelatinumab (anti-CD33), Gelatinumab (anti-carbonic anhydrase 9), Glenbartumab (CR011, anti-GPNMB), Golimumab (Simponi, anti-TNF-α), Goliximab (anti-CD23 (IgE receptor)), Iparizumab (anti-CD4), Imoximab (anti-CD20), Igovovomab (Indimacis-125, anti-CA-125), Imoximab (Myoscint, anti-cardiac myosin), Infliximab (Remicade, anti-TNF-α), Intuximab (anti-CD51), Inmoximab Monoclonal antibodies (anti-CD25 (IL-2 receptor α chain)), ipilimumab (anti-CD22), ipilimumab (anti-CD152), ipilimumab (anti-CD30 (TNFRSF8)), crixacillinab (anti-CD4), labectocillinab (CEA-Cide, anti-CEA), lejinzumab (anti-IL-13), lemamumab (anti-NCA-90 (granulocyte antigen)), levofloxacin (anti-TGF-β2), lesamumab (anti-TRAIL-R2), rivirimumab (anti-hepatitis B surface antigen), lintuzumab (anti-CD33), rucarumab (anti-CD40), ruliximab (anti-CD23 (IgE receptor)), mapamumab (anti-TRAIL-R1).Masmozumab (anti-T-cell receptor), Masmozumab (anti-EGFR), Meporibumab (Bosatria, anti-IL-5), Metimumab (anti-TGF-β1), Milatumab (anti-CD74), Minremumab (anti-TAG-72), Milatumab (BEC-2, anti-GD3 ganglioside), Moromumab (anti-rhesus monkey factor), Moramumab (Numax, anti-respiratory syncytial virus), Moromona-CD3 (Orthoclone) OKT3 (anti-CD3), Nacomumab (anti-C242), Natumumab (anti-5T4), Natalizumab (Tysabri, anti-integrin α4), Nebacubitumab (anti-endotoxin), Nexituzumab (anti-EGFR), Neremumab (anti-TNF-α), Nimotuzumab (Theracim, Theraloc, anti-EGFR), Nofetotumumab, Ogreizumab (anti-CD20), Odorumab (Afolimomab, anti-LFA-1 (CD11a)), Arzerra (Olfamumab, anti-CD20), Olarumab (anti-PDGF-Rα), Omalizumab (Xolair, anti-IgE) Fc region), Optocilizumab (anti-EpCAM), Ogovovoxel (Ov.x, anti-CA-125), Otizumab (anti-CD3), Paxizumab (anti-lipoteichoic acid), Palolizumab (Synagis, Abbosynagis, anti-respiratory syncytial virus), Panitumumab (Vectibix, ABX-EGF, anti-EGFR), Panobarumab (anti-Pseudomonas aeruginosa), Pacolizumab (anti-IL-4), Pertumumab (Theragyn, anti-MUC1), Pertizumab (Omnitarg, 2C4, anti-HER2 / neu), Percolizumab (anti-C5), Pertumumab (anti-adenocarcinoma antigen), Priliximab (anti-CD4), Pertumumab (anti-vimentin), PRO 140 (anti-CCR5), Lacotozumab (1E10, anti-(N-hydroxyacetylneuraminic acid (NeuGc, NGNA)-ganglioside GM3)), Ravirumab (anti-rabies virus glycoprotein), Ramucirumab (anti-VEGFR2), Ranibizumab (Lucentis, anti-VEGF-A), Recibacubitumab (anti-anthrax toxin protective antigen), Regavirumab (anti-cytomegalovirus glycoprotein B), Relizumab (anti-IL-5), Li Tolmumab (anti-HGF), Rituximab (MabThera, Rituxanmab, anti-CD20), Robatumumab (anti-IGF-1 receptor), Longtuzumab (anti-IFN-α), Rovirizumab (LeukArrest, anti-CD11, CD18), Lupulizumab (Antova, anti-CD154 (CD40L)), Satumumab (anti-TAG-72), Civirumab (anti-cytomegalovirus).Sirolizumab (anti-FAP), Sifamumab (anti-IFN-α), Stexoxetine (anti-IL-6), Ciprizumab (anti-CD2), (Smart) MI95 (anti-CD33), Sorapizumab (anti-β-amyloid), Sonezumab (anti-sphingosine-1-phosphate), Sontozzumab (anti-epithelial sialic acid protein), Smelurumab (anti-myosin), LeukoScan (anti-NCA-90 (granulocyte antigen)), Tatozzumab (anti-alpha-fetoprotein), Taduzumab (anti-integrin αIIbβ3), Talizumab Monoclonal antibodies (anti-IgE), tanizumab (anti-NGF), tapritumumab (anti-CD19), tefilizumab (Aurexis, anti-agglutination factor A), telimumab, tenatumab (anti-tenosynovin C), tanizumab (anti-CD40), tepritumumab (anti-CD3), TGN1412 (anti-CD28), tremelimumab (anti-CTLA-4), tegazumab (anti-TRAIL-R2), TNX-650 (anti-IL-13), tocilizumab (Atlizumab, Actemra) RoActemra (anti-IL-6 receptor), torazumab (anti-CD154 (CD40L)), tosimoumab (anti-CD20), trastuzumab (Herceptin, anti-HER2 / neu), trimelimumab (anti-CTLA-4), taucozumab (anti-EpCAM), tuvirumab (anti-hepatitis B virus), utoluzumab (anti-E. coli), ustekinumab (Stelara, anti-IL-12, IL-23), vapazumab (anti-AOC3 (VAP-1)), vedolizumab (anti-integrin α4β7) Vetuzumab (anti-CD20), Verpalimumab (anti-AOC3 (VAP-1)), Vexizumab (Nuvion, anti-CD3), Vitasin (anti-angiotensin αvβ3), Voloximab (anti-integrin α5β1), Vetuzumab (HumaSPECT, anti-tumor antigen CTAA16.88), Zanaulimumab (HuMax-EGFr, anti-EGFR), Zanaulimumab (HuMax-CD4, anti-CD4), Ziramumab (anti-CD147 (basal protein)), Zolimumab (anti-CD5), Etanercept. Alphaset Abbasip Rilosip (Arcalyst), 14F7 [anti-IRP-2 (ferroregulatory protein 2)], 14G2a (anti-GD2 ganglioside, used by the National Cancer Institute for melanoma and solid tumors), J591 (anti-PSMA, used by Weill Cornell Medical College for prostate cancer), 225.28S [anti-HMW-MAA (high molecular weight melanoma-associated antigen), used by Sorin Radiofarmaci SRL (Milan) for melanoma], COL-1 (anti-CEACAM3, CGM1, used by the National Cancer Institute for colorectal and gastric cancer), CYT-356 ( HNK20 (OraVax for respiratory syncytial virus), ImmuRAIT (Immunomedics for non-Hodgkin's lymphoma), Lym-1 (anti-HLA-DR10, Peregrine for cancer), MAK-195F (anti-TNF (tumor necrosis factor; TNFA, TNF-α; TNFSF2), Abbott / Knorr for septic shock), MEDI-500 (T10B9, anti-CD3, TRαβ (T cell receptor α / β) complex, MedImmune for graft-versus-host disease), RINGSCAN (anti-TAG) 72 (Tumor-associated glycoprotein 72), Neoprobe for breast, colon, and rectal cancer; Avicidin [anti-EPCAM (epithelial cell adhesion molecule), anti-TACSTD1 (tumor-associated calcium signaling protein 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, NeoRx for colon cancer, ovarian cancer, prostate cancer, and non-Hodgkin's lymphoma]; LymphoCide (Immunomedics, New Jersey); Smart ID10 (Protein Design) The following drugs are available: Oncolym (Techniclone, California), Allomune (BioTransplant, California), anti-VEGF (Genentech, California); CEAcide (Immunomedics, New Jersey), IMC-1C11 (ImClone, New Jersey), and cetuximab (ImClone, New Jersey).

[0379] Other antibodies that act as cell-binding molecules / ligands include, but are not limited to, antibodies against the following antigens: aminopeptidase N (CD13), annexin A1, B7-H3 (CD276, various cancers), CA125 (ovarian cancer), CA15-3 (cancer), CA19-9 (cancer), L6 (cancer), Lewis Y (cancer), Lewis X (cancer), alpha-fetoprotein (cancer), CA242 (colorectal cancer), placental alkaline phosphatase (cancer), prostate-specific antigen (prostate cancer), prostate acid phosphatase (prostate cancer), epidermal growth factor (cancer), CD2 (Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma), CD3ε (T-cell lymphoma, lung cancer, breast cancer, gastric cancer, ovarian cancer, autoimmune diseases, malignant ascites), CD19 (B-cell malignancies), CD20 (non-Hodgkin's lymphoma), CD22 (leukemia, lymphoma, multiple myeloma, systemic lupus erythematosus), CD30 (Hodgkin's lymphoma ...non-Hodgkin's lymphoma, systemic lupus erythematosus), CD20 (non-Hodgkin's lymphoma), CD22 (non-Hodgkin's lymphoma, systemic lupus erythematosus), CD20 (non-Hodgkin's lymphoma), CD22 (non-Hodgkin's lymphoma, non-Hodgkin's lymphoma), CD22 (non-Hodgkin's lymphoma, non-Hodgkin's lymphoma CD33 (leukemia, autoimmune diseases), CD38 (multiple myeloma), CD40 (lymphoma, multiple myeloma, leukemia (chronic lymphocytic leukemia)), CD51 (metastatic melanoma, sarcoma), CD52 (leukemia), CD56 (small cell lung cancer, ovarian cancer, Merkel cell carcinoma, and liquid tumor multiple myeloma), CD66e (cancer), CD70 (metastatic renal cell carcinoma and non-Hodgkin lymphoma), CD74 (multiple myeloma), CD80 (lymphoma), CD98 (cancer), mucin (cancer), CD221 (solid tumors), CD227 (breast cancer). Ovarian cancer), CD262 (non-small cell lung cancer and other cancers), CD309 (ovarian cancer), CD326 (solid tumors), CEACAM3 (colorectal cancer, gastric cancer), CEACAM5 (carcinoembryonic antigen; CEA, CD66e) (breast cancer, colorectal cancer and lung cancer), DLL3 or DLL4 (δ-like-3 or δ-like-4), epidermal growth factor receptor (EGFR, various cancers), cytotoxic T lymphocyte-associated antigen 4 (CTLA4, melanoma), CXC chemokine receptor 4 (CXCR4, CD184, hematologic malignancies, solid tumors), endothelial glycoprotein (CD184) 05, solid tumors), epithelial cell adhesion molecule (EpCAM, bladder cancer, head and neck cancer, colon cancer, non-Hodgkin's lymphoma, prostate cancer, ovarian cancer), epidermal growth factor receptor 2 (ERBB2; lung cancer, breast cancer, prostate cancer), Fcγ receptor I (FCGR1, autoimmune diseases), folate receptor (FOLR, ovarian cancer), GD2 ganglioside (cancer), G-28 (a cell surface antigen glycolipid, melanoma), GD3 idiotype (cancer), heat shock protein (cancer), human epidermal growth factor receptor 1 (HER1, lung cancer, gastric cancer), human epidermal growth factor receptor 2 (HER2,Breast cancer, lung cancer, ovarian cancer), HLA-DR10 (non-Hodgkin's lymphoma), HLA-DRB (non-Hodgkin's lymphoma, B-cell leukemia), human chorionic gonadotropin (cancer), insulin-like growth factor 1 receptor (IGF1R, solid tumors, hematologic malignancies), interleukin-2 receptor (T-cell leukemia and lymphoma), interleukin-6 receptor (multiple myeloma, rheumatoid arthritis, Kassman disease, IL6-dependent tumors), integrins (αvβ3, α5β1, α6β4, αIIbβ3, α5β5, αvβ5, targeting various cancers), MAGE-1 (cancer), MAGE-2 (Cancer), MAGE-3 (cancer), MAGE-4 (cancer), anti-transferrin receptor (cancer), p97 (melanoma), transmembrane 4-domain subfamily A member 1 (MS4A1, non-Hodgkin's B-cell lymphoma, leukemia), mucin 1 or MUC1-KLH (breast cancer, ovarian cancer, cervical cancer, bronchial cancer, and gastrointestinal cancer), mucin 16 (MUC16, CA125) (ovarian cancer), carcinoembryonic antigen (CEA, colorectal cancer), gp100 (melanoma), MART1 (melanoma), melanoma-associated proteoglycan (MPG, melanoma), transmembrane 4-domain subfamily A (MS4A1) Small cell lung cancer, non-Hodgkin's lymphoma), nucleolin, Neu oncogene product (cancer), P21 (cancer), anti-N-hydroxyacetylneuraminic acid idiosyncratic site (breast cancer, melanoma), placental-like testicular alkaline phosphatase (ovarian cancer, testicular cancer), prostate-specific membrane antigen (PSMA, prostate tumor), prostate-specific antigen (PSA, prostate cancer), ROBO4, tumor-associated glycoprotein 72 (TAG-72, acute myeloid leukemia, gastric cancer, colorectal cancer, ovarian cancer), T-cell transmembrane protein (cancer), tyrosine kinase receptor (Tie, ​​CD202b), tumor necrosis factor receptor superfamily Member 10B (TNFRSF10B, cancer), tumor necrosis factor receptor superfamily member 13B (TNFRSF13B, multiple myeloma, non-Hodgkin's lymphoma, other cancers, rheumatoid arthritis and systemic lupus erythematosus), trophoblast glycoprotein (TPBG, renal cell carcinoma), tumor necrosis factor-associated apoptosis-inducing ligand receptor 1 (TRAIL-R1, lymphoma, non-Hodgkin's lymphoma, colorectal cancer, lung cancer), vascular cell adhesion molecule-1 (VCAM-1, CD106, melanoma), vascular endothelial growth factor and its subtypes VEGF-A and VEGF-2 (CD309) (various cancers). Other tumor-associated antigens recognized by antibodies have been reviewed in the literature (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)。,

[0380] The antibody-like protein is more preferably an IgG antibody capable of combating tumor cells, virus-infected cells, microbial-infected cells, parasite-infected cells, autoimmune disease cells, activated tumor cells, myeloid cells, activated T cells, or affecting B cells or melanocytes. More specifically, the antibody is capable of combating abnormal cells expressing any 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, CD13, CD14, CD15, CD16, CD16a, CD16b, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD15, CD16, CD16a, CD16b ... 25. CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD 42c, 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, CD 94. 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、CD211、CD212、CD213、CD213a1、CD213a2、CD214、CD215、CD216、CD217、CD218、CD218a、CD218、CD21b9、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD 231、CD232、CD233、CD234、CD235、CD235a、CD235b、CD236、CD237、CD238、CD 239, CD240, CD240ce, CD240d, CD241, CD242, CD243, CD244, CD245, CD246, CD247, CD248, CD249, CD250, CD251, CD252, CD253, CD254, CD255, CD256, CD25 7, CD258, CD259, CD260, CD261, CD262, CD263, CD264, CD265, CD266, CD267, CD268, CD269, CD270, CD271, CD272, CD273, CD274, CD275, CD276, CD277, CD2 78、CD279、CD281、CD282、CD283、CD284、CD285、CD286、CD287、CD288、CD289 、CD290、CD291、CD292、CD293、CD294、CD295、CD296、CD297、CD298、CD299、CD 300、CD300a、CD300b、CD300c、CD301、CD302、CD303、CD304、CD305、CD306、C D307、CD307a、CD307b、CD307c、CD307d、CD307e、CD307f、CD308、CD309、CD3 10、CD311、CD312、CD313、CD314、CD315、CD316、CD317、CD318、CD319、CD320 、CD321、CD322、CD323、CD324、CD325、CD326、CD327、CD328、CD329、CD330、CD 331、CD332、CD333、CD334、CD335、CD336、CD337、CD338、CD339、CD340、CD34 1、CD342、CD343、CD344、CD345、CD346、CD347、CD348、CD349、CD350、CD351、C D352, CD353, CD354, CD355, CD356, CD357, CD358, CD359, CD360, CD361, CD362, CD363, CD364, CD365, CD366, CD367, CD368, CD369, CD370, CD371, CD372CD373, CD374, CD375, CD376, CD377, CD378, CD379, CD381, CD382, CD383, CD384, CD385, CD386, CD387, CD388, CD389, CRIPTO, CRIPTO, CR, CR1, CRGF, CRIPTO, CXCR5, LY64, TDGF1, 4-1BB, APO2, ASLG659, BMPR1B, 4-1BB, 5AC, 5T4 (Trophoblast glycoprotein, TPBG, WNT-activating inhibitor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS-22M6, promoter receptor Somatic kinase 1, AFP, AKAP-4, ALK, α-integrin, αvβ6, aminopeptidase N, amyloid-β, androgen receptor, angiogenic factor 2, angiogenic factor 3, annexin A1, anthrax toxin protective antigen, anti-transfer protein receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracis, BAFF (B cell initiation factor), BCMA, B lymphoma cells, bcr-abl, dermal ... CL11 (CC fragment chemokine 11), CCR4 (CC chemokine receptor 4), CCR5, CD3E (ε), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), clustering factor A, cMet, CRIPTO, FCSF1R (colony-stimulating factor 1 receptor), CSF2 (colony-stimulating factor 2, granulocyte-macrophage colony-stimulating factor (GM-CSF)), CTLA4 (cytotoxic T lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4, CXC chemokine receptor Body 4, cyclic ADP-ribonuclease, cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, Dabigatran, DLL3 (Δ-ligand 3), DLL4 (Δ-ligand 4), DPP4 (dipeptide-peptidase 4), DR5 (death receptor 5), *E. coli* Shiga toxin type, *E. coli* Shiga toxin type-2, ED-B, EGFL7 (EGF-like domain protein 7), EGFR, EGFRII, EGFRvIII, endothelial factor, endothelin B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, Episialin, ERBB2 (epidermal growth factor receptor 2), ERBB3.ERG (TMPRSS2ETS fusion gene), Escherichia coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, alpha-fetoprotein, fibroin II β chain, fibronectin extra domain-B, FOLR (folate receptor), folate receptor α, folate hydrolase, Fos-associated antigen 1, respiratory syncytial virus F protein, coiled receptor, fucose GM1, GD2 ganglioside, G-28 (cell surface antigen glycolipid), GD3 idiotype, GloboH, Glypican 3. N-hydroxyacetylneuraminic acid, GM3, GMCSF receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane glycoprotein NMB), GUCY2C (guanylate cyclase 2C), guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase C receptor, heat-stable enterotoxin receptor (hSTAR), heat shock protein, 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 / dispersion factor), HHGFR, HIV-1, histone complexes, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human dispersion factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, influenza hemagglutinin, IgE, IgE Fc region, IGH, interleukins (including 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, or IL-28), IL31RA, ILGF2 (insulin-like growth factor 2), integrin (α4, αIIbβ3, αvβ3, α4β7, α5β1, α6β4, α7β7, α11β3, α5β5, αvβ5), interferon-γ-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, 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 A3MAGE4, ​​MART1, MCP-1, MIF (macrophage migration inhibitory factor, or glycosyl repressor (GIF)), MS4A1 (transmembrane 4-domain subfamily A member 1), MSLN (mesothelin), MUC1 (mucin 1, cell surface-associated (MUC1) or polymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (monocyte chemoattractant protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1, MYCN, myelin-associated glycoprotein, myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME) NGF, neuronal apoptosis-regulating protease 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 non-mutant, P97, PAP, anti-(N-hydroxyacetylneuraminic acid) antibody binding site, PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1), PDGF-Rα (α-platelet-derived growth factor receptor), PDGFR-β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, platelet-derived growth factor receptor β, sodium phosphate cotransporter, PMEL 17. Polysialic acid, proteinase 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate cancer cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI)), Rhesus factor, RANKL, RhoC, Ras mutation, RGS5, ROBO4, respiratory syncytial virus, RON, ROR1, sarcoma translocation breakpoint, SART3, Sclerostin, SLAMF7 (SLAM) Members 7), SelectinP, SDC1 (multiligand proteoglycan 1), systemic lupus erythematosus (a), somatostatin C, SIP (sphingosine 1-phosphate), somatostatin, spermin 17, SSX2, STEAP1 (6-transmembrane prostate antigen 1), STEAP2, STn, TAG-72 (tumor-associated glycoprotein), susceptin, T cell receptor, T cell transmembrane protein, TEM1 (tumor vascular endothelial marker 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor β), TGF-β1, TGF-β2 (transforming growth factor 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-α, TNFRSF8, TNFRSF10B (tumor necrosis factor receptor superfamily member 10B).TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (TNF-associated necrosis-inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5)), tumor-associated calcium signaling sensor 2, tumor-specific glycosylated MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TRP-1 (Trop1), TRP-2 (Trop2), tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR-2, vimentin, WT1, XAGE 1, cells expressing insulin-like growth factor receptor, or cells expressing epidermal growth factor receptor.

[0381] Many tumor-associated antigens (TAAs) or tumor cell receptors are known in the prior art and can be prepared using methods and information well-known in the prior art for antibody generation. In attempting to discover effective cellular targets for cancer diagnosis and treatment, researchers have been seeking to identify transmembrane or other forms of tumor-associated peptides or glycoproteins that are specifically expressed on the surface of one or more specific types of cancer cells relative to one or more normal non-cancer cells. Typically, these tumor-associated peptides are expressed at higher levels on the surface of cancer cells than on the surface of non-cancer cells. The recognition of these tumor-associated cell surface antigen peptides makes it possible for the antibody-drug conjugate (ADC) of this application to specifically target and destroy cancer cells. Examples of tumor-associated antigens and their known complementary antibodies are as follows:

[0382] (1) BMPR1B (bone morphogenetic protein receptor type IB);

[0383] (2)E16(LAT1,SLC7A5);

[0384] (3) STEAP1 (prostatic six-transmembrane epithelial antigen);

[0385] (4)0772P(CA125, MUC16);

[0386] (5) MPF (MPF, MSLN, SMR, megakaryocyte enhancer, mesothelin);

[0387] (6) Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2, type II sodium-dependent phosphate transporter 3b);

[0388] (7) Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, Semaphorin 5bHlog, 25 Sema domains, containing 7 thromboretin repeat sequences (type 1 and type 1), Transmembrane Domain TM And short cytoplasmic domain, (Semaphorin)5B;

[0389] (8)PSCA hlg(2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene);

[0390] (9) ETBR (endothelin B receptor);

[0391] (10)MSG783(RNF124, hypothesized protein FLJ20315);

[0392] (11)STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer-related gene 1, prostate cancer-related protein 1, prostate six-transmembrane epithelial antigen 2, prostate six-transmembrane protein);

[0393] (12)TrpM4(BR22450,FLJ20041,TRPM4,TRPM4B, transient acceptor potential cation channel 5, subfamily M, member 4);

[0394] (13) CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoma-derived growth factor);

[0395] (14) CD21 (CR2 (complement receptor 2) or C3DR (C3d / Ebstein-Barr virus receptor) or Hs.73792);

[0396] (15) CD79b (CD79B, CD793, Igβ (immunoglobulin-associated β), B29);

[0397] (16)FcRH2(IFGP4,IRTA4,SPAP1A (phosphatase ankylosing protein 5La containing SH2 domain),SPAP1B,SPAP1C);

[0398] (17)HER2(ErbB2);

[0399] 18) NCA (CEACAM6);

[0400] (19) MDP(DPEP1);

[0401] (20)IL20R-Alpha (IL20Ra, ZCYTOR7);

[0402] (21) Brevican (BCAN, BEHAB);

[0403] (22)EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5);

[0404] (23)ASLG659(B7h);

[0405] (24) PSCA (prostate stem cell antigen precursor);

[0406] (25)GEDA;

[0407] (26) BAFF-R (B cell activating factor receptor, BLyS receptor 3, BR3);

[0408] (27)CD22 (B cell receptor CD22-B subtype, B lymphocyte adhesion molecule, Lyb-8, SIGLEC-2, FLJ22814);

[0409] (27A)Cd22 (Cd22 molecule);

[0410] (28) CD79a (CD79A, CD79α), immunoglobulin-associated α, a B cell-specific protein that covalently interacts with Ig Beta (CD79B) and forms a complex with Ig M 35 molecules on its surface, transmitting signals involved in B cell differentiation, isoelectric point: 4.84, molecular weight: 25028, Tm: 2 [P] gene chromosome position: 19q13.2);

[0411] (29) CXCR5 (Burkitt lymphoma receptor 1, a G protein-coupled receptor activated by CXCL13 chemokine, which plays a role in lymphocyte migration and humoral defense, and in HIV-2 infection and the possible development of AIDS, lymphoma, multiple myeloma and leukemia); 372 amino acids, isoelectric point: 8.54, molecular weight: 41959, transmembrane number: 7 [P] gene chromosome: 11q23.3;

[0412] (30) HLA-DOB (the β subunit of MHC class II molecules (La antigen), which can bind peptides and present them to CD4 T lymphocytes); 273 amino acids, isoelectric point: 6.56, molecular weight: 30820, transmembrane number: 1 [P] gene chromosome: 6p21.3;

[0413] (31) P2X5 (purine receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, which may be involved in synaptic transmission and neurogenesis, and its deficiency may lead to pathophysiology of idiopathic detrusor instability); 422 amino acids, isoelectric point: 7.63, molecular weight: 47206, transmembrane number: 1 [P] gene chromosome: 17p13.3);

[0414] (32) CD72 (B cell differentiation antigen CD72, Lyb-2); 359 amino acids, isoelectric point: 8.66, molecular weight: 40225, transmembrane region: 15[P] gene chromosome: 9p13.3;

[0415] (33)LY64 (lymphocyte antigen 64 (RP105), a type I membrane protein rich in leucine repeat sequences (LRR), regulates B cell activation and apoptosis, and its loss of function is associated with increased disease activity in patients with systemic lupus erythematosus); 661 amino acids, isoelectric point: 6.20, molecular weight: 74147, transmembrane region: 1 [P] gene chromosome: 5q12;

[0416] (34) FcRH1 (Fc receptor-like protein 1, a putative immunoglobulin Fc domain receptor containing C2 type Ig-like and ITAM domains, which may play a role in B lymphocyte differentiation); 429 amino acids, isoelectric point: 5.28, molecular weight: 46925, transmembrane: 1 [P] gene chromosome: 1q21-1q22);

[0417] (35)IRTA2 (immunoglobulin superfamily receptor translocation-associated protein 2, a putative immune receptor that may play a role in B-cell development and lymphoma development; the gene appears in some B-cell malignancies through translocation dysregulation); 977 amino acids, isoelectric point: 6.88, molecular weight: 106468, transmembrane: 1 [P] gene chromosome: 1q21);

[0418] (36)TENB2 (also known as TMEFF2, TPEF, HPP1, TR, a presumed transmembrane proteoglycan belonging to the epidermal growth factor / modulin growth factor family and follicle-stimulating hormone-related protein, with a total of 374 amino acids).

[0419] (37) PSMA-FOLH1 (folic acid hydrolase 1, i.e. prostate-specific membrane antigen);

[0420] (38) SST (Somatostatin receptor; Note: There are 5 subtypes of this receptor);

[0421] (38.1) SSTR2 (somatostatin receptor 2);

[0422] (38.2) SSTR5 (somatostatin receptor 5);

[0423] (38.3)SSTR1; (38.4)SSTR3; (38.5)SSTR4; Integrin AvB6—Dual Subunit Complex (39+40);

[0424] (39) ITGAV (integrin, αV);

[0425] (40) ITGB6 (integrin, β6);

[0426] (41) CEACAM5 (carcinoembryonic antigen-associated cell adhesion molecule 5);

[0427] (42) MET (MET proto-oncogene, i.e., hepatocyte growth factor receptor);

[0428] (43) MUC1 (mucin 1, cell surface-associated protein);

[0429] (44) CA9 (carbonic anhydrase IX);

[0430] (45) EGFRvIII (epidermal growth factor receptor transcription variant 3);

[0431] (46) CD33 (CD33 molecule);

[0432] (47) CD19 (CD19 molecule);

[0433] (48) IL2RA (interleukin-2 receptor α subunit; NCBI reference sequence number: NM_000417.2);

[0434] (49) AXL (AXL receptor tyrosine kinase);

[0435] (50)CD30-TNFRSF8 (tumor necrosis factor receptor superfamily member 8);

[0436] (51) BCMA (B cell maturation antigen) – TNFRSF17 (tumor necrosis factor receptor superfamily member 17);

[0437] (52) CT antigen—CTA (cancer testis antigen);

[0438] (53)CD174(Lewis Y)-FUT3(fucotransferase 3(galactoside 3(4)-L-fucotransferase, Lewis blood type));

[0439] (54)CLEC14A (C-type lectin domain family 14, member a);

[0440] (55)GRP78-HSPA5 (heat shock 70kDa protein 5 (glucose regulatory protein, 78kDa));

[0441] (56)CD70 (CD70 molecule)L08096;

[0442] (57) Stem cell specific antigens: such as 5T4 (see item (63) below); CD25 (see item (48) above);

[0443] (58)ASG-5;

[0444] (59)ENPP3 (exonucleotide pyrophosphatase / phosphodiesterase 3);

[0445] (60) PRR4 (proline-rich protein 4 (lacrimal gland));

[0446] (61)GCC-GUCY2C (guanylate cyclase 2C (thermothermal enterotoxin receptor));

[0447] (62) Liv-1-SLC39A6 (Solute carrier family 39 (zinc transporter), member 6);

[0448] (63) 5T4, trophoblast glycoprotein, TPBG-TPBG (trophoblast glycoprotein);

[0449] (64)CD56-NCMA 1 (neural cell adhesion molecule 1);

[0450] (65) CanAg (tumor-associated antigen CA242);

[0451] (66)FOLR1 (folate receptor 1);

[0452] (67)GPNMB (glycoprotein (transmembrane) Nmb);

[0453] (68) TIM-1—HAVCR1 (Hepatitis A virus cell receptor 1);

[0454] (69)RG-1 / Prostate tumor target Mindin—Mindin / RG-1;

[0455] (70) B7-H4——VTCN1 (T cell activation inhibitory factor 1 containing V-set domain);

[0456] (71)PTK7 (protein tyrosine kinase 7);

[0457] (72) CD37 (CD37 molecule);

[0458] (73)CD138——SDC1 (multi-ligand proteoglycan 1);

[0459] (74)CD74 (CD74 molecule, a constant chain of major histocompatibility complex type II);

[0460] (75) Tight junction proteins—CLs (tight junction protein family);

[0461] (76) EGFR (epidermal growth factor receptor);

[0462] (77) Her3(ErbB3)——ERBB3(v-Erb-b2 erythroblast leukemia virus oncogene homolog 3 (avian));

[0463] (78) RON-MST1R (macrophage stimulation 1 receptor, belonging to c-Met-associated tyrosine kinase);

[0464] (79) EPHA2 (EPH receptor A2);

[0465] (80)CD20—MS4A1 (Member A of the transmembrane 4-domain subfamily);

[0466] (81) Tenosylin C—TNC (tenosylin C);

[0467] (82) FAP (fibroblast activation protein α);

[0468] (83) DKK-1 (a homolog of the African clawed frog Dickkopf-1 protein);

[0469] (84)CD52 (CD52 molecule);

[0470] (85)CS1——SLAMF7 (SLAM family member 7);

[0471] (86) Endothelial glycoprotein—ENG (endothelial glycoprotein);

[0472] (87)PMEL17 (Silver homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp100)BC001414; BT007202; M32295; M77348; NM_006928;

[0473] (88)TMEFF1 (a transmembrane protein 1 with EGF-like and two inhibin-like domains; Tomoregulin-1); H7365; C9orf2; C90RF2; U19878; X83961; NM_080655; NM_003692;

[0474] (89) GDNF-Ral (GDNF family receptor α1; GFRA1; GDNFR; GDNFRA; RETLi; TRNR1; RET1L; GDNFR-alpha1; GFR-ALPHA-1); U95847; BC014962; NM145793; NM_005264;

[0475] (90) Ly6E (lymphocyte antigen 6 complex, locus locusE; Ly67, RIG-E, SCA-2, TSA-1); NP_002337.1; NM_002346.2;

[0476] (91) TMEM46 (Shisa homolog 2 (Xenopus laevis); SHISA2); NP_001007539.1; NM_001007538.1;

[0477] (92) Ly6G6D (lymphocyte antigen 6 complex, locusG6D; Ly6-D, MEGT1); NP_067079.2; NM_021246.2;

[0478] (93) LGR5 (G protein-coupled receptor 5 containing leucine repeat sequences; GPR49, GPR67); NP_003658.1; NM_003667.2;

[0479] (94) RET (RET proto-oncogene; also known as MEN2A, HSCR1, MEN2B, MTC1, PTC, CDHF12, Hs.168114, RET51, RET-ELE1; sequence number: NP_066124.1, NM_020975.4);

[0480] (95)LY6K (lymphocyte antigen 6 complex K site; also known as LY6K, HSJ001348, FLJ35226; sequence number: NP_059997.3, NM_017527.3);

[0481] (96) GPR19 (G protein-coupled receptor 19; also known as Mm.4787; sequence number: NP_006134.1, NM_006143.2);

[0482] (97) GPR54 (KISS1 receptor; also known as KISS1R, GPR54, HOT7T175, AXOR12; sequence number: NP_115940.2, NM_032551.4);

[0483] (98)ASPHD1 (protein 1 containing the aspartate β-hydroxylase domain; gene number LOC253982; sequence number: NP_859069.2, NM_181718.3);

[0484] (99) Tyrosinase (TYR; also known as OCAIA, OCA1A, SHEP3; sequence number: NP_000363.1, NM_000372.4);

[0485] (100)TMEM118 (circular transmembrane protein 2; also known as RNFT2, FLJ14627; sequence number: NP_001103373.1, NM_001109903.1);

[0486] (101) GPR172A (G protein-coupled receptor 172A; also known as GPCR41, FLJ11856, D15Ertd747e; sequence number: NP_078807.1, NM_024531.3);

[0487] (102) CLL-1 (i.e. CLEC12A, also known as MICL, DCAL2) encodes a member of the C-type lectin / C-type lectin-like domain (CTL / CTLD) superfamily.

[0488] (103) Annexin A1—ANXA1 (Annexin A1);

[0489] (104) V-CAM(CD106)——VCAM1 (vascular cell adhesion molecule 1);

[0490] (105)B7H3 (CD276 or B7RP-2, belonging to the B7 ligand family, with two subtypes: 2Ig-B7H3 and 41g-B7H3, with molecular weights of approximately 45kDa and 100kDa, respectively);

[0491] (106)CD54 (also known as BB2, P3.58);

[0492] (107)CA19-9 (carbohydrate antigen 19-9, a cell surface glycoprotein complex, most commonly found in pancreatic ductal adenocarcinoma);

[0493] (108) Tissue factor (coagulation factor III, also known as TF, TFA, CD142);

[0494] (109) ROR1 (receptor tyrosine kinase-like orphan receptor 1, also known as NTRKR1, dJ537F10.1);

[0495] (110)Claudin18 (Surfactant-associated protein A5, SFTA5; Surfactant protein J, SFTPJ);

[0496] (111)FGFR2 (fibroblast growth factor receptor 2, BEK; JWS; BBDS; CEK3; CFD1; ECT1; KGFR; TK14; TK25; BFR-1; CD332; K-SAM);

[0497] (112)FGFR3 (fibroblast growth factor receptor 3, ACH; CEK2; JTK4; CD333; HSFGFR3EX);

[0498] (113)FGFR4 (fibroblast growth factor receptor 4, TKF; JTK2; CD334);

[0499] (114)FGFR1 (fibroblast growth factor receptor 1, CEK; FLG; HH2; OGD; ECCL; FLT2; KAL2; BFGFR; CD331; FGFBR; FLT-2; HBGFR; N-SAM; FGFR-1; HRTFDS; bFGF-R-1);

[0500] (115) ROR2 (orphan receptor tyrosine kinase 2, BDB; BDB1; NTRKR2);

[0501] (116)SLC44A4 (SLC44A4-Solute Carrier Family 44 Member 4, CTL4; NG22; TPPT; DFNA72; hTPPT1; C6orf29);

[0502] (117)DLL3 (Delta Normal Notch Ligand 3, SCDO1);

[0503] (118)DLL4(Class Delta Normal Notch Ligand 4, AOS6; delta4; hdelta2);

[0504] (119)ALK (ALK receptor tyrosine kinase, ALK1; CD246; NBLST3);

[0505] (120)CLDN6(claudin 6);

[0506] (121) CLDN3 (claudin 3, RVP1; HRVP1; C7orf1; CPE-R2; CPETR2);

[0507] (122) EFNA4 (ephrin A4, EFL4; EPLG4; LERK4; LERK-4);

[0508] (123)Notch1 (Notch receptor 1, hN1; AOS5; TAN1; AOVD1);

[0509] (124)Notch2 (Notch receptor 2, hN2; AGS2; HJCYS);

[0510] (125)Notch3 (Notch receptor 3, IMF2; LMNS; CASIL; CADASIL; CADASIL1);

[0511] (126)LAMP-1 (lysosome-associated membrane protein 1, LAMPA; CD107a; LGP120);

[0512] Many of the antigens mentioned above have been described in our previous patent application (PCT / CN2023 / 096066, filed on May 24, 2023).

[0513] In another specific embodiment, the antibody-drug conjugate of the present invention is used for targeted cancer therapy. Targeted cancers include, but are not limited to: adrenocortical carcinoma, anal cancer, bladder cancer, brain tumors (adult brainstem glioma, pediatric brain tumor, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors and pineal gland tumors, visual pathway and hypothalamic gliomas), breast cancer, gastrointestinal carcinoid tumors, cancers of unknown primary origin, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's sarcoma family (primitive neuroectodermal tumors), and extracranial germ cells. Tumors, including: eye cancer (intraocular melanoma), gallbladder cancer, stomach cancer, gonadal genital cell tumors, gestational trophoblastic tumors, head and neck cancer, hypopharyngeal cancer, pancreatic islet cell carcinoma, kidney cancer (renal cell carcinoma), laryngeal cancer, leukemia (acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia), lip and oral cancer, liver cancer, lung cancer (non-small cell lung cancer, small cell lung cancer), and lymphomas (AIDS-related lymphoma, central nervous system lymphoma, skin lymphoma). T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma), malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma with occult primary lesions, multiple myeloma and other plasma cell tumors, mycosis fungoides, myelodysplastic syndromes, myeloproliferative disorders, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer (epithelial ovarian cancer, germ cell tumors, low-grade malignant potential tumors), pancreatic cancer (exocrine pancreatic cancer, islet cell cancer), sinuses and nasal... Cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma (kidney cancer), renal pelvis and ureter cancer (transitional cell carcinoma), salivary gland cancer, Cezari syndrome, skin cancer (cutaneous T-cell lymphoma, Kaposi's sarcoma, melanoma), small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thymoma (malignant), thyroid cancer, urethral cancer, uterine cancer (sarcoma), rare childhood cancers, vaginal cancer, vulvar cancer, Wilms' tumor.

