Antibody Drug Conjugates

Abstract

The present disclosure relates to antibody drug conjugates (ADCs) comprising an antibody or antigen-binding fragment thereof covalently linked to two pharma- ceutically active drugs via a dual linker. Linker-drug conjugates comprising a dual linker and a pharma- ceutically active drug are also disclosed. Such linkers are a conventional way to deliver two (e.g., two different or the same) drugs bound to a single antibody. Such linkers may be particularly useful for improving the solubility of antibody drug conjugates (ADCs) that contain one or more hydrophobic drug compounds.

Description

[Technical field]

[0001] The present disclosure relates to antibody drug conjugates (ADCs) comprising an antibody or antigen-binding fragment thereof covalently linked to two pharma- ceutically active drugs via a dual linker. Linker-drug conjugates comprising a dual linker and a pharma- ceutically active drug are also disclosed. Such linkers are a conventional way to deliver two (e.g., two different or the same) drugs bound to a single antibody. Such linkers may be particularly useful for improving the solubility of antibody drug conjugates (ADCs) that contain one or more hydrophobic drug compounds. [Background technology]

[0002] One aspect in the design of antibody drug conjugates (ADCs) is the design of the chemical linker that links the drug moiety to the targeting moiety. Typically, ADCs use hydrophobic drug moieties, but when such drug moieties are used in combination with relatively hydrophobic linkers, solubility problems can arise that can affect the biocompatibility and pharmaceutical efficacy of the ADC.

[0003] To overcome these challenges, hydrophilic linkers incorporating polyethylene glycol (see R.P. Lyon, T.D. Bovee, S.O. Doronina, P.J. Burke, J.H. Hunter, H.D. Neff-LaFord, M. Jonas, M.E. Anderson, J.R. Setter, P.D. Center, Nat. Biotechnol., 2015, 33, 733-735, and WO 2015057699), sulfonate linkers (R.Y. Zhao, S.D. Wilhelm, C. Audette, G. Jones, B.A. Lee, and others) have been developed. It has been reported that linker strategies have been attempted in the design of linkers with carbohydrate backbones (FSEkholm, H. Pynnoenen, A. Vilkman, V. Pitkaenen, J. Helin, J. Saarinen, T. Satomaa, ChemMedChem., 2016,11(22):2501-2505) and linkers with carbohydrate backbones (FSEkholm, H. Pynnoenen, A. Vilkman, V. Pitkaenen, J. Helin, J. Saarinen, T. Satomaa, ChemMedChem., 2016,11(22):2501-2505).

[0004] There remains a need for antibody-drug conjugate formats that allow for targeted delivery of pharmacologic active drugs, particularly hydrophobic drugs, with improved pharmacokinetic and pharmacodynamic properties, and in particular the delivery of two pharmacologic active drugs via a dual linker. Summary of the Invention

[0005] The present invention provides compounds and conjugates that achieve the delivery of two pharma- ceutical active drugs via dual linkers while simultaneously achieving high levels of solubility.The use of such linkers not only allows the delivery of two different drug molecules by a single monoclonal antibody, if necessary, but also allows the delivery of twice the number of drug moieties attached to the same antibody compared to antibody drug conjugates known in the art (2, 4, 6 or 8 drugs can be delivered per monoclonal antibody depending on the specific conjugation technology used).The compounds and conjugates described herein allow the delivery of 4, 8, 12 or 16 drug molecules per monoclonal antibody.Various embodiments of the present invention are described herein.

[0006] According to a first aspect of the present invention, the present invention provides a compound represented by formula (A-1): [ka] (In the formula, R 1 is a linking 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 pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof.

[0007] According to a second aspect of the present invention, the present specification provides a compound represented by formula (B-1): [ka] (In the formula, R 1 is a linking group; L 1is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently an enzyme cleavage element or a hydrophilic moiety (e.g., E 1 and E 2 are enzyme cleavage elements, respectively); V 1 and V 2 are each 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; and D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof.

[0008] According to a third aspect of the present invention, the present specification provides a compound represented by formula (C-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)-*, Each R a are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0009] According to a fourth aspect of the invention, there is provided herein a conjugate. In one embodiment of this aspect, the conjugate comprises an antibody or antigen-binding fragment thereof covalently linked to two pharmaceutically active drugs via a dual linker, the dual linker having one attachment point attached to the antibody and two attachment points to the two pharmaceutically active drugs, with the proviso that neither pharmaceutically active drug is a BH3 mimetic.

[0010] In another embodiment of this aspect, provided herein is a compound of formula (A-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is a branching moiety; L 2’ and L 3’ are each independently a linker; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. A conjugate of the formula:

[0011] According to a fifth aspect of the present invention, there is provided herein a compound represented by formula (B-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently an enzyme cleavage element or a hydrophilic moiety (e.g., E 1 and E 2 are enzyme cleavage elements, respectively); V 1 and V 2 are each 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; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. A conjugate of the formula:

[0012] According to a sixth aspect of the present invention, there is provided herein a compound represented by formula (C-2): [ka] (In the formula, Ab is an antibody or an antigen-binding fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; a is an integer from 1 to 16; A 1 and A 2 are each independently a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)-*, Each R a are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. A conjugate of the formula:

[0013] According to a seventh aspect of the invention, there is provided herein a pharmaceutical composition comprising a conjugate according to the fourth, fifth or sixth aspect of the invention and a pharma- ceutically acceptable carrier.

[0014] According to an eighth aspect of the present invention, there is provided herein a method of treating a subject having or suspected of having cancer, 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.

[0015] According to a ninth aspect of the invention, there is provided herein a method of reducing or inhibiting the growth of a tumour in a subject 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.

[0016] According to a tenth aspect of the invention, there is provided herein a method of reducing or inhibiting a haematological cancer in a subject 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.

[0017] According to an eleventh aspect of the present invention, there is provided herein 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 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.

[0018] According to a twelfth aspect of the present invention, there is provided herein use 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, for the manufacture of a medicament for (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting the growth of a tumour in a subject, (iii) reducing or inhibiting a hematological cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

[0019] According to a thirteenth aspect of the invention, there is provided herein an antibody drug conjugate of the fourth, fifth or sixth aspect of the invention, or a pharmaceutical composition of the seventh aspect of the invention, for use in (i) treating a subject having or suspected of having cancer, (ii) reducing or inhibiting the growth of a tumour in a subject, (iii) reducing or inhibiting a hematological cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject. [Brief description of the drawings]

[0020] [Figure 1] Dose response curves of Trastuzumab-Example 8 and Trastuzumab-Example 7 against representative cancer cell lines. [Diagram 2] Dose response curves of Trastuzumab-Example 5 against representative cancer cell lines. [Diagram 3] Dose response curves of Trastuzumab-Example 6 against representative cancer cell lines. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The disclosed compositions and methods may be more readily understood by reference to the following detailed description in connection with the accompanying drawings, which form a part of this disclosure.

[0022] Throughout this specification, the description refers to compositions and methods of using the compositions. When the present disclosure describes or claims features or embodiments related to compositions, such features or embodiments also apply to methods of using the compositions. Similarly, when the present disclosure describes or claims features or embodiments related to methods of using the compositions, such features or embodiments also apply to the compositions.

[0023] When a range of values ​​is expressed, it includes embodiments using any specific value within that range. Moreover, reference to values ​​stated within a range includes each and every value within that range. All ranges are inclusive of their endpoints and are combinable. When values ​​are expressed as approximations by use of the antecedent "about," it will be understood that the specific value forms another embodiment. Reference to a specific numerical value includes at least that specific value unless the context clearly dictates otherwise. The use of "or" is intended to mean "and / or" unless specifically indicated otherwise in relation to its use. All references cited herein are incorporated by reference for any purpose. In the event of a conflict between the reference and the specification, the specification will control.

[0024] Unless otherwise indicated in the context of the description, e.g., in the absence of a symbol indicating a particular point of attachment, when a structure or fragment of a structure is depicted, it may be used by itself, may be attached to other components of the ADC, and may do so in any orientation, e.g., when an antibody is attached to a chemical moiety such as a linker-drug at any suitable attachment point. However, when shown, the components of the ADC are attached in the orientation shown in the given formula. For example, when formula (1) is [ka] It is described as [ka] but, [ka] When written as: the detailed structure of formula (1) is: [ka] It is. [ka] but, [ka] But no.

[0025] It will be understood that certain features of the disclosed compositions and methods that are described herein in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are described in the context of a single embodiment for brevity, may also be provided separately or in any subcombination.

[0026] As used throughout the specification, antibody drug conjugates may be identified using a naming convention in the general format of "target antigen / antibody-payload-dual linker-payload". For example, if and only if an antibody drug conjugate is referred to as "target X-P1-L1-P2", such conjugate will comprise an antibody that binds to target X, a dual linker denoted as L1, and two payloads denoted as P1 and P2, respectively. Alternatively, if an antibody drug conjugate is referred to as "anti-target X-P1-L1-P2", such conjugate will comprise an antibody that binds to target X, a dual linker denoted as L1, and two payloads denoted as P1 and P2, respectively. In another alternative, if an antibody drug conjugate is referred to as "AbX-P1-L1-P2", such conjugate will comprise an antibody that binds to target X, a dual linker denoted as L1, and two payloads denoted as P1 and P2, respectively. A control antibody drug conjugate that includes a non-specific isotype control antibody may be referred to as "isotype control IgG1-P1-L1-P2" or "IgG1-P1-L1-P2."

[0027] Any formula provided herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure depicted by the formula provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. Thus, the present disclosure includes, for example, 3 H and 14 Radioisotopes such as C, or 2 H and 13It should be understood that compounds incorporating one or more of any of the aforementioned isotopes are included, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction rate tests (e.g. 2 H or 3 3H), 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 radiotherapy of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those of skill in the art, for example by substituting an appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0028] According to one aspect of the present invention, the present invention relates to a compound of formula (A-1): [ka] (In the formula, R 1 is a linking 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 pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof is disclosed.

[0029] In one embodiment, L 2’ and L 3’each comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0030] In one embodiment, L 2’ and L 3’ Each of the formulas comprises a peptide group and a self-immolative group.

[0031] In one embodiment, L 2’ and L 3’ each comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (e.g., glucuronamide) group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0032] In certain embodiments, the compound has the formula (B-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic moiety; V 1 and V 2 may independently comprise: i) a self-immolative group; ii) an enzymatic cleavage element (e.g., V 1 and V 2are each independently a self-immolative group; or iii) comprise a self-immolative group and an enzymatic cleavage element; and D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound has the formula (B-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic moiety; V 1 and V 2 are each 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; and D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof.

[0033] In certain embodiments, W is N or CH.

[0034] In one embodiment, E 1 and E 2 are each enzyme cleavage elements.

