Antibody drug conjugates

Abstract

The present disclosure relates to antibody-drug conjugates (ADCs) comprising antibodies or antigen binding fragments thereof covalently linked to two pharmaceutically active drugs by a dual linker. Also disclosed are linker-drug conjugates comprising the dual linker and the pharmaceutically active drugs. Such linkers are a convenient way to deliver two (e.g., two different or two identical) drugs linked to a single antibody. Such linkers are particularly useful for improving the solubility of antibody drug conjugates (ADCs) comprising one or more hydrophobic drug compounds.

Description

Technical Field

[0001] This disclosure relates to antibody-drug conjugates (ADCs) comprising an antibody or an antigen-binding fragment thereof covalently linked to two pharmaceutically active drugs via a dual-linker. Linker-drug conjugates comprising the dual-linker and the pharmaceutically active drugs are also disclosed. Such linkers are a convenient way to deliver two (e.g., two different or two identical) drugs linked to a single antibody. Such linkers can be particularly used to improve the solubility of antibody-drug conjugates (ADCs) comprising one or more hydrophobic drug compounds. Background Art

[0002] One aspect of antibody-drug conjugate (ADC) design is the design of chemical linkers that connect the drug portion to the target portion. Typically, ADCs use hydrophobic drug portions, but when such drug portions are combined with relatively hydrophobic linkers, solubility issues arise, which can affect the biocompatibility and drug efficacy of the ADC.

[0003] Reportedly, various linker strategies have been developed to address these challenges, particularly hydrophilic linkers containing polyethylene glycol (see R. Plyon, T.D. Bovee, S.O. Doronina, P.J. Burke, J.H. Hunter, H.D. N. E. LaFord, M. Jonas, M.E. Anderson, J.R. Stetter, P.D. Senter, Nat. Biotechnol. [Nature Biotechnology], 2015, 33, 733-735 and WO 2015057699), linkers containing sulfonate groups (R.Y. Zhao, S.D. Wilhelm, C. Audette, G. Jones, B.A. Leece, C.A. Ac. Zar, V.S. Goldmacher, R. Singh, Y. Kovtun, W.C. Widdison, J.M. Lambert, RV. J. Chari, J. Med. Chem. [Journal of Medicinal Chemistry], 2011, 54, 3606-3623), and linkers with carbohydrate backbones (F.S. Kholm, H.). A.Vilkman, V. J. Helin, J. Saarinen, T. Satomaa, ChemMedChem. [Chemical Pharmaceutical Chemistry], 2016, 11(22):2501-2505) design.

[0004] There remains a need to allow targeted delivery of pharmaceutically active drugs, particularly in antibody-drug conjugates of hydrophobic drugs with improved pharmacokinetic and pharmacodynamic properties, especially in cases where delivery of two pharmaceutically active drugs via dual connectors is required. Summary of the Invention

[0005] This invention provides compounds and conjugates that enable the delivery of two pharmaceutically active drugs via dual connectors, while achieving a high level of solubility. If desired, the use of such connectors not only allows the delivery of two different drug molecules via a single monoclonal antibody, but also allows the delivery of twice the number of drug portions attached to the same antibody (which can deliver 2, 4, 6, or 8 drugs per monoclonal antibody, depending on the specific conjugation technique used) compared to antibody-drug conjugates known in the art. The compounds and conjugates described herein allow the delivery of 4, 8, 12, or 16 drug molecules per monoclonal antibody.

[0006] This document describes various embodiments of the present invention.

[0007] According to a first aspect of the invention, a compound having formula (A-1) or a pharmaceutically acceptable salt thereof is provided herein:

[0008]

[0009] in:

[0010] R 1 It is an attachment group;

[0011] L 1 It is a bridging spacer;

[0012] W is the branched part;

[0013] L 2' and L 3' Each is an independent connector; and

[0014] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs.

[0015] According to a second aspect of the invention, a compound having formula (B-1) or a pharmaceutically acceptable salt thereof is provided herein:

[0016]

[0017] in:

[0018] R 1 It is an attachment group;

[0019] L 1 It is a bridging spacer;

[0020] W is N or CR w, where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0021] L 2 and L 3 Each is an independent connecting spacer;

[0022] E 1 and E 2 Each is independently an enzyme cleavage element or a hydrophilic part (e.g., E). 1 and E 2 Each is an enzyme cleavage element;

[0023] V 1 and V 2 Each independently consists of i) a self-immolative group, or ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is an independent self-exfoliating group; and

[0024] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs.

[0025] According to a third aspect of the invention, a compound having formula (C-1) or a pharmaceutically acceptable salt thereof is provided herein:

[0026]

[0027] in:

[0028] R 1 It is an attachment group;

[0029] L 1 It is a bridging spacer;

[0030] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0031] L 2 and L 3 Each is an independent connecting spacer;

[0032] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[0033] A1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[0034] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D. 1 or D 2 Attachment point;

[0035] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0036] L 4 and L 5 Each is an independent spacer component;

[0037] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[0038] m and n are each independently 0 or 1.

[0039] According to a fourth aspect of the invention, a conjugate is provided herein. In one embodiment of this aspect, the conjugate comprises an antibody or an antigen-binding fragment thereof covalently linked to two pharmaceutically active pharmaceutical ingredients via a dual-connector, wherein the dual-connector has one attachment site connected to the antibody and two attachment sites connected to the two pharmaceutically active pharmaceutical ingredients, provided that neither of the two pharmaceutically active pharmaceutical ingredients is a BH3 mimic.

[0040] In another embodiment of this aspect, a conjugate having formula (A-2) is provided herein:

[0041]

[0042] in:

[0043] Ab is an antibody or a fragment thereof;

[0044] R 100It is a coupling group;

[0045] L 1 It is a bridging spacer;

[0046] W is the branched part;

[0047] L 2' and L 3' Each is an independent connector;

[0048] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 None of them are BH3 analogs; and

[0049] a is an integer from 1 to 16.

[0050] According to a fifth aspect of the invention, a conjugate having formula (B-2) is provided herein:

[0051]

[0052] in:

[0053] Ab is an antibody or a fragment thereof;

[0054] R 100 It is a coupling group;

[0055] L 1 It is a bridging spacer;

[0056] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0057] L 2 and L 3 Each is an independent connecting spacer;

[0058] E 1 and E 2 Each is independently an enzyme cleavage element or a hydrophilic part (e.g., E). 1 and E 2 Each is an enzyme cleavage element;

[0059] V 1 and V 2 Each independently consists of i) a self-detaching group, or ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is an independent self-exfoliating group;

[0060] D 1 and D2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 None of them are BH3 analogs; and

[0061] a is an integer from 1 to 16.

[0062] According to a sixth aspect of the invention, a conjugate having formula (C-2) is provided herein:

[0063]

[0064] in:

[0065] Ab is an antibody or its antigen-binding fragment;

[0066] R 100 It is a coupling group;

[0067] L 1 It is a bridging spacer;

[0068] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0069] L 2 and L 3 Each is an independent connecting spacer;

[0070] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[0071] a is an integer from 1 to 16;

[0072] A 1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[0073] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D. 1 or D 2 Attachment point;

[0074] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0075] L 4 and L 5 Each is an independent spacer component;

[0076] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[0077] m and n are each independently 0 or 1.

[0078] According to a seventh aspect of the invention, a pharmaceutical composition is provided comprising a conjugate of the fourth, fifth, or sixth aspect of the invention and a pharmaceutically acceptable carrier.

[0079] According to an eighth aspect of the invention, a method for treating a subject who has or is suspected of having cancer is provided, the method comprising administering to the subject a therapeutically effective amount of a conjugate of the fourth, fifth, or sixth aspect of the invention or a pharmaceutical composition of the seventh aspect of the invention.

[0080] According to a ninth aspect of the invention, a method for reducing or inhibiting tumor growth in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of a conjugate of the fourth, fifth, or sixth aspect of the invention or a pharmaceutical composition of the seventh aspect of the invention.

[0081] According to a tenth aspect of the invention, a method for reducing or inhibiting blood cancer in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of a conjugate of the fourth, fifth, or sixth aspect of the invention or a pharmaceutical composition of the seventh aspect of the invention.

[0082] According to the eleventh aspect of the present invention, a method for reducing or slowing the proliferation of cancer cell populations in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of a conjugate of the fourth, fifth, or sixth aspect of the present invention or a pharmaceutical composition of the seventh aspect of the present invention.

[0083] According to the twelfth aspect of the invention, the use of the conjugates of the fourth, fifth or sixth aspect of the invention or the pharmaceutical composition of the seventh aspect of the invention in the preparation of a medicament is provided for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in the subject, (iii) reducing or inhibiting blood cancer in the subject, or (iv) reducing or slowing the expansion of a population of cancer cells in the subject.

[0084] According to the thirteenth aspect of the invention, antibody-drug conjugates of the fourth, fifth or sixth aspects of the invention or pharmaceutical compositions of the seventh aspect of the invention are provided herein for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of tumors in the subject, (iii) reducing or inhibiting blood cancers in the subject, or (iv) reducing or slowing the expansion of cancer cell populations in the subject. Attached Figure Description

[0085] Figure 1 Dose-response curves of trastuzumab (Example 8) and trastuzumab (Example 7) against representative cancer cell lines.

[0086] Figure 2 Trastuzumab - Example 5: Dose-response curves for representative cancer cell lines.

[0087] Figure 3 Trastuzumab - Example 6: Dose-response curves for representative cancer cell lines. DETAILED DESCRIPTION

[0088] The disclosed compositions and methods can be more readily understood by taking into account the accompanying drawings, which form part of this disclosure.

[0089] Throughout this document, descriptions relate to compositions and methods of using those compositions. Where features or examples related to a composition are described or stated in this disclosure, such features or examples are equally applicable to methods of using that composition. Similarly, where features or examples related to methods of using a composition are described or stated in this disclosure, such features or examples are equally applicable to that composition.

[0090] When expressing a range of values, it includes embodiments using any particular value within that range. Furthermore, references to values ​​stated within a range include every value within that range. All ranges include their endpoints and are composable. When a value is expressed as an approximation using the antecedent “about,” it should be understood that the particular value forms another embodiment. Unless the context explicitly indicates otherwise, references to a particular numerical value include at least that particular value. Unless otherwise indicated regarding its specific use, the use of “or” means “and / or.” All references cited herein are incorporated by way of citation for any purpose. In the event of a conflict between the references and the specification, the specification shall prevail.

[0091] Unless otherwise indicated by the context of the specification, for example, in the absence of a symbol indicating a particular attachment point, when drawing a structure or fragment of a structure, it may be used alone or attached to other components of the ADC, and it may be attached in any orientation, for example, where an antibody is attached to a chemical part, such as a linker-drug, at any suitable attachment point. However, where indicated, the components of the ADC are attached in the orientation shown in the given formula. For example, if formula (1) is described as And groups Described as Then the detailed structure of equation (1) is It is neither It is not .

[0092] It should be understood that, for clarity, certain features of the compositions and methods disclosed herein in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for the purpose of brevity, different features of the compositions and methods disclosed herein in the context of a single embodiment may also be provided separately or in any sub-combination.

[0093] As used throughout this application, antibody-drug conjugates can be identified using the common naming convention of “target antigen / antibody-payload-dual connector-payload”. For example, if an antibody-drug conjugate is referred to as “target X-P1-L1-P2”, such a conjugate would contain an antibody that binds to target X, a dual connector designated as L1, and two payloads designated as P1 and P2, respectively. Alternatively, if an antibody-drug conjugate is referred to as “anti-target X-P1-L1-P2”, such a conjugate would contain an antibody that binds to target X, a dual connector designated as L1, and two payloads designated as P1 and P2, respectively. In yet another alternative, if an antibody-drug conjugate is referred to as “AbX-P1-L1-P2”, such a conjugate would contain an antibody designated as AbX, a dual connector designated as L1, and two payloads designated as P1 and P2, respectively. Control antibody drug conjugates containing nonspecific isotype control antibodies can be referred to as "isotype control IgG1-P1-L1-P2" or "IgG1-P1-L1-P2".

[0094] Any formulas given herein are also intended to represent the unlabeled form of the compound as well as the isotopically labeled form. Isotopically labeled compounds have the structure described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as... 3 H. 11 C. 13 C. 14 C. 15 N. 18 F and 36 Cl. Therefore, it should be understood that this disclosure includes the doping of any of the aforementioned isotopes (including, for example, radioactive isotopes such as...). 3 H and 14 One or more of the compounds in C) or containing a non-radioactive isotope (such as 2 H and 13 Those of C). Such isotopically labeled compounds can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or those used for radiation therapy to patients. In particular, 18F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds can typically be prepared using conventional techniques known to those skilled in the art, such as using an appropriate isotope-labeled reagent instead of the previously used unlabeled reagent.

[0095] According to one aspect of the invention, a compound having formula (A-1) or a pharmaceutically acceptable salt thereof is disclosed herein:

[0096]

[0097] in:

[0098] R 1 It is an attachment group;

[0099] L 1 It is a bridging spacer;

[0100] W is the branched part;

[0101] L 2' and L 3' Each is an independent connector; and

[0102] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs.

[0103] In an embodiment, L 2' and L 3' Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a peptide group, and / or a self-removing group (e.g., a peptide group and a self-removing group).

[0104] In an embodiment, L 2' and L 3' Each of them contains a peptide group and a self-detaching group.

[0105] In an embodiment, L 2' and L 3' Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a sugar (e.g., glucuronide) group, a peptide group, and / or a self-detaching group (e.g., a peptide group and a self-detaching group).

[0106] In the embodiments, the compound is a compound having formula (B-1):

[0107]

[0108] in:

[0109] R 1 It is an attachment group;

[0110] L 1 It is a bridging spacer;

[0111] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0112] L 2 and L 3 Each is an independent connecting spacer;

[0113] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic portion;

[0114] V 1 and V 2 Independently contains i) a self-detaching group, ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is independently a self-detached group (or iiii) a self-detached group and an enzyme cleavage element; and

[0115] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0116] Or a pharmaceutically acceptable salt thereof. In the examples, the compound is a compound having formula (B-1):

[0117]

[0118] in:

[0119] R 1 It is an attachment group;

[0120] L 1 It is a bridging spacer;

[0121] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0122] L 2 and L 3 Each is an independent connecting spacer;

[0123] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic portion;

[0124] V 1 and V 2 Each independently consists of i) a self-detaching group, or ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is an independent self-exfoliating group; and

[0125] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0126] or a pharmaceutically acceptable salt thereof.

[0127] In the embodiments, W is N or CH.

[0128] In the embodiment, E 1 and E 2 Each is an enzyme cleavage element.

[0129] In the embodiment, V 1 and V 2 Each is an independent exfoliating group.

[0130] In the embodiments, (i) the cleavable connector comprises a phosphate ester group, a pyrophosphate ester group, and / or a self-detaching group; (ii) the cleavable connector comprises a self-detaching group; (iii) the cleavable connector comprises a self-detaching group, the self-detaching group including -O-CH2-, -NH-CH2-, -OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxylate tetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxylate tetrahydropyranyl)alkyl-benzyl-ammonium; or (iv) V 1 and / or V 2 Each of them independently contains a group containing p-aminobenzyl-phosphate or p-aminobenzyl-pyrophosphate.

[0131] In the embodiments, (i) the cuttable connector comprises a phosphate ester group, a pyrophosphate ester group and / or a self-detaching group; (ii) the cuttable connector comprises a self-detaching group; or (iii) the cuttable connector comprises a self-detaching group including -O-CH2-, -NH-CH2-, OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(sulfonyl)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0132] In the embodiments, the compound is a compound having the formula (C-1):

[0133]

[0134] in:

[0135] R 1 It is an attachment group;

[0136] L 1 It is a bridging spacer;

[0137] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0138] L 2 and L 3 Each is an independent connecting spacer;

[0139] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[0140] A 1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[0141] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D.1 or D 2 Attachment point;

[0142] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0143] L 4 and L 5 Each is an independent spacer component;

[0144] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[0145] m and n are each independently 0 or 1;

[0146] or a pharmaceutically acceptable salt thereof.

[0147] In the embodiments, W is N or CH.

[0148] In an embodiment, R 2 and R 3 Each of them is a hydrophilic group.

[0149] In the embodiments, the compound is a compound having the formula (D1-1), (D2-1), or (D3-1):

[0150]

[0151]

[0152] or a pharmaceutically acceptable salt thereof.

[0153] In the embodiment, equation (D1-1), R 2 and R 3 Each is an independent hydrophilic group, wherein for formula (D2-1), R 2 and R 3 Each is an independent enzyme cleavage element; and for formula (D3-1), R 2 It is a hydrophilic group and R 3 It is an enzyme cleavage element; or a pharmaceutically acceptable salt thereof.

[0154] In an embodiment, R 1 Choose from the following groups:

[0155] -ONH2, -NH2, -N3、 -SH、-SR 11 -SSR 12 , -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NR 11 C(=O)CH2Br, for example -NHC(=O)CH2Br, -NR 11 C(=O)CH2I, for example -NHC(=O)CH2I, -C(O)NHNH2、

[0156] in:

[0157] Each R 11 Independently selected from H and C1-C6 alkyl groups;

[0158] Each R 12 It is 2-pyridinyl or 4-pyridinyl;

[0159] Each R 13 Independently selected from H, C1-C6 alkyl groups, F, Cl, and -OH;

[0160] Each R 14 Independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2, and -OH; and

[0161] Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy group substituted with -C(=O)OH, benzyl group substituted with -C(=O)OH, C6 alkyl group substituted with -C(=O)OH 1- C4 alkoxy groups and C groups substituted with -C(=O)OH 1- C4 alkyl.

[0162] In an embodiment, R 1 Choose from the following groups:

[0163] -ONH2、 NHC(=O)CH2Br and -NHC(=O)CH2I.

[0164] In an embodiment, R 1 yes

[0165] In the embodiment, (1)L 1 Include:

[0166] or *-CH(OH)CH(OH)CH(OH)CH(OH)-**,

[0167] where each n is an integer from 1 to 12, and L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[0168] (2)L 1 yes And n is an integer from 1 to 12, or n is 1 or n is 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[0169] (3)L 1 yes And n is an integer from 1 to 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a connection point to R. 1 The direct or indirect (e.g., direct) attachment point;

[0170] (4)L 1 Include Among them L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 Direct or indirect (e.g., direct) attachment points; or

[0171] (5)L 1 It is a bridging spacer, which includes:

[0172] *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) mSSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1The direct or indirect (e.g., direct) attachment point;

[0173] X1 is and

[0174] Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0175] Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

[0176] Each t is independently selected from 1, 2, 3, 4, 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, and 30; and

[0177] Each R L1 Independently selected from H and C1-C6 alkyl groups.

[0178] In an embodiment, L 1 Includes the portion represented by the following:

[0179]

[0180] Where n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8), where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect attachment point.

[0181] In the embodiment, n is an integer from 4 to 8.

[0182] In the embodiments, n is 4 or 8.

[0183] In an embodiment, L 1 It can be expressed by the following formula:

[0184]

[0185] in

[0186] n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8);

[0187] x is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[0188] y is 0 or 1;

[0189] z is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[0190] u is 0 or 1; and

[0191] Among them L 1 The asterisk (*) indicates a direct attachment point to W, and L 1 The **representation of R 1 The direct attachment point.

[0192] In the embodiment, n is an integer from 4 to 8.

[0193] In the embodiments, n is 4 or 8.

[0194] In the embodiment, x is an integer from 0 to 2.

[0195] In the embodiments, x is 0 or 2.

[0196] In the embodiment, z is an integer from 0 to 2.

[0197] In the embodiments, z is 0 or 2.

[0198] In an embodiment, L 1 Choose from the following groups:

[0199]

[0200] In an embodiment, L 2 and L 3 Each is an independent connecting spacer, which comprises parts represented by the following:

[0201]

[0202] in

[0203] k is an integer from 0 to 6;

[0204] r is 0 or 1;

[0205] o is an integer from 0 to 12;

[0206] p is an integer from 0 to 6; and

[0207] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct or indirect attachment point, and L 2 or L 3 The ## symbol indicates a direct or indirect attachment point to W.

[0208] In an embodiment, L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[0209]

[0210]

[0211] as well as

[0212]

[0213] in

[0214] k is an integer from 0 to 4 each time it appears;

[0215] r is 0 or 1 independently each time it appears;

[0216] o is an integer from 0 to 10 each time it appears;

[0217] p is an integer from 0 to 4 each time it appears;

[0218] R L23 Is it hydrogen or C? 1- C6 alkyl;

[0219] R L It is hydrogen or -C(O)-R H ;

[0220] R H It is a hydrophilic group; and

[0221] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol indicates a direct attachment point to W;

[0222] The condition is that when W is N, L 2 and L 3 It is not (L2c), (L2d), (L2f), or (L2k).

[0223] In an embodiment, L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[0224]

[0225]

[0226]

[0227] as well as

[0228]

[0229] in

[0230] k is an integer from 1 to 3 each time it appears;

[0231] o is an integer from 1 to 9 each time it appears;

[0232] p is an integer from 1 to 3 each time it appears;

[0233] R L23 Is it hydrogen or C? 1- C3 alkyl;

[0234] R L It is hydrogen or -C(O)-R H ;

[0235] R H It is a hydrophilic group; and

[0236] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol represents the direct attachment point to W; the condition is that L is N when W is N. 2 and L 3 It is not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

[0237] In an embodiment, L 2 and L 3 The connecting spacers are independently selected from the following groups:

[0238]

[0239]

[0240] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 direct attachment point, L 2 or L 3 The ## symbol indicates the direct attachment point to W; R L It is hydrogen or -C(O)-R H ;and

[0241] R H yes And d is an integer between 20 and 30 (e.g., 25).

[0242] In this embodiment, d is 25.

[0243] In the embodiments, each peptide group independently contains 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

[0244] In the embodiments, each peptide group independently contains two amino acid residues.

[0245] In the examples, each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfonyl-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

[0246] In the examples, each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly, and sulfon-Ala-Val-Ala.

[0247] In the embodiment, E 1 and / or E 2 Each peptide group is independently selected from the following groups:

[0248]

[0249] Where the ^ of E1-1 or E1-2 represents the same as V in equation (B). 1 or V 2 The direct attachment point or the direct attachment point with the -NH- group in formulas (C) and (D); and the ^^ of E1-1 or E1-2 respectively represent the direct attachment point with L 2 or L 3 The direct attachment point (e.g., where E) 1 and E 2 Each is an independently selected peptide group from (E1-1) and (E1-2).

[0250] In the embodiment, E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

[0251] In the embodiment, E 1 and / or E 2 Each is independently represented by the following peptide groups:

[0252]

[0253] where R E It is a hydrophilic group R H .

[0254] In the embodiments, the hydrophilic group R in (E1-3) H yes Where e is an integer between 20 and 30 (e.g., 25).

[0255] In the embodiment, e is 25.

[0256] In the embodiment, E 1 and E 2 Each is

[0257] In the embodiment, A 1 and A 2 Independently selected from the bond and -OC (=O)-*, where * indicates that it is related to D respectively. 1 or D 2 Attachment point.

[0258] In the embodiment, A 1 and A 2 Independently selected from keys, and -OC(=O)-*, where * represents the relationship with D respectively. 1 or D 2 Attachment point.

[0259] In the embodiment, A 1 and A 2 Each is a key.

[0260] In the embodiment, A 1 and A 2 Both are -OC(=O)-*.

[0261] In the embodiment, A 1 and A 2 One of them is OC (=O)-*, and A 1 and A 2 The other one is the key.

[0262] In the embodiment, A 1 and A 2 Independently is a key or Where * indicates a relationship with D 1 or D 2 Attachment point.

[0263] In the embodiment, A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

[0264] In the embodiment, A 1 and A 2 All

[0265] In the embodiment, A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

[0266] In the embodiment, (i)A 1 and A 2 It is -OC(=O)-*;

[0267] (ii)A 1 and A 2 yes

[0268] (iii)A 1 It is -OC(=O)-* and A 2 Is a key

[0269] (iv)A 1 It is -OC(=O)-* and A 2 yes

[0270] (v)A 1 It is a key and A 2 yes or

[0271] (vi)A 1 It is a key and A 2 It is -OC(=O)-*,

[0272] Where * indicates a relationship with D 1 or D 2 Attachment point.

[0273] In the embodiment, i)L 4 and L 5 Each is an independent spacer sub-part, which has a structure

[0274] in:

[0275] Z is -O-, -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45)2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[0276] X is a bond, a triazole group, or -CH2-triazole-.

[0277] Where X is connected to R 2 or R 3 ;or

[0278] (ii)L 4 and L 5 Independently, there is a spacer sub-part, which has a structure

[0279] in:

[0280] Z represents -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[0281] X is -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene group -OC(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -,-CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n - where each n is independently 1, 2, or 3.

[0282] Where X is connected to R 2 or R 3 .

[0283] In the embodiment, Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazole group, or -CH2-triazole-; and R L45 It is either H or C each time it appears. 1- C3 alkyl.

[0284] In an embodiment, L 4 and L 5 Each is an independent sub-part of the interval selected from the following groups:

[0285]

[0286] Among them L 4 or L 5 The @ symbol represents the direct attachment point to the phenyl group, and L 4 or L 5 @@ represents R 2 or R 3 The direct attachment point.

[0287] In the embodiment, by R 2 and R 3 The hydrophilic groups represented independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, and 1 to 3 [unclear - possibly referring to specific compounds or groups]. The substituted C2-C6 alkyl group, or the alkyl group independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C2-C6 alkyl groups substituted with C4 alkylene groups -P(O)(OCH2CH3)2 and -COOH groups.

[0288] In an embodiment, R 2 or / and R 3 Each person independently chooses from the following groups:

[0289]

[0290] Where n is an integer between 1 and 6;

[0291]

[0292] In an embodiment, R 2 or / and R 3 Independently included:

[0293] (i) Polysarcosine having the following components:

[0294] in

[0295] f is an integer between 3 and 25; and

[0296] R 23 It is H, -CH3, or -CH2CH2C(=O)OH;

[0297] (ii) Polyethylene glycol having the following formula: in

[0298] g and h are independent integers between 2 and 30; or

[0299] (iii) by The part that is indicated.

[0300] In an embodiment, R 2 or / and R 3 Each independently chooses freedom The group consisting of;

[0301] g and h are independent integers between 20 and 30 (e.g., 23 or 24).

[0302] In an embodiment, R 2 or / and R 3 Include:

[0303]

[0304] In the embodiment, by R 2 or R 3 The hydrophilic groups represented each contain independently:

[0305] (i) Polysarcosine having the following components:

[0306] Where f is an integer between 3 and 25; and R 23 It is H, -CH3, or -CH2CH2C(=O)OH; or (ii) polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[0307] In an embodiment, R 2 and R 3 Each independently contains polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[0308] In the embodiment, D 1 and D 2 They are the same.

[0309] In the embodiment, D 1 and D 2 They are different.

[0310] In the embodiment, D 1 and D 2 Each drug is independently selected from cytotoxic drugs, cell growth inhibitors, and immunosuppressants.

[0311] In the embodiment, D 1 and D 2 Each ingredient was independently selected from auristatin, camptothecin, pyroxine, etoposide, maytansine, maytansinoid, taxane, and benzodiazepines. Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and periwinkle alkaloids.

[0312] In the embodiment, D 1 and D 2 Each person independently chooses from the following groups:

[0313] (For example ), (For example ), (For example )and (For example ),

[0314] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt. It should be understood that if other trivalent compounds (such as...) When an N atom with an asterisk (*) is attached to a linker, a cationic structure is produced (the cation is not shown in the fragments of the molecule described in this article).

[0315] In the embodiment, i)D 1 yes And D 2 yes

[0316] ii)D 1 yes And D 2 yes

[0317] iii)D 1 yes And D 2 yes

[0318] iv)D 1 yes And D 2 yes

[0319] v)D 1 yes And D 2 yes

[0320] vi)D 1 yes And D 2 yes

[0321] vii)D 1 yes And D 2 yes

[0322] viii)D 1 yes And D 2 yes

[0323] ix)D 1 yes And D 2 yes

[0324] x)D 1 yes And D 2 yes

[0325] xi)D 1 yes And D 2 yes

[0326] xii)D 1 yes And D 2 yes

[0327] xiii)D 1 yes And D 2 yes

[0328] xiv)D 1 yes And D 2 yes

[0329] xv)D 1 yes And D 2 yes

[0330] xvi)D 1 yes And D 2 yes

[0331] xvii)D 1 yes And D 2 yes

[0332] xviii)D 1 yes And D 2 yes

[0333] xix)D 1 yes And D 2 yes

[0334] xx)D 1 yes And D 2 yes

[0335] xxi)D 1 yes And D 2 yes

[0336] xxii)D 1 yes And D 2 yes

[0337] xxiii)D 1 yes And D 2 yes

[0338] xxiv)D 1 yes And D 2 yes

[0339] xxv)D 1 yes And D 2 yes

[0340] xxvi)D 1 yes And D 2 yes

[0341] xxvii)D 1 yes And D 2 yes

[0342] xxviii)D 1 yes And D 2 yes

[0343] xxix)D 1 yes And D 2 yes

[0344] xxx)D 1 yes And D 2 yes

[0345] xxxi)D 1 yes And D 2 yes

[0346] xxxii)D 1 yes And D 2 yes

[0347] xxxiii)D 1 yes And D 2 yes

[0348] xxxiv)D 1 yes And D 2 yes

[0349] xxxv)D 1 yes And D 2 yes

[0350] xxxvi)D 1 yes And D 2 yes

[0351] xxxvii)D 1 yes And D 2 yes

[0352] xxxviii)D 1 yes And D 2 yes

[0353] xxxix)D 1 yes And D 2 yes

[0354] xl)D 1 yes And D 2 yes

[0355] xli)D 1 yes And D 2 yes

[0356] xlii)D 1 yes And D 2 yes

[0357] xliii)D 1 yes And D 2 yes

[0358] xliv)D 1 yes And D 2 yes

[0359] vl)D 1 yes And D 2 yes

[0360] xlvi)D 1 yes And D 2 yes

[0361] xlvii)D 1 yes And D 2 yes

[0362] xlviii)D 1 yes And D 2 yes

[0363] il)D 1 yes And D 2 yes

[0364] l)D 1 yes And D 2 yes

[0365] li)D 1 yes And D 2 yes

[0366] lii)D 1 yes And D 2 yes

[0367] liii)D 1 yes And D 2 yes

[0368] liv)D 1 yes And D 2 yes

[0369] lv)D 1 yes And D 2 yes

[0370] lvi)D 1 yes And D 2 yes

[0371] lvii)D 1 yes And D 2 yes

[0372] lviii)D 1 yes And D 2 yes

[0373] lix)D 1 yes And D 2 yes

[0374] lx)D 1 yes And D 2 yes

[0375] lxi)D 1 yes And D 2 yes

[0376] lxii)D 1 yes And D 2 yes

[0377] lxiii)D 1 yes And D 2 yes ,or

[0378] lxiv)D 1 yes And D 2 yes

[0379] The asterisk (*) indicates a connection point with the rest of the molecule.

[0380] In the embodiment, A 1 -D 1 and A 2 -D 2 Each person independently chooses from the following groups:

[0381]

[0382] and The asterisk (*) indicates a connection point with the rest of the molecule.

[0383] In the examples:

[0384] i)A 1 -D 1 yes And A 2 -D 2 yes

[0385] ii)A 1 -D 1 yes And A 2 -D 2 yes

[0386] iii)A 1 -D 1 yes And A 2 -D 2 yes

[0387] iv)A 1 -D 1 yes And A 2 -D 2 yes

[0388] v)A 1 -D 1 yes And A 2 -D 2 yes

[0389] vi)A 1 -D 1 yes And A 2 -D 2 yes

[0390] vii)A 1 -D 1 yes And A2 -D 2 yes

[0391] viii)A 1 -D 1 yes And A 2 -D 2 yes

[0392] ix)A 1 -D 1 yes And A 2 -D 2 yes

[0393] x)A 1 -D 1 yes And A 2 -D 2 yes

[0394] xi)A 1 -D 1 yes And A 2 -D 2 yes

[0395] xii)A 1 -D 1 yes And A 2 -D 2 yes

[0396] xiii)A 1 -D 1 yes And A 2 -D 2 yes

[0397] xiv)A 1 -D 1 yes And A 2 -D 2 yes

[0398] xv)A 1 -D 1 yes And A 2 -D 2 yes

[0399] xvi)A 1 -D 1 yes And A 2 -D 2 yes

[0400] xvii)A 1 -D 1 yes And A 2 -D 2 yes

[0401] xviii)A 1 -D 1 yes And A 2 -D 2 yes

[0402] xix)A 1 -D 1 yes And A 2 -D 2 yes

[0403] xx)A 1 -D 1 yes And A 2 -D 2 yes

[0404] xxi)A 1 -D 1 yes And A 2 -D 2 yes

[0405] xxii)A 1 -D 1 yes And A 2 -D 2 yes

[0406] xxiii)A 1 -D 1 yes And A 2 -D 2 yes

[0407] xxiv)A 1 -D 1 yes And A 2 -D 2 yes

[0408] xxv)A 1 -D 1 yes And A 2 -D 2 yes

[0409] xxvi)A 1 -D 1 yes And A 2 -D 2 yes

[0410] xxvii)A 1 -D 1 yes And A 2 -D 2 yes

[0411] xxviii)A 1 -D 1 yes And A 2 -D 2 yes

[0412] xxix)A 1 -D 1 yes And A 2 -D 2 yes

[0413] xxx)A 1 -D 1 yes And A 2 -D 2 yes

[0414] xxxi)A 1 -D 1 yes And A 2 -D 2 yes

[0415] xxxii)A 1 -D 1 yes And A 2 -D 2 yes

[0416] xxxiii)A 1 -D 1 yes And A 2 -D 2 yes

[0417] xxxiv)A 1 -D 1 yes And A 2 -D 2 yes

[0418] xxxv)A 1 -D 1 yes And A 2 -D 2 yes

[0419] xxxvi)A 1 -D 1 yes And A 2 -D 2 yes

[0420] xxxvii)A 1 -D 1 yes And A 2 -D 2 yes

[0421] xxxviii)A 1 -D 1 yes And A 2 -D 2 yes

[0422] xxxix)A 1 -D 1 yes And A 2 -D 2 yes

[0423] xl)A 1 -D 1 yes And A 2 -D 2 yes

[0424] xli)A 1 -D 1 yes And A 2 -D 2 yes

[0425] xlii)A 1 -D 1 yes And A 2 -D 2 yes

[0426] xliii)A 1 -D 1 yes And A 2 -D 2 yes

[0427] xliv)A 1 -D 1 yes And A 2 -D 2 yes

[0428] xlv)A 1 -D 1 yes And A 2 -D 2 yes

[0429] xlvi)A 1 -D 1 yes And A 2 -D 2 yes

[0430] xlvii)A 1 -D 1 yes And A 2 -D 2 yes

[0431] xlviii)A 1 -D 1 yes And A 2 -D 2 yes

[0432] xlix)A 1 -D 1 yes And A 2 -D 2 yes

[0433] l)A 1 -D 1 yes And A 2 -D 2 yes

[0434] li)A 1 -D 1 yes And A 2 -D 2 yes

[0435] lii)A 1 -D 1 yes And A 2 -D 2 yes

[0436] liii)A 1 -D 1 yes And A 2 -D 2 yes

[0437] liv)A 1 -D 1 yes And A 2 -D 2 yes

[0438] lv)A 1 -D 1 yes And A 2 -D 2 yes

[0439] lvi)A 1 -D 1 yes And A 2 -D 2 yes

[0440] lvii)A 1 -D 1 yes And A 2 -D 2 yes

[0441] lviii)A 1 -D 1 yes And A 2 -D 2 yes

[0442] lix)A 1 -D 1 yes And A 2 -D 2 yes

[0443] lx)A 1 -D 1 yes And A 2 -D 2 yes

[0444] lxi)A 1 -D 1 yes And A 2 -D 2 yes

[0445] lxii)A 1 -D 1 yes And A 2 -D 2 yes

[0446] lxiii)A 1 -D 1 yes And A 2 -D 2 yes or

[0447] lxiv)A 1 -D 1 yes And A 2 -D 2 yes

[0448] The asterisk (*) indicates a connection point with the rest of the molecule.

[0449] In the embodiment, D 1 and / or D 2 It's Aurestatin.

[0450] In the embodiment, D 1 and D 2 They are all Aurestatin.

[0451] In the embodiment, D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

[0452] In the embodiment, D 1 and D 2 They are all topoisomerase 1 inhibitors.

[0453] In the embodiment, D 1 and D 2 One of them is auristatin, and D 1 and D 2 The other one is a topoisomerase 1 inhibitor.

[0454] In the embodiment, D 1 It is Aurestatin and D 2 It is a topoisomerase 1 inhibitor.

[0455] In the embodiment, D 1 It is a topoisomerase 1 inhibitor and D 2 It's Aurestatin.

[0456] In the embodiment, D 1 and D 2 Choose independently from the following groups:

[0457] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[0458] In the embodiment, D 1 and D 2 Choose independently from the following groups:

[0459]

[0460] In the embodiment, D 1 and D 2 Choose independently from the following groups:

[0461]

[0462] In the embodiment, D1 and D2 are each independently selected from...

[0463] In the embodiment, D 1 and D 2Each is independently selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, anti-folate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[0464] In the embodiment, D 1 and D 2 Each of the following is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, aurestatin, dolalastatin, maytansine-like substances, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or apoptosis-promoting agents, with the optional condition being D. 1 and D 2 Neither of them are BH3 analogs.