[0514] In another specific embodiment, the antibody-drug conjugate of the present invention is used, according to relevant compositions and methods, to treat or prevent autoimmune diseases. Autoimmune diseases include, but are not limited to: achlorhydria-associated autoimmune chronic active hepatitis, acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiglomerular basement membrane / tubular basement membrane nephritis, antiphospholipid syndrome, antisynthetic enzyme syndrome, arthritis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, and autoimmune polyendocrine syndrome type I, II, and... Type III, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune uveitis, Balo's disease / concentric sclerosis, Behçet's syndrome, Beger's disease, Bickerstaff encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, Chagas disease, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, chronic Lyme disease, chronic obstructive pulmonary disease, eosinophilic granulomatous polyangiitis, cicatricial pemphigoid, celiac disease, Cogan's syndrome, cold agglutinin disease, complement component 2 deficiency, cranial arteritis, CREST syndrome, Crohn's disease (a specific type of disease) This list includes various skin conditions and related conditions, such as: inflammatory bowel disease, Cushing's syndrome, cutaneous leukocytic vasculitis, Dego's disease, Delken's disease, herpetic dermatitis, dermatomyositis, type 1 diabetes, diffuse systemic cutaneous sclerosis, Dressler's syndrome, discoid lupus erythematosus, eczema, endometriosis, enthesitis-associated arthritis, eosinophilic fasciitis, acquired epidermolysis bullosa, erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, progressive ossifying fibrodysplasia, fibromyalgia, fibromyositis, fibrotic alveolitis, gastritis, gastrointestinal pemphigoid, giant cell arteritis, glomerulonephritis, Goodpasser syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, and Hashimoto's thyroiditis. Hemolytic anemia, Henno-Schlan purpura, herpes gestationis, hidradenitis suppurativa, Hughes syndrome (see antiphospholipid syndrome), hypogammaglobulinemia, idiopathic inflammatory demyelinating disease, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (see autoimmune thrombocytopenic purpura), IgA nephropathy (also known as Beagle's disease), inclusion body myositis, inflammatory demyelinating polyneuropathy, interstitial cystitis, irritable bowel syndrome, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, Kawasaki disease, Lambert-Eton myasthenia gravis, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease, Lughrick's disease (also known as amyotrophic lateral sclerosis), lupus hepatitis.Systemic lupus erythematosus, Majeed syndrome, Meniere's disease, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue disease, scleroderma, Mucha-Habermann disease, Muckle-Wells syndrome, multiple myeloma, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devik's disease), neuromuscular rigidity, ocular cicatricial pemphigoid, strabismus-ocular clonus-myoclonus syndrome, Ord thyroiditis, relapsing rheumatic disease, streptococcal-associated pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Parsonage-Turner syndrome, pars plana cyclitis, pemphigus, pemphigus vulgaris, pernicious anemia, peripheral encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosa, pure red cell aplasia, Rasmussen encephalitis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, restless legs syndrome, retroperitoneal fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, mental disorders Schizophrenia, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, Sjögren's syndrome, spondyloarthritis, hyperviscosity syndrome, Still's disease, stiff-person syndrome, subacute bacterial endocarditis, Susac syndrome, Sweet syndrome, Siddenham's chorea, sympathetic ophthalmia, hyperaorticitis, temporal arteritis (giant cell arteritis), Tolosa-Hunter syndrome, transverse myelitis, ulcerative colitis (an idiopathic inflammatory bowel disease), undifferentiated connective tissue disease, undifferentiated spondyloarthritis, vasculitis, vitiligo, Wegener's granulomatosis, Wilson's syndrome, and Wilson-Austen syndrome.

[0515] In another specific embodiment, the antibody-drug conjugate of the present invention for treating or preventing autoimmune diseases may include, but is not limited to: anti-elastin antibodies, anti-epithelial cell antibodies, anti-type IV basement membrane collagen antibodies, antinuclear antibodies, anti-double-stranded DNA antibodies, anti-single-stranded DNA antibodies, anticardiolipin antibodies (IgM and IgG types), anti-celiac disease antibodies, antiphospholipid antibodies (IgK and IgG types), anti-Sm antibodies, anti-mitochondrial antibodies, thyroid antibodies, microsomal antibodies, T-cell antibodies, thyroglobulin antibodies, anti-SCL-70 antibodies, anti-Jo-1 antibodies, anti-U1RNP antibodies, and anti-La antibodies. Anti-SSB antibody, anti-SSA antibody, anti-SSB antibody, anti-parietal cell antibody, anti-histone antibody, anti-RNP antibody, cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA), perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA), anti-centromere antibody, anti-nucleolar fibrin antibody, anti-glomerular basement membrane antibody, anti-ganglioside antibody, anti-desmosome core protein 3 antibody, anti-p62 antibody, anti-sp100 antibody, anti-mitochondrial (M2) antibody, rheumatoid factor antibody, anti-mutant citrullinated vimentin antibody, anti-topoisomerase antibody, anti-neutrophil cytoplasmic (cANCA) antibody.

[0516] In some preferred embodiments, the binding molecule used in the conjugates of the present invention can simultaneously bind to a receptor and a receptor complex expressed on the surface of activated lymphocytes associated with autoimmune diseases. This receptor or receptor complex may comprise members of the immunoglobulin gene superfamily (such as CD2, CD3, CD4, CD8, CD19, CD20, CD22, CD28, CD30, CD33, CD37, CD38, CD56, CD70, CD79, CD79b, CD90, CD125, CD137, CD138, CD147, CD152 / CTLA-4, PD-1, or ICOS) or members of the tumor necrosis factor receptor superfamily (such as C...). D27, CD40, CD95 / Fas, CD134 / OX40, CD137 / 4-1BB, INF-R1, TNFR-2, RANK, TACI, BCMA, osteoprotein, Apo2 / TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4 and APO-3), integrins, cytokine receptors, chemokine receptors, major histocompatibility proteins, lectins (C type, S type or I type) or complement regulatory proteins.

[0517] In another specific embodiment, the available cell-binding ligands that have immune specificity against viral or microbial antigens are humanized or fully human monoclonal antibodies. The term "viral antigen" as used herein includes, but is not limited to, any viral peptide, polypeptide, or protein capable of evoking an immune response (such as HIV gp120, HIV nef, respiratory syncytial virus F glycoprotein, influenza virus neuraminidase, influenza virus hemagglutinin, HTLV tax, herpes simplex virus glycoproteins (such as gB, gC, gD, gE), and hepatitis B surface antigen). The term "microbial antigen" as used herein includes, but is not limited to, any microbial peptide, polypeptide, protein, sugar, polysaccharide, or lipid molecule capable of evoking an immune response (such as bacterial, fungal, pathogenic protozoan, or yeast polypeptides, including lipopolysaccharides and capsular polysaccharides 5 / 8, etc.). Examples of available antibodies against viral or microbial infections include, but are not limited to: humanized anti-respiratory syncytial virus monoclonal antibody palizumab for treating respiratory syncytial virus infection; CD4 fusion antibody PRO542 for treating HIV infection; fully human antibody Ostavir for treating hepatitis B virus; humanized IgG1 antibody PROTVIR for treating cytomegalovirus; and anti-lipopolysaccharide antibodies.

[0518] The antibody-drug conjugates of this invention can be used to treat infectious diseases. These infectious diseases include, but are not limited to: Acinetobacter infections, actinomycosis, African sleeping sickness (African trypanosomiasis), AIDS (Acquired Immunodeficiency Syndrome), amoebiasis, anaplasmosis, anthrax, Cryptococcus hemolyticus infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroidetes infection, balanitis, Ascaris lumbricoides infection, BK virus infection, Trichophyton mentagrophytes infection, Blastomycosis, Bolivian hemorrhagic fever, spirochetal infection, botulism (and infant botulism), Brazilian hemorrhagic fever, brucellosis, Burkholderia infection, brucellosis ulcer, and calicivirus infection (norovirus). (And zarovirus), Campylobacteriosis, Candidiasis (candidiasis; thrush), Cat scratch disease, Cellulitis, Chagas disease (American trypanosomiasis), Chancroid, Chickenpox, Chlamydia infection, Chlamydia pneumoniae infection, Cholera, Chromobacterium chromoblastomycosis, Clostridium difficile infection, Coccidioidomycosis, Colorado tick-borne fever, Common cold (acute viral nasopharyngitis; acute rhinitis), Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, Cryptococcosis, Cryptosporidiosis, Cutaneous larval migration syndrome, Cyclosporidiosis, Cysticercosis, Cytomegalovirus infection, Dengue fever, Binuclear amoebiasis, Diphtheria, Broad tapeworm infection, Dracnia marina infection, Ebola hemorrhagic fever, Echinococcosis, Ehrlich ascites, Pinworm infection, Enterococcal infection Enterovirus infection, epidemic typhus, erythema infectiosum (fifth disease), roseola infantum, fascioliasis, fascioliasis, fatal familial insomnia, filariasis, Clostridium perfringens food poisoning, free-living amoeba infection, fusobacterium infection, gas gangrene (clostridium myonecrosis), geomycosis, Gerstmann-Straussler-Schenck syndrome, Giardiasis, glanders, gnathostomiasis, gonorrhea, granuloma inguinale (Dunofan disease), group A streptococcal infection, group B streptococcal infection, Haemophilus influenzae infection, hand-foot-mouth disease, Hantavirus pulmonary syndrome, Helicobacter pylori infection, hemolytic uremic syndrome, hemorrhagic fever with renal syndrome, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, herpes simplex. Histoplasmosis, hookworm infection, human bocavirus infection, human erythrozoonosis, human granulocytic anaplasmosis, human metapneumovirus infection, human monocytic erythrozoonosis, human papillomavirus infection, human parainfluenza virus infection, hymenolepis taeniasis, Epstein-Barr virus infectious mononucleosis, influenza, isosporidioidomycosis, Kawasaki disease, keratitis, Chlorella vulgaris infection, kuru, Lassa fever, Legionnaires' disease, Legionnaires' disease, leishmaniasis, leptospirosis, listeriosis, Lyme disease, lymphatic filariasis (elephantiasis), lymphocytic choriomeningitis, malaria, Marburg hemorrhagic fever, measles, melioidosis (Whitmore's disease), meningitis, meningococcal infection.Heteroschisis, Microsporidiosis, Molluscum contagiosum, Mumps, Endemic typhus, Mycoplasma pneumonia, Mycoticoma, Myiasis, Neonatal conjunctivitis (neonatal ophthalmia), Creutzfeldt-Jakob disease (vCJD, nvCJD), Nocardia, Onchocerciasis (river blindness), Paracoccidioidomycosis (South American blastomycosis), Paragonimiasis, Pasteurization, Head lice, Body lice, Pubic lice, Pelvic inflammatory disease, Pertussis, Plague, Pneumococcal infection, Pneumocystis pneumonia, Pneumonia, Poliomyelitis, Prevotella infection, Primary amoebic meningoencephalitis, Progressive multifocal leukoencephalopathy, Psittacosis, Q fever, Rabies, Rat bite fever, Respiratory syncytial virus infection, Narcosis, Rhinovirus infection, Rickettsia infection, Rickettsial pox, Rift Valley fever, Rocky Mountain fever Spotted fever, rotavirus infection, rubella, salmonellosis, severe acute respiratory syndrome (SARS), scabies, schistosomiasis, sepsis, shigella (bacterial dysentery), herpes zoster, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis, syphilis, tapeworm infection, tetanus, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea manuum, tinea pedis, onychomycosis, tinea versicolor (pityriasis versicolor), ocular toxocariasis (ocular larval migration syndrome), visceral toxocariasis (visceral larval migration syndrome), toxoplasmosis, trichinosis, trichomoniasis, whipworm infection, tuberculosis, tularemia, ureaplasma urealyticum infection, Venezuelan equine encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, trichomonadiasis, pseudotuberculosis Yersinia infection, Yersinia infection, yellow fever, zygomycosis.

[0519] The pathogenic strains targeted by the cell-binding molecules (more preferably antibodies) of this invention include, but are not limited to: Acinetobacter baumannii, Actinobacter spp., Actinobacter jejuni and Propionibacterium acnes, Trypanosoma brucellosis, Human immunodeficiency virus (HIV), Entamoeba histolytica, Anaplasma, Bacillus anthracis, Cryptobacterium hemolyticus, Junin virus, Ascaris lumbricoides, Aspergillus, Astroviridae, Babesia, Bacillus cereus, various bacteria, Bacteroides, Balantidium coli, Ascaris lumbricoides, BK virus, Nodula hota, Blastocystis hominis, Blastocystis dermatitidis, Machupo virus, Leptospira, Clostridium botulinum, Sabiya virus, Brucella (usually Burkholderia cepacia and other Burkholderia species), Mycobacterium ulcerans, Caliciformis, etc. Viridae, Campylobacter (usually Candida albicans and other Candida species), Bartonella henselae, Group A Streptococcus and Staphylococcus, Trypanosoma krusei, Haemophilus ducreyi, Varicella-zoster virus (VZV), Chlamydia trachomatis, Chlamydia pneumoniae, Vibrio cholerae, Chromosomalosis pylori, Clonorchis sinensis, Clostridium difficile, Coccidioides immitis and Coccidioides posadas, Colorado tick-borne heat virus, rhinovirus, coronavirus, Creutzfeldt-Jakob prions, Crimean-Congo hemorrhagic fever virus, Cryptococcus neoformans, Cryptosporidium, Acanthopanax brasiliensis (various parasites), Cyclospora cayetta, Taenia solium, Cytomegalovirus, Dengue virus (DEN-1, DEN-2, DEN-3 and DEN-4) – Flavivir, Entamoeba fibrilliosa, Corynebacterium diphtheriae, *C. broadenum*, *Dracinidia medinae*, Ebola virus, *Echinococcus*, *Ehrlich*, *Enterocera*, *Enterococcus*, *Enterovirus*, *Rickettsia prowleri*, parvovirus B19, human herpesviruses 6 and 7, *Fasciolopsis buski*, *Fasciola hepatica* and *Fasciola gigantea*, lethal familial insomnia prions, *Filarialea*, *Clostridium perfringens*, *Clostridium* (other *Clostridium* species), *Geotrichum candida*, *Göstahlmann-Straussler-Schenck syndrome prions*, *Giardia lamblia*, *Burkholderia melioides*, *Gnathostoma spinigerum* and *Gnathostoma spinigerum*, *Neisseria gonorrhoeae*, *Klebsiella granulomatosa*, *Streptococcus pyogenes*, *Streptococcus agalactiae*, *Haemophilus influenzae*, enteroviruses (mainly Coxsackievirus A and enteroviruses) Hepatitis B virus type 71), Sinopharm virus, Helicobacter pylori, Escherichia coli O157:H7, Bunyaviridae, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Herpes simplex virus type 1 and 2, Histoplasma capsulatum, Acletospira duodenalis and Mechanostoma aequalis, Haemophilus influenzae, human bocavirus, Ehrlich aspergillus, Anaplasma phagocytophilum, human metapneumovirus, Ehrlich aspergillus chafing, human papillomavirus, human parainfluenza virus, Hymenolepis microspinipes and Hymenolepis atrophus, Epstein-Barr virus, Orthomyxoviridae, Isococcus bereaves, Chlorella vulgaris, Klebsiella pneumoniae, Klebsiella odorinae, Klebsiella rhinosclerotiorum, kuru prions, Lassa virus, Legionella pneumophila, Legionella pneumophilaLeishmania, Mycobacterium leprae and Mycobacterium nodosa, Leptospira, Listeria monocytogenes, Borrelia burgdorferi and other Borrelia species, Nematoda bancella and Brucella malayi, Lymphocytic choriomeningitis virus (LCMV), Plasmodium, Marburg virus, Measles virus, Burkholderia melioides, Neisseria meningitidis, Paragonimus yokokawa, Microsporidia, Molluscum contagiosum virus (MCV), Mumps virus, Rickettsia typhus, Mycoplasma pneumoniae, Various bacteria (actinomycosis) and fungi (fungalosis), Parasitic Diptera fly larvae, Chlamydia trachomatis and Neisseria gonorrhoeae, Variant Creutzfeldt-Jakob disease prions, Nocardia asteroides and other Nocardia species, Spirocera spiralis, Paracoccidioides brasiliensis, Westermani Paragonimus and other paragonimus species, Pasteurella spp., head lice, body lice, pubic lice, Bordetella pertussis, Yersinia pestis, Streptococcus pneumoniae, Pneumocystis jirovecii, poliovirus, Prevotella spp., Naegleria fowleri, JC virus, Chlamydia psittaci, Coxiella burgdorferi, rabies virus, Streptococcus moniliforme and Spirochetes microsporidia, respiratory syncytial virus, Hebrew rhinosporidia, rhinovirus, Rickettsia spp., Rickettsia arachnoidea, Rift Valley fever virus, Rickettsia rickettsiae, rotavirus, rubella virus, Salmonella spp., SARS coronavirus, human scabies mite, Schistosoma spp., Shigella spp., varicella-zoster virus, smallpox macrovirus or smallpox parvovirus, Sporothrix schenckii, Staphylococcus spp., Staphylococcus spp., Staphylococcus aureus, pyogenic bacteria Streptococcus faecium, Strongyloides stercoralis, Treponema pallidum, Taenia spp., Clostridium tetani, Trichophyton spp., Trichophyton tonsurans, Trichophyton spp., Epidermophyton floccosum, Trichophyton rubrum and Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton nodules of Wernicke's, Trichophyton spp., Malassezia spp., Toxocara canis or Toxocara felis, Toxoplasma gondii, Trichophyton trichinella, Trichophyton vaginalis, Trichophyton mentagrophytes, Mycobacterium tuberculosis, Tula Francisella, Ureaplasma urealyticum, Venezuelan equine encephalitis virus, Vibrio cholerae, Guanarito virus, West Nile virus, Trichophyton baumannii, Yersinia pseudotuberculosis, Yersinia enterocolitica, Yellow fever virus, Mucorales (Mucor) and Entomales (Enteromorphia), Pseudomonas aeruginosa, Campylobacter fetus (Vibrio), Aeromonas hydrophila Bacteria, Edwardsiella tarda, Yersinia pestis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Salmonella typhimurium, Treponema pallidum, Treponema pallidum, Treponema ventriculophilus, Treponema burgdorferi, Leptospira hemorrhagic jaundice, Pneumocystis carinii, Brucella abortus, Brucella suis, Brucella ovis, Mycoplasma, Rickettsia prowleri, Rickettsia scrub typhus, Chlamydia; pathogenic fungi (Aspergillus fumigatus, Candida albicans, Histoplasma capsulatum); protozoa (Entamoeba histolytica, Ciliophora, Trichomonas vaginalis, Trypanosoma gambiae, Trypanosoma rhodesianum, Leishmania donovani, Leishmania tropicalis, Leishmania brasiliensis, Pneumocystis pneumoniae, Plasmodium vivax, Plasmodium falciparum, Plasmodium malariae); or worms (Schistosoma japonicum,Schistosoma mansoni, Schistosoma haematobium, and hookworms.

[0520] Other antibodies used in this invention as cell-binding ligands for treating viral diseases include, but are not limited to, antibodies against pathogenic viral antigens, including viruses (exemplary but not exhaustive): poxviridae, herpesviridae, adenoviridae, papillomaviridae, enteroviridae, pituriviridae, parvoviridae, reoviridae, retroviridae, influenza virus, parainfluenza virus, mumps virus, measles virus, respiratory syncytial virus, rubella virus, arboviridae, rhinoviridae, acanthoviridae, non-A, non-B hepatitis virus, rhinoviridae, coronavirusidae, rotavirusidae, and tumor viruses [e.g., hepatitis B virus (hepatocellular carcinoma), human papillomavirus]. (Cervical cancer, anal cancer), Kaposi's sarcoma-associated herpesvirus (Kaposi's sarcoma), Epstein-Barr virus (Epstein-Barr virus) (nasopharyngeal carcinoma, Burkitt lymphoma, primary central nervous system lymphoma), MCPyV (Merkel cell carcinoma), SV40 (simian virus 40), hepatitis C virus (hepatocellular carcinoma), human T-cell lymphovirus type 1 (adult T-cell leukemia / lymphoma)]; viruses that cause immune system diseases: [such as human immunodeficiency virus (AIDS)]; central nervous system viruses: [e.g., JCV (progressive multifocal leukoencephalopathy), measles virus (subacute sclerosing panencephalitis), LCMV (lymphocytic choroid plexus meningitis), arboviruses] Encephalitis, Orthomyxoviridae (possibly related) (encephalitis dormantis), rabies virus (rabies), Chandipra virus, herpesvirus meningitis, Ramsey Hunt syndrome type II; poliovirus (poliomyelitis, post-poliomyelitis syndrome), HTLV-I (tropical spastic paraplegia)]; cytomegalovirus (cytomegalovirus retinitis, herpes simplex virus (herpetic keratitis)); cardiovascular viruses [e.g., Coxsackie B virus (pericarditis, myocarditis)]; respiratory system / acute viral nasopharyngitis / viral pneumonia: [Epstein-Barr virus (EBV infection / infectious mononucleosis), cytomegalovirus; SARS coronavirus] Viruses (Severe Acute Respiratory Syndrome) Orthomyxoviridae: Influenza A / B / C virus (influenza / avian influenza), Paramyxoviruses: Human parainfluenza virus (parainfluenza), Respiratory syncytial virus, Human metapneumovirus]; Digestive system viruses [Mumps virus (mumps), Cytomegalovirus (cytomegalovirus esophagitis); Adenovirus (adenovirus infection); Rotavirus, Norovirus, Astrovirus, Coronavirus; Hepatitis B virus, Coxsackie B virus, Hepatitis A virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Hepatitis G virus]; Genitourinary system viruses [e.g., BK virus, Mumps virus (mumps)].

[0521] According to another object of the invention, the invention also relates to pharmaceutical compositions comprising the conjugate of the invention and pharmaceutically acceptable carriers, diluents, or excipients for the treatment of cancer, infection, or autoimmune diseases. Methods for treating cancer, infection, and autoimmune diseases can be performed in vitro, in vivo, or ex vivo. Examples of in vitro application include treating cell cultures to kill all cells except for desired variants that do not express the target antigen; or killing variants that express the unwanted antigen. Examples of ex vivo application include treating hematopoietic stem cells prior to transplantation (hematopoietic stem cell transplantation) into the same patient to kill diseased or malignant cells. For example, clinical ex vivo treatment to remove tumor cells or lymphocytes from bone marrow before autologous transplantation in cancer treatment or autoimmune disease treatment; or to remove T cells and other lymphocytes to prevent graft-versus-host disease before allogeneic bone marrow or tissue transplantation, can be performed by collecting bone marrow from a patient or other individual, incubating it in a serum-containing culture medium, adding the conjugate of the invention to it at a concentration ranging from about 1 pM to 0.1 mM, and incubating at about 37°C for about 30 minutes to about 48 hours. Specific concentration and incubation time (i.e., dosage) conditions can be easily determined by skilled clinical technicians. After incubation, the bone marrow cells are washed with serum-containing culture medium and reinfused into the patient intravenously according to known methods. In cases where the patient receives other treatments (such as ablation chemotherapy or total body irradiation) between bone marrow collection and infusion of treated cells, the treated bone marrow cells can be cryopreserved using standard medical equipment in liquid nitrogen.

[0522] In a further preferred embodiment, the present invention also provides an antibody-drug conjugate comprising a monoclonal antibody or its antigen-binding fragment, conjugated to a cytotoxin via a linker, the linker containing a small glutamate urea molecule (e.g., 2-[3-(1,3-dicarboxypropyl)urea]-glutamate (DUPA), urea-based glutamate heterodimer, 2-(phosphonomethyl)-glutamate (PMPA), phosphoramide, glu-urea-lys, or a 2-(phosphonomethyl)glutamate analog) to target prostate-specific antigens of tumor cells, and / or to target dermalin receptors (gastrin-releasing peptide receptors, neurotensin receptors (including neurotensin)). The antigen-binding protein is conjugated to an affinity ligand of receptor 1 and neuropeptide-Y receptor, and / or a cell-penetrating peptide, and / or an affinity peptide that binds to programmed death ligand-1 (PD-L1, or CD274) (expressed on tumor cells and tumor-infiltrating immune cells), blocking its interaction with PD-1 and B7.1 receptors. These peptides have an affinity for the receptor of at least EC50 < 10 μM, preferably EC50 < 100 nM, more preferably EC50 < 50 nM. In another embodiment, the antigen-binding protein is conjugated to a cytotoxin, such as, but not limited to, a microtubule inhibitor analog, a camptothecin analog, a PBD dimer, anthracyclines, or an oliquistatin analog.

[0523] In some embodiments, the cell-penetrating peptides (CPPs) used in this invention may be sequences of fewer than 100 amino acids screened from a CPP database (http: / / crdd.osdd.net / raghava / cppsite) or from known publications, or modified by replacing one or more amino acids in a known peptide sequence and then performing a redundancy check. Preferred CPPs are linear or cyclic peptides containing fewer than 50 amino acids, preferably fewer than 20 natural or non-natural amino acids, more preferably fewer than 15 amino acids and containing one, two, or several arginines and / or lysines. CPPs are more preferably cyclic peptides, particularly cyclic peptides of fewer than 8 amino acids. Typically, the selected peptides are further analyzed to filter out ambiguous peptides with undesirable chemical modifications. Amphiphilicity prediction can be performed via the online server AMPHIPASEEK (…). https: / / npsa-prabi.ibcp.fr / cgibin / npsa automat.pl? page= / NPSA / npsaamphipaseek.html AMPHIPASEEK assigns a score between 0 and 5 to each residue of a given peptide sequence. A higher score indicates higher amphiphilicity, and vice versa (0 = low, 5 = high). An online server (K-Me3) is used. https: / / www.peptide2.com / N peptide hydrophobicity hydrophilicity.php Calculate the hydrophilicity value. Typically, it's necessary to use the Innovagen peptide solubility calculator separately. https: / / pepcalc.com / ) and CPPpred( http: / / biow.ucd.ie / ~compass / biow web / Server pages / cpppred.php Solubility and cell permeability are calculated to meet certain standards. CPP scores are given in the range of 0-1, with peptides scoring >0.5 indicating better cell permeability. The efficiency of CPP penetration into cells can be measured using several different methods (Lee HM et al., Nature Communications Biology, 2021, 4:205; Penedo M. et al., Scientific Reports, 2021, 11:7756, and their cited references). Generally, a good CPP should be able to internalize (transport) more than 40% of ligands bound to the cell within 2 hours, or assist in the internalization of 40% of ADCs bound to the cell, crossing the cell membrane.

[0524] In some embodiments, the present invention provides antigen-binding antibody-drug conjugates that bind to membrane-bound targets and are internalized. In a further embodiment, an immunoconjugate comprising the antigen-binding protein of the present invention and a cytotoxic agent is provided. In a further embodiment, the antigen-binding protein has antibody-dependent cell-mediated cytotoxicity (ADCC) effector function, for example, the antigen-binding protein has enhanced ADCC effector function. In one such embodiment, an antigen-binding antibody / protein or antibody fragment thereof for constructing antibody-drug conjugates against various cancers is provided.

[0525] In one aspect of the invention, the antibody / protein provided for constructing the antibody-drug conjugate is preferably an antibody with affinity for antigens highly expressed on tumor cells. The sequence information of the relevant antibody can be found in known public domain databases, such as those of the World Intellectual Property Organization, the United States Patent and Trademark Office, the European Patent Office, the China National Intellectual Property Administration, and the Japan Patent Office.

[0526] The antigen-binding antibody / protein of the present invention may include the variable regions of the antibody heavy chain and light chain as described herein, which may be constructed as natural antibodies or functional fragments or equivalents thereof. Therefore, the antigen-binding protein of the present invention may include the VH region of an antibody, paired with a suitable light chain, and constructed as a full-length antibody, a (Fab′)2 fragment, a Fab fragment, or equivalents thereof (e.g., scFV, double-chain antibodies, triple-chain antibodies, or quadruple-chain antibodies, Tandabs, etc.). The antibody may be IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, IgD, or modified variants thereof. The constant region of the antibody heavy chain may be selected accordingly. The constant region of the light chain may be kappa or lambda structure. Furthermore, the antigen-binding protein may include all classes of modifications, such as IgG dimers, Fc mutants that no longer bind to Fc receptors, or Fc mutants that mediate C1q binding. The antigen-binding protein may also be a chimeric antibody as described in WO86 / 001533, which includes an antigen-binding region and a non-immunoglobulin region.

[0527] The choice of constant regions depends on the desired function. For example, IgG1 can have the ability to lyse cells by binding to complement, or mediate antibody-dependent cytotoxicity (ADCC).

[0528] In one aspect, the antigen-binding protein is an antibody or an antigen-binding fragment thereof, comprising one or more complementarity-determining regions (CDRs) as described in this invention, and / or one or two of the heavy or light chain variable domains as described in this invention. The antigen-binding protein is selected from the following: dAb (domain antibody), Fab (antigen-binding fragment), Fab′ (modified Fab fragment), F(ab′)2 (bivalent Fab fragment), Fv (variable region fragment), bispecific antibodies, trispecific antibodies, tetraspecific antibodies, microantibodies, and small antibodies.

[0529] In one aspect of the invention, the antigen-binding protein is a humanized or chimeric antibody; in a further aspect, the antibody is a humanized antibody. In one aspect, the antibody is a monoclonal antibody.

[0530] On the other hand, antigen-binding proteins bind to human antigens with high affinity, for example, when measured by Biacore or ForteBio, antigen-binding proteins bind to human antigens with an affinity of 20 nM or less, or an affinity of 15 nM or less, or an affinity of 5 nM or less, or an affinity of 1000 pM or less, or an affinity of 500 pM or less, or an affinity of 400 pM or less, or 300 pM or less, such as about 120 pM. In a further embodiment, antigen-binding proteins bind to human antigens when measured by Biacore between about 100 pM and about 500 pM, or between about 100 pM and about 400 pM, or between about 100 pM and about 300 pM. In one embodiment of the invention, antigen-binding proteins bind to antigens with an affinity of less than 150 pM.

[0531] In one such embodiment, this is measured using Biacore or ForteBio.

[0532] On the other hand, antigen-binding proteins / antibodies bind to human antigens in cells and in assays, where the IC50 of antigen-binding proteins... 50 The concentration is between about 1 nM and about 500 nM, or between about 1 nM and about 100 nM, or between about 1 nM and about 50 nM, or between about 1 nM and about 25 nM, or between about 5 nM and about 15 nM. In a further embodiment of the invention, the antigen-binding protein binds to and neutralizes the antigen in cells and in assays, wherein the IC50 of the antigen-binding protein is... 50 It is approximately 10 nM.

[0533] Antigen-binding proteins, preferably antibodies of the present invention, can be generated by transfecting host cells with an expression vector containing the coding sequence of the antigen-binding protein of the present invention. Expression vectors or recombinant plasmids are generated by efficiently binding these coding sequences of the antigen-binding protein to conventional regulatory sequences capable of controlling replication, expression, and / or secretion within the host cell. Regulatory sequences include promoter sequences, such as the CMV promoter, and signal sequences that can be derived from other known antibodies. Similarly, a second expression vector having DNA sequences encoding the light or heavy chain of a complementary antigen-binding protein can be generated. In some embodiments, the second expression vector is identical to the first expression vector except for the coding sequence and optional markers involved, in order to ensure, as far as possible, functional expression of each polypeptide chain. Alternatively, the coding sequences for the heavy and light chains of the antigen-binding protein can reside on a single vector.

[0534] Selected host cells are co-transfected with first and second vectors (or simply transfected with a single vector) using conventional techniques to create transfected host cells of the present invention containing recombinant or synthetic light and heavy chains. The transfected cells are then cultured using conventional techniques to produce the engineered antigen-binding protein of the present invention. The antigen-binding protein, comprising the binding of recombinant heavy and / or light chains, is screened from the culture by appropriate assays, such as ELISA or RIA. Similar conventional techniques can be used to construct other antigen-binding proteins.

[0535] The suitable vectors used for the cloning and subcloning steps in the methods and constructions of the compositions of the present invention can be selected by those skilled in the art. For example, conventional pUC series cloning vectors can be used. One such vector, pUC19, is available from suppliers such as Amersham Bioscience (Buckinghamshire, UK) or GenScript (Nanjing, China). Furthermore, any vector that can be easily replicated, has abundant cloning sites and selectable genes (e.g., antibiotic resistance), and is easy to manipulate can be used for cloning. Therefore, the choice of cloning vector is not a limiting factor in the present invention.

[0536] Expression vectors can also be characterized by genes suitable for amplifying heterologous DNA sequences, such as the mammalian dihydrofolate reductase gene (DHFR). Other vector sequences include poly A signal sequences, such as those derived from bovine growth hormone (BGH) and protein promoter sequences (betaglopro). The expression vectors useful herein can be synthesized using techniques well known to those skilled in the art.

[0537] The components of these vectors, such as replicons, selection genes, enhancers, promoters, signal sequences, etc., are available from commercial or natural sources or synthesized using known procedures, and are used to direct the expression and / or secretion of recombinant DNA products in selected hosts. Many other suitable expression vectors of various types known in the art for expression in mammals, bacteria, insects, yeast, and fungi may also be used for this purpose.

[0538] The present invention also includes cell lines transfected with recombinant plasmids containing the coding sequence of the antigen-binding protein of the present invention. Host cells used for cloning and other operations on these cloning vectors are also conventional. However, cells from various strains of *E. coli* can be used to replicate the cloning vectors of the present invention and for other steps in constructing the antigen-binding protein.

[0539] Suitable host cells or cell lines for expressing the antigen-binding protein of this invention include mammalian cells such as NSO, Sp2 / O, CHO (e.g., DG44), COS, HEK, fibroblasts (e.g., 3T3), and myeloma cells, for example, it can be expressed in CHO or myeloma cells. Human cells can be used, thereby allowing the molecule to be modified with human glycosylation patterns.

[0540] Alternatively, other eukaryotic cell lines can be used. The selection of suitable mammalian host cells and the methods for transformation, culture, amplification, screening, and product production and purification are known in the art. See, for example, Sambrook et al., (1989). Molecular Cloning: A Laboratory Manual, 2nd Edition. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

[0541] Bacterial cells can be shown to be suitable host cells for expressing recombinant Fabs or other embodiments of the invention (e.g., see Pluckthun, A., Immunol. Rev., 130:151-188 (1992)). However, since proteins expressed in bacterial cells tend to be in unfolded or improperly folded or non-glycosylated forms, any recombinant Fabs generated in bacterial cells must be screened to retain antigen-binding capacity. If a molecule expressed by a bacterial cell is generated in an properly folded form, the bacterial cell will be an ideal host, or in other embodiments, the molecule can be expressed in a bacterial host and then subsequently refolded. For example, various Escherichia coli strains used for expression are referred to as host cells in the field of biotechnology. The method can also employ various strains such as Bacillus subtilis, Streptomyces, and other bacilli.

[0542] When needed, yeast cell strains known to those skilled in the art can also be used as host cells, as well as insect cells, such as fruit flies and lepidopterans, and viral expression systems. See, for example, Miller et al., Genetic Engineering, 8: 277-298, Plenum Press (1986) and McGuire, S. et al., Trends Genet. (2004) 20, 384-391 and their cited references.

[0543] The general methods for constructing the vector, the transfection methods required to generate the host cells of the present invention, and the culture methods required to produce the antigen-binding protein of the present invention from such host cells can all be conventional techniques. Typically, the culture method of the present invention is a serum-free culture method, usually by culturing serum-free cells in a suspension. Similarly, once produced, the antigen-binding protein of the present invention can be purified from the cell culture contents according to standard procedures in the art, including ammonium precipitation, affinity column, column chromatography, gel electrophoresis, etc. These techniques are within the scope of the art and do not limit the invention. For example, methods for preparing modified antibodies are described in WO 99 / 058679 and WO 96 / 016990. Another method of expressing the antigen-binding protein can utilize expression in transgenic animals, as described in US Patent 4,873,316. ​​This relates to expression systems using animal casein promoters, whereby females can produce the desired recombinant protein in their milk when the transgene is incorporated into mammals.

[0544] In another embodiment of the invention, a method for producing the antibody of the invention is provided, the method comprising the steps of culturing host cells transformed or transfected with a vector encoding the light chain and / or heavy chain of the antibody of the invention and recovering the antibody thereby generated.

[0545] According to the present invention, a method for producing the antibody of the present invention, the antibody binding to and neutralizing the activity of human antigens, the method comprising the steps of: providing a first vector encoding an antibody heavy chain; providing a second vector encoding an antibody light chain; transforming mammalian host cells (e.g., CHO) with the first and second vectors; culturing the host cells of step (c) under conditions conducive to the secretion of the antibody from the host cells into the culture medium; and recovering the antibody secreted in step (d).

[0546] Once expressed using the desired method, the antibody's in vitro activity is then examined using appropriate assays. Currently, standard ELISA assays are used to assess the qualitative and quantitative binding of antibodies to antigens. In addition, other in vitro assays can be used to validate neutralization effects and assess antibody persistence in vivo prior to subsequent human clinical studies, although clearance mechanisms are typically employed.

[0547] The dosage and duration of treatment are related to the relative duration of the molecules of the present invention (antibodies and antibody-drug conjugates) in human circulation and can be adjusted by those skilled in the art based on the condition being treated and the patient's general health condition. It is anticipated that repeated administration (e.g., once weekly, once every two weeks, once every three weeks, or once every four weeks) may be necessary over a longer period (e.g., 4 to 6 months) to achieve maximum therapeutic effect.

[0548] In one embodiment of the invention, a host cell is provided that has been recombinantly transformed, transfected, or transduced, comprising at least one expression cassette, for example, the expression cassette comprising a polynucleotide encoding a heavy chain of the antigen-binding protein described herein, and further comprising a polynucleotide encoding a light chain of the antigen-binding protein described herein, or wherein two expression cassettes, one encoding the light chain and the other encoding the heavy chain, are provided. For example, in one embodiment, a first expression cassette comprises a polynucleotide encoding the heavy chain of the antigen-binding protein, the polynucleotide comprising a constant region or antigen-binding fragment thereof linked to the constant region described herein, and further comprises a second cassette comprising a polynucleotide encoding the light chain of the antigen-binding protein, the polynucleotide comprising a constant region or antigen-binding fragment thereof linked to the constant region described herein; for example, the first expression cassette comprises a polynucleotide encoding the heavy chain and the second expression cassette comprises a polynucleotide encoding the light chain.

[0549] In another embodiment of the invention, a stably transformed host cell is provided, the vector of which comprises one or more expression cassettes encoding an antibody heavy chain and a domain light chain, the expression cassette containing a constant region or antigen-binding fragment associated with the constant region described herein. For example, such a host cell may comprise a first vector encoding a light chain and a second vector encoding a heavy chain, such as a first vector encoding a heavy chain and a second vector encoding a light chain.

[0550] In another embodiment of the invention, a host cell as described herein is provided, wherein the cell is a eukaryotic cell, such as a mammalian cell. Examples of such cell lines include CHO or NSO.

[0551] In another embodiment of the invention, a method for producing an antibody comprising a constant region or an antigen-binding fragment thereof, which is attached to the constant region described herein, the method comprising the step of culturing host cells in a culture medium, such as a serum-free culture medium.

[0552] In another embodiment of the invention, a method of the invention described herein is provided, wherein the antibody is further purified to at least 95% or higher (e.g., 98% or higher) relative to the antibody containing a serum-free culture medium.

[0553] In yet another embodiment, a pharmaceutical composition comprising an antigen-binding protein and a pharmaceutically acceptable carrier is provided.

[0554] In another embodiment of the invention, a component kit comprising the inventive compositions described herein, along with instructions for use, is provided.

[0555] The therapeutic agents of the present invention can be administered via any suitable route of delivery to the host. The antigen-binding protein and pharmaceutical composition of the present invention are particularly suitable for parenteral administration, i.e., subcutaneous (sc), intrathecal, intraperitoneal, intramuscular (im), or intravenous (iv). In one such embodiment, the antigen-binding protein of the present invention is administered by intravenous or subcutaneous injection.

[0556] The therapeutic agents of the present invention can be prepared as pharmaceutical compositions containing an effective amount of the antigen-binding protein of the present invention as an active ingredient in a pharmaceutically acceptable carrier. In one embodiment, the prophylactic agent of the present invention contains an aqueous suspension or solution of the antigen-binding protein, in an injectable form. In one embodiment, the suspension or solution is buffered at physiological pH. In one embodiment, the composition for parenteral administration will comprise a solution or mixture thereof of the antigen-binding protein of the present invention dissolved in a pharmaceutically acceptable carrier. In one embodiment, the carrier is an aqueous carrier. Various aqueous carriers can be used, such as 0.9% physiological saline, 0.3% glycine, etc. These solutions can be sterile and generally free of particulate matter. These solutions can be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The composition may contain pharmaceutically acceptable adjuvants, such as pH adjusters and buffers, as required for near-physiological conditions. In such pharmaceutical formulations, the concentration of the antigen-binding protein of the present invention can vary considerably, i.e., from less than about 0.5% by weight, typically or at least about 1% to up to about 15% or 20%, and will be selected primarily based on the specific route of administration chosen, primarily based on liquid volume, viscosity, etc.