[0035] In one embodiment, V 1 and V 2 are each independently a self-immolative group.

[0036] In certain embodiments, (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; (iii) the cleavable linker is -O-CH 2 -, -NH-CH 2 or (iv) V, which contains a self-immolative group comprising -, -OC(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or (iv) V, 1 and / or V 2 each independently comprises a group containing para-aminobenzyl phosphate or para-aminobenzyl pyrophosphate.

[0037] In certain embodiments, (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 is -O-CH 2 -, -NH-CH 2Self-immolative groups include -, -OC(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0038] In one embodiment, the compound has the formula (C-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(R a )2 C(R a ) 2 N(CH 3 )C(=O)-*, Each R a are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0039] In certain embodiments, W is N or CH.

[0040] In one embodiment, R 2 and R 3 are each a hydrophilic group.

[0041] In certain embodiments, the compound has the formula (D1-1), (D2-1), or (D3-1): [ka] or a pharma- ceutically acceptable salt thereof.

[0042] In one embodiment, the formula (D1-1), R 2 and R 3 are each independently a hydrophilic group, and in formula (D2-1), R 2 and R 3 are each independently an enzyme cleavage element; and with respect to formula (D3-1), R 2 is a hydrophilic group, and R 3 is an enzyme cleavage element; or a pharma- ceutically acceptable salt thereof.

[0043] In one embodiment, R 1 teeth, [ka] , -ONH 2 , -NH 2 , [ka] , -N 3 , [ka] , -SH, -SR 11 , -SSR 12 , -S(=O) 2 (CH=CH 2 ), -(CH 2 ) 2 S(=O) 2 (CH=CH 2 ), -NHS(=O) 2 (CH=CH 2 ), -NR 11 C(=O)CH 2 Br, e.g. -NHC(=O)CH 2 Br, -NR 11 C(=O)CH 2 I, e.g. -NHC(=O)CH 2 I, [ka] , -C(O)NHNH 2 , [ka] (In the formula, Each R 11 are independently H and C 1 ~C 6 alkyl; Each R 12 is 2-pyridyl or 4-pyridyl; Each R 13 are independently H, C 1 ~C 6 selected from alkyl, F, Cl and -OH; Each R 14 are independently H, C 1 ~C 6 Alkyl, F, Cl, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and -OH; and Each R 15 are independently H, C 1 ~C 6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1 ~C 4 Alkoxy and -C(=O)OH substituted C 1 ~C 4 alkyl) is selected from the group consisting of:

[0044] In one embodiment, R 1 teeth, [ka] , -ONH 2 , [ka] , NHC(=O)CH 2 Br and -NHC(=O)CH 2 I is selected from the group consisting of

[0045] In one embodiment, R 1 teeth, [ka] It is.

[0046] In one embodiment, (1) L 1 teeth, [ka] or *-CH(OH)CH(OH)CH(OH)CH(OH)-** (wherein each n is an integer from 1 to 12). Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (2)L 1 teeth, [ka] and n is an integer from 1 to 12, or n is 1, or n is 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (3) L 1 teeth, [ka] and n is an integer from 1 to 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (4) L 1 teeth, [ka] Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; or (5) L 1 is *-C(=O)(CH 2 ) m O(CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)(CH 2 ) m -**;*-C(=O)NH((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)O(CH 2 ) m SSC(R L1 ) 2 (CH 2 ) m C(=O)NR L1 (CH 2 ) m NR L1 C(=O)(CH 2 ) m -**;*-C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)-**;*-C(=O)(CH 2 ) m X 1 (CH 2 ) m-**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m C(R L1 ) 2 -** or *-C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m -** (In the formula, L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1indicating a direct or indirect (e.g., direct) point of attachment to; X 1 teeth, [ka] 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 are independently H and C 1 ~C 6 alkyl) is a bridging spacer comprising:

[0047] In one embodiment, L 1 teeth, [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8), and L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 (Indicating a direct or indirect point of attachment to The part represented by

[0048] In one embodiment, n is an integer from 4 to 8.

[0049] In certain embodiments, n is 4 or 8.

[0050] In one embodiment, L 1 is the formula [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); u is 0 or 1; L 1 The * in indicates the direct point of attachment to W, and L 1 The ** is R 1 (Indicates the direct attachment point to It is represented by:

[0051] In one embodiment, n is an integer from 4 to 8.

[0052] In certain embodiments, n is 4 or 8.

[0053] In one embodiment, x is an integer from 0 to 2.

[0054] In certain embodiments, x is 0 or 2.

[0055] In one embodiment, z is an integer from 0 to 2.

[0056] In certain embodiments, n is 0 or 2.

[0057] In one embodiment, L 1 teeth, [ka] is selected from the group consisting of:

[0058] In one embodiment, L 2 and L 3 are each independently [ka] (In the formula, 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; L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 (## indicates the direct or indirect point of attachment to W) is a linking spacer comprising a portion represented by:

[0059] In one embodiment, L 2 and L 3 are each independently [ka] [ka] (In the formula, k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R L23 is hydrogen or C 1 ~C 6 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; If W is N, then L 2 and L 3 (provided that it is not (L2c), (L2d), (L2f) or (L2k)) is a linking spacer selected from the group consisting of:

[0060] In one embodiment, L 2 and L 3 are each independently [ka] [ka] [ka] (In the formula, k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1 ~C 3 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; if W is N, then L 2 and L 3 (provided that it is not (L2FF), (L2MM), (L2NN), (L2OO) or (L2PP)) is a linking spacer selected from the group consisting of:

[0061] In one embodiment, L 2and L 3 is, independently, [ka] [ka] (In the formula, L 2 Or L 3 # is E 1 Or E 2 indicates the direct attachment point to L 2 Or L 3 ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H and R H teeth, [ka] and D is an integer from 20 to 30 (e.g., 25). is a linking spacer selected from the group consisting of:

[0062] In one embodiment, d is 25.

[0063] In certain embodiments, each peptide group independently comprises 1-4, 1-3, or 1-2 amino acid residues.

[0064] In certain embodiments, each peptide group independently comprises two amino acid residues.

[0065] In one embodiment, each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (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).

[0066] In certain embodiments, 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.

[0067] In one embodiment, E 1 and / or E 2 are each independently [ka] (Wherein, E1-1 or E1-2 is V in formula (B) 1 Or V 2 or the direct point of attachment to the -NH- group in formulas (C) and (D); and E1-1 or E1-2 ^^ respectively represent L 2 Or L 3 indicates the direct point of attachment to 1 and E 2 are peptide groups independently selected from (E1-1) and (E1-2). is a peptide group selected from the group consisting of:

[0068] In one embodiment, E 1 and E 2 are each a peptide group independently selected from (E1-1) and (E1-2).

[0069] In one embodiment, E 1 and / or E 2 are each independently [ka] (In the formula, R E is a hydrophilic group R H is) is a peptide group represented by:

[0070] In one embodiment, the hydrophilic group RH teeth, [ka] (wherein e is an integer of 20 to 30 (e.g., 25)) It is.

[0071] In one embodiment, e is 25.

[0072] In one embodiment, E 1 and E 2 are respectively [ka] It is.

[0073] In one embodiment, A 1 and A 2 are independently a bond and -OC(=O)-* (wherein * represents D 1 Or D 2 (indicating the point of attachment to the

[0074] In one embodiment, A 1 and A 2 are independent, combined, [ka] and -OC(=O)-* (wherein * represents D 1 Or D 2 (indicating the point of attachment to the

[0075] In one embodiment, A 1 and A 2 are bonds.

[0076] In one embodiment, A 1 and A 2 are both -OC(=O)-*.

[0077] In one embodiment, A 1 and A 2One of the groups is OC(=O)-* and A 1 and A 2 The other is a bond.

[0078] In one embodiment, A 1 and A 2 is independently a bond, or [ka] (In the formula, * represents D 1 Or D 2 (Indicates the attachment point to It is.

[0079] In one embodiment, A 1 and A 2 On the other hand, [ka] And A 1 and A 2 The other is a bond.

[0080] In one embodiment, A 1 and A 2 Both [ka] It is.

[0081] In one embodiment, A 1 and A 2 On the other hand, [ka] And A 1 and A 2 The other is OC(=O)-*.

[0082] In one embodiment, (i) A 1 and A 2 is -OC(=O)-*; (ii)A 1 and A 2 teeth, [ka] or (iii)A 1 is -OC(=O)-*, and A 2 is a bond, (iv)A 1 is -OC(=O)-*, and A 2 teeth, [ka] or (v)A 1 is a bond, and A 2 teeth, [ka] or (vi) A 1 is a bond, and A 2 is -OC(=O)-* (wherein * is D 1 Or D 2 (showing the attachment point to the

[0083] In one embodiment, i) L 4 and L 5 are each independently [ka] (In the formula, Z is -O-, -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR L45 -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NRL45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is a bond, triazolyl or -CH 2 -triazolyl-, X is R 2 or R 3 (connected to or a spacer moiety having the structure (ii) L 4 and L 5 is, independently, [ka] (In the formula, Z is -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n where each n is independently 1, 2, or 3; X is R 2 or R 3 (connected to It is a spacer portion having the structure:

[0084] In certain embodiments, Z is -O-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH- or -CH 2 X is a bond, triazolyl or -CH 2 -triazolyl-; and R L45 is, at each occurrence, independently H or C 1 ~C 3 It is an alkyl.

[0085] In one embodiment, L 4 and L 5 are each independently [ka] (In the formula, L 4 Or L 5 @ indicates the direct point of attachment to the phenyl group, and L 4 Or L 5 @@ is R 2 or R 3 (Indicates the direct attachment point to is a spacer moiety selected from the group consisting of:

[0086] In one embodiment, R 2 and R 3 Each of the hydrophilic groups represented by the formula (I) is independently selected from polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 [ka] C replaced with 2 ~C 6 Alkyl or -OC(=O)NHS(O) 2 NHCH 2 CH 2 OCH 3 , -NHC(=O)C 1 ~C 4 Alkylene-P(O)(OCH 2 CH 3 ) 2and C substituted with 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 Contains alkyl.

[0087] In one embodiment, R 2 or / and R 3 are each independently [ka] (wherein n is an integer of 1 to 6). [ka] is selected from the group consisting of:

[0088] In one embodiment, R 2 or / and R 3 is, independently, (i) the following part: [ka] (In the formula, f is an integer from 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) Polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by Includes.

[0089] In one embodiment, R 2 or / and R 3 are each independently [ka] (In the formula, g and h are independently an integer of 20 to 30 (e.g., 23 or 24). is selected from the group consisting of:

[0090] In one embodiment, R 2 or / and R 3 teeth, [ka] Includes.

[0091] In one embodiment, R 2 or R 3 Each hydrophilic group represented by the formula: (i) the following part: [ka] (In the formula, f is an integer of 3 to 25; R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) or polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) Contains polyethylene glycol.