[0465] In the embodiments, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0466] P1-L1-P1、P1-L1-P2、P1-L1-P3、P1-L1-P4、P1-L1-P5、P1-L1-P6、P1-L1-P7、P1-L1-P8、P1-L2-P1、P1-L2-P2、P1-L2-P3、P1-L2-P4、P1-L2-P5、P1-L2-P 6、P1-L2-P7、P1-L2-P8、P1-L3-P1、P1-L3-P2、P1-L3-P3、P1-L3-P4、P1-L3- P5、P1-L3-P6、P1-L3-P7、P1-L3-P8、P1-L4-P1、P1-L4-P2、P1-L4-P3、P1-L4- P4、P1-L4-P5、P1-L4-P6、P1-L4-P7、P1-L4-P8、P1-L5-P1、P1-L5-P2、P1-L5 -P3、P1-L5-P4、P1-L5-P5、P1-L5-P6、P1-L5-P7、P1-L5-P8、P1-L6-P1、P1-L6 -P2、P1-L6-P3、P1-L6-P4、P1-L6-P5、P1-L6-P6、P1-L6-P7、P1-L6-P8、P1-L 7-P1、P1-L7-P2、P1-L7-P3、P1-L7-P4、P1-L7-P5、P1-L7-P6、P1-L7-P7、P1-L 7-P8、P1-L8-P1、P1-L8-P2、P1-L8-P3、P1-L8-P4、P1-L8-P5、P1-L8-P6、P1-L8-P7、P1-L8-P8、P1-L9-P1、P1-L9-P2、P1-L9-P3、P1-L9-P4、P1-L9-P5、P1 -L9-P6、P1-L9-P7、P1-L9-P8、P1-L10-P1、P1-L10-P2、P1-L10-P3、P1-L10- P4、P1-L10-P5、P1-L10-P6、P1-L10-P7、P1-L10-P8、P1-L11-P1、P1-L11-P2、 P1-L11-P3、P1-L11-P4、P1-L11-P5、P1-L11-P6、P1-L11-P7、P1-L11-P8、P1 -L12-P1、P1-L12-P2、P1-L12-P3、P1-L12-P4、P1-L12-P5、P1-L12-P6、P1-L1 2-P7、P1-L12-P8、P1-L13-P1、P1-L13-P2、P1-L13-P3、P1-L13-P4、P1-L13-P5、P1-L13-P6、P1-L13-P7、P1-L13-P8、P1-L14-P1、P1-L14-P2、P1-L14-P3、P1-L14-P4、P1-L14-P5、P1-L14-P6、P1-L14-P7、P1-L14-P8、P1-L15-P1、P1 -L15-P2、P1-L15-P3、P1-L15-P4、P1-L15-P5、P1-L15-P6、P1-L15-P7、P1-L1 5-P8、P1-L16-P1、P1-L16-P2、P1-L16-P3、P1-L16-P4、P1-L16-P5、P1-L16-P6、P1-L16-P7、P1-L16-P8、P1-L17-P1、P1-L17-P2、P1-L17-P3、P1-L17-P4、 P1-L17-P5、P1-L17-P6、P1-L17-P7、P1-L17-P8、P1-L18-P1、P1-L18-P2、P1 -L18-P3、P1-L18-P4、P1-L18-P5、P1-L18-P6、P1-L18-P7、P1-L18-P8、P1-L1 9-P1、P1-L19-P2、P1-L19-P3、P1-L19-P4、P1-L19-P5、P1-L19-P6、P1-L19-P7、P1-L19-P8、P1-L20-P1、P1-L20-P2、P1-L20-P3、P1-L20-P4、P1-L20-P5、 P1-L20-P6、P1-L20-P7、P1-L20-P8、P1-L21-P1、P1-L21-P2、P1-L21-P3、P1 -L21-P4、P1-L21-P5、P1-L21-P6、P1-L21-P7、P1-L21-P8、P1-L22-P1、P1-L2 2-P2、P1-L22-P3、P1-L22-P4、P1-L22-P5、P1-L22-P6、P1-L22-P7、P1-L22- P8、P1-L23-P1、P1-L23-P2、P1-L23-P3、P1-L23-P4、P1-L23-P5、P1-L23-P6、 P1-L23-P7、P1-L23-P8、P1-L24-P1、P1-L24-P2、P1-L24-P3、P1-L24-P4、P1-L24-P5、P1-L24-P6、P1-L24-P7、P1-L24-P8、P1-L25-P1、P1-L25-P2、P1-L2 5-P3、P1-L25-P4、P1-L25-P5、P1-L25-P6、P1-L25-P7、P1-L25-P8、P1-L26-P1、P1-L26-P2、P1-L26-P3、P1-L26-P4、P1-L26-P5、P1-L26-P6、P1-L26-P7、P1-L26-P8、P1-L27-P1、P1-L27-P2、P1-L27-P3、P1-L27-P4、P1-L27-P5、P1 -L27-P6、P1-L27-P7、P1-L27-P8、P1-L28-P1、P1-L28-P2、P1-L28-P3、P1-L 28-P4、P1-L28-P5、P1-L28-P6、P1-L28-P7、P1-L28-P8、P1-L29-P1、P1-L29 -P2、P1-L29-P3、P1-L29-P4、P1-L29-P5、P1-L29-P6、P1-L29-P7、P1-L29-P8 、P1-L30-P1、P1-L30-P2、P1-L30-P3、P1-L30-P4、P1-L30-P5、P1-L30-P6、P 1-L30-P7、P1-L30-P8、P1-L31-P1、P1-L31-P2、P1-L31-P3、P1-L31-P4、P1-L 31-P5、P1-L31-P6、P1-L31-P7、P1-L31-P8、P1-L32-P1、P1-L32-P2、P1-L32 -P3、P1-L32-P4、P1-L32-P5、P1-L32-P6、P1-L32-P7、P1-L32-P8、P1-L33-P1 、P1-L33-P2、P1-L33-P3、P1-L33-P4、P1-L33-P5、P1-L33-P6、P1-L33-P7、P 1-L33-P8、P1-L34-P1、P1-L34-P2、P1-L34-P3、P1-L34-P4、P1-L34-P5、P1-L 34-P6、P1-L34-P7、P1-L34-P8、P1-L35-P1、P1-L35-P2、P1-L35-P3、P1-L35 -P4、P1-L35-P5、P1-L35-P6、P1-L35-P7、P1-L35-P8、P1-L36-P1、P1-L36-P2 、P1-L36-P3、P1-L36-P4、P1-L36-P5、P1-L36-P6、P1-L36-P7、P1-L36-P8、P 2-L1-P1、P2-L1-P2、P2-L1-P3、P2-L1-P4、P2-L1-P5、P2-L1-P6、P2-L1-P7、P 2-L1-P8, P2-L2-P1, P2-L2-P2, P2-L2-P3, P2-L2-P4, P2-L2-P5, P2-L2-P6, P2-L2-P7, P2-L2-P8, P2-L3-P1, P2-L3-P2, P2-L3-P3, P2-L3-P4, P2-L3-P5P2-L3-P6、P2-L3-P7、P2-L3-P8、P2-L4-P1、P2-L4-P2、P2-L4-P3、P2-L4-P4 、P2-L4-P5、P2-L4-P6、P2-L4-P7、P2-L4-P8、P2-L5-P1、P2-L5-P2、P2-L5-P 3, P2-L5-P4, P2-L5-P5, P2-L5-P6, P2-L5-P7, P2-L5-P8, P2-L6-P1, P2-L6-P2, P2-L6-P3, P2-L6-P4, P2-L6-P5, P2-L6-P6, P2-L6-P7, P2-L6-P8, P2-L7- P1、P2-L7-P2、P2-L7-P3、P2-L7-P4、P2-L7-P5、P2-L7-P6、P2-L7-P7、P2-L7 -P8、P2-L8-P1、P2-L8-P2、P2-L8-P3、P2-L8-P4、P2-L8-P5、P2-L8-P6、P2-L8 -P7、P2-L8-P8、P2-L9-P1、P2-L9-P2、P2-L9-P3、P2-L9-P4、P2-L9-P5、P2-L 9-P6、P2-L9-P7、P2-L9-P8、P2-L10-P1、P2-L10-P2、P2-L10-P3、P2-L10-P4、 P2-L10-P5、P2-L10-P6、P2-L10-P7、P2-L10-P8、P2-L11-P1、P2-L11-P2、P2 -L11-P3、P2-L11-P4、P2-L11-P5、P2-L11-P6、P2-L11-P7、P2-L11-P8、P2-L1 2-P1、P2-L12-P2、P2-L12-P3、P2-L12-P4、P2-L12-P5、P2-L12-P6、P2-L12- P7、P2-L12-P8、P2-L13-P1、P2-L13-P2、P2-L13-P3、P2-L13-P4、P2-L13-P5、 P2-L13-P6、P2-L13-P7、P2-L13-P8、P2-L14-P1、P2-L14-P2、P2-L14-P3、P2 -L14-P4、P2-L14-P5、P2-L14-P6、P2-L14-P7、P2-L14-P8、P2-L15-P1、P2-L1 5-P2、P2-L15-P3、P2-L15-P4、P2-L15-P5、P2-L15-P6、P2-L15-P7、P2-L15- P8、P2-L16-P1、P2-L16-P2、P2-L16-P3、P2-L16-P4、P2-L16-P5、P2-L16-P6、P2-L16-P7、P2-L16-P8、P2-L17-P1、P2-L17-P2、P2-L17-P3、P2-L17-P4、P2-L17-P5、P2-L17-P6、P2-L17-P7、P2-L17-P8、P2-L18-P1、P2-L18-P2、P2-L18-P3、P2-L18-P4、P2-L18-P5、P2-L18-P6、P2-L18-P7、P2-L18-P8、P2-L19-P1、P2-L19-P2、P2-L19-P3、P2-L19-P4、P2-L19-P5、P2-L19-P6、P2-L19-P7、P2-L19-P8、P2-L20-P1、P2-L20-P2、P2-L20-P3、P2-L20-P4、P2-L20-P5、P2-L20-P6、P2-L20-P7、P2-L20-P8、P2-L21-P1、P2-L21-P2、P2-L21-P3、P2-L21-P4、P2-L21-P5、P2-L21-P6、P2-L21-P7、P2-L21-P8、P2-L22-P1、P2-L22-P2、P2-L22-P3、P2-L22-P4、P2-L22-P5、P2-L22-P6、P2-L22-P7、P2-L22-P8、P2-L23-P1、P2-L23-P2、P2-L23-P3、P2-L23-P4、P2-L23-P5、P2-L23-P6、P2-L23-P7、P2-L23-P8、P2-L24-P1、P2-L24-P2、P2-L24-P3、P2-L24-P4、P2-L24-P5、P2-L24-P6、P2-L24-P7、P2-L24-P8、P2-L25-P1、P2-L25-P2、P2-L25-P3、P2-L25-P4、P2-L25-P5、P2-L25-P6、P2-L25-P7、P2-L25-P8、P2-L26-P1、P2-L26-P2、P2-L26-P3、P2-L26-P4、P2-L26-P5、P2-L26-P6、P2-L26-P7、P2-L26-P8、P2-L27-P1、P2-L27-P2、P2-L27-P3、P2-L27-P4、P2-L27-P5、P2-L27-P6、P2-L27-P7、P2-L27-P8、P2-L28-P1、P2-L28-P2、P2-L28-P3、P2-L28-P4、P2-L28-P5、P2-L28-P6、P2-L28-P7、P2-L28-P8、P2-L29-P1、P2-L29-P2、P2-L29-P3、P2-L29-P4、P2-L29-P5、P2-L29-P6、P2-L29-P7、P2-L29-P8、P2 -L30-P1、P2-L30-P2、P2-L30-P3、P2-L30-P4、P2-L30-P5、P2-L30-P6、P2-L 30-P7、P2-L30-P8、P2-L31-P1、P2-L31-P2、P2-L31-P3、P2-L31-P4、P2-L31 -P5、P2-L31-P6、P2-L31-P7、P2-L31-P8、P2-L32-P1、P2-L32-P2、P2-L32-P3 P2-L32-P4, P2-L32-P5, P2-L32-P6, P2-L32-P7, P2-L32-P8, P2-L33-P1, P2-L33-P2, P2-L33-P3, P2-L33-P4, P2-L33-P5, P2-L33-P6, P2-L33-P7, P2-L 33-P8、P2-L34-P1、P2-L34-P2、P2-L34-P3、P2-L34-P4、P2-L34-P5、P2-L34 -P6、P2-L34-P7、P2-L34-P8、P2-L35-P1、P2-L35-P2、P2-L35-P3、P2-L35-P4 、P2-L35-P5、P2-L35-P6、P2-L35-P7、P2-L35-P8、P2-L36-P1、P2-L36-P2、P 2-L36-P3、P2-L36-P4、P2-L36-P5、P2-L36-P6、P2-L36-P7、P2-L36-P8、P3- L1-P1, P3-L1-P2, P3-L1-P3, P3-L1-P4, P3-L1-P5, P3-L1-P6, P3-L1-P7, P3-L1-P8, P3-L2-P1, P3-L2-P2, P3-L2-P3, P3-L2-P4, P3-L2-P5, P3-L2-P6, P3 -L2-P7, P3-L2-P8, P3-L3-P1, P3-L3-P2, P3-L3-P3, P3-L3-P4, P3-L3-P5, P3-L3-P6, P3-L3-P7, P3-L3-P8, P3-L4-P1, P3-L4-P2, P3-L4-P3, P3-L4-P4, P 3-L4-P5, P3-L4-P6, P3-L4-P7, P3-L4-P8, P3-L5-P1, P3-L5-P2, P3-L5-P3, P3-L5-P4, P3-L5-P5, P3-L5-P6, P3-L5-P7, P3-L5-P8, P3-L6-P1, P3-L6-P2P3-L6-P3, P3-L6-P4, P3-L6-P5, P3-L6-P6, P3-L6-P7, P3-L6-P8, P3-L7-P1, P3-L7-P2, P3-L7-P3, P3-L7-P4, P3-L7-P5, P3-L7-P6, P3-L7-P7, P3-L7-P8 P3-L8-P1, P3-L8-P2, P3-L8-P3, P3-L8-P4, P3-L8-P5, P3-L8-P6, P3-L8-P7, P3-L8-P8, P3-L9-P1, P3-L9-P2, P3-L9-P3, P3-L9-P4, P3-L9-P5, P3-L9-P 6、P3-L9-P7、P3-L9-P8、P3-L10-P1、P3-L10-P2、P3-L10-P3、P3-L10-P4、P3 -L10-P5、P3-L10-P6、P3-L10-P7、P3-L10-P8、P3-L11-P1、P3-L11-P2、P3-L1 1-P3、P3-L11-P4、P3-L11-P5、P3-L11-P6、P3-L11-P7、P3-L11-P8、P3-L12- P1、P3-L12-P2、P3-L12-P3、P3-L12-P4、P3-L12-P5、P3-L12-P6、P3-L12-P7、 P3-L12-P8、P3-L13-P1、P3-L13-P2、P3-L13-P3、P3-L13-P4、P3-L13-P5、P3 -L13-P6、P3-L13-P7、P3-L13-P8、P3-L14-P1、P3-L14-P2、P3-L14-P3、P3-L1 4-P4、P3-L14-P5、P3-L14-P6、P3-L14-P7、P3-L14-P8、P3-L15-P1、P3-L15- P2、P3-L15-P3、P3-L15-P4、P3-L15-P5、P3-L15-P6、P3-L15-P7、P3-L15-P8、 P3-L16-P1、P3-L16-P2、P3-L16-P3、P3-L16-P4、P3-L16-P5、P3-L16-P6、P3 -L16-P7、P3-L16-P8、P3-L17-P1、P3-L17-P2、P3-L17-P3、P3-L17-P4、P3-L1 7-P5、P3-L17-P6、P3-L17-P7、P3-L17-P8、P3-L18-P1、P3-L18-P2、P3-L18- P3、P3-L18-P4、P3-L18-P5、P3-L18-P6、P3-L18-P7、P3-L18-P8、P3-L19-P1、P3-L19-P2、P3-L19-P3、P3-L19-P4、P3-L19-P5、P3-L19-P6、P3-L19-P7、P3 -L19-P8、P3-L20-P1、P3-L20-P2、P3-L20-P3、P3-L20-P4、P3-L20-P5、P3-L2 0-P6、P3-L20-P7、P3-L20-P8、P3-L21-P1、P3-L21-P2、P3-L21-P3、P3-L21-P4、P3-L21-P5、P3-L21-P6、P3-L21-P7、P3-L21-P8、P3-L22-P1、P3-L22-P2、 P3-L22-P3、P3-L22-P4、P3-L22-P5、P3-L22-P6、P3-L22-P7、P3-L22-P8、P3 -L23-P1、P3-L23-P2、P3-L23-P3、P3-L23-P4、P3-L23-P5、P3-L23-P6、P3-L2 3-P7、P3-L23-P8、P3-L24-P1、P3-L24-P2、P3-L24-P3、P3-L24-P4、P3-L24-P5、P3-L24-P6、P3-L24-P7、P3-L24-P8、P3-L25-P1、P3-L25-P2、P3-L25-P3、 P3-L25-P4、P3-L25-P5、P3-L25-P6、P3-L25-P7、P3-L25-P8、P3-L26-P1、P3 -L26-P2、P3-L26-P3、P3-L26-P4、P3-L26-P5、P3-L26-P6、P3-L26-P7、P3-L2 6-P8、P3-L27-P1、P3-L27-P2、P3-L27-P3、P3-L27-P4、P3-L27-P5、P3-L27-P6、P3-L27-P7、P3-L27-P8、P3-L28-P1、P3-L28-P2、P3-L28-P3、P3-L28-P4、 P3-L28-P5、P3-L28-P6、P3-L28-P7、P3-L28-P8、P3-L29-P1、P3-L29-P2、P3-L29-P3、P3-L29-P4、P3-L29-P5、P3-L29-P6、P3-L29-P7、P3-L29-P8、P3-L3 0-P1、P3-L30-P2、P3-L30-P3、P3-L30-P4、P3-L30-P5、P3-L30-P6、P3-L30- P7、P3-L30-P8、P3-L31-P1、P3-L31-P2、P3-L31-P3、P3-L31-P4、P3-L31-P5、P3-L31-P6、P3-L31-P7、P3-L31-P8、P3-L32-P1、P3-L32-P2、P3-L32-P3、P3-L32-P4、P3-L32-P5、P3-L32-P6、P3-L32-P7、P3-L32-P8、P3-L33-P1、P3-L33-P2、P3-L33-P3、P3-L33-P4、P3-L33-P5、P3-L33-P6、P3-L33-P7、P3-L33-P8、P3-L34-P1、P3-L34-P2、P3-L34-P3、P3-L34-P4、P3-L34-P5、P3-L34-P6、P3-L34-P7、P3-L34-P8、P3-L35-P1、P3-L35-P2、P3-L35-P3、P3-L35-P4、P3-L35-P5、P3-L35-P6、P3-L35-P7、P3-L35-P8、P3-L36-P1、P3-L36-P2、P3-L36-P3、P3-L36-P4、P3-L36-P5、P3-L36-P6、P3-L36-P7、P3-L36-P8、P4-L1-P1、P4-L1-P2、P4-L1-P3、P4-L1-P4、P4-L1-P5、P4-L1-P6、P4-L1-P7、P4-L1-P8、P4-L2-P1、P4-L2-P2、P4-L2-P3、P4-L2-P4、P4-L2-P5、P4-L2-P6、P4-L2-P7、P4-L2-P8、P4-L3-P1、P4-L3-P2、P4-L3-P3、P4-L3-P4、P4-L3-P5、P4-L3-P6、P4-L3-P7、P4-L3-P8、P4-L4-P1、P4-L4-P2、P4-L4-P3、P4-L4-P4、P4-L4-P5、P4-L4-P6、P4-L4-P7、P4-L4-P8、P4-L5-P1、P4-L5-P2、P4-L5-P3、P4-L5-P4、P4-L5-P5、P4-L5-P6、P4-L5-P7、P4-L5-P8、P4-L6-P1、P4-L6-P2、P4-L6-P3、P4-L6-P4、P4-L6-P5、P4-L6-P6、P4-L6-P7、P4-L6-P8、P4-L7-P1、P4-L7-P2、P4-L7-P3、P4-L7-P4、P4-L7-P5、P4-L7-P6、P4-L7-P7、P4-L7-P8、P4-L8-P1、P4-L8-P2、P4-L8-P3、P4-L8-P4、P4-L8-P5、P4-L8-P6、P4-L8-P7、P4-L8-P8、P4-L9-P1、P4-L9-P2、P4-L9-P3、P4-L9-P4、P4-L9-P5、P4-L9-P6、P4-L9-P7、P4-L9-P8、P4-L10-P1、P4-L10-P2、P4-L10-P3、P4-L10-P4、P4-L10-P5、P4-L10-P6、P4-L10-P7、P4-L10-P8、P4-L11-P1、P4-L11-P2、P4-L11-P3、P4-L11-P4、P4-L11-P5、P4-L11-P6、P4-L11-P7、P4-L11-P8、P4-L12-P1、P4-L12-P2、P4-L12-P3、P4-L12-P4、P4-L12-P5、P4-L12-P6、P4-L12-P7、P4-L12-P8、P4-L13-P1、P4-L13-P2、P4-L13-P3、P4-L13-P4、P4-L13-P5、P4-L13-P6、P4-L13-P7、P4-L13-P8、P4-L14-P1、P4-L14-P2、P4-L14-P3、P4-L14-P4、P4-L14-P5、P4-L14-P6、P4-L14-P7、P4-L14-P8、P4-L15-P1、P4-L15-P2、P4-L15-P3、P4-L15-P4、P4-L15-P5、P4-L15-P6、P4-L15-P7、P4-L15-P8、P4-L16-P1、P4-L16-P2、P4-L16-P3、P4-L16-P4、P4-L16-P5、P4-L16-P6、P4-L16-P7、P4-L16-P8、P4-L17-P1、P4-L17-P2、P4-L17-P3、P4-L17-P4、P4-L17-P5、P4-L17-P6、P4-L17-P7、P4-L17-P8、P4-L18-P1、P4-L18-P2、P4-L18-P3、P4-L18-P4、P4-L18-P5、P4-L18-P6、P4-L18-P7、P4-L18-P8、P4-L19-P1、P4-L19-P2、P4-L19-P3、P4-L19-P4、P4-L19-P5、P4-L19-P6、P4-L19-P7、P4-L19-P8、P4-L20-P1、P4-L20-P2、P4-L20-P3、P4-L20-P4、P4-L20-P5、P4-L20-P6、P4-L20-P7、P4-L20-P8、P4-L21-P1、P4-L21-P2、P4-L21-P3、P4-L21-P4、P4-L21-P5、P4-L21-P6、P4-L21-P7、P4-L21-P8、P4-L22-P1、P4-L22-P2、P4-L22-P3、P4-L22-P4、P4-L22-P5、P4-L22-P6、P4-L22-P7、P4-L22-P8、P4-L23-P1、P4-L23-P2、P4-L23-P3、P4-L23-P4、P4-L23-P5、P4-L23-P6、P4-L23-P7、P4-L23-P8、P4-L24-P1、P4-L24-P2、P4-L24-P3、P4-L24-P4、P4-L24-P5、P4-L24-P6、P4-L24-P7、P4-L24-P8、P4-L25-P1、P4-L25-P2、P4-L25-P3、P4-L25-P4、P4-L25-P5、P4-L25-P6、P4-L25-P7、P4-L25-P8、P4-L26-P1、P4-L26-P2、P4-L26-P3、P4-L26-P4、P4-L26-P5、P4-L26-P6、P4-L26-P7、P4-L26-P8、P4-L27-P1、P4-L27-P2、P4-L27-P3、P4-L27-P4、P4-L27-P5、P4-L27-P6、P4-L27-P7、P4-L27-P8、P4-L28-P1、P4-L28-P2、P4-L28-P3、P4-L28-P4、P4-L28-P5、P4-L28-P6、P4-L28-P7、P4-L28-P8、P4-L29-P1、P4-L29-P2、P4-L29-P3、P4-L29-P4、P4-L29-P5、P4-L29-P6、P4-L29-P7、P4-L29-P8、P4-L30-P1、P4-L30-P2、P4-L30-P3、P4-L30-P4、P4-L30-P5、P4-L30-P6、P4-L30-P7、P4-L30-P8、P4-L31-P1、P4-L31-P2、P4-L31-P3、P4-L31-P4、P4-L31-P5、P4-L31-P6、P4-L31-P7、P4-L31-P8、P4-L32-P1、P4-L32-P2、P4-L32-P3、P4-L32-P4、P4-L32-P5、P4-L32-P6、P4-L32-P7、P4-L32-P8、P4-L33-P1、P4-L33-P2、P4-L33-P3、P4-L33-P4、P4-L33-P5、P4-L33-P6、P4-L33-P7、P4-L33-P8、P4-L34-P1、P4-L34-P2、P4-L34-P3、P4-L34-P4、P4-L34-P5、P4-L34-P6、P4 -L34-P7、P4-L34-P8、P4-L35-P1、P4-L35-P2、P4-L35-P3、P4-L35-P4、P4-L 35-P5、P4-L35-P6、P4-L35-P7、P4-L35-P8、P4-L36-P1、P4-L36-P2、P4-L36 -P3、P4-L36-P4、P4-L36-P5、P4-L36-P6、P4-L36-P7、P4-L36-P8、P5-L1-P1、 P5-L1-P2, P5-L1-P3, P5-L1-P4, P5-L1-P5, P5-L1-P6, P5-L1-P7, P5-L1-P8, P5-L2-P1, P5-L2-P2, P5-L2-P3, P5-L2-P4, P5-L2-P5, P5-L2-P6, P5-L2-P7 P5-L2-P8, P5-L3-P1, P5-L3-P2, P5-L3-P3, P5-L3-P4, P5-L3-P5, P5-L3-P6, P5-L3-P7, P5-L3-P8, P5-L4-P1, P5-L4-P2, P5-L4-P3, P5-L4-P4, P5-L4-P 5, P5-L4-P6, P5-L4-P7, P5-L4-P8, P5-L5-P1, P5-L5-P2, P5-L5-P3, P5-L5-P4, P5-L5-P5, P5-L5-P6, P5-L5-P7, P5-L5-P8, P5-L6-P1, P5-L6-P2, P5-L6 -P3, P5-L6-P4, P5-L6-P5, P5-L6-P6, P5-L6-P7, P5-L6-P8, P5-L7-P1, P5-L7-P2, P5-L7-P3, P5-L7-P4, P5-L7-P5, P5-L7-P6, P5-L7-P7, P5-L7-P8, P5-L 8-P1、P5-L8-P2、P5-L8-P3、P5-L8-P4、P5-L8-P5、P5-L8-P6、P5-L8-P7、P5- L8-P8、P5-L9-P1、P5-L9-P2、P5-L9-P3、P5-L9-P4、P5-L9-P5、P5-L9-P6、P5- L9-P7、P5-L9-P8、P5-L10-P1、P5-L10-P2、P5-L10-P3、P5-L10-P4、P5-L10- P5、P5-L10-P6、P5-L10-P7、P5-L10-P8、P5-L11-P1、P5-L11-P2、P5-L11-P3、P5-L11-P4、P5-L11-P5、P5-L11-P6、P5-L11-P7、P5-L11-P8、P5-L12-P1、P5-L12-P2、P5-L12-P3、P5-L12-P4、P5-L12-P5、P5-L12-P6、P5-L12-P7、P5-L1 2-P8、P5-L13-P1、P5-L13-P2、P5-L13-P3、P5-L13-P4、P5-L13-P5、P5-L13-P6、P5-L13-P7、P5-L13-P8、P5-L14-P1、P5-L14-P2、P5-L14-P3、P5-L14-P4、 P5-L14-P5、P5-L14-P6、P5-L14-P7、P5-L14-P8、P5-L15-P1、P5-L15-P2、P5-L15-P3、P5-L15-P4、P5-L15-P5、P5-L15-P6、P5-L15-P7、P5-L15-P8、P5-L1 6-P1、P5-L16-P2、P5-L16-P3、P5-L16-P4、P5-L16-P5、P5-L16-P6、P5-L16-P7、P5-L16-P8、P5-L17-P1、P5-L17-P2、P5-L17-P3、P5-L17-P4、P5-L17-P5、 P5-L17-P6、P5-L17-P7、P5-L17-P8、P5-L18-P1、P5-L18-P2、P5-L18-P3、P5-L18-P4、P5-L18-P5、P5-L18-P6、P5-L18-P7、P5-L18-P8、P5-L19-P1、P5-L1 9-P2、P5-L19-P3、P5-L19-P4、P5-L19-P5、P5-L19-P6、P5-L19-P7、P5-L19- P8、P5-L20-P1、P5-L20-P2、P5-L20-P3、P5-L20-P4、P5-L20-P5、P5-L20-P6、 P5-L20-P7、P5-L20-P8、P5-L21-P1、P5-L21-P2、P5-L21-P3、P5-L21-P4、P5 -L21-P5、P5-L21-P6、P5-L21-P7、P5-L21-P8、P5-L22-P1、P5-L22-P2、P5-L2 2-P3、P5-L22-P4、P5-L22-P5、P5-L22-P6、P5-L22-P7、P5-L22-P8、P5-L23-P1、P5-L23-P2、P5-L23-P3、P5-L23-P4、P5-L23-P5、P5-L23-P6、P5-L23-P7、P5-L23-P8、P5-L24-P1、P5-L24-P2、P5-L24-P3、P5-L24-P4、P5-L24-P5、P5 -L24-P6、P5-L24-P7、P5-L24-P8、P5-L25-P1、P5-L25-P2、P5-L25-P3、P5-L2 5-P4、P5-L25-P5、P5-L25-P6、P5-L25-P7、P5-L25-P8、P5-L26-P1、P5-L26- P2、P5-L26-P3、P5-L26-P4、P5-L26-P5、P5-L26-P6、P5-L26-P7、P5-L26-P8、 P5-L27-P1、P5-L27-P2、P5-L27-P3、P5-L27-P4、P5-L27-P5、P5-L27-P6、P5 -L27-P7、P5-L27-P8、P5-L28-P1、P5-L28-P2、P5-L28-P3、P5-L28-P4、P5-L2 8-P5、P5-L28-P6、P5-L28-P7、P5-L28-P8、P5-L29-P1、P5-L29-P2、P5-L29-P3、P5-L29-P4、P5-L29-P5、P5-L29-P6、P5-L29-P7、P5-L29-P8、P5-L30-P1、 P5-L30-P2、P5-L30-P3、P5-L30-P4、P5-L30-P5、P5-L30-P6、P5-L30-P7、P5-L30-P8、P5-L31-P1、P5-L31-P2、P5-L31-P3、P5-L31-P4、P5-L31-P5、P5-L3 1-P6、P5-L31-P7、P5-L31-P8、P5-L32-P1、P5-L32-P2、P5-L32-P3、P5-L32- P4、P5-L32-P5、P5-L32-P6、P5-L32-P7、P5-L32-P8、P5-L33-P1、P5-L33-P2、 P5-L33-P3、P5-L33-P4、P5-L33-P5、P5-L33-P6、P5-L33-P7、P5-L33-P8、P5 -L34-P1、P5-L34-P2、P5-L34-P3、P5-L34-P4、P5-L34-P5、P5-L34-P6、P5-L3 4-P7、P5-L34-P8、P5-L35-P1、P5-L35-P2、P5-L35-P3、P5-L35-P4、P5-L35- P5、P5-L35-P6、P5-L35-P7、P5-L35-P8、P5-L36-P1、P5-L36-P2、P5-L36-P3、P5-L36-P4、P5-L36-P5、P5-L36-P6、P5-L36-P7、P5-L36-P8、P6-L1-P1、P6- L1-P2、P6-L1-P3、P6-L1-P4、P6-L1-P5、P6-L1-P6、P6-L1-P7、P6-L1-P8、P6 -L2-P1, P6-L2-P2, P6-L2-P3, P6-L2-P4, P6-L2-P5, P6-L2-P6, P6-L2-P7, P6-L2-P8, P6-L3-P1, P6-L3-P2, P6-L3-P3, P6-L3-P4, P6-L3-P5, P6-L3-P6, P 6-L3-P7、P6-L3-P8、P6-L4-P1、P6-L4-P2、P6-L4-P3、P6-L4-P4、P6-L4-P5、 P6-L4-P6、P6-L4-P7、P6-L4-P8、P6-L5-P1、P6-L5-P2、P6-L5-P3、P6-L5-P4、 P6-L5-P5, P6-L5-P6, P6-L5-P7, P6-L5-P8, P6-L6-P1, P6-L6-P2, P6-L6-P3, P6-L6-P4, P6-L6-P5, P6-L6-P6, P6-L6-P7, P6-L6-P8, P6-L7-P1, P6-L7-P2 、P6-L7-P3、P6-L7-P4、P6-L7-P5、P6-L7-P6、P6-L7-P7、P6-L7-P8、P6-L8-P 1、P6-L8-P2、P6-L8-P3、P6-L8-P4、P6-L8-P5、P6-L8-P6、P6-L8-P7、P6-L8- P8、P6-L9-P1、P6-L9-P2、P6-L9-P3、P6-L9-P4、P6-L9-P5、P6-L9-P6、P6-L9 -P7、P6-L9-P8、P6-L10-P1、P6-L10-P2、P6-L10-P3、P6-L10-P4、P6-L10-P5、 P6-L10-P6、P6-L10-P7、P6-L10-P8、P6-L11-P1、P6-L11-P2、P6-L11-P3、P6 -L11-P4、P6-L11-P5、P6-L11-P6、P6-L11-P7、P6-L11-P8、P6-L12-P1、P6-L1 2-P2、P6-L12-P3、P6-L12-P4、P6-L12-P5、P6-L12-P6、P6-L12-P7、P6-L12- P8、P6-L13-P1、P6-L13-P2、P6-L13-P3、P6-L13-P4、P6-L13-P5、P6-L13-P6、P6-L13-P7、P6-L13-P8、P6-L14-P1、P6-L14-P2、P6-L14-P3、P6-L14-P4、P6 -L14-P5、P6-L14-P6、P6-L14-P7、P6-L14-P8、P6-L15-P1、P6-L15-P2、P6-L1 5-P3、P6-L15-P4、P6-L15-P5、P6-L15-P6、P6-L15-P7、P6-L15-P8、P6-L16-P1、P6-L16-P2、P6-L16-P3、P6-L16-P4、P6-L16-P5、P6-L16-P6、P6-L16-P7、 P6-L16-P8、P6-L17-P1、P6-L17-P2、P6-L17-P3、P6-L17-P4、P6-L17-P5、P6 -L17-P6、P6-L17-P7、P6-L17-P8、P6-L18-P1、P6-L18-P2、P6-L18-P3、P6-L1 8-P4、P6-L18-P5、P6-L18-P6、P6-L18-P7、P6-L18-P8、P6-L19-P1、P6-L19- P2、P6-L19-P3、P6-L19-P4、P6-L19-P5、P6-L19-P6、P6-L19-P7、P6-L19-P8、 P6-L20-P1、P6-L20-P2、P6-L20-P3、P6-L20-P4、P6-L20-P5、P6-L20-P6、P6 -L20-P7、P6-L20-P8、P6-L21-P1、P6-L21-P2、P6-L21-P3、P6-L21-P4、P6-L2 1-P5、P6-L21-P6、P6-L21-P7、P6-L21-P8、P6-L22-P1、P6-L22-P2、P6-L22- P3、P6-L22-P4、P6-L22-P5、P6-L22-P6、P6-L22-P7、P6-L22-P8、P6-L23-P1、 P6-L23-P2、P6-L23-P3、P6-L23-P4、P6-L23-P5、P6-L23-P6、P6-L23-P7、P6 -L23-P8、P6-L24-P1、P6-L24-P2、P6-L24-P3、P6-L24-P4、P6-L24-P5、P6-L2 4-P6、P6-L24-P7、P6-L24-P8、P6-L25-P1、P6-L25-P2、P6-L25-P3、P6-L25-P4、P6-L25-P5、P6-L25-P6、P6-L25-P7、P6-L25-P8、P6-L26-P1、P6-L26-P2、P6-L26-P3、P6-L26-P4、P6-L26-P5、P6-L26-P6、P6-L26-P7、P6-L26-P8、P6 -L27-P1、P6-L27-P2、P6-L27-P3、P6-L27-P4、P6-L27-P5、P6-L27-P6、P6-L 27-P7、P6-L27-P8、P6-L28-P1、P6-L28-P2、P6-L28-P3、P6-L28-P4、P6-L28 -P5、P6-L28-P6、P6-L28-P7、P6-L28-P8、P6-L29-P1、P6-L29-P2、P6-L29-P 3、P6-L29-P4、P6-L29-P5、P6-L29-P6、P6-L29-P7、P6-L29-P8、P6-L30-P1、 P6-L30-P2、P6-L30-P3、P6-L30-P4、P6-L30-P5、P6-L30-P6、P6-L30-P7、P6 -L30-P8、P6-L31-P1、P6-L31-P2、P6-L31-P3、P6-L31-P4、P6-L31-P5、P6-L 31-P6、P6-L31-P7、P6-L31-P8、P6-L32-P1、P6-L32-P2、P6-L32-P3、P6-L32- P4、P6-L32-P5、P6-L32-P6、P6-L32-P7、P6-L32-P8、P6-L33-P1、P6-L33-P2 、P6-L33-P3、P6-L33-P4、P6-L33-P5、P6-L33-P6、P6-L33-P7、P6-L33-P8、P 6-L34-P1、P6-L34-P2、P6-L34-P3、P6-L34-P4、P6-L34-P5、P6-L34-P6、P6- L34-P7、P6-L34-P8、P6-L35-P1、P6-L35-P2、P6-L35-P3、P6-L35-P4、P6-L35 -P5、P6-L35-P6、P6-L35-P7、P6-L35-P8、P6-L36-P1、P6-L36-P2、P6-L36-P 3、P6-L36-P4、P6-L36-P5、P6-L36-P6、P6-L36-P7、P6-L36-P8、P7-L1-P1、P 7-L1-P2, P7-L1-P3, P7-L1-P4, P7-L1-P5, P7-L1-P6, P7-L1-P7, P7-L1-P8, P7-L2-P1, P7-L2-P2, P7-L2-P3, P7-L2-P4, P7-L2-P5, P7-L2-P6, P7-L2-P7P7-L2-P8, P7-L3-P1, P7-L3-P2, P7-L3-P3, P7-L3-P4, P7-L3-P5, P7-L3-P6, P7-L3-P7, P7-L3-P8, P7-L4-P1, P7-L4-P2, P7-L4-P3, P7-L4-P4, P7-L4-P 5, P7-L4-P6, P7-L4-P7, P7-L4-P8, P7-L5-P1, P7-L5-P2, P7-L5-P3, P7-L5-P4, P7-L5-P5, P7-L5-P6, P7-L5-P7, P7-L5-P8, P7-L6-P1, P7-L6-P2, P7-L6 -P3, P7-L6-P4, P7-L6-P5, P7-L6-P6, P7-L6-P7, P7-L6-P8, P7-L7-P1, P7-L7-P2, P7-L7-P3, P7-L7-P4, P7-L7-P5, P7-L7-P6, P7-L7-P7, P7-L7-P8, P7- L8-P1, P7-L8-P2, P7-L8-P3, P7-L8-P4, P7-L8-P5, P7-L8-P6, P7-L8-P7, P7-L8-P8, P7-L9-P1, P7-L9-P2, P7-L9-P3, P7-L9-P4, P7-L9-P5, P7-L9-P6, P 7-L9-P7、P7-L9-P8、P7-L10-P1、P7-L10-P2、P7-L10-P3、P7-L10-P4、P7-L1 0-P5、P7-L10-P6、P7-L10-P7、P7-L10-P8、P7-L11-P1、P7-L11-P2、P7-L11- P3、P7-L11-P4、P7-L11-P5、P7-L11-P6、P7-L11-P7、P7-L11-P8、P7-L12-P1 、P7-L12-P2、P7-L12-P3、P7-L12-P4、P7-L12-P5、P7-L12-P6、P7-L12-P7、P 7-L12-P8、P7-L13-P1、P7-L13-P2、P7-L13-P3、P7-L13-P4、P7-L13-P5、P7- L13-P6、P7-L13-P7、P7-L13-P8、P7-L14-P1、P7-L14-P2、P7-L14-P3、P7-L1 4-P4、P7-L14-P5、P7-L14-P6、P7-L14-P7、P7-L14-P8、P7-L15-P1、P7-L15- P2、P7-L15-P3、P7-L15-P4、P7-L15-P5、P7-L15-P6、P7-L15-P7、P7-L15-P8、P7-L16-P1、P7-L16-P2、P7-L16-P3、P7-L16-P4、P7-L16-P5、P7-L16-P6、P7-L16-P7、P7-L16-P8、P7-L17-P1、P7-L17-P2、P7-L17-P3、P7-L17-P4、P7-L17-P5、P7-L17-P6、P7-L17-P7、P7-L17-P8、P7-L18-P1、P7-L18-P2、P7-L18-P3、P7-L18-P4、P7-L18-P5、P7-L18-P6、P7-L18-P7、P7-L18-P8、P7-L19-P1、P7-L19-P2、P7-L19-P3、P7-L19-P4、P7-L19-P5、P7-L19-P6、P7-L19-P7、P7-L19-P8、P7-L20-P1、P7-L20-P2、P7-L20-P3、P7-L20-P4、P7-L20-P5、P7-L20-P6、P7-L20-P7、P7-L20-P8、P7-L21-P1、P7-L21-P2、P7-L21-P3、P7-L21-P4、P7-L21-P5、P7-L21-P6、P7-L21-P7、P7-L21-P8、P7-L22-P1、P7-L22-P2、P7-L22-P3、P7-L22-P4、P7-L22-P5、P7-L22-P6、P7-L22-P7、P7-L22-P8、P7-L23-P1、P7-L23-P2、P7-L23-P3、P7-L23-P4、P7-L23-P5、P7-L23-P6、P7-L23-P7、P7-L23-P8、P7-L24-P1、P7-L24-P2、P7-L24-P3、P7-L24-P4、P7-L24-P5、P7-L24-P6、P7-L24-P7、P7-L24-P8、P7-L25-P1、P7-L25-P2、P7-L25-P3、P7-L25-P4、P7-L25-P5、P7-L25-P6、P7-L25-P7、P7-L25-P8、P7-L26-P1、P7-L26-P2、P7-L26-P3、P7-L26-P4、P7-L26-P5、P7-L26-P6、P7-L26-P7、P7-L26-P8、P7-L27-P1、P7-L27-P2、P7-L27-P3、P7-L27-P4、P7-L27-P5、P7-L27-P6、P7-L27-P7、P7-L27-P8、P7-L28-P1、P7-L28-P2、P7-L28-P3、P7-L28-P4、P7-L28-P5, P7-L28-P6, P7-L28-P7, P7-L28-P8, P7-L29-P1, P7-L29-P2, P7-L29-P3, P7-L29-P4, P7-L29-P5, P7-L29-P6, P7-L29-P7, P7-L29-P8, P7-L 30-P1、P7-L30-P2、P7-L30-P3、P7-L30-P4、P7-L30-P5、P7-L30-P6、P7-L30 -P7、P7-L30-P8、P7-L31-P1、P7-L31-P2、P7-L31-P3、P7-L31-P4、P7-L31-P 5、P7-L31-P6、P7-L31-P7、P7-L31-P8、P7-L32-P1、P7-L32-P2、P7-L32-P3、 P7-L32-P4、P7-L32-P5、P7-L32-P6、P7-L32-P7、P7-L32-P8、P7-L33-P1、P7 -L33-P2, P7-L33-P3, P7-L33-P4, P7-L33-P5, P7-L33-P6, P7-L33-P7, P7-L33-P8, P7-L34-P1, P7-L34-P2, P7-L34-P3, P7-L34-P4, P7-L34-P5, P7-L34- P6, P7-L34-P7, P7-L34-P8, P7-L35-P1, P7-L35-P2, P7-L35-P3, P7-L35-P4, P7-L35-P5, P7-L35-P6, P7-L35-P7, P7-L35-P8, P7-L36-P1, P7-L36-P2, P 7-L36-P3、P7-L36-P4、P7-L36-P5、P7-L36-P6、P7-L36-P7、P7-L36-P8、P8- L1-P1、P8-L1-P2、P8-L1-P3、P8-L1-P4、P8-L1-P5、P8-L1-P6、P8-L1-P7、P8- L1-P8, P8-L2-P1, P8-L2-P2, P8-L2-P3, P8-L2-P4, P8-L2-P5, P8-L2-P6, P8-L2-P7, P8-L2-P8, P8-L3-P1, P8-L3-P2, P8-L3-P3, P8-L3-P4, P8-L3-P5, P 8-L3-P6、P8-L3-P7、P8-L3-P8、P8-L4-P1、P8-L4-P2、P8-L4-P3、P8-L4-P4、 P8-L4-P5、P8-L4-P6、P8-L4-P7、P8-L4-P8、P8-L5-P1、P8-L5-P2、P8-L5-P3、P8-L5-P4, P8-L5-P5, P8-L5-P6, P8-L5-P7, P8-L5-P8, P8-L6-P1, P8-L6-P2, P8-L6-P3, P8-L6-P4, P8-L6-P5, P8-L6-P6, P8-L6-P7, P8-L6-P8, P8-L7-P 1, P8-L7-P2, P8-L7-P3, P8-L7-P4, P8-L7-P5, P8-L7-P6, P8-L7-P7, P8-L7-P8, P8-L8-P1, P8-L8-P2, P8-L8-P3, P8-L8-P4, P8-L8-P5, P8-L8-P6, P8-L8 -P7、P8-L8-P8、P8-L9-P1、P8-L9-P2、P8-L9-P3、P8-L9-P4、P8-L9-P5、P8-L 9-P6、P8-L9-P7、P8-L9-P8、P8-L10-P1、P8-L10-P2、P8-L10-P3、P8-L10-P4 、P8-L10-P5、P8-L10-P6、P8-L10-P7、P8-L10-P8、P8-L11-P1、P8-L11-P2、P 8-L11-P3、P8-L11-P4、P8-L11-P5、P8-L11-P6、P8-L11-P7、P8-L11-P8、P8- L12-P1、P8-L12-P2、P8-L12-P3、P8-L12-P4、P8-L12-P5、P8-L12-P6、P8-L1 2-P7、P8-L12-P8、P8-L13-P1、P8-L13-P2、P8-L13-P3、P8-L13-P4、P8-L13- P5、P8-L13-P6、P8-L13-P7、P8-L13-P8、P8-L14-P1、P8-L14-P2、P8-L14-P3 、P8-L14-P4、P8-L14-P5、P8-L14-P6、P8-L14-P7、P8-L14-P8、P8-L15-P1、P 8-L15-P2、P8-L15-P3、P8-L15-P4、P8-L15-P5、P8-L15-P6、P8-L15-P7、P8- L15-P8、P8-L16-P1、P8-L16-P2、P8-L16-P3、P8-L16-P4、P8-L16-P5、P8-L1 6-P6、P8-L16-P7、P8-L16-P8、P8-L17-P1、P8-L17-P2、P8-L17-P3、P8-L17- P4、P8-L17-P5、P8-L17-P6、P8-L17-P7、P8-L17-P8、P8-L18-P1、P8-L18-P2、P8-L18-P3、P8-L18-P4、P8-L18-P5、P8-L18-P6、P8-L18-P7、P8-L18-P8、P8 -L19-P1、P8-L19-P2、P8-L19-P3、P8-L19-P4、P8-L19-P5、P8-L19-P6、P8-L1 9-P7、P8-L19-P8、P8-L20-P1、P8-L20-P2、P8-L20-P3、P8-L20-P4、P8-L20-P5、P8-L20-P6、P8-L20-P7、P8-L20-P8、P8-L21-P1、P8-L21-P2、P8-L21-P3、 P8-L21-P4、P8-L21-P5、P8-L21-P6、P8-L21-P7、P8-L21-P8、P8-L22-P1、P8 -L22-P2、P8-L22-P3、P8-L22-P4、P8-L22-P5、P8-L22-P6、P8-L22-P7、P8-L2 2-P8、P8-L23-P1、P8-L23-P2、P8-L23-P3、P8-L23-P4、P8-L23-P5、P8-L23- P6、P8-L23-P7、P8-L23-P8、P8-L24-P1、P8-L24-P2、P8-L24-P3、P8-L24-P4、 P8-L24-P5、P8-L24-P6、P8-L24-P7、P8-L24-P8、P8-L25-P1、P8-L25-P2、P8 -L25-P3、P8-L25-P4、P8-L25-P5、P8-L25-P6、P8-L25-P7、P8-L25-P8、P8-L2 6-P1、P8-L26-P2、P8-L26-P3、P8-L26-P4、P8-L26-P5、P8-L26-P6、P8-L26-P7、P8-L26-P8、P8-L27-P1、P8-L27-P2、P8-L27-P3、P8-L27-P4、P8-L27-P5、 P8-L27-P6、P8-L27-P7、P8-L27-P8、P8-L28-P1、P8-L28-P2、P8-L28-P3、P8 -L28-P4、P8-L28-P5、P8-L28-P6、P8-L28-P7、P8-L28-P8、P8-L29-P1、P8-L2 9-P2、P8-L29-P3、P8-L29-P4、P8-L29-P5、P8-L29-P6、P8-L29-P7、P8-L29- P8、P8-L30-P1、P8-L30-P2、P8-L30-P3、P8-L30-P4、P8-L30-P5、P8-L30-P6、P8-L30-P7, P8-L30-P8, P8-L31-P1, P8-L31-P2, P8-L31-P3, P8-L31-P4, P8 -L31-P5, P8-L31-P6, P8-L31-P7, P8-L31-P8, P8-L32-P1, P8-L32-P2, P8-L3 2-P3, P8-L32-P4, P8-L32-P5, P8-L32-P6, P8-L32-P7, P8-L32-P8, P8-L33- P1, P8-L33-P2, P8-L33-P3, P8-L33-P4, P8-L33-P5, P8-L33-P6, P8-L33-P7, P8-L33-P8, P8-L34-P1, P8-L34-P2, P8-L34-P3, P8-L34-P4, P8-L34-P5, P8 -L34-P6, P8-L34-P7, P8-L34-P8, P8-L35-P1, P8-L35-P2, P8-L35-P3, P8-L3 5-P4, P8-L35-P5, P8-L35-P6, P8-L35-P7, P8-L35-P8, P8-L36-P1, P8-L36- P2, P8-L36-P3, P8-L36-P4, P8-L36-P5, P8-L36-P6, P8-L36-P7, P8-L36-P8,

[0467] According to one aspect of the invention, a conjugate is provided comprising an antibody or an antigen-binding fragment thereof covalently linked to two pharmaceutically active pharmaceutical ingredients via a dual-connector, wherein the dual-connector has one attachment site for the antibody and two attachment sites for the two pharmaceutically active pharmaceutical ingredients, provided that neither of the two pharmaceutically active pharmaceutical ingredients is a BH3 mimic. In one embodiment, the two pharmaceutically active pharmaceutical ingredients may be the same or different. In another embodiment, the pharmaceutically active pharmaceutical ingredients are selected from cytotoxic drugs, cell growth inhibitors, and immunosuppressive drugs. In yet another embodiment, the pharmaceutically active pharmaceutical ingredients are selected from aurestatin, camptothecin, pyruvic acid, etoposide, maytansin, quasi-matansin, taxanes, and benzodiazepines. Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and vinca alkaloids. In the examples, the pharmaceutically active pharmaceutical ingredient is auristatin. In the examples, the pharmaceutically active pharmaceutical ingredient is selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, antifolate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors, and / or vinca alkaloids. In another embodiment, the pharmaceutically active drug is selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, auratestatin, dolalastatin, maytansine-like drugs, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or pro-apoptotic agents. In another embodiment, the pharmaceutically active drug is selected from topoisomerase 1 inhibitors or their enantiomers, diastereomers, transisomers, deuterated derivatives, and / or addition salts with pharmaceutically acceptable acids or bases. In one embodiment, the pharmaceutically active pharmaceutical ingredient is a topoisomerase 1 inhibitor selected from topotecan, eczemacon, delutec, and SN-38. In yet another embodiment, the pharmaceutically active pharmaceutical ingredient is selected from antimitotic pharmaceutical ingredients or their enantiomers, diastereomers, transisomers, deuterated derivatives, and / or addition salts with pharmaceutically acceptable acids or bases. In another embodiment, the antimitotic pharmaceutical ingredient is monomethylaurestatin E (MMAE) or taxane. In another embodiment, taxane is selected from docetaxel, paclitaxel, or cabazitaxel. In yet another embodiment, the conjugate comprises any compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0468] As described above, according to one aspect of the present invention, a conjugate having formula (A-2) is provided:

[0469]

[0470] in:

[0471] Ab is an antibody or a fragment thereof;

[0472] R 100 It is a coupling group;

[0473] L 1 It is a bridging spacer;

[0474] W is the branched part;

[0475] L 2'and L 3' Each is an independent connector;

[0476] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 None of them are BH3 analogs; and

[0477] a is an integer from 1 to 16.