[0557] Therefore, the pharmaceutical composition of the present invention for intravenous infusion can be prepared containing about 250 ml of sterile Ringer's solution and about 1 to 30 mg, or 5 mg to about 25 mg, of the antigen-binding protein of the present invention per milliliter of Ringer's solution. Practical methods for preparing compositions for parenteral administration are well known or obvious to those skilled in the art and are described in more detail, for example, in Remington's Pharmaceutical Science, 15th edition, Mack Publishing Company, Easton, PA. For the preparation of the intravenously administered antigen-binding protein formulation of the present invention, see Parkins D. and Lasmar U. “The formulation of biopharmaceutical products”, Pharm. Sci. Tech. Today, 3 (2000) 129-137; Wang, W. “Instability, stabilization and formulation of liquid protein pharmaceuticals”, Int. J. Pharm 185 (1999) 129-188; Jorgensen, L. et al. “Recent trends in stabilizing peptides and proteins in pharmaceutical formulation - considerations in the choice of excipients”, Expert Opin Drug Deliv 6 (2009) 1219-1230; Akers, MJ. “Effects of types of sugar on stabilization of protein in the dried state”, J. Pharm Sci 91 (2002) 2283-2300; Imamura, K. et al., “Effects of types of sugar on stabilization of Protein in the dried state", J Pharm Sci 92 (2003) 266-274; Izutsu, Kkojima, S. "Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying", J.Pharm.Pharmacol, 54 (2002) 1033-1039; Johnson, R et al., "Mannitol-sucrose mixtures--versatile formulations for protein lyophilization", J.Pharm.Sci., 91 (2002) 914-922; Kerwin B. "Polysorbates20and 80used in the formulation of protein biotherapeutics: structure and degradation pathways" J.Pharm. Sci. 97 (2008) 2924-2935; Ha, E., et al., "Peroxideformation in polysorbate 80and protein stability", J.Pharm Sci, 91 (2002), 2252-2264, and He, F., et al., "Effect of sugar molecules on the viscosity of highconcentration monoclonal antibody solutions" Pharm Res. 28 (2011) 1552-1560; the entire contents of which are incorporated herein by reference.

[0558] In one embodiment, the antibody of the present invention is present in a unit dose form in a pharmaceutical formulation. An appropriate therapeutically effective dose is determined by those skilled in the art. A suitable dose can be calculated based on the patient's weight; for example, a suitable dose may be in the range of about 0.1 to about 200 mg / kg, about 1 to about 20 mg / kg, or about 10 to about 20 mg / kg. For example, about 1 to about 15 mg / kg, or about 5 to about 15 mg / kg. For effective treatment of, for example, multiple myeloma, SLE, or IPT, a suitable dose may be in the range of about 0.1 to about 2000 mg, such as about 0.1 to about 500 mg, about 500 mg, about 0.1 mg to about 150 mg, or about 0.1 to about 80 mg, or about 0.1 to about 60 mg, or about 0.1 to about 40 mg, or about 1 to about 100 mg, or about 1 to about 50 mg of the antigen-binding protein of the present invention, which can be administered parenterally, such as subcutaneously, intravenously, or intramuscularly. If necessary, the administration may be repeated at appropriate time intervals selected by a physician.

[0559] The antigen-binding proteins described herein can be lyophilized and reconstituted in a suitable carrier before use. This technique has been proven effective for conventional immunoglobulins and can be employed using known peroxidation and reconstitution techniques.

[0560] In another aspect of the invention, an antigen-binding protein for use in a medicament is provided as described herein.

[0561] In one aspect of the invention, an antigen-binding protein according to the invention is provided for treating rheumatoid arthritis, type 1 diabetes, multiple sclerosis, or psoriasis, wherein the method includes the step of administering to the patient a therapeutically effective amount of the antigen-binding protein as described herein.

[0562] In one embodiment of the invention, a method for treating human cancer is provided, comprising administering to the population an antigen-binding protein that specifically binds to antigens on tumor cells. In some cases, the antigen-binding protein is part of an immunoconjugate.

[0563] As used herein, the term "antibody-drug conjugate (ADC)" refers to a molecule containing a monoclonal antibody (mAb) linked to a cytotoxic agent (typically a small molecule drug with high systemic toxicity) via a chemical linker. The ADC of this invention is represented by the following formula:

[0564] D1-L1″-mAb (Ib，) ,

[0565] In this ADC, D1 and D2 are small molecule cytotoxins or functional small molecules, generally referred to as the payload; L1 and L2 are functional linkers with affinity ligands; and mAb is a monoclonal antibody. In some embodiments, the ADC may contain a small molecule cytotoxin that has been chemically modified to contain a linker with affinity ligands, or the linker containing affinity ligands may be part of a payload referred to as a traceless linker. Linkers are typically used to conjugate cytotoxins to antibodies or their antigen-binding fragments. After binding to a target antigen on the cell surface, the ADC is endocytosed and transported to the lysosome, where the cytotoxin is released via proteolysis of the linker that can cleave it (e.g., via cathepsin B found in lysosomes) or by proteolytic degradation of the antibody, if it is attached to the cytotoxin via an inclevable linker. The cytotoxin is then transported from the lysosome to the cytoplasm or nucleus, where it binds to the target according to its mechanism of action.

[0566] The antibody-drug conjugates described herein may include whole antibodies or antibody fragments. A complete antibody typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each heavy chain contains one N-terminal variable region (VH) and three C-terminal constant regions (CH1, CH2, and CH3), and each light chain contains one N-terminal variable region (VL) and one C-terminal constant region (CL). The variable regions of each pair of light and heavy chains form the antigen-binding site of the antibody. The VH and VL regions have the same general structure, each consisting of four framework regions whose sequences are relatively conserved. The framework regions are connected by three complementarity-determining regions (CDRs). These three CDRs, referred to as CDR1, CDR2, and CDR3, form the "hypervariate region" of the antibody, responsible for antigen binding.

[0567] An antibody-drug conjugate (ADC) may contain an antigen-binding fragment of an antibody. The terms “antibody fragment,” “antigen-binding fragment,” “functional fragment of an antibody,” and “antigen-binding moiety” are used interchangeably herein to refer to one or more fragments or portions of an antibody that retain the ability to bind specifically to an antigen. Antibody fragments may include, for example, one or more CDRs, variable regions (or portions thereof), constant regions (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL, and CH1 domains; (ii) an F(ab′)2 fragment, a bivalent fragment consisting of two Fab fragments linked by disulfide bonds in a hinge region; (iii) an Fv fragment consisting of the VL and VH domains of an antibody single arm; and (iv) a single-chain Fv (scFv), a monovalent molecule consisting of the two domains (i.e., VL and VH) of an Fv fragment linked by a synthetic linker, enabling the two domains to be synthesized into a single polypeptide chain (see, for example, Kabat EA, Wu...). TT., J Immunol. 1991, 147(5): 1709-19) and (v) dimers, which are dimers of polypeptide chains in which each polypeptide chain includes a VH linked to a VL by a peptide linker that is too short to pair between VH and VL on the same polypeptide chain, thereby driving pairing between complementary domains on different VH-VL polypeptide chains to produce a dimer molecule with two functional antigen-binding sites (see, for example, Hudson PJ, Kortt AA, J Immunol Methods. 1999, 231(1-2): 177-89; Holliger P, Winter G. Cancer Immunol Immunother. 1997, 45(3-4): 128-30).

[0568] A monoclonal antibody or its antigen-binding fragment against an antigen may contain any suitable binding affinity to that antigen or its epitope. The term "affinity" refers to the equilibrium constant for the reversible binding of two reagents, expressed as the dissociation constant (KD). The affinity of an antibody or its antigen-binding fragment for a target antigen or epitope can be measured using any method known in the art. For example, these methods include fluorescence-activated cell sorting (FACS), surface plasmon resonance (e.g., Biacore)... TM ProteOn TM Biolayer Interference (BLI, e.g., Octet) and KinExA exclusion method (e.g., KinExA) TM Separable microbeads (e.g., magnetic beads), antigen screening, and / or ELISA (see, e.g., JR Crowther, Methods MolBiol. 2000, 149: III-IV, 1-413). It is known in the art that the binding affinity of a particular antibody will depend on the method used to analyze that binding affinity.

[0569] The affinity of the binder for the ligand, such as the affinity of the antibody for the epitope, can range from about 1 picomolar (pM) to about 1 micromolar (μM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (μM)). In one embodiment, a monoclonal antibody or its antigen-binding fragment can bind to an antigen with a Kd less than or equal to 100 nanomolars (e.g., 100 nM, about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, about 20 nM, or about 10 nM, or a range defined by any two of the foregoing values).

[0570] In another embodiment, the monoclonal antibody may bind to an antigen at a concentration of Kd less than or equal to 10 nanomoles (e.g., about 9 nM, about 8 nM, about 7 nM, about 6 nM, about 5 nM, about 4 nM, about 3 nM, about 2 nM, about 1 nM, about 0.9 nM, about 0.8 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM, about 0.4 nM, about 0.3 nM, about 0.2 nM, about 0.1 nM, about 0.05 nM, about 0.02 nM, about 0.01 nM, about 0.001 nM, or a range defined by any two of the preceding values).

[0571] In another embodiment, the monoclonal antibody may bind to an antigen with a Kd less than or equal to 200 pM (e.g., about 190 pM, about 175 pM, about 150 pM, about 125 pM, about 110 pM, about 100 pM, about 90 pM, about 80 pM, about 70 pM, about 60 pM, about 50 pM, about 40 pM, about 30 pM, about 25 pM, about 20 pM, about 15 pM, about 10 pM, about 5 pM, about 1 pM, or a range defined by any two of the preceding values).

[0572] In one embodiment, the affinity of the antibody or its antigen-binding fragment, as measured by surface plasmon resonance (SPR), is about 90 nM, about 80 nM, about 70 nM, about 60 nM, about 50 nM, about 40 nM, about 30 nM, or a range defined by any two of the preceding values, for example, about 50 nM to about 70 nM, about 55 nM to about 65 nM, or about 58 nM to about 62 nM.

[0573] In one embodiment, the affinity of the antibody or its antigen-binding fragment for a membrane-bound antigen, as determined by FACS, is less than or equal to 10 nanomoles (e.g., about 9 nM, about 8 nM, about 7 nM, about 6 nM, about 5 nM, about 4 nM, about 3 nM, about 2 nM, about 1 nM, about 0.9 nM, about 0.8 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM, about 0.4 nM, about 0.3 nM, about 0.2 nM, about 0.1 nM, about 0.05 nM, about 0.02 nM, about 0.01 nM, about 0.001 nM, or a range defined by any two of the preceding values).

[0574] The antigen-binding portion or fragment of a monoclonal antibody can be of any size, as long as the portion binds to the antigen. In this regard, the antigen-binding portion or fragment of a monoclonal antibody against a particular antigen preferably contains about 5 to 35 amino acids (e.g., about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or a range defined by any two of the preceding values).

[0575] In one embodiment, the antibody-drug conjugate comprises a variable region of a monoclonal antibody. In this respect, the ADC may comprise a light chain variable region, a heavy chain variable region, or both of a light chain and heavy chain variable region of a monoclonal antibody.

[0576] Monoclonal antibodies or their antigen-binding fragments can be conjugated to cytotoxic agents using any suitable method known in the art, including site-specific or non-site-specific conjugation methods. Conventional antibody conjugation strategies typically rely on the random (i.e., non-specific) conjugation of the payload to the antibody and its antigen-binding fragment via lysine or cysteine ​​residues. Thus, in some respects, the antibody or its antigen-binding fragment is randomly conjugated to a cytotoxic agent, for example, by partially reducing the antibody or antibody fragment and then reacting it with a desired agent, with or without a linker moiety. For example, the antibody or its antigen-binding fragment can be reduced using dithiothreitol (DTT), TCEP, thiovinyl alcohol, or similar reducing agents. The cytotoxic agent (with or without a linker moiety) can then be added to the reduced antibody or antibody fragment in a molar excess in the presence of dimethyl sulfoxide (DMSO) or DMA. After conjugation, an excess of free cysteine ​​can be added to quench any unreacted reagent. In the presence of DMSO or DMA, cytotoxic agents can be added directly in molar excess to antibodies or antibody fragments to form conjugates, with or without linker moieties containing amino-reactive, phenol-reactive, or other reactive groups (e.g., NHS, PFP). The reaction mixture can then be purified by chromatography or by exchanging the buffer with a suitable buffer, such as phosphate-buffered saline (PBS), citrate buffer, or histidine buffer.

[0577] The terms "cytotoxic agent" and "cytotoxic agent" refer to any molecule that inhibits or prevents cellular function and / or causes cell destruction (cell death) and / or exerts an antiproliferative effect. The cytotoxic agent or cytotoxic agent of an ADC is also referred to in the art as the "payload" of the ADC. Many classes of cytotoxic agents known in the art have potential utility in ADC molecules and can be used in the ADCs described herein. These cytotoxic agents include, for example, antimicrotubule agents (e.g., microtubule lysin, aurestatin, and maytansine), DNA minor groove binding agents (e.g., pyrrolobenzodiazepine (PBD) or indololobenzodiazepine (IGN) and their dimers), RNA polymerase II inhibitors (e.g., amatoxins), DNA topoisomerase I inhibitors (e.g., camptothecin), and DNA alkylating agents (e.g., docalamycin, CC-1065, pyrrolobenzodiazepine dimers, or pseudodimers of indolinobenzodiazepine pseudodimers). Examples of specific cytotoxic agents that can be used in ADCs described herein include, but are not limited to: microtubule lysin, amatoxins, aurestatin, chachomycosis, camptothecin, donomycin, daunorubicin, docamycin, sea hare toxin, enediynes, lexitropsins, taxanes, puromycin, maytansines, vinca alkaloids, and pyrrolobenzodiazepines (PBD). More specifically, the cytotoxic agent can be, for example, microtubule lysin, aurestatin (AFP, MMAF, MMAE, AEB, AEB, E), paclitaxel, docetaxel, CC-1065 (docalamycin, DC1, DC4, CBI-dimer), camptothecin (SN-38, topotecan), morpholino-doxorubicin, rhizobactin, cyanolino-doxorubicin, dorastatin-10, echinomycin, cambrestatin, galic acid, maytansine (DM1, DM4, DM21), vincristine, methotrexate, fusiformin, or derivatives or analogs thereof. Cytotoxins suitable for ADCs are also described, for example, in PCT application: PCT / CN2021 / 128453.

[0578] Typically, chemotherapeutic agents or functional compounds can also be conjugated to the antibodies of this invention. The chemotherapeutic agents or functional compounds are selected from the following:

[0579] a) Alkylating agents, nitrogen mustard: chlorpheniramine, chlorpromazine, cyclophosphamide, dacarbazine, estradiol nitrogen mustard, ifosfamide, nitrogen mustard, dimethoxyamine hydrochloride, dioxane mustard oxide, amlodipine hydrochloride, mycophenolic acid, eugenol, guanobromide, neonitrogen mustard, benzyl mustard cholesterol, pine oxychloride, thiotetracycline, trefocillin, uracil; CC-1065 (including its adolaxine, carzeoline, pyrazoline and their synthetic analogs); docalamycin (including KW-2189 and CBI-TMI and their synthetic analogs); benzodiazepine dimers (including pyrrolobenzodiazepine (PBD) or tometacin), Dimers of indobenzobenzodiazepine, imidazobenzobenzothiazodiazepine, or oxazolidinonebenzobenzodiazepine; nitrosoureas (carmustine, lomustine, clostridium chloride, formustine, nimustine, lamustine); alkyl sulfonates (benzylsulfamethoxazole, styrosine, sulfamethoxazole, and pisufen); triazene (dacarbazine); platinum-containing compounds (carboplatin, cisplatin, oxaliplatin); aproidines, benzodihydropyranone, calcodone, methotrexate, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenetriamine, triethylphosphamide, triethylenethiophosphamide, and trimethylolpropionate;

[0580] b) Plant alkaloids: Vinca minor alkaloids (vincristine, vinblastine, vinorelbine, norvincristine); taxanes (paclitaxel, docetaxel and their analogues); maytansines (DM1, DM2, DM3, DM4, maytansine, salinomycin and their analogues); cryptophycin (especially cryptophycin 1 and cryptophycin 8); epothilone, soft coral alcohol, demoridone, bryophylloidin, sea haretoxin, olistatin, tubulysin, ephalostatin; pancratistatin; sarcodictyin; spongistatin;

[0581] c) DNA topoisomerase inhibitors, including etoposide (9-aminocamptothecin, camptothecin, cristatol, doramycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, norsoxamine, retinoid (retinol), teniposide, topotecan, 9-nitrocamptothecin (RFS 2000)); mitomycin (mitomycin C);

[0582] d) Antimetabolites, antifolate agents, DHFR inhibitors (methotrexate, tromethorphan, folate, pteroxate, aminopterin (4-aminobenzoic acid) or other folic acid analogs); IMP dehydrogenase inhibitors (mycophenolate mofetil, thiazolidinyl sulfadiazine, ribavirin, EICAR); ribonucleotide reductase inhibitors (hydroxyurea, deferoxamine); pyrimidine analogs, uracil analogs (ancitabine, azacitidine, 6-azouramidine, capecitabine (hexamethasone)). Rhoda, carmoflu, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, 5-fluorouracil, fluorouridine, ratitrexed (Tomudex); cytosine analogs (cytarabine, cytosine arabinoside, fludarabine); purine analogs (azathioprine, fludarabine, mercaptopurine, thiamine, thioguanine); folic acid supplements, florrin; nicotinamide phosphoribosyltransferase (NAMPT) inhibitors;

[0583] e) Hormone therapy agents, receptor antagonists, anti-estrogens (medroxyprogesterone acetate, raloxifene, tamoxifen), LHRH agonists (gostalin, leuprorelin acetate); anti-androgens (bicalutamide, flutamide, calusone, betahistelone propionate, epiandrogen, goserelin, leuprorelin, methemetidine, nilumid, testosterone, tralostertan and other androgen inhibitors); retinoids, vitamin D3 analogs (CB1093, EB1089, KH1060, cholecalciferol, ergocalciferol); photodynamic therapy agents (verteporfin, phthalocyanine, photosensitizer Pc4, demethoxy-rubigin A); cytokines (interferon-α, interferon-γ, tumor necrosis factor (TNF), TNF-containing human proteins);

[0584] f) Kinase inhibitors, BIBW 2992 (anti-EGFR / Erb2), imatinib, gefitinib, guaranatinib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, vemodega, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, ispinib;

[0585] g) Poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib, iniparib, taraparib, veliparib, CEP 9722 (Cephalon's), E7016 (Eisai's), BGB-290 (BeiGene) or 3-aminobenzamide.

[0586] h) Antibiotics, such as acetylenic antibiotics (galicarmycin, especially galicarmycin γ1, δ1, α1 and β1, dyinmycin, including dyinmycin A and deoxymimycin, esperamycin, katimycin, C-1027, madroopeptin, neocarcinoxine, and related chromogen acetylenic antibiotics), aclacinomysins, actinomycins, atrazomycin, diazoserine, bleomycin, carnomycin, kanamycin, erythromycin, carcinogens, chromogens, dachlormycin, rutin, etc. Erythromycin, desaural erythromycin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholine-doxorubicin, cyanomorpholine-doxorubicin, 2-pyrrolidone doxorubicin and desaural erythromycin, epirubicin, arubicin, idarubicin, macromycin, nitomycin, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramycin, rodolmycin, streptomycin, streptozotocin, tuberculin, ubenimex, fenestrated statin, zorubicin;

[0587] i) Polyketides (anthocyanins), especially bullatacin and bullatacinone; gemcitabine, cyclooxygenases (such as carfenomib), bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allolactin-7, Xegeva, Provenge, Yervoy, isoprenoidation inhibitors (such as lovastatin), dopaminergic neurotoxins (such as asteroides), actinomycins (such as actinomycin D, bleomycin), bleomycins (such as bleomycin A2, bleomycin B2, pepromycin), anthracycline antibiotics (such as daunorubicin). (e.g., mitoxam), amatoxins, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone, MDR inhibitors (e.g., verapamil), Ca2+ ATPase inhibitors (e.g., carotenoids), histone deacetylase inhibitors (vorinostat, romidesin, pabisostat, valproic acid, mocetinostat (MGCD0103), Belinostat, PCI-24781, entenotide, SB939, resminostat, givinostat, AR-42, CUDC-101, sulforaphane, trachomatis A); celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A; Anti-adrenergic drugs, aminoglutethimide, mitotane, tralostertan, glucuronolactone, aldehyde phosphoramide, aminolevulinic acid, acridine, arabinoside, bestrabucil, bisacodyl, edatraxate, defofamine, mecosine, diazinon, efornithine (DFMO), elfomithine, elifonitrile, etoglutarate, gallium nitrate, cytosine, hydroxyurea, ibandronate, lentinan, chlorhexidine Damage, Mitoguanidine, Mitoantrone, Moguardol, Diaminonitroacetyl, Pentostatin, Methamidomus, Pirarubicin, Podophyllotoxin, 2-Ethylhydrazine, Procarbazine; Piperazine dionepropane; Rhizomycin; Cizole; Spirocyclogermanium; Sciglioside; Triaminoquinone; 2,2′,2″-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, Verrucin A, Baculosporin A and anguidine), Polyurethane, siRNA, Antisense drugs and Nucleases;

[0588] (2) Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Azathioprine, Bromocriptine, Chloroquine, Cyclophosphamide, Corticosteroids (including Ancinonide, Betamethasone, Budesonide, Hydrocortisone, Flunisolone, Fluticasone Propionate, Flucolone Danazol, Dexamethasone, Triamcinolone Acetonide, Beclomethasone Dipropionate), DHEA, Etanercept, Hydroxychloroquine, Infliximab, Meloxicam, Methotrexate, Mycophenolate Mofetil, Prednisone, Sirolimus, Tacrolimus.

[0589] (3) Anti-infective drugs, including:

[0590] a) Aminoglycosides: Amikacin, Asmicin, Gentamicin (Netilmicin, Sisomicin, Isapamicin), Hygromycin B, Kanamycin (Amikacin, Abekaricin, Aminodeoxykanamycin, Dibekacin, Tobramycin), Neomycin (Framycetin, Paromomycin, Ribomycin), Netilmicin, Spectinomycin, Streptomycin, Tobramycin, Methylstilbestrol;

[0591] b) Amide alcohols: chloramphenicol, chloramphenicol, florfenicol, thiamphenicol;

[0592] c) Ansarmycin: Gerdemycin, except for atrazine;

[0593] d) Carbapenems: biapenem, doripenem, ertapenem, imipenem / cilastatin, meropenem, panipenem;

[0594] e) Cephalosporins: Carbazosporins (Loracarb), cefaclor, clobetasol propionate, cefadroxil, cefadroxil, cefotaxime, cefalothin or cephalosporin, cephalexin, cefotaxime, cefamandole, cefepime, hydroxyzine cephalosporins, fluoxetine cephalosporins, cefoxitin, azoline cephalosporins, cefadroxil, cefacarium, cefotaxime, cefdapoxetine, cefixime, cefoxitin, cefoxitin, cefoxitin, cefoxitin, cefotaxime, cefotiam, cefotaxime, cefotiam, cefotaxime, cefotiam, cefotaxime, cefotiam, cefotaxime Pyridine, cefotaxime, cefotaxime, cefodizine, cefonicid, cefoquinone, cefradazole, cefotaxime, thiamethoxam, cephalosporin, cefazolin, cefalexin, cefimidazole, cefpirome, cefpirome, cefpodoxime, cefrozil, cefquinolone, cefsulfuron, ceftazidime, cefterenol, cefbutane, cefotaxime, cefazolin, cefpyripril, ceftriaxone, cefuroxime, cefazolin, cephalosporins (cefoxitin, cefotetan, cefcyanazole), oxocephalosporins (fluorocephalosporins, latamoxporins);

[0595] f) Glycopeptides: Bleomycin, Vancomycin (Olivancin, Tervavancin), Teicoplanin (Dabavancin), Ramolanin;

[0596] g) Glycylcycline: such as tigecycline;

[0597] h) β-lactamase inhibitors: penicillane (sulbactam, tazobactam), oxapenicillane (clavulanic acid);

[0598] i) Lincosamides: Clindamycin, Lincosamide;

[0599] j) Lipopeptides: Daptomycin, A54145, calcium-dependent antibiotic (CDA);

[0600] k) Macrolides: Azithromycin, Clotrimazole, Clarithromycin, Dierythromycin, Erythromycin, Fluremycin, Josamycin, Ketolides (Telithromycin, Seserythromycin), Midecamycin, Micardromycin, Prunycin, Rifamycin (Isoniazid, Rifampin, Rifabutin, Rifapentine), Ropimycin, Roxithromycin, Spectinomycin, Spiramycin, Tacrolimus (FK506), Prunycin, Telithromycin;

[0601] l) Monocyclic amines: aztreonam, tegamum;

[0602] m) Oxazolidinones: Linezolid;

[0603] n) Penicillins: Amoxicillin, Ampicillin (Pipacillin, Hezlocillin, Bambucil, Ampicillin, Doxorubicin), Aldacillin, Alzlocillin, Benzylpenicillin, Benzathine penicillin, Benzathine penicillin, Phenoxymethylpenicillin, Cloncillin, Procaine penicillin (Meticillin), Meloxicillin, Methicillin, Nafcillin, Oxyxacillin, Acetylpenicillin, Penicillin, Fennecillin, Phenoxymethylpenicillin, Guaricillin, Ampicillin, Sulbenicillin, Temoxicillin, Ticarcillin;

[0604] o) Polypeptides: Bacitracin, Colistin, Polymyxin B;

[0605] p) Quinolones: Aratrofloxacin, Balofloxacin, Ciprofloxacin, Clindamycin, Daflufloxacin, Diflufloxacin, Enrofloxacin, Enrofloxacin, Garefloxacin, Gatifloxacin, Gemifloxacin, Gaptafloxacin, Canotravafloxacin, Levofloxacin, Lomefloxacin, Mebofloxacin, Moxifloxacin, Naflufloxacin, Norfloxacin, Obibixin, Ofloxacin, Pefloxacin, Travafloxacin, Gaptafloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Toxacin, Travafloxacin;

[0606] q) Streptocin: Punemycin, Quinupordine / Dalfopristin;

[0607] r) Sulfonamides: ampicillin, azosulfanilamide, sulfadiazine, sulfamethoxazole, sulfaimide, sulfapyridine, sulfaisoxazole, trimethoprim, sulfamethoxazole (compound sulfamethoxazole);

[0608] s) Steroid antibiotics: such as fusidic acid;

[0609] t) Tetracyclines: Doxycycline, Chlortetracycline, Clomicycline, Demeclocycline, Ramoxil, Methionine, Methacycline, Minocycline, Oxytetracycline, Panmeclocycline, Pyrrolidine Methyl Tetracycline, Tetracycline, Glycylcycline (such as Tigecycline);

[0610] u) Other types of antibiotics: anechoic acid, arsenamin, bacterial terpene inhibitors (bacitracin), DANAL / AR inhibitors (cycloserine), dictyostatin, spongiocarbamate, soft coral alcohol, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, NAM synthesis inhibitors (e.g., fosfomycin), nitrofurantoin, paclitaxel, prancisic acid, pyrazinamide, quinupristin / dalfopristin, rifampin, tazobactam-tinidazole, purpurinol;

[0611] (4) Antiviral drugs, including:

[0612] a) Invasion / fusion inhibitors: apavirol, maraviro, vicriviroc, gp41 (enfvirtide), PRO140, CD4 (elbalizumab);

[0613] b) Integrase inhibitors: Rettagvir, elvite-gravir, globoidnan A;

[0614] c) Maturation inhibitors: bevirimat, vivecon;

[0615] d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir;

[0616] e) Nucleosides and nucleotides: Abacavir, abciximab, adefovir, amoxivir, abciximab, brivudine, cidofovir, clavudine, dexamethasone, norinosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluracillin (5-FU), 3'-fluorosubstituted 2',3'-deoxynucleoside analogs, such as 3'-fluoro-2', 3'-dideoxythymidine (FLT) and 3'-fluoro-2'... 3'-Dideoxyguanosine (FLG), formivir, 9-guanine, idoxuridine, lamivudine (3TC), 1-nucleoside (e.g., β-1-thymidine and β-1-2′-deoxycytidine), penciclovir, racivir, ribavirin, ditidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluorouridine valacyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT);

[0617] f) Non-nucleoside analogues: Amantadine, Atepiridine, Capvirine, Diarylpyrimidine (Etravirine), Delavidine, Docosanol, Emivirine, Efaviren, Phosphoric acid, Imiquimod, Pegylated interferon, Loviramide, Lode adenosine, Meinthiazone, Nevirapine, NOV-205, Long-acting interferon α, Podophyllotoxin, Rifampin, Amantadine, Requimod (R-848), Amantadine acetate;

[0618] g) Protease inhibitors: Ampranavir, Atazanavir, Boceprevir, Darunavir, Fosanavir, Indinavir, Lopinavir, Nefinavir, Pleconazole, Ritonavir, Saquinavir, Telaprevir (VX-950), Tetranavir;

[0619] h) Other types of antiviral drugs: Antibody enzymes, Arbidol, Calanolide A, Ceragenin, Cyanavirin-N, Diarylpyrimidine, Epigallocatechin Gallate (EGCG), Phosphoric acid, Griffithin, Taribavirin (viramidine), Hydroxyurea, KP-1461, Mitefocin, Precocinol, Hybrid inhibitors, Ribavirin, Seliciclib.

[0620] A radioactive isotope, selectable from (radioactive nuclides). 3 H, 11 C, 14 C, 18 F, 32 p, 35 S, 64 Cu, 68 Ga 86 Y, 90Y, 99 Tc, 111 In, 123 I, 124 I, 125 I, 131 I, 133 Xe, 177 Lu, 203 pb, 212 pb, 211 At, 213 Bi, 224 Ra and 225 Ac. Metallic radionuclides 64 Cu, 68 Ga 86 Y, 90 Y, 99 Tc, 111 In, 133 Xe, 177 Lu, 203 pb, 212 pb, 211 At, 213 Bi, 224 Ra and 225 Ac is linked to the antibody via the chelating agent and linker L1 described in this patent application. The chelating agent is selected from DOTA, TETA, NOA, NETA, DTPA, HBED, and SHBED, and its structure is shown in the figure below:

[0621]

[0622]

[0623] (6) Chromogenic molecules can absorb a type of light, such as ultraviolet light, fluorescence, infrared light, near-infrared light, or visible light; chromogenic molecules include a class or a subclass of yellow pigments, red blood cells, iridochromes, white blood cells, melanin, and blue-green pigments, a class or a subclass of fluorescent molecules (fluorescent chemical substances that absorb light and then emit light), a class or a subclass of visual light transduction molecules, a class or a subclass of photon molecules, a class or a subclass of cold light molecules, and a class or a subclass of fluorescein compounds. Non-protein organic fluorophores, such as xanthracene derivatives (fluorescein, rhodamine, Oregon Green, eosin, and Texas Red); anthocyanin derivatives (anthocyanin, indocarbonyl cyanin, xanthanocyanin, thiocyanin, and thiocyanin); squaric acid derivatives and cyclically substituted squaric acids, including Seta, SeTau, and Squ, are dyes; naphthalene derivatives (dansyl and sodium fluorosilicate derivatives); coumarin derivatives; oxadiazole derivatives (pyridyloxazole, nitrobenzoxazole, and benzoxadiazole); anthracene derivatives (anthraquinones, including DRAQ5, DRAQ7, and CyTRAK Orange); pyrene derivatives (cascade blue, etc.); oxazine derivatives (Nile Red, Nile Blue, cresol violet, oxazine 170, etc.); acridine derivatives (flavin, acridine orange, acridine yellow, etc.); arylmethylamine derivatives (auramine, crystal violet, malachite green); and tetrapyrrole derivatives (porphyrin, phthalocyanine, bilirubin). Any analogues and derivatives of the following fluorescent compounds: CF dye (Biotium), DRAQ and CyTRAK probes (BioSt-tatus), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (ThermoScientific, Pierce), Atto and Tracy (SigmaAldrich), FluoProbes (Interchim), Abberio dye (Abberio), DY and MegaStokes dyes (Dyomics), Sulfo Cy dye (Cyandye), HiLyteFluor (AnaSpec), Seta, SeTau, and Squ dyes (Biosearch). Technologies), SureLight dyes (APC, RPE PerCP, Phycobilisomes) (Columbia Biosciences), APC, APCXL, RPE, BPE (Phyco-Biotech), Allophycocyanin (APC), Aminocarmine, APC-Cy7 conjugate, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Fluorin, FluorX, Hydroxycoumarin, Rhodamine B, Fluorescent Yellow, Me-methoxycoumarin, NBD, Pacific Blue, Pacific Orange, PE-Cy5 conjugate, PE-R-phycoerythrin (PE), Red 613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS, Seta-680-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-670, SeTau-380-NHS, SeTau-405-maleimide, SeTau-405-NHS, SeTau-425-NHS, SeTau-647-NHS, Texas Red, TRITC, TruRed, X-Rhodamine, 7-AAD (7-aminoactinomycin D, CG-selective), Acridine Orange, Chromomycin A3, CyTRAK Orange (Biostatus), DAPI, DRAQ5, DRAQ7, Ethidium bromide, Hoechst 33258, Hoechst 33342, LDS 751, Spectinomycin, Propidium iodide (PI), Sytox Blue, Sytox Green, Sytox Orange, Thiazole Orange, TO-PRO, Cyanide Monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1. Fluorescent compounds that can be linked to the linker of this invention for studying cells are selected from the following compounds or their derivatives: DCFH (2′,7′-dichlorodihydrofluorescein, oxidized form), DHR (dihydrorhodamine 123, oxidized form, photocatalytic oxidation), Fluo-3 (AM ester, pH > 6), and Fluo-4 (AM ester, pH 7).2), Indo-1 (AM ester, low / high calcium (Ca 2+)), SNARF (pH 6 / 9). Preferred fluorescent compounds are selected from: allophycocyanin (APC), AmCyan1 (tetramer, Clontech), AsRed2 (tetramer, Clontech), thistle green (monomer, MBL), Azurite, β-phycoerythrin (BPE), Cerulean, CyPet, DsRed monomer (Clontech), DsRed2 (“RFP”, Clontech), EBFP, EBFP2, ECFP, EGFP (weak dimer, Clontech), Emerald (weak dimer, Invitrogen), EYFP (weak dimer, Clontech), GFP (S65A mutant), GFP (S65C mutant), GFP (S65L mutant), GFP (Y66H mutant), GFP (Y66W mutant), GFPuv, HcRed1, J-Red, Katusha, Kusabira Orange (monomer, MBL), mCFP, mCherry (monomer, MBL), mKate (TagFP635, monomer, Evrogen), mKeima-Red (monomer, MBL), mKO, mOrange, mPlum, mRaspberry, mRFP1 (monomer, Tsien Labs), mStrawberry, mTFP1, mTurquoise2, P3 (phycobilisome complex), polydinoflavin-chlorophyll-protein complex (PerCP), R-phycoerythrin (RPE), T-Sapphire, TagCFP (dimer, Evrogen), TagGFP ( Dimer (Evrogen), TagRFP (dimer, Evrogen), TagYFP (dimer, Evrogen), tdTomato (tandem dimer), Topaz, TurboFP602 (dimer, Evrogen), TurboFPP635 (dimer, Evrogen), TurboFP (dimer, Evrogen), TurboRFP (dimer, Evrogen), TurboYFP (dimer, Evrogen), Venus, wild-type GFP, YPet, Zsgreen1 (tetramer, Clontech), ZsYellow1 (tetramer, Clontech).

[0624] (7) Cell-binding ligands or receptor agonists are selected from: folic acid derivatives, glutamate urea derivatives, somatostatin and its analogues (selected from octreotide (Sandostatin) and lanreotide (Somatuline)), aryl sulfonamides, pituitary adenylate cyclase activating peptide (PACAP) (PAC1), vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2), melanocyte-stimulating hormone (α-MSH), cholecystokinin (CCK) / gastrin receptor agonists, and bufotalin (selected from Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / gastrin-releasing peptide (GRP). Neurotensin receptor ligands (NTR1, NTR2, NTR3); Substance P (NK1 receptor) ligand; neuropeptide Y (Y1-Y6); homing peptides including RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimer and multimeric cyclic RGD peptides (selected from cRGDfV), TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor ligand) and F3 peptide; cell-penetrating peptides (CPPs);Peptide hormones are selected from luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, as well as gonadotropin-releasing hormone (GnRH) agonists. They act by targeting follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone production. Examples include buserreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gosoreline (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), and gosoreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzG). Histamine (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), Leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), Nafarelin, Dilorlin, Aberelin (Ac-D-2Na) l-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyri) dyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl )-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and degarelic (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-NH2); pattern recognition receptors (PRRs), selected from Toll receptor-like (TLR) ligands, C-type lectins and nodular receptor (NLR) ligands; calcitonin receptor agonists;Integrin receptors and their receptor subclasses (selected from αvβ1, αvβ3, αvβ5, αvβ6, α6β4, α7β1, α; L β2, α IIb β3) Agonists (selected from GRGDSPK, cyclo(RGDfV)(L1) and their derivatives [cyclic (-N(Me)R-GDfV), cyclic (R-Sar-DfV), cyclic (RG-N(Me)D-fV), cyclic (RGD-N(Me)fV), cyclic (RGDf-N(Me)V-)(Silengitide)]; Single-domain antibodies (VHH(camelid)) Ig derivatives; domain antibodies (dAb, derivatives of VH or VL domains); bispecific T-cell connectors (BiTE, bispecific dimers); dual-affinity retargeting (DART, bispecific dimers); tetravalent tandem antibodies (TandAb, a dimerized bispecific dimer); anticalin (a derivative of calcitonin); adnectins (FN3 10 (fibronectin)); ankylosing repeats (DARPins); avimers; EGF receptor and VEGF receptor agonists; a short antibody-like protein, siRNA, or DNA molecule for immunotherapy.

[0625] (8) A pharmaceutically acceptable salt, acid, derivative, hydrate or hydrated salt; or crystal structure; or an optical isomer, racemate, diastereomer or enantiomer of any of the drugs mentioned above.

[0626] In another embodiment, the drug may be a polyalkylene glycol, used to prolong the half-life of a cell-binding molecule antibody or antibody molecule when administered to mammals. Polyalkylene glycols include, but are not limited to, polyethylene glycol (PEG), polypropylene glycol, and copolymers of ethylene oxide and propylene oxide; preferably PEG, more preferably monofunctional activated hydroxy PEG (e.g., single-terminal activated hydroxy PEG, including hydroxyPEG-active ester, hydroxyPEG-monoaldehyde, hydroxyPEG-monoamine, hydroxyPEG-monohydrazide, hydroxyPEG-monohydrazide carbamate, hydroxyPEG-monoiodoacetamide, hydroxyPEG-monomaleimide, hydroxyPEG-o-dithiopyridine, hydroxyPEG-monooxime, hydroxyPEG-monophenyl carbonate, hydroxyPEG-monophenylglyoxal, hydroxyPEG-monothiazolidin-2-thione, hydroxyPEG-monothioester, hydroxyPEG-monothiol, hydroxyPEG-monotriazine, and hydroxyPEG-monovinyl sulfone).

[0627] In some embodiments, the polyalkylene glycol has a molecular weight of about 10 Da to about 200 kDa, preferably about 88 Da to about 40 kDa; it has two branches, each with a molecular weight of about 88 Da to about 40 kDa; more preferably, it has two branches, each with a molecular weight of about 88 Da to about 20 kDa. In one specific embodiment, the polyalkylene glycol is polyethylene glycol with a molecular weight of about 10 kDa, 20 kDa, or 40 kDa. In a specific embodiment, the PEG is PEG 10 kDa (linear or branched), PEG 20 kDa (linear or branched), or PEG 40 kDa (linear or branched). Numerous U.S. patents disclose the preparation of linear or branched “non-antigenic” PEG polymers and their derivatives or conjugates, see U.S. patents 5,428,128; 5,621,039; 5,622,986; 5,643,575; 5,728,560; 5,730,990; 5,738,846; 5811,076; 5824,701; 5840,900; 5880,131; 5900,402; 5902,588; 5919,455; 5951,974; 5965,119; 5965,566; 5969,040; 5981,709; 6011,042; 6042,822; 6113,906; 6127,355; 6132,713; 6177,087; and 6180095.

[0628] In another embodiment, D is more preferably an effective cytotoxic agent selected from tubulysin and its analogues, maytansin and its analogues, taxane and its analogues, CC-1065 and its analogues, daunorubicin or doxorubicin and their analogues, amatoxins and their analogues, benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tometacin, amiodarone, indolebenzodiazepine, imidazobenzothiazide or oxazolidinonebenzodiazepine dimers) and their analogues, galicillin and enediyne antibiotic analogues, actinomycin and its analogues, azoxystrobin and its analogues, bleomycin and its analogues, epirubicin, and other similar antibiotics. Idarubicin and its analogues, tamoxifen and its analogues, idarubicin and its analogues, dolastatin and its analogues, auristatin (including monomethyl auristatin (MMAE), MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP)) and its analogues, compressoritine, docamycin and its analogues, camptothecin, geldemycin and its analogues, methotrexate and its analogues, thiotepa and its analogues, vincristine and its analogues, vincristine and its analogues, semi-mitalin and its analogues, nazumamide and its analogues, spliceostatin, a pladienolide, microcrystalline protein and its analogues, radiosensitin and its analogues, alterobactin and its analogues, a microsclerodermin and its analogues, theonellamide and its analogues, esperamicin and its analogues, PNU-159682 and its analogues, protein kinase inhibitors, MEK inhibitors, KSP inhibitors, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, immunotoxins, cell receptor agonists, cell stimulating molecules or intracellular signaling molecules, one, two or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) and PIWI-interacting RNA (piRNA) and stereoisomers, isosteres, analogues, or derivatives thereof.