[0092] In one embodiment, R 2 and R 3 are each independently represented by the formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) Contains polyethylene glycol.

[0093] In one embodiment, D 1 and D. 2 is the same.

[0094] In one embodiment, D 1 and D. 2 is different.

[0095] In one embodiment, D 1 and D. 2 are each independently selected from a cytotoxic drug, a cytostatic drug, and an immunosuppressant.

[0096] In one embodiment, D 1 and D. 2 are each independently selected from an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, a taxane, a benzodiazepine or a benzodiazepine-containing drug (e.g., a pyrrolo[1,4]-benzodiazepine (PBD), an indolinobenzodiazepine, and an oxazolidinobenzodiazepine), and a vinca alkaloid.

[0097] In one embodiment, D 1 and D. 2 are each independently [ka] [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof. [ka] It should be understood that when an N atom bearing an * in an otherwise trivalent compound such as is attached to a linker, a cationic structure will result (cations are not depicted with respect to the molecular fragments herein).

[0098] In one embodiment, i) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iv) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; v)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vi)D 1teeth, [ka] and D 2 teeth, [ka] Is it; vii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; viii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; x)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xi) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvi)D 1 teeth, [ka] and D2 teeth, [ka] Is it; xxxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xli)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; il)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; l)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; li)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxiii)D 1 teeth, [ka] and D 2 teeth, [ka] or lxiv)D 1 teeth, [ka] and D 2 teeth, [ka] where the * indicates the point of attachment to the rest of the molecule.

[0099] In one embodiment, A 1 -D 1 and A 2 -D 2 is, independently, [ka] where * indicates the point of attachment to the rest of the molecule. is selected from the group consisting of:

[0100] In one embodiment, i)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iv) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; v)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; viii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ix) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; x)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xix)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xl)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xli)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; l)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; li)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxiii)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] or lxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] where the * indicates the point of attachment to the rest of the molecule.

[0101] In one embodiment, D 1 and / or D. 2 is an auristatin.

[0102] In one embodiment, D 1 and D. 2 Both are auristatins.

[0103] In one embodiment, D 1 and / or D. 2 is a topoisomerase 1 inhibitor.

[0104] In one embodiment, D 1 and D. 2 Both are topoisomerase 1 inhibitors.

[0105] In one embodiment, D 1 and D. 2 one of which is an auristatin and D 1 and D. 2 The other is a topoisomerase 1 inhibitor.

[0106] In one embodiment, D 1 is an auristatin, D 2 is a topoisomerase 1 inhibitor.

[0107] In one embodiment, D 1 is a topoisomerase 1 inhibitor, D 2 is an auristatin.

[0108] In one embodiment, D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0109] In one embodiment, D 1 and D. 2 is, independently, [ka] is selected from the group consisting of:

[0110] In one embodiment, D 1 and D. 2 is, independently, [ka] is selected from the group consisting of:

[0111] In one embodiment, D1 and D2 are each independently [ka] is selected from.

[0112] In one embodiment, D 1 and D. 2are each independently selected from antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemotherapeutic sensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[0113] In one embodiment, D 1 and D. 2 are each independently 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 maytansinoid, MetAP (methionine aminopeptidase), an inhibitor of nuclear export of protein CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reaction in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, a HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA interfering agent, a DNA minor groove binder, an RNA polymerase inhibitor, an amanitin, a spliceosome inhibitor, a topoisomerase inhibitor, a DHFR inhibitor, or a proapoptotic agent; 1 Also D 2 provided that the compound is not a BH3 mimetic.

[0114] In some embodiments, compounds or compounds allowed for pharmaceutical science are 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-P6、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-L 4-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-L7-P1、P1-L7-P2、P1-L7-P3、P1-L7-P4、P1 -L7-P5、P1-L7-P6、P1-L7-P7、P1-L7-P8、P1-L8-P1、P1-L8-P2、P1-L8-P3、P 1-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-P 1、P1-L10-P2、P1-L10-P3、P1-L10-P4、P1-L10-P5、P1-L10-P6、P1-L10-P7、P 1-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-L1 2-P4、P1-L12-P5、P1-L12-P6、P1-L12-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-L1 5-P5、P1-L15-P6、P1-L15-P7、P1-L15-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-L1 8-P6、P1-L18-P7、P1-L18-P8、P1-L19-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-L2 1-P7、P1-L21-P8、P1-L22-P1、P1-L22-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-L2 4-P8、P1-L25-P1、P1-L25-P2、P1-L25-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、<h2 style=";text-align:left;direction:ltr">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-L 28-P1、P1-L28-P2、P1-L28-P3、P1-L28-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-P 5、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、P1-L30-P7、P1-L30-P8、P1-L31-P1、P1 -L31-P2、P1-L31-P3、P1-L31-P4、P1-L31-P5、P1-L31-P6、P1-L31-P7、P1-L 31-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-P 4、P1-L33-P5、P1-L33-P6、P1-L33-P7、P1-L33-P8、P1-L34-P1、P1-L34-P2、 P1-L34-P3、P1-L34-P4、P1-L34-P5、P1-L34-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-L 35-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、P2-L1-P1、P2-L1-P2、P2-L1-P3、P 2-L1-P4, P2-L1-P5, P2-L1-P6, P2-L1-P7, P2-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,<h2 style=";text-align:left;direction:ltr">P2-L3-P2, P2-L3-P3, P2-L3-P4, P2-L3-P5, P2-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-P 7, P2-L4-P8, P2-L5-P1, P2-L5-P2, P2-L5-P3, 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-L9-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-L 10-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-L12-P1、P2-L12-P2、P2-L12-P 3、P2-L12-P4、P2-L12-P5、P2-L12-P6、P2-L12-P7、P2-L12-P8、P2-L13-P1、P 2-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-L1 4-P6、P2-L14-P7、P2-L14-P8、P2-L15-P1、P2-L15-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、 <h2 style=";text-align:left;direction:ltr">-P4、P2-L30-P5、P2-L30-P6、P2-L30-P7、P2-L30-P8、P2-L31-P1、P2-L31-P 2、P2-L31-P3、P2-L31-P4、P2-L31-P5、P2-L31-P6、P2-L31-P7、P2-L31-P8、P 2-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-L33-P8、P2-L34-P1、P2-L34-P2、P2-L34-P 3、P2-L34-P4、P2-L34-P5、P2-L34-P6、P2-L34-P7、P2-L34-P8、P2-L35-P1、P 2-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、P2-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,P 3-L4-P2、P3-L4-P3、P3-L4-P4、P3-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-P2, P3-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-P6、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-L11-P3、P3-L11-P4、P3-L11-P5、P3-L11-P6、P 3-L11-P7、P3-L11-P8、P3-L12-P1、P3-L12-P2、P3-L12-P3、P3-L12-P4、P3-L 12-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-L14-P4、P3-L14-P5、P3-L14-P6、P3-L14-P7、P 3-L14-P8、P3-L15-P1、P3-L15-P2、P3-L15-P3、P3-L15-P4、P3-L15-P5、P3-L 15-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-L17-P5、P3-L17-P6、P3-L17-P7、P3-L17-P8、P 3-L18-P1、P3-L18-P2、P3-L18-P3、P3-L18-P4、P3-L18-P5、P3-L18-P6、P3-L 18-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-L20-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-L2 1-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-L23-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-L2 5-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-L26-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-L2 8-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-L30-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-L3 1-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、P、 4-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-L35-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、<h2 style=";text-align:left;direction:ltr">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-L 4-P2、P5-L4-P3、P5-L4-P4、P5-L4-P5、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-L8-P1、P5-L8-P2、P5-L8-P3、P5-L8-P4、P 5-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-L1 2-P5、P5-L12-P6、P5-L12-P7、P5-L12-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-L1 5-P6、P5-L15-P7、P5-L15-P8、P5-L16-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-L1 8-P7、P5-L18-P8、P5-L19-P1、P5-L19-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-L2 1-P8、P5-L22-P1、P5-L22-P2、P5-L22-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-L2 5-P1、P5-L25-P2、P5-L25-P3、P5-L25-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、<h2 style=";text-align:left;direction:ltr">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-L2 8-P2、P5-L28-P3、P5-L28-P4、P5-L28-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-L3 1-P3、P5-L31-P4、P5-L31-P5、P5-L31-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-L3 4-P4、P5-L34-P5、P5-L34-P6、P5-L34-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,<h2 style=";text-align:left;direction:ltr">P6-L3-P4、P6-L3-P5、P6-L3-P6、P6-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-P 1、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-P1, P6-L8-P2, P6-L8-P3, P6-L8-P4, P6-L 8-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、P 6-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-L1 1-P7、P6-L11-P8、P6-L12-P1、P6-L12-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-L1 4-P8、P6-L15-P1、P6-L15-P2、P6-L15-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-L18-P4、P6-L18-P5、P6-L18-P6、P6-L18-P 7、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-L 21-P2、P6-L21-P3、P6-L21-P4、P6-L21-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-P 6、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-L24-P6、P6-L24-P7、P6-L24-P8、P6-L2 5-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、P 6-L27-P4、P6-L27-P5、P6-L27-P6、P6-L27-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-L2 8-P8、P6-L29-P1、P6-L29-P2、P6-L29-P3、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、<h2 style=";text-align:left;direction:ltr">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-L31-P6、P6-L31-P7、P6-L31-P8、P6-L 32-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、P6-L34-P1、P6-L34-P2、P6-L34-P3、P 6-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-L3 5-P8、P6-L36-P1、P6-L36-P2、P6-L36-P3、P6-L36-P4、P6-L36-P5、P6-L36-P 6, P6-L36-P7, P6-L36-P8, P7-L1-P1, P7-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-P7, P7-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-P5、P7-L4-P6、P7-L4-P7、P7-L4-P8、P 7-L5-P1、P7-L5-P2、P7-L5-P3、P7-L5-P4、P7-L5-P5、P7-L5-P6、P7-L5-P7、P 7-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、P7-L9-P7、P7-L9-P8、P7-L10-P1、P7-L10-P2、P7-L10-P3、P7-L10-P4、P7-L10-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、P7-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-L14-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-L2 1-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-L2 5-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-L2 8-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-L30-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-L3 1-P3、P7-L31-P4、P7-L31-P5、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、<h2 style=";text-align:left;direction:ltr">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-L 34-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、P7-L36-P3、P7-L36-P4、P7-L36-P5、P7-L36-P6、P 7-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-P 3、P8-L3-P4、P8-L3-P5、P8-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-L 6-P7,P8-L6-P8,P8-L7-P1,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-L9-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、P8-L11-P3、P8-L11-P4、P8-L11-P5、P8-L11-P6、P8-L11-P7、P、 8-L11-P8、P8-L12-P1、P8-L12-P2、P8-L12-P3、P8-L12-P4、P8-L12-P5、P8- L12-P6、P8-L12-P7、P8-L12-P8、P8-L13-P1、P8-L13-P2、P8-L13-P3、P8-L1 3-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、P8-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-L1 6-P5、P8-L16-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-L1 9-P6、P8-L19-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-L2 2-P7、P8-L22-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-L2 5-P8、P8-L26-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-L2 9-P1、P8-L29-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-L3 2-P2、P8-L32-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-L3 5-P3、P8-L35-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.