[0478] In an embodiment, L 2' and L 3' Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, and / or a self-detaching group (e.g., a peptide group and a self-detaching group).

[0479] In an embodiment, L 2' and L 3' Each of them contains a peptide group and a self-detaching group.

[0480] In an embodiment, L 2' and L 3' Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a sugar (e.g., glucuronide) group, a peptide group, and / or a self-detaching group (e.g., a peptide group and a self-detaching group).

[0481] In the embodiments, the conjugate has the formula (B-2):

[0482]

[0483] in:

[0484] Ab is an antibody or a fragment thereof;

[0485] R 100 It is a coupling group;

[0486] L 1 It is a bridging spacer;

[0487] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0488] L 2 and L 3 Each is an independent connecting spacer;

[0489] E 1 and E 2 Each is independently an enzyme cleavage element or a hydrophilic part (e.g., E).1 and E 2 Each is an enzyme cleavage element;

[0490] V 1 and V 2 Independently contains i) a self-detaching group, ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is independently a self-detached group) or iii) a self-detached group and an enzyme cleavage element;

[0491] D 1 and D 2 Each is an independently pharmaceutically active drug, provided that condition D is met. 1 and D 2 None of them are BH3 analogs; and

[0492] A is an integer from 1 to 16.

[0493] In the embodiments, the conjugate has the formula (B-2):

[0494]

[0495] in:

[0496] Ab is an antibody or a fragment thereof;

[0497] R 100 It is a coupling group;

[0498] L 1 It is a bridging spacer;

[0499] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0500] L 2 and L 3 Each is an independent connecting spacer;

[0501] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic portion;

[0502] V 1 and V 2 Each independently consists of i) a self-detaching group, or ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is an independent self-exfoliating group;

[0503] D 1 and D 2Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 None of them are BH3 analogs; and

[0504] a is an integer from 1 to 16.

[0505] In the embodiments, W is N or CH.

[0506] In the embodiment, E 1 and E 2 Each is an enzyme cleavage element.

[0507] In the embodiment, V 1 and V 2 Each is an independent self-exfoliating group

[0508] In the embodiments, a is an integer from 1 to 8, or from 1 to 6, or from 1 to 4, or a is 1 or 2.

[0509] In the examples, a was determined by liquid chromatography-mass spectrometry (LC-MS).

[0510] In the embodiments, (i) the cuttable connector comprises a phosphate ester group, a pyrophosphate ester group and / or a self-detaching group; (ii) the cuttable connector comprises a self-detaching group; or (iii) the cuttable connector comprises a self-detaching group including -CH2-O-, -NH-CH2-, -C(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(sulfonyl)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0511] In the embodiments, W is N or CH.

[0512] In an embodiment, R 2 and R 3 Each of them is a hydrophilic group.

[0513] In the embodiments, the conjugate has the formula (C-2):

[0514]

[0515] in:

[0516] Ab is an antibody or its antigen-binding fragment;

[0517] R 100 It is a coupling group;

[0518] L 1It is a bridging spacer;

[0519] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0520] L 2 and L 3 Each is an independent connecting spacer;

[0521] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[0522] A 1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[0523] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D. 1 or D 2 Attachment point;

[0524] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0525] L 4 and L 5 Each is an independent spacer component;

[0526] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[0527] m and n are each independently 0 or 1.

[0528] In the embodiments, the conjugate has the formula (D1-2), (D2-2), or (D3-2):

[0529]

[0530]

[0531] In the embodiments, the conjugate has the formula (D1-2), R 2 and R 3 Each is an independent hydrophilic group, wherein for formula (D2-2), R 2 and R 3 Each is an independent enzyme cleavage element; and for formula (D3-2), R 2 It is a hydrophilic group and R 3 It is an enzyme cleavage element.

[0532] In an embodiment, R 100 Choose from the following groups:

[0533]

[0534]

[0535]

[0536]

[0537] amide;

[0538]

[0539] as well as

[0540] disulfide bond,

[0541] in:

[0542] R 16 It is H, C 1- C4 alkyl, phenyl, pyrimidine, or pyridine;

[0543] R 18 It is H, C 1- C6 alkyl, phenyl, or C6 substituted with 1 to 3 -OH groups 1- C4 alkyl;

[0544] Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy group substituted with -C(=O)OH, benzyl group substituted with -C(=O)OH, C6 alkyl group substituted with -C(=O)OH 1- C4 alkoxy groups and C groups substituted with -C(=O)OH 1- C4 alkyl;

[0545] R17 Independently selected from H, phenyl, and pyridine;

[0546] q is 0, 1, 2, or 3;

[0547] R 19 It is H or methyl; and

[0548] R 20 It is H, -CH3, or phenyl.

[0549] In an embodiment, R 100 Freedom of choice The group consisting of R 100 The *** indicates the attachment point to Ab.

[0550] In an embodiment, R 100 yes where R 100 The *** indicates the attachment point to Ab.

[0551] In the embodiment, (1)L 1 Include:

[0552] or *-CH(OH)CH(OH)CH(OH)CH(OH)-**,

[0553] where each n is an integer from 1 to 12, and L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[0554] (2)L 1 yes And n is an integer from 1 to 12, or n is 1 or n is 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[0555] (3)L 1 yes And n is an integer from 1 to 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a connection point to R. 1 The direct or indirect (e.g., direct) attachment point;

[0556] (4)L 1 Include Among them L 1The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 Direct or indirect (e.g., direct) attachment points; or

[0557] (5)L 1 It is a bridging spacer, which includes:

[0558] *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2)n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[0559] X1 is and

[0560] Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0561] Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

[0562] Each t is independently selected from 1, 2, 3, 4, 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, and 30; and

[0563] Each R L1 Independently selected from H and C1-C6 alkyl groups.

[0564] In an embodiment, L 1 Includes the portion represented by the following:

[0565]

[0566] Where n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8), where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect attachment point.

[0567] In the embodiment, n is an integer from 4 to 8.

[0568] In the embodiments, n is 4 or 8.

[0569] In an embodiment, L 1 It can be expressed by the following formula:

[0570]

[0571] in

[0572] n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8);

[0573] x is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[0574] y is 0 or 1;

[0575] z is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[0576] u is 0 or 1; and

[0577] Among them L 1 The asterisk (*) indicates a direct attachment point to W, and L 1 The **representation of R 1 The direct attachment point.

[0578] In the embodiment, n is an integer from 4 to 8.

[0579] In the embodiments, n is 4 or 8.

[0580] In the embodiment, x is an integer from 0 to 2.

[0581] In the embodiments, x is 0 or 2.

[0582] In the embodiment, z is an integer from 0 to 2.

[0583] In the embodiments, z is 0 or 2.

[0584] In an embodiment, L 1 Choose from the following groups:

[0585]

[0586] In an embodiment, L 2 and L 3 Each is an independent connecting spacer, which comprises parts represented by the following:

[0587]

[0588] in

[0589] k is an integer from 0 to 6;

[0590] r is 0 or 1;

[0591] o is an integer from 0 to 12;

[0592] p is an integer from 0 to 6; and

[0593] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct or indirect attachment point, and L 2 or L 3 The ## symbol indicates a direct or indirect attachment point to W.

[0594] In an embodiment, L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[0595]

[0596]

[0597] as well as

[0598]

[0599] in

[0600] k is an integer from 0 to 4 each time it appears;

[0601] r is 0 or 1 independently each time it appears;

[0602] o is an integer from 0 to 10 each time it appears;

[0603] p is an integer from 0 to 4 each time it appears;

[0604] R L23 Is it hydrogen or C? 1- C6 alkyl;

[0605] R L It is hydrogen or -C(O)-R H ;

[0606] R H It is a hydrophilic group; and

[0607] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L2 or L 3 The ## symbol indicates a direct attachment point to W;

[0608] The condition is that when W is N, L 2 and L 3 It is not (L2c), (L2d), (L2f), or (L2k).

[0609] In an embodiment, L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[0610]

[0611]

[0612] as well as

[0613]

[0614] in

[0615] k is an integer from 1 to 3 each time it appears;

[0616] o is an integer from 1 to 9 each time it appears;

[0617] p is an integer from 1 to 3 each time it appears;

[0618] R L23 Is it hydrogen or C? 1- C3 alkyl;

[0619] R L It is hydrogen or -C(O)-R H ;

[0620] R H It is a hydrophilic group; and

[0621] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol represents the direct attachment point to W; the condition is that L is N when W is N. 2 and L 3 It is not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

[0622] In an embodiment, L 2 and L 3 The connecting spacers are independently selected from the following groups:

[0623]

[0624]

[0625] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 direct attachment point, L 2 or L 3 The ## symbol indicates the direct attachment point to W; R L It is hydrogen or -C(O)-R H ;and

[0626] R H yes And d is an integer between 20 and 30 (e.g., 25).

[0627] In this embodiment, d is 25.

[0628] In the embodiments, each peptide group independently contains 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

[0629] In the embodiments, each peptide group independently contains two amino acid residues.

[0630] In the examples, each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfonyl-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

[0631] In the examples, each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly, and sulfon-Ala-Val-Ala.

[0632] In the embodiment, E 1 and / or E 2 Each peptide group is independently selected from the following groups:

[0633]

[0634] Where the ^ of E1-1 or E1-2 represents the same as V in equation (B). 1 or V 2 The direct attachment point or the direct attachment point with the -NH- group in formulas (C) and (D); and the ^^ of E1-1 or E1-2 respectively represent the direct attachment point with L 2 or L 3 The direct attachment point (e.g., where E) 1 and E 2 Each is an independently selected peptide group from (E1-1) and (E1-2).

[0635] In the embodiment, E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

[0636] In the embodiment, E 1 and / or E 2 Each is independently represented by the following peptide groups:

[0637]

[0638] where R E It is a hydrophilic group R H .

[0639] In the embodiments, the hydrophilic group R in (E1-3) H yes Where e is an integer between 20 and 30 (e.g., 25).

[0640] In the embodiment, e is 25.

[0641] In the embodiment, E 1 and E 2 Each is

[0642] In the embodiment, A 1 and A 2 Independently selected from the bond and -OC (=O)-*, where * indicates that it is related to D respectively. 1 or D 2 Attachment point.

[0643] In the embodiment, A 1 and A 2 Independently selected from keys, and -OC(=O)-*, where * represents the relationship with D respectively. 1 or D 2 Attachment point.

[0644] In the embodiment, A 1 and A 2 It is a key.

[0645] In the embodiment, A 1 and A 2 Independently is a key or Where * indicates that they are related to D respectively. 1 or D 2 Attachment point.

[0646] In the embodiment, A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

[0647] In the embodiment, A 1 and A 2 All

[0648] In the embodiment, A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

[0649] In the embodiment, (i)A 1 and A 2 It is -OC(=O)-*;

[0650] (ii)A 1 and A 2 yes

[0651] (iii)A 1 It is -OC(=O)-* and A 2 It is a key;

[0652] (iv)A 1 It is -OC(=O)-* and A 2 yes

[0653] (v)A 1 It is a key and A 2 yes or

[0654] (vi)A 1 It is a key and A 2 It is -OC(=O)-*,

[0655] Where * indicates a relationship with D 1 or D 2 Attachment point.

[0656] In the embodiment, i)L4 and L 5 Each is an independent spacer sub-part, which has a structure

[0657] in:

[0658] Z is -O-, -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[0659] X is a bond, a triazole group, or -CH2-triazole-.

[0660] Where X is connected to R 2 or R 3 ;or

[0661] (ii)L 4 and L 5 Independently, there is a spacer sub-part, which has a structure

[0662] in:

[0663] Z represents -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[0664] X is -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene group -OC(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -,-CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n - where each n is independently 1, 2, or 3.

[0665] Where X is connected to R 2 or R 3 .

[0666] In the embodiment, Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazole group, or -CH2-triazole-; and R L45 It is either H or C each time it appears. 1- C3 alkyl.

[0667] In an embodiment, L 4 and L 5 Each is an independent sub-part of the interval selected from the following groups:

[0668]

[0669] Among them L 4 or L 5 The @ symbol represents the direct attachment point to the phenyl group, and L 4 or L 5 @@ represents R2 or R 3 The direct attachment point.

[0670] In the embodiment, by R 2 and R 3 The hydrophilic groups represented independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, and 1 to 3 [unclear - possibly referring to specific compounds or groups]. The substituted C2-C6 alkyl group, or the alkyl group independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C2-C6 alkyl groups substituted with C4 alkylene groups -P(O)(OCH2CH3)2 and -COOH groups.

[0671] In an embodiment, R 2 or / and R 3 Each person independently chooses from the following groups:

[0672]

[0673]

[0674] Where n is an integer between 1 and 6;

[0675] In an embodiment, R 2 or / and R 3 Each contains independently:

[0676] (i) Polysarcosine having the following components:

[0677] in

[0678] f is an integer between 3 and 25; and

[0679] R 23 It is H, -CH3, or -CH2CH2C(=O)OH;

[0680] (ii) Polyethylene glycol having the following formula: in

[0681] g and h are independent integers between 2 and 30; or

[0682] (iii) by The part that is indicated.

[0683] In the embodiment, by R 2 or R 3 The hydrophilic groups represented each contain independently:

[0684] (i) Polysarcosine having the following components:

[0685] Where f is an integer between 3 and 25; and R 23 It is H, -CH3, or -CH2CH2C(=O)OH; or (ii) polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[0686] In an embodiment, R 2 and R 3 Each independently chooses freedom The group consisting of;

[0687] g and h are independent integers between 20 and 30 (e.g., 23 or 24).

[0688] In an embodiment, R 2 or / and R 3 Include:

[0689]

[0690] In an embodiment, R 2 and R 3 Each independently contains polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[0691] In the embodiment, D 1 and D 2 They are the same.

[0692] In the embodiment, D 1 and D 2 They are different.

[0693] In the embodiment, D 1 and D 2 Each drug is independently selected from cytotoxic drugs, cell growth inhibitors, and immunosuppressants.

[0694] In the embodiment, D 1 and D 2 Each ingredient was independently selected from auristatin, camptothecin, pyroxine, etoposide, maytansine, maytansine-like substances, taxanes, and benzodiazepines. Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and periwinkle alkaloids.

[0695] In the embodiment, D 1 and D 2 Each person independently chooses from the following groups:

[0696] (For example ), (For example ), (For example )and (For example ),

[0697] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[0698] In an embodiment,

[0699] i)D 1 yes And D 2 yes

[0700] ii)D 1 yes And D 2 yes

[0701] iii)D 1 yes And D 2 yes

[0702] iv)D 1 yes And D 2 yes

[0703] v)D 1 yes And D 2 yes

[0704] vi)D 1 yes And D 2 yes

[0705] vii)D 1 yes And D 2 yes

[0706] viii)D 1 yes And D 2 yes

[0707] ix)D 1 yes And D 2 yes

[0708] x)D 1 yes And D 2 yes

[0709] xi)D 1 yes And D 2 yes

[0710] xii)D 1 yes And D 2 yes

[0711] xiii)D 1 yes And D 2 yes

[0712] xiv)D 1 yes And D 2 yes

[0713] xv)D 1 yes And D 2 yes

[0714] xvi)D 1 yes And D 2 yes

[0715] xvii)D 1 yes And D 2 yes

[0716] xviii)D 1 yes And D 2 yes

[0717] xix)D 1 yes And D 2 yes

[0718] xx)D 1 yes And D 2 yes

[0719] xxi)D 1 yes And D 2 yes

[0720] xxii)D 1 yes And D 2 yes

[0721] xxiii)D 1 yes And D 2 yes

[0722] xxiv)D 1 yes And D 2 yes

[0723] xxv)D 1 yes And D 2 yes

[0724] xxvi)D 1 yes And D 2 yes

[0725] xxvii)D 1 yes And D 2 yes

[0726] xxviii)D 1 yes And D 2 yes

[0727] xxix)D 1 yes And D 2 yes

[0728] xxx)D 1 yes And D2 yes

[0729] xxxi)D 1 yes And D 2 yes

[0730] xxxii)D 1 yes And D 2 yes

[0731] xxxiii)D 1 yes And D 2 yes

[0732] xxxiv)D 1 yes And D 2 yes

[0733] xxxv)D 1 yes And D 2 yes

[0734] xxxvi)D 1 yes And D 2 yes

[0735] xxxvii)D 1 yes And D 2 yes

[0736] xxxviii)D 1 yes And D 2 yes

[0737] xxxix)D 1 yes And D 2 yes

[0738] xl)D 1 yes And D 2 yes

[0739] xli)D 1 yes And D 2 yes

[0740] xlii)D 1 yes And D 2 yes

[0741] xliii)D 1 yes And D 2 yes

[0742] xliv)D 1 yes And D 2 yes

[0743] vl)D 1 yes And D 2 yes

[0744] xlvi)D 1 yes And D 2 yes

[0745] xlvii)D 1 yes And D 2 yes

[0746] xlviii)D 1 yes And D 2 yes

[0747] il)D 1 yes And D 2 yes

[0748] l)D 1 yes And D 2 yes

[0749] li)D 1 yes And D 2 yes

[0750] lii)D 1 yes And D 2 yes

[0751] liii)D 1 yes And D 2 yes

[0752] liv)D 1 yes And D 2 yes

[0753] lv)D 1 yes And D 2 yes lvi)D 1 yes And D 2 yes

[0754] lvii)D 1 yes And D 2 yes

[0755] lviii)D 1 yes And D 2 yes

[0756] lix)D 1 yes And D 2 yes

[0757] lx)D 1 yes And D 2 yes

[0758] lxi)D 1 yes And D 2 yes

[0759] lxii)D 1 yes And D 2 yes

[0760] lxiii)D 1 yes And D 2 yes ,or

[0761] lxiv)D 1 yes And D2 yes

[0762] In the examples:

[0763] i)A 1 -D 1 yes And A 2 -D 2 yes

[0764] ii)A 1 -D 1 yes And A 2 -D 2 yes

[0765] iii)A 1 -D 1 yes And A 2 -D 2 yes

[0766] iv)A 1 -D 1 yes And A 2 -D 2 yes

[0767] v)A 1 -D 1 yes And A 2 -D 2 yes

[0768] vi)A 1 -D 1 yes And A 2 -D 2 yes

[0769] vii)A 1 -D 1 yes And A 2 -D 2 yes

[0770] viii)A 1 -D 1 yes And A 2 -D 2 yes

[0771] ix)A 1 -D 1 yes And A 2 -D 2 yes

[0772] x)A 1 -D 1 yes And A 2 -D 2 yes

[0773] xi)A 1 -D 1 yes And A 2 -D 2 yes

[0774] xii)A 1 -D 1 yes And A 2 -D 2 yes

[0775] xiii)A 1 -D 1 yes And A 2 -D 2 yes

[0776] xiv)A 1 -D 1 yes And A 2 -D 2 yes

[0777] xv)A 1 -D 1 yes And A 2 -D 2 yes

[0778] xvi)A 1 -D 1 yes And A 2 -D 2 yes

[0779] xvii)A 1 -D 1 yes And A 2 -D 2 yes

[0780] xviii)A 1 -D 1 yes And A 2 -D 2 yes

[0781] xix)A 1 -D 1 yes And A 2 -D 2 yes

[0782] xx)A 1 -D 1 yes And A 2 -D 2 yes

[0783] xxi)A 1 -D 1 yes And A 2 -D 2 yes

[0784] xxii)A 1 -D 1 yes And A 2 -D 2 yes

[0785] xxiii)A 1 -D 1 yes And A 2 -D 2 yes

[0786] xxiv)A 1 -D 1 yes And A 2 -D 2 yes

[0787] xxv)A 1 -D 1 yes And A 2 -D 2 yes

[0788] xxvi)A 1 -D 1 yes And A 2 -D 2 yes

[0789] xxvii)A 1 -D 1 yes And A 2 -D 2 yes

[0790] xxviii)A 1 -D 1 yes And A 2 -D 2 yes

[0791] xxix)A 1 -D 1 yes And A 2 -D 2 yes

[0792] xxx)A 1 -D 1 yes And A 2 -D 2 yes

[0793] xxxi)A 1 -D 1 yes And A 2 -D 2 yes

[0794] xxxii)A 1 -D 1 yes And A 2 -D 2 yes

[0795] xxxiii)A 1 -D 1 yes And A 2 -D 2 yes

[0796] xxxiv)A1 -D 1 yes And A 2 -D 2 yes

[0797] xxxv)A 1 -D 1 yes And A 2 -D 2 yes

[0798] xxxvi)A 1 -D 1 yes And A 2 -D 2 yes

[0799] xxxvii)A 1 -D 1 yes And A 2 -D 2 yes

[0800] xxxviii)A 1 -D 1 yes And A 2 -D 2 yes

[0801] xxxix)A 1 -D 1 yes And A 2 -D 2 yes

[0802] xl)A 1 -D 1 yes And A 2 -D 2 yes xli)A 1 -D 1 yes And A 2 -D 2 yes

[0803] xlii)A 1 -D 1 yes And A 2 -D 2yes

[0804] xliii)A 1 -D 1 yes And A 2 -D 2 yes

[0805] xliv)A 1 -D 1 yes And A 2 -D 2 yes

[0806] xlv)A 1 -D 1 yes And A 2 -D 2 yes

[0807] xlvi)A 1 -D 1 yes And A 2 -D 2 yes

[0808] xlvii)A 1 -D 1 yes And A 2 -D 2 yes

[0809] xlviii)A 1 -D 1 yes And A 2 -D 2 yes

[0810] xlix)A 1 -D 1 yes And A 2 -D 2 yes

[0811] l)A 1 -D 1 yes And A 2 -D 2 yes

[0812] li)A1 -D 1 yes And A 2 -D 2 yes

[0813] lii)A 1 -D 1 yes And A 2 -D 2 yes

[0814] liii)A 1 -D 1 yes And A 2 -D 2 yes

[0815] liv)A 1 -D 1 yes And A 2 -D 2 yes

[0816] lv)A 1 -D 1 yes And A 2 -D 2 yes

[0817] lvi)A 1 -D 1 yes And A 2 -D 2 yes

[0818] lvii)A 1 -D 1 yes And A 2 -D 2 yes

[0819] lviii)A 1 -D 1 yes And A 2 -D 2 yes

[0820] lix)A 1 -D 1 yes And A 2-D 2 yes

[0821] lx)A 1 -D 1 yes And A 2 -D 2 yes

[0822] lxi)A 1 -D 1 yes And A 2 -D 2 yes

[0823] lxii)A 1 -D 1 yes And A 2 -D 2 yes

[0824] lxiii)A 1 -D 1 yes And A 2 -D 2 yes or

[0825] lxiv)A 1 -D 1 yes And A 2 -D 2 yes

[0826] The asterisk (*) indicates a connection point with the rest of the molecule.

[0827] In the embodiment, D 1 and / or D 2 It's Aurestatin.

[0828] In the embodiment, D 1 and D 2 They are all Aurestatin.

[0829] In the embodiment, D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

[0830] In the embodiment, D 1 and D 2 They are all topoisomerase 1 inhibitors.

[0831] In the embodiment, D 1 and D2 One of them is auristatin, and D 1 and D 2 The other one is a topoisomerase 1 inhibitor.

[0832] In the embodiment, D 1 It is Aurestatin and D 2 It is a topoisomerase 1 inhibitor.

[0833] In the embodiment, D 1 It is a topoisomerase 1 inhibitor and D 2 It's Aurestatin.

[0834] In the embodiment, D 1 and D 2 Choose independently from the following groups:

[0835] Where * indicates a relationship with A 1 Or A 2 Attachment point.

[0836] In the embodiment, D 1 and D 2 Choose independently from the following groups:

[0837]

[0838] In the embodiment, D 1 and D 2 Each is independently selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, anti-folate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[0839] In the embodiment, D 1 and D 2 Each of the following is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, aurestatin, dolalastatin, maytansine-like substances, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or apoptosis-promoting agents, with the optional condition being D. 1 and D2 Neither of them are BH3 analogs.

[0840] In the examples, the antibody or antigen-binding fragment binds to the target antigen on the cancer cell.

[0841] In the embodiments, (i) the target antigen is selected from BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, SEZ6, DLL3, DLK1, B7-H3, EGFR, CD71, EphA2, EPCAM, FORR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2 and GPNMB;

[0842] (ii) The target antigen is selected from EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; or

[0843] (iii) The target antigen is PCAD, CD48, CD74, EphA2, HER2, TROP2, B7-H3 or 5T4.

[0844] In the embodiments, the target antigen is PCAD, CD48, CD74, EphA2, HER2, TROP2, B7-H3, or 5T4.

[0845] In the examples, the antibody or its antigen-binding fragment is selected from Table D1.

[0846] In the embodiments, the antibody or antigen-binding fragment comprises i) three heavy chain CDR sequences and three light chain CDR sequences of antibodies selected from Tables D3 and D8, ii) heavy chain variable region sequences and light chain variable region sequences of antibodies selected from Tables D2 and D8, and / or iii) heavy chain sequences and light chain sequences of antibodies selected from Tables D4, D5 and D7.

[0847] In this embodiment, the antibody or antigen-binding fragment is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0848] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:256, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:257, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:268, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:265;

[0849] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:258, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:172, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[0850] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:259, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:260, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:261; light chain CDR1 (LCDR1) composed of SEQ ID NO:269, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[0851] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:169, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:172, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[0852] 5) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:256, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:257, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:263, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:265;

[0853] 6) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:258, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:266, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[0854] 7) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:259, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:260, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:261; light chain CDR1 (LCDR1) composed of SEQ ID NO:215, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174; and

[0855] 8) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:169, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:170, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:171; light chain CDR1 (LCDR1) consisting of SEQ ID NO:266, light chain CDR2 (LCDR2) consisting of SEQ ID NO:173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:174.

[0856] In the embodiments, the antibody or antigen-binding fragment is an anti-CD74 antibody comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:262, or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:267.

[0857] In this embodiment, the antibody or antigen-binding fragment is an anti-CD74 antibody, which comprises:

[0858] (a) The heavy chain amino acid sequence of SEQ ID NO:118 or a sequence that is at least 95% identical to SEQ ID NO:118, and the light chain amino acid sequence of SEQ ID NO:237 or a sequence that is at least 95% identical to SEQ ID NO:237;

[0859] (b) The heavy chain amino acid sequence of SEQ ID NO:236 or a sequence that is at least 95% identical to SEQ ID NO:236, and the light chain amino acid sequence of SEQ ID NO:237 or a sequence that is at least 95% identical to SEQ ID NO:237; or

[0860] (c) The heavy chain amino acid sequence of SEQ ID NO:118 or a sequence that is at least 95% identical to SEQ ID NO:118, and the light chain amino acid sequence of SEQ ID NO:239 or a sequence that is at least 95% identical to SEQ ID NO:239.

[0861] In this embodiment, the antibody or antigen-binding fragment is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0862] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:271, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:272, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:281, light chain CDR2 (LCDR2) composed of SEQ ID NO:282, and light chain CDR3 (LCDR3) composed of SEQ ID NO:283;

[0863] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:274, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:275, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:284, light chain CDR2 (LCDR2) composed of SEQ ID NO:285, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286;

[0864] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:276, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:277, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:278; light chain CDR1 (LCDR1) composed of SEQ ID NO:287, light chain CDR2 (LCDR2) composed of SEQ ID NO:282, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286; and

[0865] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:279, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:275, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:284, light chain CDR2 (LCDR2) composed of SEQ ID NO:288, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286; and

[0866] 5) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:51, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:52, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:53; light chain CDR1 (LCDR1) consisting of SEQ ID NO:54, light chain CDR2 (LCDR2) consisting of SEQ ID NO:55, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:56.

[0867] In the embodiments, the antibody or antigen-binding fragment is an anti-CD48 antibody comprising a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:270 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:280; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[0868] In the embodiments, the antibody or antigen-binding fragment is an anti-CD48 antibody comprising (a) the heavy chain amino acid sequence of SEQ ID NO:240 or a sequence at least 95% identical to that of SEQ ID NO:240, and the light chain amino acid sequence of SEQ ID NO:243 or a sequence at least 95% identical to that of SEQ ID NO:243; or (b) the heavy chain amino acid sequence of SEQ ID NO:242 or a sequence at least 95% identical to that of SEQ ID NO:242, and the light chain amino acid sequence of SEQ ID NO:243 or a sequence at least 95% identical to that of SEQ ID NO:243; or (c) the heavy chain amino acid sequence of SEQ ID NO:240 or a sequence at least 95% identical to that of SEQ ID NO:240, and the light chain amino acid sequence of SEQ ID NO:69 or a sequence at least 95% identical to that of SEQ ID NO:70.

[0869] In this embodiment, the antibody or antigen-binding fragment is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0870] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:289, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:290, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:291; light chain CDR1 (LCDR1) composed of SEQ ID NO:297, light chain CDR2 (LCDR2) composed of SEQ ID NO:298, and light chain CDR3 (LCDR3) composed of SEQ ID NO:299;

[0871] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:292, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:40, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:291; light chain CDR1 (LCDR1) composed of SEQ ID NO:300, light chain CDR2 (LCDR2) composed of SEQ ID NO:301, and light chain CDR3 (LCDR3) composed of SEQ ID NO:44;

[0872] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:293, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:294, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:295; light chain CDR1 (LCDR1) composed of SEQ ID NO:302, light chain CDR2 (LCDR2) composed of SEQ ID NO:298, and light chain CDR3 (LCDR3) composed of SEQ ID NO:44; and

[0873] 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:39, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:40, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:291; light chain CDR1 (LCDR1) consisting of SEQ ID NO:300, light chain CDR2 (LCDR2) consisting of SEQ ID NO:301, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:44.

[0874] In the embodiments, the antibody or antigen-binding fragment is an anti-Her2 antibody, which comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:9 and a light chain variable region containing the amino acid sequence of SEQ ID NO:296.

[0875] In the embodiments, the antibody or antigen-binding fragment is an anti-Her2 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:245 or a sequence that is at least 95% identical to SEQ ID NO:245, and the light chain amino acid sequence of SEQ ID NO:66 or a sequence that is at least 95% identical to SEQ ID NO:66.

[0876] In this embodiment, the antibody or antigen-binding fragment is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0877] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:304, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:305, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:306; light chain CDR1 (LCDR1) composed of SEQ ID NO:312, light chain CDR2 (LCDR2) composed of SEQ ID NO:313, and light chain CDR3 (LCDR3) composed of SEQ ID NO:314;

[0878] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:307, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:308, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:306; light chain CDR1 (LCDR1) composed of SEQ ID NO:315, light chain CDR2 (LCDR2) composed of SEQ ID NO:25, and light chain CDR3 (LCDR3) composed of SEQ ID NO:316;

[0879] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:309, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:277, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:278; light chain CDR1 (LCDR1) composed of SEQ ID NO:317, light chain CDR2 (LCDR2) composed of SEQ ID NO:313, and light chain CDR3 (LCDR3) composed of SEQ ID NO:316; and

[0880] 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:310, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:308, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:306; light chain CDR1 (LCDR1) consisting of SEQ ID NO:315, light chain CDR2 (LCDR2) consisting of SEQ ID NO:25, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:316.

[0881] In the embodiments, the antibody or antigen-binding fragment is an anti-PCAD antibody, which comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:303 and a light chain variable region containing the amino acid sequence of SEQ ID NO:311.

[0882] In the embodiments, the antibody or antigen-binding fragment is an anti-PCAD antibody comprising the heavy chain amino acid sequence of SEQ ID NO:248 or a sequence that is at least 95% identical to SEQ ID NO:248, and the light chain amino acid sequence of SEQ ID NO:250 or a sequence that is at least 95% identical to SEQ ID NO:250.

[0883] In this embodiment, the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0884] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:319, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:320, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:321; light chain CDR1 (LCDR1) composed of SEQ ID NO:330, light chain CDR2 (LCDR2) composed of SEQ ID NO:331, and light chain CDR3 (LCDR3) composed of SEQ ID NO:332;

[0885] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:322, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:323, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:324; light chain CDR1 (LCDR1) composed of SEQ ID NO:333, light chain CDR2 (LCDR2) composed of SEQ ID NO:334, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335;

[0886] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:325, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:326, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:327; light chain CDR1 (LCDR1) composed of SEQ ID NO:336, light chain CDR2 (LCDR2) composed of SEQ ID NO:331, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335; and

[0887] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:328, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:323, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:321; light chain CDR1 (LCDR1) composed of SEQ ID NO:333, light chain CDR2 (LCDR2) composed of SEQ ID NO:334, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335.

[0888] In the embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:318 and a light chain variable region containing the amino acid sequence of SEQ ID NO:329.

[0889] In the embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:252 or a sequence that is at least 95% identical to SEQ ID NO:252, and the light chain amino acid sequence of SEQ ID NO:254 or a sequence that is at least 95% identical to SEQ ID NO:254.

[0890] In an embodiment, the antibody or its antigen-binding fragment contains one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or its antigen-binding fragment, wherein the position is according to the EU system number.

[0891] In the embodiments, the antibody or its antigen-binding fragment contains one or more Fc silencing mutations.

[0892] In the embodiments, the composition comprises a plurality of copies of the antibody-drug conjugate according to any one of claims 46 to 110, wherein the average a of the antibody-drug conjugate in the composition is about 1 to about 8, for example about 1 to about 6, about 1 to about 4, or about 1 to about 2.

[0893] In the embodiments, the compound or a pharmaceutically acceptable salt thereof is represented by any of the following formulas:

[0894]

[0895]

[0896]

[0897]

[0898] in:

[0899] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[0900] g is an integer between 20 and 30 each time it appears;

[0901] o is an integer between 1 and 9 each time it appears; and

[0902] n is an integer between 1 and 12.

[0903] In the embodiment, A1 and A 2 Each is independently selected from the bond and -OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[0904] In the embodiments, the conjugate is represented by any of the following formulas:

[0905]

[0906]

[0907]

[0908]

[0909] in:

[0910] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[0911] g is an integer between 20 and 30 each time it appears;

[0912] o is an integer between 1 and 9 each time it appears;

[0913] n is an integer between 1 and 12; and

[0914] **- indicates the attachment point to Ab.

[0915] In the embodiment, A 1 and A 2 Each is independently selected from the bond and OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[0916] In the embodiments, the compound or a pharmaceutically acceptable salt thereof has the formula (D5a-1):

[0917]

[0918] in:

[0919] A 1and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[0920] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[0921] o is an integer between 1 and 9 (e.g., between 1 and 3) that appears independently each time; and

[0922] n is an integer between 1 and 12 (for example, between 5 and 10).

[0923] In the embodiment, A 1 and A 2 Each is independently selected from the bond and -OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[0924] In the embodiments, the conjugate has the formula (D5a-2):

[0925]

[0926] in:

[0927] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[0928] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[0929] o is an integer between 1 and 9 (e.g., between 1 and 3) that appears independently each time;

[0930] n is an integer between 1 and 12 (e.g., between 5 and 10); and

[0931] **- indicates the attachment point to Ab.

[0932] In the embodiment, A 1 and A 2 Each is independently selected from the bond and -OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[0933] In the embodiments, the conjugate is represented by any of the following formulas:

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945] as well as

[0946]

[0947] Among them A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where * indicates the relationship with D 1 or D 2 The attachment point; **- indicates the attachment point to Ab; and Indicates D 1 or D 2 The direct attachment point.

[0948] In the embodiment, A 1 and A 2 Each is independently selected from the bond and -OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D.1 or D 2 Attachment point.

[0949] In some embodiments, this disclosure provides in part novel antibody-drug conjugate (ADC) compounds having biological activity against cancer cells. These compounds can slow, inhibit, and / or reverse tumor growth in mammals, and / or may be used to treat human cancer patients. In some embodiments, this disclosure more specifically relates to ADC compounds capable of binding to and killing cancer cells. In some embodiments, the ADC compounds disclosed herein comprise a dual-connector attaching two pharmaceutically active drugs to a full-length antibody or antigen-binding fragment, optionally provided that neither of the pharmaceutically active drugs is a BH3 mimic. In some embodiments, the ADC compound is also capable of internalization into target cells after binding.

[0950] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on cancer cells. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, EGFR, CD71, EPCAM, FORR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigens are EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, alpha-fetoprotein, angiopoietin 2, ASLG659, TCLI, BMPRIB, Brevican (BCAN), BEHAB, C242 antigen, C5, CA-125, CA-125 (generic), CA-IX (carbonic anhydrase 9), CCR4, CD140a, CD152, CD19, CD20, CD200, CD21 (C3DR)I), CD22 (B cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B cell differentiation antigen CD72), CD79a, CD80, CEA, CEA-associated antigen, ch4D5, CLDN18.2. CRIPTO (CR, CRI, CRGF, TDGF1), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Episialin, ERBB3, ETBR (endothelin B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP) IC), fibronectin extradomain-B, coiled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scattering factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor translocation-associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocytes, PD-I, PDCDI, PDGF-R u, prostate-specific membrane antigen, PSCA (prostate stem cell antigen precursor), PSCA hlg, RANKL, RON, SDCI, Sema Sb, STEAP I, STEAP2, PCANAP I, STAMP I. STEAP2, STMP, prostate cancer-associated gene I, TAG-72, TEMI, tendinin C, TENB2 (TMEFF2, brain tumor suppressor protein (tomoregulin), TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-R1, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M member 4), TWEAK-R, TYRP I (glycoprotein 75), VEGF, VEGF-A, EGFR-I, VEGFR-2, or vimentin. In some embodiments, the target antigen is EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is PCAD, HER2, CD48, CD74, EphA2, TROP2, B7-H3, or 5T4.

[0951] In some embodiments, the antibody or antigen-binding fragment is an antibody or antigen-binding fragment disclosed in the Internet go.drugbank.com / drugs / DB00002, in international applications WO 2018 / 098306, WO 2016 / 179257, WO 2011 / 097627, WO 2017 / 214282, WO 2017 / 214301, WO 2017 / 214233, WO 2013 / 126810, WO 2008 / 056833, WO 2020 / 236817, WO 2017 / 214335 and WO 2012147713, and in U.S. Patent No. US 6870034 B2, all of which are incorporated herein by reference in their entirety.

[0952] In some embodiments, the antibody or antigen-binding fragment is an anti-HER2 antibody or antigen-binding fragment (e.g., trastuzumab or Ab T). In some embodiments, the antibody or antigen-binding fragment is an anti-CD74 antibody or antigen-binding fragment (e.g., VHmil x VK1aNQAb or milatuzumab). In some embodiments, the antibody or antigen-binding fragment is an anti-CD48 antibody or antigen-binding fragment (e.g., SGN-CD48A (MEM / MEM102 or NY920)). In some embodiments, the antibody or antigen-binding fragment is an anti-PCAD antibody or antigen-binding fragment (e.g., CQY679). In some embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody or antigen-binding fragment (e.g., 1C1). In some embodiments, the antibody or antigen-binding fragment is an antibody or antigen-binding fragment having a CDR sequence selected from those in Tables D3 and D8, or an antibody or antigen-binding fragment having a variable region selected from those in Tables D2 and D8, or an antibody or antigen-binding fragment having the full length selected from those in Tables D4, D5, and D7.

[0953] In some embodiments, this document also provides compositions comprising multiple copies of an antibody-drug conjugate (e.g., any exemplary antibody-drug conjugate described herein). In some embodiments, the average p-value of the antibody-drug conjugate in the composition is from about 2 to about 4.