[0629] In some embodiments, tubulysin and its analogues are well known to those skilled in the art and can be isolated from natural sources or synthesized using known methods (e.g., Balasubramanian R., et al., J. Med. Chem., 2009, 52, 238-40; Wipf P., et al., Org. Lett., 2004, 6, 4057-60; Pando O., et al., J. Am. Chem. Soc., 2011, 133, 7692-5; Reddy, JA, et al., Mol. Pharmaceutics, 2009, 6, 1518-25; Raghavan B., et al., J. Med. Chem., 2008, 51, 1530-33; Patterson AW, 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; Friestad, GK, Org. Lett., 2004, 6, 3249-52; Peltier, HM, 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 GK, 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., Canadian Patent Application CA 2710693 (2011); Chai Y., et al., European Patent Application 2174947 (2010), WO 2010034724; Leamon, C., et al., WO2010033733, WO 2009002993; Ellman, J.=, et al., PCT WO2009134279; WO 2009012958, US Patent Application 20110263650, 20110021568; Matschiner G., et al., WO2009095447; Vlahov I., et al., WO2009055562, WO 2008112873; Low P., et al., WO2009026177; Richter W., WO200813856I; Kjems J., et al., WO 2008125116; Davis M., et al., WO2008076333; Diener J., et al., US Patent Application 20070041901, WO2006096754; Matschiner G., et al., WO2006056464; Vaghefi F., et al., WO2006033913; Doemling A., German patent applications DE102004030227, WO2004005327, WO2004005326, WO2004005269; Stanton M., et al., US patent application 20040249130; Hoefle G., et al., German patent applications DE10254439, DE10241152, DE10008089; Leung D., et al., WO2002077036; Reichenbach H., et al., German patent application DE19638870; Wolfgang R., US20120129779; Chen H., US patent application 20110027274. Preferred structures of tubulysin that can be coupled to cell-binding molecules using the process described in this application are described in patent PCT / IB2012 / 053554.

[0630] Tubulysin analogues have the structure of formula (IV):

[0631]

[0632] Or a pharmaceutically acceptable salt, hydrate or hydrated salt; or a polycrystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof;

[0633] in These are one or two independent connection sites connected to L1 and / or L2; when two Simultaneously connected to L1 and L2, R 1 and R 2 、or Z 2 and Z 3 Ideally, it should be a double-linked site;

[0634] Where R 1 R 2 R 3 and R 4 Independently, it is H, C1-C8 alkyl, C2-C8 heteroalkyl or heterocyclic, C3-C8 aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocyclic or alkylcarbonyl; or R 1 R 2 R 1 R 3 R 2 R 3 R 3 R 4 R 5 R 6 R 11 R 12 Or R 13 R 14 The resulting 3-7 membered carbon ring, cycloalkyl, heterocyclic, heterocycloalkyl, aryl, or heteroaryl ring system; when independently or simultaneously connected to L1 or L2, R 1 and R 2 Y can be left as a default value. 1 It is N or CH;

[0635] Where R 5 R 6 R 8 R 10 and R 11 Independently, it is H, or a C1-C4 alkyl or heteroalkyl group;

[0636] Where R 7 H and R independently 14 -R 14 C(=O)X 1 R 15 ; or -R 14 X 1 R 15 ;X 1 Is it O, S, SS, NH, CH2, or NR? 14 ;

[0637] Where R 9 Selected from H, OH, =O, -OR 14 -OC(=O)R 14 -OC(=O)NHR 14 -OC(=O)NR 14 R 15 OP(=O)(OR) 14 )2、-OC(=O)NR 14 R 15 OR 14OP(=O)(OR 15 )2; When R 9 When connecting L1 or L2, R 9 It is -O-, -OC(=O)NH- or -OC(=O)N(R) 14 )-;

[0638] Where R 11 H and R independently 14 -R 14 C(=O)R 15 -R 14 C(=O)X 2 R 15 , where X 2 It is -O-, -S-, -NH-, or -N(R) 14 )-;

[0639] Where R 12 It is -COOH, -COSH, -CONH2, CONHNH2, CONHNHR 15 -CONH(R) 15 -COOR 15 -R 15 COR 16 -R 15 COOR 16 -R 15 C(O)NH2、-R 15 C(O)NHR 16 -COSR 15 R 15 S(=O)2R 16 -R 15 P(=O)(OR 17 )2、-R 15 OP(=O)(OR 17 )2、-COOCH2OP(=O)(OR 17 2. -COX 2 SO2R 17 -COOR 15 X 2 R 16 Tetraazole, imidazole, or triazole, X 2 It is -O-, -S-, -NH-, -N(R) 15 )-、-OR 15 -、-SR 15 -, CH2 or -NHR 15 -;When R 12 When connecting L1 or L2, R 12 Is -C(O)O-, -C(O)NH-, -C(=O)NHS(O)2R15 -or-C(=O)N(R) 15 )-;

[0640] R 13 and R 14 Independently, they are C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl;

[0641] Z 2 and Z 3 Independently, H, O, S, NH, N(R) 15 ), NHNH, -OH, -SH, -NH2, NH, NHNH2, -NH(R 15 -OR 15 CO, -COX 2 -COX 2 R 16 R 17 F, Cl, Br, I, SR 16 NR 16 R 17 N = NR 16 N=R 16 NO2, SOR 16 R 17 SO2R 16 SO3R 16 OSO3R 16 PR 16 R 17 POR 16 R 17 PO2R 16 R 17 OP(O)(OR) 17 )2、OCH2OP(O)(OR 17 2. OC(O)R 17 OC(O)OP(O)(OR 17 2. PO(OR) 16 (OR) 17 ), OP(O)(OR 17 )OP(O)(OR 17 2. OC(O)NHR 17 ;-O-(C4-C 12 glycosides), -N-(C4-C 12 Glycosides; C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or esters, ethers or amides of 2-8 carbon atoms; or peptides containing 1-8 amino acids (NH(Aa)).1～8 Or CO(Aa) 1～8 (1-8 identical or different amino acids at the N-terminus or C-terminus), or having the formula (OCH2CH2) p Or (OCH2CH(CH3)) p The polyoxyethylene unit, wherein p is an integer from 0 to about 1000, or a combination of the aforementioned groups; X 2 It is O, S, SS, NH, CH2, OH, SH, NH2, CHR 15 or NR 15 ;

[0642] R 15 R 16 and R 17 Independently, it can be H, C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, alkylcarbonyl, or Na. + K + Cs + Li + Ca 2+ Mg + Zn 2+ N + (R 1 (R) 2 (R) 3 (R) 4 ), HN + (C2H5OH)3 salt;

[0643] Y 1 and Y 2 Independently, it is either N or CH; q is 0 or 1; when q = 0, Y 3 By default, Y 4 Y 5 Y 6 and Y 7 Independently, Y can be CH, N, NH, O, S, or N(R1). 2 Y 4 Y 5 Y 6 and Y 7 Formation of heteroaromatic rings of furan, pyrrolothiophene, thiazole, oxazole, and imidazole, pyrazole, triazole, tetraazole, and thiadiazole; when q = 1, Y + Y 4 Y 5 Y 6 and Y 7 When Y is independently CH or N, 2 Y 3 Y 4 Y5 Y 6 and Y 7 It forms aromatic rings of benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetraazine, and pentaazine;

[0644] The following are structural examples of Tubulysin analogues:

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657] Where R 20 It is H; C1-C8 straight-chain or branched alkyl or heteroalkyl, C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl straight-chain or branched; carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 (); or carboxylate, ester, ether, or amide of 1-8 carbons; or 1-8 amino acids; or having the formula (OCH2CH2) p Or (OCH2CH(CH3)) p The polyoxyethylene oxy group, where p is an integer from 0 to about 1000; or R 20 The default is that oxygen reacts with carbon to form a ketone, or a combination of the above.

[0658] Z 3 and Z 3Independently, H, OH, NH2, O, NH, COOH, COO, C(O), C(O), C(O)NH, C(O)NH2, R 18 OCH2OP(O)(OR) 18 2. OC(O)OP(O)(OR 18 2. OPO (OR) 18 2. NHPO (OR) 18 2. OP(O)(OR) 18 )OP(O)(OR 18 2. OC(O)R 18 OC(O)NHR 18 OSO2 (OR) 18 O-(C4-C) 12 - Glycosides), straight-chain or branched alkyl or heteroalkyl groups; C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl groups; C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl straight-chain or branched groups; carbonates (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 ); R 17 and R 18 Independently H, straight-chain or branched alkyl or heteroalkyl; C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight-chain or branched aryl, alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 );

[0659] R 19 It is H, OH, NH2, OSO2 (OR) 18 ), XCH2OP(O)(OR 18 2. XPO (OR) 18 2. XC(O)OP(O)(OR) 18 2. XC(O)R 18 XC(O)NHR 18 C1-C8 alkyl or carboxylic esters; C2-C8 alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl or alkylcarbonyl; or pharmaceutical salts;

[0660] X is O, S, NH, NHNH, or CH2;

[0661] R 7 The definition is the same as above; where the connection site In formula IV-01-IV-79, it is the same as that shown according to formula (IV).

[0662] In some such embodiments, descriptions of galicarmycin and its associated enediyne antibiotics can be found in: Nicolaou KC et al., Science 1992, 256, 1172-1178; Proc. Natl. Acad. Sci. USA. 1993, 90, 5881-8; U.S. Patents 4970198; 5053394; 5108912; 5264586; 5384412; 5606040; 5712374; 5714586; 5739116; 5770701; 5770710; 5773001; 5877296; 6015562; 6124310; 8153768. Exemplary enediynes include, but are not limited to, galicarmycin, esperamycin, uncialamicin, danendycin, and their derivatives. The preferred structural formula for galicariin is as follows:

[0663]

[0664] Or an elemental isotope substitute, or a pharmaceutically acceptable salt, hydrate or hydrated salt; or a polycrystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof;

[0665] in It is a site connected to L1 or L2;

[0666] In some such embodiments, geldromycin is a benzoquinone-ansarcomycin antibiotic that binds to Hsp90 (heat shock protein 90) and has been used as an antitumor drug. Exemplary geldromycins include, but are not limited to, 17-AAG (17-N-allylamino-17-demethoxygeldromycin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldromycin), having the following molecular formula:

[0667]

[0668] in It is a site connected to L1 or L2;

[0669] In some such embodiments, maytansin or its derivatives maytansin-like compounds inhibit cell proliferation by suppressing microtubule formation during mitosis, thereby inhibiting microtubule polymerization. See Remillard et al., Science 189:1002-1005 (1975).

[0670] Exemplary maytansines and maytansine-like compounds include, but are not limited to, mertansines (DM1, DM4), maytansine and its derivatives, and anesin. Maytansine is described in the following U.S. patents: 4256746; 4361650; 4307016; 4294757; 4294757; 4371533; 4424219; 4331598; 4450254; 4364866; 4313946; 4315929; 4362663; 4322348; 4 371533; 4424219; 5208020; 5416064; 5208020; 5416064; 6333410; 6441163; 6716821; 7276497; 7301019; 7303749; 7368565; 7411063; 7851432 and 8163888. The preferred structure of maytansine is as follows:

[0671]

[0672] in It is a site connected to L1 or L2;

[0673] Camptothecin (CPTs) and their derivatives are topoisomerase inhibitors that prevent DNA reconnection, thereby causing DNA damage and leading to apoptosis. They are described in: Shang, XF et al., Med Res Rev. 2018, 38(3): 775-828; Botella, P. and Rivero-Buceta, EJ 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), cilinotecan (DB-67, AR-67), coccitcon (BNP-1350), ethirinotecan, ethirinotecan, lurtotecan, gimatecan (ST1481), belotetcon (CKD-602), rubitecan and others (Shang, XF et al., Med Res Rev. 2018, 38(3): 775-828). To date, three CPT analogs, topotecan, irinotecan, and belotecone, have been approved for cancer chemotherapy (Palakurthi, S., Expert Opin Drug Deliv. 2015; 12(12): 1911-21; Shang, XF et al., MedRes Rev. 2018, 38(3): 775-828). SN-38 and Exatecan have also been used in clinical trials as payloads for ADC conjugates (Ocean, AJ, Cancer. 2017, 123(19): 3843-3854; Starodub, AN et al., Clin Cancer Res. 2015, 21(17): 3870-8; Cardillo, TM et al., Bioconjug Chem. 2015, 26(5): 919-31; Ogitani, Y. et al., Bioorg Med Chem. 2015, 26(5): 919-31). Lett. 2016, 26(20): 5069-5072; Takegawa, N. et al., Int J Cancer. 2017 Oct 15; 141(8): 1682-1689; US Patent 7591994; 7999083; 8080250; 8268317; US Patent Applications 20130090458, 20140099258, 20150297748, 20160279259).

[0674] The structure of camptothecin (CPT) is shown in the following formula:

[0675]

[0676] Or one or more elemental isotope substitutes, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or polycrystalline structures; or optical isomers, racemates, diastereomers, or enantiomers thereof; wherein R1, R2, and R4 are independently selected from H, F, Cl, Br, CN, NO2, C1-C8 alkyl; O-C1-C8 alkyl, NH-C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heterocyclic Alkylcycloalkyl, alkylcarbonyl, heteroaryl; C2-C8 ester, ether, amide, carbonate, urea, or carbamate; R3 is H, OH, NH2, C1-C8 alkyl, O-C1-C8 alkyl; NH-C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C2-C8 ester, ether, amide, carbonate, urea, or carbamate; or R1R2, R2R3, and R3R4 independently form a 5-7 membered carbon ring, heterocycle, heterocycloalkyl, aryl, or heteroaryl ring system. It is the site in the molecule that is connected to L1 or L2.

[0677] Camptothecin is preferably derived from the following structures:

[0678]

[0679]

[0680]

[0681] Or one or more elemental isotope-substituted compounds, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or polycrystalline structures of these compounds; or optical isomers, racemates, diastereomers, or enantiomers; wherein It is a site that connects to L1 or L2; P 1 R1 is independently H, F, Cl, Br, I, SO2R2, SO3H, CN, OH, NH2, COOH, C(O)NH2, OCH2OP(O)(OR) 18 2. OC(O)OP(O)(OR 18 2. OPO (OR) 18 2. NHPO (OR) 18 2. OC(O)R 18 OP(O)(OR) 18 )OP(O)(OR 18 2. OC(O)NHR 18 , OC(O)N(C2H4)2NCH3, OSO2(OR18 O-(C4-C) 12 - Glycoside), OC(O)N(C2H4)2CH2N(C2H4)2CH3, O-(C1-C8 branched or branched alkyl), O-(C1-C8 straight or branched alkyl)-OH, C1-C8 straight or branched alkyl or heteroalkyl, C2-C8 straight or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight or branched aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 R2 and R3 are independently H, C1-C8 straight-chain or branched alkyl groups, or C2-C8 straight-chain or branched heteroalkyl groups, ethers, amines, esters, or amides; furthermore, R2 and R3 can be linked together to form five- or six-membered rings or cycloalkyl groups, cycloalkylamines, or cycloalkanoamides, cyclohexylalkylamides; R 17 and R 18 Independently H, straight-chain or branched alkyl or heteroalkyl; C2-C8 straight-chain or branched alkenyl, ynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight-chain or branched aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 X is NH, O, S, S(O2), NHS(O2), NHS(O2)NH, NHP(O)(OH), N + (R2)(R3), NHC(O)NH, NHC(O), NHC(O)O, N(CH2CH2)2N, CON(CH2CH2)2N, CON(CH2CH2)2N + (R2)(R3), or CH2.

[0682] In some embodiments, compretastatins are natural phenols that have a destructive effect on blood vessels in tumors. Exemplary compretastatins and their derivatives include, but are not limited to, compretastatin A-4 (CA-4), CA4-βGals, CA-4PD, CA4-NPs, and ombrabulin, having the following molecular formula:

[0683]

[0684] Taxanes, including the cytotoxic natural product paclitaxel and its semi-synthetic derivative taxotere, and their analogues, are preferably used for conjugation, as can be found in the following literature: 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); US Patents 5475011; 5728849; 5811452; 6340701; 6372738; 6391913; 6436931; 6589979; 6596757; 6706708; 7008942; 7186851; 7217819; 7276499; 7598290; 7667054. The preferred structure of taxane is as follows:

[0685]

[0686] in It is a site attached to L1 or L2; Ar and Ar' are independently aryl or heteroaryl.

[0687] Anthracyclines are mammalian DNA topoisomerase II inhibitors that stabilize DNA-enzyme complexes at the sites where DNA strands are cleaved and covalently linked to antibodies. For decades, these anticancer agents have played a significant role in the treatment of various forms of solid tumors and acute leukemia. However, anthracyclines can lead to cardiovascular disease morbidity and death (Sagi, JC, et al., Pharmacogenomics. 2016, 17(9), 1075-87; McGowan, JV, et al., Cardiovasc Drugs Ther. 2017, 31(1), 63-75). Therefore, in order to enhance the specific activity of such molecules while reducing cardiotoxicity, researchers conjugate anthracycline drugs with cell-binding antibodies or antibody-plasmic molecules to improve 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). Exemplary anthracyclines include, but are not limited to, daunorubicin, doxorubicin (i.e., doxorubicin), epirubicin, idarubicin, vararubicin, and mitoxantrone. The structure of the anthracycline drugs in this application is preferably derived from the following formula:

[0688]

[0689]

[0690] in It is a site connected to L1 or L2.

[0691] Vinca minor alkaloids are a class of antimitotic and antimicrotubule alkaloids that act by inhibiting cancer cell division. Vinca minor alkaloids include vinblastine, vincristine, vindesine, epoxyvinblastine, vinorelbine, vinblastine, vincristine, vinblastine, vincristine, vinblastine, minoviceine, methoxyminoviceine, vinblastine alkaloid, deoxyvinblastine, vinblastine crystals, vinblastine, vinblastine oxalis, and vinblastine benzoin. Vinca minor alkaloids are preferred, with the following structural formula:

[0692]

[0693]

[0694] in It connects to either L1 or L2 sites;

[0695] Dolastatins and their peptide analogs and derivatives, such as auristatins, are potent antimitotic agents that have been shown to possess anticancer and antifungal activities. See, for example, U.S. Patent Application 5663149 and Pettit et al., Antimicrob. Agents Chemother. 42: 2961-2965, 1998. Exemplary aurelutin and aurelutin include, but are not limited to, aurelutin 10, aurelutin E (AE), aurelutin EB (AEB), aurelutin EFP (AEFP), MMAD (monomethyl aurelutin D or monomethyl aurelutin 10), MMAF (monomethyl aurelutin F or N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine), MMAE (monomethyl aurelutin E or N-methylvaline-valine-dolaisoleuine-dolaproine-norephedrine), 5-benzoylvaleric acid-AE ester (AEVB), aurelutin F-phenylenediamine (AFP), and other novel aurelutin compounds.Auristatin is described in the following literature: Int. J. Oncol. 15: 367-72 (1999); Molecular Cancer Therapeutics, vol. 3, No. 8, pp. 921-32 (2004); US Patent Applications 11134826, 20060074008, 2006022925; US Patents 4414205, 4753894, 4764368, 4816444, 4879278, 4943628, 4978744, 5122368, 5165923, 5169774, 52 86637, 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, 709 0843, 7091186, 7097840, 7098305, 7098308, 7498298, 7375078, 7462352, 7553816, 7659241, 7662387, 7745394, 7754681, 7829531, 7837980, 7837995, 7902338, 7964566, 7964567, 7851437, 7994135. The preferred structures of auristatin are (Ih-01), (Ih-02), (Ih-03), (Ih-04), (Ih-05), (Ih-06), (Ih-07), (Ih-08), (Ih-09), (Ih-10), and (Ih-11).

[0696]

[0697]

[0698]

[0699] Or an isotopic substitute of one or more elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; or a polycrystalline structure of these compounds; or an optical isomer, racemate, diastereomer, or enantiomer; wherein R 1 R 2 R 3 R 4 and R 5 Independently H; C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, heterocycloalkyl or acyloxyamine; or a peptide containing 1-8 amino acids, or having the formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to approximately 1000. Two Rs: R 1 R 2 R 2 R 3 R 1 R 3 Or R 3 R 4 It can form 3-8 membered rings of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl; Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O), and C(O)NR1; when not attached to a site When (independently connected with L1 and / or L2) the following are OH, NH2, NHNH2, NHR5, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1; R 12 Is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1-COOH, NH-(Aa) n COOH, O(CH2CH2O) p CH2CH2OH, O(CH2CH2O) p CH2CH2NH2, NH(CH2CH2O) p CH2CH2NH2, NR1R1', NHOH, NHOR1, O(CH2CH2O) p CH2CH2COOH, NH(CH2CH2O) pCH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O) p CH2CH2NH-SO3H, NH(CH2CH2O) p CH2CH2NHSO3H, R1-NHSO3H, NH-R1-NHSO3H, O(CH2CH2O) p CH2-CH2NHPO3H2, NH(CH2CH2O) p CH2CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O) p CH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, NH(CH2CH2NH) p CH2-CH2NH2, NH(CH2CH2S) p CH2CH2NH2, NH(CH2CH2NH) p CH2CH2OH, NH(CH2CH2S) p CH2-CH2OH, NH-R1-NH2, or NH(CH2CH2O) p CH2CH2NHPO3H2, where Aa consists of 1-8 identical or different amino acids; p is 1-5000; and the definitions of R1, R2, R3, R4, R5, R5', Z1, Z2, and n are the same as above.

[0700] Hemiasterlin and its analogues (e.g., HTI-286) bind to tubulin, disrupting normal microtubule dynamics and stoichiometrically depolymerizing tubulin. The preferred structure of maytansine is as follows:

[0701]

[0702] Where R 1 R 2 R 3 R 4 and R 5 Independently H; C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, heterocycloalkyl or acyloxyamine; or peptide containing 1-8 amino acids, or having the formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to approximately 5000; additionally, R 2 R 3 It can form alkyl, aryl, heteroaryl, heteroalkyl or alkylcycloalkyl groups with 3 to 8 rings.

[0703] Eribulin primarily binds to a few high-affinity sites at the positive ends of microtubules, exhibiting both cytotoxic and non-cytotoxic mechanisms of action. Its cytotoxicity is related to its antimitotic activity, inducing apoptosis in cancer cells after long-term and irreversible mitotic blockade (Kuznetsov, G. et al., Cancer Research. 2004, 64(16): 5760-6; ​​Towle, MJ, et al., Cancer Research. 2010, 71(2): 496-505). In addition to its cytotoxic and antimitotic mechanisms, preclinical studies in human breast cancer models have shown that eribulin also has complex effects on the biological functions of surviving cancer cells and residual tumors, which appear to be unrelated to its antimitotic effects. Eribulin has been approved by the FDA for the treatment of metastatic breast cancer in patients who have received at least two prior chemotherapy regimens for advanced disease, including anthracycline- and taxane-based chemotherapy, and for the treatment of liposarcoma (a type of soft tissue sarcoma) that is not surgically removable (unresectable) or has progressed (metastatic). Eribulin has been used as the payload of ADC conjugates (US20170252458). Its preferred structure is as follows: Eb01:

[0704]

[0705] These are sites that connect independently to L1 and / or L2;

[0706] Nicotinamide phosphoribosyltransferase inhibitors (NAMPTs) can be effective carriers for ADCs due to their unique mechanism of high activity (Sampath D et al., Pharmacol Ther 2015; 151, 16-31). NAMPTs regulate the levels of nicotinamide adenine dinucleotide (NAD) in cells, and NAD is an important redox cofactor for maintaining energy and compositional metabolism. NAD plays several important roles in metabolism. It acts as a coenzyme in redox reactions, as a donor of the ADP-ribose moiety in ADP-ribosylation, as a precursor of the cyclic ADP-ribose second messenger molecule, and as a substrate for bacterial DNA ligases. It is also used by a class of enzymes called Sirtuins to remove acetyl groups from proteins using NAD+. In addition to these metabolic functions, NAD+ can also spontaneously or through regulatory mechanisms release adenine nucleotides from cells (Smyth LM, et al., J. Biol. Chem. 2004, 279(47), 48893-903; Billington RA, et al., Mol Med. 2006, 12, 324-7), and therefore may have important extracellular functions (Billington RA, et al., Mol Med. 2006, 12, 324-7). In the presence of NAMPT inhibitors, NAD+ levels drop below metabolically required levels, resulting in an energy crisis and thus cell death. To date, NAMPT inhibitor candidates FK-866, CHS-828, and GMX-1777 have entered clinical trials, but each has encountered dose-limiting toxicities before achieving any objective response (Holen K., et al., InvestNew Drugs 2008, 26, 45-51; Hovstadius, P., et al., Clin Cancer Res 2002, 8, 2843-50; Pishvaian, MJ, et al., J Clin Oncol 2009, 27, 3581). Therefore, targeted delivery of NAMPT inhibitors using ADCs may avoid systemic toxicity, thereby achieving greater therapeutic endpoints. The preferred structures of NAMPT inhibitors are NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, and NP09:

[0707]

[0708] Or isotopic substitutes of one or more elements, or pharmaceutically acceptable salts, hydrates, or hydrated salts; or polycrystalline structures of these compounds; or optical isomers, racemates, diastereomers, or enantiomers; wherein Same as above; X5 is F, Cl, Br, I, OH, OR1, R1, OPO3H2, OSO3H, NHR1, OCOR1, NHCOR1.

[0709] Benzodiazepine dimers and their analogues (e.g., pyrrolobenzodiazepines) (PBD) or (tomaymycin) dimers, indolebenzodiazepines (IGN) dimers, imidazobenzothiazadiazole dimers, or oxazolidinylbenzodiazadiazole dimers contain one or more imine functional groups or equivalents that can bind to double-stranded DNA. PBD and IGN molecules are based on the natural product aprotinin and interact with DNA in a sequence-selective manner, preferentially selecting purine-guanine-purine sequences. Benzodiazepines preferred according to the present invention... Examples of dimers appear in the following documents: US Patents 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 ;7015215;6979684;6951853;6884799;6800622;6747144;6660856;6608192;6562806;6977254;6951853;6909006;6344451;5880122;4935362;4764616;4761412;4723007;4723003;4683230;4663453;4508647;4464467;4427587;4000304;US Application 20100203007, 20100316656, 20030195196. Antibody-benzodiazepine The structural examples of dimer conjugates are shown below: PB01-PB30:

[0710]

[0711]

[0712]

[0713]

[0714]

[0715] Or isotopic substitutions of one or more elements, or pharmaceutically acceptable salts, hydrates or hydrated salts; or polycrystalline structures of these compounds; or optical isomers, racemates, diastereomers or enantiomers; wherein X1, X2, Y1, Y2, R5', Z1, Z2 and n are defined as described above; preferably X1, X2, Y1 and Y2 are independently O, N, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O) and C(O)NR1;

[0716] R 1 R 2 R 3 R 1’ R 2’ and R 3’ Independently, it can be H, F, Cl, =O, =S, OH, SH, C1-C8 straight-chain or branched benzyl, aryl, alkenyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester (COOR5 or -OC(O)R5), ether (OR5), amide (CONR5), carbamate (OCONR5), amine (NHR5, NR5R5'), heterocycloalkyl, or acyloxyamine (-C(O)NHOH, -ONHC(O)R5), or a peptide containing 1-20 natural or non-natural amino acids, or a structure such as (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to 5000. Two R groups, such as 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’ It can independently form alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl rings of 3-8 members;

[0717] X3 and Y3 are independently N, NH, CH2 or CR5, and one of X3 and Y3 can be omitted;

[0718] Where R1 and R2 are C1-C8 straight-chain or branched alkyl, heteroalkyl; C3-C8 aryl, heteroaryl, alkylcycloalkyl, acyloxy, alkylaryl, alkylaryloxy, alkylarylamino, alkylarylthiol; or 1-6 identical or different amino acid / peptide sequences (Ar)r, r = 1-6.

[0719] Among them, R4, R5, R5', R6, R 12 and R 12 'Independently H, OH, NH2, NH(CH3), NHNH2, COOH, SH, OZ3, SZ3, F, Cl, or C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxyamine;

[0720] Z3 is H, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, or O-glycoside (glucosidase, galactoside, mannoside, glucuronide / glucuronic acid, alloside, fructoside, etc.), NH-glycoside, S-glycoside, or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, or NR1R2R3;

[0721] X6 is CH, N, P(O)NH, P(O)NR1, CHC(O)NH, C3-C8 aryl, heteroaryl, alkylcycloalkyl, acyloxy, alkylaryl, alkylaryloxy, alkylarylamino or Aa (amino acid, preferably Lys, Phe, Asp, Glu, Ser, Thr, His, Cys, Tyr, Trp, Gln, Asn, Arg);

[0722] X and X' can be CH2 or N independently. When the six-membered aromatic ring becomes a five-membered ring, X and / or X' can be O, S or NH.

[0723] Y 21 It is Ms(mesyl), Ts(tosyl) or Tf(trifyl), SO3H, P(O)(OH)2, CH2(O)P(O)(OH)2, glycoside;

[0724] R 31 It is H, C1-C8 alkyl or Ar, CF3; The definition is as described above.

[0725] CC-1065 analogues and docalamycin analogues are preferred for use in conjugates according to this patent application. Examples of CC-1065 analogues and docalamycin analogues and their synthesis are described in: Warpehoski, et al., J. Med. Chem. 31: 590-603 (1988); D. Boger, et al., J. Org. Chem. 66: 6654-61, 2001; U.S. Patents: 4169888, 4391904, 4671958, 4816567, 4912227, 4923990, 4952394, 4975278, 4978757, 4994578, 5037993, 5070092, 5084468, 5101038, 5117006, 51378 77, 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, 563342 5, 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, 6586618, 6593081, 6630579, 6756397, 6759509, 6762179,6884869, 6897034, 6946455, 7049316, 7087600, 7091186, 7115573, 7129261, 7214663, 7223837, 7304032, 7329507, 7329760, 7388026, 7655660, 7655661, 7906545, and 8012978. Structural examples of antibody-CC-1065 analog conjugates using the linkers of this invention are as follows: CC01, CC02, CC03, CC04, CC05, CC06, and CC07:

[0726]

[0727] When connected to the site When X1, X2, Y1, and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O), and C(O)NR1; or when not connected to a connection site When, it is OH, NH2, NHNH2, NHR1, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1; Z3 is H, PO(OM1)(OM2), SO3M1, CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)-, O(CH2CH2)2NC(O)-, R1, or glycoside; wherein the definitions of R1, R2, R3, M1, M2 and n are the same as those described above.

[0728] Amatoxins and their analogues are a subgroup containing at least ten toxic compounds, originally found in several poisonous mushroom genera, most notably *Amanita muscaria* and several other mushrooms, and are also preferred for use in the conjugates of this patent. These ten amatoxins, namely α-amatoxin, β-amatoxin, γ-amatoxin, ε-amatoxin, Amanullin, Amanullinic acid, Amaninamide, Amanin, and Proamanullin, are synthesized from a protein containing 35 amino acids. After being cleaved by prolyl oligopeptidase, they yield rigid bicyclic peptides containing 8 amino acids (Litten, W. 1975 Scientific American 232(3): 90-101; HE 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, PA, 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, OG 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, DR, Guo, H. & Price, DH 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 muscaria* mushrooms (Yocum, RR1978 Biochemistry 17(18): 3786-9; Zhang, P. et al., 2005, FEMS Microbiol. Lett. 252(2), 223-8), or by using basidiomycetes (Muraoka, S. and Shinozawa T., 2000 J. Biosci. Bioeng. 89(1): 73-6) or fermentation with *A. fissa* (Guo, XW)., et al., 2006 Wei Sheng Wu Xue Bao 46(3): 373-8), or prepared by culturing Galerina fasciculata or Galerina helvoliceps (WO / 1990 / 009799, JP11137291). However, the yields of these isolates and fermentations are very low (less than 5 mg / L of culture). Over the past thirty years, the preparation of several phallotoxins and their analogues has been reported (WESavige, 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; PA 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 ProteinRes.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 JPept Protein Res, 1990.35(3):263-70; Mullersman, JEand JFPreston, 3rd, Int JPept Protein Res, 1991.37(6): 544-51; Mullersman, JE, 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, MO, 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; JP May, DM Perrin, Chem. Eur. J. 2008, 14, 3404-9; JP May, et al., Chem. Eur. J. 2008, 14, 3410-17; Q. Wang, et al., Eur. J. Org. Chem. 2002, 834-9; May, JP and DM Perrin, Biopolymers, 2007, 88(5): 714-24; May, JP, 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), most of which are partially synthetic methods. Due to its potent efficacy and unique cytotoxic mechanism, phallotoxins have been used as effective payloads for conjugates (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, MT, Preston, JFScience 1981, 213, 1385-1388; Preston, JF, et al., Arch Biochem Biophys, 1981.209(1): 63-71; H. Faulstich, et al., Biochemistry 1981, 20, 6498-504; Barak, LS, et al., ProcNatl Acad Sci USA, 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., EkspMed Moffol, 1990.29(3):26-30; U.Bermbach, H.Faulstich, Biochemistry 1990, 29, 6839-45; Mullersman, JEand JFPreston, Int. J. Peptide Protein Res. 1991, 37, 544-51; Mullersman, JEand JFPreston, 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 studying amatoxins. Examples of amatoxins used in this application of the invention preferably have the following AmO1, AmO2 and AmO3 structures:

[0729] Or an isotopic substitute of one or more chemical elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; or a polycrystalline structure of these compounds; or an optical isomer, racemate, diastereomer, or enantiomer; wherein X1 and Y1 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, CHNH, CH2O, C(O)NHNHC(O), and C(O)NR1; R7, R8, and R9 are independently H, OH, OR1, NH2, NHR1, C1-C6 alkyl, or the default; Y2 is O, O2, NR1, NH, or the default; R 10 It is CH2, O, NH, NR1, NHC(O), NHC(O)NH, NHC(O)O, OC(O)O, C(O), OC(O), OC(O)(NR1), (NR1)C(O)(NR1), C(O)R1 or the default; R 11 Is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1-COOH, NH-(Aa)r COOH, O(CH2CH2O) p CH2CH2OH, O(CH2CH2O) p CH2CH2NH2, NH(CH2CH2O) p CH2CH2NH2, NR1R2, O(CH2CH2O) p CH2CH2-COOH, NH(CH2CH2O) p CH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O) p CH2CH2-NHSO3H, NH(CH2CH2O) p CH2CH2NHSO3H, R1-NHSO3H, NH-R1-NHSO3H, O(CH2CH2O) p -CH2CH2NHPO3H2, NH(CH2CH2O) p CH2CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O) p CH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, or NH(CH2CH2O) p CH2-CH2NHPO3H2, of which (Aa) r Refers to 1-8 amino acids; n and m1 are independently 1-20; p is 1-5000; the definitions of R1, R2 and Ar are the same throughout this patent application; The definition is as described above.

[0730] Spliceostatins and pladienolides are antitumor compounds that interact with the spliceosome SF3b, inhibiting splicing. Examples of spliceostatins include, but are not limited to, spliceostatin A, FR901464, and (2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazyl-2-oxoethyl)-4-hydroxy-1,6-dioxapyridin[2,5]oct-5-yl]-3-pentamethyl-2,4-dien-1-yl-1}-2,5-dimethyltetrahydro-2H-pyrano-3-yl]amino}-5-oxy-3-en-2-yl acetate, whose parent structure is as follows:

[0731]

[0732] Examples of Pladienolide include, but are not limited to, Pladienolide B, Pladienolide D, and E7107.

[0733] Protein kinase inhibitors can suppress the activity of kinases phosphorylated on serine, threonine, or tyrosine residues on catalytic antibodies, thereby modulating protein function. Protein kinase inhibitors can be used to treat cancers caused by overactive protein kinases (including mutated or overexpressed kinases) or to modulate cellular function to overcome other disease drivers. Preferred protein kinase inhibitors include adavasertib, afatinib, axitinib, baffitinib, bosutinib, tamexinib, crizotinib, carbopotinib, dasatinib, entrectinib, erdafiltinib, erlotinib, fantatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, mobitinib, nilotinib, pazopanib, panatinib, ponatinib, rebastinib, regorafenib, ruxotinib, sorafenib, sunitinib, SU6656, tofatinib, vandetinib, vemurafenib, entrectinib, palbociclib, ribociclib, abecil, dacomitinib, neratinib, (CO-1686), osimertinib, AZD3759, and nazatinib (EGF816), possessing the structures shown below, PK01-PK40:

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740] Z5 and Z5' are independently selected from O, NH, NHNH, NR5, 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(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1.

[0741] MEK inhibitors inhibit mitogen-activated protein kinases MEK1 and / or MEK2, which are overactive in certain cancers. MEK inhibitors are particularly indicated for the treatment of BRAF-mutant melanoma and KRAS / BRAF-mutant colorectal cancer, breast cancer, and non-small cell lung cancer (NSCLC). MEK inhibitors are selected from PD0325901, cerutinib (AZD6244), cobimetinib (XL518), refatinib, trametinib (GSK1120212), pimasertib, bimetinib (MEK162), AZD8330, RO4987655, RO5126766, WX-554, E6201, GDC-0623, PD-325901, and TAK-733. Preferred MEK inhibitors are trametinib (GSK1120212), cometinib (XL518), binitinib (MEK162), and celutinib, with the following structures:

[0742]

[0743]

[0744] Z5 is selected from O, NH, NHNH, NR5, 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(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1.

[0745] The protease inhibitors used as the payload of the conjugate are preferably selected from: carfilzomib, clindamycin, retamoline, and indibulin, with the following structures:

[0746]

[0747] Immunotoxins are large molecule drugs, typically cytotoxic proteins derived from bacteria or plants, such as diphtheria toxin (DT), cholera toxin (CT), trichosanthin (TCS), amylase, Pseudomonas exotoxin A (ETA), erythropoietin, diphtheria toxin, AB toxin, and type III exotoxin. They can also be highly toxic bacterial pore-forming protoxins that require proteolytic hydrolysis for activation. An example of such protoxins is topalysin and its genetically modified form. Topalysin is a modified recombinant protein engineered to be selectively activated by an enzyme in the prostate, thereby causing local cell death and tissue destruction without damaging adjacent tissues and nerves. The immunotoxins of this invention are preferably bound to amino acids having free amino, thiol, or carboxylic acid groups by the methods described herein; and more preferably to N-terminal amino acids.

[0748] In addition, cell receptor agonists, cell stimulating molecules, or intracellular signaling molecules can also be conjugated as chemotherapeutic / functional compounds using the method of this invention.