[0115] According to one aspect of the present invention, a conjugate is provided comprising an antibody or antigen-binding fragment thereof covalently linked to two pharma- ceutical active drugs via a dual linker, the dual linker having one attachment point attached to the antibody and two attachment points to the two pharma-ceutical active drugs, with the proviso that neither pharma-ceutical active drug is a BH3 mimetic. In one embodiment, the two pharma-ceutical active drugs are the same or different. In another embodiment, the pharma-ceutical active drug is selected from a cytotoxic drug, a cytostatic drug, and an immunosuppressant. In yet another embodiment, the pharma-ceutical active drug is selected from an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, a taxane, a benzodiazepine or a benzodiazepine-containing drug (e.g., a pyrrolo[1,4]-benzodiazepine (PBD), an indolinobenzodiazepine, and an oxazolidinobenzodiazepine), and a vinca alkaloid. In some embodiments, the pharma- ceutically active drug is an auristatin, hi some embodiments, the pharma- ceutically active drug is selected from an antitubulin agent, a tubulin inhibitor, a DNA minor groove binder, a DNA replication inhibitor, an alkylating agent, an antibiotic, an antifolate, an antimetabolite, a chemotherapy sensitizer, a topoisomerase inhibitor, and / or a vinca alkaloid. In another embodiment, the pharma- ceutically active drug is selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizing agents, microtubule destabilizing agents, auristatins, dolastatins, maytansinoids, MetAP (methionine aminopeptidase), inhibitors of nuclear export of protein CRM1, DPPIV inhibitors, inhibitors of phosphoryl transfer reactions in mitochondria, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinesin inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA interfering agents, DNA minor groove binders, RNA polymerase inhibitors, amanitin, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors, or pro-apoptotic agents.In further embodiments, the pharma- ceutically active drug is selected from a topoisomerase 1 inhibitor or its enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or addition salt with a pharma- ceutically acceptable acid or base. In one embodiment, the pharma- ceutically active drug is a topoisomerase 1 inhibitor selected from topotecan, exatecan, deruxtecan, and SN-38. In yet another embodiment, the pharma-ceutically active drug is selected from a mitotic inhibitor or its enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or addition salt with a pharma- ceutically acceptable acid or base. In a further embodiment, the mitotic inhibitor is monomethyl auristatin E (MMAE) or a taxane. In one embodiment, the taxane is selected from docetaxel, paclitaxel, or cabazitaxel. In another embodiment, the conjugate comprises any of the compounds disclosed herein or a pharma- ceutically acceptable salt thereof.

[0116] As described above, according to one embodiment of the present invention, a compound represented by formula (A-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is a branching moiety; L 2’ and L 3’ are each independently a linker; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. A conjugate of the formula:

[0117] In one embodiment, L 2’and L 3’ each comprises a cleavable group, and 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).

[0118] In one embodiment, L 2’ and L 3’ Each of the formulas comprises a peptide group and a self-immolative group.

[0119] In one embodiment, L 2’ and L 3’ each comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (e.g., glucuronamide) group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0120] In certain embodiments, the conjugate has the formula (B-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently an enzyme cleavage element or a hydrophilic moiety (e.g., E 1 and E 2 are enzyme cleavage elements, respectively); V 1 and V 2may independently comprise: i) a self-immolative group; ii) an enzymatic cleavage element (e.g., V 1 and V 2 are each independently a self-immolative group) or iii) comprise a self-immolative group and an enzyme-cleavage element; D 1 and D. 2 are each independently a pharma- ceutically active drug, but D 1 Also D 2 is not a BH3 mimetic; and A is an integer from 1 to 16. It is of the following.

[0121] In certain embodiments, the conjugate has the formula (B-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic moiety; V 1 and V 2 are each 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; D 1 and D. 2are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. It is of the following.

[0122] In certain embodiments, W is N or CH.

[0123] In one embodiment, E 1 and E 2 are each enzyme cleavage elements.

[0124] In one embodiment, V 1 and V 2 are each independently a self-immolative group.

[0125] In certain embodiments, a is an integer from 1 to 8, or from 1 to 6 or 1 to 4, or a is 1 or 2.

[0126] In certain embodiments, a is determined by liquid chromatography-mass spectrometry (LC-MS).

[0127] In certain embodiments, (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 is -CH 2 -O-, -NH-CH 2 Self-immolative groups include -, -C(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0128] In certain embodiments, W is N or CH.

[0129] In one embodiment, R 2 and R 3 are each a hydrophilic group.

[0130] In certain embodiments, the conjugate has the formula (C-2): [ka] (In the formula, Ab is an antibody or an antigen-binding fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, [ka] , -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)-*, Each Ra are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. It is of the following.

[0131] In certain embodiments, the conjugate has formula (D1-2), (D2-2) or (D3-2): [ka] It is of the following.

[0132] In certain embodiments, the conjugate is of formula (D1-2), where R 2 and R 3 are each independently a hydrophilic group, and in formula (D2-2), R 2 and R 3 are each independently an enzyme cleavage element; and with respect to formula (D3-2), R 2 is a hydrophilic group, and R 3 is an enzyme cleavage element.

[0133] In one embodiment, R100 teeth, [ka] [ka] [ka] [ka] [ka] Disulfides (In the formula, R 16 , H, C 1 ~C 4 alkyl, phenyl, pyrimidine or pyridine; R 18 , H, C 1 ~C 6 C substituted with alkyl, phenyl or 1 to 3 -OH groups 1 ~C 4 is alkyl; Each R 15 are independently H, C 1 ~C 6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1 ~C 4 Alkoxy and -C(=O)OH substituted C 1 ~C 4 alkyl; R 17 is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 19 is H or methyl; and R 20 -H, -CH 3 or phenyl) is selected from the group consisting of:

[0134] In one embodiment, R 100 teeth, [ka] (In the formula, R 100 (*** indicates the attachment point to Ab) is selected from the group consisting of:

[0135] In one embodiment, R 100 teeth, [ka] (In the formula, R 100 (*** indicates the attachment point to Ab) It is.

[0136] In one embodiment, (1) L 1 teeth, [ka] or *-CH(OH)CH(OH)CH(OH)CH(OH)-** (wherein each n is an integer from 1 to 12). Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (2)L 1 teeth, [ka] and n is an integer from 1 to 12, or n is 1, or n is 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (3) L 1 teeth, [ka] and n is an integer from 1 to 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (4) L 1 teeth, [ka] Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; or (5) L 1 is *-C(=O)(CH 2 ) m O(CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)(CH 2 ) m -**;*-C(=O)NH((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)O(CH 2 ) m SSC(R L1 ) 2 (CH 2 ) m C(=O)NR L1 (CH 2 ) m NR L1 C(=O)(CH 2 ) m -**;*-C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m -**;*-C(=O)(CH2 ) m NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)-**;*-C(=O)(CH 2 ) m X 1 (CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 )m C(R L1 ) 2 -** or *-C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m -** (In the formula, L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicating a direct or indirect (e.g., direct) point of attachment to; X 1 teeth, [ka] 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 are independently H and C 1 ~C 6 alkyl) is a bridging spacer comprising:

[0137] In one embodiment, L 1 teeth, [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8), and L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 (Indicating a direct or indirect point of attachment to The part represented by

[0138] In one embodiment, n is an integer from 4 to 8.

[0139] In certain embodiments, n is 4 or 8.

[0140] In one embodiment, L 1 is the formula [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); u is 0 or 1; L 1 The * in indicates the direct point of attachment to W, and L 1 The ** is R 1 (Indicates the direct attachment point to It is represented by:

[0141] In one embodiment, n is an integer from 4 to 8.

[0142] In certain embodiments, n is 4 or 8.

[0143] In one embodiment, x is an integer from 0 to 2.

[0144] In certain embodiments, x is 0 or 2.

[0145] In one embodiment, z is an integer from 0 to 2.

[0146] In certain embodiments, z is 0 or 2.

[0147] In one embodiment, L 1 teeth, [ka] is selected from the group consisting of:

[0148] In one embodiment, L 2 and L 3 are each independently [ka] (In the formula, 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; L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 (## indicates the direct or indirect point of attachment to W) is a linking spacer comprising a portion represented by:

[0149] In one embodiment, L 2 and L 3 are each independently [ka] [ka] [ka] (In the formula, k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R L23 is hydrogen or C 1 ~C 6is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; If W is N, then L 2 and L 3 (provided that it is not (L2c), (L2d), (L2f) or (L2k)) is a linking spacer selected from the group consisting of:

[0150] In one embodiment, L 2 and L 3 are each independently [ka] [ka] [ka] (In the formula, k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1 ~C 3 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E2 and L 2 Or L 3 ## indicates the direct point of attachment to W; if W is N, then L 2 and L 3 (provided that it is not (L2FF), (L2MM), (L2NN), (L2OO) or (L2PP)) is a linking spacer selected from the group consisting of:

[0151] In one embodiment, L 2 and L 3 is, independently, [ka] [ka] (In the formula, L 2 Or L 3 # is E 1 Or E 2 indicates the direct attachment point to L 2 Or L 3 ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H and R H teeth, [ka] and D is an integer from 20 to 30 (e.g., 25). is a linking spacer selected from the group consisting of:

[0152] In one embodiment, d is 25.

[0153] In certain embodiments, each peptide group independently comprises 1-4, 1-3, or 1-2 amino acid residues.

[0154] In certain embodiments, each peptide group independently comprises two amino acid residues.

[0155] In one embodiment, each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (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).

[0156] In certain embodiments, 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.

[0157] In one embodiment, E 1 and / or E 2 are each independently [ka] (Wherein, E1-1 or E1-2 is V in formula (B) 1 Or V 2 or the direct point of attachment to the -NH- group in formulas (C) and (D); and E1-1 or E1-2 ^^ respectively represent L 2 Or L 3 indicates the direct point of attachment to 1 and E 2 are peptide groups independently selected from (E1-1) and (E1-2). is a peptide group selected from the group consisting of:

[0158] In one embodiment, E 1 and E 2 are each a peptide group independently selected from (E1-1) and (E1-2).

[0159] In one embodiment, E 1 and / or E 2 are each independently [ka] (In the formula, R E is a hydrophilic group R H is) is a peptide group represented by:

[0160] In one embodiment, the hydrophilic group R H teeth, [ka] (wherein e is an integer of 20 to 30 (e.g., 25)) It is.