[0954] In the embodiments, the antibody or its antigen-binding fragment is conjugated to a group selected from any of the following. In the embodiments, the compound or its pharmaceutically acceptable salt is selected from the group consisting of:

[0955] P1-L1-P1、P1-L1-P2、P1-L1-P3、P1-L1-P4、P1-L1-P5、P1-L1-P6、P1-L1-P7、P1-L1-P8、P1-L2-P1、P1-L2-P2、P1-L2-P3、P1-L2-P4、P1-L2-P5、P1-L2-P 6、P1-L2-P7、P1-L2-P8、P1-L3-P1、P1-L3-P2、P1-L3-P3、P1-L3-P4、P1-L3- P5、P1-L3-P6、P1-L3-P7、P1-L3-P8、P1-L4-P1、P1-L4-P2、P1-L4-P3、P1-L4- P4、P1-L4-P5、P1-L4-P6、P1-L4-P7、P1-L4-P8、P1-L5-P1、P1-L5-P2、P1-L5 -P3、P1-L5-P4、P1-L5-P5、P1-L5-P6、P1-L5-P7、P1-L5-P8、P1-L6-P1、P1-L6 -P2、P1-L6-P3、P1-L6-P4、P1-L6-P5、P1-L6-P6、P1-L6-P7、P1-L6-P8、P1-L 7-P1、P1-L7-P2、P1-L7-P3、P1-L7-P4、P1-L7-P5、P1-L7-P6、P1-L7-P7、P1-L 7-P8、P1-L8-P1、P1-L8-P2、P1-L8-P3、P1-L8-P4、P1-L8-P5、P1-L8-P6、P1-L8-P7、P1-L8-P8、P1-L9-P1、P1-L9-P2、P1-L9-P3、P1-L9-P4、P1-L9-P5、P1 -L9-P6、P1-L9-P7、P1-L9-P8、P1-L10-P1、P1-L10-P2、P1-L10-P3、P1-L10- P4、P1-L10-P5、P1-L10-P6、P1-L10-P7、P1-L10-P8、P1-L11-P1、P1-L11-P2、 P1-L11-P3、P1-L11-P4、P1-L11-P5、P1-L11-P6、P1-L11-P7、P1-L11-P8、P1 -L12-P1、P1-L12-P2、P1-L12-P3、P1-L12-P4、P1-L12-P5、P1-L12-P6、P1-L1 2-P7、P1-L12-P8、P1-L13-P1、P1-L13-P2、P1-L13-P3、P1-L13-P4、P1-L13-P5、P1-L13-P6、P1-L13-P7、P1-L13-P8、P1-L14-P1、P1-L14-P2、P1-L14-P3、P1-L14-P4、P1-L14-P5、P1-L14-P6、P1-L14-P7、P1-L14-P8、P1-L15-P1、P1 -L15-P2、P1-L15-P3、P1-L15-P4、P1-L15-P5、P1-L15-P6、P1-L15-P7、P1-L1 5-P8、P1-L16-P1、P1-L16-P2、P1-L16-P3、P1-L16-P4、P1-L16-P5、P1-L16-P6、P1-L16-P7、P1-L16-P8、P1-L17-P1、P1-L17-P2、P1-L17-P3、P1-L17-P4、 P1-L17-P5、P1-L17-P6、P1-L17-P7、P1-L17-P8、P1-L18-P1、P1-L18-P2、P1 -L18-P3、P1-L18-P4、P1-L18-P5、P1-L18-P6、P1-L18-P7、P1-L18-P8、P1-L1 9-P1、P1-L19-P2、P1-L19-P3、P1-L19-P4、P1-L19-P5、P1-L19-P6、P1-L19-P7、P1-L19-P8、P1-L20-P1、P1-L20-P2、P1-L20-P3、P1-L20-P4、P1-L20-P5、 P1-L20-P6、P1-L20-P7、P1-L20-P8、P1-L21-P1、P1-L21-P2、P1-L21-P3、P1 -L21-P4、P1-L21-P5、P1-L21-P6、P1-L21-P7、P1-L21-P8、P1-L22-P1、P1-L2 2-P2、P1-L22-P3、P1-L22-P4、P1-L22-P5、P1-L22-P6、P1-L22-P7、P1-L22- P8、P1-L23-P1、P1-L23-P2、P1-L23-P3、P1-L23-P4、P1-L23-P5、P1-L23-P6、 P1-L23-P7、P1-L23-P8、P1-L24-P1、P1-L24-P2、P1-L24-P3、P1-L24-P4、P1-L24-P5、P1-L24-P6、P1-L24-P7、P1-L24-P8、P1-L25-P1、P1-L25-P2、P1-L2 5-P3、P1-L25-P4、P1-L25-P5、P1-L25-P6、P1-L25-P7、P1-L25-P8、P1-L26-P1、P1-L26-P2、P1-L26-P3、P1-L26-P4、P1-L26-P5、P1-L26-P6、P1-L26-P7、P1-L26-P8、P1-L27-P1、P1-L27-P2、P1-L27-P3、P1-L27-P4、P1-L27-P5、P1 -L27-P6、P1-L27-P7、P1-L27-P8、P1-L28-P1、P1-L28-P2、P1-L28-P3、P1-L 28-P4、P1-L28-P5、P1-L28-P6、P1-L28-P7、P1-L28-P8、P1-L29-P1、P1-L29 -P2、P1-L29-P3、P1-L29-P4、P1-L29-P5、P1-L29-P6、P1-L29-P7、P1-L29-P8 、P1-L30-P1、P1-L30-P2、P1-L30-P3、P1-L30-P4、P1-L30-P5、P1-L30-P6、P 1-L30-P7、P1-L30-P8、P1-L31-P1、P1-L31-P2、P1-L31-P3、P1-L31-P4、P1-L 31-P5、P1-L31-P6、P1-L31-P7、P1-L31-P8、P1-L32-P1、P1-L32-P2、P1-L32 -P3、P1-L32-P4、P1-L32-P5、P1-L32-P6、P1-L32-P7、P1-L32-P8、P1-L33-P1 、P1-L33-P2、P1-L33-P3、P1-L33-P4、P1-L33-P5、P1-L33-P6、P1-L33-P7、P 1-L33-P8、P1-L34-P1、P1-L34-P2、P1-L34-P3、P1-L34-P4、P1-L34-P5、P1-L 34-P6、P1-L34-P7、P1-L34-P8、P1-L35-P1、P1-L35-P2、P1-L35-P3、P1-L35 -P4、P1-L35-P5、P1-L35-P6、P1-L35-P7、P1-L35-P8、P1-L36-P1、P1-L36-P2 、P1-L36-P3、P1-L36-P4、P1-L36-P5、P1-L36-P6、P1-L36-P7、P1-L36-P8、P 2-L1-P1、P2-L1-P2、P2-L1-P3、P2-L1-P4、P2-L1-P5、P2-L1-P6、P2-L1-P7、P 2-L1-P8, P2-L2-P1, P2-L2-P2, P2-L2-P3, P2-L2-P4, P2-L2-P5, P2-L2-P6, P2-L2-P7, P2-L2-P8, P2-L3-P1, P2-L3-P2, P2-L3-P3, P2-L3-P4, P2-L3-P5P2-L3-P6、P2-L3-P7、P2-L3-P8、P2-L4-P1、P2-L4-P2、P2-L4-P3、P2-L4-P4 、P2-L4-P5、P2-L4-P6、P2-L4-P7、P2-L4-P8、P2-L5-P1、P2-L5-P2、P2-L5-P 3, P2-L5-P4, P2-L5-P5, P2-L5-P6, P2-L5-P7, P2-L5-P8, P2-L6-P1, P2-L6-P2, P2-L6-P3, P2-L6-P4, P2-L6-P5, P2-L6-P6, P2-L6-P7, P2-L6-P8, P2-L7- P1、P2-L7-P2、P2-L7-P3、P2-L7-P4、P2-L7-P5、P2-L7-P6、P2-L7-P7、P2-L7 -P8、P2-L8-P1、P2-L8-P2、P2-L8-P3、P2-L8-P4、P2-L8-P5、P2-L8-P6、P2-L8 -P7、P2-L8-P8、P2-L9-P1、P2-L9-P2、P2-L9-P3、P2-L9-P4、P2-L9-P5、P2-L 9-P6、P2-L9-P7、P2-L9-P8、P2-L10-P1、P2-L10-P2、P2-L10-P3、P2-L10-P4、 P2-L10-P5、P2-L10-P6、P2-L10-P7、P2-L10-P8、P2-L11-P1、P2-L11-P2、P2 -L11-P3、P2-L11-P4、P2-L11-P5、P2-L11-P6、P2-L11-P7、P2-L11-P8、P2-L1 2-P1、P2-L12-P2、P2-L12-P3、P2-L12-P4、P2-L12-P5、P2-L12-P6、P2-L12- P7、P2-L12-P8、P2-L13-P1、P2-L13-P2、P2-L13-P3、P2-L13-P4、P2-L13-P5、 P2-L13-P6、P2-L13-P7、P2-L13-P8、P2-L14-P1、P2-L14-P2、P2-L14-P3、P2 -L14-P4、P2-L14-P5、P2-L14-P6、P2-L14-P7、P2-L14-P8、P2-L15-P1、P2-L1 5-P2、P2-L15-P3、P2-L15-P4、P2-L15-P5、P2-L15-P6、P2-L15-P7、P2-L15- P8、P2-L16-P1、P2-L16-P2、P2-L16-P3、P2-L16-P4、P2-L16-P5、P2-L16-P6、P2-L16-P7、P2-L16-P8、P2-L17-P1、P2-L17-P2、P2-L17-P3、P2-L17-P4、P2-L17-P5、P2-L17-P6、P2-L17-P7、P2-L17-P8、P2-L18-P1、P2-L18-P2、P2-L18-P3、P2-L18-P4、P2-L18-P5、P2-L18-P6、P2-L18-P7、P2-L18-P8、P2-L19-P1、P2-L19-P2、P2-L19-P3、P2-L19-P4、P2-L19-P5、P2-L19-P6、P2-L19-P7、P2-L19-P8、P2-L20-P1、P2-L20-P2、P2-L20-P3、P2-L20-P4、P2-L20-P5、P2-L20-P6、P2-L20-P7、P2-L20-P8、P2-L21-P1、P2-L21-P2、P2-L21-P3、P2-L21-P4、P2-L21-P5、P2-L21-P6、P2-L21-P7、P2-L21-P8、P2-L22-P1、P2-L22-P2、P2-L22-P3、P2-L22-P4、P2-L22-P5、P2-L22-P6、P2-L22-P7、P2-L22-P8、P2-L23-P1、P2-L23-P2、P2-L23-P3、P2-L23-P4、P2-L23-P5、P2-L23-P6、P2-L23-P7、P2-L23-P8、P2-L24-P1、P2-L24-P2、P2-L24-P3、P2-L24-P4、P2-L24-P5、P2-L24-P6、P2-L24-P7、P2-L24-P8、P2-L25-P1、P2-L25-P2、P2-L25-P3、P2-L25-P4、P2-L25-P5、P2-L25-P6、P2-L25-P7、P2-L25-P8、P2-L26-P1、P2-L26-P2、P2-L26-P3、P2-L26-P4、P2-L26-P5、P2-L26-P6、P2-L26-P7、P2-L26-P8、P2-L27-P1、P2-L27-P2、P2-L27-P3、P2-L27-P4、P2-L27-P5、P2-L27-P6、P2-L27-P7、P2-L27-P8、P2-L28-P1、P2-L28-P2、P2-L28-P3、P2-L28-P4、P2-L28-P5、P2-L28-P6、P2-L28-P7、P2-L28-P8、P2-L29-P1、P2-L29-P2、P2-L29-P3、P2-L29-P4、P2-L29-P5、P2-L29-P6、P2-L29-P7、P2-L29-P8、P2 -L30-P1、P2-L30-P2、P2-L30-P3、P2-L30-P4、P2-L30-P5、P2-L30-P6、P2-L 30-P7、P2-L30-P8、P2-L31-P1、P2-L31-P2、P2-L31-P3、P2-L31-P4、P2-L31 -P5、P2-L31-P6、P2-L31-P7、P2-L31-P8、P2-L32-P1、P2-L32-P2、P2-L32-P3 P2-L32-P4, P2-L32-P5, P2-L32-P6, P2-L32-P7, P2-L32-P8, P2-L33-P1, P2-L33-P2, P2-L33-P3, P2-L33-P4, P2-L33-P5, P2-L33-P6, P2-L33-P7, P2-L 33-P8、P2-L34-P1、P2-L34-P2、P2-L34-P3、P2-L34-P4、P2-L34-P5、P2-L34 -P6、P2-L34-P7、P2-L34-P8、P2-L35-P1、P2-L35-P2、P2-L35-P3、P2-L35-P4 、P2-L35-P5、P2-L35-P6、P2-L35-P7、P2-L35-P8、P2-L36-P1、P2-L36-P2、P 2-L36-P3、P2-L36-P4、P2-L36-P5、P2-L36-P6、P2-L36-P7、P2-L36-P8、P3- L1-P1, P3-L1-P2, P3-L1-P3, P3-L1-P4, P3-L1-P5, P3-L1-P6, P3-L1-P7, P3-L1-P8, P3-L2-P1, P3-L2-P2, P3-L2-P3, P3-L2-P4, P3-L2-P5, P3-L2-P6, P3 -L2-P7, P3-L2-P8, P3-L3-P1, P3-L3-P2, P3-L3-P3, P3-L3-P4, P3-L3-P5, P3-L3-P6, P3-L3-P7, P3-L3-P8, P3-L4-P1, P3-L4-P2, P3-L4-P3, P3-L4-P4, P 3-L4-P5, P3-L4-P6, P3-L4-P7, P3-L4-P8, P3-L5-P1, P3-L5-P2, P3-L5-P3, P3-L5-P4, P3-L5-P5, P3-L5-P6, P3-L5-P7, P3-L5-P8, P3-L6-P1, P3-L6-P2P3-L6-P3, P3-L6-P4, P3-L6-P5, P3-L6-P6, P3-L6-P7, P3-L6-P8, P3-L7-P1, P3-L7-P2, P3-L7-P3, P3-L7-P4, P3-L7-P5, P3-L7-P6, P3-L7-P7, P3-L7-P8 P3-L8-P1, P3-L8-P2, P3-L8-P3, P3-L8-P4, P3-L8-P5, P3-L8-P6, P3-L8-P7, P3-L8-P8, P3-L9-P1, P3-L9-P2, P3-L9-P3, P3-L9-P4, P3-L9-P5, P3-L9-P 6、P3-L9-P7、P3-L9-P8、P3-L10-P1、P3-L10-P2、P3-L10-P3、P3-L10-P4、P3 -L10-P5、P3-L10-P6、P3-L10-P7、P3-L10-P8、P3-L11-P1、P3-L11-P2、P3-L1 1-P3、P3-L11-P4、P3-L11-P5、P3-L11-P6、P3-L11-P7、P3-L11-P8、P3-L12- P1、P3-L12-P2、P3-L12-P3、P3-L12-P4、P3-L12-P5、P3-L12-P6、P3-L12-P7、 P3-L12-P8、P3-L13-P1、P3-L13-P2、P3-L13-P3、P3-L13-P4、P3-L13-P5、P3 -L13-P6、P3-L13-P7、P3-L13-P8、P3-L14-P1、P3-L14-P2、P3-L14-P3、P3-L1 4-P4、P3-L14-P5、P3-L14-P6、P3-L14-P7、P3-L14-P8、P3-L15-P1、P3-L15- P2、P3-L15-P3、P3-L15-P4、P3-L15-P5、P3-L15-P6、P3-L15-P7、P3-L15-P8、 P3-L16-P1、P3-L16-P2、P3-L16-P3、P3-L16-P4、P3-L16-P5、P3-L16-P6、P3 -L16-P7、P3-L16-P8、P3-L17-P1、P3-L17-P2、P3-L17-P3、P3-L17-P4、P3-L1 7-P5、P3-L17-P6、P3-L17-P7、P3-L17-P8、P3-L18-P1、P3-L18-P2、P3-L18- P3、P3-L18-P4、P3-L18-P5、P3-L18-P6、P3-L18-P7、P3-L18-P8、P3-L19-P1、P3-L19-P2、P3-L19-P3、P3-L19-P4、P3-L19-P5、P3-L19-P6、P3-L19-P7、P3 -L19-P8、P3-L20-P1、P3-L20-P2、P3-L20-P3、P3-L20-P4、P3-L20-P5、P3-L2 0-P6、P3-L20-P7、P3-L20-P8、P3-L21-P1、P3-L21-P2、P3-L21-P3、P3-L21-P4、P3-L21-P5、P3-L21-P6、P3-L21-P7、P3-L21-P8、P3-L22-P1、P3-L22-P2、 P3-L22-P3、P3-L22-P4、P3-L22-P5、P3-L22-P6、P3-L22-P7、P3-L22-P8、P3 -L23-P1、P3-L23-P2、P3-L23-P3、P3-L23-P4、P3-L23-P5、P3-L23-P6、P3-L2 3-P7、P3-L23-P8、P3-L24-P1、P3-L24-P2、P3-L24-P3、P3-L24-P4、P3-L24-P5、P3-L24-P6、P3-L24-P7、P3-L24-P8、P3-L25-P1、P3-L25-P2、P3-L25-P3、 P3-L25-P4、P3-L25-P5、P3-L25-P6、P3-L25-P7、P3-L25-P8、P3-L26-P1、P3 -L26-P2、P3-L26-P3、P3-L26-P4、P3-L26-P5、P3-L26-P6、P3-L26-P7、P3-L2 6-P8、P3-L27-P1、P3-L27-P2、P3-L27-P3、P3-L27-P4、P3-L27-P5、P3-L27-P6、P3-L27-P7、P3-L27-P8、P3-L28-P1、P3-L28-P2、P3-L28-P3、P3-L28-P4、 P3-L28-P5、P3-L28-P6、P3-L28-P7、P3-L28-P8、P3-L29-P1、P3-L29-P2、P3-L29-P3、P3-L29-P4、P3-L29-P5、P3-L29-P6、P3-L29-P7、P3-L29-P8、P3-L3 0-P1、P3-L30-P2、P3-L30-P3、P3-L30-P4、P3-L30-P5、P3-L30-P6、P3-L30- P7、P3-L30-P8、P3-L31-P1、P3-L31-P2、P3-L31-P3、P3-L31-P4、P3-L31-P5、P3-L31-P6、P3-L31-P7、P3-L31-P8、P3-L32-P1、P3-L32-P2、P3-L32-P3、P3-L32-P4、P3-L32-P5、P3-L32-P6、P3-L32-P7、P3-L32-P8、P3-L33-P1、P3-L33-P2、P3-L33-P3、P3-L33-P4、P3-L33-P5、P3-L33-P6、P3-L33-P7、P3-L33-P8、P3-L34-P1、P3-L34-P2、P3-L34-P3、P3-L34-P4、P3-L34-P5、P3-L34-P6、P3-L34-P7、P3-L34-P8、P3-L35-P1、P3-L35-P2、P3-L35-P3、P3-L35-P4、P3-L35-P5、P3-L35-P6、P3-L35-P7、P3-L35-P8、P3-L36-P1、P3-L36-P2、P3-L36-P3、P3-L36-P4、P3-L36-P5、P3-L36-P6、P3-L36-P7、P3-L36-P8、P4-L1-P1、P4-L1-P2、P4-L1-P3、P4-L1-P4、P4-L1-P5、P4-L1-P6、P4-L1-P7、P4-L1-P8、P4-L2-P1、P4-L2-P2、P4-L2-P3、P4-L2-P4、P4-L2-P5、P4-L2-P6、P4-L2-P7、P4-L2-P8、P4-L3-P1、P4-L3-P2、P4-L3-P3、P4-L3-P4、P4-L3-P5、P4-L3-P6、P4-L3-P7、P4-L3-P8、P4-L4-P1、P4-L4-P2、P4-L4-P3、P4-L4-P4、P4-L4-P5、P4-L4-P6、P4-L4-P7、P4-L4-P8、P4-L5-P1、P4-L5-P2、P4-L5-P3、P4-L5-P4、P4-L5-P5、P4-L5-P6、P4-L5-P7、P4-L5-P8、P4-L6-P1、P4-L6-P2、P4-L6-P3、P4-L6-P4、P4-L6-P5、P4-L6-P6、P4-L6-P7、P4-L6-P8、P4-L7-P1、P4-L7-P2、P4-L7-P3、P4-L7-P4、P4-L7-P5、P4-L7-P6、P4-L7-P7、P4-L7-P8、P4-L8-P1、P4-L8-P2、P4-L8-P3、P4-L8-P4、P4-L8-P5、P4-L8-P6、P4-L8-P7、P4-L8-P8、P4-L9-P1、P4-L9-P2、P4-L9-P3、P4-L9-P4、P4-L9-P5、P4-L9-P6、P4-L9-P7、P4-L9-P8、P4-L10-P1、P4-L10-P2、P4-L10-P3、P4-L10-P4、P4-L10-P5、P4-L10-P6、P4-L10-P7、P4-L10-P8、P4-L11-P1、P4-L11-P2、P4-L11-P3、P4-L11-P4、P4-L11-P5、P4-L11-P6、P4-L11-P7、P4-L11-P8、P4-L12-P1、P4-L12-P2、P4-L12-P3、P4-L12-P4、P4-L12-P5、P4-L12-P6、P4-L12-P7、P4-L12-P8、P4-L13-P1、P4-L13-P2、P4-L13-P3、P4-L13-P4、P4-L13-P5、P4-L13-P6、P4-L13-P7、P4-L13-P8、P4-L14-P1、P4-L14-P2、P4-L14-P3、P4-L14-P4、P4-L14-P5、P4-L14-P6、P4-L14-P7、P4-L14-P8、P4-L15-P1、P4-L15-P2、P4-L15-P3、P4-L15-P4、P4-L15-P5、P4-L15-P6、P4-L15-P7、P4-L15-P8、P4-L16-P1、P4-L16-P2、P4-L16-P3、P4-L16-P4、P4-L16-P5、P4-L16-P6、P4-L16-P7、P4-L16-P8、P4-L17-P1、P4-L17-P2、P4-L17-P3、P4-L17-P4、P4-L17-P5、P4-L17-P6、P4-L17-P7、P4-L17-P8、P4-L18-P1、P4-L18-P2、P4-L18-P3、P4-L18-P4、P4-L18-P5、P4-L18-P6、P4-L18-P7、P4-L18-P8、P4-L19-P1、P4-L19-P2、P4-L19-P3、P4-L19-P4、P4-L19-P5、P4-L19-P6、P4-L19-P7、P4-L19-P8、P4-L20-P1、P4-L20-P2、P4-L20-P3、P4-L20-P4、P4-L20-P5、P4-L20-P6、P4-L20-P7、P4-L20-P8、P4-L21-P1、P4-L21-P2、P4-L21-P3、P4-L21-P4、P4-L21-P5、P4-L21-P6、P4-L21-P7、P4-L21-P8、P4-L22-P1、P4-L22-P2、P4-L22-P3、P4-L22-P4、P4-L22-P5、P4-L22-P6、P4-L22-P7、P4-L22-P8、P4-L23-P1、P4-L23-P2、P4-L23-P3、P4-L23-P4、P4-L23-P5、P4-L23-P6、P4-L23-P7、P4-L23-P8、P4-L24-P1、P4-L24-P2、P4-L24-P3、P4-L24-P4、P4-L24-P5、P4-L24-P6、P4-L24-P7、P4-L24-P8、P4-L25-P1、P4-L25-P2、P4-L25-P3、P4-L25-P4、P4-L25-P5、P4-L25-P6、P4-L25-P7、P4-L25-P8、P4-L26-P1、P4-L26-P2、P4-L26-P3、P4-L26-P4、P4-L26-P5、P4-L26-P6、P4-L26-P7、P4-L26-P8、P4-L27-P1、P4-L27-P2、P4-L27-P3、P4-L27-P4、P4-L27-P5、P4-L27-P6、P4-L27-P7、P4-L27-P8、P4-L28-P1、P4-L28-P2、P4-L28-P3、P4-L28-P4、P4-L28-P5、P4-L28-P6、P4-L28-P7、P4-L28-P8、P4-L29-P1、P4-L29-P2、P4-L29-P3、P4-L29-P4、P4-L29-P5、P4-L29-P6、P4-L29-P7、P4-L29-P8、P4-L30-P1、P4-L30-P2、P4-L30-P3、P4-L30-P4、P4-L30-P5、P4-L30-P6、P4-L30-P7、P4-L30-P8、P4-L31-P1、P4-L31-P2、P4-L31-P3、P4-L31-P4、P4-L31-P5、P4-L31-P6、P4-L31-P7、P4-L31-P8、P4-L32-P1、P4-L32-P2、P4-L32-P3、P4-L32-P4、P4-L32-P5、P4-L32-P6、P4-L32-P7、P4-L32-P8、P4-L33-P1、P4-L33-P2、P4-L33-P3、P4-L33-P4、P4-L33-P5、P4-L33-P6、P4-L33-P7、P4-L33-P8、P4-L34-P1、P4-L34-P2、P4-L34-P3、P4-L34-P4、P4-L34-P5、P4-L34-P6、P4 -L34-P7、P4-L34-P8、P4-L35-P1、P4-L35-P2、P4-L35-P3、P4-L35-P4、P4-L 35-P5、P4-L35-P6、P4-L35-P7、P4-L35-P8、P4-L36-P1、P4-L36-P2、P4-L36 -P3、P4-L36-P4、P4-L36-P5、P4-L36-P6、P4-L36-P7、P4-L36-P8、P5-L1-P1、 P5-L1-P2, P5-L1-P3, P5-L1-P4, P5-L1-P5, P5-L1-P6, P5-L1-P7, P5-L1-P8, P5-L2-P1, P5-L2-P2, P5-L2-P3, P5-L2-P4, P5-L2-P5, P5-L2-P6, P5-L2-P7 P5-L2-P8, P5-L3-P1, P5-L3-P2, P5-L3-P3, P5-L3-P4, P5-L3-P5, P5-L3-P6, P5-L3-P7, P5-L3-P8, P5-L4-P1, P5-L4-P2, P5-L4-P3, P5-L4-P4, P5-L4-P 5, P5-L4-P6, P5-L4-P7, P5-L4-P8, P5-L5-P1, P5-L5-P2, P5-L5-P3, P5-L5-P4, P5-L5-P5, P5-L5-P6, P5-L5-P7, P5-L5-P8, P5-L6-P1, P5-L6-P2, P5-L6 -P3, P5-L6-P4, P5-L6-P5, P5-L6-P6, P5-L6-P7, P5-L6-P8, P5-L7-P1, P5-L7-P2, P5-L7-P3, P5-L7-P4, P5-L7-P5, P5-L7-P6, P5-L7-P7, P5-L7-P8, P5-L 8-P1、P5-L8-P2、P5-L8-P3、P5-L8-P4、P5-L8-P5、P5-L8-P6、P5-L8-P7、P5- L8-P8、P5-L9-P1、P5-L9-P2、P5-L9-P3、P5-L9-P4、P5-L9-P5、P5-L9-P6、P5- L9-P7、P5-L9-P8、P5-L10-P1、P5-L10-P2、P5-L10-P3、P5-L10-P4、P5-L10- P5、P5-L10-P6、P5-L10-P7、P5-L10-P8、P5-L11-P1、P5-L11-P2、P5-L11-P3、P5-L11-P4、P5-L11-P5、P5-L11-P6、P5-L11-P7、P5-L11-P8、P5-L12-P1、P5-L12-P2、P5-L12-P3、P5-L12-P4、P5-L12-P5、P5-L12-P6、P5-L12-P7、P5-L1 2-P8、P5-L13-P1、P5-L13-P2、P5-L13-P3、P5-L13-P4、P5-L13-P5、P5-L13-P6、P5-L13-P7、P5-L13-P8、P5-L14-P1、P5-L14-P2、P5-L14-P3、P5-L14-P4、 P5-L14-P5、P5-L14-P6、P5-L14-P7、P5-L14-P8、P5-L15-P1、P5-L15-P2、P5-L15-P3、P5-L15-P4、P5-L15-P5、P5-L15-P6、P5-L15-P7、P5-L15-P8、P5-L1 6-P1、P5-L16-P2、P5-L16-P3、P5-L16-P4、P5-L16-P5、P5-L16-P6、P5-L16-P7、P5-L16-P8、P5-L17-P1、P5-L17-P2、P5-L17-P3、P5-L17-P4、P5-L17-P5、 P5-L17-P6、P5-L17-P7、P5-L17-P8、P5-L18-P1、P5-L18-P2、P5-L18-P3、P5-L18-P4、P5-L18-P5、P5-L18-P6、P5-L18-P7、P5-L18-P8、P5-L19-P1、P5-L1 9-P2、P5-L19-P3、P5-L19-P4、P5-L19-P5、P5-L19-P6、P5-L19-P7、P5-L19- P8、P5-L20-P1、P5-L20-P2、P5-L20-P3、P5-L20-P4、P5-L20-P5、P5-L20-P6、 P5-L20-P7、P5-L20-P8、P5-L21-P1、P5-L21-P2、P5-L21-P3、P5-L21-P4、P5 -L21-P5、P5-L21-P6、P5-L21-P7、P5-L21-P8、P5-L22-P1、P5-L22-P2、P5-L2 2-P3、P5-L22-P4、P5-L22-P5、P5-L22-P6、P5-L22-P7、P5-L22-P8、P5-L23-P1、P5-L23-P2、P5-L23-P3、P5-L23-P4、P5-L23-P5、P5-L23-P6、P5-L23-P7、P5-L23-P8、P5-L24-P1、P5-L24-P2、P5-L24-P3、P5-L24-P4、P5-L24-P5、P5 -L24-P6、P5-L24-P7、P5-L24-P8、P5-L25-P1、P5-L25-P2、P5-L25-P3、P5-L2 5-P4、P5-L25-P5、P5-L25-P6、P5-L25-P7、P5-L25-P8、P5-L26-P1、P5-L26- P2、P5-L26-P3、P5-L26-P4、P5-L26-P5、P5-L26-P6、P5-L26-P7、P5-L26-P8、 P5-L27-P1、P5-L27-P2、P5-L27-P3、P5-L27-P4、P5-L27-P5、P5-L27-P6、P5 -L27-P7、P5-L27-P8、P5-L28-P1、P5-L28-P2、P5-L28-P3、P5-L28-P4、P5-L2 8-P5、P5-L28-P6、P5-L28-P7、P5-L28-P8、P5-L29-P1、P5-L29-P2、P5-L29-P3、P5-L29-P4、P5-L29-P5、P5-L29-P6、P5-L29-P7、P5-L29-P8、P5-L30-P1、 P5-L30-P2、P5-L30-P3、P5-L30-P4、P5-L30-P5、P5-L30-P6、P5-L30-P7、P5-L30-P8、P5-L31-P1、P5-L31-P2、P5-L31-P3、P5-L31-P4、P5-L31-P5、P5-L3 1-P6、P5-L31-P7、P5-L31-P8、P5-L32-P1、P5-L32-P2、P5-L32-P3、P5-L32- P4、P5-L32-P5、P5-L32-P6、P5-L32-P7、P5-L32-P8、P5-L33-P1、P5-L33-P2、 P5-L33-P3、P5-L33-P4、P5-L33-P5、P5-L33-P6、P5-L33-P7、P5-L33-P8、P5 -L34-P1、P5-L34-P2、P5-L34-P3、P5-L34-P4、P5-L34-P5、P5-L34-P6、P5-L3 4-P7、P5-L34-P8、P5-L35-P1、P5-L35-P2、P5-L35-P3、P5-L35-P4、P5-L35- P5、P5-L35-P6、P5-L35-P7、P5-L35-P8、P5-L36-P1、P5-L36-P2、P5-L36-P3、P5-L36-P4、P5-L36-P5、P5-L36-P6、P5-L36-P7、P5-L36-P8、P6-L1-P1、P6- L1-P2、P6-L1-P3、P6-L1-P4、P6-L1-P5、P6-L1-P6、P6-L1-P7、P6-L1-P8、P6 -L2-P1, P6-L2-P2, P6-L2-P3, P6-L2-P4, P6-L2-P5, P6-L2-P6, P6-L2-P7, P6-L2-P8, P6-L3-P1, P6-L3-P2, P6-L3-P3, P6-L3-P4, P6-L3-P5, P6-L3-P6, P 6-L3-P7、P6-L3-P8、P6-L4-P1、P6-L4-P2、P6-L4-P3、P6-L4-P4、P6-L4-P5、 P6-L4-P6、P6-L4-P7、P6-L4-P8、P6-L5-P1、P6-L5-P2、P6-L5-P3、P6-L5-P4、 P6-L5-P5, P6-L5-P6, P6-L5-P7, P6-L5-P8, P6-L6-P1, P6-L6-P2, P6-L6-P3, P6-L6-P4, P6-L6-P5, P6-L6-P6, P6-L6-P7, P6-L6-P8, P6-L7-P1, P6-L7-P2 、P6-L7-P3、P6-L7-P4、P6-L7-P5、P6-L7-P6、P6-L7-P7、P6-L7-P8、P6-L8-P 1、P6-L8-P2、P6-L8-P3、P6-L8-P4、P6-L8-P5、P6-L8-P6、P6-L8-P7、P6-L8- P8、P6-L9-P1、P6-L9-P2、P6-L9-P3、P6-L9-P4、P6-L9-P5、P6-L9-P6、P6-L9 -P7、P6-L9-P8、P6-L10-P1、P6-L10-P2、P6-L10-P3、P6-L10-P4、P6-L10-P5、 P6-L10-P6、P6-L10-P7、P6-L10-P8、P6-L11-P1、P6-L11-P2、P6-L11-P3、P6 -L11-P4、P6-L11-P5、P6-L11-P6、P6-L11-P7、P6-L11-P8、P6-L12-P1、P6-L1 2-P2、P6-L12-P3、P6-L12-P4、P6-L12-P5、P6-L12-P6、P6-L12-P7、P6-L12- P8、P6-L13-P1、P6-L13-P2、P6-L13-P3、P6-L13-P4、P6-L13-P5、P6-L13-P6、P6-L13-P7、P6-L13-P8、P6-L14-P1、P6-L14-P2、P6-L14-P3、P6-L14-P4、P6 -L14-P5、P6-L14-P6、P6-L14-P7、P6-L14-P8、P6-L15-P1、P6-L15-P2、P6-L1 5-P3、P6-L15-P4、P6-L15-P5、P6-L15-P6、P6-L15-P7、P6-L15-P8、P6-L16-P1、P6-L16-P2、P6-L16-P3、P6-L16-P4、P6-L16-P5、P6-L16-P6、P6-L16-P7、 P6-L16-P8、P6-L17-P1、P6-L17-P2、P6-L17-P3、P6-L17-P4、P6-L17-P5、P6 -L17-P6、P6-L17-P7、P6-L17-P8、P6-L18-P1、P6-L18-P2、P6-L18-P3、P6-L1 8-P4、P6-L18-P5、P6-L18-P6、P6-L18-P7、P6-L18-P8、P6-L19-P1、P6-L19- P2、P6-L19-P3、P6-L19-P4、P6-L19-P5、P6-L19-P6、P6-L19-P7、P6-L19-P8、 P6-L20-P1、P6-L20-P2、P6-L20-P3、P6-L20-P4、P6-L20-P5、P6-L20-P6、P6 -L20-P7、P6-L20-P8、P6-L21-P1、P6-L21-P2、P6-L21-P3、P6-L21-P4、P6-L2 1-P5、P6-L21-P6、P6-L21-P7、P6-L21-P8、P6-L22-P1、P6-L22-P2、P6-L22- P3、P6-L22-P4、P6-L22-P5、P6-L22-P6、P6-L22-P7、P6-L22-P8、P6-L23-P1、 P6-L23-P2、P6-L23-P3、P6-L23-P4、P6-L23-P5、P6-L23-P6、P6-L23-P7、P6 -L23-P8、P6-L24-P1、P6-L24-P2、P6-L24-P3、P6-L24-P4、P6-L24-P5、P6-L2 4-P6、P6-L24-P7、P6-L24-P8、P6-L25-P1、P6-L25-P2、P6-L25-P3、P6-L25-P4、P6-L25-P5、P6-L25-P6、P6-L25-P7、P6-L25-P8、P6-L26-P1、P6-L26-P2、P6-L26-P3、P6-L26-P4、P6-L26-P5、P6-L26-P6、P6-L26-P7、P6-L26-P8、P6 -L27-P1、P6-L27-P2、P6-L27-P3、P6-L27-P4、P6-L27-P5、P6-L27-P6、P6-L 27-P7、P6-L27-P8、P6-L28-P1、P6-L28-P2、P6-L28-P3、P6-L28-P4、P6-L28 -P5、P6-L28-P6、P6-L28-P7、P6-L28-P8、P6-L29-P1、P6-L29-P2、P6-L29-P 3、P6-L29-P4、P6-L29-P5、P6-L29-P6、P6-L29-P7、P6-L29-P8、P6-L30-P1、 P6-L30-P2、P6-L30-P3、P6-L30-P4、P6-L30-P5、P6-L30-P6、P6-L30-P7、P6 -L30-P8、P6-L31-P1、P6-L31-P2、P6-L31-P3、P6-L31-P4、P6-L31-P5、P6-L 31-P6、P6-L31-P7、P6-L31-P8、P6-L32-P1、P6-L32-P2、P6-L32-P3、P6-L32- P4、P6-L32-P5、P6-L32-P6、P6-L32-P7、P6-L32-P8、P6-L33-P1、P6-L33-P2 、P6-L33-P3、P6-L33-P4、P6-L33-P5、P6-L33-P6、P6-L33-P7、P6-L33-P8、P 6-L34-P1、P6-L34-P2、P6-L34-P3、P6-L34-P4、P6-L34-P5、P6-L34-P6、P6- L34-P7、P6-L34-P8、P6-L35-P1、P6-L35-P2、P6-L35-P3、P6-L35-P4、P6-L35 -P5、P6-L35-P6、P6-L35-P7、P6-L35-P8、P6-L36-P1、P6-L36-P2、P6-L36-P 3、P6-L36-P4、P6-L36-P5、P6-L36-P6、P6-L36-P7、P6-L36-P8、P7-L1-P1、P 7-L1-P2, P7-L1-P3, P7-L1-P4, P7-L1-P5, P7-L1-P6, P7-L1-P7, P7-L1-P8, P7-L2-P1, P7-L2-P2, P7-L2-P3, P7-L2-P4, P7-L2-P5, P7-L2-P6, P7-L2-P7P7-L2-P8, P7-L3-P1, P7-L3-P2, P7-L3-P3, P7-L3-P4, P7-L3-P5, P7-L3-P6, P7-L3-P7, P7-L3-P8, P7-L4-P1, P7-L4-P2, P7-L4-P3, P7-L4-P4, P7-L4-P 5, P7-L4-P6, P7-L4-P7, P7-L4-P8, P7-L5-P1, P7-L5-P2, P7-L5-P3, P7-L5-P4, P7-L5-P5, P7-L5-P6, P7-L5-P7, P7-L5-P8, P7-L6-P1, P7-L6-P2, P7-L6 -P3, P7-L6-P4, P7-L6-P5, P7-L6-P6, P7-L6-P7, P7-L6-P8, P7-L7-P1, P7-L7-P2, P7-L7-P3, P7-L7-P4, P7-L7-P5, P7-L7-P6, P7-L7-P7, P7-L7-P8, P7- L8-P1, P7-L8-P2, P7-L8-P3, P7-L8-P4, P7-L8-P5, P7-L8-P6, P7-L8-P7, P7-L8-P8, P7-L9-P1, P7-L9-P2, P7-L9-P3, P7-L9-P4, P7-L9-P5, P7-L9-P6, P 7-L9-P7、P7-L9-P8、P7-L10-P1、P7-L10-P2、P7-L10-P3、P7-L10-P4、P7-L1 0-P5、P7-L10-P6、P7-L10-P7、P7-L10-P8、P7-L11-P1、P7-L11-P2、P7-L11- P3、P7-L11-P4、P7-L11-P5、P7-L11-P6、P7-L11-P7、P7-L11-P8、P7-L12-P1 、P7-L12-P2、P7-L12-P3、P7-L12-P4、P7-L12-P5、P7-L12-P6、P7-L12-P7、P 7-L12-P8、P7-L13-P1、P7-L13-P2、P7-L13-P3、P7-L13-P4、P7-L13-P5、P7- L13-P6、P7-L13-P7、P7-L13-P8、P7-L14-P1、P7-L14-P2、P7-L14-P3、P7-L1 4-P4、P7-L14-P5、P7-L14-P6、P7-L14-P7、P7-L14-P8、P7-L15-P1、P7-L15- P2、P7-L15-P3、P7-L15-P4、P7-L15-P5、P7-L15-P6、P7-L15-P7、P7-L15-P8、P7-L16-P1、P7-L16-P2、P7-L16-P3、P7-L16-P4、P7-L16-P5、P7-L16-P6、P7-L16-P7、P7-L16-P8、P7-L17-P1、P7-L17-P2、P7-L17-P3、P7-L17-P4、P7-L17-P5、P7-L17-P6、P7-L17-P7、P7-L17-P8、P7-L18-P1、P7-L18-P2、P7-L18-P3、P7-L18-P4、P7-L18-P5、P7-L18-P6、P7-L18-P7、P7-L18-P8、P7-L19-P1、P7-L19-P2、P7-L19-P3、P7-L19-P4、P7-L19-P5、P7-L19-P6、P7-L19-P7、P7-L19-P8、P7-L20-P1、P7-L20-P2、P7-L20-P3、P7-L20-P4、P7-L20-P5、P7-L20-P6、P7-L20-P7、P7-L20-P8、P7-L21-P1、P7-L21-P2、P7-L21-P3、P7-L21-P4、P7-L21-P5、P7-L21-P6、P7-L21-P7、P7-L21-P8、P7-L22-P1、P7-L22-P2、P7-L22-P3、P7-L22-P4、P7-L22-P5、P7-L22-P6、P7-L22-P7、P7-L22-P8、P7-L23-P1、P7-L23-P2、P7-L23-P3、P7-L23-P4、P7-L23-P5、P7-L23-P6、P7-L23-P7、P7-L23-P8、P7-L24-P1、P7-L24-P2、P7-L24-P3、P7-L24-P4、P7-L24-P5、P7-L24-P6、P7-L24-P7、P7-L24-P8、P7-L25-P1、P7-L25-P2、P7-L25-P3、P7-L25-P4、P7-L25-P5、P7-L25-P6、P7-L25-P7、P7-L25-P8、P7-L26-P1、P7-L26-P2、P7-L26-P3、P7-L26-P4、P7-L26-P5、P7-L26-P6、P7-L26-P7、P7-L26-P8、P7-L27-P1、P7-L27-P2、P7-L27-P3、P7-L27-P4、P7-L27-P5、P7-L27-P6、P7-L27-P7、P7-L27-P8、P7-L28-P1、P7-L28-P2、P7-L28-P3、P7-L28-P4、P7-L28-P5, P7-L28-P6, P7-L28-P7, P7-L28-P8, P7-L29-P1, P7-L29-P2, P7-L29-P3, P7-L29-P4, P7-L29-P5, P7-L29-P6, P7-L29-P7, P7-L29-P8, P7-L 30-P1、P7-L30-P2、P7-L30-P3、P7-L30-P4、P7-L30-P5、P7-L30-P6、P7-L30 -P7、P7-L30-P8、P7-L31-P1、P7-L31-P2、P7-L31-P3、P7-L31-P4、P7-L31-P 5、P7-L31-P6、P7-L31-P7、P7-L31-P8、P7-L32-P1、P7-L32-P2、P7-L32-P3、 P7-L32-P4、P7-L32-P5、P7-L32-P6、P7-L32-P7、P7-L32-P8、P7-L33-P1、P7 -L33-P2, P7-L33-P3, P7-L33-P4, P7-L33-P5, P7-L33-P6, P7-L33-P7, P7-L33-P8, P7-L34-P1, P7-L34-P2, P7-L34-P3, P7-L34-P4, P7-L34-P5, P7-L34- P6, P7-L34-P7, P7-L34-P8, P7-L35-P1, P7-L35-P2, P7-L35-P3, P7-L35-P4, P7-L35-P5, P7-L35-P6, P7-L35-P7, P7-L35-P8, P7-L36-P1, P7-L36-P2, P 7-L36-P3、P7-L36-P4、P7-L36-P5、P7-L36-P6、P7-L36-P7、P7-L36-P8、P8- L1-P1、P8-L1-P2、P8-L1-P3、P8-L1-P4、P8-L1-P5、P8-L1-P6、P8-L1-P7、P8- L1-P8, P8-L2-P1, P8-L2-P2, P8-L2-P3, P8-L2-P4, P8-L2-P5, P8-L2-P6, P8-L2-P7, P8-L2-P8, P8-L3-P1, P8-L3-P2, P8-L3-P3, P8-L3-P4, P8-L3-P5, P 8-L3-P6、P8-L3-P7、P8-L3-P8、P8-L4-P1、P8-L4-P2、P8-L4-P3、P8-L4-P4、 P8-L4-P5、P8-L4-P6、P8-L4-P7、P8-L4-P8、P8-L5-P1、P8-L5-P2、P8-L5-P3、P8-L5-P4, P8-L5-P5, P8-L5-P6, P8-L5-P7, P8-L5-P8, P8-L6-P1, P8-L6-P2, P8-L6-P3, P8-L6-P4, P8-L6-P5, P8-L6-P6, P8-L6-P7, P8-L6-P8, P8-L7-P 1, P8-L7-P2, P8-L7-P3, P8-L7-P4, P8-L7-P5, P8-L7-P6, P8-L7-P7, P8-L7-P8, P8-L8-P1, P8-L8-P2, P8-L8-P3, P8-L8-P4, P8-L8-P5, P8-L8-P6, P8-L8 -P7、P8-L8-P8、P8-L9-P1、P8-L9-P2、P8-L9-P3、P8-L9-P4、P8-L9-P5、P8-L 9-P6、P8-L9-P7、P8-L9-P8、P8-L10-P1、P8-L10-P2、P8-L10-P3、P8-L10-P4 、P8-L10-P5、P8-L10-P6、P8-L10-P7、P8-L10-P8、P8-L11-P1、P8-L11-P2、P 8-L11-P3、P8-L11-P4、P8-L11-P5、P8-L11-P6、P8-L11-P7、P8-L11-P8、P8- L12-P1、P8-L12-P2、P8-L12-P3、P8-L12-P4、P8-L12-P5、P8-L12-P6、P8-L1 2-P7、P8-L12-P8、P8-L13-P1、P8-L13-P2、P8-L13-P3、P8-L13-P4、P8-L13- P5、P8-L13-P6、P8-L13-P7、P8-L13-P8、P8-L14-P1、P8-L14-P2、P8-L14-P3 、P8-L14-P4、P8-L14-P5、P8-L14-P6、P8-L14-P7、P8-L14-P8、P8-L15-P1、P 8-L15-P2、P8-L15-P3、P8-L15-P4、P8-L15-P5、P8-L15-P6、P8-L15-P7、P8- L15-P8、P8-L16-P1、P8-L16-P2、P8-L16-P3、P8-L16-P4、P8-L16-P5、P8-L1 6-P6、P8-L16-P7、P8-L16-P8、P8-L17-P1、P8-L17-P2、P8-L17-P3、P8-L17- P4、P8-L17-P5、P8-L17-P6、P8-L17-P7、P8-L17-P8、P8-L18-P1、P8-L18-P2、P8-L18-P3、P8-L18-P4、P8-L18-P5、P8-L18-P6、P8-L18-P7、P8-L18-P8、P8 -L19-P1、P8-L19-P2、P8-L19-P3、P8-L19-P4、P8-L19-P5、P8-L19-P6、P8-L1 9-P7、P8-L19-P8、P8-L20-P1、P8-L20-P2、P8-L20-P3、P8-L20-P4、P8-L20-P5、P8-L20-P6、P8-L20-P7、P8-L20-P8、P8-L21-P1、P8-L21-P2、P8-L21-P3、 P8-L21-P4、P8-L21-P5、P8-L21-P6、P8-L21-P7、P8-L21-P8、P8-L22-P1、P8 -L22-P2、P8-L22-P3、P8-L22-P4、P8-L22-P5、P8-L22-P6、P8-L22-P7、P8-L2 2-P8、P8-L23-P1、P8-L23-P2、P8-L23-P3、P8-L23-P4、P8-L23-P5、P8-L23- P6、P8-L23-P7、P8-L23-P8、P8-L24-P1、P8-L24-P2、P8-L24-P3、P8-L24-P4、 P8-L24-P5、P8-L24-P6、P8-L24-P7、P8-L24-P8、P8-L25-P1、P8-L25-P2、P8 -L25-P3、P8-L25-P4、P8-L25-P5、P8-L25-P6、P8-L25-P7、P8-L25-P8、P8-L2 6-P1、P8-L26-P2、P8-L26-P3、P8-L26-P4、P8-L26-P5、P8-L26-P6、P8-L26-P7、P8-L26-P8、P8-L27-P1、P8-L27-P2、P8-L27-P3、P8-L27-P4、P8-L27-P5、 P8-L27-P6、P8-L27-P7、P8-L27-P8、P8-L28-P1、P8-L28-P2、P8-L28-P3、P8 -L28-P4、P8-L28-P5、P8-L28-P6、P8-L28-P7、P8-L28-P8、P8-L29-P1、P8-L2 9-P2、P8-L29-P3、P8-L29-P4、P8-L29-P5、P8-L29-P6、P8-L29-P7、P8-L29- P8、P8-L30-P1、P8-L30-P2、P8-L30-P3、P8-L30-P4、P8-L30-P5、P8-L30-P6、P8-L30-P7, P8-L30-P8, P8-L31-P1, P8-L31-P2, P8-L31-P3, P8-L31-P4, P8 -L31-P5, P8-L31-P6, P8-L31-P7, P8-L31-P8, P8-L32-P1, P8-L32-P2, P8-L3 2-P3, P8-L32-P4, P8-L32-P5, P8-L32-P6, P8-L32-P7, P8-L32-P8, P8-L33- P1, P8-L33-P2, P8-L33-P3, P8-L33-P4, P8-L33-P5, P8-L33-P6, P8-L33-P7, P8-L33-P8, P8-L34-P1, P8-L34-P2, P8-L34-P3, P8-L34-P4, P8-L34-P5, P8 -L34-P6, P8-L34-P7, P8-L34-P8, P8-L35-P1, P8-L35-P2, P8-L35-P3, P8-L3 5-P4, P8-L35-P5, P8-L35-P6, P8-L35-P7, P8-L35-P8, P8-L36-P1, P8-L36- P2, P8-L36-P3, P8-L36-P4, P8-L36-P5, P8-L36-P6, P8-L36-P7 and P8-L36-P8. ,