[0749] Cell-binding ligands or receptor agonists are selected from: folic acid derivatives, glutamate urea derivatives, somatostatin and its analogues (selected from octreotide (Sandostatin) and lanreotide (Somatuline)), aryl sulfonamides, pituitary adenylate cyclase activating peptide (PACAP) (PAC1), vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2), melanocyte-stimulating hormone (α-MSH), cholecystokinin (CCK) / gastrin receptor agonists, and bufotalin (selected from Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / gastrin-releasing peptide (GRP). Neurotensin receptor ligands (NTR1, NTR2, NTR3); Substance P (NK1 receptor) ligand; neuropeptide Y (Y1-Y6); homing peptides including RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimer and multimeric cyclic RGD peptides (selected from cRGDfV), TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor ligand) and F3 peptide; cell-penetrating peptides (CPPs);Peptide hormones are selected from luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, as well as gonadotropin-releasing hormone (GnRH) agonists. They act by targeting follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone production. Examples include buserreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gosoreline (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), and gosoreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzG). Histamine (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), Leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), Nafarelin, Dilorlin, Aberelin (Ac-D-2Na) l-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyri) dyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl )-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and degarelic (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-NH2); pattern recognition receptors (PRRs), selected from Toll receptor-like (TLR) ligands, C-type lectins and nodular receptor (NLR) ligands; calcitonin receptor agonists;Integrin receptors and their receptor subclasses (selected from αvβ1, αvβ3, avβ5, αvβ6, α6β4, α7β1, α; L β2, α IIb β3) agonists (selected from GRGDSPK, cyclo(RGDfV)(L1) and its derivatives [cyclic (-N(Me)R-GDfV), cyclic (R-Sar-DfV), cyclic (RG-N(Me)D-fV), cyclic (RGD-N(Me)fV), cyclic (RGDf-N(Me)V-)(Silengitide)]; Anticalin (a derivative of lipid transport protein); Adnectins (10 FN3 (fibronectin)); designed ankylosing repeats (DARPins); Avimers; EGF receptor, or VEGF receptor agonists;

[0750] Cell-binding molecules / ligands or cell receptor agonists are selected from LB01 (folic acid), LB02 (PMSA ligand), LB03 (PMSA ligand), LB04 (PMSA ligand), LB05 (somatostatin), LB06 (somatostatin), LB07 (octreotide, somatostatin analog), LB08 (lanreotide, somatostatin analog), LB09 (Sanvar, somatostatin analog), LB10 (CAIX ligand), LB11 (CAIX ligand), LB12 (gastrin-releasing peptide receptor (GRPr), MBA), LB13 (luteinizing hormone-releasing hormone receptor (GRPr)). LB14 (LH-RH and GnRH ligands), LB15 (GnRH antagonist, Ab is Iix), LB16 (cobalamin, vitamin B12 analog), LB17 (cobalamin, vitamin B12 analog), LB18 (for αvβ3 integrin receptor, cyclic RGD pentapeptide), LB19 (VEGF receptor isodivalent peptide ligand), LB20 (neuromycin B), LB21 (frog dermalin, acting on G protein-coupled receptors), LB22 (TLR2, acting on Toll-like receptors), LB23 (acting on androgen receptors). ), LB24 (silengiptide or cyclic (-RGDfV-)αv integrin receptor), LB23 (flucortisone), LB25 (rifabutin analog), LB26 (rifabutin analog), LB27 (rifabutin analog), LB28 (fludrocortisone), LB29 (dexamethasone), LB30 (fluticasone propionate), LB31 (beclomethasone propionate), LB32 (triamcinolone acetate), LB33 (prednisolone), LB34 (prednisolone), LB35 (methylprednisolone), LB36 (betamethasone), LB37 (irinotecan analog), LB38 (crizotinib analog), LB3 The structures of LB40 (bortezomib analog), LB41 (carfilzomib analog), LB42 (leuprorelin analog), LB43 (triptorelin analog), LB44 (clindamycin), LB45 (liraglutide analog), LB46 (vincristine analog), LB47 (retapalline analog), LB48 (timpani analog), LB49 (vincristine analog), LB50 (lixisenatide analog), LB51 (osidinib analog), LB52 (nucleoside analog), LB53 (erlotinib analog), and LB54 (lapatinib analog) are shown below:

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759] Where X4, Y1 are independently O, NH, NHNH, NR1, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, C(O)NHNHC(O) and C(O)NR1 and R1 are C1-C8 alkyl groups.

[0760] In another embodiment, one, two, or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA), and PIWI-interacting RNA (piRNA) are coupled as chemotherapeutic / functional compounds via the method of the present invention:

[0761]

[0762] in This is the site where the branch connector of this patent is connected; It is single-stranded or double-stranded DNA, RNA, mRNA, siRNA, miRNA, or piRNA; X1 and Y are independently O, NH, NHNH, NR1, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, C(O)NHNHC(O) and C(O)NR1.

[0763] In another embodiment, the connectors L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 may be the same or different, and are independently selected from O, NH, S, SS, NHNH, N(R3), N(R3)N(R 3’C1-C8 alkyl groups; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl groups; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; C2-C8 (2-8 carbon atoms) esters, ethers, or amides; 1-8 natural or non-natural amino acids as defined; structural formula (OCH2CH2) p (OCH2CH(CH3)) p (OCH2CH2) p OR3、(OCH2CH(CH3)) p OR3, NH(CH2CH2O) p R3, NH(CH2CH(CH3)O) p R3, N[(CH2CH2-O)] p R3][(CH2CH2O) p R3']、(OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p The polyethylene glycol unit of COOR3, wherein p and p' are independently selected from integers from 0 to about 1000, or combinations thereof, wherein R3 and R3' are independently H, C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl;

[0764] L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 may independently contain self-destructive or non-self-destructive components, peptide units, hydrazone bonds, disulfides, esters, oximes, amides, or thioether bonds. Self-destructive units include, but are not limited to, aromatic compounds with electronic structures similar to p-aminobenzylcarbamoyl (PAB), such as derivatives of 2-aminoimidazolium-5-methanol, heterocyclic PAB analogs, β-glucuronide, and ortho- or p-aminobenzyl acetals.

[0765] Preferred self-destructive linker components have one of the following structures:

[0766]

[0767] Where (*) represents additional spacers or breakable linker units, or linkers for cytotoxic agents and / or fine antibodies; X 1 Y 1 Z 2 and Z 3 Independently NH, O, or S; Z 1 Independently, it is H, NH, O, or S; v is 0 or 1; U 1 Independently, it can be H, OH, C1-C6 alkyl, or (OCH2CH2).n F, Cl, Br, I, OR5, SR5, NR5R5', N=NR5, N=R5, NR5R5', NO2, SOR5R5', SO2R5, SO3R5, OSO3R5, PR5R5', POR5R5', PO2R5R5', OPO(OR5)(OR5'), or OCH2PO(OR5(OR5') wherein R5 and R5' are as defined above; preferably R5 and R5' are independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, alkynyl or heteroalkyl, C3-C8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocyclic alkyl, heteroaryl, alkyl carbonyl or glycoside; or pharmaceutical cationic salts.

[0768] Non-self-destructive connective components have one of the following structures:

[0769] *(CH2CH20) r ＊ ;

[0770]

[0771] Where (*) represents another spacer R1 or a breakable linker unit, or a junction of a cytotoxic molecule and / or a cell-binding molecule; X 1 Y 1 U 1 R5 and R5' are defined as above; r is 0-100; m and n are independently 0-6.

[0772] More preferably, L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 may be independently composed of one or more of the following linker components: 6-maleimide hexanoyl (“MC”), maleimide propionyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe” or “af”), p-aminobenzyloxycarbonyl (“PAB”), 4-thiopentanoyl (“SPP”), 4-(N-maleimidemethyl)cyclohexane-1-acyl (“MCC”), (4-acetyl)aminobenzoyl (“SIAB”), 4-thiobutyryl (SPDB), 4-thio-2-hydroxysulfonyl-butyryl (2-Sulfo-SPDB), or a natural or non-natural peptide containing 1 to 8 natural or non-natural amino acid units. Lysine, glutamic acid, aspartic acid, cysteine, or tyrosine may contain the formula (OCH2CH2). p OR3, (OCH2CH(CH3)) p OR3, NH(CH2CH2O) pR3, C(O)(CH2CH2O) p R3, C(O)(CH2CH2OCH2CH) p R3,NH(CH2CH(CH3)O) p R3C(O)(CH2OCH2CH) p R3,N[(CH2CH2O) p R3][(CH2CH2O) p’ R 3’ ],(OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p COOR3, NH(CH2CH2O) p CH2CH2R3, wherein p and p' are independently integers selected from 0 to about 100 or combinations thereof; wherein R3 and R3' are independently H, OH, NH2, N(CH2)2, N(C2H5)2, N(C3H7), C(=O)H, C(=O)CH3, C1-C8 alkyl, NH (C4-C7 glycoside) or NH (C 4～77 2 glycosides; or combinations thereof;

[0773] More preferably, L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 are independently breakable linkers. The term "breakable" means that the linker contains at least one bond that can be broken under physiological conditions, such as pH, acid, base, oxidation, metabolism, biochemistry, or enzymatic instability. It should be understood that bond breaking is not necessarily a biological or metabolic process, but may be a standard chemical reaction, such as hydrolysis or substitution. Examples of such physiological conditions include endosomes with a pH lower than the intracellular pH, and / or endosomes capable of disulfide exchange reactions with intracellular sulfhydryl groups, and the presence of millimolecular concentrations of glutathione in malignant cells.

[0774] Examples of breakable connectors (L, L1, or L2) include, but are not limited to:

[0775] -(CR5R6) m (Aa)r(CR7R8) n (OCH2CH2) t -、-(CR5R6) m (CR7R8) n (Aa) r (OCH2CH2) t -、-(Aa) r -(CR5R6) m (CR7R8) n (OCH2CH2) t -、-(CR5R6)m (CR7R8) n (OCH2CH2) r (Aa) t -、-(CR5R6) m -(CR7=CR8)(CR9R 10 ) n (Aa) t (OCH2CH2) r -、-(CR5R6) m (NR 11 CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (Aa) t (NR 11 CO)(CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (OCO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (CO)(Aa) t -(CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (NR 11 CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m -(OCO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n(OCH2CH2) r -(CR5R6) m (CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m -phenyl-CO(Aa) t (CR7R8) n -、-(CR5R6) m -furan-CO(Aa) t (CR7R8) n -、-(CR5R6) m -Oxazole-CO(Aa)1(CR7R8) n -、-(CR5R6) m Oxazole-CO-(Aa) t (CCR7R8) n -、-(CR5R6) t -Thiophene-CO(CR7R8) n -、-(CR5R6) t -imidazolium-CO-(CR7R8) n -、-(CR5R6) t -morpholine-CO(Aa) t -(CR7R8) n -、-(CR5R6) t Piperazine-CO(Aa) t (CR7R8) n -、-(CR5R6) t -N-methylpiperazine-CO(Aa) t -(CR7R8) n -、-(CR5R) m -(Aa) t Phenyl-,-(CR5R6) m -(Aa) t Furan-, -(CR5R6) m -Oxazole (Aa) t -、-(CR5R6) m -Oxazole (Aa) t -、-(CR5R6) m -thiophene-(Aa) t -、-(CR5R6) m -Imidazole (Aa) t -、-(CR5R6) m -morpholine-(Aa) t -、-(CR5R6) m-Piperazine-(Aa) t -、-(CR5R6) m -N-Methylpiperazine-(Aa) t -、-K(CR5R6) m (Aa)r(CR7R8) n (OCH2CH2) t -、-K(CR5R6) m (CR7R8) n -(Aa) r (OCH2CH2) t -、-K(Aa) r (CR5R6) m (CR7R8) n (OCH2CH2) t -、-K(CR5R6) m (CR7R8) n -(OCH2CH2) r (Aa) t -、-K(CR5R6) m (CR7=CR8)(CR9R 10 ) n (Aa) t (OCH2CH2) r -、-K(CR5R6) m -(NR 11 CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (Aa)<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​n (OCH2CH2) r -、-K(CR5R6) m (NR 11 CO)-(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m -(OCO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-K(CR5R6) m -phenyl-CO(Aa) t (CR7R8) n -、-K-(CR5R6) m -furan-CO(Aa) t -(CR7R8) n -、-K(CR5R6) m -Oxazole-CO(Aa) t (CR7R8) n -、-K(CR5R6) m -Oxazole-CO(Aa) t -(CR7R8) n -、-K(CR5R6) t -Thiophene-CO(CR7R8) n -、-K(CR5R6) t Imidazole-CO-(CR7R8) n -、-K(CR5R6) t Morpholine-CO(Aa) t (CR7R8) n -、-K(CR5R6) t Piperazine-CO(Aa) t -(CR7R8) n -、-K(CR5R6) t -N-methylpiperazine CO(Aa)t (CR7R8) n -、-K(CR5R) m (Aa) t Phenyl, -K-(CR5R6) m -(Aa) t Furan-,-K(CR5R6) m -Oxazole (Aa) t -、-K(CR5R6) m -Oxazole (Aa) t -、-K(CR5R6) m -thiophene-(Aa) t -、-K(CR5R6) m -Imidazole (Aa) t -、-K(CR5R6) m -morpholine (Aa) t -、-K(CR5R6) m -piperazine-(Aa) t G, -K(CR5R6) m N-methylpiperazine (Aa) t -; where m, Aa, m, n, R3, R4, and R5 are defined as described above; t and r are independently 0-100; R6, R7, and R8 are independently selected from H; halides; C1-C8 alkyl, aryl, alkenyl, alkynyl, ether, ester, amine, or amide, optionally substituted with one or more halides, CN, NR1R2, CF3, OR1, Aryl, heterocycles, S(O)R1, SO2R1, -CO2H, -SO3H, -OR1, -CO2R1, -CONR1, -PO2R1R2, -PO3H or P(O)R1R2R3; K is NR1, -SS-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, S, Se, B or C3-C6 heteroaryl.

[0776] Example structures of the components of connectors L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 independently include one or more of the following structures:

[0777]

[0778]

[0779]

[0780] Or a combination of the preceding text, in which These are connection sites; X2, X3, X4, X5, or X6, independently selected from NH, NHNH, N(R) 12 ), N(R 12 )N(R 12’ ), O, S, C1-C6 alkyl, C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, CH2OR 12 CH2SR 12 CH2NHR 12 , or 1-8 amino acids; of which R 12 and R 12’ Independently, it can be H, C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or C1-C8 ester, ether, or amide; or have the structural formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyethylene glycol unit, where p is an integer from 0 to about 1000.

[0781] In another embodiment, L1, L2, La1, La2, Lb1, Lb2, E1, E2, Lv1', Lv2', Lc1, and Lc2 constructed in the structures of formulas (I), (II), and (III) are respectively selected from the following preferred options:

[0782] In formula (I) The structure preferably has the structure of formula (Ia); wherein, in formula (II) The structure preferably has the structure of formula (Ib) or (Ic); wherein, in formula (III) The structure preferably has the structure of formula (Id), (Ie), (If), or (Ig), as illustrated below; or wherein In formula (IV), it is preferable to have the structure of formula (Ia) as shown below:

[0783]

[0784] in, "#" represents the site that connects to the drug or the linker L1 or L2; "#" represents the site that connects to the S (thiol), O (phenol), NH (amino), CHO (aldehyde), C(=O) (ketone), C(O)(NH) (amide), and C(O)(OH) (carboxylate) of the antibody; Aa represents an L- or D-natural or non-natural amino acid; "@" represents the site that connects to Lc1 or Lc2 as described in molecular formulas (I), (II), and (III).

[0785] R1 is H, C1-C8 alkyl, OH, CH2OH, CH2CH2OH, NH2, SH, SCH3, CH2COOH, CH2CH2COOH, CH2CH2CH2CH2NH2, C6H5, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2;

[0786] r is 0-12; when r is not 0, (Aa)r are the same or different amino acids or peptide units;

[0787] m1=1-18; m2=1-100; m3=1-8; m4=0-8; m5=1-8;

[0788] Y 7 is NH, OCH2NH, NHC(=O), NHNH, C(=O)NH, N(R1), SO2, P(O)(OH), NHS(O)2, NHS(O)2NH, NH S(O)2NHC(O), NHS(O)2NHC(O)O, NHS(O)2NHC(O)NH, NHP(O)(OH), NHP(O)(OH)NH, OP(O )(OH)O, NHP(O)(OH)O, OP(O)(OH)NH, S, O, OP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)O, OCH2CH2O, OCH2CH2NH, N(CH2CH2)2N, NHC6H4NH, CH2;

[0789] Y 8 Is NHC(=O), NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH, C(O)NH, OC(O)NH, NHC(O)NH, C(O), N, NH, CH2, or CH;

[0790] Lv1' and Lv2' are independently selected from:

[0791]

[0792]

[0793]

[0794]

[0795] in These are the sites for connecting to the linker components; "#" represents sites as shown in the formulas Lv1' and Lv2', used to connect the antibody's thiol (S), phenolic hydroxyl (O), amino (NH), aldehyde (CHO), carbonyl (C(=O)), amide (C(O)(NH)), and carboxyl (C(O)(OH)); where R1, X1', and X2' are as described above; X represents O, NH, S, or CH2; and the bond connecting the two atoms is... This indicates that any one of the atoms can be attached; Ar is an aromatic group.

[0796] More preferably, the following core linker substructure (L1') has an affinity ligand in formula (I) (or L1” in formula (Ib'), specifically:

[0797] Preferably selected from:

[0798]

[0799] Where Aa is an L- or D-natural or non-natural amino acid; A1 is the same affinity ligand as defined above;

[0800] R1 is H, C1-C8 alkyl, OH, CH2OH, CH2CH2OH, NH2, SH, SCH3, CH2COOH, CH2CH2COOH, CH2CH2CH2CH2NH2, C6H5, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2;

[0801] r is 0-12; when r is not 0, (Aa)r are the same or different amino acids or peptide units;

[0802] m1=1-18; m2=1-100; m3=1-8; m4=0-8; m5=1-6; m7=1-8;

[0803] Y 7is NH, OCH2NH, NHC(=O), NHNH, C(=O)NH, N(R1), SO2, P(O)(OH), NHS(O)2, NHS(O)2NH, NH S(O)2NHC(O), NHS(O)2NHC(O)O, NHS(O)2NHC(O)NH, NHP(O)(OH), NHP(O)(OH)NH, OP(O )(OH)O, NHP(O)(OH)O, OP(O)(OH)NH, S, O, OP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)O, OCH2CH2O, OCH2CH2NH, N(CH2CH2)2N, NHC6H4NH, CH2;

[0804] Y 8 It is NHC(=O), NH, O, NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH, C(O)O, C(O), OC(O)NH, C(O)NH, or Ar;

[0805] R 9 It is (O=)CR1, (O=)CNHR1, NHC(=O), NH, O, NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH or C(O)NH, R1(COCH2NH)m4H, R1(Aa) r , (Aa)r, C(O), Ar or R3 is H, C1-C8 alkyl, ester, amide, aryl, ketone, alkyl acid, alkanol, alkylamine, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2; R1 is as defined above.

[0806] Or the following core structures in equation (III) (referred to as the L1” and L2” merge) (or correspondingly the L1” and L2” merge in equation (IIIb'):

[0807]

[0808] Preferably, the following formulas (Ib) and (Ic) are used:

[0809]

[0810] Among them, R1, Y 7 Y 8The definitions of R9, A1, Aa, r, m1, m2, m4, and m5 are the same as those in the previous text.

[0811] In some embodiments, examples of the couplings in formulas (I), (II), (III) and (IV) are shown in the following figure:

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907] The definitions of Ra and Rb are the same as above.

[0908]

[0909]

[0910] Where R 41 and R 42Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[0911] R 43 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are cytotoxic drugs described in this application, and A1 and A2 are small molecule ligands or drugs described in this application.

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926] Where R 41 and R 42Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[0927] R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out).

[0928]

[0929]

[0930]

[0931]

[0932]

[0933] Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[0934] R 34The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out).

[0935]

[0936]

[0937]

[0938]

[0939] The mAb mentioned above is an antibody with n ranging from 1 to 30, preferably from 1 to 20, and more preferably from 2 to 8.

[0940] In some embodiments, conjugates of formulas (I), (II), (III), and (IV) can be readily prepared by coupling antibodies with compounds having formulas (V), (VI), and (VII), respectively.

[0941]

[0942] Alternatively, conjugates of formula (IV) can be prepared by sequentially conjugating formulas (V) and (V') with antibodies:

[0943]

[0944] Among them, D1, D2, L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, Ld6, A1, A2, A3, A4, A5, A6, E1, m1, m2, m3, m4, m5, m6, m7, m8, m9, m 10 m 11 , and m 12 Same as the definitions in equations (I), (II) and (III);

[0945] Lv1 and Lv2 are reactive groups, and are selected independently or jointly from: Where X1' and X2' are independently F, Cl, Br, I, OTf, OMs, OC6H4(NO2), OC6H3(NO2)2, OC6F5, OC6HF4, or Lv3; X2 is O, NH, N(R1), or CH2; R3 and R5 are independently H, R1, aromatic, heteroaromatic, or aromatic groups, wherein one or more H atoms are independently surrounded by -R1, halogen, -OR1, -SR1, -NR1R2, -NO2, -S(O)R1, -S(O)2R1, or -COOR1; Lv3 Lv3′ is independently selected from F, Cl, Br, I, leaving group of nitrophenol, N-hydroxysuccinimide (NHS), phenol, benzenethiol, dinitrophenol, pentafluorophenol, tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, trifluoromethanesulfonate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxybenzotriazole toluenesulfonate methanesulfonate, 2-ethyl-5-phenylisoxazole-3′-sulfonate, anhydrides formed by themselves or anhydrides formed with other anhydrides, such as acetic anhydride, formic anhydride, or intermediate molecules produced by condensation reagents used in peptide coupling reactions or Mitsunobu reactions;

[0946] In equations (VI) and (VII) Accordingly selected from:

[0947]

[0948]

[0949]

[0950]

[0951] Among them, Lv3, Lv3 ’ x l ', and x2', as described above; connect key Being located between two atoms means that it can connect to either of them.

[0952] Equations (V), (VI), (VII) and (V') are shown below:

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048] Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[1049] R 43 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are cytotoxic drugs described in this application, and A1 and A2 are small molecule ligands or drugs described in this application.

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065] Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[1066] R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out).

[1067]

[1068]

[1069]

[1070]

[1071]

[1072] Where R 41 and R 42 It can be independently H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH;

[1073] R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out).

[1074]

[1075]

[1076]

[1077]

[1078] In some embodiments, the antibody-drug conjugate is preferably prepared via a homogeneous conjugation process, which includes the following three key steps:

[1079] (a) In a solution containing an effective amount of zinc cation-amino chelate / complex (Zn(NR1R2R3)) m1 m2+ ) and buffer systems containing reducing agents (such as tris(2-carboxyethyl)phosphine (TCEP)) (e.g., PBS, Mes, Bis-Tris, Bis-Tris propane, Pipes, Aces, Mopso, Bes, Mops, Hepes, Tes, Pipps, Dipso, Tapso, Heppso, Tris-up, Tris-HCl, Tricine, Hepps, Gly - Gly, Bicine, Taps, Hepee, Acetates, Histidine, Cirates, MES, or Borates, etc., are used to incubate antibodies at pH 4.5-8.5, 1-10℃, for 1-24 hours, selectively reducing interchain disulfide bonds within the antibody and generating thiol groups.

[1080] (b) Add an effective amount of a cytotoxic drug linker of formula (V), (VI), (VII), or (V'), bearing a thiol reactive group (e.g., a drug containing a maleimide terminus), to react with the thiol group generated in step (a); and

[1081] (c) Add an effective amount of oxidant (e.g., dehydroascorbic acid (DHAA)) to reoxidize the unreacted thiol group, and then purify the resulting conjugate;

[1082] (d) Step (c) can also be replaced by: adding an effective amount of cystine to quench excess linkers or linker / load complexes containing thiol reactive groups (e.g., maleimide); simultaneously or sequentially adding an azide compound (e.g., 4-(azidomethyl)benzoic acid) or a disulfide compound (e.g., cystine) to quench unreacted reducing agents (e.g., TCEP or tris(hydroxypropyl)phosphine). Adding cystine to quench unreacted reducing agents (e.g., TCEP) can form cysteine, which can simultaneously quench excess conjugated linkers or linker / load complexes containing thiol reactive groups (e.g., maleimide) in formulas (V), (VI), (VII), or (VIVIII).

[1083] Where Zn(NR1R2R3) m1 m2+ In the molecular formula, R1, R2, and R3 are independently selected from C1-C8 alkyl groups; C2-C8 heteroalkyl, alkylcycloalkyl, and heterocycloalkyl groups; C3-C8 aryl, aryl-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, and heteroaryl groups; m1 is selected from 1, 2, 3, 4, 5, 6, 7, or 8; m1 may be 1, 2, 3, or 4.

[1084] In addition, (NR1R2R3) m1 It can form dimers, trimers, tetramers, pentamers or hexamers, and these polymers are covalently linked between N, R1, R2 and R3; N, R1, R2 or R3 themselves can form heterocycles, carbocycles, bi-heterocycles or bi-carbocycles.

[1085] The zinc cation-amino chelate / complex (Zn(NR1R2R3)) used in step (a) m1 m2+ The concentration of the reagent is 0.01mM-1.0mM, or 0.5-20 protein molar equivalents. It can be dissolved in a water-soluble organic solvent, selected from ethanol, methanol, propanol, propylene glycol, DMA, DMF, DMSO, THF, CH3CN, and then added to the reaction system.

[1086] The reducing agent is an organophosphorus compound, preferably tris(2-carboxyethyl)phosphorus (TECP) or tris(hydroxypropyl)phosphorus, at a concentration of 0.02 mM-1.0 mM, or 1.0-20 protein molar equivalents, in the reaction solution. The oxidizing agent added in step (c) can be DHAA, Fe... 3+ I2, Cu 2+ Mn 3+ MnO2 or Fe 3+ / I - The mixture. The concentration of the oxidant used in the reaction solution is 0.02 mM to 1.0 mM, or 0.2 to 100 protein molar equivalents. The preferred pH for the coupling reaction is generally between about 5.0 and 8.0, more preferably between about 5.5 and 7.5. The preferred temperature for the coupling reaction is generally between about -5 and about 40°C, more preferably between about 0 and 37°C; optimally between about 2 and 8°C; furthermore, preferably between about 2 and 6°C. The preferred time for the coupling reaction is generally between about 15 minutes and about 48 hours, more preferably between about 30 minutes and overnight (10-16 hours), more preferably between about 2 and 6 hours. The optimal reaction conditions (e.g., pH, temperature, buffer, reactant concentration) will, of course, depend specifically on the antibody-like protein, payload / linker complex, reducing agent, and / or Zn(NR1R2R3) used. m1 m2+ .

[1087] In a further embodiment, Zn(NR1R2R3) m1 2+ Preferred from: Zn(NH2CH3)2 2+ Zn(NH2CH2CH3)2 2+ Zn(NH2CH2CH2CH3)2 2+ Zn(NH2CH(CH3)2)2 2+ Zn(NH2C(CH3)3)2 2+,Zn(NH2CH2C(CH3)3)2 2+ ,Zn(NH(CH3)2)2 2+ ,Zn(NH(CH2CH3)2)2 2+ ,Zn(NH(CH(CH3)2)2)2 2+ ,Zn(NH(C(CH3)3)2)2 2+ ,Zn(NH(CH(CH2CH3)2)2)2 2+ ,Zn(NH(CH2C(CH3)3)2)2 2+ ,Zn(NH(CH2C(CH2CH3)3)2)2 2+ ,Zn(NH(CH2CH2C(CH3)3)2)2 2+ ,Zn(NH2CH2CH2OH)2 2+ ,Zn(NH(CH2CH2OH)2)2 2+ ,Zn(N(CH2CH2OH)3)2 2+ ,Zn(NH2CH2COOH)2 2+ ,Zn(NH2CH2CONH2)2 2+ ,Zn(NH2CH2COOCH3)2 2+ ,Zn(NH2CH2COOCH2CH3)2 2+ ,Zn(NH2CH2COOC(CH3)3)2 2+ ,Zn(NH2CH2COOCH(CH3)2)2 2+ ,Zn(NH2CH2CH2COOH)2 2+ ,Zn(NH(CH2COOH)2)2 2+ ,Zn(N(CH2CH2COOH)3)2 2+ ,Zn(NH2CH3)4 2+ ,Zn(NH2CH2CH3)4 2+ ,Zn(NH2CH2CH2CH3)4 2+ ,Zn(NH2CH(CH3)2)4 2+ ,Zn(NH2C(CH3)3)4 2+ ,Zn(NH2CH2C(CH3)3)4 2+ ,Zn(NH(CH3)2)4 2+ ,Zn(NH(CH2CH3)2)4 2+ ,Zn(NH(CH(CH3)2)2)4 2+ ,Zn(NH(C(CH3)3)2)4 2+ ,Zn(NH(CH(CH2CH3)2)2)42+ Zn(NH(CH2C(CH3)3)2)4 2+ Zn(NH(CH2C(CH2CH3)3)2)4 2+ Zn(NH(CH2CH2C(CH3)3)2)4 2+ Zn(NH2CH2CH2OH)4 2+ Zn(NH(CH2CH2OH)2)4 2+ Zn(N(CH2CH2OH)3)4 2+ Zn(NH2CH2COOH)4 2+ Zn(NH2CH2CONH2)4 2+ Zn(NH2CH2COOCH3)4 2+ Zn(NH2CH2COOCH2CH3)4 2+ Zn(NH2CH2COOC(CH3)3)4 2+ Zn(NH2CH2COOCH(CH3)2)4 2+ Zn(NH2CH2CH2COOH)4 2+ Zn(NH(CH2COOH)2)4 2+ Zn(N(CH2CH2COOH)3)4 2+ ,

[1088] All of the above complex cations can form salts with anions, and the anions are selected from, but are not limited to, the following: Cl - ,Br - I - SO4 2- HSO4 - NO3 - PO4 3- HPO4 2- H2PO4 - CO3 2- HCO3 - HCOO - CH3COO - F3CCOO - Cl3CCOO - FCH2COO - ClCH2COO - F2CHCOO - Cl2CHCOO - BF4 - SO3 2- HSO3 - CH3SO3- C6H5CH2SO 3- C6H5SO 3 -、C6H5COO - C6H5CH2COO - C6F5O - C6H4(OH)COO - C6H2F3O - C6H4(NO2)O - C6H2(NO2)3O - ,wait.

[1089] In other embodiments, during homogeneous coupling, the percentage of conjugates obtained in formulas (I), (II), (III), or (IV) linked to cysteine ​​sites between the antibody heavy and light chains exceeds 75%, while the percentage linked to cysteine ​​sites between the antibody heavy and heavy chains (hinge regions) is less than 15%. Typically, for formulas (I), (II), (III), or (IV), when the drug / antibody ratio (DAR) is set to 4 and the drug-to-linker ratio is 1:1, the percentage distribution of the amount of drug on the antibody is: D0 < 1%, D2 < 10%, D4 > 65%, D6 < 10%, D8 < 10%. If the drug-to-linker ratio is greater than 1, for example, each linker links 2, 3, 4, 5, or 6 drug molecules (when using side-chain or multi-branched linkers), the percentage distribution of the amount of drug in the antibody or antibody-like protein can be improved by adjusting the drug / linker ratio accordingly. The drug-to-linker ratio (DAR) can also be set at around 6, with most of D6 > 65%. This can be achieved by increasing the equivalent of the reducing agent (e.g., TCEP) and the equivalent of the payload linked to each linker in the payload / linker complex (equations (V), (VI), (VII), and (V'), where the drug is mainly coupled to the disulfide bond sites between the heavy and light chains and the disulfide bond sites in the hinge region of the IgG antibody.

[1090] The resulting conjugates can be purified using standard biochemical methods, such as Sephadex G25 or Sephacryl S300 gel column filtration, adsorption chromatography, ion (cation or anion) exchange chromatography, affinity chromatography (e.g., protein A column), or dialysis (ultrafiltration (UF) and dialysis filtration (DF)). In some cases, small molecule antibodies (e.g., <100 kDa) conjugated to small molecule drugs can be purified by chromatography, such as (reversed-phase) high-performance liquid chromatography (HPLC) or rapid protein liquid chromatography (FPLC), size exclusion chromatography, medium-pressure column chromatography, ion exchange chromatography, or hydroxyapatite chromatography.

[1091] In other embodiments, to prepare the conjugate of formula (IV), the cytotoxic drug / cytotoxic drug-linker complex of formulas (V) and (V') can be reacted simultaneously or sequentially with the amino acids in the antibody under the same or different conditions in a one-pot reaction. If the conjugation reaction is carried out simultaneously under the same conditions, then Lv1 of formula (V) and Lv1 of formula (V') are... v2 Typically, different functional groups are used. For example, if a thiol reactive group (e.g., maleimide, vinylsulfonyl, haloacetyl, acrylate, substituted propynyl alcohol) is chosen as Lv1, an amino reactive group, such as N-hydroxysuccinimide (NHS), pentafluorophenyl, dinitrophenyl, or carboxylic acid chloride, can be chosen as Lv2. If a click chemical reactive group is introduced onto the antibody beforehand, a click chemical group (e.g., azide, alkyne, dibenzocyclooctylene, BCN((1R,8S,9S)-bicyclo[6.1.0]non-4-yn-9-ylmethanol)) can be chosen as Lv1 or Lv2. Lv1 and Lv2 can be selected from a variety of functional group / reactive group pairs adapted to different functional groups, such as: amine-thiol (succinimide ester / maleimide, NHS ester / pyridine dithiol, NHS ester / haloacetyl), diazopropylene (SDA)-thiol, azide-thiol, alkyne-thiol, thiol-carbonyl compounds (maleimide / acylhydrazine, pyridine dithiol / acylhydrazine, haloacetyl / acylhydrazine), hydroxy-thiol (isocyanate / maleimide), thiol-DNA (maleimide / psoralen, pyridine dithiol / psoralen, haloacetyl / psoralen), and thiol-carboxyl (carbodiimide). As long as Lv1 and Lv2 have different reactivity with the amino acids in the antibody / antibody-like protein, the coupling reaction with formulas (V) and (V') can also proceed sequentially. For example, when both Lv1 and Lv2 are chosen to react with the thiol group (cysteine) in the antibody / protein, Lv1 can be a maleimide group, which reacts with the thiol group within seconds under conditions of pH 5.0–7.5 and 2.0–37°C; while Lv2 can be a slower-reacting vinylsulfonyl group or a haloacetyl group, whose coupling reaction with the thiol group in the antibody requires at least 6 hours under conditions of pH > 7.0 and temperature above 30°C. If L... v1 and L v2If the product has the same (terminal) coupling group, such as maleimide, haloacetyl, or pyridine dithiol, it can be coupled to formula (V) in the first step according to the homogeneous coupling method described above, that is, the payload / linker complex is coupled to the disulfide bond site between the heavy and light chains of the IgG antibody Fab region. Then, formula (V') is added sequentially to the reaction mixture to couple to the disulfide bond of the IgG antibody hinge region. The first step coupling reaction can be carried out at low temperature without purifying the product of the first step reaction. The second step coupling reaction can be carried out at room temperature (25°C) or higher, as long as the amount of formula (V') added is much greater than the amount of formula (V) added (3 eq. or more).

[1092] In the above-described homogeneous coupling process of thiol ether links, the same pH and / or temperature conditions are selected when using more than four times the equivalent of a cytotoxic drug-linker complex containing a double-terminal thiol reactive group for cross-coupling of antibody heavy-chain-light-chain disulfide bonds. It should be noted that the preferred synthetic method for disulfide bond or thiol ether linker conjugates is as follows: first, a drug-linker complex having formula (V), (VI), (VII), or (V') containing a disulfide bond or thiol reactive functional group is chemically synthesized; then, it is reacted with the thiol group in the protein (antibody) according to the method of the present invention. Synthesizing conjugates with acid-labile hydrazone bonds can be achieved by reacting the carbonyl group with an acylhydrazine in the linker, methods well known in the art (e.g., see 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). Synthesizing conjugates with triazole linkages can be achieved via click chemistry (Huisgen cycloaddition reaction) by reacting a 1-alkynyl group on the cytotoxic drug / cytotoxic drug-linker complex, or on the binding ligand / binding ligand-linker complex, with an azide group in linkers of formulas (V), (VI), (VII), or (V') (Lutz, JF. et al., 2008, Adv. Drug Del. Rev. 60, 958-70; Sletten, EM et al., 2011, Acc. Chem. Research 44, 666-76). Synthesizing oxime-linked conjugates can be achieved by reacting a ketone or aldehyde contained on the modified antibody with a hydroxylamine group on the cytotoxic drug / cytotoxic drug-linker complex or on the binding ligand / binding ligand-linker complex. Cytotoxic drugs / cytotoxic drug complexes containing amino groups, or binding ligands / binding ligand-linker complexes, can be condensed with carboxylic acid esters of NHS, imidazole, nitrophenoxy, N-hydroxysuccinimide (NHS) group, methanesulfonylphenoxy, dinitrophenoxy, pentafluorophenoxy, tetrafluorophenoxy, difluorophenoxy, monofluorophenoxy, pentachlorophenoxy, trifluoromethanesulfonate, imidazole, dichlorophenoxy, tetrachlorophenoxy, 1-hydroxybenzotriazolyl, toluenesulfonic acid, methanesulfonic acid, 2-ethyl-5-phenylisoxazole-3′-sulfonic acid, etc., in antibody-linker complexes to form amide bonds of formula (I), (II), (III), or (IV) to obtain conjugates.Many conventional antibody-drug conjugation chemistry and biochemistry methods are also known in the art (see, for example, Matsuda, Y. and Mendelsohn, BA, Expert Opin Biol Ther. 2021, 21(7): 963-975; Puthenveetil, S., Methods Mol Biol. 2020, 2078: 99-112; van Delft, F., and Lambert, JM, eds., "Chemical Linkers in Antibody-Drug Conjugates (ADCs)", Royal...

Claims

1. Antibody-drug conjugates with small molecule branched chain functions, as shown in formulas (I), (II), (III), and (IV): in, D1 and D2 are cytotoxic agents; mAb is an antibody or antibody-like protein; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and these numbers may be decimals; L1, L2, L a1 La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, Ld6 are linkers independently selected from O, NH, S, N, NH-NH, N-N, N(R3), N(R3)N(R 3’ ), C(=O)N, C(=O)NH, C(=O)N-N, C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocycle, carbocycle, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or ester, ether, urea, carbamate, carbonate, thiourea, thioether, thiourea, amide, aminoalkylcarboxyl, thioalkylcarboxyl, or oxoalkylcarboxyl of 1-8 carbon atoms; 1-8 natural or unnatural amino acids; or polyethyleneoxy units of the structural formula (OCH2CH2) p OR3, or (OCH2CH(CH3) p OR3, or NH(CH2CH2O) p R3, or NH(CH2CH(CH3)O) p R3, or N[(CH2CH2O) p R3][(CH2CH2O) p’ R 3’ ], or (OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p COOR3, wherein p and p' are independently selected from an integer from 0 to about 1000, or a combination thereof; wherein R3and R 3’ are H, C(=O)H, C(=O)CH3, C1-C8 alkyl; or a combination of the two. Lv1' and Lv2' have the following structure, either independently or jointly: in "#" represents the site where the drug is linked or the linker L1 or L2; "#" represents the site where the antibody is linked to S (thiol), O (phenol), NH (amino), CHO (aldehyde), C(=O) (ketone), C(O)(NH) (amide), or C(O)(OH) (carboxylate); R1 and R2 are H, C1-C6 alkyl groups, or a peptide containing 1 to 4 amino acid units; X, X1', and X2' are the connecting bonds between two atoms of O, NH, S, and CH2. This means it can connect to either of two atoms; Ar is an aromatic group. E1 and E2 are linking groups that connect two reactive groups, and are independently selected from CH, CH2, CH-CH, NH, NHNH, N(R3), N(R3)N(R 3’ N=N, NN, P, P(=O), S, Si, C2-C8 alkyl, heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, aromatic-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; peptides containing 1-4 amino acid units, or the following structures: in This is the connection site; X1, X2, X3, X4, X5, or X6 are independently selected from NH; NHNH; N(R3); N(R3)N(R3'); O; S; C1-C6 alkyl; R3 and R3' are H, C1-C6 alkyl; In addition, E1 may be omitted, then La1 or / and La2 may be directly connected to Lv1' or Lv2'; m1, m2, m3, m4, m5, m6, m7, m8, m9, m 10 , m 11 , and m 12 are each 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and can be a fraction; further, m2, m3, m8, m9, and / or m 10 may be 0, in which case Ld2-A2, Ld3-A3, Ld5-A5, and / or Ld6-A6 can be omitted; A1, A2, A3, A4, A5 and A6 are independently selected from the following functional small molecules: (1) affinity ligands: cell-penetrating peptides (CPPs), including ligands of dermalin receptor / neuroendocrine receptors or neuropeptide-Y receptors; (2) and / or nucleoside antimetabolites / analytes; which have synergistic effects with D1 or D2 or enhance affinity for mAbs.