[0161] In one embodiment, e is 25.

[0162] In one embodiment, E 1 and E 2 are respectively [ka] It is.

[0163] In one embodiment, A 1 and A 2 are independently a bond and -OC(=O)-* (wherein * represents D 1 Or D 2 (indicating the point of attachment to the

[0164] In one embodiment, A 1 and A 2 are independent, combined, [ka] and -OC(=O)-* (wherein * represents D 1 Or D 2 (indicating the point of attachment to the

[0165] In one embodiment, A 1 and A 2 is a bond.

[0166] In one embodiment, A 1 and A 2 is independently a bond, or [ka] (In the formula, * represents D 1 Or D 2 (Indicates the attachment point to It is.

[0167] In one embodiment, A 1 and A 2 On the other hand, [ka] And A 1 and A 2 The other is a bond.

[0168] In one embodiment, A 1 and A 2 Both [ka] It is.

[0169] In one embodiment, A 1 and A 2 On the other hand, [ka] And A 1 and A 2 The other is OC(=O)-*.

[0170] In one embodiment, (i) A 1 and A 2 is -OC(=O)-*; (ii)A 1 and A 2 teeth, [ka] Is it; (iii)A 1 is -OC(=O)-*, and A 2 is a bond; (iv)A 1 is -OC(=O)-*, and A 2 teeth, [ka] Is it; (v)A 1 is a bond, and A 2 teeth, [ka] or (vi) A 1 is a bond, and A 2 is -OC(=O)-* (wherein * is D 1 Or D 2 (showing the attachment point to the

[0171] In one embodiment, i) L 4 and L 5 are each independently [ka] (In the formula, Z is -O-, -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR L45 -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is a bond, triazolyl or -CH 2 -triazolyl-, X is R 2 or R 3 (connected to or a spacer moiety having the structure (ii) L 4 and L 5 is, independently, [ka] (In the formula, Z is -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n where each n is independently 1, 2, or 3; X is R 2 or R 3 (connected to It is a spacer portion having the structure:

[0172] In certain embodiments, Z is -O-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH- or -CH 2 X is a bond, triazolyl or -CH 2 -triazolyl-; and R L45 is, at each occurrence, independently H or C 1 ~C 3 It is an alkyl.

[0173] In one embodiment, L 4 and L 5 are each independently [ka] (In the formula, L 4 Or L 5 @ indicates the direct point of attachment to the phenyl group, and L 4 Or L 5 @@ is R 2 or R 3 (Indicates the direct attachment point to is a spacer moiety selected from the group consisting of:

[0174] In one embodiment, R 2 and R 3 Each of the hydrophilic groups represented by the formula (I) is independently selected from polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 [ka] C replaced with 2 ~C 6 Alkyl or -OC(=O)NHS(O) 2 NHCH 2 CH 2 OCH 3 , -NHC(=O)C 1 ~C 4 Alkylene-P(O)(OCH 2 CH 3 ) 2and C substituted with 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 Contains alkyl.

[0175] In one embodiment, R 2 or / and R 3 are each independently [ka] (wherein n is an integer of 1 to 6). [ka] is selected from the group consisting of:

[0176] In one embodiment, R 2 or / and R 3 are each independently (i) the following part: [ka] (In the formula, f is an integer from 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) Polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by Contains:

[0177] In one embodiment, R 2 or R 3Each hydrophilic group represented by the formula: (i) the following part: [ka] (In the formula, f is an integer of 3 to 25; R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) or polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) Contains polyethylene glycol.

[0178] In one embodiment, R 2 and R 3 are each independently [ka] (In the formula, g and h are independently an integer of 20 to 30 (e.g., 23 or 24). is selected from the group consisting of:

[0179] In one embodiment, R 2 or / and R 3 teeth, [ka] Includes.

[0180] In one embodiment, R 2 and R 3 are each independently represented by the formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) Contains polyethylene glycol.

[0181] In one embodiment, D 1 and D. 2 is the same.

[0182] In one embodiment, D 1 and D. 2 is different.

[0183] In one embodiment, D 1 and D. 2 are each independently selected from a cytotoxic drug, a cytostatic drug, and an immunosuppressant.

[0184] In one embodiment, D 1 and D. 2 are each independently selected from an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, a taxane, a benzodiazepine or a benzodiazepine-containing drug (e.g., a pyrrolo[1,4]-benzodiazepine (PBD), an indolinobenzodiazepine, and an oxazolidinobenzodiazepine), and a vinca alkaloid.

[0185] In one embodiment, D 1 and D. 2 are each independently [ka] [ka] [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0186] In one embodiment, i)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iv) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; v)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; viii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; x)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xi) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvii)D1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xli)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; il)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; l)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; li)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxiii)D 1 teeth, [ka] and D 2 teeth, [ka] or lxiv)D 1 teeth, [ka] and D 2 teeth, [ka] It is.

[0187] In one embodiment, i)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iv) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; v)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; viii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ix) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; x)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxv)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xl)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xli)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlii)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] Is it; xliii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; l)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; li)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] or lxiv)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] where the * indicates the point of attachment to the rest of the molecule.

[0188] In one embodiment, D 1 and / or D. 2 is an auristatin.

[0189] In one embodiment, D 1 and D. 2 Both are auristatins.

[0190] In one embodiment, D 1 and / or D. 2 is a topoisomerase 1 inhibitor.

[0191] In one embodiment, D 1 and D. 2 Both are topoisomerase 1 inhibitors.

[0192] In one embodiment, D 1 and D. 2 one of which is an auristatin and D 1 and D. 2 The other is a topoisomerase 1 inhibitor.

[0193] In one embodiment, D 1 is an auristatin, D 2 is a topoisomerase 1 inhibitor.

[0194] In one embodiment, D 1 is a topoisomerase 1 inhibitor, D 2 is an auristatin.

[0195] In one embodiment, D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to is selected from the group consisting of:

[0196] In one embodiment, D 1 and D. 2 is, independently, [ka] is selected from the group consisting of:

[0197] In one embodiment, D 1 and D. 2 are each independently selected from antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemotherapeutic sensitizers, topoisomerase inhibitors, and / or vinca alkaloids.

[0198] In one embodiment, D 1 and D. 2 are each independently 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 maytansinoid, MetAP (methionine aminopeptidase), an inhibitor of nuclear export of protein CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reaction in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, a HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA interfering agent, a DNA minor groove binder, an RNA polymerase inhibitor, an amanitin, a spliceosome inhibitor, a topoisomerase inhibitor, a DHFR inhibitor, or a proapoptotic agent; 1 Also D 2 provided that the compound is not a BH3 mimetic.

[0199] In certain embodiments, the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

[0200] In certain 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, 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.

[0201] In certain embodiments, the target antigen is PCAD, CD48, CD74, EphA2, HER2, TROP2, B7-H3, or 5T4.

[0202] In certain embodiments, the antibody or antigen-binding fragment thereof is selected from Table D1.

[0203] In some embodiments, the antibody or antigen-binding fragment comprises i) three heavy chain CDR sequences and three light chain CDR sequences selected from an antibody in Tables D3 and D8, ii) a heavy chain variable region sequence and a light chain variable region sequence selected from an antibody in Tables D2 and D8, and / or iii) a heavy chain sequence and a light chain sequence selected from an antibody in Tables D4, D5 and D7.

[0204] In certain embodiments, the antibody or antigen-binding fragment comprises: 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, 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, 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) 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: 172, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 5) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 263, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 6) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, 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; 7) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 215, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and 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 and three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0205] In one embodiment, 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.

[0206] In certain embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; (b) a heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence at least 95% identical to SEQ ID NO: 236, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; or (c) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 239, or a sequence at least 95% identical to SEQ ID NO: 239. is an anti-CD74 antibody comprising

[0207] In certain embodiments, the antibody or antigen-binding fragment comprises: 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, 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, 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, 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) 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 and three light chain CDRs selected from the group consisting of:

[0208] In one embodiment, 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.

[0209] In one embodiment, 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 that is at least 95% identical to SEQ ID NO:240, and a light chain amino acid sequence of SEQ ID NO:243, or a sequence that is 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 that is at least 95% identical to SEQ ID NO:242, and a light chain amino acid sequence of SEQ ID NO:243, or a sequence that is at least 95% identical to SEQ ID NO:243; c) a heavy chain amino acid sequence of SEQ ID NO:240, or a sequence that is at least 95% identical to SEQ ID NO:240, and a light chain amino acid sequence of SEQ ID NO:69, or a sequence that is at least 95% identical to SEQ ID NO:70.

[0210] In certain embodiments, the antibody or antigen-binding fragment comprises: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, 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, 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, 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) 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 and three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0211] In one embodiment, 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.

[0212] In one embodiment, 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.

[0213] In certain embodiments, the antibody or antigen-binding fragment comprises: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, 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, 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, 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) 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 and three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0214] In one embodiment, 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.

[0215] In one embodiment, 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.

[0216] In certain embodiments, the antibody or antigen-binding fragment comprises: 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, 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, 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) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335 and three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0217] In one embodiment, 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.

[0218] In one embodiment, 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.

[0219] In some embodiments, the antibody or antigen-binding fragment thereof comprises one or more cysteine ​​substitutions selected from E152C, S375C, or both E152C and S375C in the heavy chain of the antibody or antigen-binding fragment thereof, where positions are numbered according to the EU system.

[0220] In certain embodiments, the antibody or antigen-binding fragment thereof comprises one or more Fc-silencing mutations.

[0221] In one embodiment, the composition comprises multiple copies of the antibody drug conjugate of any one of claims 46 to 110, and the average a of the antibody drug conjugate in the composition is from about 1 to about 8, e.g., from about 1 to about 6, from about 1 to about 4, or from about 1 to about 2.

[0222] In certain embodiments, the compound, or a pharma- ceutically acceptable salt thereof, is represented by any one of the following formulas: [ka] [ka] [ka] [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30; o for each occurrence is independently an integer from 1 to 9; and and n is an integer from 1 to 12.

[0223] In one embodiment, A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the

[0224] In certain embodiments, the conjugate is represented by any one of the following formulas: [ka] [ka] [ka] [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30; o for each occurrence is independently an integer from 1 to 9; n is an integer from 1 to 12; and **--- indicates the point of attachment to Ab).

[0225] In one embodiment, A 1 and A 2 each independently represents a bond and OC(=O)-* (wherein A1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the

[0226] In one embodiment, the compound or a pharma- ceutically acceptable salt thereof has the formula (D5a-1): [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); and n is an integer from 1 to 12 (e.g., 5 to 10). It is of the following.

[0227] In one embodiment, A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the

[0228] In certain embodiments, the conjugate has formula (D5a-2): [ka] (In the formula, A 1 and A2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); n is an integer from 1 to 12 (e.g., 5 to 10); and **--- indicates the attachment point to Ab) It is of the following.