[0956] According to one aspect of the invention, a pharmaceutical composition comprising a conjugate and a pharmaceutically acceptable carrier is provided herein.

[0957] According to one aspect of the invention, a method for treating a subject who has or is suspected of having cancer is provided, the method comprising administering to the subject a therapeutically effective amount of the conjugate or pharmaceutical composition of the invention.

[0958] In the examples, cancer expresses target antigens.

[0959] In the embodiments, cancer is a tumor or blood cancer. Optionally, cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoma of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

[0960] According to one aspect of the invention, a method for reducing or inhibiting tumor growth in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of the conjugate or pharmaceutical composition of the invention.

[0961] In this embodiment, the tumor expresses the target antigen.

[0962] In the embodiments, the tumor is breast cancer, stomach cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

[0963] According to one aspect of the invention, a method for reducing or inhibiting blood cancer in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of the conjugate or pharmaceutical composition of the invention.

[0964] In this embodiment, blood cancer expresses target antigens.

[0965] In the embodiments, blood cancers are chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

[0966] In the embodiments, the application of the conjugate or pharmaceutical composition reduces or inhibits the growth of tumors or blood cancers by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0967] According to one aspect of the invention, a method for reducing or slowing the proliferation of cancer cell populations in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of the conjugate or pharmaceutical composition of the invention.

[0968] In this embodiment, the cancer cell population expresses the target antigen.

[0969] In the embodiments, the cancer cell population originates from tumors or blood cancers, optionally including breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoma of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

[0970] In the embodiments, the application of the conjugate or pharmaceutical composition reduces the cancer cell population or slows its growth by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0971] In one embodiment, the antibody-drug conjugate is administered as a monotherapy. In another embodiment, the antibody-drug conjugate is administered as an adjunct to another therapeutic agent or radiotherapy. In another embodiment, the antibody-drug conjugate is administered in an amount that effectively sensitizes tumor cells to one or more additional therapeutic agents and / or radiotherapy.

[0972] In an embodiment, the method further includes administering at least one additional therapeutic agent to a subject in need.

[0973] In the embodiments, another therapeutic agent is taxane, vinca alkaloid, MEK inhibitor, ERK inhibitor, topoisomerase inhibitor, or RAF inhibitor.

[0974] According to one aspect of the invention, the use of the conjugates or pharmaceutical compositions of the invention in the preparation of a medicament is provided herein for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in the subject, (iii) reducing or inhibiting blood cancers in the subject, or (iv) reducing or slowing the expansion of a population of cancer cells in the subject.

[0975] According to one aspect of the invention, antibody-drug conjugates or pharmaceutical compositions of the invention are provided herein for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in a subject, (iii) reducing or inhibiting blood cancers in a subject, or (iv) reducing or slowing the expansion of a population of cancer cells in a subject.

[0976] The method for generating the ADC compound and composition is also disclosed. An exemplary embodiment is a method for generating antibody-drug conjugates by reacting an antibody or antigen-binding fragment with a cleavable dual-connector linked or covalently attached to a pharmaceutically active drug that is not a BH3 mimic under conjugation-permitting conditions.

[0977] Therefore, the present invention provides embodiments numbered as follows. It should be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0978] Example 1. A compound having formula (A-1), or a pharmaceutically acceptable salt thereof:

[0979]

[0980] in:

[0981] R 1 It is an attachment group;

[0982] L 1 It is a bridging spacer;

[0983] W is the branched part;

[0984] L 2' and L 3' Each is an independent connector; and

[0985] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs.

[0986] Example 2. The compound or a pharmaceutically acceptable salt thereof according to Example 1, wherein L 2' and L 3' Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a peptide group, and / or a self-removing group (e.g., a peptide group and a self-removing group).

[0987] Example 2a. The compound or a pharmaceutically acceptable salt thereof according to Example 2, wherein L 2' and L 3' Each of them contains a peptide group and a self-detaching group.

[0988] Example 2b. The compound or a pharmaceutically acceptable salt thereof according to Example 1, wherein L 2' and L 3'Each of them contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a sugar (e.g., glucuronide) group, a peptide group, and / or a self-detaching group (e.g., a peptide group and a self-detaching group).

[0989] Example 3. The compound or its pharmaceutically acceptable salt according to Example 1, Example 2 or Example 2a, having formula (B-1):

[0990]

[0991] in:

[0992] R 1 It is an attachment group;

[0993] L 1 It is a bridging spacer;

[0994] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[0995] L 2 and L 3 Each is an independent connecting spacer;

[0996] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic portion;

[0997] V 1 and V 2 Each independently contains i) a self-detaching group, ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is independently a self-detached group) or iii) a self-detached group and an enzyme cleavage element; and

[0998] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[0999] or a pharmaceutically acceptable salt thereof.

[1000] Example 3aa. The compound or a pharmaceutically acceptable salt thereof according to Example 3, wherein V 1 and V 2 Each independently consists of i) a self-detaching group or ii) an enzyme cleavage element (e.g., V). 1 and V 2Each is an independent exfoliating group.

[1001] Example 3a. The compound or a pharmaceutically acceptable salt thereof according to Example 3 or Example 3aa, wherein W is N or CH.

[1002] Example 3b. The compound or a pharmaceutically acceptable salt thereof according to Example 3, Example 3aa or Example 3a, wherein E 1 and E 2 Each is an enzyme cleavage element.

[1003] Example 3c. The compound or a pharmaceutically acceptable salt thereof according to Example 3, Example 3aa, Example 3a or Example 3b, wherein V 1 and V 2 Each is an independent exfoliating group.

[1004] Example 4. A compound or a pharmaceutically acceptable salt thereof according to Example 3, Example 3aa, Example 3a, Example 3b or Example 3c, wherein (i) the cleavable terminator comprises a phosphate ester group, a pyrophosphate ester group and / or a self-detaching group; (ii) the cleavable terminator comprises a self-detaching group; or (iii) the cleavable terminator comprises a self-detaching group including -O-CH2-, -NH-CH2-, -OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(sulfonyl)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or (iv) V 1 and / or V 2 Each of them independently contains a group containing p-aminobenzyl-phosphate or p-aminobenzyl-pyrophosphate.

[1005] Example 4a. The compound of Example 4 or a pharmaceutically acceptable salt thereof, wherein (i) the cleavable connector comprises a phosphate group, a pyrophosphate group and / or a self-detaching group; (ii) the cleavable connector comprises a self-detaching group; or (iii) the cleavable connector comprises a self-detaching group including -O-CH2-, -NH-CH2-, -OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(sulfonyl)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[1006] Example 5. The compound or a pharmaceutically acceptable salt thereof according to Example 3, Example 4 or Example 4a, having the formula (C-1):

[1007]

[1008] in:

[1009] R 1 It is an attachment group;

[1010] L 1 It is a bridging spacer;

[1011] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[1012] L 2 and L 3 Each is an independent connecting spacer;

[1013] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[1014] A 1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[1015] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D. 1 or D 2 Attachment point;

[1016] D 1 and D 2 Each is an independently pharmaceutically active drug, and the optional condition is D. 1 and D 2 Neither of them are BH3 analogs;

[1017] L 4 and L 5 Each is an independent spacer component;

[1018] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[1019] m and n are each independently 0 or 1;

[1020] or a pharmaceutically acceptable salt thereof.

[1021] Example 5a. The compound or a pharmaceutically acceptable salt thereof according to Example 5, wherein W is N or CH.

[1022] Example 5b. The compound or a pharmaceutically acceptable salt thereof according to Example 5 or Example 5a, wherein R 2 and R 3 Each of them is a hydrophilic group.

[1023] Example 6. The compound or a pharmaceutically acceptable salt thereof according to Example 5, Example 5a or Example 5b, having the formula (D1-1), (D2-1) or (D3-1):

[1024]

[1025] or a pharmaceutically acceptable salt thereof.

[1026] Example 7. The compound or a pharmaceutically acceptable salt thereof according to Example 6, wherein for formula (D1-1), R 2 and R 3 Each is an independent hydrophilic group, wherein for formula (D2-1), R 2 and R 3 Each is an independent enzyme cleavage element; and for formula (D3-1), R 2 It is a hydrophilic group and R 3 It is an enzyme cleavage element; or a pharmaceutically acceptable salt thereof.

[1027] Example 8. A compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein R 1 Choose from the following groups:

[1028] -ONH2, -NH2, -N3、 -SH、-SR 11 -SSR 12, -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NR 11 C(=O)CH2Br, for example -NHC(=O)CH2Br, -NR 11 C(=O)CH2I, for example -NHC(=O)CH2I, -C(O)NHNH2、

[1029] in:

[1030] Each R 11 Independently selected from H and C1-C6 alkyl groups;

[1031] Each R 12 It is 2-pyridinyl or 4-pyridinyl;

[1032] Each R 13 Independently selected from H, C1-C6 alkyl groups, F, Cl, and -OH;

[1033] Each R 14 Independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2, and -OH; and

[1034] Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy group substituted with -C(=O)OH, benzyl group substituted with -C(=O)OH, C6 alkyl group substituted with -C(=O)OH 1- C4 alkoxy groups and C groups substituted with -C(=O)OH 1- C4 alkyl.

[1035] Example 9. A compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein R 1 Choose from the following groups:

[1036] -ONH2、 NHC(=O)CH2Br and -NHC(=O)CH2I.

[1037] Example 9a. A compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein R 1 Choose from the following groups:

[1038] -ONH2、

[1039] Example 10. A compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein R 1 yes

[1040] Example 11. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein:

[1041] (1)L 1 Include:

[1042] or *-CH(OH)CH(OH)CH(OH)CH(OH)-**,

[1043] where each n is an integer from 1 to 12, and L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1044] (2)L 1 yes And n is an integer from 1 to 12, or n is 1 or n is 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1045] (3)L 1 yes And n is an integer from 1 to 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a connection point to R. 1 The direct or indirect (e.g., direct) attachment point;

[1046] (4)L 1 Include Among them L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 Direct or indirect (e.g., direct) attachment points; or

[1047] (5)L 1 It is a bridging spacer, which includes:

[1048] *-C(=O)(CH2) m O(CH2) m-**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2)m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1049] X1 is and

[1050] Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[1051] Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

[1052] Each t is independently selected from 1, 2, 3, 4, 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, and 30; and

[1053] Each R L1 Independently selected from H and C1-C6 alkyl groups.

[1054] Example 12. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein L 1 Includes the portion represented by the following:

[1055]

[1056] Where n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8), where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect attachment point.

[1057] Example 12a. The compound or a pharmaceutically acceptable salt thereof according to Example 12, wherein n is an integer from 4 to 8.

[1058] Example 12b. The compound or a pharmaceutically acceptable salt thereof according to Example 12a, wherein n is 4 or 8.

[1059] Example 13. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein L1 It can be expressed by the following formula:

[1060]

[1061] in

[1062] n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8);

[1063] x is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[1064] y is 0 or 1;

[1065] z is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[1066] u is 0 or 1; and

[1067] Among them L 1 The asterisk (*) indicates a direct attachment point to W, and L 1 The **representation of R 1 The direct attachment point.

[1068] Example 13a. The compound or a pharmaceutically acceptable salt thereof according to Example 13, wherein n is an integer from 4 to 8.

[1069] Example 13b. The compound or a pharmaceutically acceptable salt thereof according to Example 13a, wherein n is 4 or 8.

[1070] Example 13c. The compound or a pharmaceutically acceptable salt thereof according to Example 13, Example 13a or Example 13b, wherein x is an integer from 0 to 2.

[1071] Example 13d. The compound or a pharmaceutically acceptable salt thereof according to Example 13c, wherein x is 0 or 2.

[1072] Example 13e. The compound or a pharmaceutically acceptable salt thereof according to Example 13, Example 13a, Example 13b, Example 13c or Example 13d, wherein z is an integer from 0 to 2.

[1073] Example 13f. The compound or a pharmaceutically acceptable salt thereof according to Example 13e, wherein z is 0 or 2.

[1074] Example 14. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, wherein L 1 Choose from the following groups:

[1075]

[1076]

[1077] Example 15. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 3 to 14, wherein L 2 and L 3 Each is an independent connecting spacer, which comprises parts represented by the following:

[1078]

[1079] in

[1080] k is an integer from 0 to 6;

[1081] r is 0 or 1;

[1082] o is an integer from 0 to 12;

[1083] p is an integer from 0 to 6; and

[1084] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct or indirect attachment point, and L 2 or L 3 The ## symbol indicates a direct or indirect attachment point to W.

[1085] Example 16. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 3 to 15, wherein

[1086] L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[1087]

[1088]

[1089] as well as

[1090]

[1091] in

[1092] k is an integer from 0 to 4 each time it appears;

[1093] r is 0 or 1 independently each time it appears;

[1094] o is an integer from 0 to 10 each time it appears;

[1095] p is an integer from 0 to 4 each time it appears;

[1096] R L23 Is it hydrogen or C? 1- C6 alkyl;

[1097] R L It is hydrogen or -C(O)-R H ;

[1098] R H It is a hydrophilic group; and

[1099] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol indicates a direct attachment point to W;

[1100] The condition is that when W is N, L 2 and L 3 It is not (L2c), (L2d), (L2f), or (L2k).

[1101] Example 17. The compound or a pharmaceutically acceptable salt thereof according to Example 16, wherein L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[1102]

[1103]

[1104] as well as

[1105]

[1106] in

[1107] k is an integer from 1 to 3 each time it appears;

[1108] o is an integer from 1 to 9 each time it appears;

[1109] p is an integer from 1 to 3 each time it appears;

[1110] R L23 Is it hydrogen or C? 1- C3 alkyl;

[1111] R L It is hydrogen or -C(O)-R H ;

[1112] R HIt is a hydrophilic group; and

[1113] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol represents the direct attachment point to W; the condition is that L is N when W is N. 2 and L 3 It is not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

[1114] Example 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 3 to 17, wherein L 2 and L 3 The connecting spacers are independently selected from the following groups:

[1115]

[1116]

[1117] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 direct attachment point, L 2 or L 3 The ## symbol indicates the direct attachment point to W; R L It is hydrogen or -C(O)-R H ;and

[1118] R H yes And d is an integer between 20 and 30 (e.g., 25).

[1119] Example 18a. The compound or a pharmaceutically acceptable salt thereof according to Example 18, wherein d is 25.

[1120] Example 19. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 5 to 18a, wherein each peptide group independently comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

[1121] Example 19a. The compound or a pharmaceutically acceptable salt thereof according to Example 19, wherein each peptide group independently comprises two amino acid residues.

[1122] Example 20. The compound or a pharmaceutically acceptable salt thereof according to Example 19 or Example 19a, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfonyl-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

[1123] Example 21. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 19 and 20, wherein each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly, and sulfon-Ala-Val-Ala.

[1124] Example 22. A compound or pharmaceutically acceptable salt according to any one of Examples 3 to 19a, wherein E 1 and / or E 2 Each peptide group is independently selected from the following groups:

[1125]

[1126] Where the ^ of E1-1 or E1-2 represents the same as V in equation (B). 1 or V 2 The direct attachment point or the direct attachment point with the -NH- group in formulas (C) and (D); and the ^^ of E1-1 or E1-2 respectively represent the direct attachment point with L 2 or L 3 The direct attachment point (e.g., where E) 1 and E 2 Each is an independently selected peptide group from (E1-1) and (E1-2).

[1127] Example 22a. The compound or a pharmaceutically acceptable salt thereof according to Example 22, wherein E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

[1128] Example 23. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 3 to 19a, wherein E 1 and / or E 2 Each is independently represented by the following peptide groups:

[1129]

[1130] where R E It is a hydrophilic group R H .

[1131] Example 24. The compound according to Example 23 or a pharmaceutically acceptable salt thereof, wherein the hydrophilic group R in (E1-3) H yes Where e is an integer between 20 and 30 (e.g., 25).

[1132] Example 24a. The compound or a pharmaceutically acceptable salt thereof according to Example 24, wherein e is 25.

[1133] Example 25. The compound or pharmaceutically acceptable salt according to Example 22, wherein E 1 and E 2 Each is

[1134] Example 26. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 25, wherein A 1 and A 2 Independently selected from the bond and -OC (=O)-*, where * indicates that it is related to D respectively. 1 or D 2 Attachment point.

[1135] Example 26a. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 25, wherein A 1 and A 2 Independently selected from keys, and -OC(=O)-*, where * represents the relationship with D respectively. 1 or D 2 Attachment point.

[1136] Example 27. The compound or pharmaceutically acceptable salt according to Example 26, wherein A 1 and A 2 Each is a key.

[1137] Example 27a. The compound or pharmaceutically acceptable salt according to Example 26, wherein A 1 and A 2 Both are -OC(=O)-*.

[1138] Example 27b. The compound or pharmaceutically acceptable salt according to Example 26, wherein A 1 and A 2 One of them is OC (=O)-*, and A1 and A 2 The other one is the key.

[1139] Example 27c. The compound or pharmaceutically acceptable salt according to Example 26a, wherein A 1 and A 2 Independently is a key or Where * indicates a relationship with D 1 or D 2 Attachment point.

[1140] Example 27d. The compound or pharmaceutically acceptable salt according to Example 27c, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

[1141] Example 27e. The compound or pharmaceutically acceptable salt according to Example 27c, wherein A 1 and A 2 All

[1142] Example 27f. The compound or pharmaceutically acceptable salt according to Example 26a, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

[1143] Example 27g. The compound or pharmaceutically acceptable salt according to Example 26a, wherein) A 1 and A 2 It is -OC(=O)-*;

[1144] (ii)A 1 and A 2 yes

[1145] (iii)A 1 It is -OC(=O)-* and A 2 Is a key

[1146] (iv)A 1 It is -OC(=O)-* and A 2 yes

[1147] (v)A 1 It is a key and A 2 yes or

[1148] (vi)A 1 It is a key and A 2 It is -OC(=O)-*,

[1149] Where * indicates a relationship with D 1 or D 2 Attachment point.

[1150] Example 28. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 27b, wherein:

[1151] i)L 4 and L 5 Each is an independent spacer sub-part, which has a structure

[1152] in:

[1153] Z is -O-, -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[1154] X is a bond, a triazole group, or -CH2-triazole-.

[1155] Where X is connected to R 2 or R 3 ;or

[1156] (ii)L 4 and L 5 Independently, there is a spacer sub-part, which has a structure

[1157] in:

[1158] Z represents -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[1159] X is -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene group -OC(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -,-CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n - where each n is independently 1, 2, or 3.

[1160] Where X is connected to R 2 or R 3 .

[1161] Example 29. A compound or pharmaceutically acceptable salt according to Example 28, wherein Z is -O-, -CH2NR. L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazole group, or -CH2-triazole-; and R L45 It is either H or C each time it appears.1- C3 alkyl.

[1162] Example 30. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 29, wherein L 4 and L 5 Each is an independent sub-part of the interval selected from the following groups:

[1163]

[1164] Among them L 4 or L 5 The @ symbol represents the direct attachment point to the phenyl group, and L 4 or L 5 @@ represents R 2 or R 3 The direct attachment point.

[1165] Example 31. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 5 to 30, wherein R 2 and R 3 The hydrophilic groups represented independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, and 1 to 3 [unclear - possibly referring to specific compounds or groups]. The substituted C2-C6 alkyl group, or the alkyl group independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C2-C6 alkyl groups substituted with C4 alkylene groups -P(O)(OCH2CH3)2 and -COOH groups.

[1166] Example 32. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 5 to 30, wherein R 2 or / and R 3 Each person independently chooses from the following groups:

[1167] Where n is an integer between 1 and 6;

[1168] Example 33. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 30, wherein R 2 or / and R 3 Independently included:

[1169] (i) Polysarcosine having the following components:

[1170] in

[1171] f is an integer between 3 and 25; and

[1172] R 23 It is H, -CH3, or -CH2CH2C(=O)OH;

[1173] (ii) Polyethylene glycol having the following formula: in

[1174] g and h are independent integers between 2 and 30; or

[1175] (iii) by The part that is indicated.

[1176] Example 33a. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 30, wherein R 2 or R 3 The hydrophilic groups represented each contain independently:

[1177] (i) Polysarcosine having the following components:

[1178]

[1179] Where f is an integer between 3 and 25; and R 23 It is H, -CH3, or -CH2CH2C(=O)OH; or

[1180] (ii) Polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30; or

[1181] (iii) by The part that is indicated.

[1182] Example 34. A compound or pharmaceutically acceptable salt according to any one of Examples 5 to 30, wherein R 2 or / and R 3 Each person independently chooses from the following groups: in

[1183] g and h are independent integers between 20 and 30 (e.g., 23 or 24).

[1184] Example 35. The compound or a pharmaceutically acceptable salt thereof according to Example 34, wherein R 2 or / and R 3 Include:

[1185]

[1186] Example 35a. The compound or a pharmaceutically acceptable salt thereof according to Example 34, wherein R 2 and R 3 Each independently contains polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[1187] Example 36. A compound or pharmaceutically acceptable salt according to any one of the foregoing examples, wherein D 1 and D 2 They are the same.

[1188] Example 37. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 35a, wherein D 1 and D 2 They are different.

[1189] Example 38. A compound or pharmaceutically acceptable salt according to any one of the foregoing examples, wherein D 1 and D 2 Each drug is independently selected from cytotoxic drugs, cell growth inhibitors, and immunosuppressants.

[1190] Example 39. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and D 2 Each ingredient was independently selected from auristatin, camptothecin, pyroxine, etoposide, maytansine, maytansine-like substances, taxanes, and benzodiazepines. Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and periwinkle alkaloids.

[1191] Example 39a. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and D 2 Each person independently chooses from the following groups:

[1192] (For example )and (For example ),

[1193] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1194] Example 39b. The compound or pharmaceutically acceptable salt according to Example 39a, wherein:

[1195] i)D 1 yes And D 2 yes

[1196] ii)D 1 yes And D 2 yes

[1197] iii)D 1 yes And D 2 yes

[1198] iv)D 1 yes And D 2 yes

[1199] v)D 1 yes And D 2 yes

[1200] vi)D 1 yes And D 2 yes

[1201] vii)D 1 yes And D 2 yes

[1202] viii)D 1 yes And D 2 yes

[1203] ix)D 1 yes And D 2 yes

[1204] x)D 1 yes And D 2 yes

[1205] xi)D 1 yes And D 2 yes

[1206] xii)D 1 yes And D 2 yes

[1207] xiii)D 1 yes And D 2 yes

[1208] xiv)D 1 yes And D 2 yes

[1209] xv)D 1 yes And D 2 yes

[1210] xvi)D 1 yes And D 2 yes

[1211] xvii)D 1 yes And D 2 yes

[1212] xviii)D 1 yes And D 2 yes

[1213] xix)D 1 yes And D 2 yes

[1214] xx)D 1 yes And D 2 yes

[1215] xxi)D 1 yes And D 2 yes

[1216] xxii)D 1 yes And D 2 yes

[1217] xxiii)D 1 yes And D 2 yes

[1218] xxiv)D 1 yes And D 2 yes

[1219] xxv)D 1 yes And D 2 yes

[1220] xxvi)D 1 yes And D 2 yes

[1221] xxvii)D 1 yes And D 2 yes

[1222] xxviii)D 1 yes And D 2 yes

[1223] xxix)D 1 yes And D 2 yes

[1224] xxx)D 1 yes And D 2 yes

[1225] xxxi)D 1 yes And D 2 yes

[1226] xxxii)D 1 yes And D 2 yes

[1227] xxxiii)D 1 yes And D 2 yes

[1228] xxxiv)D1 yes And D 2 yes

[1229] xxxv)D 1 yes And D 2 yes

[1230] xxxvi)D 1 yes And D 2 yes

[1231] xxxvii)D 1 yes And D 2 yes

[1232] xxxviii)D 1 yes And D 2 yes

[1233] xxxix)D 1 yes And D 2 yes

[1234] xl)D 1 yes And D 2 yes

[1235] xli)D 1 yes And D 2 yes

[1236] xlii)D 1 yes And D 2 yes

[1237] xliii)D 1 yes And D 2 yes

[1238] xliv)D 1 yes And D 2 yes

[1239] vl)D 1 yes And D 2 yes

[1240] xlvi)D 1 yes And D 2 yes

[1241] xlvii)D 1 yes And D 2 yes

[1242] xlviii)D 1 yes And D 2 yes

[1243] il)D 1 yes And D 2 yes

[1244] l)D 1 yes And D 2 yes

[1245] li)D 1 yes And D 2 yes

[1246] lii)D 1 yes And D 2 yes

[1247] liii)D 1 yes And D 2 yes

[1248] liv)D 1 yes And D 2 yes

[1249] lv)D 1 yes And D 2 yes

[1250] lvi)D 1 yes And D 2 yes

[1251] lvii)D 1 yes And D 2 yes

[1252] lviii)D 1 yes And D 2 yes

[1253] lix)D 1 yes And D 2 yes

[1254] lx)D 1 yes And D 2 yes

[1255] lxi)D 1 yes And D 2 yes

[1256] lxii)D 1 yes And D 2 yes

[1257] lxiii)D 1 yes And D 2 yes or

[1258] lxiv)D 1 yes And D 2 yes

[1259] The asterisk (*) indicates a connection point with the rest of the molecule.

[1260] Example 39c. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein:

[1261] i)A 1 -D 1 yes And A 2 -D 2 yes

[1262] ii)A 1 -D1 yes And A 2 -D 2 yes

[1263] iii)A 1 -D 1 yes And A 2 -D 2 yes

[1264] iv)A 1 -D 1 yes And A 2 -D 2 yes

[1265] v)A 1 -D 1 yes And A 2 -D 2 yes

[1266] vi)A 1 -D 1 yes And A 2 -D 2 yes

[1267] vii)A 1 -D 1 yes And A 2 -D 2 yes

[1268] viii)A 1 -D 1 yes And A 2 -D 2 yes

[1269] ix)A 1 -D 1 yes And A 2 -D 2 yes

[1270] x)A 1 -D 1 yes And A 2 -D 2 yes

[1271] xi)A 1 -D 1 yes And A 2 -D 2 yes

[1272] xii)A 1 -D 1 yes And A 2 -D 2 yes

[1273] xiii)A 1 -D 1 yes And A 2 -D 2 yes

[1274] xiv)A 1 -D 1 yes And A 2 -D 2 yes

[1275] xv)A 1 -D 1 yes And A 2 -D 2 yes

[1276] xvi)A 1 -D 1 yes And A 2 -D 2 yes

[1277] xvii)A 1 -D 1 yes And A 2 -D 2 yes

[1278] xviii)A 1 -D 1 yes And A 2 -D 2 yes

[1279] xix)A 1-D 1 yes And A 2 -D 2 yes

[1280] xx)A 1 -D 1 yes And A 2 -D 2 yes

[1281] xxi)A 1 -D 1 yes And A 2 -D 2 yes

[1282] xxii)A 1 -D 1 yes And A 2 -D 2 yes

[1283] xxiii)A 1 -D 1 yes And A 2 -D 2 yes

[1284] xxiv)A 1 -D 1 yes And A 2 -D 2 yes

[1285] xxv)A 1 -D 1 yes And A 2 -D 2 yes

[1286] xxvi)A 1 -D 1 yes And A 2 -D 2 yes

[1287] xxvii)A 1 -D 1 yes And A 2 -D2 yes

[1288] xxviii)A 1 -D 1 yes And A 2 -D 2 yes

[1289] xxix)A 1 -D 1 yes And A 2 -D 2 yes

[1290] xxx)A 1 -D 1 yes And A 2 -D 2 yes

[1291] xxxi)A 1 -D 1 yes And A 2 -D 2 yes

[1292] xxxii)A 1 -D 1 yes And A 2 -D 2 yes

[1293] xxxiii)A 1 -D 1 yes And A 2 -D 2 yes

[1294] xxxiv)A 1 -D 1 yes And A 2 -D 2 yes

[1295] xxxv)A 1 -D 1 yes And A 2 -D 2 yes

[1296] xxxvi)A 1 -D 1 yes And A 2 -D 2 yes

[1297] xxxvii)A 1 -D 1 yes And A 2 -D 2 yes

[1298] xxxviii)A 1 -D 1 yes And A 2 -D 2 yes

[1299] xxxix)A 1 -D 1 yes And A 2 -D 2 yes

[1300] xl)A 1 -D 1 yes And A 2 -D 2 yes

[1301] xli)A 1 -D 1 yes And A 2 -D 2 yes

[1302] xlii)A 1 -D 1 yes And A 2 -D 2 yes

[1303] xliii)A 1 -D 1 yes And A 2 -D 2 yes

[1304] xliv)A 1 -D 1yes And A 2 -D 2 yes

[1305] xlv)A 1 -D 1 yes And A 2 -D 2 yes

[1306] xlvi)A 1 -D 1 yes And A 2 -D 2 yes

[1307] xlvii)A 1 -D 1 yes And A 2 -D 2 yes

[1308] xlviii)A 1 -D 1 yes And A 2 -D 2 yes

[1309] xlix)A 1 -D 1 yes And A 2 -D 2 yes

[1310] l)A 1 -D 1 yes And A 2 -D 2 yes

[1311] li)A 1 -D 1 yes And A 2 -D 2 yes

[1312] lii)A 1 -D 1 yes And A 2 -D 2 yes

[1313] liii)A 1 -D 1 yes And A 2 -D 2 yes

[1314] liv)A 1 -D 1 yes And A 2 -D 2 yes

[1315] lv)A 1 -D 1 yes And A 2 -D 2 yes

[1316] lvi)A 1 -D 1 yes And A 2 -D 2 yes

[1317] lvii)A 1 -D 1 yes And A 2 -D 2 yes

[1318] lviii)A 1 -D 1 yes And A 2 -D 2 yes

[1319] lix)A 1 -D 1 yes And A 2 -D 2 yes

[1320] lx)A 1 -D 1 yes And A 2 -D 2 yes

[1321] lxi)A 1-D 1 yes And A 2 -D 2 yes

[1322] lxii)A 1 -D 1 yes And A 2 -D 2 yes

[1323] lxiii)A 1 -D 1 yes And A 2 -D 2 yes or

[1324] lxiv)A 1 -D 1 yes And A 2 -D 2 yes

[1325] The asterisk (*) indicates a connection point with the rest of the molecule.

[1326] Example 40. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and / or D 2 It's Aurestatin.

[1327] Example 40a. The compound or pharmaceutically acceptable salt according to Example 40, wherein D 1 and D 2 They are all Aurestatin.

[1328] Example 40b. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

[1329] Example 40c. The compound or pharmaceutically acceptable salt according to Example 40b, wherein D 1 and D 2 They are all topoisomerase 1 inhibitors.

[1330] Example 40d. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and D 2 It's Aurestatin, and D 1 and D2 The other one is a topoisomerase 1 inhibitor.

[1331] Example 40e. The compound or pharmaceutically acceptable salt according to Example 40d, wherein D 1 It is Aurestatin and D 2 It is a topoisomerase 1 inhibitor.

[1332] Example 40f. The compound or pharmaceutically acceptable salt according to Example 40d, wherein D 1 It is a topoisomerase 1 inhibitor and D 2 It's Aurestatin.

[1333] Example 41. A compound or pharmaceutically acceptable salt according to any one of the foregoing examples, wherein D 1 and D 2 Choose independently from the following groups: Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1334] Example 41a. The compound or pharmaceutically acceptable salt according to Example 41, wherein D 1 and D 2 Choose independently from the following groups:

[1335]

[1336] Example 41b. The compound or pharmaceutically acceptable salt according to Example 39a, wherein D 1 and D 2 Choose independently from the following groups:

[1337] (For example )and (For example ),

[1338] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1339] Example 41c. The compound or pharmaceutically acceptable salt according to Example 39a, wherein D 1 and D 2 Choose independently from the following groups:

[1340]

[1341] Where * indicates a relationship with A1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1342] Example 42. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and D 2 Each is independently selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, anti-folate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[1343] Example 43. A compound or pharmaceutically acceptable salt according to any one of Examples 1 to 37, wherein D 1 and D 2 Each of the following is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, aurestatin, dolalastatin, maytansine-like substances, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or apoptosis-promoting agents, with the optional condition being D. 1 and D 2 Neither of them are BH3 analogs.

[1344] Example 44. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, selected from the group consisting of:

[1345]

[1346]

[1347]

[1348]

[1349]

[1350]

[1351]

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367] or a pharmaceutically acceptable salt thereof.

[1368] Example 44a. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, selected from the group consisting of:

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381] or a pharmaceutically acceptable salt thereof.

[1382] Example 45. The compound or a pharmaceutically acceptable salt thereof according to any one of the foregoing examples, selected from the group consisting of:

[1383]

[1384] Or, or a pharmaceutically acceptable salt thereof.

[1385] Example 45a. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45, selected from the group consisting of:

[1386]

[1387] Or, or a pharmaceutically acceptable salt thereof.

[1388] Example 45b. The compound or a pharmaceutically acceptable salt thereof according to Example 45a, selected from the group consisting of:

[1389]

[1390] or a pharmaceutically acceptable salt thereof.

[1391] Example 45c. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, selected from:

[1392]

[1393] Or, or a pharmaceutically acceptable salt thereof.

[1394] Example 45d. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, selected from:

[1395]

[1396] Or, or a pharmaceutically acceptable salt thereof.

[1397] Example 45e. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, selected from:

[1398]

[1399] or a pharmaceutically acceptable salt thereof.

[1400] Example 45f. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, selected from:

[1401]

[1402]

[1403] or a pharmaceutically acceptable salt thereof.

[1404] Example 46. A conjugate comprising an antibody or an antigen-binding fragment thereof covalently linked to two pharmaceutically active pharmaceutical ingredients via a dual-connector, wherein the dual-connector has one attachment site linked to the antibody and two attachment sites linked to the two pharmaceutically active pharmaceutical ingredients, provided that neither of the two pharmaceutically active pharmaceutical ingredients is a BH3 mimic.

[1405] Example 46a. A conjugate according to Example 46, wherein the two pharmaceutically active pharmaceutical ingredients are the same or different.

[1406] Example 46b. The conjugate according to Example 46 or 46a, wherein the pharmaceutically active drug is selected from cytotoxic drugs, cell growth inhibitors and immunosuppressants.

[1407] Example 46c. A conjugate according to any one of Examples 46 to 46b, wherein the pharmaceutically active drug is selected from auripitin, camptothecin, pyruvic acid, etoposide, maytansine, quasi-matansine, taxane, benzodiazepine Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and periwinkle alkaloids.

[1408] Example 46d. The conjugate according to Example 46c, wherein the pharmaceutically active drug is auristatin.

[1409] Example 46e. The conjugate according to Example 46 or 46a, wherein the pharmaceutically active drug is selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, antifolate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors and / or vinca alkaloids.

[1410] Example 46f. The conjugate according to Example 46 or 46a, wherein the pharmaceutically active drug is selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, auristatin, dolalastatin, maytansine-like drugs, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or apoptosis-promoting agents.

[1411] Example 46g. The conjugate according to Example 46 or 46a, wherein the pharmaceutically active pharmaceutical ingredient is selected from topoisomerase 1 inhibitors or their enantiomers, diastereomers, transisomers, deuterated derivatives and / or addition salts with pharmaceutically acceptable acids or bases.

[1412] Example 46h. The conjugate according to Example 46g, wherein the pharmaceutically active pharmaceutical ingredient is a topoisomerase 1 inhibitor selected from topotecan, eczetidine, delutec and SN-38.

[1413] Example 46i. The conjugate according to Example 46 or 46a, wherein the pharmaceutically active drug is selected from antimitotic drugs or their enantiomers, diastereomers, transisomers, deuterated derivatives and / or addition salts of pharmaceutically acceptable acids or bases.

[1414] Example 46j. The conjugate according to Example 46i, wherein the antimitotic drug is monomethylaurestatin E (MMAE) or taxane.

[1415] Example 46k. The conjugate according to Example 46j, wherein the taxane is selected from docetaxel, paclitaxel or cabazitaxel.

[1416] Example 46l. The conjugate according to Example 46, wherein the conjugate comprises a compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 45f.

[1417] Example 46m. A conjugate having formula (A-2):

[1418]

[1419] in:

[1420] Ab is an antibody or a fragment thereof;

[1421] R 100 It is a coupling group;

[1422] L 1 It is a bridging spacer;

[1423] W is the branched part;

[1424] L 2' and L 3' Each is an independent connector;

[1425] D 1 and D 2 Each is an independently pharmaceutically active drug, provided that condition D is met. 1 and D 2 None of them are BH3 analogs; and

[1426] a is an integer from 1 to 16.

[1427] Example 47. The conjugate according to Example 46m, wherein L 2' and L 3 Each of the groups contains a cleavable group, and optionally at least one cleavable group contains a phosphate group, a pyrophosphate group, and / or a self-detaching group (e.g., a peptide group and a self-detaching group).

[1428] Example 47a. The conjugate according to Example 47, wherein L 2' and L 3 Each of the components in ' contains a peptide group and a self-detaching group.