2. The functional small molecules A1, A2, A3, A4, A5, and A6 according to claim 1 are independently selected from: (1) Affinity ligands: LyP-1 peptide: iRGD: K237 peptide (binds to VEGFR-2): RVG peptide: IN (CD206): GALA peptide: IL4R-binding peptide: L17E endocytosis peptide: C16K-protoporphyrin IX: E-selectin targeting peptide: (KLAKLAK)2: CD44v6 - Combination: Her-2 binding: Targeted therapy for prostate tumors: Targeted therapy for bladder tumors: Defensive element 1: Antimicrobial peptide B: Magainin (frog skin extract): dermaseptin, an antibacterial peptide for skin: lactoferrin 5 derivatives: eMTD peptide: H3 peptide: Octreotide: RP527 peptide: Minigastrin: Nectin-4: in dC = D-cysteine; TIM-3-binding peptide: LAG-3-binding peptide: TIGIT-binding peptide: CM7 peptide (cMet): HB10: HB10(sHB-EGF): A8 peptide (Hsp72): Somatostatin: KRpep-2d peptide: KS36 peptide: Among them, Dap is (S)-2,3-diaminopropionic acid, Nle is L-ortholeucine, Anon is (S)-2-aminononanoic acid, and Cha is L-cyclohexylalanine. The others are all natural amino acids. KS58 peptide: Where βAla is β-alanine, Nle is L-leucine, Anon is (S)-2-aminononanoic acid, 4fF is 4-fluoro-1-phenylalanine, and dCys is D-cysteine. Goserelin: Its analogues are shown below: Angiopep-2: CBX-12: SG3299: TH1902: Angiopep-2: Thr-Phe-Phe-Tyr-Gly-Gly-Ser-Arg-Gly-Lys-Arg-Asn-Asn-Phe-Lys-Thr-Glu-Glu-Tyr-Cys Transportan: Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Lys-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu (GWTLNSAGYLLGKINLKALAALAKKIL): TfR-T12: Thr-His-Arg-Pro-Pro-Met-Trp-Ser-Pro-Val-Trp-Pro(THRPPMWSPVWP): Glutathione: γ-L-Glutamyl-L-cysteinylglycine: RVG29: (YTIWMPENPRPGTPCDIFTNSRGKRASNG), Tyr-Thr-Ile-Trp-Met-Pro-Glu-Asn-Pro-Arg-Pro-Gly-Thr-Pro-Cys-Asp-Ile-Phe-Thr-Asn-Ser-Arg-Gly-Lys-Arg-Ala-Ser-Asn-Gly-Cys: K-FGF: Ala-Ala-Val-Leu-Leu-Pro-Val-Leu-Leu-Ala-Ala-Pro(AAVLLPVLLAAP) NF-κB:Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro(VQRKRQKLMP): β1-tail: Tyr-Lys-Ser-Ala-Val-Thr-Thr-Val-Val-Asn-Pro-Lys-Tyr-Glu-Gly-Lys(YKSAVTTVVNPKYEGK): BIP: Val-Pro-Met-Leu-Lys-Glu(VPMLK(E)): C105Y: Cys-Ser-Ile-Pro-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val-Tyr-Leu-Ile (CSIPPEVKFNK) PFVYLI: MAP12: Leu-Lys-Thr-Leu-Thr-Glu-Thr-Leu-Lys-Glu-Leu-Thr-Lys-Thr-Leu-Thr-Glu-Leu (LKTLTETLKELTKTLTEL): GALA: Trp-Glu-Ala-Ala-Leu-Ala-Glu-Ala-Leu-Ala-Glu-Ala-Leu-Ala-Glu-His-Leu-Ala-Glu-Ala-Leu-Ala-Glu-Ala-Leu-Glu-Ala-Leu-Ala-Ala (WEAALAEALAEALAEHLAE-ALAEALEALAA): PTD4: Tyr-Ala-Arg-Ala-Ala-Ala-Arg-Gln-Ala-Arg-Ala(YARAAARQARA): PreS2: Pro-Leu-Ser-Ser-Ile-Phe-Ser-Arg-Ile-Gly-Asp-Pro(PLSSIFSRIGDP): AIP6: Arg-Leu-Arg-Trp-Arg (RLRWR): EB-1: Leu-Ile-Arg-Leu-Trp-Ser-His-Leu-Ile-His-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Leu-Lys-Trp-Lys-Lys-Lys (LIRLWSHLIHIWFQNRRLKWKKK): DPV6: Gly-Arg-Pro-Arg-Glu-Ser-Gly-Lys-Lys-Arg-Lys-Arg-Lys-Arg-Leu-Lys-Pro (GRPRESGKKRKRKRLKP): THRre: Pro-Trp-Val-Pro-Ser-Trp-Met-Pro-Pro-Arg-His-Thr (PWVPSWMPPRHT): TGN: Thr-Gly-Asn-Tyr-Lys-Ala-Leu-His-Pro-His-Asn-Gly (TGNYKALHPHNG): THR:Thr-His-Arg-Pro-Pro-Met-Trp-Ser-Pro-Val-Trp-Pro(THRPPMWSPVWP): K16APoE: His-Ala-Tyr-Glu-Asp (HAYED): Neuroleptin-1-targeting peptide: Arg-Gly-Glu-Arg-Pro-Arg-Arg (RGERPRR): pPAC: Cys-Asn-Ala-Phe-Thr-Pro-Asp (CNAFTPD): R9F2C:Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Phe-Phe-Cys(RRRRRRRRRFFC): Mini-penetratin: Arg-Arg-Met-Lys-Trp-Lys-Lys (RRMKWKK): IRS-tag: Arg-Tyr-Ile-Arg-Ser (RYIRS): CPPP-2: Lys-Leu-Pro-Val-Met (KLPVM): Apamin: Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-Ala-Arg-Arg-Cys-Gln-Gln-His (Disulfide bonds: Cys1-Cys11-Cys3-Cys15)(CNCKAPETALCARRCQQH-NH2): hApoE: Leu-Arg-Lys-Leu-Arg-Lys-Arg-Leu-Leu (LRKLRKRLL): PepH3: Ala-Gly-Ile-Leu-Lys-Arg-Trp (AGILKRW): B6 peptide: Cys-Gly-His-Lys-Ala-Lys-Gly-Pro-Arg-Lys (CGHKAKGPRK): HIV-Tat: Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg (YGRKKRRQRR): Pep-7: Ser-Asp-Leu-Trp-Glu-Met-Met-Met-Val-Ser-Leu-Ala-Cys-Gln-Tyr (SDL-WEMMMVSLACQY): YTA4: Ile-Ala-Trp-Val-Lys-Ala-Phe-Ile-Arg-Lys-Leu-Arg-Lys-Gly-Pro-Leu-Gly (IAWVKAFIRKLRKGPLG): RGD: Arg-Gly-Asp: TAT: Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg (YGRKKRRQRRR): R9: Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg (RRRRRRRRR): R4: Arg-Arg-Arg-Arg (RRRR): R6: Arg-Arg-Arg-Arg-Arg-Arg (RRRRRR): R3: Arg-Arg-Arg (RRR): Cyclo(His-Pro): gHoPe2: Asn-His-Gln-Gln-Gln-Asn-Pro-His-Gln-Pro-Pro-Met (NHQQQNPHQPPM): Phage-derived peptide: Cys-Asn-Ser-Arg-Leu-His-Leu-Arg-Cys (CNSRLHLRC): SynB3: Arg-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe (RRLSYSRRRF): SV40 nuclear transport signal peptide analog: Cys-Gly-Tyr-Gly-Pro-Lys-Lys-Lys-Arg-Lys-Val-Gly-Gly (CGYGPKKKRKVGG): TAT2-4: Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly (YGRKKRRQRRRGYGRKKRRQRRRG): pVEC: Leu-Leu-Ile-Ile-Leu-Arg-Arg-Arg-Ile-Arg-Lys-Gln-Ala-His-Ala-his-Ser-Lys (LLIILRRRIRKQAHAHSK): Pep-1: Cya-Lys-Glu-Thr-Trp-Trp-Glu-Thr-Trp-Trp-Thr-Glu-Trp-Ser-Gln-Pro-Lys-Lys-Lys-Arg-Lys-Val (Cya-KETWWETWWTEWSQPKKKRKV): MAP: Lys-Leu-Ala-Leu-Lys-Leu-Ala-Leu-Lys-Ala-Leu-Lys-Ala-Ala-Leu-Lys-Leu-Ala (KLALKLALKALKAALKIA): Calcitonin(9-32) (free acid): Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro (LGTYTQDFNKFHTFPQTAIGVGAP): PTD-5: Arg-Arg-Gln-Arg-Arg-Thr-Ser-Lys-Leu-Met-Lys-Arg (RRQRRTSKLMKR): SynB1: Arg-Gly-Gly-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe-Ser-Thr-Ser-Thr-Gly-Arg-Ala (RGGRLSYSRRRFSTSTGRA): Penetratin: Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Gly-Gly (RQIKIWFQNRRMKWKKGG): Activable CPPs\ACPP:Glu-Glu-Glu-Glu-Glu-Glu-Glu-Gly-Ala-Leu-Gly-Leu-Pro-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Lys-Lys-Arg(EEEEEEEGALGLLPRRRRRRRRKKR): M918: Met-Val-Thr-Val-Leu-Phe-Arg-Arg-Leu-Arg-Ile-Arg-Arg-Ala-Cys-Gly-Pro-Pro-Arg-Val-Arg-Val(MVTVLFRRLRIRRACGPPRVRV): Hel 13-5;Lys-Leu-Leu-Lys-Leu-Leu-Leu-Lys-Leu-Trp-Leu-Lys-Leu-Leu-Lys-Leu-Leu-Leu(KLLKLLLKLWLKLLKLLL): POD: Gly-Gly-Gly-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys -Lys-Ala-Ala-Lys-Ala-Ala-Arg-Lys-Lys-Ala-Ala-Lys-Ala(GGGARK-KAAKAARKKAAKAARKKAAKAARKKAAKA): (iRGD): LyP-1 peptide: in It is a connection site with Ld1, Ld2, Ld3, Ld4, Ld5, or Ld6, where Ra is Ar, preferably from: Rb is OH, COOH, COOCH3, CH3OH, CH3NH2, CONH2; (2). Nucleoside antimetabolites / analytes:

3. According to claim 1, the cytotoxic drugs D1 and D2 are independently selected from: (1) Chemotherapy drugs: a) Alkylating agents selected from nitrogen mustards: chlorpheniramine, chlorpromazine, cyclophosphamide, dacarbazine, estradiol nitrogen mustard, isocyclophosphamide, nitrogen mustard, dimethoxyamine hydrochloride, dioxane mustard oxide, amlodipine hydrochloride, mycophenolic acid, eugenol, guanobromide, neonitrogen mustard, benzyl mustard cholesterol, pine oxychloride, thiotetracycline, trefocillin, uracil; CC-1065 and its analogues adolaxine, calcetaxel, pyrazinazole and their synthetic analogues; docamycin and its synthetic analogues KW-2189 and CBI-TMI or CBI dimer; benzodiazepine dimer or pyrrolobenzodiazepine (PBD), tometamycin dimer Dimers of indobenzobenzodiazepine, imidazobenzobenzothiazodiazepine, or oxazolidinonebenzobenzodiazepine; nitrosoureas: including carmustine, lomustine, clostridium chloride, formustine, nimustine, and lamustine; alkyl sulfonates: including betamethrin, styrene, sulfamethoxazole, and pisufen; triazine or dacarbazine; platinum-containing compounds: carboplatin, cisplatin, and oxaliplatin; acridine derivatives, benzodihydropyranone, calcodone, methotrexate, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenetriamine, triethylphosphamide, triethylenethiophosphamide, and trimethylolpropionate; b) Plant alkaloids: selected from periwinkle alkaloids: including vincristine, vinblastine, vinorelbine, vinorelbine, norvinblastine; taxols: including paclitaxel, docetaxel and their analogues; Maytansine derivatives include DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine, anesarcomycin and their analogues; cryptophycin (including cryptophycin 1 and cryptophycin 8); epothilone, soft coral alcohol, dimolide, bryophyll, sea haretoxin, oliquistatin, microtubule toxin, cephalostatin; pancratistatin; erbulins, a sarcodictyin; spongistatin; c) DNA topoisomerase inhibitors: selected from etoposide: including 9-aminocamptothecin, camptothecin, cristatin, doramycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, norsoxamine, retinoid (retinol), teniposide, topotecan, 9-nitrocamptothecin or RFS2000; mitomycin and its analogues; d) Antimetabolites: selected from {[Antifolate agents: (DHFR inhibitors: including methotrexate, tromethorphan, folate, pteroxate, aminopterin (4-aminobenzoic acid) or other folic acid analogs; IMP dehydrogenase inhibitors: (including mycophenolate mofetil, thiazolidinedione, ribavirin, EICAR); ribonucleotide reductase inhibitors: (including hydroxyurea, deferoxamine)]; [Pyrimidine analogs, uracil analogs: (including ancitabine, azacitidine, 6-azouracil, capecitabine (Xeloda), carmoflu, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, 5-fluorouracil, fluorouridine, ratitrexed (Tomudex)); cytosine analogs: (including cytarabine, cytosine arabinoside, fludarabine); purine analogs (including azathioprine, fludarabine, mercaptopurine, thiamine, thioguanine)]: folic acid supplements, florrin; nicotinamide phosphoribosyltransferase (NAMPT) inhibitors; e). Hormone therapy agents: selected from {receptor antagonists: [anti-estrogens: (including medroxyprogesterone acetate, raloxifene, tamoxifen), LHRH agonists: (including gostalin, leuprorelin acetate); anti-androgens: (including bicalutamide, flutamide, carlusone, beta-testosterone propionate, epiandrogen, goserelin, leuprorelin, methemetidine, nilumet, testrolide, tralostertan and other androgen inhibitors)]; retinoids: [vitamin D3 analogs: (including CB1093, EB1089, KH1060, cholecalciferol, ergocalciferol); photodynamic therapy agents: (including verteporfin, phthalocyanine, photosensitizer Pc4, demethoxy-rubigin A); cytokines: (including interferon-α, interferon-γ, tumor necrosis factor (TNF), TNF-containing human proteins)]}; f) Kinase inhibitors selected from BIBW 2992 (anti-EGFR / Erb2), imatinib, gefitinib, guaranatinib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, vemodega, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, and ispinib. g) Poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib, iniparib, taraparib, veliparib, CEP 9722 (Cephalon's), E7016 (Eisai's), BGB-290 (BeiGene) or 3-aminobenzamide. h). Antibiotics, such as acetylenic antibiotics (galicarmycin, especially galicarmycin γ1, δ1, α1 and β1, dyinmycin, including dyinmycin A and deoxymimycin, esperamycin, katimycin, C-1027, ma-duropeptin, neocarcinoxine oseltine and related chromogen acetylenic antibiotics), aclacinomysins, actinomycins, atracheomycin, diazoserine, bleomycin, carnomycin, kanamycin, erythromycin, carcinogens, chromogens, dachlortetracycline, etc. Daunorubicin, dedarubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholine-doxorubicin, cyanomorpholine-doxorubicin, 2-pyrrolidone doxorubicin and deoxydaunorubicin, epirubicin, arubicin, idarubicin, macromycin, nitomycin, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramycin, rodolmycin, streptomycin, streptozotocin, tuberculin, ubenmethoxazole, fenbendazole, fenbendazole, zolrubicin; i). polyketides (campothecins), in particular bullatacin and bullatacinone; gemcitabine, epoxide hydrolase (e.g. carzelesin), bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovectin-7, Xegeva, Provenge, Yervoy, isoprenylation inhibitors and lovastatin, dopaminergic neurotoxins and 1-methyl-4-phenylpyridinium ion, cell cycle inhibitors (e.g. staurosporine), dactinomycin (e.g. actinomycin D, actinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, pepleomycin), anthracyclines (e.g. daunorubicin), amatoxins, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, valrubicin, mitoxantrone, MDR inhibitors or verapamil, Ca 2+ ATPase inhibitors or thapsigargin, histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, valproic acid, Mocetinostat (MGCD0103), Belinostat, PCI-24781, entinostat, SB939, Resminostat, Givinostat, AR-42, CUDC-101, sulforaphane, trichostatin A); celecoxib, glitazones, epigallocatechin gallate, disulfiram, Salinosporamide A; anti-adrenal drugs, aminoglutethimide, mitotane, trilostane, acetretin, aldo-phosphamide, aminolevulinic acid, amsacrine, araboside, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, difluoromethylornithine (DFMO), elfomithine, elliptinium acetate, etoglucid, gallium nitrate, cytosine, hydroxyurea, ibandronate, lentinan, lonidamide, mitoguazone, mitoxantrone, mopidamol, nitracine, pentostatin, phenamet, pirarubicin, podophyllinic acid, 2-ethylhydrazine, procarbazine; pyrazidinopropane; rhizoxin; Cizole; Spirocyclic germanium; Scirrhozanol; Triaminoquinone; 2,2′,2″-trichlorotriethylamine; Trichothecene (especially T-2 toxin, wartycin A, baculosporin A and an-guidine), polyurethane, siRNA, antisense drugs and nucleases; (2). Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Azathioprine, Bromocriptine, Chloroquine, Cyclophosphamide, Corticosteroids (including Ancinonide, Betamethasone, Budesonide, Hydrocortisone, Flunisolone, Fluticasone Propionate, Flucolone Danazol, Dexamethasone, Triamcinolone, Beclomethasone Dipropionate), DHEA, Etanercept, Hydroxychloroquine, Infliximab, Meloxicam, Methotrexate, Mycophenolate Mofetil, Prednisone, Sirolimus, Tacrolimus. (3) Anti-infective drugs, including: a) Aminoglycosides: Amikacin, Asmicin, Gentamicin (Netilmicin, Sisomicin, Isapamicin), Hygromycin B, Kanamycin (Amikacin, Abekaricin, Aminodeoxykanamycin, Dibekacin, Tobramycin), Neomycin (Framycetin, Paromomycin, Ribomycin), Netilmicin, Spectinomycin, Streptomycin, Tobramycin, Methylstilbestrol; b) Amide alcohols: chloramphenicol, chloramphenicol, florfenicol, thiamphenicol; c) Ansarmycin: Gerdemycin, except for atrazine; d) Carbapenems: biapenem, doripenem, ertapenem, imipenem / cilastatin, meropenem, panipenem; e) Cephalosporins: Carbazosporins (Loracarb), Cefaclor, Claminophen, Cefradine, Cefadroxil, Cefranine, Cefotaxime, Cefalothin or Cefadroxil, Cephalexin, Cefalecin, Cefamandole, Cephalexin, Hydroxylamine Cephalosporins, Fluoxetine Cephalosporins, Folic acid, Zoltidine Cephalosporins, Cefadroxil, Cefacarpine, Cefotaxime, Cefepime, Cefixime, Cefoxitin, Cefradine, Cefoxitin, Cefoxitin, Cefoxitin, Cefotaxime, Cefotiam, Cefotaxime, Cefotiam Pyridine, cefotaxime, cefotaxime, cefodizine, cefonicid, cefoquinone, cefradazole, cefotaxime, thiamethoxam, cephalosporin, cefazolin, cefalexin, cefimidazole, cefpirome, cefpirome, cefpodoxime, cefrozil, cefquinolone, cefsulfuron, ceftazidime, cefterenol, cefbutane, cefotaxime, cefazolin, cefpyripril, ceftriaxone, cefuroxime, cefazolin, cephalosporins (cefoxitin, cefotetan, cefcyanazole), oxocephalosporins (fluorocephalosporins, latamoxporins); f) Glycopeptides: Bleomycin, Vancomycin (Olivancin, Tervavancin), Teicoplanin (Dabavancin), Ramolanin; g) Glycylcycline: such as tigecycline; h). β-lactamase inhibitors: penicillane (sulbactam, tazobactam), oxapenem (clavulanic acid); i) Lincosamides: Clindamycin, Lincosamide; j). Lipopeptides: Daptomycin, A54145, calcium-dependent antibiotic (CDA); k) Macrolides: Azithromycin, Clotrimazole, Clarithromycin, Dierythromycin, Erythromycin, Fluremycin, Josamycin, Ketolides (Telithromycin, Seserythromycin), Midecamycin, Micardromycin, Prunycin, Rifamycin (Isoniazid, Rifampin, Rifabutin, Rifapentine), Ropimycin, Roxithromycin, Spectinomycin, Spiramycin, Tacrolimus (FK506), Prunycin, Telithromycin; l) Monocyclic amines: aztreonam, tegamum; m). Oxazolidinones: Linezolid; n) Penicillins: Amoxicillin, Ampicillin (Pipacillin, Hezlocillin, Bambucil, Ampicillin, Doxorubicin), Aldacillin, Alzlocillin, Benzylpenicillin, Benzathine penicillin, Benzathine penicillin, Phenoxymethylpenicillin, Cloncillin, Procaine penicillin (Meticillin), Meloxicillin, Methicillin, Nafcillin, Oxyxacillin, Acetylpenicillin, Penicillin, Fennecillin, Phenoxymethylpenicillin, Guaricillin, Ampicillin, Sulbenicillin, Temoxicillin, Ticarcillin; o). Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: Aratrofloxacin, Balofloxacin, Ciprofloxacin, Clindamycin, Daflufloxacin, Diflufloxacin, Enrofloxacin, Enrofloxacin, Garefloxacin, Gatifloxacin, Gemmifloxacin, Gaptafloxacin, Canotravafloxacin, Levofloxacin, Lomefloxacin, Mebofloxacin, Moxifloxacin, Naflufloxacin, Norfloxacin, Obibixacin, Ofloxacin, Pefloxacin, Travafloxacin, Gaptafloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Toxacin, Travafloxacin; q) Streptocin: Punemycin, Quinupordine / Dalfopristin; r). Sulfonamides: ampicillin, azosulfanilamide, sulfadiazine, sulfamethoxazole, sulfaimide, sulfapyridine, sulfaisoxazole, trimethoprim, sulfamethoxazole (compound sulfamethoxazole); s) Steroid antibiotics: such as fusidic acid; t). Tetracyclines: Doxycycline, Chlortetracycline, Clomicycline, Demeclocycline, Ramoxil, Methionine, Methacycline, Minocycline, Oxytetracycline, Panmeclocycline, Pyrrolidine Methyl Tetracycline, Tetracycline, Glycylcycline (e.g., Tigecycline); u). Other types of antibiotics: anechoic acid, arsenamin, bacterial terpene inhibitors (bacitracin), DANAL / AR inhibitors (cycloserine), dictyostatin, spongiocarbamate, soft coral alcohol, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, NAM synthesis inhibitors (e.g., fosfomycin), nitrofurantoin, paclitaxel, prancisic acid, pyrazinamide, quinupristin / dalfopristin, rifampin, tazobactam-tinidazole, chamomile; (4) Antiviral drugs, including: a) Invasion / fusion inhibitors: apavirol, maraviro, vicriviroc, gp41 (enfvirtide), PRO 140, CD4 (elbalizumab); b) Integrase inhibitors: Rettagvir, elvite-gravir, globoidnan A; c) Maturation inhibitors: bevirimat, vivecon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: abacavir, abciximab, adefovir, amoxivir, abciximab, brivudine, cidofovir, clavudine, dexamethasone, norinosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluracillin (5-FU), 3'-fluorosubstituted 2',3'-deoxynucleoside analogs, such as 3'-fluoro-2', 3'-dideoxythymidine (FLT) and 3'-fluoro-2'... 3'-Dideoxyguanosine (FLG), formivir, 9-guanine, idoxuridine, lamivudine (3TC), 1-nucleoside (e.g., β-1-thymidine and β-1-2′-deoxycytidine), penciclovir, racivir, ribavirin, ditidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluorouridine valacyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT); f) Non-nucleoside analogues: Amantadine, Atepiridine, Capvirine, Diarylpyrimidine (Etravirine), Delavidine, Docosanol, Emivirine, Efaviren, Phosphoric acid, Imiquimod, Pegylated interferon, Loviramide, Lodeadenosine, Meinthiazone, Nevirapine, NOV-205, Long-acting Interferon Alpha, Podophyllotoxin, Rifampin, Amantadine, Requimod (R-848), Amantadine acetamide; g) Protease inhibitors: Ampranavir, Atazanavir, Boceprevir, Darunavir, Fosanavir, Indinavir, Lopinavir, Nefinavir, Pleconazole, Ritonavir, Saquinavir, Telaprevir (VX-950), Tiranavir; h) Other types of antiviral drugs: antibody enzymes, arbidol, calanolide A, ceragenin, cyaniverine-N, diarylpyrimidine, epigallocatechin gallate (EGCG), phosphonoformic acid, griffithin, tari-bavirin (viramidine), hydroxyurea, KP-1461, mitefoxin, precocinone, hybrid inhibitors, ribavirin, seliciclib. (5). the radioisotope is selected from (the radionuclide): 3 H, 11 C, 14 C, 18 F, 32 p, 35 S, 64 Cu, 68 Ga, 86 Y, 90 Y, 99 Tc, 111 In, 123 I, 124 I, 125 I, 131 I, 133 Xe, 177 Lu, 203 Pb, 212 Pb, 211 At, 213 Bi, 224 Ra and 225 Ac. Among them, the metal radionuclide 64 Cu, 68 Ga, 86 Y, 90 Y, 99 Tc, 111 In, 133 Xe, 177 Lu, 203 Pb, 212 Pb, 211 At, 213 Bi, 224 Ra and 225 Ac is connected by a chelating agent and a linking group L1 in this patent application. The chelating agent is selected from: (6). a chromophore molecule that can absorb ultraviolet light, fluorescent light, infrared light, near-infrared light, or visible light; a chromophore molecule includes one or a subcategory of a group of yellow pigments, red pigments, iridescent pigments, white pigments, black pigments, and blue-green pigments, one or a subcategory of a group of fluorescent molecules (fluorescent chemicals that emit light after absorbing light), one or a subcategory of a group of visual light transduction molecules, one or a subcategory of a group of photon molecules, one or a subcategory of a group of luminescent molecules, and one or a subcategory of a group of fluorescein compounds. Non-protein organic fluorophores, such as xanthene derivatives (fluorescein, rhodamine, Oregon green, eosin, and Texas red); cyanine derivatives (cyanine, indocyanine, oxonol, thiacarbocyanine, and merocyanine); squaraine derivatives and ring-substituted squaraines, including Seta, SeTau, and Square dyes; naphthalene derivatives (naphthalene and fluorosilicate derivatives); coumarin derivatives; oxadiazole derivatives (pyridyl oxadiazole, nitrobenzoxadiazole, and benzoxadiazole); anthracene derivatives (anthraquinones, including DRAQ5, DRAQ7, and CyTRAK Orange); pyrene derivatives (Cascade Blue, etc.); oxazine derivatives (Nile red, Nile blue, cresyl violet, oxazine 170, etc.); acridine derivatives (lutein, acridine orange, acridine yellow, etc.); arylmethylamine derivatives (malachite green, crystal violet, malachite green); and tetrapyrrole derivatives (porphyrin, phthalocyanine, bilirubin). Any analogues and derivatives of the following fluorescent compounds: CF dyes (Biotium), DRAQ and CyTRAK probes (BioStatus), BODIPY (Invitrogen), Alexa Fluor (Invitrogen), DyLight Fluor (Thermo Scientific, Pierce), Atto and Tracy (Sigma Aldrich), FluoProbes (Interchim), Abberior dyes (Abberior), DY and MegaStokes dyes (Dyomics), SulfoCy dyes (Cyandye), HiLyte Fluor (AnaSpec), Seta, SeTau, and Square dyes (Biosearch Technologies), SureLight dyes (APC, RPE PerCP, Phycobilisomes) (Columbia Biosciences), APC, APCXL, RPE, BPE (Phyco-Biotech), Allophycocyanin (APC), Aminomalcite, APC-Cy7 conjugates, BODIPY-FL, Cascade Blue, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, Cy7a, Cy7b, Cy7c, Cy7d, Cy7e, Cy7f, Cy7g, Cy7h, Cy7i, Cy7j, Cy7k, Cy7l, Cy7m, Cy7n, Cy7o, Cy7p, Cy7q, Cy7r, Cy7s, Cy7t, Cy7u, Cy7v, Cy7w, Cy7x, Cy7y, Cy7z, Cy7aa, Cy7ab, Cy7ac, Cy7ad, Cy7ae, Cy7af, Cy7ag, Cy7ah, Cy7ai, Cy7aj, Cy7ak, Cy7al, Cy7am, Cy7an, Cy7ao, Cy7ap, Cy7aq, Cy7ar, Cy7as, Cy7at, Cy7au, Cy7av, Cy7aw, Cy7ax, Cy7ay, Cy7az, Cy7ba, Cy7bb, Cy7bc, Cy7bd, Cy7be, Cy7bf, Cy7bg, Cy7bh, Cy7bi, Cy7bj, Cy7bk, Cy7bl, Cy7bm, Cy7bn, Cy7bo, Cy7bp, Cy7bq, Cy7br, Cy7bs, Cy7bt, Cy7bu, Cy7bv, Cy7bw, Cy7bx, Cy7by, Cy7bz, Cy7ca, Cy7cb, Cy7cc, Cy7cd, Cy7ce, Cy7cf, Cy7cg, Cy7ch, Cy7ci, Cy7cj, Cy7ck, Cy7cl, Cy7cm, Cy7cn, Cy7co, Cy7cp, Cy7cq, Cy7cr, Cy7cs, Cy7ct, Cy7cu, Cy7cv, Cy7cw, Cy7cx, Cy7cy, Cy7cz, Cy7da, Cy7db, Cy7dc, Cy7dd, Cy7de, Cy7df, Cy7dg, Cy7dh, Cy7di, Cy7dj, Cy7dk, Cy7dl, Cy7dm, Cy7dn, Cy7do, Cy7dp, Cy7dq, Cy7dr, Cy7ds, Cy7dt, Cy7du, Cy7dv, Cy7dw, Cy7dx, Cy7dy, Cy7dz, Cy7ea, Cy7eb, Cy7ec, Cy7ed, Cy7ee, Cy7ef, Cy7eg, Cy7eh, Cy7ei, Cy7ej, Cy7ek, Cy7el, Cy7em, Cy7en, Cy7eo, Cy7ep, Cy7eq, Cy7er, Cy7es, Cy7et, Cy7eu, Cy7ev, Cy7ew, Cy7ex, Cy7ey, Cy7ez, Cy7fa, Cy7fb, Cy7fc, Cy7fd, Cy7fe, Cy7ff, Cy7fg, Cy7fh, Cy7fi, Cy7fj, Cy7fk, Cy7fl, Cy7fm, Cy7fn, Cy7fo, Cy7fp, Cy7fq, Cy7fr, Cy7fs, Cy7ft, Cy7fu, Cy7fv, Cy7fw, Cy7fx, Cy7fy, Cy7fz, Cy7ga, Cy7gb, Cy7gc, Cy7gd, Cy7ge, Cy7gf, Cy7gg, Cy7gh, Cy7gi, Cy7gj, Cy7gk, Cy7gl, Cy7gm, Cy7gn, Cy7go, Cy7gp, Cy7gq, Cy7gr, Cy7gs, Cy7gt, Cy7gu, Cy7gv, Cy7gw, Cy7gx, Cy7gy, Cy7gz, Cy7ha, Cy7hb, Cy7hc, Cy7hd, Cy7he, Cy7hi, Cy7hj, Cy7hk, Cy7hl, Cy7hm, Cy7hn, Cy7ho, Cy7hp, Cy7hq, Cy7hr, Cy7hs, Cy7ht, Cy7hu, Cy7hv, Cy7hw, Cy7hx, Cy7hy, Cy7hz, Cy7ia, Cy7ib, Cy7ic, Cy7id, Cy7ie, Cy7if, Cy7ig, Cy7ih, Cy7ii, Cy7ij, Cy7ik, Cy7il, Cy7im, Cy7in, Cy7io, Cy7ip, Cy7iq, Cy7ir, Cy7is, Cy7it, Cy7iu, Cy7iv, Cy7iw, Cy7ix, Cy7iy, Cy7iz, Cy7ja, Cy7jb, Cy7jc, Cy7jd, Cy7je, Cy7jf, Cy7jg, Cy7jh, Cy7ji, Cy7jj, Cy7jk, Cy7jl, Cy7jm, Cy7jn, Cy7jo, Cy7jp, Cy7jq, Cy7jr, Cy7js, Cy7jt, Cy7ju, Cy7jv, Cy7jw, Cy7jx, Cy7jy, Cy7jz, Cy7ka, Cy7kb, Cy7kc, Cy7kd, Cy7ke, Cy7kf, Cy7kg, Cy7kh, Cy7ki, Cy7kj, Cy7kk, Cy7kl, Cy7km, Cy7kn, Cy7ko, Cy7kp, Cy7kq, Cy7kr, Cy7ks, Cy7kt, Cy7ku, Cy7kv, Cy7kw, Cy7kx, Cy7ky, Cy7kz, Cy7la, Cy7lb, Cy7lc, Cy7ld, Cy7le, Cy7lf, Cy7lg, Cy7lh, Cy7li, Cy7lj, Cy7lk, Cy7ll, Cy7lm, Cy7ln, Cy7lo, Cy7lp, Cy7lq, Cy7lr, Cy7ls, Cy7lt, Cy7lu, Cy7lv, Cy7lw, Cy7lx, Cy7ly, Cy7lz, Cy7ma, Cy7mb, Cy7mc, Cy7md, Cy7me, Cy7mf, Cy7mg, Cy7mh, Cy7mi, Cy75, Cy7, Fluorin, FluorX, Hydroxycoumarin, Rhodamine B, Fluorochromic Acid, Me-Methoxycoumarin, NBD, Pacific Blue, Pacific Orange, PE-Cy5 Conjugate, PE-R-Phycoerythrin (PE), Red613, Seta-555-Azide, Seta-555-DBCO, Seta-555-NHS, Seta-580-NHS, Seta-680-NHS, Seta-APC-780, Seta-PerCP-680, Seta-R-PE-6 70, SeTau-380-NHS, SeTau-405-maleimide, SeTau-405-NHS, SeTau-425-NHS, SeTau-647-NHS, TexasRed, TRITC, TruRed, X-Rhodamine, 7-AAD (7-aminoactinomycin D, CG-selective), acridine orange, chromomycin A3, CyTRAK orange (Biostatus), DAPI, DRAQ5, DRAQ7, ethidium bromide, Hoechst 33258, Hoechst 33342, LDS 751, scintillans, propidium iodide (PI), SYTOX blue, SYTOX green, SYTOX orange, thiazole orange, TO-PRO, cyanine dye monomer, TOTO-1, TO-PRO-1, TOTO-3, TO-PRO-3, YOSeta-1, YOYO-1. Fluorescent compounds that can be linked to the linker of this invention for studying cells are selected from the following compounds or their derivatives: DCFH (2′,7′-dichlorodihydrofluorescein, oxidized form), DHR (dihydrorhodamine 123, oxidized form, photocatalytic oxidation), Fluo-3 (AM ester, pH > 6), and Fluo-4 (AM ester, pH 7).2), Indo-1 (AM ester, low / high calcium (Ca 2+)), SNARF (pH 6 / 9). Preferred fluorescent compounds are selected from: allophycocyanin (APC), AmCyanl (tetramer, Clontech), AsRed2 (tetramer, Clontech), thistle green (monomer), Azurite, β-phycoerythrin (BPE), Cerulean, CyPet, DsRed monomer (Clontech), DsRed2 ("RFP"), EBFP, EBFP2, ECFP, EGFP (weak dimer), Emerald (weak dimer), EYFP (weak dimer), GFP (S65A mutant), GFP (S65C mutant), GFP (S65L mutant), GFP (Y66H mutant), GFP (Y66W mutant), GFPuv, HcRed1, J-Red, Katusha, Kusabira Orange (monomer, MBL), mCFP, mCherry, mCitrine, Midoriishi Cyan (weak dimer, MBL), mKate (TagFP635, monomer), mKeima-Red (monomer), mKO, mOrange, mPlum, mRaspberry, mRFP1 (monomer), mStrawberry, mTFP1, mTurquoise2, P3 (phycobilisome complex), polydinoflavin-chlorophyll-protein complex (PerCP), R-phycoerythrin (RPE), T-Sapphire, TagCFP (Dimer), TagGFP (dimer), TagRFP (dimer), TagYFP (dimer), tdTomato (tandem dimer), Topaz, TurboFP602 (dimer), TurboFPP635 (dimer), TurboFP (dimer), TurboRFP (dimer), TurboYFP (dimer), Venus, wild-type GFP, YPet, Zsgreen1 (tetramer), ZsYellow1 (tetramer) and their derivatives. (7) Cell-binding ligands or receptor agonists are selected from: folic acid derivatives, glutamate urea derivatives, somatostatin and its analogues (selected from octreotide (Sandostatin) and lanreotide (Somatuline)), aryl sulfonamides, pituitary adenylate cyclase activating peptide (PACAP) (PAC1), vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2), melanocyte-stimulating hormone (α-MSH), cholecystokinin (CCK) / gastrin receptor agonists, and bufotalin (selected from Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / gastrin-releasing peptide (GRP). Neurotensin receptor ligands (NTR1, NTR2, NTR3); Substance P (NK1 receptor) ligand; neuropeptide Y (Y1-Y6); homing peptides including RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimer and multimeric cyclic RGD peptides (selected from cRGDfV), TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor ligand) and F3 peptide; cell-penetrating peptides (CPPs);Peptide hormones are selected from luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, as well as gonadotropin-releasing hormone (GnRH) agonists. They act by targeting follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone production. Examples include buserreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gosoreline (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), and gosoreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzG). Histamine (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), Leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), Nafarelin, Dilorlin, Aberelin (Ac-D-2Na) l-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyri) dyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl )-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and degarelic (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-NH2); pattern recognition receptors (PRRs), selected from Toll receptor-like (TLR) ligands, C-type lectins and nodular receptor (NLR) ligands; calcitonin receptor agonists;Integrin receptors and their receptor subclasses (selected from αvβ1, αvβ3, αvβ5, αvβ6, α6β4, α7β1, α; L β2, α IIb β3) Agonists (selected from GRGDSPK, cyclo(RGDfV)(L1) and their derivatives [cyclic (-N(Me)R-GDfV), cyclic (R-Sar-DfV), cyclic (RG-N(Me)D-fV), cyclic (RGD-N(Me)fV), cyclic (RGDf-N(Me)V-)(Silengitide)]; Single-domain antibodies (VHH(camelid)) Ig derivatives; domain antibodies (dAb, derivatives of VH or VL domains); bispecific T-cell connectors (BiTE, bispecific dimers); dual-affinity retargeting (DART, bispecific dimers); tetravalent tandem antibodies (TandAb, a dimerized bispecific dimer); anticalin (a derivative of calcitonin); adnectins (FN3 10 (fibronectin)); ankylosing repeats (DARPins); avimers; EGF receptor and VEGF receptor agonists; a short antibody-like protein, siRNA, or DNA molecule for immunotherapy. (8) A pharmaceutically acceptable salt, acid, derivative, hydrate or hydrated salt; or crystal structure; or an optical isomer, racemate, diastereomer or enantiomer of any of the above drugs.