[0229] In one embodiment, A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the

[0230] In certain embodiments, the conjugate is represented by any one of the following formulas: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein * is D 1 Or D 2 **--- indicates point of attachment to Ab; and [ka] D 1 Or D 2 (Indicating a direct attachment point to the

[0231] In one embodiment, A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the

[0232] In some embodiments, the present disclosure provides, in part, novel antibody drug conjugate (ADC) compounds that have biological activity against cancer cells. The compounds may slow, inhibit, and / or reverse tumor growth in mammals and / or may be useful for treating human cancer patients. The present disclosure more specifically relates to ADC compounds that can bind to and kill cancer cells in some embodiments. In some embodiments, the ADC compounds disclosed herein include a dual linker that connects a full-length antibody or antigen-binding fragment with, optionally, two pharma- ceutically active drugs, provided that neither is a BH3 mimetic. In some embodiments, the ADC compounds can also be internalized into target cells after binding.

[0233] In some embodiments, the antibody or antigen-binding fragment binds to a target antigen on a cancer cell, hi 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, FOLR1, ENPP3, MET, AXL, SLC34A2, Nectin4, TROP2, LIV1, CD46, MSLN, F3, MUC16, SLC39A6, TFRC, TACSTD2, or GPNMB. In some embodiments, the target antigen is 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 (mimetics), 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-related 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 type B receptor), FCRHI (Fc receptor-like protein I), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (immunoglobulin superfamily receptor metastasis-associated 2), Lewis-Y antigen, LY64 (RP105), MCP-I, MDP (DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-Ru, 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, tenascin-C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-Rl, 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.

[0234] In some embodiments, the antibody or antigen-binding fragment is selected from the group consisting of antibodies and antigen-binding fragments described in International Publication Nos. WO 2018 / 098306, WO 2016 / 179257, WO 2011 / 097627, WO 2017 / 214282, WO 2017 / 214301, WO 2017 / 214233, WO 201 and in U.S. Pat. No. 6,870,034 B2, and on the internet at go.drugbank.com / drugs / DB00002.

[0235] 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., VHmilxVK1aNQAb 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 CDR sequences selected from those in Tables D3 and D8, or an antibody or antigen-binding fragment having variable regions selected from those in Tables D2 and D8, or an antibody or antigen-binding fragment having a full length selected from those in Tables D4, D5, and D7.

[0236] Also provided herein, in some embodiments, are compositions comprising multiple copies of an antibody drug conjugate (e.g., any of the exemplary antibody drug conjugates described herein). In some embodiments, the average p of the antibody drug conjugate in the composition is about 2 to about 4.

[0237] In some embodiments, the antibody or antigen-binding fragment thereof is conjugated to a group selected from any one of: 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-P6, 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-L 4-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-L7-P1, P1 -L7-P2, P1-L7-P3, P1-L7-P4, P1-L7-P5, P1-L7-P6, P1-L7-P7, P1-L7-P 8, 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, P 1-L11-P2, P1-L11-P3, P1-L11-P4, P1-L11-P5, P1-L11-P6, P1-L11-P7, P 1-L11-P8, P1-L12-P1, P1-L12-P2, P1-L12-P3, P1-L12-P4, P1-L12-P5, P1-L12-P6, P1-L12-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-L1 4-P8、P1-L15-P1、P1-L15-P2、P1-L15-P3、P1-L15-P4、P1-L15-P5、P1-L15-P6、P1-L15-P7、P1-L15-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-L1 8-P1、P1-L18-P2、P1-L18-P3、P1-L18-P4、P1-L18-P5、P1-L18-P6、P1-L18- P7、P1-L18-P8、P1-L19-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-L2 1-P2、P1-L21-P3、P1-L21-P4、P1-L21-P5、P1-L21-P6、P1-L21-P7、P1-L21- P8、P1-L22-P1、P1-L22-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-L2 4-P3、P1-L24-P4、P1-L24-P5、P1-L24-P6、P1-L24-P7、P1-L24-P8、P1-L25-P1、P1-L25-P2、P1-L25-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-L 27-P4、P1-L27-P5、P1-L27-P6、P1-L27-P7、P1-L27-P8、P1-L28-P1、P1-L28-P2、P1-L28-P3、P1-L28-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-L 30-P5、P1-L30-P6、P1-L30-P7、P1-L30-P8、P1-L31-P1、P1-L31-P2、P1-L31 -P3、P1-L31-P4、P1-L31-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、P 1-L32-P8、P1-L33-P1、P1-L33-P2、P1-L33-P3、P1-L33-P4、P1-L33-P5、P1- L33-P6、P1-L33-P7、P1-L33-P8、P1-L34-P1、P1-L34-P2、P1-L34-P3、P1-L3 4-P4、P1-L34-P5、P1-L34-P6、P1-L34-P7、P1-L34-P8、P1-L35-P1、P1-L35-P 2、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、P2-L1-P1、P2-L1-P2、P2-L1-P3、P2-L1-P4、P2-L1-P5、 P2-L1-P6、P2-L1-P7、P2-L1-P8、P2-L2-P1、P2-L2-P2、P2-L2-P3、P2-L2-P4、<h2 style=";text-align:left;direction:ltr">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-P5, P2-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-P 1、P2-L5-P2、P2-L5-P3、P2-L5-P4、P2-L5-P5、P2-L5-P6、P2-L5-P7、P2-L5-P 8, 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-L9-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-L1 1-P1、P2-L11-P2、P2-L11-P3、P2-L11-P4、P2-L11-P5、P2-L11-P6、P2-L11- P7、P2-L11-P8、P2-L12-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-L1 4-P2、P2-L14-P3、P2-L14-P4、P2-L14-P5、P2-L14-P6、P2-L14-P7、P2-L14- P8、P2-L15-P1、P2-L15-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-L、 <h2 style=";text-align:left;direction:ltr">29-P7、P2-L29-P8、P2-L30-P1、P2-L30-P2、P2-L30-P3、P2-L30-P4、P2-L30 -P5、P2-L30-P6、P2-L30-P7、P2-L30-P8、P2-L31-P1、P2-L31-P2、P2-L31-P 3、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-L33-P8, P2-L34-P1, P2-L34-P2, P2-L34-P3, P2-L34-P 4、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、P2-L36-P3、P2-L36-P4、P2-L36-P5、P2-L36-P6、P2-L3 6-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、P 3-L4-P3、P3-L4-P4、P3-L4-P5、P3-L4-P6、P3-L4-P7、P3-L4-P8、P3-L5-P1、P 3-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-P2, P3-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-P6、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-L11-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-L14-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-L17-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-L20-P6、P3-L20-P7、P3-L20-P8、P3-L21-P1、P3-L2 1-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-L23-P7、P3-L23-P8、P3-L24-P1、P3-L24-P2、P3-L2 4-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-L26-P8、P3-L27-P1、P3-L27-P2、P3-L27-P3、P3-L2 7-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-L30-P1、P3-L30-P2、P3-L30-P3、P3-L30-P4、P3-L3 0-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-L35-P5、P4-L35-P6、P4-L35-P7、P4-L35-P8、P4-L36-P1、<h2 style=";text-align:left;direction:ltr">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-P5, P5-L4-P6, P5-L4-P7, P5-L4-P8, P5-L5-P1, P5-L5-P 2、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-L8-P1, P5-L8-P2, P5-L8-P3, P5-L8-P4, P5-L8-P5, P5-L 8-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-L1 1-P8、P5-L12-P1、P5-L12-P2、P5-L12-P3、P5-L12-P4、P5-L12-P5、P5-L12- P6、P5-L12-P7、P5-L12-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-L1 5-P1、P5-L15-P2、P5-L15-P3、P5-L15-P4、P5-L15-P5、P5-L15-P6、P5-L15- P7、P5-L15-P8、P5-L16-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-L1 8-P2、P5-L18-P3、P5-L18-P4、P5-L18-P5、P5-L18-P6、P5-L18-P7、P5-L18-P8、P5-L19-P1、P5-L19-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-L2 1-P3、P5-L21-P4、P5-L21-P5、P5-L21-P6、P5-L21-P7、P5-L21-P8、P5-L22-P1、P5-L22-P2、P5-L22-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-L2 4-P4、P5-L24-P5、P5-L24-P6、P5-L24-P7、P5-L24-P8、P5-L25-P1、P5-L25- P2、P5-L25-P3、P5-L25-P4、P5-L25-P5、P5-L25-P6、P5-L25-P7、P5-L25-P8、<h2 style=";text-align:left;direction:ltr">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-L 27-P5、P5-L27-P6、P5-L27-P7、P5-L27-P8、P5-L28-P1、P5-L28-P2、P5-L28 -P3、P5-L28-P4、P5-L28-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、P 5-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-L3 1-P4、P5-L31-P5、P5-L31-P6、P5-L31-P7、P5-L31-P8、P5-L32-P1、P5-L32-P 2、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-L34-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,<h2 style=";text-align:left;direction:ltr">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, P6-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-P 2、P6-L5-P3、P6-L5-P4、P6-L5-P5、P6-L5-P6、P6-L5-P7、P6-L5-P8、P6-L6-P 1、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-P1、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、P 6-L10-P4、P6-L10-P5、P6-L10-P6、P6-L10-P7、P6-L10-P8、P6-L11-P1、P6-L 11-P2、P6-L11-P3、P6-L11-P4、P6-L11-P5、P6-L11-P6、P6-L11-P7、P6-L11 -P8、P6-L12-P1、P6-L12-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、P 6-L13-P5、P6-L13-P6、P6-L13-P7、P6-L13-P8、P6-L14-P1、P6-L14-P2、P6-L 14-P3、P6-L14-P4、P6-L14-P5、P6-L14-P6、P6-L14-P7、P6-L14-P8、P6-L15- P1、P6-L15-P2、P6-L15-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-L、 17-P4、P6-L17-P5、P6-L17-P6、P6-L17-P7、P6-L17-P8、P6-L18-P1、P6-L18 -P2、P6-L18-P3、P6-L18-P4、P6-L18-P5、P6-L18-P6、P6-L18-P7、P6-L18-P 8、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-L21-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-L24-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、P 6-L26-P7、P6-L26-P8、P6-L27-P1、P6-L27-P2、P6-L27-P3、P6-L27-P4、P6- L27-P5、P6-L27-P6、P6-L27-P7、P6-L27-P8、P6-L28-P1、P6-L28-P2、P6-L2 8-P3、P6-L28-P4、P6-L28-P5、P6-L28-P6、P6-L28-P7、P6-L28-P8、P6-L29-P1、P6-L29-P2、P6-L29-P3、P6-L29-P4、P6-L29-P5、P6-L29-P6、P6-L29-P7、<h2 style=";text-align:left;direction:ltr">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-L 31-P4、P6-L31-P5、P6-L31-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-P 8、P6-L33-P1、P6-L33-P2、P6-L33-P3、P6-L33-P4、P6-L33-P5、P6-L33-P6、 P6-L33-P7、P6-L33-P8、P6-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-L 35-P3、P6-L35-P4、P6-L35-P5、P6-L35-P6、P6-L35-P7、P6-L35-P8、P6-L36 -P1、P6-L36-P2、P6-L36-P3、P6-L36-P4、P6-L36-P5、P6-L36-P6、P6-L36-P 7、P6-L36-P8、P7-L1-P1、P7-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-P7,P7-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-P5, P7-L4-P6, P7-L4-P7, P7-L4-P8, P7-L5-P1, P 7-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,<h2 style=";text-align:left;direction:ltr">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-P 5、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、P7-L9-P7、P7-L9-P8、P7-L10-P1、P7-L10-P2、P7- L10-P3、P7-L10-P4、P7-L10-P5、P7-L10-P6、P7-L10-P7、P7-L10-P8、P7-L1 1-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、P7-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-L 14-P2、P7-L14-P3、P7-L14-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-P 6、P7-L15-P7、P7-L15-P8、P7-L16-P1、P7-L16-P2、P7-L16-P3、P7-L16-P4、P 7-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-L1 8-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-L2 1-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-L2 4-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-L2 7-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-L30-P1、P7-L30-P2、P7-L30-P3、P7-L30-P4、P7-L3 0-P5、P7-L30-P6、P7-L30-P7、P7-L30-P8、P7-L31-P1、P7-L31-P2、P7-L31- P3、P7-L31-P4、P7-L31-P5、P7-L31-P6、P7-L31-P7、P7-L31-P8、P7-L32-P1、<h2 style=";text-align:left;direction:ltr">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-L 33-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-P 2、P7-L35-P3、P7-L35-P4、P7-L35-P5、P7-L35-P6、P7-L35-P7、P7-L35-P8、 P7-L36-P1、P7-L36-P2、P7-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-P 4、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、P8-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-L 5-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-P1, P8-L7-P2, P8-L7-P3, P8-L7-P4, P8-L7-P5, P 8-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-L9-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、 、P8-L11-P3、P8-L11-P4、P8-L11-P5、P8-L11-P6、P8-L11-P7、P8-L11-P8、P 8-L12-P1、P8-L12-P2、P8-L12-P3、P8-L12-P4、P8-L12-P5、P8-L12-P6、P8-L 12-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-L 15-P8、P8-L16-P1、P8-L16-P2、P8-L16-P3、P8-L16-P4、P8-L16-P5、P8-L16 -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、P 8-L18-P3、P8-L18-P4、P8-L18-P5、P8-L18-P6、P8-L18-P7、P8-L18-P8、P8-L 19-P1、P8-L19-P2、P8-L19-P3、P8-L19-P4、P8-L19-P5、P8-L19-P6、P8-L19 -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、P 8-L21-P4、P8-L21-P5、P8-L21-P6、P8-L21-P7、P8-L21-P8、P8-L22-P1、P8-L 22-P2、P8-L22-P3、P8-L22-P4、P8-L22-P5、P8-L22-P6、P8-L22-P7、P8-L22-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-L2 5-P3、P8-L25-P4、P8-L25-P5、P8-L25-P6、P8-L25-P7、P8-L25-P8、P8-L26-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-L2 8-P4、P8-L28-P5、P8-L28-P6、P8-L28-P7、P8-L28-P8、P8-L29-P1、P8-L29-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-L3 1-P5、P8-L31-P6、P8-L31-P7、P8-L31-P8、P8-L32-P1、P8-L32-P2、P8-L32- 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-L3 4-P6、P8-L34-P7、P8-L34-P8、P8-L35-P1、P8-L35-P2、P8-L35-P3、P8-L35- P4、P8-L35-P5、P8-L35-P6、P8-L35-P7、P8-L35-P8、P8-L36-P1、P8-L36-P2、Selected from the group consisting of P8-L36-P3, P8-L36-P4, P8-L36-P5, P8-L36-P6, P8-L36-P7 and P8-L36-P8.