[1429] Example 47b. The conjugate according to Example 46m, wherein L 2' and L 3 Each of the groups contains a cleavable group, and optionally at least one cleavable group contains a phosphate ester group, a pyrophosphate ester group, a sugar (e.g., glucuronide) group, a peptide group, and / or a self-detaching group (e.g., peptide group and self-detaching group).

[1430] Example 48. The conjugate according to Example 46m, Example 47 or Example 47a has the formula (B-2):

[1431]

[1432] in:

[1433] Ab is an antibody or a fragment thereof;

[1434] R 100 It is a coupling group;

[1435] L 1 It is a bridging spacer;

[1436] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[1437] L 2 and L 3 Each is an independent connecting spacer;

[1438] E 1 and E 2 Each is independently an enzyme cleavage element or a hydrophilic part (e.g., E). 1 and E 2 Each is an enzyme cleavage element;

[1439] V 1 and V 2 Independently contains i) a self-detaching group, ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is independently a self-detached group) or iii) a self-detached group and an enzyme cleavage element;

[1440] D 1 and D 2 Each is an independently pharmaceutically active drug, provided that condition D is met. 1 and D 2 None of them are BH3 analogs; and

[1441] a is an integer from 1 to 16.

[1442] Example 48aa. The conjugate according to Example 48, wherein V 1 and V 2 Each independently consists of i) a self-detaching group or ii) an enzyme cleavage element (e.g., V). 1 and V 2 Each is an independent exfoliating group.

[1443] Example 48a. The conjugate according to Example 48 or Example 48aa, wherein W is N or CH.

[1444] Example 48b. The conjugate according to Example 48, Example 48aa or Example 48a, wherein E 1 and E 2 Each is an enzyme cleavage element.

[1445] Example 48c. The conjugate according to Example 48, Example 48aa, Example 48a or Example 48b, wherein V 1 and V 2 Each is an independent exfoliating group.

[1446] Example 49. The conjugate according to any one of Examples 46m to 48c, wherein a is an integer from 1 to 8, 1 to 6, 1 to 4, or a is 1 or 2.

[1447] Example 49a. The conjugate according to Examples 46m to 49, wherein a is determined by liquid chromatography-mass spectrometry (LC-MS).

[1448] Example 50. A conjugate according to any one of Examples 46m to 49, wherein (i) the cleavable connector comprises a phosphate group, a pyrophosphate group and / or a self-detachable group; (ii) the cleavable connector comprises a self-detachable group; or (iii) the cleavable connector comprises a self-detachable group including -CH2-O-, -NH-CH2-, -C(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfonyl)benzyl-ammonium, p-amino-(sulfonyl)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[1449] Example 50a. The conjugate according to Example 50, wherein W is N or CH.

[1450] Example 50b. The conjugate according to Example 50 or Example 50a, wherein R 2 and R 3 Each of them is a hydrophilic group.

[1451] Example 51. The conjugate according to any one of Examples 46m to 50b, having formula (C-2):

[1452]

[1453] in:

[1454] Ab is an antibody or its antigen-binding fragment;

[1455] R 100 It is a coupling group;

[1456] L 1 It is a bridging spacer;

[1457] W is N or CR w , where R w It is H or C1-C6 alkyl (e.g., R) w It is H);

[1458] L 2 and L 3 Each is an independent connecting spacer;

[1459] E 1 and E 2 Each is independently a peptide group containing 1 to 6 amino acids, wherein the peptide group is optionally replaced by a hydrophilic group;

[1460] A 1 and A 2 Each is an independent bond, -OC (=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*,

[1461] Each R a Independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 Or A 2 The asterisk (*) represents D. 1 or D 2 Attachment point;

[1462] D 1 and D 2 Each is an independently pharmaceutically active drug, provided that condition D is met. 1 and D 2 Neither of them are BH3 analogs;

[1463] L 4 and L 5 Each is an independent spacer component;

[1464] R 2 and R 3 Each is independently a hydrophilic group or an enzyme cleavage element (e.g., R...). 2 and R 3 Each of them is a hydrophilic group); and

[1465] m and n are each independently 0 or 1.

[1466] Example 52. The conjugate according to Example 51 has the formula (D1-2), (D2-2) or (D3-2):

[1467]

[1468] Example 53. The conjugate according to Example 52, wherein for formula (D1-2), R 2 and R 3 Each is an independent hydrophilic group, wherein for formula (D2-2), R 2 and R3 Each is an independent enzyme cleavage element; and for formula (D3-2), R 2 It is a hydrophilic group and R 3 It is an enzyme cleavage element.

[1469] Example 54. The conjugate according to any one of Examples 46m to 53, wherein R 100 Choose from the following groups:

[1470]

[1471]

[1472]

[1473] amide;

[1474]

[1475] as well as

[1476] disulfide bond,

[1477] in:

[1478] R 16 It is H, C 1- C4 alkyl, phenyl, pyrimidine, or pyridine;

[1479] R 18 It is H, C 1- C6 alkyl, phenyl, or C6 substituted with 1 to 3 -OH groups 1- C4 alkyl;

[1480] Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy group substituted with -C(=O)OH, benzyl group substituted with -C(=O)OH, C6 alkyl group substituted with -C(=O)OH 1- C4 alkoxy groups and C groups substituted with -C(=O)OH 1- C4 alkyl;

[1481] R 17 Independently selected from H, phenyl, and pyridine;

[1482] q is 0, 1, 2, or 3;

[1483] R 19 It is H or methyl; and

[1484] R 20 It is H, -CH3, or phenyl.

[1485] Example 55. The conjugate according to any one of Examples 46m to 54, wherein R 100 Freedom of choice The group consisting of R 100 The *** indicates the attachment point to Ab.

[1486] Example 56. The conjugate according to Example 55, wherein R 100 yes where R 100 The *** indicates the attachment point to Ab.

[1487] Example 57. The conjugate according to any one of Examples 46m to 56, wherein:

[1488] (1)L 1 Include:

[1489] or *-CH(OH)CH(OH)CH(OH)CH(OH)-**,

[1490] where each n is an integer from 1 to 12, and L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1491] (2)L 1 yes And n is an integer from 1 to 12, or n is 1 or n is 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1492] (3)L 1 yes And n is an integer from 1 to 12, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a connection point to R. 1 The direct or indirect (e.g., direct) attachment point;

[1493] (4)L 1 Include Among them L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 Direct or indirect (e.g., direct) attachment points; or

[1494] (5)L 1 It is a bridging spacer, which includes:

[1495] *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2)n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect (e.g., direct) attachment point;

[1496] X1 is and

[1497] Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[1498] Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and

[1499] Each t is independently selected from 1, 2, 3, 4, 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, and 30; and

[1500] Each R L1 Independently selected from H and C1-C6 alkyl groups.

[1501] Example 58. The conjugate according to any one of Examples 46m to 57, wherein L 1 Includes the portion represented by the following:

[1502]

[1503] Where n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8), where L 1 The asterisk (*) indicates a direct or indirect (e.g., direct) attachment point to W, and L 1 The **representation of R 1 The direct or indirect attachment point.

[1504] Example 58a. The conjugate according to Example 58, wherein n is an integer from 4 to 8.

[1505] Example 58b. The conjugate according to Example 58a, wherein n is 4 or 8.

[1506] Example 59. The conjugate according to any one of Examples 46m to 58b, wherein L 1 It can be expressed by the following formula:

[1507]

[1508] in

[1509] n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 4 or 8);

[1510] x is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[1511] y is 0 or 1;

[1512] z is an integer from 0 to 6 (e.g., 0 to 4, 0 to 2, 0 or 2);

[1513] u is 0 or 1; and

[1514] Among them L 1 The asterisk (*) indicates a direct attachment point to W, and L 1 The **representation of R 1 The direct attachment point.

[1515] Example 59a. The conjugate according to Example 59, wherein n is an integer from 4 to 8.

[1516] Example 59b. The conjugate according to Example 59a, wherein n is 4 or 8.

[1517] Example 59c. The conjugate according to Example 59, Example 59a or Example 59b, wherein x is an integer from 0 to 2.

[1518] Example 59d. The conjugate according to Example 59c, wherein x is 0 or 2.

[1519] Example 59e. The conjugate according to Example 59, Example 59a, Example 59b, Example 59c or Example 59d, wherein z is an integer from 0 to 2.

[1520] Example 59f. The conjugate according to Example 59e, wherein z is 0 or 2.

[1521] Example 60. The conjugate according to any one of Examples 46m to 59f, wherein L 1 Choose from the following groups:

[1522]

[1523] Example 61. The conjugate according to any one of Examples 48 to 60, wherein L 2 and L 3 Each is an independent connecting spacer, which comprises parts represented by the following:

[1524]

[1525] in

[1526] k is an integer from 0 to 6;

[1527] r is 0 or 1;

[1528] o is an integer from 0 to 12;

[1529] p is an integer from 0 to 6; and

[1530] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct or indirect attachment point, and L 2 or L 3 The ## symbol indicates a direct or indirect attachment point to W.

[1531] Example 62. The conjugate according to any one of Examples 48 to 60, wherein L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[1532]

[1533] as well as

[1534] in

[1535] k is an integer from 0 to 4 each time it appears;

[1536] r is 0 or 1 independently each time it appears;

[1537] o is an integer from 0 to 10 each time it appears;

[1538] p is an integer from 0 to 4 each time it appears;

[1539] R L23 Is it hydrogen or C? 1- C6 alkyl;

[1540] R L It is hydrogen or -C(O)-R H ;

[1541] R H It is a hydrophilic group; and

[1542] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L 2 or L 3 The ## symbol indicates a direct attachment point to W;

[1543] The condition is that when W is N, L 2 and L 3 It is not (L2c), (L2d), (L2f), or (L2k).

[1544] Example 63. The conjugate according to Example 62, wherein L 2 and L 3 Each of the following is an independent selection of connecting spacers from a set of groups:

[1545]

[1546]

[1547]

[1548] as well as

[1549]

[1550] in

[1551] k is an integer from 1 to 3 each time it appears;

[1552] o is an integer from 1 to 9 each time it appears;

[1553] p is an integer from 1 to 3 each time it appears;

[1554] R L23 Is it hydrogen or C? 1- C3 alkyl;

[1555] R L It is hydrogen or -C(O)-R H ;

[1556] R H It is a hydrophilic group; and

[1557] L 2 or L 3 The # symbol represents E respectively. 1 or E 2 The direct attachment point, and L2 or L 3 The ## symbol represents the direct attachment point to W; the condition is that L is N when W is N. 2 and L 3 It is not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

[1558] Example 64. The conjugate according to any one of Examples 48 to 63, wherein L 2 and L 3 The connecting spacers are independently selected from the following groups:

[1559]

[1560]

[1561]

[1562] Among them L 2 or L 3 The # symbol represents E respectively. 1 or E 2 direct attachment point, L 2 or L 3 The ## symbol indicates the direct attachment point to W; R L It is hydrogen or -C(O)-R H ;and

[1563] R H yes And d is an integer between 20 and 30 (e.g., 25).

[1564] Example 64a. The conjugate according to Example 64, wherein d is 25.

[1565] Example 65. A conjugate according to any one of Examples 51 to 64a, wherein each peptide group independently comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

[1566] Example 65a. The conjugate according to Example 65, wherein each peptide group independently comprises 2 amino acid residues.

[1567] Example 66. The conjugate according to Example 65 or Example 65a, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfonyl-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

[1568] Example 67. A conjugate according to any one of Examples 51 to 65, wherein each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly and sulfon-Ala-Val-Ala.

[1569] Example 68. The conjugate according to any one of Examples 48 to 65, wherein E 1 and / or E 2 Each peptide group is independently selected from the following groups:

[1570]

[1571] Where the ^ of E1-1 or E1-2 represents the same as V in equation (B). 1 or V 2 The direct attachment point or the direct attachment point with the -NH- group in formulas (C) and (D); and the ^^ of E1-1 or E1-2 respectively represent the direct attachment point with L 2 or L 3 The direct attachment point (e.g., where E) 1 and E 2 Each is an independently selected peptide group from (E1-1) and (E1-2).

[1572] Example 68a. The compound or a pharmaceutically acceptable salt thereof according to Example 68, wherein E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

[1573] Example 69. The conjugate according to any one of Examples 48 to 65, wherein E 1 and / or E 2 Each is independently represented by the following peptide groups:

[1574]

[1575] where R E It is a hydrophilic group R H .

[1576] Example 70. The conjugate according to Example 69, wherein the hydrophilic group R in (E1-3) H yes Where e is an integer between 20 and 30 (e.g., 25).

[1577] Example 70a. The conjugate according to Example 70, wherein e is 25.

[1578] Example 71. The conjugate according to Example 68, wherein E 1 and E 2 Each is

[1579]

[1580] Example 72. The conjugate according to any one of Examples 51 to 71, wherein A 1 and A 2 Independently selected from the bond and -OC (=O)-*, where * indicates that it is related to D respectively. 1 or D 2 Attachment point.

[1581] Example 72a. The conjugate according to any one of Examples 51 to 71, wherein A 1 and A 2 Independently selected from keys, and -OC(=O)-*, where * represents the relationship with D respectively. 1 or D 2 Attachment point.

[1582] Example 73. The conjugate according to Example 72, wherein A 1 and A 2 It is a key.

[1583] Example 73a. The conjugate according to Example 72, wherein A 1 and A 2 Both are -OC(=O)-*.

[1584] Example 73b. The conjugate according to Example 72, wherein A 1 and A 2 One of them is OC (=O)-*, and A 1 and A 2 The other one is the key.

[1585] Example 73c. ​​The conjugate according to Example 72a, wherein A1 and A 2 Independently is a key or Where * indicates that they are related to D respectively. 1 or D 2 Attachment point.

[1586] Example 73d. The conjugate according to Example 72a, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

[1587] Example 73e. The conjugate according to Example 72a, wherein A 1 and A 2 All

[1588] Example 73f. The conjugate according to Example 72a, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

[1589] Example 73g. The conjugate according to Example 72a, wherein A 1 and A 2 It is -OC(=O)-*;

[1590] (ii)A 1 and A 2 yes

[1591] (iii)A 1 It is -OC(=O)-* and A 2 Is a key

[1592] (iv)A 1 It is -OC (=O) - *and A 2 yes

[1593] (v)A 1 It is a key and A 2 yes or

[1594] (vi)A 1 It is a key and A 2 It is -OC(=O)-*,

[1595] Where * indicates a relationship with D 1 or D2 Attachment point.

[1596] Example 74. The conjugate according to any one of Examples 51 to 73b, wherein:

[1597] i)L 4 and L 5 Each is an independent spacer sub-part, which has a structure

[1598] in:

[1599] According to the compound or pharmaceutically acceptable salt described in Example 41, wherein D 1 and D 2 Choose independently from the following groups:

[1600] X is a bond, a triazole group, or -CH2-triazole-.

[1601] Where X is connected to R 2 or R 3 ;or

[1602] (ii)L 4 and L 5 Independently, there is a spacer sub-part, which has a structure

[1603] in:

[1604] Z represents -CH2-, -CH2O-, -CH2N(R) L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-、-CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, where each R L45 Independently selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl; and

[1605] X is -CH2-triazolyl-C 1-C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene group -OC(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -,-CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n - where each n is independently 1, 2, or 3.

[1606] Where X is connected to R 2 or R 3 .

[1607] Example 75. The conjugate according to Example 74, wherein Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazole group, or -CH2-triazole-; and R L45 It is either H or C each time it appears. 1- C3 alkyl.

[1608] Example 76. The conjugate according to any one of Examples 51 to 75, wherein L 4 and L 5 Each is an independent sub-part of the interval selected from the following groups:

[1609]

[1610] Among them L 4 or L 5 The @ symbol represents the direct attachment point to the phenyl group, and L 4 or L 5 @@ represents R 2 or R 3 The direct attachment point.

[1611] Example 77. The conjugate according to any one of Examples 51 to 76, wherein R 2 and R 3 The hydrophilic groups represented independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, and 1 to 3 [unclear - possibly referring to specific compounds or groups]. The substituted C2-C6 alkyl group, or the alkyl group independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C2-C6 alkyl groups substituted with C4 alkylene groups -P(O)(OCH2CH3)2 and -COOH groups.

[1612] Example 78. The conjugate according to any one of Examples 51 to 76, wherein R 2 or / and R 3 Each person independently chooses from the following groups:

[1613]

[1614] Where n is an integer between 1 and 6;

[1615]

[1616] Example 79. The conjugate according to any one of Examples 51 to 76, wherein R 2 or / and R 3 Each contains independently:

[1617] (i) Polysarcosine having the following components:

[1618] in

[1619] f is an integer between 3 and 25; and

[1620] R 23 It is H, -CH3, or -CH2CH2C(=O)OH;

[1621] (ii) Polyethylene glycol having the following formula: in

[1622] g and h are independent integers between 2 and 30; or

[1623] (iii) by The part that is indicated.

[1624] Example 79a. The conjugate according to any one of Examples 51 to 76, wherein R 2 or R 3 The hydrophilic groups represented each contain independently:

[1625] (i) Polysarcosine having the following components:

[1626]

[1627] Where f is an integer between 3 and 25; and R 23 It is H, -CH3, or -CH2CH2C(=O)OH; or

[1628] (ii) Polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30;

[1629] or

[1630] (iii) by The part that is indicated.

[1631] Example 80. The conjugate according to any one of Examples 51 to 76, wherein R 2 and R 3 Each person independently chooses from the following groups: in

[1632] g and h are independent integers between 20 and 30 (e.g., 23 or 24).

[1633] Example 81. The conjugate according to Example 80, wherein R 2 or / and R 3 Include:

[1634]

[1635] Example 81a. The conjugate according to Example 80, wherein R 2 and R 3 Each independently contains polyethylene glycol having the following formula: Where g and h are independent integers between 2 and 30.

[1636] Example 82. The conjugate according to any one of Examples 46m to 81a, wherein D 1 and D 2 They are the same.

[1637] Example 83. The conjugate according to any one of Examples 46m to 81a, wherein D 1 and D 2 They are different.

[1638] Example 84. The conjugate according to any one of Examples 46m to 83, wherein D 1 and D 2 Each drug is independently selected from cytotoxic drugs, cell growth inhibitors, and immunosuppressants.

[1639] Example 85. The conjugate according to any one of Examples 46m to 83, wherein D1 and D 2 Each ingredient was independently selected from auristatin, camptothecin, pyroxine, etoposide, maytansine, maytansine-like substances, taxanes, and benzodiazepines. Class or containing benzodiazepines Class of drugs (e.g., pyrrolo[1,4]-benzodiazepines) PBD (Phenolic Benzyl Dioxide), Indolebenzodiazepine Benzyl and oxazolidinone dibenzodiazepines (Class) and periwinkle alkaloids.

[1640] Example 85a. The conjugate according to Example 85, wherein D 1 and D 2 Choose independently from the following groups:

[1641]

[1642] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1643] Example 85b. The conjugate according to Example 85a, wherein

[1644] i)D 1 yes And D 2 yes

[1645] ii)D 1 yes And D 2 yes

[1646] iii)D 1 yes And D 2 yes

[1647] iv)D 1 yes And D 2 yes

[1648] v)D 1 yes And D 2 yes

[1649] vi)D 1 yes And D 2 yes

[1650] vii)D1 yes And D 2 yes

[1651] viii)D 1 yes And D 2 yes

[1652] ix)D 1 yes And D 2 yes

[1653] x)D 1 yes And D 2 yes

[1654] xi)D 1 yes And D 2 yes

[1655] xii)D 1 yes And D 2 yes

[1656] xiii)D 1 yes And D 2 yes

[1657] xiv)D 1 yes And D 2 yes

[1658] xv)D 1 yes And D 2 yes

[1659] xvi)D 1 yes And D 2 yes

[1660] xvii)D 1 yes And D 2 yes

[1661] xviii)D 1 yes And D2 yes

[1662] xix)D 1 yes And D 2 yes

[1663] xx)D 1 yes And D 2 yes

[1664] xxi)D 1 yes And D 2 yes

[1665] xxii)D 1 yes And D 2 yes

[1666] xxiii)D 1 yes And D 2 yes

[1667] xxiv)D 1 yes And D 2 yes

[1668] xxv)D 1 yes And D 2 yes

[1669] xxvi)D 1 yes And D 2 yes

[1670] xxvii)D 1 yes And D 2 yes

[1671] xxviii)D 1 yes And D 2 yes

[1672] xxix)D 1 yes And D 2 yes

[1673] xxx)D 1 yes And D 2 yes

[1674] xxxi)D 1 yes And D 2 yes

[1675] xxxii)D 1 yes And D 2 yes

[1676] xxxiii)D 1 yes And D 2 yes

[1677] xxxiv)D 1 yes And D 2 yes

[1678] xxxv)D 1 yes And D 2 yes

[1679] xxxvi)D 1 yes And D 2 yes

[1680] xxxvii)D 1 yes And D 2 yes

[1681] xxxviii)D 1 yes And D 2 yes

[1682] xxxix)D 1 yes And D 2 yes

[1683] xl)D 1 yes And D 2 yes

[1684] xli)D 1 yes And D 2 yes

[1685] xlii)D 1 yes And D 2 yes

[1686] xliii)D 1 yes And D 2 yes

[1687] xliv)D 1 yes And D 2 yes

[1688] vl)D 1 yes And D 2 yes

[1689] xlvi)D 1 yes And D 2 yes

[1690] xlvii)D 1 yes And D 2 yes

[1691] xlviii)D 1 yes And D 2 yes

[1692] il)D 1 yes And D 2 yes

[1693] l)D 1 yes And D 2 yes

[1694] li)D 1 yes And D 2 yes

[1695] lii)D 1yes And D 2 yes

[1696] liii)D 1 yes And D 2 yes

[1697] liv)D 1 yes And D 2 yes

[1698] lv)D 1 yes And D 2 yes

[1699] lvi)D 1 yes And D 2 yes

[1700] lvii)D 1 yes And D 2 yes

[1701] lviii)D 1 yes And D 2 yes

[1702] lix)D 1 yes And D 2 yes

[1703] lx)D 1 yes And D 2 yes

[1704] lxi)D 1 yes And D 2 yes

[1705] lxii)D 1 yes And D 2 yes

[1706] lxiii)D 1 yes And D 2yes or

[1707] lxiv)D 1 yes And D 2 yes

[1708] The asterisk (*) indicates a connection point with the rest of the molecule.

[1709] Example 85c. The conjugate according to any one of Examples 46 to 85b, wherein:

[1710] i)A 1 -D 1 yes And A 2 -D 2 yes

[1711] ii)A 1 -D 1 yes And A 2 -D 2 yes

[1712] iii)A 1 -D 1 yes And A 2 -D 2 yes

[1713] iv)A 1 -D 1 yes And A 2 -D 2 yes

[1714] v)A 1 -D 1 yes And A 2 -D 2 yes

[1715] vi)A 1 -D 1 yes And A 2 -D 2 yes

[1716] vii)A 1 -D 1 yes And A 2 -D2 yes

[1717] viii)A 1 -D 1 yes And A 2 -D 2 yes

[1718] ix)A 1 -D 1 yes And A 2 -D 2 yes

[1719] x)A 1 -D 1 yes And A 2 -D 2 yes

[1720] xi)A 1 -D 1 yes And A 2 -D 2 yes

[1721] xii)A 1 -D 1 yes And A 2 -D 2 yes

[1722] xiii)A 1 -D 1 yes And A 2 -D 2 yes

[1723] xiv)A 1 -D 1 yes And A 2 -D 2 yes

[1724] xv)A 1 -D 1 yes And A 2 -D 2 yes

[1725] xvi)A1 -D 1 yes And A 2 -D 2 yes

[1726] xvii)A 1 -D 1 yes And A 2 -D 2 yes

[1727] xviii)A 1 -D 1 yes And A 2 -D 2 yes

[1728] xix)A 1 -D 1 yes And A 2 -D 2 yes

[1729] xx)A 1 -D 1 yes And A 2 -D 2 yes

[1730] xxi)A 1 -D 1 yes And A 2 -D 2 yes

[1731] xxii)A 1 -D 1 yes And A 2 -D 2 yes

[1732] xxiii)A 1 -D 1 yes And A 2 -D 2 yes

[1733] xxiv)A 1 -D 1 yes And A2 -D 2 yes

[1734] xxv)A 1 -D 1 yes And A 2 -D 2 yes

[1735] xxvi)A 1 -D 1 yes And A 2 -D 2 yes

[1736] xxvii)A 1 -D 1 yes And A 2 -D 2 yes

[1737] xxviii)A 1 -D 1 yes And A 2 -D 2 yes

[1738] xxix)A 1 -D 1 yes And A 2 -D 2 yes

[1739] xxx)A 1 -D 1 yes And A 2 -D 2 yes

[1740] xxxi)A 1 -D 1 yes And A 2 -D 2 yes

[1741] xxxii)A 1 -D 1 yes And A 2 -D 2 yes

[1742] xxxiii)A 1 -D 1 yes And A 2 -D 2 yes

[1743] xxxiv)A 1 -D 1 yes And A 2 -D 2 yes

[1744] xxxv)A 1 -D 1 yes And A 2 -D 2 yes

[1745] xxxvi)A 1 -D 1 yes And A 2 -D 2 yes

[1746] xxxvii)A 1 -D 1 yes And A 2 -D 2 yes

[1747] xxxviii)A 1 -D 1 yes And A 2 -D 2 yes

[1748] xxxix)A 1 -D 1 yes And A 2 -D 2 yes

[1749] xl)A 1 -D 1 yes And A 2 -D 2 yes

[1750] xli)A 1-D 1 yes And A 2 -D 2 yes

[1751] xlii)A 1 -D 1 yes And A 2 -D 2 yes

[1752] xliii)A 1 -D 1 yes And A 2 -D 2 yes

[1753] xliv)A 1 -D 1 yes And A 2 -D 2 yes

[1754] xlv)A 1 -D 1 yes And A 2 -D 2 yes

[1755] xlvi)A 1 -D 1 yes And A 2 -D 2 yes

[1756] xlvii)A 1 -D 1 yes And A 2 -D 2 yes

[1757] xlviii)A 1 -D 1 yes And A 2 -D 2 yes

[1758] xlix)A 1 -D 1 yes And A 2-D 2 yes

[1759] l)A 1 -D 1 yes And A 2 -D 2 yes

[1760] li)A 1 -D 1 yes And A 2 -D 2 yes

[1761] lii)A 1 -D 1 yes And A 2 -D 2 yes

[1762] liii)A 1 -D 1 yes And A 2 -D 2 yes

[1763] liv)A 1 -D 1 yes And A 2 -D 2 yes

[1764] lv)A 1 -D 1 yes And A 2 -D 2 yes

[1765] lvi)A 1 -D 1 yes And A 2 -D 2 yes

[1766] lvii)A 1 -D 1 yes And A 2 -D 2 yes

[1767] lviii)A 1 -D 1 yes And A 2 -D 2 yes

[1768] lix)A 1 -D 1 yes And A 2 -D 2 yes

[1769] lx)A 1 -D 1 yes And A 2 -D 2 yes

[1770] lxi)A 1 -D 1 yes And A 2 -D 2 yes

[1771] lxii)A 1 -D 1 yes And A 2 -D 2 yes

[1772] lxiii)A 1 -D 1 yes And A 2 -D 2 yes or

[1773] lxiv)A 1 -D 1 yes And A 2 -D 2 yes

[1774] The asterisk (*) indicates a connection point with the rest of the molecule.

[1775] Example 86. The conjugate according to any one of Examples 46m to 83, wherein D 1 and / or D 2 It's Aurestatin.

[1776] Example 86a. The conjugate according to Example 86, wherein D1 and D 2 They are all Aurestatin.

[1777] Example 86b. The conjugate according to any one of Examples 46m to 83, wherein D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

[1778] Example 86c. The conjugate according to Example 86b, wherein D 1 and D 2 They are all topoisomerase 1 inhibitors.

[1779] Example 86d. The conjugate according to any one of Examples 46m to 83, wherein D 1 and D 2 One of them is auristatin, and D 1 and D 2 The other one is a topoisomerase 1 inhibitor.

[1780] Example 86e. The conjugate according to Example 86d, wherein D 1 It is Aurestatin and D 2 It is a topoisomerase 1 inhibitor.

[1781] Example 86f. The conjugate according to Example 86d, wherein D 1 It is a topoisomerase 1 inhibitor and D 2 It's Aurestatin.

[1782] Example 87. The conjugate according to Example 86, wherein D 1 and D 2 Choose independently from the following groups:

[1783] Where * indicates a relationship with A 1 Or A 2 Attachment point.

[1784] Example 87a. The conjugate according to Example 87, wherein D 1 and D 2 Choose independently from the following groups:

[1785]

[1786] Example 87b. The conjugate according to Example 85a, wherein D 1 and D 2 Choose independently from the following groups:

[1787] (For example )and (For example ),

[1788] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1789] Example 87c. The conjugate according to Example 85a, wherein D 1 and D 2 Choose independently from the following groups:

[1790]

[1791] Where * indicates a relationship with A 1 Or A 2 The attachment point; or its pharmaceutically acceptable salt.

[1792] Example 88. The conjugate according to any one of Examples 46m to 83, wherein D 1 and D 2 Each is independently selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, anti-folate agents, antimetabolites, chemosensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[1793] Example 89. The conjugate according to any one of Examples 46m to 83, wherein D 1 and D 2 Each of the following is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, aurestatin, dolalastatin, maytansine-like substances, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer reaction inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinase inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalating agents, DNA minor groove conjugates, RNA polymerase inhibitors, muscarinic acid, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or apoptosis-promoting agents, with the optional condition being D. 1 and D 2 Neither of them are BH3 analogs.

[1794] Example 90. A conjugate comprising an antibody or antigen-binding fragment that binds independently to one or more (e.g., 1 to 16, e.g., 1 to 4) compounds selected independently from Example 44 or Example 45.

[1795] Example 91. A conjugate according to any one of Examples 46m to 90, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

[1796] Example 92. The conjugate according to Example 91, wherein:

[1797] (i) The target antigens are selected from BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, SEZ6, DLL3, DLK1, B7-H3, EGFR, CD71, EphA2, EPCAM, FORR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2 and GPNMB;

[1798] (ii) The target antigen is selected from EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; or

[1799] (iii) The target antigen is selected from PCAD, CD48, CD74, EphA2, TROP2, B7-H3, 5T4 and HER2.

[1800] Example 92a. A conjugate according to Example 91 or 92, wherein the antibody or its antigen-binding fragment is selected from Table D1.

[1801] Example 93. A conjugate according to any one of Examples 91 to 92a, wherein the antibody or antigen-binding fragment comprises i) three heavy chain CDR sequences and three light chain CDR sequences selected from Tables D3 and D8, ii) heavy chain variable region sequences and light chain variable region sequences selected from Tables D2 and D8, or iii) heavy chain sequences and light chain sequences selected from Tables D4, D5 and D7.

[1802] Example 94. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[1803] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:256, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:257, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:268, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:265;

[1804] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:258, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:172, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[1805] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:259, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:260, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:261; light chain CDR1 (LCDR1) composed of SEQ ID NO:269, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[1806] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:169, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:172, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[1807] 5) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:256, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:257, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:263, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:265;

[1808] 6) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:258, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:170, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:171; light chain CDR1 (LCDR1) composed of SEQ ID NO:266, light chain CDR2 (LCDR2) composed of SEQ ID NO:173, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174;

[1809] 7) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:259, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:260, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:261; light chain CDR1 (LCDR1) composed of SEQ ID NO:215, light chain CDR2 (LCDR2) composed of SEQ ID NO:264, and light chain CDR3 (LCDR3) composed of SEQ ID NO:174; and

[1810] 8) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:169, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:170, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:171; light chain CDR1 (LCDR1) consisting of SEQ ID NO:266, light chain CDR2 (LCDR2) consisting of SEQ ID NO:173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:174.

[1811] Example 95. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:262, or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:267.

[1812] Example 96. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising:

[1813] (a) The heavy chain amino acid sequence of SEQ ID NO:118 or a sequence that is at least 95% identical to SEQ ID NO:118, and the light chain amino acid sequence of SEQ ID NO:237 or a sequence that is at least 95% identical to SEQ ID NO:237;

[1814] (b) The heavy chain amino acid sequence of SEQ ID NO:236 or a sequence that is at least 95% identical to SEQ ID NO:236, and the light chain amino acid sequence of SEQ ID NO:237 or a sequence that is at least 95% identical to SEQ ID NO:237; or

[1815] (c) The heavy chain amino acid sequence of SEQ ID NO:118 or a sequence that is at least 95% identical to SEQ ID NO:118, and the light chain amino acid sequence of SEQ ID NO:239 or a sequence that is at least 95% identical to SEQ ID NO:239.

[1816] Example 97. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[1817] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:271, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:272, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:281, light chain CDR2 (LCDR2) composed of SEQ ID NO:282, and light chain CDR3 (LCDR3) composed of SEQ ID NO:283;

[1818] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:274, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:275, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:284, light chain CDR2 (LCDR2) composed of SEQ ID NO:285, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286;

[1819] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:276, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:277, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:278; light chain CDR1 (LCDR1) composed of SEQ ID NO:287, light chain CDR2 (LCDR2) composed of SEQ ID NO:282, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286; and

[1820] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:279, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:275, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:273; light chain CDR1 (LCDR1) composed of SEQ ID NO:284, light chain CDR2 (LCDR2) composed of SEQ ID NO:288, and light chain CDR3 (LCDR3) composed of SEQ ID NO:286; and

[1821] 5) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:51, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:52, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:53; light chain CDR1 (LCDR1) consisting of SEQ ID NO:54, light chain CDR2 (LCDR2) consisting of SEQ ID NO:55, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:56.

[1822] Example 98. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:270 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:280; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:14.

[1823] Example 99. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising (a) the heavy chain amino acid sequence of SEQ ID NO:240 or a sequence at least 95% identical to SEQ ID NO:240, and the light chain amino acid sequence of SEQ ID NO:243 or a sequence at least 95% identical to SEQ ID NO:243; or (b) the heavy chain amino acid sequence of SEQ ID NO:242 or a sequence at least 95% identical to SEQ ID NO:242, and the light chain amino acid sequence of SEQ ID NO:243 or a sequence at least 95% identical to SEQ ID NO:243; or (c) the heavy chain amino acid sequence of SEQ ID NO:240 or a sequence at least 95% identical to SEQ ID NO:240, and the light chain amino acid sequence of SEQ ID NO:69 or a sequence at least 95% identical to SEQ ID NO:70.

[1824] Example 100. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[1825] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:289, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:290, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:291; light chain CDR1 (LCDR1) composed of SEQ ID NO:297, light chain CDR2 (LCDR2) composed of SEQ ID NO:298, and light chain CDR3 (LCDR3) composed of SEQ ID NO:299;

[1826] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:292, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:40, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:291; light chain CDR1 (LCDR1) composed of SEQ ID NO:300, light chain CDR2 (LCDR2) composed of SEQ ID NO:301, and light chain CDR3 (LCDR3) composed of SEQ ID NO:44;

[1827] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:293, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:294, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:295; light chain CDR1 (LCDR1) composed of SEQ ID NO:302, light chain CDR2 (LCDR2) composed of SEQ ID NO:298, and light chain CDR3 (LCDR3) composed of SEQ ID NO:44; and

[1828] 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:39, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:40, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:291; light chain CDR1 (LCDR1) consisting of SEQ ID NO:300, light chain CDR2 (LCDR2) consisting of SEQ ID NO:301, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:44.

[1829] Example 101. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:9 and a light chain variable region containing the amino acid sequence of SEQ ID NO:296.

[1830] Example 102. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:245 or a sequence that is at least 95% identical to SEQ ID NO:245, and the light chain amino acid sequence of SEQ ID NO:66 or a sequence that is at least 95% identical to SEQ ID NO:66.

[1831] Example 103. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[1832] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:304, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:305, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:306; light chain CDR1 (LCDR1) composed of SEQ ID NO:312, light chain CDR2 (LCDR2) composed of SEQ ID NO:313, and light chain CDR3 (LCDR3) composed of SEQ ID NO:314;

[1833] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:307, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:308, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:306; light chain CDR1 (LCDR1) composed of SEQ ID NO:315, light chain CDR2 (LCDR2) composed of SEQ ID NO:25, and light chain CDR3 (LCDR3) composed of SEQ ID NO:316;

[1834] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:309, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:277, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:278; light chain CDR1 (LCDR1) composed of SEQ ID NO:317, light chain CDR2 (LCDR2) composed of SEQ ID NO:313, and light chain CDR3 (LCDR3) composed of SEQ ID NO:316; and

[1835] 4) Heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:310, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:308, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:306; light chain CDR1 (LCDR1) consisting of SEQ ID NO:315, light chain CDR2 (LCDR2) consisting of SEQ ID NO:25, and light chain CDR3 (LCDR3) consisting of SEQ ID NO:316.

[1836] Example 104. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:303 and a light chain variable region containing the amino acid sequence of SEQ ID NO:311.

[1837] Example 105. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising the heavy chain amino acid sequence of SEQ ID NO:248 or a sequence that is at least 95% identical to SEQ ID NO:248, and the light chain amino acid sequence of SEQ ID NO:250 or a sequence that is at least 95% identical to SEQ ID NO:250.

[1838] Example 106. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[1839] 1) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:319, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:320, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:321; light chain CDR1 (LCDR1) composed of SEQ ID NO:330, light chain CDR2 (LCDR2) composed of SEQ ID NO:331, and light chain CDR3 (LCDR3) composed of SEQ ID NO:332;

[1840] 2) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:322, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:323, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:324; light chain CDR1 (LCDR1) composed of SEQ ID NO:333, light chain CDR2 (LCDR2) composed of SEQ ID NO:334, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335;

[1841] 3) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:325, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:326, and heavy chain CDR3 (HCDR3) composed of SEQ ID NO:327; light chain CDR1 (LCDR1) composed of SEQ ID NO:336, light chain CDR2 (LCDR2) composed of SEQ ID NO:331, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335; and

[1842] 4) Heavy chain CDR1 (HCDR1) composed of SEQ ID NO:328, heavy chain CDR2 (HCDR2) composed of SEQ ID NO:323, heavy chain CDR3 (HCDR3) composed of SEQ ID NO:321; light chain CDR1 (LCDR1) composed of SEQ ID NO:333, light chain CDR2 (LCDR2) composed of SEQ ID NO:334, and light chain CDR3 (LCDR3) composed of SEQ ID NO:335.

[1843] Example 107. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO:318 and a light chain variable region containing the amino acid sequence of SEQ ID NO:329.

[1844] Example 108. The conjugate according to Example 91, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:252 or a sequence that is at least 95% identical to SEQ ID NO:252, and the light chain amino acid sequence of SEQ ID NO:254 or a sequence that is at least 95% identical to SEQ ID NO:254.

[1845] Example 109. A conjugate according to any one of Examples 94 to 108, wherein the antibody or its antigen-binding fragment comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or its antigen-binding fragment, wherein the position is according to the EU system number.

[1846] Example 110. A conjugate according to any one of Examples 94 to 108, wherein the antibody or its antigen-binding fragment contains one or more Fc silencing mutations.

[1847] Example 111. A composition comprising a plurality of copies of the conjugate according to any one of Examples 46m to 110, wherein the average a of the conjugate in the composition is about 1 to about 8, for example about 1 to about 6, about 1 to about 4, or about 1 to about 2.

[1848] Example 112. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, which is represented by any one of the following formulas:

[1849]

[1850]

[1851]

[1852]

[1853] in:

[1854] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[1855] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[1856] o is an integer between 1 and 9 (e.g., between 2 and 5) that appears independently each time; and

[1857] n is an integer between 1 and 12 (for example, between 2 and 5).

[1858] Example 112a. The compound or a pharmaceutically acceptable salt thereof according to Example 112, wherein A 1 and A 2 Each is independently selected from the bond and OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[1859] Example 113. The conjugate according to any one of Examples 46m to 110, which is represented by any one of the following formulas:

[1860]

[1861]

[1862]

[1863]

[1864] in:

[1865] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[1866] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[1867] o is an integer between 1 and 9 (e.g., between 2 and 5) that appears independently each time;

[1868] n is an integer between 1 and 12 (e.g., between 2 and 5); and

[1869] **- indicates the attachment point to Ab.

[1870] Example 113a. The conjugate according to Example 113, wherein A 1 and A 2 Each is independently selected from the bond and OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[1871] Example 114. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 43, having the formula (D5a-1):

[1872]

[1873] in:

[1874] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[1875] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[1876] o is an integer between 1 and 9 (e.g., between 1 and 3) that appears independently each time; and

[1877] n is an integer between 1 and 12 (for example, between 5 and 10).

[1878] Example 114a. The compound or a pharmaceutically acceptable salt thereof according to Example 114, wherein A 1 and A 2 Each is independently selected from the bond and -OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[1879] Example 115. The conjugate according to any one of Examples 46m to 110, having the formula (D5a-2):

[1880]

[1881] in:

[1882] A 1 and A 2 Each is independently selected from the key, and -OC(=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point;

[1883] g is an integer between 20 and 30 each time it appears (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30);

[1884] o is an integer between 1 and 9 (e.g., between 1 and 3) that appears independently each time;

[1885] n is an integer between 1 and 12 (e.g., between 5 and 10); and

[1886] **- indicates the attachment point to Ab.

[1887] Example 115a. The conjugate according to Example 115, wherein A 1 and A 2 Each is independently selected from the bond and OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[1888] Example 116. The conjugate according to any one of Examples 46m to 110, which is represented by the following formula:

[1889]

[1890]

[1891]

[1892]

[1893]

[1894]

[1895]

[1896]

[1897]

[1898]

[1899]

[1900] as well as

[1901]

[1902] Among them A 1 Or A 2 Each is independently selected from the key, and -OC(=O)-*, where * indicates the relationship with D 1 or D 2 The attachment point; **- indicates the attachment point to Ab; and Indicates D 1 or D 2 The direct attachment point.

[1903] Example 116a. The conjugate according to Example 116, wherein A 1 and A 2 Each is independently selected from the bond and OC (=O)-*, where A 1 and A 2 The asterisk (*) in the figure represents D. 1 or D 2 Attachment point.

[1904] Example 117. A pharmaceutical composition comprising a conjugate according to any one of Examples 46 to 110, 113, 115 and 116, and a pharmaceutically acceptable carrier.

[1905] Example 118. A method of treating a subject who has or is suspected of having cancer, comprising administering to the subject a therapeutically effective amount of the conjugate according to any one of Examples 46 to 110, 113, 115 and 116 or the pharmaceutical composition according to Example 117.

[1906] Example 119. The method according to Example 118, wherein the cancer expresses a target antigen.

[1907] Example 120. The method according to Example 118 or Example 119, wherein the cancer is a tumor or a blood cancer, optionally, the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoma of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

[1908] Example 121. A method for reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate according to any one of Examples 46 to 110, 113, 115 and 116 or the pharmaceutical composition according to Example 117.

[1909] Example 122. The method according to Example 121, wherein the tumor expresses the target antigen.

[1910] Example 123. The method according to Example 121 or Example 122, wherein the tumor is breast cancer, gastric cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

[1911] Example 124. A method for reducing or inhibiting blood cancer in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate according to any one of Examples 46 to 110, 113, 115 and 116 or the pharmaceutical composition according to Example 117.

[1912] Example 125. The method according to Example 124, wherein the blood cancer expresses the target antigen.