4. The cytotoxic drugs D1 and D2 according to claim 1 are independently selected from: tubulysin and its analogues, maytansin and its analogues, taxane and its analogues, CC-1065 and its analogues, daunorubicin or doxorubicin and their analogues, amatoxins and their analogues, benzodiazepine dimers (e.g., pyrrolobenzodiazepine (PBD), tometacin, ampicillin, indolebenzodiazepine, imidazobenzothiazide or oxazolidinbenzodiazepine dimers) and their analogues, galicillin and enediyne antibiotic analogues, actinomycin and its analogues, azoxystrobin and its analogues, bleomycin and its analogues, epirubicin and its analogues, tamoxifen and its analogues. Analogs of idarubicin, dolastatin, auristatin (including monomethyl auristatin (MMAE), MMAF, auristatin PYE, auristatin TP, auristatin 2-AQ, 6-AQ, EB (AEB), and EFP (AEFP)) and their analogs, compressoritine, docamycin and its analogs, camptothecin, gerdemycin and its analogs, methotrexate and its analogs, thiotepa and its analogs, vincristine and its analogs, vincristine and its analogs, semi-mitalin and its analogs, nazuma-mide and its analogs, spliceostatin, a pladienolide, microcrystalline protein and its analogues, radiosensitin and its analogues, alterobactin and its analogues, a microsclerodermin and its analogues, theonellamide and its analogues, esperamicin and its analogues, PNU-159682 and its analogues, protein kinase inhibitors, MEK inhibitors, KSP inhibitors, nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, immunotoxins, cell receptor agonists, cell stimulating molecules or intracellular signaling molecules, one, two or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA) and PIWI-interacting RNA (piRNA) and stereoisomers, isosteres, analogues, or derivatives thereof. in: (a) Tubulysin analogues have the structure of formula (IV): Or a pharmaceutically acceptable salt, hydrate, or hydrated salt; or a crystal structure; or an optical isomer, racemate, diastereomer, or enantiomer thereof. in One or two connectors that can be independently connected to L1 and / or L2; when two Simultaneously connected to L1 and L2, R 1 and R 2 、or Z 2 and Z 3 This is the preferred dual-connection site; Where R 1 R 1’ R 2 R 3 and R 4 Independently, it is H, C1-C8 alkyl; C2-C8 heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroalkylcycloalkyl, carbocycloalkyl or alkylcarbonyl; or R 1 R 2 R 1 R 3 R 2 R 3 R 3 R 4 Or forming a 3-7 membered carbon ring, cycloalkyl, heterocyclic, heterocycloalkyl, aryl, or heteroaryl ring system; when independently or simultaneously connected to L1 or L2, R 1 and R 2 Y can be left as a default value. 1 It is N or CH; Where R 5 R 6 R 8 R 10 and R 11 Independently, it is H, or a C1-C4 alkyl or heteroalkyl group; Where R 7 Independently for H, R 14 -R 14 C(=O)X 1 R 15 ; or -R 14 X 1 R 15 ;X 1 Is it O, S, SS, NH, CH2, or NR? 14 ; Where R 9 Selected from H, OH, =O, -OR 14 -OC(=O)R 14 -OC(=O)NHR 14 -OC(=O)NR 14 R 15 OP(=O)(OR) 14 )2、-OC(=O)NR 14 R 15 OR 14 OP(=O)(OR 15 )2; When R 9 When connecting L1 or L2, R 9 It is -O-, -OC(=O)NH- or -OC(=O)N(R) 14 )-; Where R 11 Independently for H, R 14 -R 14 C(=O)R 15 -R 14 C(=O)X 2 R 15 , where X 2 It is -O-, -S-, -NH-, or -N(R) 14 )-; Where R 12 It is -COOH, -COSH, -CONH2, CONHNH2, CONHNHR 15 -CONH(R) 15 -COOR 15 -R 15 COR 16 -R 15 COOR 16 -R 15 C(O)NH2、-R 15 C(O)NHR 16 -COSR 15 R 15 S(=O)2R 16 -R 15 P(=O)(OR 17 )2、-R 15 OP(=O)(OR 17 )2、-COOCH2OP(=O)(OR 17 2. -COX 2 SO2R 17 -COOR 15 X 2 R 16 , tetrazole, imidazole, or triazole, X 2 It is -O-, -S-, -NH-, -N(R) 15 )-、-OR 15 -、-SR 15 -, CH2 or -NHR 15 -;When R 12 When connecting L1 or L2, R 12 Is -C(O)O-, -C(O)NH-, -C(=O)NHS(O)2R 15 -or-C(=O)N(R) 15 )-; R 13 and R 14 Independently, they are C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl; Z 2 and Z 3 Independently, H, O, S, NH, N(R) 15 ), NHNH, -OH, -SH, -NH2, NH, NHNH2, -NH(R 15 -OR 15 CO, -COX 2 -COX 2 R 16 R 17 F, Cl, Br, I, SR 16 NR 16 R 17 N = NR 16 N=R 16 NO2, SOR 16 R 17 SO2R 16 SO3R 16 OSO3R 16 PR 16 R 17 POR 16 R 17 PO2R 16 R 17 OP(O)(OR) 17 )2、OCH2OP(O)(OR 17 2. OC(O)R 17 OC(O)OP(O)(OR 17 2. PO(OR) 16 (OR) 17 ), OP(O)(OR 17 )OP(O)(OR 17 2. OC(O)NHR 17 ;-O-(C4-C 12 glycosides), -N-(C4-C 12 Glycosides; C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, or esters, ethers or amides of 2-8 carbon atoms; or peptides containing 1-8 amino acids (NH(Aa)). 1～8 Or CO(Aa) 1～8 (1-8 identical or different amino acids at the N-terminus or C-terminus), or having the formula (OCH2CH2) p Or (OCH2CH(CH3)) p The polyoxyethylene unit, wherein p is an integer from 0 to about 1000, or a combination of the aforementioned groups; X 2 It is O, S, SS, NH, CH2, OH, SH, NH2, CHR 15 or NR 15 ; R 15 R 16 and R 17 Independently, it can be H, C1-C8 alkyl, heteroalkyl; C2-C8 alkenyl, ynyl, heteroalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, alkylcarbonyl, or Na. + K + Cs + Li + Ca 2+ Mg + Zn 2+ N + (R 1 (R) 2 (R) 3 (R) 4 ), HN + (C2H5OH)3 salt; Y 1 and Y 2 Independently, it is either N or CH; q is 0 or 1; when q = 0, Y 3 By default, Y 4 Y 5 Y 6 and Y 7 Independently, Y can be CH, N, NH, O, S, or N(R1). 2 Y 4 Y 5 Y 6 and Y 7 Formation of heteroaromatic rings of furan, pyrrolothiophene, thiazole, oxazole, and imidazole, pyrazole, triazole, tetraazole, and thiadiazole; when q = 1, Y 3 Y 4 Y 5 Y 6 and Y 7 When Y is independently CH or N, 2 Y 3 Y 4 Y 5 Y 6 and Y 7 Formation of aromatic rings of benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetraazine, and pentaazine: The following are structural examples of Tubulysin analogues: Where R 20 It is H; C1-C8 straight-chain or branched alkyl or heteroalkyl, C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl straight-chain or branched; carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 (); or carboxylate, ester, ether, or amide of 1-8 carbons; or 1-8 amino acids; or having the formula (OCH2CH2) p Or (OCH2CH(CH3)) p The polyoxyethylene oxy group, where p is an integer from 0 to about 1000; or R 20 The default is that oxygen reacts with carbon to form a ketone, or a combination thereof; Z 3 and Z 3 Independently, H, OH, NH2, O, NH, COOH, COO, C(O), C(O), C(O)NH, C(O)NH2, R 18 OCH2OP(O)(OR) 18 2. OC(O)OP(O)(OR 18 2. OPO (OR) 18 2. NHPO (OR) 18 2. OP(O)(OR) 18 )OP(O)(OR 18 2. OC(O)R 18 OC(O)NHR 18 OSO2 (OR) 18 O-(C4-C) 12 - Glycosides), straight-chain or branched alkyl or heteroalkyl groups; C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl groups; C3-C8 aryl, aralkyl, heterocycloyl, carbocycloyl, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl straight-chain or branched groups; carbonates (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 ); R 17 and R 18 Independently H, straight-chain or branched alkyl or heteroalkyl; C2-C8 straight-chain or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight-chain or branched aryl, alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 ); R 19 It is H, OH, NH2, OSO2 (OR) 18 ), XCH2OP(O)(OR 18 2. XPO (OR) 18 2. XC(O)OP(O)(OR) 18 2. XC(O)R 18 XC(O)NHR 18 C1-C8 alkyl or carboxylic esters; C2-C8 alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl or alkylcarbonyl; or pharmaceutical salts; X is O, S, NH, NHNH, or CH2; R 7 The definition is the same as above; where the connection site In formula IV-01-IV-79, it is the same as that shown according to formula (IV); (b) Galiciacin and its related enediyne antibiotics have the following molecular formulas: Or an elemental isotope substitute, or a pharmaceutically acceptable salt, hydrate or hydrated salt; or a polycrystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof; in It is a site connected to L1 or L2; (c) Geldemycin is a benzoquinone ansarmycin antibiotic, consisting of 17-AAG (17-N-allylamino-17-demethoxygeldemycin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldemycin), with the following molecular formula: in It is a site connected to L1 or L2; (d) Maytansin or its derivatives, including maytansin-type compounds, have the following molecular formulas: in It is a site connected to L1 or L2; (e) The structure of camptothecin (CPT) is shown in the following formula: Or a substitute for one or more elemental isotopes, or a pharmaceutically acceptable salt, hydrate or hydrated salt; or a polycrystalline structure; or an optical isomer, racemate, diastereomer or enantiomer thereof; R1, R2, and R4 are independently selected from H, F, Cl, Br, CN, NO2, C1-C8 alkyl; O-C1-C8 alkyl, NH-C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or esters, ethers, amides, carbonates, ureas, or carbamates containing 2-8 carbon atoms; R3 can be H, OH, NH2, C1-C8 alkyl, O-C1-C8 alkyl; NH-C1-C8 alkyl; C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C2-C8 ester, ether, amide, carbonate, urea, or carbamate; or R1R2, R2R3, and R3R4 can independently form a 5-7 membered carbon ring, heterocycle, heterocycloalkyl, aryl, or heteroaryl ring system. These are the sites in the molecule that are connected to L1 or L2. Camptothecin (CPTs) and its derivatives have the following structural formulas: Or a substitute for one or more elemental isotopes, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; Or the polycrystalline structure of these compounds; or optical isomers, racemates, diastereomers or enantiomers; in It is a site that connects to L1 or L2; P 1 R1 is independently H, F, Cl, Br, I, SO2R2, SO3H, CN, OH, NH2, COOH, C(O)NH2, OCH2OP(O)(OR) 18 2. OC(O)OP(O)(OR 18 2. OPO (OR) 18 2. NHPO (OR) 18 2. OC(O)R 18 OP(O)(OR) 18 )OP(O)(OR 18 2. OC(O)NHR 18 , OC(O)N(C2H4)2NCH3, OSO2(OR 18 O-(C4-C) 12 - Glycoside), OC(O)N(C2H4)2CH2N(C2H4)2CH3, O-(C1-C8 branched or branched alkyl), O-(C1-C8 straight or branched alkyl)-OH, C1-C8 straight or branched alkyl or heteroalkyl, C2-C8 straight or branched alkenyl, alkynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight or branched aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 R2 and R3 are independently H, C1-C8 straight-chain or branched alkyl groups, or C2-C8 straight-chain or branched heteroalkyl groups, ethers, amines, esters, or amides; furthermore, R2 and R3 can be linked together to form five- or six-membered rings or cycloalkyl groups, cycloalkylamines, or cycloalkanoamides, cyclohexylalkylamides; R 17 and R 18 Independently H, straight-chain or branched alkyl or heteroalkyl; C2-C8 straight-chain or branched alkenyl, ynyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 straight-chain or branched aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, carbonate (-C(O)OR) 17 ), carbamate (-C(O)NR 17 R 18 X is NH, O, S, S(O2), NHS(O2), NHS(O2)NH, NHP(O)(OH), N + (R2)(R3), NHC(O)NH, NHC(O), NHC(O)O, N(CH2CH2)2N, CON(CH2CH2)2N, CON(CH2CH2)2N + (R2)(R3), or CH2. (f) Combretastatins are natural phenols with the following molecular formula: (g) Taxane has the following structure: in It is a site attached to L1 or L2; Ar and Ar' are independently aryl or heteroaryl. (h) The structures of anthracycline drugs are as follows: Among them is the site that links to L1 or L2. (i) Vinca alkaloids are a class of antimitotic and antimicrotubule alkaloids that act by inhibiting cancer cell division. Vinca alkaloids include vinblastine, vincristine, vindesine, epoxyvinblastine, vinorelbine, vinblastine, vincatin, vincatin, vincristine, vincatinol, minoviceine, methoxyminoviceine, vincatinol, deoxyvincatinol, vincatinol, vincatinol, vincatinol, vincatinol, vincatinol, and vincatinol. Their structural formulas are as follows: in It connects to either L1 or L2 sites; (i) Dolastatins and their peptide analogs and derivatives, including Dolastatin 10, Aurestatin E (AE), Aurestatin EB (AEB), Aurestatin EFP (AEFP), MMAD (monomethyl Aurestatin D or monomethyl Dolastatin 10), MMAF (monomethyl Aurestatin F or N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine), MMAE (monomethyl Aurestatin E or N-methylvaline-valine-dolaisoleuine-dolaproine-norephedrine), 5-benzoylvaleric acid-AE ester (AEVB), and Aurestatin F-phenylenediamine (AFP): Or an isotopic substitute of one or more elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; Or the polycrystalline structure of these compounds; or optical isomers, racemates, diastereomers or enantiomers; Where R 1 R 2 R 3 R 4 and R 5 Independently H; C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, heterocycloalkyl or acyloxyamine; or a peptide containing 1-8 amino acids, or having the formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to approximately 1000. Two Rs: R 1 R 2 R 2 R 3 R 1 R 3 Or R 3 R 4 It can form 3-8 membered rings of alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl groups; Y1 and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1; when not connected to the site When (independently connected with L1 and / or L2) the values ​​are OH, NH2, NHNH2, NHR5, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1; R 12 Is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1-COOH, NH-(Aa) n COOH, O(CH2CH2O) p CH2CH2OH, O(CH2CH2O) p CH2CH2NH2, NH(CH2CH2O) p CH2CH2NH2, NR1R1', NHOH, NHOR1, O(CH2CH2O) p CH2CH2COOH, NH(CH2CH2O) p CH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O) p CH2CH2NH-SO3H, NH(CH2CH2O) p CH2CH2NHSO3H, R1-NHSO3H, NH-R1-NHSO3H, O(CH2CH2O) p CH2-CH2NHPO3H2, NH(CH2CH2O) p CH2CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O) p CH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, NH(CH2CH2NH) p CH2-CH2NH2, NH(CH2CH2S) p CH2CH2NH2, NH(CH2CH2NH) p CH2CH2OH, NH(CH2CH2S) p CH2-CH2OH, NH-R1-NH2, or NH(CH2CH2O) p CH2CH2NHPO3H2, where Aa consists of 1-8 identical or different amino acids; p is 1-5000; and the definitions of R1, R2, R3, R4, R5, R5', Z1, Z2, and n are the same as above. (k) Hemiasterlin and its analogues have the following formula: Where R 1 R 2 R 3 R 4 and R 5 Independently H; C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester, ether, amide, amine, heterocycloalkyl or acyloxyamine; or peptide containing 1-8 amino acids, or having the formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to approximately 5000; additionally, R 2 R 3 It can form alkyl, aryl, heteroaryl, heteroalkyl or alkylcycloalkyl groups with 3 to 8 rings. (l) Eribulin has the following formula: These are sites that connect independently to L1 and / or L2; (m) Nicotinamide phosphoribosyltransferase inhibitors (NAMPT) have the following structures: NP01, NP02, NP03, NP04, NP05, NP06, NP07, NP08, and NP09: Or an isotopic substitute of one or more elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; These compounds may have polycrystalline structures; or optical isomers, racemates, diastereomers, or enantiomers; among which Same as above; X5 is F, Cl, Br, I, OH, OR1, R1, OPO3H2, OSO3H, NHR1, OCOR1, NHCOR1. The structures of (n) benzodiazepine dimers and their analogues are shown below: Or an isotopic substitute of one or more elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; Or the polycrystalline structure of these compounds; or optical isomers, racemates, diastereomers or enantiomers; in, The definitions of Z1, Z2 and n are as described above; X1, X2, Y1, and Y2 are independently O, N, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH, C(O)NHNHC(O), and C(O)NR1; R 1 R 2 R 3 R 1’ R 2’ and R 3’ Independently, it can be H, F, Cl, =O, =S, OH, SH, C1-C8 straight-chain or branched benzyl, aryl, alkenyl, heteroaryl, heteroalkyl, alkylcycloalkyl, ester (COOR5 or -OC(O)R5), ether (OR5), amide (CONR5), carbamate (OCONR5), amine (NHR5, NR5R5'), heterocycloalkyl, or acyloxyamine (-C(O)NHOH, -ONHC(O)R5), or a peptide containing 1-20 natural or non-natural amino acids, or a structure such as (OCH2CH2). p Or (OCH2CH(CH3)) p The polyoxyethylene unit, where p is an integer from 1 to 5000. Two R groups, such as 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’ It can independently form alkyl, aryl, heteroaryl, heteroalkyl, or alkylcycloalkyl rings of 3-8 members; X3 and Y3 are independently N, NH, CH2 or CR5, and one of X3 and Y3 can be omitted; Where R1 and R2 are C1-C8 straight-chain or branched alkyl, heteroalkyl; C3-C8 aryl, heteroaryl, alkylcycloalkyl, acyloxy, alkylaryl, alkylaryloxy, alkylarylamino, alkylarylthiol; or 1-6 identical or different amino acid / peptide sequences (Ar)r, r = 1-6. Among them, R4, R5, R5', R6, R 12 and R 12 'Independently H, OH, NH2, NH(CH3), NHNH2, COOH, SH, OZ3, SZ3, F, Cl, or C1-C8 straight-chain or branched alkyl, aryl, heteroaryl, heteroalkyl, alkylcycloalkyl, acyloxyamine; Z3 is H, OP(O)(OM1)(OM2), OCH2OP(O)(OM1)(OM2), OSO3M1, or O-glycoside (glucosidase, galactoside, mannoside, glucuronide / glucuronic acid, alloside, fructoside, etc.), NH-glycoside, S-glycoside, or CH2-glycoside; M1 and M2 are independently H, Na, K, Ca, Mg, NH4, or NR1R2R3; X6 is CH, N, P(O)NH, P(O)NR1, CHC(O)NH, C3-C8 aryl, heteroaryl, alkylcycloalkyl, acyloxy, alkylaryl, alkylaryloxy, alkylarylamino or Aa (amino acid, preferably Lys, Phe, Asp, Glu, Ser, Thr, His, Cys, Tyr, Trp, Gln, Asn, Arg); X and X' can be CH2 or N independently. When the six-membered aromatic ring becomes a five-membered ring, X and / or X' can be O, S or NH. Y 21 It is Ms(mesyl), Ts(tosyl) or Tf(trifyl), SO3H, P(O)(OH)2, CH2(O)P(O)(OH)2, glycoside; R 31 It is H, C1-C8 alkyl or Ar, CF3; The definition is as described above. (o) CC-1065 analogues and duocarmycin analogues have the following structural formulas: CC01, CC02, CC03, CC04, CC05, CC06 and CC07: When connected to the site When X1, X2, Y1, and Y2 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R2), C(O)NHNHC(O), and C(O)NR1; or when not connected to a connection site When, it is OH, NH2, NHNH2, NHR1, SH, C(O)OH, C(O)NH2, OC(O)NH2, OC(O)OH, NHC(O)NH2, NHC(O)SH, OC(O)NH(R1), N(R1)C(O)NH(R2), C(O)NHNHC(O)OH and C(O)NHR1; Z3 is H, PO(OM1)(OM2), SO3M1, CH2PO(OM1)(OM2), CH3N(CH2CH2)2NC(O)-, O(CH2CH2)2NC(O)-, R1, or glycoside; wherein the definitions of R1, R2, R3, M1, M2 and n are the same as those described above. (p) Amatoxins and their analogues have the following chemical formulas: AmO1, AmO2 and AmO3: Or an isotopic substitute of one or more chemical elements, or a pharmaceutically acceptable salt, hydrate, or hydrated salt; Or the polycrystalline structure of these compounds; or optical isomers, racemates, diastereomers, or enantiomers; wherein X1 and Y1 are independently O, NH, NHNH, NR5, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, CHNH, CH2O, C(O)NHNHC(O) and C(O)NR1; R7, R8, and R9 are independently H, OH, OR1, NH2, NHR1, C1-C6 alkyl, or default; Y2 is O, O2, NR1, NH, or default; R 10 It is CH2, O, NH, NR1, NHC(O), NHC(O)NH, NHC(O)O, OC(O)O, C(O), OC(O), OC(O)(NR1), (NR1)C(O)(NR1), C(O)R1 or the default; R 11 Is OH, NH2, NHR1, NHNH2, NHNHCOOH, O-R1-COOH, NH-R1-COOH, NH-(Aa) r COOH, O(CH2CH2O) p CH2CH2OH, O(CH2CH2O) p CH2CH2NH2, NH(CH2CH2O) p CH2CH2NH2, NR1R2, O(CH2CH2O) p CH2CH2-COOH, NH(CH2CH2O) p CH2CH2COOH, NH-Ar-COOH, NH-Ar-NH2, O(CH2CH2O) p CH2CH2-NHSO3H, NH(CH2CH2O) p CH2CH2NHSO3H, R1-NHSO3H, NH-R1-NHSO3H, O(CH2CH2O) p -CH2CH2NHPO3H2, NH(CH2CH2O) p CH2CH2NHPO3H2, OR1, R1-NHPO3H2, R1-OPO3H2, O(CH2CH2O) p CH2CH2OPO3H2, OR1-NHPO3H2, NH-R1-NHPO3H2, or NH(CH2CH2O) p CH2-CH2NHPO3H2, of which (Aa) r Refers to 1-8 amino acids; n and m1 are independently 1-20; p is 1-5000; the definitions of R1, R2 and Ar are the same throughout this patent application; The definition is as described above. (q)Spliceostatins and pladienolides are spliceostatin A, FR901464, and 2S,3Z)-5-{[(2R,3R,5S,6S)-6-{(2E,4E)-5-[(3R,4R,5R,7S)-7-(2-hydrazyl-2-oxoethyl)-4-hydroxy-1,6-dioxapyridin[2,5]oct-5-yl]-3-pentamethyl-2,4-dien-1-yl-1}-2,5-dimethyltetrahydro-2H-pyrano-3-yl]amino}-5-oxy-3-en-2-yl acetate, pladienolide B, pladienolide D, and E7107 have the following parent nucleus structure Sp-01: (r) Protein kinase inhibitors selected from Adavasertib, Afatinib, Axitinib, Baffitinib, Bosutinib, Kemetinib, Crizotinib, Carboplatinib, Dasatinib, Entrectinib, Erdafiltinib, Erlotinib, Fotatinib, Gefitinib, Ibrutinib, Imatinib, Lapatinib, Lenvatinib, Mobitinib, Nilotinib, Pazopanib, Panatinib, Ponatinib, Rebastinib, Regorafenib, Ruxotinib, Sorafenib, Sunitinib, SU6656, Tofatinib, Vandetinib, Verafenib, Entrectinib, Palbociclib, Ribociclib, Abecil, Dacomitinib, Lenatinib, (CO-1686), Osimertinib, AZD3759, and Nazartinib (EGF816), with the following structures, PK01~PK41: Z5 and Z5' are independently selected from O, NH, NHNH, NR5, 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(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1. (s) MEK inhibitors are selected from PD0325901, celutinib (AZD6244), cobimetinib (XL518), refatinib, trametinib (GSK1120212), pimasertib, bimetinib (MEK162), AZD8330, RO4987655, RO5126766, WX-554, E6201, GDC-0623, PD-325901, and TAK-733, and their structures are as follows: Z5 is selected from O, NH, NHNH, NR5, 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(R1), N(R1)C(O)N(R2), C(O)NHNHC(O) and C(O)NR1. (t) The protease inhibitors are selected from carfilzomib, clindamycin, retamoline, and indibulin, and their structures are shown below: (u) Immunotoxins are selected from diphtheria toxin (DT), cholera toxin (CT), trichosporine protein (TCS), amylase, Pseudomonas exotoxin A (ETA), erythrotoxin, diphtheria toxin, AB toxin, type III exotoxin, proaeroly-sin, and topsalysin; (v) Cell-binding ligands or receptor agonists are selected from: folic acid derivatives, glutamate derivatives, somatostatin and its analogues (selected from octreotide (Sandostatin) and lanreotide (Somatuline)), aryl sulfonamides, pituitary adenylate cyclase activating peptide (PACAP) (PAC1), vasoactive intestinal peptide (VIP / PACAP) (VPAC1, VPAC2), melanocyte-stimulating hormone (α-MSH), cholecystokinin (CCK) / gastrin receptor agonists, and bufotalin (selected from Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) / gastrin-releasing peptide (GRP). Neurotensin receptor ligands (NTR1, NTR2, NTR3); Substance P (NK1 receptor) ligand; neuropeptide Y (Y1-Y6); homing peptides including RGD (Arg-Gly-Asp), NGR (Asn-Gly-Arg), dimer and multimeric cyclic RGD peptides (selected from cRGDfV), TAASGVRSMH and LTLRWVGLMS (chondroitin sulfate proteoglycan NG2 receptor ligand) and F3 peptide; cell-penetrating peptides (CPPs);Peptide hormones are selected from luteinizing hormone-releasing hormone (LHRH) agonists and antagonists, as well as gonadotropin-releasing hormone (GnRH) agonists. They act by targeting follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone production. Examples include buserreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt), gosoreline (Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), and gosoreline (Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzG). Histamine (Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt), Leuprorelin (Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), Nafarelin (Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2), Triptorelin (Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2), Nafarelin, Dilorlin, Aberelin (Ac-D-2Na) l-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2), Cetrorelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyri) dyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2), degarelix (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl )-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2), and degarelic (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-NH2); pattern recognition receptors (PRRs), selected from Toll receptor-like (TLR) ligands, C-type lectins and nodular receptor (NLR) ligands; calcitonin receptor agonists; Integrin receptors and their receptor subclasses (selected from αvβ1, αvβ3, αvβ5, αvβ6, α6β4, α7β1, α) L β2, α IIb β3) agonists (selected from GRGDSPK, cyclo(RGDfV)(L1) and its derivatives [cyclic (-N(Me)R-GDfV), cyclic (R-Sar-DfV), cyclic (RG-N(Me)D-fV), cyclic (RGD-N(Me)fV), cyclic (RGDf-N(Me)V-)(Silengitide)]; Anticalin (a derivative of lipid transport protein); Adnectins (10 FN3 (fibronectin)); designed ankylosing repeats (DARPins); Avimers; EGF receptor, or VEGF receptor agonists; Cellular receptor agonists are selected from LB01 (folic acid), LB02 (PMSA ligand), LB03 (PMSA ligand), LB04 (PMSA ligand), LB05 (somatostatin), LB06 (somatostatin), LB07 (octreotide, somatostatin analog), LB08 (lanreotide, somatostatin analog), LB09 (Sanvar, somatostatin analog), LB10 (CAIX ligand), LB11 (CAIX ligand), LB12 (gastrin-releasing peptide receptor (GRPr), MBA), LB13 (luteinizing hormone-releasing hormone (LH-RH) and G... LB14 (LH-RH and GnRH ligand), LB15 (GnRH antagonist, Ab-lix), LB16 (cobalamin, vitamin B12 analog), LB17 (cobalamin, vitamin B12 analog), LB18 (for αvβ3 integrin receptor, cyclic RGD pentapeptide), LB19 (VEGF receptor isodivalent peptide ligand), LB20 (neuromycin B), LB21 (frog dermalin, acting on G protein-coupled receptors), LB22 (TLR2, acting on Toll-like receptors), LB23 (acting on androgen receptors), LB2 4 (Cialex or cyclic (-RGDfV-)αv integrin receptor, LB23 (flucortisone), LB25 (rifabutin analog), LB26 (rifabutin analog), LB27 (rifabutin analog), LB28 (fludrocortisone), LB29 (dexamethasone), LB30 (fluticasone propionate), LB31 (beclomethasone propionate), LB32 (triamcinolone acetate), LB33 (prednisolone), LB34 (prednisolone), LB35 (methylprednisolone), LB36 (betamethasone), LB37 (irinotecan analog), LB38 (crizotinib analog), LB39 (boron) The following are biosynthetic peptides: tezomib analogue, LB40 (carfizzomib analogue), LB41 (carfizzomib analogue), LB42 (leuprorelin analogue), LB43 (triptorelin analogue), LB44 (clindamycin), LB45 (liraglutide analogue), LB46 (vincristine analogue), LB47 (retapalline analogue), LB48 (timpanib analogue), LB49 (vincristine analogue), LB50 (lixisenpeptide analogue), LB51 (osidinib analogue), LB52 (nucleoside analogue), LB53 (erlotinib analogue), and LB54 (lapatinib analogue), the structures of which are shown below: Where X4, Y1 are independently O, NH, NHNH, NR1, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, C(O)NHNHC(O) and C(O)NR1 and R1 are C1-C8 alkyl groups. (w) One, two, or more DNA, RNA, mRNA, small interfering RNA (siRNA), microRNA (miRNA), and PIWI-interacting RNA (piRNA) have the following structures: in These are the sites that connect to the branch connectors; It is single-stranded or double-stranded DNA, RNA, mRNA, siRNA, miRNA, or piRNA; X1 and Y are independently O, NH, NHNH, NR1, S, C(O)O, C(O)NH, OC(O)NH, OC(O)O, NHC(O)NH, NHC(O)S, OC(O)N(R1), N(R1)C(O)N(R1), CH2, C(O)NHNHC(O) or C(O)NR1.

5. According to claim 1, the binder components L1, L2, La1, La2, Lb1, Lb2, Lc1, and Lc2 independently comprise: (a) A self-destructive connective component having one of the following structures: Where (*) represents additional spacers or breakable linker units, or linkers for cytotoxic agents and / or fine antibodies; X 1 Y 1 Z 2 and Z 3 Independently NH, O, or S; Z 1 Independently, it is H, NH, O, or S; v is 0 or 1; U 1 Independently, it can be H, OH, C1-C6 alkyl, or (OCH2CH2). n F, Cl, Br, I, OR5, SR5, NR5R5', N=NR5, N=R5, NR5R5', NO2, SOR5R5', SO2R5, SO3R5, OSO3R5, PR5R5', POR5R5'PO2R5R5', OPO(OR5)(OR5'), or OCH2PO(OR5(OR5') wherein R5 and R5' are as defined above; preferably R5 and R5' are independently selected from H, C1-C8 alkyl, C2-C8 alkenyl, alkynyl or heteroalkyl, C3-C8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocyclic alkyl, heteroaryl, alkyl carbonyl or glycoside; or pharmaceutical cationic salts. (b) Non-self-destructive connective components have one of the following structures: ＊ (CH2CH2O) r ＊ ; Where (*) represents another spacer R1 or a breakable linker unit, or a junction of a cytotoxic molecule and / or a cell-binding molecule; X 1 Y 1 U 1 R5 and R5' are defined as above; r is 0-100; m and n are independently 0-6. (c) Constituting one or more of the following linker components: 6-maleimide hexanoyl ("MC"), maleimide propionyl ("MP"), valine-citrulline ("val-cit" or "vc"), alanine-phenylalanine ("ala-phe" or "af"), p-aminobenzyloxycarbonyl ("PAB"), 4-thiopentanoyl ("SPP"), 4-(N-maleimidemethyl)cyclohexane-1-acyl ("MCC"), (4-acetyl)aminobenzoyl ("SIAB"), 4-thiobutyryl (SPDB), 4-thio-2-hydroxysulfonyl-butyryl (2-Sulfo-SPDB), or a natural or non-natural peptide containing 1 to 8 natural or non-natural amino acid units. Lysine, glutamic acid, aspartic acid, cysteine, or tyrosine may contain the formula (OCH2CH2). p OR3, (OCH2CH(CH3)) p OR3, NH(CH2CH2O) p R3, C(O)(CH2CH2O) p R3, C(O)(CH2CH2OCH2CH) p R3, NH(CH2CH(CH3)O) p R3, C(O)(CH2OCH2CH) p R3, N[(CH2CH2O) p R3][(CH2CH2O) p’ R 3’ ],(OCH2CH2) p COOR3, or CH2CH2(OCH2CH2) p COOR3, NH(CH2CH2O) p CH2CH2R3, wherein p and p' are independently integers selected from 0 to about 100 or combinations thereof; wherein R3 and R3' are independently H, OH, NH2, N(CH2)2, N(C2H5)2, N(C3H7), C(=O)H, C(=O)CH3, C1-C8 alkyl, NH (C4-C7 glycoside) or NH (C 4～77 2 glycosides; or combinations thereof; (d) One or more breakable connectors, with the following structure: -(CR5R6) m (Aa)r(CR7R8) n (OCH2CH2) t -、-(CR5R6) m (CR7R8) n (Aa) r (OCH2CH2) t -、-(Aa) r -(CR5R6) m (CR7R8) n (OCH2CH2) t -、-(CR5R6) m (CR7R8) n (OCH2CH2) r (Aa) t -、-(CR5R6) m -(CR7=CR8)(CR9R 10 ) n (Aa) t (OCH2CH2) r -、-(CR5R6) m (NR 11 CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (Aa) t (NR 11 CO)(CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (OCO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (CO)(Aa)t-(CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (NR 11 CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m -(OCO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-(CR5R6) m (CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-(CR5R6) m -phenyl-CO(Aa) t (CR7R8) n -、-(CR5R6) m -furan-CO(Aa) t (CR7R8) n -、-(CR5R6) m -Oxazole-CO(Aa) t (CR7R8) n -、-(CR5R6) m Oxazole-CO-(Aa) t (CCR7R8) n -、-(CR5R6) t -Thiophene-CO(CR7R8) n -、-(CR5R6) t -imidazolium-CO-(CR7R8) n -、-(CR5R6) t -morpholine-CO(Aa) t -(CR7R8) n -、-(CR5R6) t Piperazine-CO(Aa) t (CR7R8) n -、-(CR5R6) t -N-methylpiperazine-CO(Aa) t -(CR7R8) n -、-(CR5R) m -(Aa) t Phenyl-,-(CR5R6) m -(Aa) t Furan-, -(CR5R6) m -Oxazole (Aa) t -、-(CR5R6) m -Oxazole (Aa) t -、-(CR5R6) m -thiophene-(Aa) t -、-(CR5R6) m -Imidazole (Aa) t -、-(CR5R6) m -morpholine-(Aa) t -、-(CR5R6) m -piperazine-(Aa) t -、-(CR5R6) m -N-methylpiperazine-(Aa) t -、-K(CR5R6) m (Aa)r(CR7R8) n (OCH2CH2) t -、-K(CR5R6) m (CR7R8) n -(Aa) r (OCH2CH2) t -、-K(Aa) r (CR5R6) m (CR7R8) n (OCH2CH2) t -、-K(CR5R6) m (CR7R8) n -(OCH2CH2) r (Aa) t -、-K(CR5R6) m (CR7=CR8)(CR9R 10 ) n (Aa) t (OCH2CH2) r -、-K(CR5R6) m -(NR 11 CO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (Aa) t (NR 11 CO)(CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (OCO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-K(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-K(CR5R6) m (CO)(Aa) t -(CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (NR 11 CO)-(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m -(OCO)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (OCNR7)(Aa) t (CR9R 10 ) n (OCH2CH2) r -、-K(CR5R6) m (CO)(Aa) t (CR9R 10 ) n -(OCH2CH2) r -、-K(CR5R6) m -phenyl-CO(Aa) t (CR7R8) n -、-K-(CR5R6) m -furan-CO(Aa) t -(CR7R8) n -、-K(CR5R6) m -Oxazole-CO(Aa) t (CR7R8) n -、-K(CR5R6) m -Oxazole-CO(Aa) t -(CR7R8) n -、-K(CR5R6) t -Thiophene-CO(CR7R8) n -、-K(CR5R6) t Imidazole-CO-(CR7R8) n -、-K(CR5R6) t Morpholine-CO(Aa) t (CR7R8) n -、-K(CR5R6) t Piperazine-CO(Aa) t -(CR7R8) n -、-K(CR5R6) t -N-methylpiperazine CO(Aa) t (CR7R8) n -、-K(CR5R) m (Aa) t Phenyl, -K-(CR5R6) m -(Aa) t Furan-,-K(CR5R6) m -Oxazole (Aa) t -、-K(CR5R6) m -Oxazole (Aa) t -、-K(CR5R6) m -thiophene-(Aa) t -、-K(CR5R6) m -Imidazole (Aa) t -、-K(CR5R6) m -morpholine (Aa) t -、-K(CR5R6) m -piperazine-(Aa) t G, -K(CR5R6) m N-methylpiperazine (Aa) t -; where m, Aa, m, n, R3, R4, and R5 are defined as described above; t and r are independently 0-100; R6, R7, and R8 are independently selected from H; halides; C1-C8 alkyl, aryl, alkenyl, alkynyl, ether, ester, amine, or amide, optionally substituted with one or more halides, CN, NR1R2, CF3, OR1, Aryl, heterocycles, S(O)R1, SO2R1, -CO2H, -SO3H, -OR1, -CO2R1, -CONR1, -PO2R1R2, -PO3H or P(O)R1R2R3; K is NR1, -SS-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -C=NH-O-, -C=N-NH-, -C(=O)NH-NH-, O, S, Se, B or C3-C6 heteroaryl. (e) One or more of the following structural units: Or a combination of the preceding text, in which These are connection sites; X2, X3, X4, X5, or X6, independently selected from NH, NHNH, N(R) 12 ), N(R 12 )N(R 12’ ), O, S, C1-C6 alkyl, C2-C6 heteroalkyl, alkylcycloalkyl, heterocycloalkyl, C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl, CH2OR 12 CH2SR 12 CH2NHR 12 , or 1-8 amino acids; of which R 12 and R 12’ Independently, it can be H, C1-C8 alkyl, C2-C8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C3-C8 aryl, arylalkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or C1-C8 ester, ether, or amide; or have the structural formula (OCH2CH2). p Or (OCH2CH(CH3)) p The polyethylene glycol unit, where p is an integer from 0 to about 100.

6. According to claim 1, wherein in formula (I) The structure preferably has the structure of formula (Ia); wherein in formula (II) The structure preferably has the structure of formula (Ib) or (Ic); wherein in formula (III) The structure preferably has the structure of formula (Id), (Ie), (If), or (Ig), or In equation (IV), there is a structure similar to that of equation (Ia) as shown below: in, "#" represents the site that connects to the drug or the linker L1 or L2; "#" represents the site that connects to the S (thiol), O (phenol), NH (amino), CHO (aldehyde), C(=O)(ketone), C(O)(NH)(amide), and C(O)(OH)(carboxylate) of the antibody; Aa represents an L- or D-natural or non-natural amino acid; "@" represents the site that connects to Lc1 or Lc2 as described in molecular formulas (I), (II), and (III). R1 is H, C1-C8 alkyl, OH, CH2OH, CH2CH2OH, NH2, SH, SCH3, CH2COOH, CH2CH2COOH, CH2CH2CH2CH2NH2, C6H5, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2; r is 0-12; when r is not 0, (Aa)r are the same or different amino acids or peptide units; m1=1-18; m2=1-100; m3=1-8; m4=0-8; m5=1-8; Y 7 is NH, OCH2NH, NHC(=O), NHNH, C(=O)NH, N(R1), SO2, P(O)(OH), NHS(O)2, NHS(O)2NH, NHS(O)2NHC(O), NHS(O)2NHC(O)O, NHS(O)2NHC(O)NH, NHP(O)(OH), NHP(O)(OH)NH, OP(O)(OH)O, NHP(O)(OH)O, OP(O)(OH)NH, S, O, OP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)O, OCH2CH2O, OCH2CH2NH, N(CH2CH2)2N, NHC6H4NH, CH2; Y 8 is NHC(=O), NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH, C(O)NH, OC(O)NH, NHC(O)NH, C(O), N, NH, CH2, or CH; Lv1' and Lv2' are independently selected from: in These are the sites for connecting to the linker components; "#" represents sites as shown in the formulas Lv1' and Lv2', used to connect the antibody's thiol (S), phenolic hydroxyl (O), amino (NH), aldehyde (CHO), carbonyl (C(=O)), amide (C(O)(NH)), and carboxyl (C(O)(OH)); where R1, X1', and X2' are as described above; X represents O, NH, S, or CH2; and the bond connecting the two atoms is... This indicates that any one of the atoms can be attached; Ar is an aromatic group.

7. According to claim 1, the core connector substructure (L1') has the affinity ligand in formula (I): Where (L1”) is further selected from equation (Ia'): Where Aa is an L- or D-natural or non-natural amino acid; A1 is the affinity ligand as defined in claim 1; R1 is H, C1-C8 alkyl, OH, CH2OH, CH2CH2OH, NH2, SH, SCH3, CH2COOH, CH2CH2COOH, CH2CH2CH2CH2NH2, C6H5, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2; r is 0-12; when r is not 0, (Aa)r are the same or different amino acids or peptide units; m1=1-18; m2=1-100; m3=1-8; m4=0-8; m5=1-6; m7=1-8; Y 7 is NH, OCH2NH, NHC(=O), NHNH, C(=O)NH, N(R1), SO2, P(O)(OH), NHS(O)2, NHS(O)2NH, NHS(O)2NHC(O), NHS(O)2NHC(O)O, NHS(O)2NHC(O)NH, NHP(O)(OH), NHP(O)(OH)NH, OP(O)(OH)O, NHP(O)(OH)O, OP(O)(OH)NH, S, O, OP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)NH, NHP(O)(OH)OP(O)(OH)O, OCH2CH2O, OCH2CH2NH, N(CH2CH2)2N, NHC6H4NH, CH2; Y 8 is NHC(=O), NH, O, NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH, C(O)O, C(O), OC(O)NH, C(O)NH, or Ar; R9 is (O=)CR1, (O=)CNHR1, NHC(=O), NH, O, NHS(O2), NH(SO), NHS(O2)NH, NHP(O)(OH)NH or C(O)NH, R1(COCH2NH m4 H, R1(Aa) r , (Aa)r, C(O), Ar or R3 is H, C1-C8 alkyl, ester, amide, aryl, ketone, alkyl acid, alkanol, alkylamine, CH2C6H5, CH2C6H4OH, CH(OH)CH3, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(=NH)NH2; R1 is as defined above.