[0238] In accordance with one aspect of the present invention, provided herein is a pharmaceutical composition comprising a conjugate and a pharma- ceutically acceptable carrier.

[0239] According to certain aspects of the invention, provided herein is a method of treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a conjugate or pharmaceutical composition of the invention.

[0240] In some embodiments, the cancer expresses the target antigen.

[0241] In certain embodiments, the cancer is a tumor or 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 neoplasms 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.

[0242] According to certain aspects of the invention, provided herein is a method of reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate or pharmaceutical composition of the invention.

[0243] In certain embodiments, the tumor expresses a target antigen.

[0244] In certain embodiments, 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, splenic cancer, pancreatic cancer, stomach cancer, colon cancer, or head and neck cancer.

[0245] According to certain aspects of the invention, provided herein is a method of reducing or inhibiting hematological cancer in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate or pharmaceutical composition of the invention.

[0246] In certain embodiments, the hematological cancer expresses a target antigen.

[0247] In certain embodiments, 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 myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myelodysplastic syndrome (MDS).

[0248] In certain embodiments, administration of the conjugate or pharmaceutical composition reduces or inhibits the growth of a 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%.

[0249] According to certain aspects of the invention, provided herein is 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 a conjugate or pharmaceutical composition of the invention.

[0250] In certain embodiments, the cancer cell population expresses a target antigen.

[0251] In certain embodiments, the cancer cell population is derived from a tumor or hematological cancer, optionally the cancer cell population is derived 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 neoplasms 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, splenic cancer, pancreatic cancer, gastric cancer, colon cancer, or head and neck cancer.

[0252] In certain embodiments, administration of the conjugate or pharmaceutical composition reduces or slows the expansion of a 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%.

[0253] In some embodiments, the antibody drug conjugate is administered as a monotherapy. In other embodiments, the antibody drug conjugate is administered concomitantly with another therapeutic agent or radiation therapy. In some embodiments, 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.

[0254] In certain embodiments, the method further comprises administering at least one additional therapeutic agent to a subject in need thereof.

[0255] In certain embodiments, the additional therapeutic agent is a taxane, a vinca alkaloid, a MEK inhibitor, an ERK inhibitor, a topoisomerase inhibitor, or a RAF inhibitor.

[0256] According to certain aspects of the invention, there is provided herein a use of a conjugate or pharmaceutical composition of the invention for the manufacture 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 hematological cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

[0257] According to certain aspects of the invention, there is provided herein an antibody drug conjugate or pharmaceutical composition of the invention 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 hematological cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

[0258] Methods of producing the described ADC compounds and compositions are also disclosed. An exemplary embodiment is a method of producing an antibody drug conjugate by reacting an antibody or antigen-binding fragment with a cleavable dual linker attached or covalently linked to a pharma- ceutically active drug that is not a BH3 mimetic under conditions that allow for conjugation.

[0259] Accordingly, the present invention provides the following numbered embodiments: It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0260] Embodiment 1. Formula (A-1): [ka] (In the formula, R 1 is a linking 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 pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof.

[0261] Embodiment 2.L 2’ and L 3’ or a pharma- ceutically acceptable salt thereof, according to embodiment 1, wherein each of said cleavable groups comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0262] Embodiment 2a.L 2’ and L 3’ or a pharma- ceutically acceptable salt thereof, according to embodiment 2, wherein each of

[0263] Embodiment 2b.L 2’ and L 3’ or a pharma- ceutically acceptable salt thereof, according to embodiment 1, wherein each of comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (e.g., glucuronamide) group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0264] Embodiment 3. Formula (B-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., Rw is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic moiety; V 1 and V 2 each independently represent: i) a self-immolative group; ii) an enzymatic cleavage element (e.g., V 1 and V 2 are each independently a self-immolative group, or iii) comprise a self-immolative group and an enzymatic cleavage element; and D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 (Provided that the drug is not a BH3 mimetic) or a pharma- ceutically acceptable salt thereof. A compound according to embodiment 1, embodiment 2 or embodiment 2a or a pharma- ceutically acceptable salt thereof.

[0265] Embodiment 3aa.V 1 and V 2 are each 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, a compound according to embodiment 3, or a pharma- ceutically acceptable salt thereof.

[0266] Embodiment 3a. A compound according to embodiment 3 or embodiment 3aa, or a pharma- ceutically acceptable salt thereof, wherein W is N or CH.

[0267] Embodiment 3b.E 1 and E 2 or a pharma- ceutically acceptable salt thereof, according to embodiment 3, embodiment 3aa or embodiment 3a, wherein each is an enzymatic cleavage element;

[0268] Embodiment 3c.V 1 and V 2 is each independently a self-immolative group; or a pharma- ceutically acceptable salt thereof.

[0269] Embodiment 4. (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 is -O-CH 2 -, -NH-CH 2 or (iv) V, which contains a self-immolative group comprising -, -OC(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium; or (iv) V, 1 and / or V 2 each independently comprises a group that comprises para-aminobenzyl-phosphate or para-aminobenzyl-pyrophosphate, or a pharma- ceutically acceptable salt thereof, according to embodiment 3, embodiment 3aa, embodiment 3a, embodiment 3b, or embodiment 3c.

[0270] Embodiment 4a. (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 is -O-CH 2 -, -NH-CH 2The compound according to embodiment 4 or a pharma- ceutically acceptable salt thereof, comprising a self-immolative group comprising -, -OC(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0271] Embodiment 5. Formula (C-1): [ka] (In the formula, R 1 is a linking group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; A 1 and A 2 are each independently a bond, -OC(=O)-*, [ka] -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(Ra ) 2 C(R a ) 2 N(CH 3 )C(=O)-*, Each R a are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, and optionally D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. or a pharma- ceutically acceptable salt thereof. A compound according to embodiment 3, embodiment 4 or embodiment 4a or a pharma- ceutically acceptable salt thereof.

[0272] Embodiment 5a. A compound according to embodiment 5, or a pharma- ceutically acceptable salt thereof, wherein W is N or CH.

[0273] Embodiment 5b.R 2 and R 3 A compound according to embodiment 5 or embodiment 5a, or a pharma- ceutically acceptable salt thereof, wherein each is a hydrophilic group.

[0274] Embodiment 6. Formula (D1-1), (D2-1) or (D3-1): [ka] or a pharma- ceutically acceptable salt thereof. A compound according to embodiment 5, embodiment 5a, or embodiment 5b, or a pharma- ceutically acceptable salt thereof.

[0275] Embodiment 7. Regarding formula (D1-1), R 2 and R 3 are each independently a hydrophilic group, and in formula (D2-1), R 2 and R 3 are each independently an enzyme cleavage element; and with respect to formula (D3-1), R 2 is a hydrophilic group, and R 3 is an enzymatic cleavage element; or a pharma- ceutically acceptable salt thereof.