[1913] Example 126. The method according to Example 124 or Example 125, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloid monocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

[1914] Example 127. The method according to any one of Examples 121 to 126, wherein the application of the conjugate or pharmaceutical composition reduces or inhibits the growth of a tumor or blood cancer by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[1915] Example 128. A method for reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate according to any one of Examples 46 to 110, 113, 115 and 116 or the pharmaceutical composition according to Example 117.

[1916] Example 129. The method according to Example 128, wherein the cancer cell population expresses the target antigen.

[1917] Example 130. The method according to Example 128 or Example 129, wherein the cancer cell population originates from a tumor or blood cancer, optionally wherein the cancer cell population originates from breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoma of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

[1918] Example 131. The method according to any one of Examples 128 to 130, wherein the application of the conjugate or pharmaceutical composition reduces or slows the proliferation of cancer cell populations by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[1919] Example 132. The method according to any one of Examples 118 to 131, wherein the conjugate is administered as a single therapy.

[1920] Example 133. The method according to any one of Examples 118 to 131, wherein the conjugate is administered as an adjunct to another therapeutic agent or radiotherapy.

[1921] Example 134. The method according to Example 133, wherein the conjugate is administered in an amount that effectively sensitizes tumor cells to one or more additional therapeutic agents and / or radiotherapy.

[1922] Example 135. The method according to any one of Examples 118 to 131, further comprising administering at least one additional therapeutic agent to a subject in need.

[1923] Example 136. According to the method of Example 135, one of the additional therapeutic agents is taxane, vinca alkaloids, MEK inhibitors, ERK inhibitors, topoisomerase inhibitors, or RAF inhibitors.

[1924] Example 137. Use of the conjugate according to any one of Examples 46 to 110, 113, 115 and 116 or the pharmaceutical composition according to Example 117 in the preparation of a medicament for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in the subject, (iii) reducing or inhibiting blood cancer in the subject, or (iv) reducing or slowing the expansion of a cancer cell population in the subject.

[1925] Example 138. A conjugate according to any one of Examples 46 to 113, 110, 115 and 116 or a pharmaceutical composition according to Example 117, for (i) treating a subject who has or is suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in the subject, (iii) reducing or inhibiting blood cancer in the subject, or (iv) reducing or slowing the expansion of a cancer cell population in the subject.

[1926] definition

[1927] Various terms are used throughout the specification and claims in connection with the described aspects. Unless otherwise indicated, such terms have their ordinary meaning in the art. Other specifically defined terms will be interpreted in a manner consistent with the definitions provided herein.

[1928] As used herein, the singular forms “a / an” and “the” include the plural forms unless the context clearly indicates otherwise. Unless otherwise stated, the terms “comprising,” “having,” “being of” (as in “having a chemical formula”), “including,” and “containing” should be interpreted as open-ended terms (i.e., meaning “including but not limited to”). Furthermore, whenever “comprising” or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be claimed more narrowly using the intermediate term “consistently composed of” or the closed term “composed of.”

[1929] The term "about" or "approximately," when used in the context of numerical values ​​and ranges, refers to a value or range approximately or close to the stated value or range, enabling the embodiments to proceed as expected, as will be apparent to those skilled in the art from the teachings contained herein. In some embodiments, "about" means adding or subtracting 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of the quantity. In one embodiment, the term "about" refers to a range of values ​​that are 10% larger or smaller than a specified value. In another embodiment, the term "about" refers to a range of values ​​that are 5% larger or smaller than a specified value. In yet another embodiment, the term "about" refers to a range of values ​​that are 1% larger or smaller than a specified value.

[1930] The terms “antibody-drug conjugate,” “antibody conjugate,” “conjugate,” “immunoconjugate,” and “ADC” are used interchangeably and refer to one or more therapeutic compounds (not BH3-mimics) linked to one or more antibody or antigen-binding fragments. In some embodiments, an ADC is defined by the general formula: Where Ab = antibody or antigen-binding fragment, L = dual-linker portion, and D = antibody or antigen-binding fragment. 1 and D 2 = Not the drug portion of a BH3-mimicry, and a = Each antibody or antigen-binding fragment has an attached D 1 and D 2 The number of dual-connector sections.

[1931] The term "antibody" in its broadest sense refers to an immunoglobulin molecule that recognizes and specifically binds to a target (such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination thereof) through at least one antigen recognition site within the variable region of an immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and can be derived from natural or recombinant sources. An "intact" antibody is typically a glycoprotein containing at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (abbreviated as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains: CH1, CH2, and CH3. Each light chain contains a light chain variable region (abbreviated as VL) and a light chain constant region. The light chain constant region contains one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Antibodies can be monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, or chimeric antibodies. These antibodies can have any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Antibodies can be intact antibodies or their antigen-binding fragments.

[1932] In some embodiments, the antibodies or antibody fragments disclosed herein comprise modified or engineered amino acid residues, such as one or more cysteine ​​residues, as sites for partial conjugation with a drug substance (Junutula JR et al.: Nat Biotechnol [Nature Biotechnology] 2008, 26: 925-932). In one embodiment, this disclosure provides modified antibodies or antibody fragments comprising a substitution of one or more amino acids with cysteine ​​at the positions described herein. The sites for cysteine ​​substitution are in constant regions of the antibody or antibody fragment and are therefore applicable to a variety of antibodies or antibody fragments, and the sites are selected to provide stable and homogeneous conjugates. Modified antibodies or fragments may have one, two, or more cysteine ​​substitutions, and these substitutions may be used in combination with other modification and conjugation methods as described herein. Methods for inserting cysteine ​​residues at specific sites on antibodies are known in the art, see, for example, Lyons et al., (1990) Protein Eng. 3:703-708, WO 2011 / 005481, WO 2014 / 124316, WO 2015 / 138615. In some embodiments, the modified antibody comprises a substitution of one or more amino acids with cysteine ​​in a constant region selected from the following positions on the heavy chain of the antibody: positions 117, 119, 121, 124, 139, 152, 153, 155, 157, 164, 169, 171, 174, 189, 191, 195, 197, 205, 207, 246, 258, 269, 274, 286, 288, 290, 292, 293, 320, 322, 326, 333, 334, 335, 337, 344, 355, 360, 375, 382, ​​390, 392, 398, 400, and 422, and wherein the positions are numbered according to the EU system. In some embodiments, the modified antibody or antibody fragment comprises substitutions of one or more amino acids with cysteine ​​at constant regions selected from positions 107, 108, 109, 114, 129, 142, 143, 145, 152, 154, 156, 159, 161, 165, 168, 169, 170, 182, 183, 197, 199, and 203 of the light chain of the antibody or antibody fragment, wherein the positions are according to EU system numbers, and wherein the light chain is a human κ light chain. In some embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two or more amino acids with cysteine ​​at constant regions of the antibody, wherein the combination comprises substitutions at position 375 of the antibody heavy chain, position 152 of the antibody heavy chain, position 360 of the antibody heavy chain, or position 107 of the antibody light chain, and wherein the positions are according to EU system numbers.In some embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​in its constant region, wherein the substitution is at position 375, position 152, position 360, position 107, position 165, or position 159 of the antibody light chain, and wherein the positions are according to EU system numbers, and wherein the light chain is a κ chain. In particular embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two amino acids with cysteine ​​in its constant region, wherein the combination comprises substitutions at positions 375 and 152 of the antibody heavy chain, wherein the positions are according to EU system numbers. In particular embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​at position 360 of the antibody heavy chain, wherein the position is according to EU system numbers. In other particular embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid with cysteine ​​at position 107 of the antibody light chain, wherein the position is according to EU system numbers, and wherein the light chain is a κ chain.

[1933] As used herein, the terms "antibody fragment," "antigen-binding fragment," or "functional antibody fragment" refer to at least a portion of an antibody that retains epitope-specific interactions with an antigen (e.g., through binding, steric hindrance, stabilization / destabilization, spatial distribution) with an antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, TROP2, B7-H3, or 5T4). Antigen-binding fragments may also retain the ability to be internalized into cells expressing the antigen. In some embodiments, antigen-binding fragments also retain immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, etc., are intended to encompass the use of binding domains from antibodies in the context of larger macromolecules such as ADCs. It has been shown that fragments of full-length antibodies can perform the antigen-binding function of full-length antibodies. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fv (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single-domain antibodies such as sdAb (VL or VH), Camelidae VHH domain, multispecific antibodies formed from antibody fragments (such as bivalent fragments containing two Fab fragments linked by disulfide bonds in the hinge region), and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single-domain antibodies, macrobodies, minibodies, nanobodies, intracellular antibodies, bispecific antibodies, trisomic antibodies, tetrasomic antibodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bi-scFv (see, for example, Holliger and Hudson (2005) Nat Biotechnol. [Nature Biotechnology] 23(9):1126-36). Antigen-binding fragments can also be grafted into scaffolds based on peptides such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, which describes fibronectin peptide microantibodies). The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment containing a light chain variable region and at least one antigen-binding fragment containing a heavy chain variable region, wherein the light chain variable region and the heavy chain variable region are sequentially linked, for example, via a synthetic linker (e.g., a short, flexible peptide linker) and are capable of being expressed as a single-chain peptide, and wherein the scFv retains the specificity of its derived intact antibody. Unless otherwise stated, the scFv may have VL and VH variable regions, for example, in any order relative to the N-terminus and C-terminus of the peptide, and the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. The antigen-binding fragments are obtained using conventional techniques known to those skilled in the art and are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies.For example, antigen-binding fragments can be prepared by cleaving intact proteins (e.g., by protease or chemical cleavage).

[1934] As used herein, the term “complementarity-determining region” or “CDR” refers to the amino acid sequence within an antibody variable region that confers antigen specificity and binding affinity. For example, typically, there are three CDRs (e.g., HCDR1, HCDR2, and HCDR3) in each heavy chain variable region and three CDRs (LCDR1, LCDR2, and LCDR3) in each light chain variable region. The precise amino acid sequence boundaries of a given CDR can be determined using any of many well-known schemes, including those described in: Kabat et al. (1991) "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al. (1997) J Mol Biol. 273(4):927-48 ("Chothia" numbering scheme); ImMunoGenTics (IMGT) numbering (Lefranc (2001) Nucleic Acids Res. 29(1):207-9; Lefranc et al. (2003) Dev Comp Immunol. [Developmental and Comparative Immunology] 27(1):55-77 (“IMGT” numbering scheme); or combinations thereof. In combinations of Kabat and Chothia numbering schemes for a given CDR region (e.g., HC CDR1, HC CDR2, HCCDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, these CDRs correspond to amino acid residues defined as part of a Kabat CDR and amino acid residues defined as part of a Chothia CDR. As used herein, CDRs defined according to the “Chothia” numbering scheme are sometimes also referred to as “hypervariant rings”.

[1935] In some embodiments, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1) (e.g., one or more insertions after position 35), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1) (e.g., one or more insertions after position 27), 50-56 (LCDR2), and 89-97 (LCDR3). In some embodiments, according to Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1) (e.g., one or more insertions after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in the VL are numbered 26-32 (LCDR1) (e.g., one or more insertions after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of Kabat and Chothia, in some embodiments, the CDR comprises, for example, amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL, or is composed of thereof. In some embodiments, according to IMGT, the CDR amino acid residues in VH are numbered approximately 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered approximately 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, according to IMGT, the CDR region of the antibody can be determined using the procedure IMGT / DomainGap Align.

[1936] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, meaning that the individual antibodies comprising that population are identical except for the possibility of naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific for a single antigenic epitope. In contrast, conventional (polyclonal) antibody formulations typically comprise multiple antibodies targeting different epitopes (or specific to different epitopes). The modifier "monoclonal" indicates that the antibody's properties are obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the antibody to be produced by any specific method. For example, monoclonal antibodies used according to this disclosure can be prepared by a hybridoma method first described by Kohler et al. (1975) Nature 256:495, or by a recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). For example, monoclonal antibodies can also be isolated from phage antibody libraries using techniques described in Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J Mol Biol. 222:581-97. The term also includes formulations of antibody molecules having a single molecular composition. Monoclonal antibody compositions exhibit single binding specificity and affinity for a specific epitope.

[1937] The monoclonal antibodies described herein can be non-human, human, or humanized. Specifically, the term includes "chimeric" antibodies, wherein a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided they specifically bind to the target antigen and / or exhibit the desired biological activity.

[1938] As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having an amino acid sequence of a human-produced antibody. This term includes antibodies with variable regions, wherein both the frame region and the CDR region are derived from human-derived sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from such human sequences, such as human germline sequences, or mutant forms of human germline sequences, or antibodies containing a common frame sequence derived from human frame sequence analysis, for example, as described by Knappik et al. ((2000) J Mol Biol. [Journal of Molecular Biology] 296(1):57-86). The structure and location of immunoglobulin variable domains (e.g., CDRs) can be defined using well-known numbering schemes (e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia and / or ImMunoGenTics (IMGT) numbering). The human antibodies of this invention may include amino acid residues not encoded by human sequences (e.g., introduced by random or site-specific mutagenesis in vitro, or by somatic mutations or conserved substitutions in vivo to promote stability or production). However, as used herein, the term “human antibody” is not intended to include antibodies in which the CDR sequence of a lineage derived from another mammal species (such as a mouse) has been transplanted onto a human scaffold region sequence.

[1939] As used herein, the term "recombinant human antibody" refers to human antibodies prepared, expressed, generated, or isolated in a recombinant manner, such as antibodies isolated from animals (e.g., mice) (which are transgenic or transchromosomally modified for human immunoglobulins) or hybridomas prepared therefrom; antibodies isolated from host cells transformed to express human antibodies (e.g., from transfected tumors); antibodies isolated from recombinant, combined human antibody libraries; and antibodies prepared, expressed, generated, or isolated by any other means (involving the splicing of all or part of the human immunoglobulin gene or sequence into other DNA sequences). Such recombinant human antibodies have variable regions, wherein the framework region and CDR region are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be mutagenized in vitro (or, when using animals with transgenic human Ig sequences, in vivo somatic cell mutagenesis), and thus the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and associated with human germline VH and VL sequences that may not be naturally present in human antibody germline libraries in vivo.

[1940] As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequence of an immunoglobulin molecule is derived from two or more species. In some cases, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species with the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., humans) to minimize the immune response in the latter species.

[1941] As used herein, the term "humanized antibody" refers to an antibody form containing sequences derived from non-human (e.g., mouse) antibodies as well as human antibodies. Such antibodies are chimeric antibodies containing minimal sequences derived from non-human immunoglobulins. Typically, humanized antibodies will contain substantially all of the following: at least one (typically two) variable domains, wherein all or substantially all hypervariable loops correspond to those hypervariable loops of non-human immunoglobulins, and all or substantially all frame (FR) regions are those FR regions of human immunoglobulin sequences. Humanized antibodies may optionally also contain immunoglobulin constant regions (Fc), typically at least a portion of human immunoglobulin constant regions. Humanized antibodies can be further modified by residue substitution within the Fv frame regions and / or substituted non-human residues to improve and optimize antibody specificity, affinity, and / or activity.

[1942] As used herein, the term "Fc region" refers to a polypeptide that includes at least a portion of the CH3, CH2, and hinge regions of the constant structural domains of an antibody. Optionally, the Fc region may include the CH4 domain present in some antibody species. The Fc region may include the entire hinge region of the constant structural domains of the antibody. In some embodiments, an antibody or antigen-binding fragment includes the Fc region and CH1 region of the antibody. In some embodiments, an antibody or antigen-binding fragment includes the CH3 region of the Fc region of the antibody. In some embodiments, an antibody or antigen-binding fragment includes the Fc region, CH1 region, and κ / λ region from the constant structural domains of the antibody. In some embodiments, an antibody or antigen-binding fragment includes a constant region, such as a heavy chain constant region and / or a light chain constant region. In some embodiments, such a constant region is modified compared to a wild-type constant region. That is, the polypeptide may include alterations or modifications to one or more of the three heavy chain constant structural domains (CH1, CH2, or CH3) and / or to the light chain constant region (CL) domain. Exemplary modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains. Such modifications may be included to optimize effector function, half-life, etc.

[1943] As used herein, “internalization” of an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that, upon binding to a cell, can be taken up across the cell’s lipid bilayer membrane into an internal compartment (i.e., “internalized”), preferably into a degradation compartment within the cell. For example, an internalized anti-HER2 antibody is an antibody that can be taken up into the cell upon binding to HER2 on the cell membrane. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, TROP2, B7-H3, or 5T4) and is an internalized antibody or internalized antigen-binding fragment (i.e., the ADC is transferred across the cell membrane after antigen binding). In some embodiments, the internalized antibody or antigen-binding fragment binds to a receptor on the cell surface. Internalized antibodies or internalized antigen-binding fragments targeting receptors on the cell membrane can induce receptor-mediated endocytosis. In some embodiments, the internalized antibody or internalized antigen-binding fragment is taken up into the cell via receptor-mediated endocytosis.

[1944] As used herein, “non-internalized” in relation to an antibody or antigen-binding fragment means an antibody or antigen-binding fragment that remains on the cell surface after binding to a cell. In some embodiments, the antibody or antigen-binding fragment used in the ADCs disclosed herein targets a cell surface antigen and is a non-internalized antibody or non-internalized antigen-binding fragment (i.e., the ADC remains on the cell surface and does not migrate across the cell membrane after antigen binding). In some embodiments, the non-internalized antibody or antigen-binding fragment binds to a non-internalized receptor or other cell surface antigen. Exemplary non-internalized cell surface antigens include, but are not limited to, CA125 and CEA, and antibodies that bind to non-internalized antigen targets are also known in the art (see, for example, Bast et al. (1981) J Clin Invest. [Journal of Clinical Research] 68(5):1331-7; Scholler and Urban (2007) Biomark Med. [Medical Biomarkers] 1(4):513-23; and Boudousq et al. (2013) PLoS One [PLOS ONE] 8(7):e69613).

[1945] As used herein, the term “EPH receptor A2” or “EphA2” refers to any natural form of human EphA2 (also known as liver glycoprotein A receptor 2). The term encompasses full-length human EphA2 (e.g., NCBI reference sequence: NP_004422.2; SEQ ID NO: 337) and any form of human EphA2 that can be produced by cellular processing. The term also encompasses functional variants or fragments of human EphA2, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human EphA2 (i.e., encompassing variants and fragments unless the context indicates that the term is used only to refer to the wild-type protein). EphA2 can be isolated from humans or can be produced recombinantly or synthetically.

[1946] As used herein, the term "anti-EphA2 antibody" or "antibody binding to EphA2" refers to any form of antibody or antigen-binding fragment thereof that binds to (e.g., specifically binds to) EphA2. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, provided they bind to (e.g., specifically bind to) EphA2. WO 2007 / 030642 provides exemplary EphA2 binding sequences, including exemplary anti-EphA2 antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-EphA2 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. 1C1 (WO 2007 / 030642) is an exemplary anti-EphA2 antibody.

[1947] As used herein, the term “P-cadherin” or “PCAD” refers to any naturally occurring form of human PCAD (also known as cadherin type 1 3 or CDH3). The term encompasses full-length human PCAD (e.g., UniProt reference sequence: P22223; SEQ ID NO: 74) and any form of human PCAD that can be produced by cellular processing. The term also encompasses functional variants or fragments of human PCAD, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human PCAD (i.e., encompassing variants and fragments unless the context indicates that the term is used only to refer to wild-type proteins). PCAD can be isolated from humans or can be produced recombinantly or synthetically.

[1948] As used herein, the term "anti-PCAD antibody" or "antibody that binds to PCAD" refers to any form of antibody or antigen-binding fragment thereof that binds to (e.g., specifically binds to) PCAD. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, as long as they bind to (e.g., specifically bind to) PCAD. WO 2016 / 203432 provides exemplary PCAD binding sequences, including exemplary anti-PCAD antibody sequences, and is incorporated herein by reference. In some embodiments, the anti-PCAD antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. NOV169N31Q (WO 2016 / 203432) is an exemplary anti-PCAD antibody.

[1949] As used herein, the terms “human epidermal growth factor receptor 2,” “HER2,” or “HER2 / NEU” refer to any natural form of human HER2. The term encompasses full-length human HER2 (e.g., UniProt reference sequence: P04626; SEQ ID NO: 75) and any form of human HER2 that can be produced by cellular processing. The term also encompasses functional variants or fragments of human HER2, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human HER2 (i.e., encompassing variants and fragments unless the context indicates that the term is used only to refer to the wild-type protein). HER2 can be isolated from humans or can be produced recombinantly or synthetically.

[1950] As used herein, the term “anti-HER2 antibody” or “HER2-binding antibody” refers to any form of antibody or antigen-binding fragment thereof that binds (e.g., specifically binds) HER2. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, provided that they bind (e.g., specifically bind) HER2. U.S. Patent Nos. 5,821,337 and 6,870,034 provide exemplary HER2-binding sequences, including exemplary anti-HER2 antibody sequences, and are incorporated herein by reference. In some embodiments, the anti-HER2 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. Trastuzumab (U.S. Patent Nos. 5,821,337 and 6,870,034; see also Molina et al. (2001) Cancer Res. 61(12):4744-9) is an exemplary anti-HER2 antibody.

[1951] As used herein, the terms “differentiation cluster 48” or “CD48” refer to any natural form of human CD48 (also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocyte activation molecule 2 (SLAMF2)). The term encompasses full-length human CD48 (e.g., UniProt reference sequence: P09326; SEQ ID NO: 77) and any form of human CD48 that can be produced by cellular processing. The term also encompasses functional variants or fragments of human CD48, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD48 (i.e., encompassing variants and fragments unless the context indicates that the term is used only to refer to the wild-type protein). CD48 can be isolated from humans or can be produced recombinantly or synthetically.

[1952] As used herein, the term "anti-CD48 antibody" or "CD48-binding antibody" refers to any form of antibody or antigen-binding fragment thereof that binds (e.g., specifically binds) CD48. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, provided they bind (e.g., specifically bind) CD48. International patent applications PCT / IB2021 / 060871, PCT / US2021 / 060560, and PCT / US2021 / 060620 provide exemplary CD48 binding sequences, including exemplary anti-CD48 antibody sequences, and are incorporated herein by reference. In some embodiments, the anti-CD48 antibody used in the ADCs disclosed herein is an internalizing antibody or an internalizing antigen-binding fragment. SGN-CD48A (MEM / MEM102) and NY920 are exemplary anti-CD48 antibodies.

[1953] As used herein, the terms “differentiation cluster 74” or “CD74” refer to any naturally occurring form of human CD74 (also known as the HLA class II histocompatibility antigen γ chain or the HLA-DR antigen-associated invariant chain). The term encompasses full-length human CD74 (e.g., NCBI reference sequence: NP_001020330.1; SEQ ID NO: 140) and any form of human CD74 that can be produced by cellular processing. The term also encompasses functional variants or fragments of human CD74, including but not limited to splice variants, allelic variants, and isoforms that retain one or more biological functions of human CD74 (i.e., encompassing variants and fragments unless the context indicates that the term is used only to refer to the wild-type protein). CD74 can be isolated from humans or can be produced recombinantly or synthetically.

[1954] As used herein, the term "anti-CD74 antibody" or "CD74-binding antibody" refers to any form of antibody or antigen-binding fragment thereof that binds (e.g., specifically binds) CD74. This term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments, provide...

Claims

1. A compound of formula (A-1), or a pharmaceutically acceptable salt thereof: in: R 1 is an attachment group; L 1 is a bridging spacer; W is a branching moiety; L 2 ' and L 3 ' are each independently a linker; and D 1 and D 2 are each independently a pharmaceutically active drug, optionally with the proviso that D 1 and D 2 Neither is a BH3 mimetic.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 ' and L 3 Each of ' comprises a cleavable group, optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a peptide group and / or a self-immolative group (eg, a peptide group and a self-immolative group).

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein L 2 ' and L 3 Each of ' comprises a peptide group and a self-immolative group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L 2 ' and L 3 Each of ' comprises a cleavable group, optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (eg, glucuronamide) group, a peptide group, and / or a self-immolative group (eg, a peptide group and a self-immolative group).

5. The compound according to claim 1, claim 2 or claim 3, or a pharmaceutically acceptable salt thereof, which has formula (B-1): in: R 1 is an attachment group; L 1 is a bridging spacer; W is N or CR w , where R w is H or C1-C6 alkyl (e.g. R w is H); L 2 and L 3 each independently a linker spacer; E 1 and E 2 each independently a peptide group comprising 1 to 6 amino acids, wherein the peptide group is optionally substituted with a hydrophilic moiety; V 1 and V 2 Each independently comprises i) a self-immolative group, ii) an enzymatic cleavage element (e.g. 1 and V 2 each independently a self-immolative group) or iii) a self-immolative group and an enzymatic cleavage element; and D 1 and D 2 are each independently a pharmaceutically active drug, optionally with the proviso that D 1 and D 2 None are BH3 mimetics; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein V 1 and V 2 Each is independently i) a self-immolative group, or ii) an enzymatic cleavage element (e.g., V 1 and V 2 are each independently a self-immolative group).

7. The compound according to claim 5 or claim 6, or a pharmaceutically acceptable salt thereof, wherein W is N or CH.

8. The compound according to any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof, wherein E 1 and E 2 Each is an enzymatic cleavage element.

9. The compound according to any one of claims 5 to 8, or a pharmaceutically acceptable salt thereof, wherein V 1 and V 2 Each is independently a self-immolative group.

10. The compound of any one of claims 5 to 9, or a pharmaceutically acceptable salt thereof, wherein (i) the cleavable linker comprises a phosphate group, a pyrophosphate group and / or a self-immolative group; (ii) the cleavable linker comprises a self-immolative group; or (iii) the cleavable linker comprises a self-immolative group, the self-immolative group comprising -O-CH2-, -NH-CH2-, -OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or (iv) V 1 and / or V 2 Each independently comprises a group containing p-aminobenzyl-phosphate or p-aminobenzyl-pyrophosphate.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein (i) the cleavable linker comprises a phosphate group, a pyrophosphate group and / or a self-immolative group; (ii) the cleavable linker comprises a self-immolative group; or (iii) the cleavable linker comprises a self-immolative group, the self-immolative group comprising -O-CH2-, -NH-CH2-, -OC(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

12. The compound according to any one of claims 5 to 11 or a pharmaceutically acceptable salt thereof, which has the formula (C-1): in: R 1 is an attachment group; L 1 is a bridging spacer; W is N or CR w , where R w is H or C1-C6 alkyl (e.g. R w is H); L 2 and L 3 each independently a linker spacer; E 1 and E 2 each independently a peptide group comprising 1 to 6 amino acids, wherein the peptide group is optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 or A 2 * indicates that the 1 or D 2 attachment points; D 1 and D 2 are each independently a pharmaceutically active drug, optionally with the proviso that D 1 and D 2 None are BH3 mimetics; L 4 and L 5 each independently a spacer moiety; R 2 and R 3 Each is independently a hydrophilic group or an enzymatic cleavage element (e.g., R 2 and R 3 each a hydrophilic group); and m and n are each independently 0 or 1; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein W is N or CH.

14. The compound according to claim 12 or claim 13, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each is a hydrophilic group.

15. The compound according to any one of claims 12 to 14, or a pharmaceutically acceptable salt thereof, having formula (D1-1), (D2-1) or (D3-1): or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein for formula (D1-1), R 2 and R 3 are each independently a hydrophilic group, wherein for formula (D2-1), R 2 and R 3 are each independently an enzyme cleavage element; and for formula (D3-1), R 2 is a hydrophilic group and R 3 is an enzymatic cleavage element; or a pharmaceutically acceptable salt thereof.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: -ONH2, -NH2, -N3, -SH, -SR 11 、-SSR 12 , -S(=O)2(CH=CH2), -(CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NR 11 C(=O)CH2Br, such as -NHC(=O)CH2Br, -NR 11 C(=O)CH2I, for example -NHC(=O)CH2I, -C(O)NHNH2, in: Each R 11 Independently selected from H and C1-C6 alkyl; Each R 12 is 2-pyridyl or 4-pyridyl; Each R 13 Independently selected from H, C1-C6 alkyl, F, Cl and -OH; Each R 14 is independently selected from H, C1-C6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2, and -OH; and Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1- C4 alkoxy and C substituted by -C(=O)OH 1- C4 alkyl.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: -ONH2, NHC(=O)CH2Br and -NHC(=O)CH2I.

19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of: -ONH2、 20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 yes 21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: (1)L 1 Include: or *-CH(OH)CH(OH)CH(OH)CH(OH)-**, wherein each n is an integer from 1 to 12, wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; (2)L 1 yes and n is an integer from 1 to 12 or n is 1 or n is 12, wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; (3)L 1 yes and n is an integer from 1 to 12, wherein L 1 The * of L1 indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a direct or indirect (e.g., direct) attachment point to R 1 direct or indirect (e.g. direct) point of attachment; (4)L 1 Include Among them L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 a direct or indirect (e.g. direct) point of attachment; or (5)L 1 is a bridging spacer comprising: *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; X1 is and Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and each t is independently selected from 1, 2, 3, 4, 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, and 30; and Each R L1 Independently selected from H and C1-C6 alkyl.

22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 1 Contains the sections represented by: wherein n is an integer from 1 to 12 (e.g., 4 to 8, such as 4 or 8), wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect attachment point. 23 . The compound according to claim 22 , or a pharmaceutically acceptable salt thereof, wherein n is an integer from 4 to 8.

24. The compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein n is 4 or 8.

25. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 1 It is expressed by the following formula: in n is an integer from 1 to 12 (e.g., 4 to 8, such as 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, e.g., 0 to 2, e.g., 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, e.g., 0 to 2, e.g., 0 or 2); u is 0 or 1; and Among them L 1 The * indicates the direct attachment point with W, and L 1 ** indicates that the 1 Direct attachment point. The compound according to claim 25 , or a pharmaceutically acceptable salt thereof, wherein n is an integer from 4 to 8.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein n is 4 or 8.

28. The compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof, wherein x is an integer from 0 to 2.

29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein x is 0 or 2. 30 . The compound according to claim 25 , or a pharmaceutically acceptable salt thereof, wherein z is an integer from 0 to 2.

31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein z is 0 or 2.

32. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from the group consisting of:

33. A compound according to any one of claims 5 to 32, or a pharmaceutically acceptable salt thereof, wherein L 2 and L 3 are each independently a linker spacer comprising a moiety represented by: in k is an integer from 0 to 6; r is 0 or 1; o is an integer from 0 to 12; p is an integer from 0 to 6; and Among them L 2 or L 3 The # represents the E 1 or E 2 direct or indirect attachment point, and L 2 or L 3 The ## indicates a direct or indirect attachment point to W.

34. A compound according to any one of claims 5 to 33, or a pharmaceutically acceptable salt thereof, wherein L 2 and L 3 are each independently a linker spacer selected from the group consisting of: as well as in k is independently an integer from 0 to 4 at each occurrence; r is independently 0 or 1 at each occurrence; o is independently an integer from 0 to 10 at each occurrence; p is independently an integer from 0 to 4 at each occurrence; R L23 is hydrogen or C 1- C6 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, and L 2 or L 3 The ## indicates the direct attachment point to W; The condition is that when W is N, L 2 and L 3 Not (L2c), (L2d), (L2f), or (L2k).

35. The compound according to claim 34 or a pharmaceutically acceptable salt thereof, wherein L 2 and L 3 are each independently a linker spacer selected from the group consisting of: as well as in k is independently an integer from 1 to 3 at each occurrence; o is independently an integer from 1 to 9 at each occurrence; p is independently an integer from 1 to 3 at each occurrence; R L23 is hydrogen or C 1- C3 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, and L 2 or L 3 The ## indicates the direct attachment point to W; the condition is that when W is N, L 2 and L 3 Not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

36. A compound according to any one of claims 5 to 35, or a pharmaceutically acceptable salt thereof, wherein L 2 and L 3 are independently a linking spacer selected from the group consisting of: Among them L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, L 2 or L 3 The ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H ;and R H yes And d is an integer from 20 to 30 (eg, 25).

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein d is 25.

38. A compound according to any one of claims 12 to 37, or a pharmaceutically acceptable salt thereof, wherein each peptide group independently comprises 1 to 4, 1 to 3 or 1 to 2 amino acid residues.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein each peptide group independently comprises 2 amino acid residues.

40. The compound of claim 38 or claim 39, or a pharmaceutically acceptable salt thereof, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

41. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 38 and 40, wherein each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly and Sulfo-Ala-Val-Ala.

42. A compound or pharmaceutically acceptable salt according to any one of claims 5 to 39, wherein E 1 and / or E 2 Each is independently a peptide group selected from the group consisting of: Wherein ^ of E1-1 or E1-2 represents V in formula (B) 1 or V 2 The direct attachment point of or the direct attachment point of -NH- group in formula (C) and (D); and ^^ of E1-1 or E1-2 respectively represents the direct attachment point of L 2 or L 3 Direct attachment point (e.g., where E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2)).

43. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, wherein E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

44. A compound according to any one of claims 5 to 39, or a pharmaceutically acceptable salt thereof, wherein E 1 and / or E 2 Each is independently a peptide group represented by: where R E is a hydrophilic group R H .

45. The compound according to claim 44 or a pharmaceutically acceptable salt thereof, wherein the hydrophilic group R in (E1-3) H yes Wherein e is an integer between 20 and 30 (eg, 25).

46. ​​The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein e is 25.

47. The compound or pharmaceutically acceptable salt of claim 42, wherein E 1 and E 2 Each is 48. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 47, wherein A 1 and A 2 independently selected from a bond and -OC(=O)-*, wherein * represents 1 or D 2 attachment point.

49. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 48, wherein A 1 and A 2 are independently selected from a bond, and -OC(=O)-*, where * represents the 1 or D 2 attachment point.

50. The compound or pharmaceutically acceptable salt of claim 48, wherein A 1 and A 2 Each is a key.

51. The compound or pharmaceutically acceptable salt of claim 48, wherein A 1 and A 2 All are -OC(=O)-*.

52. The compound or pharmaceutically acceptable salt of claim 48, wherein A 1 and A 2 One of them is OC(=O)-*, and A 1 and A 2 The other one is the key.

53. The compound or pharmaceutically acceptable salt of claim 49, wherein A 1 and A 2 independently a key or * indicates the same as D 1 or D 2 attachment point.

54. The compound or pharmaceutically acceptable salt of claim 53, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

55. The compound or pharmaceutically acceptable salt of claim 53, wherein A 1 and A 2 All 56. The compound or pharmaceutically acceptable salt of claim 49, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

57. The compound or pharmaceutically acceptable salt of claim 49, wherein A 1 and A 2 All are OC(=O)-*; (ii)A 1 and A 2 yes (iii)A 1 is OC(=O)-* and A 2 Yes Key (iv)A 1 is OC(=O)-* and A 2 yes (v)A 1 is a key and A 2 yes or (vi)A 1 is a key and A 2 is OC(=O)-*, * indicates the same as D 1 or D 2 attachment point.

58. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 57, wherein: i)L 4 and L 5 Each independently is a spacer moiety having the structure in: Z is -O-, -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-, -NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 is independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is a bond, triazolyl or -CH2-triazolyl-, Where X is connected to R 2 or R 3 ;or (ii)L 4 and L 5 is independently a spacer moiety having the structure in: Z is -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 is independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -, -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -, wherein each n is independently 1, 2 or 3, Where X is connected to R 2 or R 3 .

59. The compound or pharmaceutically acceptable salt of claim 58, wherein Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazolyl or -CH2-triazolyl-; and R L45 is independently H or C at each occurrence 1- C3 alkyl.

60. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 59, wherein L 4 and L 5 are each independently a spacer moiety selected from the group consisting of: Among them L 4 or L 5 The @ indicates the direct attachment point to the phenyl group, and L 4 or L 5 @@ indicates the same as R 2 or R 3 Direct attachment point.

61. A compound according to any one of claims 12 to 60, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 The hydrophilic groups represented by each independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, substituted C2-C6 alkyl, or substituted by 1 to 2 independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C4 alkylene -P(O)(OCH2CH3)2 and C2-C6 alkyl substituted with substituents of the -COOH group.

62. A compound according to any one of claims 12 to 60, or a pharmaceutically acceptable salt thereof, wherein R 2 or / and R 3 Each independently selected from the group consisting of: Where n is an integer between 1 and 6; 63. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 60, wherein R 2 or / and R 3 Independently contains: (i) Polysarcosine having the following moieties: in f is an integer between 3 and 25; and R 23 is H, -CH3 or -CH2CH2C(=O)OH; (ii) polyethylene glycol having the formula: in g and h are independently integers between 2 and 30; or (iii) By The part that is indicated.

64. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 60, wherein R 2 or R 3 The hydrophilic groups represented by each independently comprise: (i) Polysarcosine having the following moieties: wherein f is an integer between 3 and 25; and R 23 is H, -CH3 or -CH2CH2C(=O)OH; or (ii) polyethylene glycol having the formula: wherein g and h are independently integers between 2 and 30; or (iii) By The part that is indicated.

65. A compound or pharmaceutically acceptable salt according to any one of claims 12 to 60, wherein R 2 or / and R 3 Independently choose freedom a group consisting of g and h are independently integers between 20 and 30 (eg, 23 or 24).

66. The compound according to claim 65 or a pharmaceutically acceptable salt thereof, wherein R 2 or / and R 3 Include:

67. The compound according to claim 65 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each independently comprises a polyethylene glycol having the formula: wherein g and h are independently integers between 2 and 30.

68. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein D 1 and D 2 are the same.

69. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 67, wherein D 1 and D 2 are different.

70. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein D 1 and D 2 Each is independently selected from cytotoxic drugs, cytostatic drugs and immunosuppressive drugs.

71. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each independently selected from auristatin, camptothecin, duocarmycin, etoposide, maytansine, maytansine-like, taxane, benzodiazepine Benzodiazepines drugs (eg, pyrrolo[1,4]-benzodiazepines PBD, indolebenzodiazepine Oxazolidinone and benzodiazepine class) and vinca alkaloids.

72. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each independently selected from the group consisting of: (For example ) (For example ), * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

73. The compound or pharmaceutically acceptable salt of claim 72, in: i)D 1 yes And D 2 yes ii)D 1 yes And D 2 yes iii)D 1 yes And D 2 yes iv)D 1 yes And D 2 yes v)D 1 yes And D 2 yes vi)D 1 yes And D 2 yes vii)D 1 yes And D 2 yes viii)D 1 yes And D 2 yes ix)D 1 yes And D 2 yes x)D 1 yes And D 2 yes xi)D 1 yes And D 2 yes xii)D 1 yes And D 2 yes xiii)D 1 yes And D 2 yes xiv)D 1 yes And D 2 yes xv)D 1 yes And D 2 yes xvi)D 1 yes And D 2 yes xvii)D 1 yes And D 2 yes xviii)D 1 yes And D 2 yes xix)D 1 yes And D 2 yes xx)D 1 yes And D 2 yes xxi)D 1 yes And D 2 yes xxii)D 1 yes And D 2 yes xxiii)D 1 yes And D 2 yes xxiv)D 1 yes And D 2 yes xxv)D 1 yes And D 2 yes xxvi)D 1 yes And D 2 yes xxvii)D 1 yes And D 2 yes xxviii)D 1 yes And D 2 yes xxix)D 1 yes And D 2 yes xxx)D 1 yes And D 2 yes xxxi)D 1 yes And D 2 yes xxxii)D 1 yes And D 2 yes xxxiii)D 1 yes And D 2 yes xxxiv)D 1 yes And D 2 yes xxxv)D 1 yes And D 2 yes xxxvi)D 1 yes And D 2 yes xxxvii)D 1 yes And D 2 yes xxxviii)D 1 yes And D 2 yes xxxix)D 1 yes And D 2 yes xl)D 1 yes And D 2 yes xli)D 1 yes And D 2 yes xlii)D 1 yes And D2 is xliii)D 1 yes And D 2 yes xliv)D 1 yes And D 2 yes vl)D 1 yes And D 2 yes xlvi)D 1 yes And D 2 yes xlvii)D 1 yes And D 2 yes xlviii)D 1 yes And D 2 yes il)D 1 yes And D 2 yes l)D 1 yes And D 2 yes li)D 1 yes And D 2 yes lii)D 1 yes And D 2 yes liii)D 1 yes And D 2 yes liv)D 1 yes And D 2 yes lv)D 1 yes And D 2 yes lvi)D 1 yes And D 2 yes lvii)D 1 yes And D 2 yes lviii)D 1 yes And D 2 yes lix)D 1 yes And D 2 yes lx)D 1 yes And D 2 yes lxi)D 1 yes And D 2 yes lxii)D 1 yes And D 2 yes lxiii)D 1 yes And D 2 yes lxiv)D 1 yes And D 2 yes where * indicates the point of attachment to the rest of the molecule.

74. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein: i)A 1 -D 1 yes And A 2- D 2 yes ii)A 1 -D 1 yes And A 2 -D 2 yes iii)A 1 -D 1 yes And A 2 -D 2 yes iv)A 1 -D 1 yes And A 2 -D 2 yes v)A 1 -D 1 yes And A 2 -D 2 yes vi)A 1 -D 1 yes And A 2 -D 2 yes vii)A 1 -D 1 yes And A 2 -D 2 yes viii)A 1 -D 1 yes And A 2 -D 2 yes ix)A 1 -D 1 yes And A 2 -D 2 yes x)A 1 -D 1 yes And A 2 -D 2 yes xi)A 1 -D 1 yes And A 2 -D 2 yes xii)A 1 -D 1 yes And A 2 -D 2 yes xiii)A 1 -D 1 yes And A 2 -D 2 yes xiv)A 1 -D 1 yes And A 2 -D 2 yes xv)A 1 -D 1 yes And A 2 -D 2 yes xvi)A 1 -D 1 yes And A 2 -D 2 yes xvii)A 1 -D 1 yes And A 2 -D 2 yes xviii)A 1 -D 1 yes And A 2 -D 2 yes xix)A 1 -D 1 yes And A 2 -D 2 yes xx)A 1 -D 1 yes And A 2 -D 2 yes xxi)A 1 -D 1 yes And A 2 -D 2 yes xxii)A 1 -D 1 yes And A 2 -D 2 yes xxiii)A 1 -D 1 yes And A 2 -D 2 yes xxiv)A 1 -D 1 yes And A 2 -D 2 yes xxv)A 1 -D 1 yes And A 2 -D 2 yes xxvi)A 1 -D 1 yes And A 2 -D 2 yes xxvii)A 1 -D 1 yes And A 2 -D 2 yes xxviii)A 1 -D 1 yes And A 2 -D 2 yes xxix)A 1 -D 1 yes And A 2 -D 2 yes xxx)A 1 -D 1 yes And A 2 -D 2 yes xxxi)A 1 -D 1 yes And A 2 -D 2 yes xxxii)A 1 -D 1 yes And A 2 -D 2 yes xxxiii)A 1 -D 1 yes And A 2 -D 2 yes xxxiv)A 1 -D 1 yes And A 2 -D 2 yes xxxv)A 1 -D 1 yes And A 2 -D 2 yes xxxvi)A 1 -D 1 yes And A 2 -D 2 yes xxxvii)A 1 -D 1 yes And A 2 -D 2 yes xxxviii)A 1 -D 1 yes And A 2 -D 2 yes xxxix)A 1 -D 1 yes And A 2 -D 2 yes xl)A 1 -D 1 yes And A 2 -D 2 yes xli)A 1 -D 1 yes And A 2 -D 2 yes xlii)A 1 -D 1 yes And A 2 -D 2 yes xliii)A 1 -D 1 yes And A 2 -D 2 yes xliv)A 1 -D 1 yes And A 2 -D 2 yes xlv)A 1 -D 1 yes And A 2 -D 2 yes xlvi)A 1 -D 1 yes And A 2 -D 2 yes xlvii)A 1 -D 1 yes And A 2 -D 2 yes xlviii)A 1 -D 1 yes And A 2 -D 2 yes xlix)A 1 -D 1 yes And A 2 -D 2 yes l) A1-D1 is And A2-D2 is li)A 1 -D 1 yes And A 2 -D 2 yes lii)A 1 -D 1 yes And A 2 -D 2 yes liii)A 1 -D 1 yes And A 2 -D 2 yes liv)A 1 -D 1 yes And A 2 -D 2 yes lv)A 1 -D 1 yes And A 2 -D 2 yes lvi)A 1 -D 1 yes And A 2 -D 2 yes lvii)A 1 -D 1 yes And A 2 -D 2 yes lviii)A 1 -D 1 yes And A 2 -D 2 yes lix)A 1 -D 1 yes And A 2 -D 2 yes lx)A 1 -D 1 yes And A 2 -D 2 yes lxi)A 1 -D 1 yes And A 2 -D 2 yes lxii)A 1 -D 1 yes And A 2 -D 2 yes lxiii)A 1 -D 1 yes And A 2 -D 2 yes or lxiv)A 1 -D 1 yes And A 2 -D 2 yes where * indicates the point of attachment to the rest of the molecule.

75. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and / or D 2 It's Auristatin.

76. The compound or pharmaceutically acceptable salt of claim 75, wherein D 1 and D 2 They are all auristatins.

77. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

78. The compound or pharmaceutically acceptable salt of claim 77, wherein D 1 and D 2 Both are topoisomerase 1 inhibitors.

79. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 It is auristatin, and D 1 and D 2 Another of the agents is a topoisomerase 1 inhibitor.

80. The compound or pharmaceutically acceptable salt of claim 79, wherein D 1 It is Auristatin and D 2 It is a topoisomerase 1 inhibitor.

81. The compound or pharmaceutically acceptable salt of claim 79, wherein D 1 is a topoisomerase 1 inhibitor and D 2 It's Auristatin.

82. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein D 1 and D 2 Independently selected from the group consisting of: * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

83. The compound or pharmaceutically acceptable salt of claim 82, wherein D 1 and D 2 Independently selected from the group consisting of:

84. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69 or 72, wherein D 1 and D 2 Independently selected from the group consisting of: (For example )and (For example ), * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

85. The compound or pharmaceutically acceptable salt of claim 72, wherein D 1 and D 2 Independently selected from the group consisting of: * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

86. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each is independently selected from antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemosensitizers, topoisomerase inhibitors and / or vinca alkaloids.

87. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, auristatins, dolastatins, maytansines, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinesin inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalators, DNA minor groove binders, RNA polymerase inhibitors, amanitin, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors or pro-apoptotic agents, optionally with the proviso that D 1 and D 2 Neither is a BH3 mimetic.

88. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each is independently selected from a topoisomerase 1 inhibitor or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or a pharmaceutically acceptable acid or base addition salt thereof.

89. The compound or pharmaceutically acceptable salt of claim 88, wherein the topoisomerase 1 inhibitor is topotecan, exitecan, delutecan, or SN-38.

90. The compound or pharmaceutically acceptable salt of claim 88, wherein D 1 and D 2 Independently selected from the group consisting of: where * indicates the point of attachment to the rest of the molecule.

91. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 69, wherein D 1 and D 2 Each is independently selected from antimitotic drugs or enantiomers, diastereomers, atropisomers, deuterated derivatives and / or addition salts with pharmaceutically acceptable acids or bases.

92. The compound or pharmaceutically acceptable salt of claim 91, wherein the antimitotic drug is monomethyl auristatin E (MMAE) or a taxane.

93. The compound or pharmaceutically acceptable salt of claim 92, wherein the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

94. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: as well as 95. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

96. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: ， or a pharmaceutically acceptable salt thereof.

97. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

98. The compound of claim 97 or a pharmaceutically acceptable salt thereof, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

99. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, selected from: ， or a pharmaceutically acceptable salt thereof.

100. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, selected from: or a pharmaceutically acceptable salt thereof.

101. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, selected from: or a pharmaceutically acceptable salt thereof.

102. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, selected from: or a pharmaceutically acceptable salt thereof.

103. A conjugate comprising an antibody or antigen-binding fragment thereof covalently linked to two pharmaceutically active drugs via a double linker, and wherein the double linker has one point of attachment to the antibody and two points of attachment to the two pharmaceutically active drugs, with the proviso that neither pharmaceutically active drug is a BH3 mimetic.

104. The conjugate of claim 103, wherein the two pharmaceutically active drugs are the same or different.

105. The conjugate of claim 103 or claim 104, wherein the pharmaceutically active drug is selected from a cytotoxic drug, a cytostatic drug, and an immunosuppressive drug.

106. The conjugate of any one of claims 103 to 105, wherein the pharmaceutically active drug is selected from auristatin, camptothecin, duocarmycin, etoposide, maytansine, maytansine-like, taxane, benzodiazepine Benzodiazepines drugs (eg, pyrrolo[1,4]-benzodiazepines PBD, indolebenzodiazepine Oxazolidinone and benzodiazepine class) and vinca alkaloids.

107. The conjugate of claim 106, wherein the pharmaceutically active drug is auristatin.

108. The conjugate of claim 103 or claim 104, wherein the pharmaceutically active drug is selected from anti-tubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemosensitizers, topoisomerase inhibitors and / or vinca alkaloids.

109. The conjugate of claim 103 or claim 104, wherein the pharmaceutically active drug is selected from an Eg5 inhibitor, a V-ATPase inhibitor, an HSP90 inhibitor, an IAP inhibitor, an mTor inhibitor, a microtubule stabilizer, a microtubule destabilizer, an auristatin, a dolastatin, a maytansine, a MetAP (methionine aminopeptidase), an inhibitor of nuclear export protein CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reactions in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, an HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA intercalator, a DNA minor groove binder, an RNA polymerase inhibitor, an amanitin, a spliceosome inhibitor, a topoisomerase inhibitor, a DHFR inhibitor, or a pro-apoptotic agent.

110. The conjugate of claim 103 or claim 104, wherein the pharmaceutically active drug is selected from a topoisomerase 1 inhibitor or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or an addition salt with a pharmaceutically acceptable acid or base thereof.

111. The conjugate of claim 110, wherein the pharmaceutically active drug is wherein the topoisomerase 1 inhibitor is selected from topotecan, exitecan, delutecan, and SN-38.

112. The conjugate of claim 103 or claim 104, wherein the pharmaceutically active drug is selected from an antimitotic drug or an enantiomer, diastereomer, atropisomer, deuterated derivative and / or an addition salt with a pharmaceutically acceptable acid or base thereof.

113. The conjugate of claim 112, wherein the anti-mitotic drug is monomethyl auristatin E (MMAE) or a taxane.

114. The conjugate of claim 113, wherein the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

115. The conjugate of claim 103, wherein the conjugate comprises a compound according to any one of claims 1 to 102, or a pharmaceutically acceptable salt thereof.

116. A conjugate of formula (A-2): in: Ab is an antibody or its fragment; R 100 is a coupling group; L 1 is a bridging spacer; W is a branching moiety; L 2 ' and L 3 'Each independently is a joint; D 1 and D 2 are each independently a pharmaceutically active drug, provided that D 1 and D 2 Neither is a BH3 mimetic; and a is an integer from 1 to 16.

117. The conjugate of claim 116, wherein L 2 ' and L 3 Each of ' comprises a cleavable group, optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group and / or a self-immolative group (eg, a peptide group and a self-immolative group).

118. The conjugate of claim 117, wherein L 2 ' and L 3 Each of ' comprises a peptide group and a self-immolative group.

119. The conjugate of claim 116, wherein L 2 ' and L 3 Each of ' comprises a cleavable group, optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (eg, glucuronamide) group, a peptide group, and / or a self-immolative group (eg, a peptide group and a self-immolative group).

120. The conjugate according to any one of claims 116 to 118, which has formula (B-2): in: Ab is an antibody or its fragment; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w , where R w is H or C1-C6 alkyl (e.g. R w is H); L 2 and L 3 each independently a linker spacer; E 1 and E 2 Each is independently an enzymatic cleavage element or a hydrophilic moiety (e.g., E 1 and E 2 each an enzymatic cleavage element); V 1 and V 2 independently comprising i) a self-immolative group, ii) an enzymatic cleavage element (e.g. 1 and V 2 each independently a self-immolative group) or iii) a self-immolative group and an enzymatic cleavage element; D 1 and D 2 are each independently a pharmaceutically active drug, provided that D 1 and D 2 Neither is a BH3 mimetic; and a is an integer from 1 to 16.

121. The conjugate of claim 120, wherein V 1 and V 2 Each is independently i) a self-immolative group, or ii) an enzymatic cleavage element (e.g., V 1 and V 2 are each independently a self-immolative group).

122. The conjugate of claim 120 or claim 121, wherein W is N or CH.

123. The conjugate of any one of claims 120 to 122, wherein E 1 and E 2 Each is an enzymatic cleavage element.

124. The conjugate of any one of claims 120 to 123, wherein V 1 and V 2 Each is independently a self-immolative group.

125. The conjugate of any one of claims 116 to 124, wherein a is an integer from 1 to 6 or from 1 to 4, or a is 1 or 2.

126. The conjugate of any one of claims 116 to 125, wherein a is determined by liquid chromatography-mass spectrometry (LC-MS).

127. The conjugate of any one of claims 116 to 126, wherein (i) the cleavable linker comprises a phosphate group, a pyrophosphate group and / or a self-immolative group; (ii) the cleavable linker comprises a self-immolative group; or (iii) the cleavable linker comprises a self-immolative group, the self-immolative group comprising -CH2-O-, -NH-CH2-, -C(=O)-, p-aminobenzyl-carbamate, p-aminobenzyl-ammonium, p-amino-(sulfo)benzyl-ammonium, p-amino-(sulfo)benzyl-carbamate, p-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or p-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

128. The conjugate of claim 127, wherein W is N or CH.

129. The conjugate of claim 127 or claim 128, wherein R 2 and R 3 Each is a hydrophilic group.

130. The conjugate of any one of claims 116 to 129, which has formula (C-2): in: Ab is an antibody or its antigen-binding fragment; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w , where R w is H or C1-C6 alkyl (e.g. R w is H); L 2 and L 3 each independently a linker spacer; E 1 and E 2 each independently a peptide group comprising 1 to 6 amino acids, wherein the peptide group is optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-*or-OC(=O)N(CH3)C(R a )2C(R a )2N(CH3)C(=O)-*, Each R a are independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl, and A 1 or A 2 * indicates that the 1 or D 2 attachment points; D 1 and D 2 are each independently a pharmaceutically active drug, provided that D 1 and D 2 None are BH3 mimetics; L 4 and L 5 each independently a spacer moiety; R 2 and R 3 Each is independently a hydrophilic group or an enzymatic cleavage element (e.g., R 2 and R 3 each a hydrophilic group); and m and n are each independently 0 or 1.

131. The conjugate of claim 130, which has formula (D1-2), (D2-2), or (D3-2):

132. The conjugate of claim 131, wherein for formula (D1-2), R 2 and R 3 are each independently a hydrophilic group, wherein for formula (D2-2), R 2 and R 3 are each independently an enzyme cleavage element; and for formula (D3-2), R 2 is a hydrophilic group and R 3 It is an enzyme cleavage element.

133. The conjugate of any one of claims 116 to 131, wherein R 100 Selected from the group consisting of: amide; as well as disulfide bonds, in: R 16 It is H, C 1- C4 alkyl, phenyl, pyrimidine or pyridine; R 18 It is H, C 1- C6 alkyl, phenyl or C6 substituted by 1 to 3 -OH groups 1- C4 alkyl; Each R 15 Independently selected from H, C 1- C6 alkyl, fluorine, benzyloxy substituted by -C(=O)OH, benzyl substituted by -C(=O)OH, C 1- C4 alkoxy and C substituted by -C(=O)OH 1- C4 alkyl; R 17 independently selected from H, phenyl and pyridine; q is 0, 1, 2, or 3; R 19 is H or methyl; and R 20 It is H, -CH3 or phenyl.

134. The conjugate of any one of claims 116 to 133, wherein R 100 Choose Free The group consisting of R 100 The *** indicates the attachment point to the Ab.

135. The conjugate of claim 134, wherein R 100 yes where R 100 The *** indicates the attachment point to the Ab.

136. The conjugate of any one of claims 116 to 135, wherein: (1)L 1 Include: or *-CH(OH)CH(OH)CH(OH)CH(OH)-*, wherein each n is an integer from 1 to 12, wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; (2)L 1 yes and n is an integer from 1 to 12 or n is 1 or n is 12, wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; (3)L 1 yes and n is an integer from 1 to 12, wherein L 1 The * of L1 indicates a direct or indirect (e.g., direct) attachment point to W, and the ** of L1 indicates a direct or indirect (e.g., direct) attachment point to R 1 direct or indirect (e.g. direct) point of attachment; (4)L 1 Include Among them L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 a direct or indirect (e.g. direct) point of attachment; or (5)L 1 is a bridging spacer comprising: *-C(=O)(CH2) m O(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n -**;*-C(=O)(CH2) m -**;*-C(=O)NH((CH2) m O) t (CH2) n -**;*-C(=O)O(CH2) m SSC(R L1 )2(CH2) m C(=O)NR L1 (CH2) m NR L1 C(=O)(CH2) m -**;*-C(=O)O(CH2) m C(=O)NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) m -**;*-C(=O)(CH2) m NH(CH2) n C(=O)-**;*-C(=O)(CH2) m X1(CH2) m -**;*-C(=O)((CH2) m O) t (CH2) n X1(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n -**;*-C(=O)(CH2) m NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n NHC(=O)(CH2) n X1(CH2) n -**;*-C(=O)((CH2) m O) t (CH2) n C(=O)NH(CH2) m -**;*-C(=O)(CH2) m C(R L1 )2-** or *-C(=O)(CH2) m C(=O)NH(CH2) m -**, where L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect (e.g. direct) point of attachment; X1 is and Each m is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Each n is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and each t is independently selected from 1, 2, 3, 4, 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, and 30; and Each R L1 Independently selected from H and C1-C6 alkyl.

137. The conjugate of any one of claims 116 to 136, wherein L 1 Contains the sections represented by: wherein n is an integer from 1 to 12 (e.g., 4 to 8, such as 4 or 8), wherein L 1 The * indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 ** indicates that the 1 direct or indirect attachment point.

138. The conjugate of claim 137, wherein n is an integer from 4 to 8.

139. The conjugate of claim 138, wherein n is 4 or 8.

140. The conjugate of any one of claims 116 to 110, wherein L 1 It is expressed by the following formula: in n is an integer from 1 to 12 (e.g., 4 to 8, such as 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, e.g., 0 to 2, e.g., 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, e.g., 0 to 2, e.g., 0 or 2); u is 0 or 1; and Among them L 1 The * indicates the direct attachment point with W, and L 1 ** indicates that the 1 Direct attachment point.

141. The conjugate of claim 140, wherein n is an integer from 4 to 8.

142. The conjugate of claim 141, wherein n is 4 or 8.

143. The conjugate of any one of claims 140 to 142, wherein x is an integer from 0 to 2.

144. The conjugate of claim 143, wherein x is 0 or 2.

145. The conjugate of any one of claims 140 to 144, wherein z is an integer from 0 to 2.

146. The conjugate of claim 145, wherein z is 0 or 2.

147. The conjugate of any one of claims 116 to 146, wherein L 1 Selected from the group consisting of:

148. The conjugate of any one of claims 120 to 147, wherein L 2 and L 3 are each independently a linker spacer comprising a moiety represented by: in k is an integer from 0 to 6; r is 0 or 1; o is an integer from 0 to 12; p is an integer from 0 to 6; and Among them L 2 or L 3 The # represents the E 1 or E 2 direct or indirect attachment point, and L 2 or L 3 The ## indicates a direct or indirect attachment point to W.

149. The conjugate of any one of claims 120 to 147, wherein L 2 and L 3 are each independently a linker spacer selected from the group consisting of: as well as in k is independently an integer from 0 to 4 at each occurrence; r is independently 0 or 1 at each occurrence; o is independently an integer from 0 to 10 at each occurrence; p is independently an integer from 0 to 4 at each occurrence; R L23 is hydrogen or C 1- C6 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, and L 2 or L 3 The ## indicates the direct attachment point to W; The condition is that when W is N, L 2 and L 3 Not (L2c), (L2d), (L2f), or (L2k).

150. The conjugate of claim 149, wherein L 2 and L 3 are each independently a linker spacer selected from the group consisting of: as well as in k is independently an integer from 1 to 3 at each occurrence; o is independently an integer from 1 to 9 at each occurrence; p is independently an integer from 1 to 3 at each occurrence; R L23 is hydrogen or C 1- C3 alkyl; R L is hydrogen or -C(O)-R H ; R H is a hydrophilic group; and L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, and L 2 or L 3 The ## indicates the direct attachment point to W; the condition is that when W is N, L 2 and L 3 Not (L2FF), (L2MM), (L2NN), (L2OO), or (L2PP).

151. The conjugate of any one of claims 120 to 150, wherein L 2 and L 3 are independently a linking spacer selected from the group consisting of: Among them L 2 or L 3 The # represents the E 1 or E 2 Direct attachment point, L 2 or L 3 The ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H ;and R H yes And d is an integer from 20 to 30 (eg, 25).

152. The conjugate of claim 151, wherein d is 25.

153. The conjugate of any one of claims 130 to 152, wherein each peptide group independently comprises 1 to 4, 1 to 3 or 1 to 2 amino acid residues.

154. The conjugate of claim 153, wherein each peptide group independently comprises 2 amino acid residues.

155. The conjugate of claim 153 or claim 154, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteine ​​(sulfo-Ala), L-lysine (Lys), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Tyr), and β-alanine (β-Ala).

156. The conjugate of any one of claims 130 to 153, wherein each peptide group is independently selected from Val-Cit, Phe-Lys, Val-Ala, Val-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gly-Gly-Phe-Gly and Sulfo-Ala-Val-Ala.

157. The conjugate of any one of claims 120 to 153, wherein E 1 and / or E 2 Each is independently a peptide group selected from the group consisting of: Wherein ^ of E1-1 or E1-2 represents V in formula (B) 1 or V 2 The direct attachment point of or the direct attachment point of -NH- group in formula (C) and (D); and ^^ of E1-1 or E1-2 respectively represents the direct attachment point of L 2 or L 3 Direct attachment point (e.g., where E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2)).

158. The conjugate of claim 157, wherein E 1 and E 2 Each is a peptide group independently selected from (E1-1) and (E1-2).

159. The conjugate of any one of claims 120 to 153, wherein E 1 and / or E 2 Each is independently a peptide group represented by: where R E is a hydrophilic group R H .

160. The conjugate of claim 159, wherein the hydrophilic group R in (E1-3) H yes Wherein e is an integer between 20 and 30 (eg, 25).

161. The conjugate of claim 160, wherein e is 25.

162. The conjugate of claim 157, wherein E 1 and E 2 Each is 163. The conjugate of any one of claims 130 to 162, wherein A 1 and A 2 independently selected from a bond and -OC(=O)-*, wherein * represents 1 or D 2 attachment point.

164. The conjugate of any one of claims 130 to 162, wherein A 1 and A 2 are independently selected from a bond, and -OC(=O)-*, where * represents the 1 or D 2 attachment point.

165. The conjugate of claim 163, wherein A 1 and A 2 Yes key.

166. The conjugate of claim 163, wherein A 1 and A 2 All are -OC(=O)-*.

167. The conjugate of claim 163, wherein A 1 and A 2 One of them is OC(=O)-*, and A 1 and A 2 The other one is the key.

168. The conjugate of claim 164, wherein A 1 and A 2 independently a key or * indicates that the 1 or D 2 attachment point.

169. The conjugate of claim 164, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is the key.

170. The conjugate of claim 164, wherein A 1 and A 2 All 171. The conjugate of claim 164, wherein A 1 and A 2 One of them is And A 1 and A 2 The other one is OC(=O)-*.

172. The conjugate of claim 164, wherein: i)A 1 Japanese A 2 Corre-OC(=O)-*; (ii)A 1 and A 2 yes (iii)A 1 is OC(=O)-* and A 2 Yes Key (iv)A 1 is OC(=O)-* and A 2 yes (v)A 1 is a key and A 2 yes or (vi)A 1 is a key and A 2 is OC(=O)-*, * indicates the same as D 1 or D 2 attachment point.

173. The conjugate of any one of claims 130 to 167, wherein: i)L 4 and L 5 Each independently is a spacer moiety having the structure in: Z is -O-, -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR L45 -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 is independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is a bond, triazolyl or -CH2-triazolyl-, Where X is connected to R 2 or R 3 ;or (ii)L 4 and L 5 is independently a spacer moiety having the structure in: Z is -CH2-, -CH2O-, -CH2N(R L45 )C(=O)O-、-NHC(=O)C(R L45 )2NHC(=O)O-、-NHC(=O)C(R L45 )2NH-、-NHC(=O)C(R L45 )2NHC(=O)-、-C(=O)NR b -、-C(=O)NH-、-CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH-, -CH2NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each R L45 is independently selected from H, C1-C6 alkyl and C3-C8 cycloalkyl; and X is -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O) n -C(O)NHS(O)2NH-、-(CH2CH2O) n -C(O)NHS(O)2NH-(CH2CH2O) n -, -CH2-triazolyl-C 1- C4 alkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -、-C 4- C6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O) n -, wherein each n is independently 1, 2 or 3, Where X is connected to R 2 or R 3 .

174. The conjugate of claim 173, wherein Z is -O-, -CH2NR L45 C(=O)-、-CH2NR L45 C(=O)NH- or -CH2O-; X is a bond, triazolyl or -CH2-triazolyl-; and R L45 is independently H or C at each occurrence 1- C3 alkyl.

175. The conjugate of any one of claims 130 to 174, wherein L 4 and L 5 are each independently a spacer moiety selected from the group consisting of: Among them L 4 or L 5 The @ indicates the direct attachment point to the phenyl group, and L 4 or L 5 @@ indicates the same as R 2 or R 3 Direct attachment point.

176. The conjugate of any one of claims 130 to 175, wherein R 2 and R 3 The hydrophilic groups represented by each independently include polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, substituted C2-C6 alkyl, or substituted by 1 to 2 independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)C 1- C4 alkylene -P(O)(OCH2CH3)2 and C2-C6 alkyl substituted with substituents of the -COOH group.

177. The conjugate of any one of claims 130 to 175, wherein R 2 or / and R 3 Each independently selected from the group consisting of: Where n is an integer between 1 and 6; 178. The conjugate of any one of claims 130 to 175, wherein R 2 or / and R 3 Each independently contains: (i) Polysarcosine having the following moieties: in f is an integer between 3 and 25; and R 23 is H, -CH3 or -CH2CH2C(=O)OH; (ii) polyethylene glycol having the formula: wherein g and h are independently integers between 2 and 30; or (iii) By The part that is indicated.

179. The conjugate of any one of claims 130 to 175, wherein R 2 or R 3 The hydrophilic groups represented by each independently comprise: (i) Polysarcosine having the following moieties: wherein f is an integer between 3 and 25; and R 23 is H, -CH3 or -CH2CH2C(=O)OH; or (ii) polyethylene glycol having the formula: wherein g and h are independently integers between 2 and 30; or (iii) By The part that is indicated.

180. The conjugate of any one of claims 130 to 175, wherein R 2 and R 3 Independently choose freedom a group consisting of g and h are independently integers between 20 and 30 (eg, 23 or 24).

181. The conjugate according to claim 180, wherein R 2 or / and R 3 Include:

182. The conjugate of claim 151, wherein R 2 and R 3 Each independently comprises a polyethylene glycol having the formula: wherein g and h are independently integers between 2 and 30.

183. The conjugate of any one of claims 103 to 182, wherein D 1 and D 2 are the same.

184. The conjugate of any one of claims 103 to 182, wherein D 1 and D 2 are different.

185. The conjugate of any one of claims 103 to 184, wherein D 1 and D 2 Each is independently selected from cytotoxic drugs, cytostatic drugs and immunosuppressive drugs.

186. The conjugate of any one of claims 103 to 184, wherein D 1 and D 2 Each independently selected from auristatin, camptothecin, duocarmycin, etoposide, maytansine, maytansine-like, taxane, benzodiazepine Benzodiazepines drugs (eg, pyrrolo[1,4]-benzodiazepines PBD, indolebenzodiazepine Oxazolidinone and benzodiazepine class) and vinca alkaloids.

187. The conjugate of claim 186, wherein D 1 and D 2 Independently selected from the group consisting of: (For example ) (For example ), where * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

188. The conjugate of claim 187, wherein: i)D 1 yes And D 2 yes ii)D 1 yes And D 2 yes iii)D 1 yes And D 2 yes iv)D 1 yes And D 2 yes v)D 1 yes And D 2 yes vi)D 1 yes And D 2 yes vii)D 1 yes And D 2 yes viii)D 1 yes And D 2 yes ix)D 1 yes And D 2 yes x)D 1 yes And D 2 yes xi)D 1 yes And D 2 yes xii)D 1 yes And D 2 yes xiii)D 1 yes And D 2 yes xiv)D 1 yes And D 2 yes xv)D 1 yes And D 2 yes xvi)D 1 yes And D 2 yes xvii)D 1 yes And D 2 yes xviii)D 1 yes And D 2 yes xix)D 1 yes And D 2 yes xx)D 1 yes And D 2 yes xxi)D 1 yes And D 2 yes xxii)D 1 yes And D 2 yes xxiii)D 1 yes And D 2 yes xxiv)D 1 yes And D 2 yes xxv)D 1 yes And D 2 yes xxvi)D 1 yes And D 2 yes xxvii)D 1 yes And D 2 yes xxviii)D 1 yes And D 2 yes xxix)D 1 yes And D 2 yes xxx)D 1 yes And D 2 yes xxxi)D 1 yes And D 2 yes xxxii)D 1 yes And D 2 yes xxxiii)D 1 yes And D 2 yes xxxiv)D 1 yes And D 2 yes xxxv)D 1 yes And D 2 yes xxxvi)D 1 yes And D 2 yes xxxvii)D 1 yes And D 2 yes xxxviii)D 1 yes And D 2 yes ; xxxix)D 1 yes And D 2 yes xl)D 1 yes And D 2 yes xli)D 1 yes And D 2 yes xlii)D 1 yes And D 2 yes xliii)D 1 yes And D 2 yes xliv)D 1 yes And D 2 yes vl)D 1 yes And D 2 yes xlvi)D 1 yes And D 2 yes xlvii)D 1 yes And D 2 yes xlviii)D 1 yes And D 2 yes il)D 1 yes And D 2 yes l)D 1 yes And D 2 yes li)D 1 yes And D 2 yes lii)D 1 yes And D 2 yes liii)D 1 yes And D 2 yes liv)D 1 yes And D 2 yes lv)D 1 yes And D 2 yes lvi)D 1 yes And D 2 yes lvii)D 1 yes And D 2 yes lviii)D 1 yes And D 2 yes lix)D 1 yes And D 2 yes lx)D 1 yes And D 2 yes lxi)D 1 yes And D 2 yes lxii)D 1 yes And D 2 yes lxiii)D 1 yes And D 2 yes or lxiv)D 1 yes And D 2 yes where * indicates the point of attachment to the rest of the molecule.

189. The conjugate of any one of claims 103 to 188, wherein: i)A 1 -D 1 yes And A 2 -D 2 yes ii)A 1 -D 1 yes And A 2 -D 2 yes iii)A 1 -D 1 yes And A 2 -D 2 yes iv)A 1 -D 1 yes And A 2 -D 2 yes v)A 1 -D 1 yes And A 2 -D 2 yes vi)A 1 -D 1 yes And A 2 -D 2 yes vii)A 1 -D 1 yes And A 2 -D 2 yes viii)A 1 -D 1 yes And A 2 -D 2 yes ix)A 1 -D 1 yes And A 2 -D 2 yes x)A 1 -D 1 yes And A 2 -D 2 yes xi)A 1 -D 1 yes And A 2 -D 2 yes xii)A 1 -D 1 yes And A 2 -D 2 yes xiii)A 1 -D 1 yes And A 2 -D 2 yes xiv)A 1 -D 1 yes And A 2 -D 2 yes xv)A 1 -D 1 yes And A 2 -D 2 yes xvi)A 1 -D 1 yes And A 2 -D 2 yes xvii)A 1 -D 1 yes And A 2 -D 2 yes xviii)A 1 -D 1 yes And A 2 -D 2 yes xix)A 1 -D 1 yes And A 2 -D 2 yes xx)A 1 -D 1 yes And A 2 -D 2 yes xxi)A 1 -D 1 yes And A 2 -D 2 yes xxii)A 1 -D 1 yes And A 2 -D 2 yes xxiii)A 1 -D 1 yes And A 2 -D 2 yes xxiv)A 1 -D 1 yes And A 2 -D 2 yes xxv)A 1 -D 1 yes And A 2 -D 2 yes xxvi)A 1 -D 1 yes And A 2 -D 2 yes xxvii)A 1 -D 1 yes And A 2 -D 2 yes xxviii)A 1 -D 1 yes And A 2 -D 2 yes xxix)A 1 -D 1 yes And A 2 -D 2 yes xxx)A 1 -D 1 yes And A 2 -D 2 yes xxxi)A 1 -D 1 yes And A 2 -D 2 yes xxxii)A 1 -D 1 yes And A 2 -D 2 yes xxxiii)A 1 -D 1 yes And A 2 -D 2 yes xxxiv)A 1 -D 1 yes And A 2 -D 2 yes xxxv)A 1 -D 1 yes And A 2 -D 2 yes xxxvi)A 1 -D 1 yes And A 2 -D 2 yes xxxvii)A 1 -D 1 yes And A 2 -D 2 yes xxxviii)A 1 -D 1 yes And A 2 -D 2 yes xxxix)A 1 -D 1 yes And A 2 -D 2 yes xl)A 1 -D 1 yes And A 2 -D 2 yes xli)A 1 -D 1 yes And A 2 -D 2 yes xlii)A 1 -D 1 yes And A 2 -D 2 yes xliii)A 1 -D 1 yes And A 2 -D 2 yes xliv)A 1 -D 1 yes And A 2 -D 2 yes xlv)A 1 -D 1 yes And A 2 -D 2 yes xlvi)A 1 -D 1 yes And A 2 -D 2 yes xlvii)A 1 -D 1 yes And A 2 -D 2 yes xlviii)A 1 -D 1 yes And A 2 -D 2 yes xlix)A 1 -D 1 yes And A 2 -D 2 yes l)A 1 -D 1 yes And A 2 -D 2 yes li)A 1 -D 1 yes And A 2 -D 2 yes lii)A 1 -D 1 yes And A 2 -D 2 yes liii)A 1 -D 1 yes And A 2 -D 2 yes liv)A 1 -D 1 yes And A 2 -D 2 yes lv)A 1 -D 1 yes And A 2 -D 2 yes lvi)A 1 -D 1 yes And A 2 -D 2 yes lvii)A 1 -D 1 yes And A 2 -D 2 yes lviii)A 1 -D 1 yes And A 2 -D 2 yes lix)A 1 -D 1 yes And A 2 -D 2 yes lx)A 1 -D 1 yes And A 2 -D 2 yes lxi)A 1 -D 1 yes And A 2 -D 2 yes lxii)A 1 -D 1 yes And A 2 -D 2 yes lxiii)A 1 -D 1 yes And A 2 -D 2 yes or lxiv)A 1 -D 1 yes And A 2 -D 2 yes where * indicates the point of attachment to the rest of the molecule.

190. The conjugate of any one of claims 103 to 184, wherein D 1 and / or D 2 It's Auristatin.

191. The conjugate of claim 190, wherein D 1 and D 2 They are all auristatins.

192. The conjugate of any one of claims 116 to 184, wherein D 1 and / or D 2 It is a topoisomerase 1 inhibitor.

193. The conjugate of claim 192, wherein D 1 and D 2 Both are topoisomerase 1 inhibitors.

194. The conjugate of any one of claims 116 to 184, wherein D 1 and D 2 One of which is auristatin, and D 1 and D 2 Another of the agents is a topoisomerase 1 inhibitor.

195. The conjugate of claim 194, wherein D 1 It is Auristatin and D 2 It is a topoisomerase 1 inhibitor.

196. The conjugate of claim 194, wherein D 1 is a topoisomerase 1 inhibitor and D 2 It's Auristatin.

197. The conjugate of claim 190, wherein D 1 and D 2 Independently selected from the group consisting of: * indicates the same as A 1 or A 2 attachment point.

198. The conjugate of claim 197, wherein D 1 and D 2 Independently selected from the group consisting of:

199. The conjugate of claim 187, wherein D 1 and D 2 Independently selected from the group consisting of: (For example ) (For example ), * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

200. The conjugate of claim 187, wherein D 1 and D 2 Independently selected from the group consisting of: * indicates the same as A 1 or A 2 or a pharmaceutically acceptable salt thereof.

201. The conjugate of any one of claims 103 to 184, wherein D 1 and D 2 Each is independently selected from antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemosensitizers, topoisomerase inhibitors and / or vinca alkaloids.

202. The conjugate of any one of claims 103 to 184, wherein D 1 and D 2 Each is independently selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizers, microtubule destabilizers, auristatins, dolastatins, maytansines, MetAP (methionine aminopeptidase), nuclear export protein CRM1 inhibitors, DPPIV inhibitors, mitochondrial phosphoryl transfer inhibitors, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinesin inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA intercalators, DNA minor groove binders, RNA polymerase inhibitors, amanitin, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors or pro-apoptotic agents, optionally with the proviso that D 1 and D 2 Neither is a BH3 mimetic.

203. A conjugate comprising an antibody or antigen-binding fragment bound to one or more (eg, 1 to 16, eg, 1 to 4) compounds independently selected from claim 94 or claim 96.

204. The conjugate of any one of claims 103 to 203, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

205. The conjugate of claim 204, wherein: (i) the target antigen is selected from BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, SEZ6, DLL3, DLK1, B7-H3, EGFR, CD71, EphA2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; (ii) the target antigen is selected from EGFR, CD7, HER2, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, and GPNMB; or (iii) the target antigen is PCAD, CD48, CD74, EphA2, HER2, TROP2, B7-H3 or 5T4.

206. The conjugate of claim 204 or claim 205, wherein the antibody or antigen-binding fragment thereof is selected from Table D1.

207. The conjugate of claim 204, wherein the antibody or antigen-binding fragment having CDR sequences is selected from those in Tables D3 and D8, or the antibody or antigen-binding fragment having variable regions is selected from those in Tables D2 and D8, or the antibody or antigen-binding fragment having full length is selected from those in Tables D4, D5 and D7.

208. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 268, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 172, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 269, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 172, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 263, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 6) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 7) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 215, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and 8) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 169, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 170, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 266, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

174.

209. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 262, or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

267.

210. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD74 antibody comprising: (a) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; (b) the heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence at least 95% identical to SEQ ID NO: 236, and the light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; or (c) the heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and the light chain amino acid sequence of SEQ ID NO: 239, or a sequence at least 95% identical to SEQ ID NO:

239.

211. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 271, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 272, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 281, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 282, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 283; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 274, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 275, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 284, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 285, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 276, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 278; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 287, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 282, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; and 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 279, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 275, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 273; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 284, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 288, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 286; and 5) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:51, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:52, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:53; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:54, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:55, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

56.

212. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 270 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 280; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

14.

213. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-CD48 antibody comprising (a) a heavy chain amino acid sequence of SEQ ID NO: 240, or a sequence at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 243, or a sequence at least 95% identical to SEQ ID NO: 243; or (b) a heavy chain amino acid sequence of SEQ ID NO: 242, or a sequence at least 95% identical to SEQ ID NO: 242, and a light chain amino acid sequence of SEQ ID NO: 243, or a sequence at least 95% identical to SEQ ID NO: 243; c) a heavy chain amino acid sequence of SEQ ID NO: 240, or a sequence at least 95% identical to SEQ ID NO: 240, and a light chain amino acid sequence of SEQ ID NO: 69, or a sequence at least 95% identical to SEQ ID NO:

70.

214. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 291; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 297, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 298, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 299; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 292, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 40, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 291; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 300, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 301, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 293, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 294, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 295; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 302, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 298, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 44; and 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO:39, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO:40, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO:291; a light chain CDR1 (LCDR1) consisting of SEQ ID NO:300, a light chain CDR2 (LCDR2) consisting of SEQ ID NO:301, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

44.

215. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

296.

216. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-Her2 antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 245 or a sequence at least 95% identical to SEQ ID NO: 245, and a light chain amino acid sequence of SEQ ID NO: 66 or a sequence at least 95% identical to SEQ ID NO:

66.

217. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 312, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 314; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 307, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 309, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 277, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 278; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 317, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 313, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 316; and 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 310, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 308, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 306; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 315, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 25, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

316.

218. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 303 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

311.

219. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-PCAD antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 248, or a sequence at least 95% identical to SEQ ID NO: 248, and a light chain amino acid sequence of SEQ ID NO: 250, or a sequence at least 95% identical to SEQ ID NO:

250.

220. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 319, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 320, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 330, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 331, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 332; 2) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 322, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 324; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335; 3) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 325, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 326, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 327; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 336, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 331, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335; and 4) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, and a heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; a light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, a light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and a light chain CDR3 (LCDR3) consisting of SEQ ID NO:

335.

221. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 318 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

329.

222. The conjugate of claim 204, wherein the antibody or antigen-binding fragment is an anti-EphA2 antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 252 or a sequence at least 95% identical to SEQ ID NO: 252, and a light chain amino acid sequence of SEQ ID NO: 254 or a sequence at least 95% identical to SEQ ID NO:

254.

223. The conjugate of any one of claims 208 to 222, wherein the antibody or antigen-binding fragment thereof comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C of the heavy chain of the antibody or antigen-binding fragment thereof, wherein positions are numbered according to the EU system.

224. The conjugate of any one of claims 208 to 222, wherein the antibody or antigen-binding fragment thereof comprises one or more Fc silent mutations.

225. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 103 to 224, wherein the average a of the antibody-drug conjugates in the composition is about 1 to about 8, e.g., about 1 to about 6, about 1 to about 4, or about 1 to about 2.

226. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, which is represented by any one of the following formulae: in: A 1 and A 2 are each independently selected from a bond, and -OC(=O)-*, where A 1 and A 2 * indicates the same as D 1 or D 2 attachment points; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., between 2 and 5); and n is an integer between 1 and 12 (eg, between 2 and 5).

227. The compound according to claim 226, or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 are each independently selected from a bond and OC(=O)-*, wherein A 1 and A 2 * indicates the same as D 1 or D 2 attachment point.

228. The conjugate of any one of claims 116 to 224, which is represented by any one of the following formulae: in: A 1 and A 2 are each independently selected from a bond, and -OC(=O)-*, where A 1 and A 2 * indicates the same as D 1 or D 2 attachment points; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., between 2 and 5); n is an integer between 1 and 12 (e.g., between 2 and 5); and **- indicates the attachment point to Ab.

229. The conjugate of claim 228, wherein A 1 and A 2 are each independently selected from a bond and -OC(=O)-*, wherein A 1 and A 2 * indicates the same as D 1 or D 2 attachment point.

230. A compound according to any one of claims 1 to 87, or a pharmaceutically acceptable salt thereof, having formula (D5a-1): in: A 1 and A 2 are each independently selected from a bond, and -OC(=O)-*, where A 1 and A 2 * indicates the same as D 1 or D 2 attachment points; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., between 1 and 3); and n is an integer between 1 and 12 (eg, between 5 and 10).

231. The compound according to claim 230, or a pharmaceutically acceptable salt thereof, wherein A 1 and A 2 are each independently selected from a bond and -OC(=O)-*, wherein A 1 and A 2 * indicates the same as D 1 or D 2 attachment point.

232. The conjugate of any one of claims 116 to 224, which has formula (D5a-2): in: A 1 and A 2 are each independently selected from a bond, and -OC(=O)-*, where A 1 and A 2 * indicates the same as D 1 or D 2 attachment points; g, independently at each occurrence, is an integer between 20 and 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o is independently at each occurrence an integer between 1 and 9 (e.g., between 1 and 3); n is an integer between 1 and 12 (e.g., between 5 and 10); and **- indicates the attachment point to Ab.

233. The conjugate of claim 232, wherein A 1 and A 2 are each independently selected from a bond and -OC(=O)-*, wherein A 1 and A 2 * indicates the same as D 1 or D 2 attachment point.

234. The conjugate of any one of claims 116 to 224, which is represented by the following formula: as well as Among them A 1 or A 2 are each independently selected from a bond, and -OC(=O)-*, where * represents the 1 or D 2 ** indicates the attachment point to Ab; and Indicates that D 1 or D 2 Direct attachment point.

235. The conjugate of claim 234, wherein A 1 and A 2 are each independently selected from a bond and -OC(=O)-*, wherein A 1 and A 2 * indicates the same as D 1 or D 2 attachment point.

236. A pharmaceutical composition comprising the conjugate of any one of claims 103 to 224 and 234 and a pharmaceutically acceptable carrier.

237. A method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 236.

238. The method of claim 237, wherein the cancer expresses a target antigen.

239. The method of claim 237 or claim 238, wherein the cancer is a tumor or a blood cancer, optionally the cancer is breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

240. A method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 236.

241. The method of claim 240, wherein the tumor expresses a target antigen.

242. The method of claim 240 or claim 241, wherein the tumor is breast cancer, stomach cancer, bladder cancer, brain cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, melanoma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

243. A method of reducing or inhibiting a blood cancer in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 236.

244. The method of claim 243, wherein the hematological cancer expresses a target antigen.

245. The method of claim 243 or claim 244, wherein the hematological cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

246. The method of any one of claims 240 to 245, wherein administration of the conjugate or pharmaceutical composition reduces or inhibits the growth of the tumor or hematological cancer by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

247. A method of reducing or slowing the expansion of a cancer cell population in a subject, comprising administering to the subject a therapeutically effective amount of the conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 236.

248. The method of claim 247, wherein the cancer cell population expresses a target antigen.

249. The method of claim 247 or claim 248, wherein the cancer cell population is from a tumor or a blood cancer, optionally wherein the cancer cell population is from breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myeloid leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

250. The method of any one of claims 247 to 249, wherein administration of the conjugate or pharmaceutical composition reduces the cancer cell population or slows the expansion of the cancer cell population by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

251. The method of any one of claims 237 to 250, wherein the antibody-drug conjugate is administered as a monotherapy.

252. The method of any one of claims 237 to 250, wherein the antibody-drug conjugate is administered as an adjunct to another therapeutic agent or radiation therapy.

253. The method of claim 252, wherein the antibody-drug conjugate is administered in an amount effective to sensitize tumor cells to one or more additional therapeutic agents and / or radiation therapy.

254. The method of any one of claims 237 to 250, further comprising administering at least one additional therapeutic agent to a subject in need thereof.

255. The method of claim 254, wherein the one additional therapeutic agent is a taxane, a vinca alkaloid, a MEK inhibitor, an ERK inhibitor, a topoisomerase inhibitor, or a RAF inhibitor.

256. Use of the conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 198 in the preparation of a medicament for (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in a subject, (iii) reducing or inhibiting a blood cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

257. The conjugate of any one of claims 103 to 235 or the pharmaceutical composition of claim 198 for use in (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting the growth of a tumor in a subject, (iii) reducing or inhibiting a blood cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

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