8. According to claim 1, the core connecting substructure (referred to as the L1' and L2' merging) has the affinity ligand in formula (III): Preferably, the following formulas (Ib) and (Ic) are used: Among them, R1, Y 7 Y 8 The definitions of R9, A1, Aa, r, m1, m2, m4, and m5 are the same as those in claims 6 and 7.

9. According to claim 1, the antibody drug binds to a branched affinity ligand having the following structure: The definitions of R and Rb are the same as above. Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH; R 43 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are cytotoxic drugs described in this application, and A1 and A2 are small molecule ligands or drugs described in this application. Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH; R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out). Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH; R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out). The mAb mentioned above is an antibody, and n ranges from 1 to 30.

10. According to claim 1, the conjugates of formulas (I), (II), (III), and (IV) can be readily prepared by coupling an antibody with a compound having formulas (V), (VI), and (VII), respectively: Alternatively, conjugates of formula (IV) can be prepared by sequentially conjugating formulas (V) and (V') with antibodies: Among them, D1, D2, L1, L2, La1, La2, Lb1, Lb2, Lc1, Lc2, Ld1, Ld2, Ld3, Ld4, Ld5, Ld6, A1, A2, A3, A4, A5, A6, E1, m1, m2, m3, m4, m5, m6, m7, m8, m9, m 10 m 11 , and m 12 Same as defined in claim 1; Lv1 and Lv2 are reactive groups, and are selected independently or jointly from: Where X1' and X2' are independently F, Cl, Br, l, OTf, OMs, OC6H4(NO2), OC6H3(NO2)2, OC6F5, OC6HF4, or Lv3; X2 is O, NH, N(R1), or CH2; R3 and R5 are independently H, R1, aromatic, heteroaromatic, or aromatic groups, wherein one or more H atoms are independently surrounded by -R1, halogen, -OR1, -SR1, -NR1R2, -NO2, -S(O)R1, -S(O)2R1, or -COOR1; Lv3 Lv3′ is independently selected from F, Cl, Br, I, leaving group of nitrophenol, N-hydroxysuccinimide (NHS), phenol, benzenethiol, dinitrophenol, pentafluorophenol, tetrafluorophenol, difluorophenol, monofluorophenol, pentachlorophenol, trifluoromethanesulfonate, imidazole, dichlorophenol, tetrachlorophenol, 1-hydroxybenzotriazole toluenesulfonate methanesulfonate, 2-ethyl-5-phenylisoxazole-3′-sulfonate, anhydrides formed by themselves or anhydrides formed with other anhydrides, such as acetic anhydride, formic anhydride, or intermediate molecules produced by condensation reagents used in peptide coupling reactions or Mitsunobu reactions.

11. The compound of formula (VI) and (VII) according to claim 10, wherein, The connection structure is as follows: Accordingly selected from: Where Lv3, Lv3', X1', and X2' are as described above; connection key Being located between two atoms means that it can connect to either of them.

12. The compound according to claim 10 is represented by the following structure: The definitions of Ra and Rb are the same as above. Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH; R 43 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are cytotoxic drugs described in this application, and A1 and A2 are small molecule ligands or drugs described in this application. Where R 41 and R 42 Independently, H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH: R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out). Where R 41 and R 42 Independently, it can be H, CH3, CH(CH3)2, CH(CH3)(C2H5), CH2COOH, CH2CH2COOH, CH2CONH2, CH2CH2CONH2, (CH2)4NH2, (CH2)4N(CH3)2, (CH2)4N(CH2CH3)2, (CH2)4N(CH2CH2CH3)2, (CH2)4N(CH(CH3)2)2, (CH2)3NHC(=NH)NH2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2CH2S(O2)CH3, CH2SH, CH2SO3H, CH2C6H5, and CH2C6H4OH; R 34 The molecule is H, CH3, CH2CH3, C(O)H, and C(O)CH3; D1, D2, D3, and D4 are the cytotoxic drugs described in this application, and A1, A2, and A3 are the small molecule ligands or drugs described in this application; m 11 The numbers are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and m 12 The numbers are 0, 1, 2, 3, and 4; when the number in the parentheses is 0, it means that the structure in the parentheses can be omitted (crossed out).

13. The antibody or antibody-like protein according to claim 1 or 9 is selected from: dAb, Fab, Fab′, F(ab′)2, Fv, nanobodies, bivalent antibodies, trivalent antibodies, tetravalent antibodies, microantibodies, full-length antibodies (polyclonal antibodies, monoclonal antibodies, antibody dimers, antibody multimers), multispecific antibodies (selected from bispecific antibodies, trispecific antibodies, or tetraspecific antibodies); single-chain antibodies, antibody fragments binding to target cells, monoclonal antibodies, single-chain monoclonal antibodies, monoclonal antibody fragments binding to target cells, chimeric antibodies, chimeric antibody fragments binding to target cells, domain antibodies, domain antibody fragments binding to target cells, surface-reconstructed antibodies, surface-reconstructed single-chain antibodies, or surface-reconstructed antibodies binding to target cells. Reconstructed antibody fragments, humanized antibodies or surface-reconstructed antibodies, humanized single-chain antibodies or humanized antibody fragments that bind to target cells, anti-idiotype (anti-Id) antibodies, CDRs, precursor antibodies, precursor antibody fragments, small immunoproteins (SIPs), lymphokines, hormones, vitamins, growth factors, colony-stimulating factors, nutrient transport molecules, high molecular weight proteins, fusion proteins, kinase inhibitors, gene targets, nanoparticles or polymers modified with antibodies or high molecular weight proteins; vitamins (including folic acid); or large molecular weight peptides, polymer micelles, liposomes, lipoprotein-based drug carriers, nanoparticle drug carriers, dendritic polymers, and the above particles coated or linked with cell-binding ligands or proteins.

14. The antibody or antibody-like protein according to claim 1, 9, or 13 is capable of targeting tumor cells, virus-infected cells, microbial-infected cells, parasite-infected cells, autoimmune disease cells, activated tumor cells, myeloid cells, activated T cells, affected B cells or melanocytes, or any dysfunctional cells expressing any 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, CD13, CD14, CD15, CD16, CD17, CD18, CD1 ...12w, CD13, CD14, CD15, CD16, CD17, CD18, CD19, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD11d, CD11c, CD 14. CD15, CD16, CD16a, CD16b, CDw17, CD18, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD26, CD27, CD28, CD29, CD30, CD31, CD32, CD32a, CD32b, CD33, CD 34. CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42, CD42a, CD42b, CD42c, CD42d, CD43, CD44, CD45, CD46, CD47, CD48, CD49b, CD49c, CD49c, CD49d, CD49 f, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD60, CD60a, CD60b, CD60c, CD61, CD62E, CD62L, CD62P, CD63, CD64, CD65, CD65s, CD66, C D66a, CD66b, CD66c, CD66d, CD66e, CD66f, CD67, CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD75, CD75s, CD76, CD77, CD78, CD79, CD79a, CD79b, CD80, CD 81. 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、CD211、CD212、CD213、CD213a1、CD213a2、CD214、CD215、CD216、CD217、CD218、CD218a、CD218、CD21b9、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD 231、CD232、CD233、CD234、CD235、CD235a、CD235b、CD236、CD237、CD238、CD 239, CD240, CD240ce, CD240d, CD241, CD242, CD243, CD244, CD245, CD246, CD247, CD248, CD249, CD250, CD251, CD252, CD253, CD254, CD255, CD256, CD25 7, CD258, CD259, CD260, CD261, CD262, CD263, CD264, CD265, CD266, CD267, CD268, CD269, CD270, CD271, CD272, CD273, CD274, CD275, CD276, CD277, CD2 78、CD279、CD281、CD282、CD283、CD284、CD285、CD286、CD287、CD288、CD289 、CD290、CD291、CD292、CD293、CD294、CD295、CD296、CD297、CD298、CD299、CD 300、CD300a、CD300b、CD300c、CD301、CD302、CD303、CD304、CD305、CD306、C D307、CD307a、CD307b、CD307c、CD307d、CD307e、CD307f、CD308、CD309、CD3 10、CD311、CD312、CD313、CD314、CD315、CD316、CD317、CD318、CD319、CD320 、CD321、CD322、CD323、CD324、CD325、CD326、CD327、CD328、CD329、CD330、CD 331、CD332、CD333、CD334、CD335、CD336、CD337、CD338、CD339、CD340、CD34 1、CD342、CD343、CD344、CD345、CD346、CD347、CD348、CD349、CD350、CD351、C D352, CD353, CD354, CD355, CD356, CD357, CD358, CD359, CD360, CD361, CD362, CD363, CD364, CD365, CD366, CD367, CD368, CD369, CD370, CD371, CD372CD373, CD374, CD375, CD376, CD377, CD378, CD379, CD381, CD382, CD383, CD384, CD385, CD386, CD387, CD388, CD389, CRIPTO, CRIPTO, CR, CR1, CRGF, CRIPTO, CXCR5, LY64, TDGF1, 4-1BB, APO2, ASLG659, BMPR1B, 4-1BB, 5AC, 5T4 (Trophoblast glycoprotein, TPBG, WNT-activating inhibitor 1 or WAIF1), adenocarcinoma antigen, AGS-5, AGS-22M6, initiator Antagonist receptor kinase 1, AFP, AKAP-4, ALK, α-integrin, αvβ6, aminopeptidase N, amyloid-β, androgen receptor, angiogenic factor 2, angiogenic factor 3, annexin A1, anthrax toxin protective antigen, anti-transfer protein receptor, AOC3 (VAP-1), B7-H3, Bacillus anthracis, BAFF (B cell initiation factor), BCMA, B lymphoma cells, bcr-abl, dermal ... CCL11 (CC fragment chemokine 11), CCR4 (CC chemokine receptor 4), CCR5, CD3E (ε), CEA (carcinoembryonic antigen), CEACAM3, CEACAM5 (carcinoembryonic antigen), CFD (factor D), Ch4D5, cholecystokinin 2 (CCK2R), CLDN18 (Claudin-18), clustering factor A, cMet, CRIPTO, FCSF1R (colony-stimulating factor 1 receptor), CSF2 (colony-stimulating factor 2, granulocyte-macrophage colony-stimulating factor (GM-CSF)), CTLA4 (cytotoxic T lymphocyte-associated protein 4), CTAA16.88 tumor antigen, CXCR4, CXC chemokine Factor receptor 4, cyclic ADP-ribonuclease, cyclin B1, CYP1B1, cytomegalovirus, cytomegalovirus glycoprotein B, Dabigatran, DLL3 (Δ-ligand 3), DLL4 (Δ-ligand 4), DPP4 (dipeptide-peptidase 4), DR5 (death receptor 5), E. coli Shiga toxin type-1, E. coli Shiga toxin type-2, ED-B, EGFL7 (EGF-like domain protein 7), EGFR, EGFRII, EGFRvIII, endothelial factor, endothelin B receptor, endotoxin, EpCAM (epithelial cell adhesion molecule), EphA2, Episialin, ERBB2 (epidermal growth factor receptor 2)ERBB3, ERG (TMPRSS2ETS fusion gene), E. coli, ETV6-AML, FAP (fibroblast activation protein α), FCGR1, alpha-fetoprotein, fibroin II β chain, fibronectin extra domain-B, FOLR (folate receptor), folate receptor α, folate hydrolase, Fos-associated antigen 1, respiratory syncytial virus F protein, coiled receptor, fucose GM1, GD2 ganglioside, G-28 (cell surface antigen glycolipid), GD3 idiotype, GloboH, Glypican 3. N-hydroxyacetylneuraminic acid, GM3, GMCSF receptor α chain, growth differentiation factor 8, GP100, GPNMB (transmembrane glycoprotein NMB), GUCY2C (guanylate cyclase 2C), guanylate cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase C receptor, heat-stable enterotoxin receptor (hSTAR), heat shock protein, 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 / dispersion factor), HHGFR, HIV-1, histone complexes, HLA-DR (human leukocyte antigen), HLA-DR10, HLA-DRB, HMWMAA, human chorionic gonadotropin, HNGF, human dispersion factor receptor kinase, HPV E6 / E7, Hsp90, hTERT, ICAM-1 (intercellular adhesion molecule 1), idiotype, IGF1R (IGF-1, insulin-like growth factor 1 receptor), IGHE, IFN-γ, influenza hemagglutinin, IgE, IgE Fc region, IGH, interleukins (including 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, or IL-28), IL31RA, ILGF2 (insulin-like growth factor 2), integrin (α4, αIIbβ3, αvβ3, α4β7, α5β1, α6β4, α7β7, α11β3, α5β5, αvβ5), interferon-γ-induced protein, ITGA2, ITGB2, KIR2D, Kappa Ig, 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 A1MAGE A3, MAGE 4, MART1, MCP-1, MIF (macrophage migration inhibitory factor, or glycosyl repressor (GIF)), MS4A1 (transmembrane 4-domain subfamily A member 1), MSLN (mesothelin), MUC1 (mucin 1, cell surface-associated (MUC1) or polymorphic epithelial mucin (PEM)), MUC1-KLH, MUC16 (CA125), MCP1 (monocyte chemoattractant protein 1), MelanA / MART1, ML-IAP, MPG, MS4A1, MYCN, myelin-associated glycoprotein, myostatin, NA17, NARP-1, NCA-90 (granulocyte antigen), Nectin-4 (ASG-22ME), N GF, neuronal apoptosis-regulating protease 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 non-mutant, P97, PAP, anti-(N-hydroxyacetylneuraminic acid) antibody binding site, PAX3, PAX5, PCSK9, PDCD1 (PD-1, programmed cell death protein 1), PDGF-Rα (α-platelet-derived growth factor receptor), PDGFR-β, PDL-1, PLAC1, PLAP-like testicular alkaline phosphatase, platelet-derived growth factor receptor β, sodium phosphate cotransporter, PMEL 17. Polysialic acid, proteinase 3 (PR1), prostate cancer, PS (phosphatidylserine), prostate cancer cells, Pseudomonas aeruginosa, PSMA, PSA, PSCA, rabies virus glycoprotein, RHD (Rh polypeptide 1 (RhPI)), Rhesus factor, RANKL, RhoC, Ras mutation, RGS5, ROBO4, respiratory syncytial virus, RON, ROR1, sarcoma translocation breakpoint, SART3, Sclerostin, SLAMF7 (SLAM) Member 7), SelectinP, SDC1 (multiligand proteoglycan 1), systemic lupus erythematosus (a), somatostatin C, SIP (sphingosine 1-phosphate), somatostatin, spermin 17, SSX2, STEAP1 (6-transmembrane prostate antigen 1), STEAP2, STn, TAG-72 (tumor-associated glycoprotein), susceptin, T cell receptor, T cell transmembrane protein, TEM1 (tumor vascular endothelial marker 1), TENB2, Tenascin C (TN-C), TGF-α, TGF-β (transforming growth factor β), TGF-β1, TGF-β2 (transforming growth factor 2), Tie (CD202b), Tie2, TIM-1 (CDX-014), Tn, TNF, TNF-α, TNFRSF8TNFRSF10B (tumor necrosis factor receptor superfamily member 10B), TNFRSF13B (tumor necrosis factor receptor superfamily member 13B), TPBG (trophoblast glycoprotein), TRAIL-R1 (TNF-associated necrosis-inducing ligand receptor 1), TRAILR2 (death receptor 5 (DR5)), tumor-associated calcium signaling sensor 2, tumor-specific glycosylated MUC1, TWEAK receptor, TYRP1 (glycoprotein 75), TRP-1 (Trop1), TRP-2 (Trop2), tyrosinase, VCAM-1, VEGF, VEGF-A, VEGF-2, VEGFR-1, VEGFR-2, vimentin, WT1, XAGE1, cells expressing insulin-like growth factor receptor, or cells expressing epidermal growth factor receptor.

15. The tumor cells according to claim 14 are selected from lymphoma cells, myeloma cells, renal cell carcinoma cells, breast cancer cells, prostate cancer cells, ovarian cancer cells, colorectal cancer cells, gastric cancer cells, squamous cell carcinoma cells, small cell lung cancer cells, non-small cell lung cancer cells, testicular cancer cells, malignant cells, or any cells whose growth and division rates are unregulated and accelerated, leading to cancer.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 or 9 and a pharmaceutically acceptable salt, carrier, diluent or excipient, or a combination thereof, for the treatment or prevention of cancer.

17. The pharmaceutical composition of claim 16 is a liquid or lyophilized solid dosage form, comprising, by weight: 0.01%-99% of one or more polyols, which are any one or more conjugates of claim 1 or 9; 0.0%-20.0% of one or more polyols; 0.0%-2.0% of one or more surfactants; 0.0%-5.0% of one or more preservatives; 0.0%-30% of one or more amino acids; 0.0%-5.0% of one or more antioxidants; 0.0%-0.3% of one or more metal chelators; 0.0%-30.0% of one or more buffer salts for adjusting the pH of the formulation to 4.5 to 7.5; and 0.0%-30.0% of one or more isotonic agents for adjusting the osmotic pressure to between about 250 and 350 mOsm when reconstituted for use in a patient. in, The polyols are selected from fructose, mannose, maltose, lactose, arabinose, xylose, ribose, rhamnose, galactose, and glucose. Non-reducing sugars include sucrose, trehalose, sorbitol, flocculated sugar, and raffinose. Sugar alcohols are selected from mannitol, xylitol, erythritol, maltitol, lactitol, erythritol, threitol, sorbitol, glycerol, or L-gluconate and their metal salts; The surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 65, polysorbate 80, polysorbate 81 or polysorbate 85, poloxamer, poly(ethylene oxide)-poly(propylene oxide), polyethylene-polypropylene, Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glycoside; dodecyl, myristoyl, linoleyl or stearyl sulfobetaine; dodecyl, myristoyl, linoleyl or stearyl sarcosine; linoleic acid, myristoyl or hexadecyl betaine. Bases; lauroylaminopropyl, cocamidopropyl, linoleamidopropyl, myristoylpropyl, palmitoylpropyl, or isostearylaminopropyl-betaine (e.g., lauroamide propyl); myristamidopropyl, palmitoylpropyl, or isostearylaminopropyl-dimethylamine; sodium methylcocoyl or disodium methyl taurate; dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropyl betaine, and cocoa amphoteric glycine ester; or isostearyl ethyliminomonoethyl sulfate; polyethylene glycol, polypropylene glycol, copolymers of ethylene glycol and propylene glycol; The preservative is selected from benzyl alcohol, octadecyl dimethyl benzyl ammonium chloride, hexamethyl ammonium chloride, benzalkonium chloride, phenol, butyl and benzyl alcohol, alkyl p-hydroxybenzoate esters such as methyl ester or propyl ester, catechol, resorcinol, cyclohexanol, 3-pentanol or m-cresol; The amino acids are selected from arginine, cystine, glycine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glycine, glutamic acid, or aspartic acid. The antioxidant is selected from ascorbic acid, glutathione, cystine or methionine; The chelating agent is selected from EDTA or EGTA; The buffer salt is selected from sodium, potassium, ammonium salts or trihydroxyethylamino salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid; triethylamine or aminobutanetriol hydrochloride, phosphate or sulfate; arginine, glycine, glycylglycine or histidine with anionic acetate, chloride, phosphate, sulfate or succinate; The isotonic agent is selected from mannitol, sorbitol, sodium acetate, potassium chloride, sodium phosphate, potassium phosphate, trisodium citrate, or sodium chloride.

18. The pharmaceutical composition according to claim 16 or 17, packaged in liquid or lyophilized solid form in vials, bottles, pre-filled syringes or pre-filled auto-injectors.

19. The conjugate according to claim 1 or 9, or the conjugate in the form of a pharmaceutical composition according to claim 16 or 17, having in vitro, in vivo, or ex vivo cell-killing activity.

20. The pharmaceutical composition according to claim 16 or 17, wherein the pharmaceutical composition is administered simultaneously with a chemotherapeutic agent, radiotherapy, immunotherapy agent, autoimmune disease agent, anti-infective agent or other conjugate to synergistically and effectively treat or prevent cancer.

21. The chemotherapeutic agent according to claim 20 is selected from: (1).a). Alkylating agents selected from nitrogen mustards: chlorpheniramine, chlorpromazine, cyclophosphamide, dacarbazine, estradiol nitrogen mustard, isocyclophosphamide, nitrogen mustard, dimethoxyamine hydrochloride, dioxane mustard oxide, amlodipine hydrochloride, mycophenolic acid, eugenol, guanobromide, neonitrogen mustard, benzyl mustard cholesterol, pine oxychloride, thiotetracycline, trefocillin, uracil; CC-1065 and its analogues adolaxine, calcetaxel, pyrazinazole and their synthetic analogues; docamycin and its synthetic analogues KW-2189 and CBI-TMI or CBI dimer; benzodiazepine dimer or pyrrolobenzodiazepine (PBD), thiamethoxam Dimers, including indobenzobenzodiazepine, imidazobenzobenzothiazodiazepine, or oxazolidinonebenzobenzodiazepine; nitrosoureas: including carmustine, lomustine, clostridium chloride, formustine, nimustine, and lamustine; alkyl sulfonates: including betamethrin, sulphurine, sulfamethoxazole, and pisufen; triazine or dacarbazine; platinum-containing compounds: carboplatin, cisplatin, and oxaliplatin; aproidines, benzodihydropyranone, calcodone, methotrexate, and uredopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenetriamine, triethylphosphamide, triethylthiophosphamide, and trimethylolpropionate; b) Plant alkaloids: selected from periwinkle alkaloids: including vincristine, vinblastine, vinorelbine, vinorelbine, norvinblastine; taxols: including paclitaxel, docetaxel and their analogues; Maytansine derivatives include DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine, anesarcomycin and their analogues; cryptophycin (including cryptophycin 1 and cryptophycin 8); epothilone, soft coral alcohol, dimolide, bryophyll, sea haretoxin, oliquistatin, microtubule toxin, cephalostatin; pancratistatin; erbulins, a sarcodictyin; spongistatin; c) DNA topoisomerase inhibitors: selected from etoposide: including 9-aminocamptothecin, camptothecin, cristatin, doramycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, norsoxamine, retinoid (retinol), teniposide, topotecan, 9-nitrocamptothecin or RFS2000; mitomycin and its analogues; d) Antimetabolites: selected from {[Antifolate agents: (DHFR inhibitors: including methotrexate, tromethorphan, folate, pteroxate, aminopterin (4-aminobenzoic acid) or other folic acid analogs; IMP dehydrogenase inhibitors: (including mycophenolate mofetil, thiazolidinedione, ribavirin, EICAR); ribonucleotide reductase inhibitors: (including hydroxyurea, deferoxamine)]; [Pyrimidine analogs, uracil analogs: (including ancitabine, azacitidine, 6-azouracil, capecitabine (Xeloda), carmoflu, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, 5-fluorouracil, fluorouridine, ratitrexed (Tomudex)); cytosine analogs: (including cytarabine, cytosine arabinoside, fludarabine); purine analogs (including azathioprine, fludarabine, mercaptopurine, thiamine, thioguanine)]; folic acid supplements, florrin; nicotinamide phosphoribosyltransferase (NAMPT) inhibitors; e). Hormone therapy agents: selected from {receptor antagonists: [anti-estrogens: (including medroxyprogesterone acetate, raloxifene, tamoxifen), LHRH agonists: (including gostalin, leuprorelin acetate); anti-androgens: (including bicalutamide, flutamide, carlusone, beta-testosterone propionate, epiandrogen, goserelin, leuprorelin, methemetidine, nilumet, testrolide, tralostertan and other androgen inhibitors)]; retinoids: [vitamin D3 analogs: (including CB1093, EB1089, KH1060, cholecalciferol, ergocalciferol); photodynamic therapy agents: (including verteporfin, phthalocyanine, photosensitizer Pc4, demethoxy-rubigin A); cytokines: (including interferon-α, interferon-γ, tumor necrosis factor (TNF), TNF-containing human proteins)]}; f) Kinase inhibitors selected from BIBW 2992 (anti-EGFR / Erb2), imatinib, gefitinib, guaranatinib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib (AP24534), bafetinib (INNO-406), bosutinib (SKI-606), cabozantinib, vemodega, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, and ispinib. g) Poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, niraparib, iniparib, taraparib, veliparib, CEP 9722 (Cephalon's), E7016 (Eisai's), BGB-290 (BeiGene) or 3-aminobenzamide. h). Antibiotics, such as acetylenic antibiotics (galicarmycin, especially galicarmycin γ1, δ1, α1 and β1, dyinmycin, including dyinmycin A and deoxymimycin, esperamycin, katimycin, C-1027, ma-duropeptin, neocarcinoxine oseltine and related chromogen acetylenic antibiotics), aclacinomysins, actinomycins, atracheomycin, diazoserine, bleomycin, carnomycin, kanamycin, erythromycin, carcinogens, chromogens, dachlortetracycline, etc. Daunorubicin, dedarubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, morpholine-doxorubicin, cyanomorpholine-doxorubicin, 2-pyrrolidone doxorubicin and deoxydaunorubicin, epirubicin, arubicin, idarubicin, macromycin, nitomycin, mycophenolic acid, nogamycin, olivomycin, peplomycin, potfiromycin, puromycin, queramycin, rodolmycin, streptomycin, streptozotocin, tuberculin, ubenmethoxazole, fenbendazole, fenbendazole, zolrubicin; i) Polyketides (anthocyanins), especially bullatacin and bullatacinone; gemcitabine, cyclooxygenase (such as carfenomib), bortezomib, thalidomide, lenalidomide, pomalidomide, tosedostat, zybrestat, PLX4032, STA-9090, Stimuvax, allovocin-7, Xegeva, Provenge, Yervo y, isoprenein inhibitors and lovastatin, dopaminergic neurotoxins and 1-methyl-4-phenylpyridinium ions, cell cycle inhibitors (such as asteroides), actinomycins (such as actinomycin D, dermatomycin), bleomycins (such as bleomycin A2, bleomycin B2, pepromycin), anthracycline antibiotics (such as daunorubicin), amatoxins, doxorubicin (adriamycin), idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone, MDR inhibitors or verapamil, Ca 2+ ATPase inhibitors or carotenoids, histone deacetylase inhibitors (vorinostat, romidesin, pabistal, valproic acid, mocetinostat (MGCD0103), Belinostat, PCI-24781, entenolide, SB939, resminostat, givinostat, AR-42, CUDC-101, sulforaphane, trachomatis A); celecoxib, glitazones, epigallocatechin gallate, disulfiram, salinosporamide A; Antiadrenergic drugs, aminoglutethimide, mitotane, tralostertan, glucuronolactone, aldehyde phosphoramide, aminolevulinic acid, acridine, arabinoside, bestrabucil, bisacodyl, edatraxate, defofamine, mecosine, diazinon, efornithine (DFMO), elfomithine, elifonitrile, etoglucopyranoside, gallium nitrate, cytosine, hydroxyurea, ibandronate, lentinan, clonidine, mitotane, mitotane, movadoxamol, diammonium nitrate, pentostatin, methamidoxamethasone, pirarubicin, podophyllotoxin, 2-ethylhydrazine, methylbenzylhydrazine; guanidine dione propane; rhizomycin; Cizole; Spirocyclic germanium; Scirrhozanol; Triaminoquinone; 2,2′,2″-trichlorotriethylamine; Trichothecene (especially T-2 toxin, wartycin A, baculosporin A and an-guidine), polyurethane, siRNA, antisense drugs and nucleases; (2). Anti-autoimmune disease drugs: Cyclosporine, Cyclosporine A, Aminocaproic acid, Azathioprine, Bromocriptine, Chloroquine, Cyclophosphamide, Corticosteroids (including Ancinonide, Betamethasone, Budesonide, Hydrocortisone, Flunisolone, Fluticasone Propionate, Flucolone Danazol, Dexamethasone, Triamcinolone, Beclomethasone Dipropionate), DHEA, Etanercept, Hydroxychloroquine, Infliximab, Meloxicam, Methotrexate, Mycophenolate Mofetil, Prednisone, Sirolimus, Tacrolimus. (3) Anti-infective drugs, including: a) Aminoglycosides: Amikacin, Asmicin, Gentamicin (Netilmicin, Sisomicin, Isapamicin), Hygromycin B, Kanamycin (Amikacin, Abekaricin, Aminodeoxykanamycin, Dibekacin, Tobramycin), Neomycin (Framycetin, Paromomycin, Ribomycin), Netilmicin, Spectinomycin, Streptomycin, Tobramycin, Methylstilbestrol; b) Amide alcohols: chloramphenicol, chloramphenicol, florfenicol, thiamphenicol; c) Ansarmycin: Gerdemycin, except for atrazine; d) Carbapenems: biapenem, doripenem, ertapenem, imipenem / cilastatin, meropenem, panipenem; e) Cephalosporins: Carbazosporins (Loracarb), Cefaclor, Claminophen, Cefradine, Cefadroxil, Cefranine, Cefotaxime, Cefalothin or Cefadroxil, Cephalexin, Cefalecin, Cefamandole, Cephalexin, Hydroxylamine Cephalosporins, Fluoxetine Cephalosporins, Folic acid, Zoltidine Cephalosporins, Cefadroxil, Cefacarpine, Cefotaxime, Cefepime, Cefixime, Cefoxitin, Cefradine, Cefoxitin, Cefoxitin, Cefoxitin, Cefotaxime, Cefotiam, Cefotaxime, Cefotiam Pyridine, cefotaxime, cefotaxime, cefodizine, cefonicid, cefoquinone, cefradazole, cefotaxime, thiamethoxam, cephalosporin, cefazolin, cefalexin, cefimidazole, cefpirome, cefpirome, cefpodoxime, cefrozil, cefquinolone, cefsulfuron, ceftazidime, cefterenol, cefbutane, cefotaxime, cefazolin, cefpyripril, ceftriaxone, cefuroxime, cefazolin, cephalosporins (cefoxitin, cefotetan, cefcyanazole), oxocephalosporins (fluorocephalosporins, latamoxporins); f) Glycopeptides: Bleomycin, Vancomycin (Olivancin, Tervavancin), Teicoplanin (Dabavancin), Ramolanin; g) Glycylcycline: such as tigecycline; h). β-lactamase inhibitors: penicillane (sulbactam, tazobactam), oxapenem (clavulanic acid); i) Lincosamides: Clindamycin, Lincosamide; j). Lipopeptides: Daptomycin, A54145, calcium-dependent antibiotic (CDA); k) Macrolides: Azithromycin, Clotrimazole, Clarithromycin, Dierythromycin, Erythromycin, Fluremycin, Josamycin, Ketolides (Telithromycin, Seserythromycin), Midecamycin, Micardromycin, Prunycin, Rifamycin (Isoniazid, Rifampin, Rifabutin, Rifapentine), Ropimycin, Roxithromycin, Spectinomycin, Spiramycin, Tacrolimus (FK506), Prunycin, Telithromycin; l) Monocyclic amines: aztreonam, tegamum; m). Oxazolidinones: Linezolid; n) Penicillins: Amoxicillin, Ampicillin (Pipacillin, Hezlocillin, Bambucil, Ampicillin, Doxorubicin), Aldacillin, Alzlocillin, Benzylpenicillin, Benzathine penicillin, Benzathine penicillin, Phenoxymethylpenicillin, Cloncillin, Procaine penicillin (Meticillin), Meloxicillin, Methicillin, Nafcillin, Oxyxacillin, Acetylpenicillin, Penicillin, Fennecillin, Phenoxymethylpenicillin, Guaricillin, Ampicillin, Sulbenicillin, Temoxicillin, Ticarcillin; o). Polypeptides: bacitracin, colistin, polymyxin B; p) Quinolones: Aratrofloxacin, Balofloxacin, Ciprofloxacin, Clindamycin, Daflufloxacin, Diflufloxacin, Enrofloxacin, Enrofloxacin, Garefloxacin, Gatifloxacin, Gemmifloxacin, Gaptafloxacin, Canotravafloxacin, Levofloxacin, Lomefloxacin, Mebofloxacin, Moxifloxacin, Naflufloxacin, Norfloxacin, Obibixacin, Ofloxacin, Pefloxacin, Travafloxacin, Gaptafloxacin, Sitafloxacin, Sparfloxacin, Temafloxacin, Toxacin, Travafloxacin; q) Streptocin: Punemycin, Quinupordine / Dalfopristin; r). Sulfonamides: ampicillin, azosulfanilamide, sulfadiazine, sulfamethoxazole, sulfaimide, sulfapyridine, sulfaisoxazole, trimethoprim, sulfamethoxazole (compound sulfamethoxazole); s) Steroid antibiotics: such as fusidic acid; t). Tetracyclines: Doxycycline, Chlortetracycline, Clomicycline, Demeclocycline, Ramoxil, Methionine, Methacycline, Minocycline, Oxytetracycline, Panmeclocycline, Pyrrolidine Methyl Tetracycline, Tetracycline, Glycylcycline (e.g., Tigecycline); u). Other types of antibiotics: anechoic acid, arsenamin, bacterial terpene inhibitors (bacitracin), DANAL / AR inhibitors (cycloserine), dictyostatin, spongiocarbamate, soft coral alcohol, epothilone, ethambutol, etoposide, faropenem, fusidic acid, furazolidone, isoniazid, laulimalide, metronidazole, mupirocin, NAM synthesis inhibitors (e.g., fosfomycin), nitrofurantoin, paclitaxel, prancisic acid, pyrazinamide, quinupristin / dalfopristin, rifampin, tazobactam-tinidazole, chamomile; (4) Antiviral drugs, including: a) Invasion / fusion inhibitors: apavirol, maraviro, vicriviroc, gp41 (enfvirtide), PRO 140, CD4 (elbalizumab); b) Integrase inhibitors: Rettagvir, elvite-gravir, globoidnan A; c) Maturation inhibitors: bevirimat, vivecon; d) Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir; e) Nucleosides and nucleotides: abacavir, abciximab, adefovir, amoxivir, abciximab, brivudine, cidofovir, clavudine, dexamethasone, norinosine (ddI), elvucitabine, emtricitabine (FTC), entecavir, famciclovir, fluracillin (5-FU), 3'-fluorosubstituted 2',3'-deoxynucleoside analogs, such as 3'-fluoro-2', 3'-dideoxythymidine (FLT) and 3'-fluoro-2'... 3'-Dideoxyguanosine (FLG), formivir, 9-guanine, idoxuridine, lamivudine (3TC), 1-nucleoside (e.g., β-1-thymidine and β-1-2′-deoxycytidine), penciclovir, racivir, ribavirin, ditidine, stavudine (d4T), taribavirin (viramidine), telbivudine, tenofovir, trifluorouridine valacyclovir, valganciclovir, zalcitabine (ddC), zidovudine (AZT); f) Non-nucleoside analogues: Amantadine, Atepiridine, Capvirine, Diarylpyrimidine (Etravirine), Delavidine, Docosanol, Emivirine, Efaviren, Phosphoric acid, Imiquimod, Pegylated interferon, Loviramide, Lodeadenosine, Meinthiazone, Nevirapine, NOV-205, Long-acting Interferon Alpha, Podophyllotoxin, Rifampin, Amantadine, Requimod (R-848), Amantadine acetamide; g) Protease inhibitors: Ampranavir, Atazanavir, Boceprevir, Darunavir, Fosanavir, Indinavir, Lopinavir, Nefinavir, Pleconazole, Ritonavir, Saquinavir, Telaprevir (VX-950), Tiranavir; h) Other types of antiviral drugs: antibody enzymes, arbidol, calanolide A, ceragenin, cyaniverine-N, diarylpyrimidine, epigallocatechin gallate (EGCG), phosphonoformic acid, griffithin, tari-bavirin (viramidine), hydroxyurea, KP-1461, mitefoxin, precocinone, hybrid inhibitors, ribavirin, seliciclib. (5) Pharmaceutically acceptable salt, acid, derivative, hydrate or hydrated salt; or crystal structure; or optical isomer, racemate, diastereomer or enantiomer of any of the above drugs.

22. The compound of claim 20 for the synergistic treatment or prevention of cancer is selected from one or more of the following drugs: abatacept, abecipiride, abiraterone acetate, abraxane, acetaminophen / hydrocodone, acalabrutinib, aducanumab, adalimumab, ADXS31-142, ADXS-HER2, afatinib dimaleate, aldesleukin alectinib, alemtuzumab, alitretinoin, ado-trastuzumab emtansine, amphetamine / dextroamphetamine, anastrozole, aripiprazole, anthracyclines, aripiprazole, atazanavir, atozoltuzumab, atorvastatin, avirapumab, axibuxitine, brentuximab Vedotin, Brigatinib, Budesonide, Budesonide / Formoterol, Buprenorphine, Cabazitaxel, Cabozantinib, Capmatiinib, Capecitabine, carfiilzomib, Chimeric antigen receptor engineered T (CAR-T) cells, Celecoxib, Ceritinib, Cetuxib, Cetuximab, Crizotinib, Cosentes, Crizotinib, CTL019, Dabigatran, Dabrafenib, Dacarbazine, Dacizumab, Dacotinib, Daptomycin, Dalatazumab, Dabiposi alpha, Darunavir, Dasatinib, Diniprofen, Denoxin, Depakote, Lansoprazole Dexamethasone, Dinutuximab, Doxycycline, Duloxetine, Duvelisib, Durvalumab, Elotizumab, Elotizumab / Emeropamivir, Enoxaparin, Ensartinib, Enzalutamide, Epoetin Alpha, Erlotinib, Esomeprazole, Ezopiclone, Enalapril, Everolimus, Exemestane, Everolimus, Exenatide ER, Ezetimibe, Ezopiclone Zatimibe / Simvastatin, Fenofibrate, Feglastin, Fingolimod, Fluticasone Propionate, Fluticasone / Sameterol, Fulvestrant, Gazyva, Gefitinib, Glatiramer, Gasreline Acetate, Icotinib, Imatinib, Ibrutinib, Ibrutinib, Idelixib, Ifosfamide, Infliximab, Imiquimod, ImmuCyst, ImmunoBCG, Inipari, Aspartate Insulin, Dexamir Insulin, Glargine Insulin, Lispro Insulin, Alpha-Interferon, Alpha-1b Interferon, Alpha-2a Interferon, Alpha-2b Interferon, Beta-Interferon, Beta-1a Interferon, Beta-1b Interferon, Gamma-1a Interferon, Lapatini, Ipulimab, Ipratropium Bromide / Salbutamol, Isozolol MIB, Kanuma, Lanoletide Acetate, Linedolmine, Linenamide, Linetinib Mesylate, Letrozole, Levothyroxine, Levothyroxine, Lidocaine, Linezolid, Lira Lutide, Ridesamethasone, LN-144 Loratadine, Memantine, Methylpiperidone, Metoprolol, Mekinist, Mecitabine / Ripirine / Tenofovir, Modafinil, Mometasone, Mycidac-C, Nicetumab, Neratinib, Nilotinib, Niraparib, Niraparib, Nikolaimab, Ofatumumab, Obituzumab, Olaparib, Olmesartan, Olmesartan / Hydrochlorothiazide, Omalizumab, Omega-3 Fatty Acid Ethyl Ester, Oncorine, Oselta-miv ir, Osimertinib, Oxycodone, Palbociclib, Palolizumab, Panitumumab, Panobinostat, Pazopanib, Pembrolizumab, PD-1 antibody, PD-L1 antibody, Pemetrexed, Pertuzumab, Pneumococcal conjugate vaccine, Pomalidomide, Pregabalin, ProscaVax, Propranolol, Quetiapine, Rabeprazole, Propaxin 223 radium chloride, Raloxifene, Raloxifene, Ramoximumab, Ranibizumab, Regorafenib, Rituximab Rivaroxaban, Romidisin, Rosuvastatin, Ruxotinib Phosphate, Salbutamol, Savolidinib, Semaglutide, Sevelamer, Sildenafil, Siltuximab, Sipuleucel-T, Sitagliptin, Sitagliptin / Metformin, Solifenacin, Solanezumab, Sonidegib, Sorafenib, Sunitinib, Tacrolimus, Tacrimus, Tapasilafil, Tacrimus tataparal, Tazopanib, Temozolomide, Tessiromoxim, Tenofovir / Emtricitabine, Tenofovir Disoproxil Fumarate, Testosterone Gel, Thalidomide, TICE BCG, Iotropium Bromide, Tessagiline, Toremifene, Trametinib, Trastuzumab, Trabetin (Ecteinascidin)743), trametinib, trametumab, triflupyridine / tiprazine, retinoic acid, Uro-BCG, Ustekinumab, Valsartan, Veliparib, Vandetanib, Vemuraf-enib, Venetoclax, Voronostat, Ziv-aflibercept, Zostavax and their analogues and derivatives, pharmaceutically acceptable salts, carriers, diluents or excipients, or combinations thereof.

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