[0276] Embodiment 8.R 1 teeth, [ka] -ONH 2 , -NH 2 , [ka] , -N 3 , [ka] -SH, -SR 11 , -SSR 12 , -S(=O) 2 (CH=CH 2 ), -(CH 2 ) 2 S(=O) 2 (CH=CH 2 ), -NHS(=O) 2 (CH=CH 2 ), -NR 11 C(=O)CH 2 Br, e.g. -NHC(=O)CH 2 Br, -NR 11 C(=O)CH 2I, e.g. -NHC(=O)CH 2 I, [ka] -C(O)NHNH 2 , [ka] (In the formula, Each R 11 are independently H and C 1 ~C 6 alkyl; Each R 12 is 2-pyridyl or 4-pyridyl; Each R 13 are independently H, C 1 ~C 6 selected from alkyl, F, Cl and -OH; Each R 14 are independently H, C 1 ~C 6 Alkyl, F, Cl, -NH 2 , -OCH 3 , -OCH 2 CH 3 , -N(CH 3 ) 2 , -CN, -NO 2 and -OH; and Each R 15 are independently H, C 1 ~C 6 Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1 ~C 4 Alkoxy and -C(=O)OH substituted C 1 ~C 4 alkyl) or a pharma- ceutically acceptable salt thereof, according to any one of the preceding embodiments, selected from the group consisting of:

[0277] Embodiment 9.R 1 teeth, [ka] -ONH 2 , [ka] NHC(=O)CH 2 Br and -NHC(=O)CH 2 A compound according to any one of the preceding embodiments selected from the group consisting of I, or a pharma- ceutically acceptable salt thereof.

[0278] Embodiment 9a.R 1 teeth, [ka] -ONH 2 , [ka] or a pharma- ceutically acceptable salt thereof, according to any one of the preceding embodiments, selected from the group consisting of:

[0279] Embodiment 10.R 1 teeth, [ka] or a pharma- ceutically acceptable salt thereof, according to any one of the preceding embodiments.

[0280] Embodiment 11.(1)L 1 teeth, [ka] or *-CH(OH)CH(OH)CH(OH)CH(OH)-** (wherein each n is an integer from 1 to 12). Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (2)L 1 teeth, [ka] and n is an integer from 1 to 12, or n is 1, or n is 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (3) L 1 teeth, [ka] and n is an integer from 1 to 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (4) L 1 teeth, [ka] Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; or (5) L 1 is *-C(=O)(CH 2 ) m O(CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)(CH 2 ) m -**;*-C(=O)NH((CH 2 ) m O) t (CH2 ) n -**;*-C(=O)O(CH 2 ) m SSC(R L1 ) 2 (CH 2 ) m C(=O)NR L1 (CH 2 ) m NR L1 C(=O)(CH 2 ) m -**;*-C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)-**;*-C(=O)(CH 2 ) m X 1 (CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n-**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m C(R L1 ) 2 -** or *-C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m -** (In the formula, L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicating a direct or indirect (e.g., direct) point of attachment to; X 1 teeth, [ka] 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 are independently H and C 1 ~C 6 alkyl) or a pharma- ceutically acceptable salt thereof.

[0281] Embodiment 12.L 1 teeth, [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8), and L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 (Indicating a direct or indirect point of attachment to or a pharma- ceutically acceptable salt thereof.

[0282] Embodiment 12 A compound according to embodiment 12, wherein a.n is an integer from 4 to 8, or a pharma- ceutically acceptable salt thereof.

[0283] Embodiment 12b.n is a compound according to embodiment 12a, which is 4 or 8, or a pharma- ceutically acceptable salt thereof.

[0284] Embodiment 13.L 1 is the formula [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); u is 0 or 1; L 1 The * in indicates the direct point of attachment to W, and L 1 The ** is R 1 (Indicates the direct attachment point to or a pharma- ceutically acceptable salt thereof.

[0285] Embodiment 13: A compound according to embodiment 13, wherein a.n is an integer from 4 to 8, or a pharma- ceutically acceptable salt thereof.

[0286] Embodiment 13b.n is a compound according to embodiment 13a, which is 4 or 8, or a pharma- ceutically acceptable salt thereof.

[0287] Embodiment 13c. A compound according to embodiment 13, embodiment 13a or embodiment 13b, wherein x is an integer from 0 to 2, or a pharma- ceutically acceptable salt thereof.

[0288] Embodiment 13d. A compound according to embodiment 13c, wherein x is 0 or 2, or a pharma- ceutically acceptable salt thereof.

[0289]

[0043] Embodiment 13e.z is an integer from 0 to 2, a compound according to embodiment 13, embodiment 13a, embodiment 13b, embodiment 13c or embodiment 13d, or a pharma- ceutically acceptable salt thereof.

[0290] Embodiment 13f. A compound according to embodiment 13e, wherein z is 0 or 2, or a pharma- ceutically acceptable salt thereof.

[0291] Embodiment 14.L 1 teeth, [ka] or a pharma- ceutically acceptable salt thereof, according to any one of the preceding embodiments, selected from the group consisting of:

[0292] Embodiment 15.L 2 and L 3 are each independently [ka] (In the formula, 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; L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 (## indicates the direct or indirect point of attachment to W) or a pharma- ceutically acceptable salt thereof.

[0293] Embodiment 16.L 2 and L 3 are each independently [ka] [ka] (In the formula, k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R L23 is hydrogen or C 1 ~C 6 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; If W is N, then L2 and L 3 (provided that it is not (L2c), (L2d), (L2f) or (L2k)) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 3 to 15, wherein the linking spacer is selected from the group consisting of:

[0294] Embodiment 17.L 2 and L 3 are each independently [ka] [ka] (In the formula, k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1 ~C 3 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; if W is N, then L 2 and L 3 (provided that it is not (L2FF), (L2MM), (L2NN), (L2OO) or (L2PP)) or a pharma- ceutically acceptable salt thereof, according to embodiment 16, wherein the linking spacer is selected from the group consisting of:

[0295] Embodiment 18.L 2 and L3 is, independently, [ka] [ka] (In the formula, L 2 Or L 3 # is E 1 Or E 2 indicates the direct attachment point to L 2 Or L 3 ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H and R H teeth, [ka] and d is an integer from 20 to 30 (e.g., 25). or a pharma- ceutically acceptable salt thereof according to any one of embodiments 3 to 17, wherein the linking spacer is selected from the group consisting of:

[0296] Embodiment 18a.d is a compound according to embodiment 18, which is 25, or a pharma- ceutically acceptable salt thereof.

[0297] Embodiment 19. A compound according to any one of embodiments 5-18a, or a pharma- ceutically acceptable salt thereof, wherein each peptide group independently comprises 1-4, 1-3, or 1-2 amino acid residues.

[0298] Embodiment 19a. A compound according to embodiment 19, or a pharma- ceutically acceptable salt thereof, wherein each peptide group independently comprises two amino acid residues.

[0299] Embodiment 20. A compound according to embodiment 19 or embodiment 19a, or a pharma- ceutically acceptable salt thereof, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (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).

[0300] Embodiment 21. A compound or a pharma- ceutically acceptable salt according to any one of embodiments 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 Sulfo-Ala-Val-Ala.

[0301] Embodiment 22.E 1 and / or E 2 are each independently [ka] (Wherein, E1-1 or E1-2 is V in formula (B) 1 Or V 2 or the direct point of attachment to the -NH- group in formulas (C) and (D); and E1-1 or E1-2 ^^ respectively represent L 2 Or L 3 indicates the direct point of attachment to 1 and E 2 are peptide groups independently selected from (E1-1) and (E1-2). The compound or pharma- ceutically acceptable salt according to any one of embodiments 3-19a, wherein the peptide group is selected from the group consisting of:

[0302] Embodiment 22a.E 1 and E2 is a peptide group independently selected from (E1-1) and (E1-2), or a pharma- ceutically acceptable salt thereof.

[0303] Embodiment 23.E 1 and / or E 2 are each independently [ka] (In the formula, R E is a hydrophilic group R H is) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 3-19a, wherein R is a peptide group represented by:

[0304] The group R in embodiment 24 (E1-3) H teeth, [ka] (wherein e is an integer of 20 to 30 (e.g., 25)) 24. The compound according to embodiment 23, which is:

[0305] Embodiment 24a.e is a compound according to embodiment 24, which is 25, or a pharma- ceutically acceptable salt thereof.

[0306] Embodiment 25.E 1 and E 2 are respectively [ka] 23. The compound according to embodiment 22, or a pharma- ceutically acceptable salt thereof, wherein:

[0307] Embodiment 26.A 1 and A 2 are independently a bond and -OC(=O)-* (wherein * represents D 1 Or D 2or a pharma- ceutically acceptable salt according to any one of embodiments 5 to 25, selected from:

[0308] Embodiment 26a.A 1 and A 2 are independent, combined, [ka] and -OC(=O)-* (wherein * represents D 1 Or D 2 or a pharma- ceutically acceptable salt according to any one of embodiments 5 to 25, selected from:

[0309] Embodiment 27.A 1 and A 2 and R are each a bond.

[0310] Embodiment 27a.A 1 and A 2 or a pharma- ceutically acceptable salt thereof according to embodiment 26, wherein:

[0311] Embodiment 27b.A 1 and A 2 One of the groups is OC(=O)-* and A 1 and A 2 The compound or pharma- ceutically acceptable salt according to embodiment 26, wherein the other is a bond.

[0312] Embodiment 27c.A 1 and A 2 is independently a bond, or [ka] (In the formula, * represents D 1 Or D 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt according to embodiment 26a, which is

[0313] Embodiment 27d.A1 and A 2 On the other hand, [ka] And A 1 and A 2 The compound or pharma- ceutically acceptable salt according to embodiment 27c, wherein the other is a bond.

[0314] Embodiment 27e.A 1 and A 2 Both [ka] or a pharma- ceutically acceptable salt according to embodiment 27c, wherein:

[0315] Embodiment 27f.A 1 and A 2 On the other hand, [ka] And A 1 and A 2 and the other is OC(=O)-*.

[0316] Embodiment 27g.A 1 and A 2 is -OC(=O)-*; (ii)A 1 and A 2 teeth, [ka] Is it; (iii)A 1 is -OC(=O)-*, and A 2 is a bond or (iv)A 1 is -OC(=O)-*, and A 2 teeth, [ka] Is it; (v)A 1 is a bond, and A 2 teeth, [ka] or (vi) A 1 is a bond, and A 2 is -OC(=O)-* (wherein * is D 1 Or D 2 or a pharma- ceutically acceptable salt according to embodiment 26a, wherein:

[0317] Embodiment 28.i)L 4 and L 5 are each independently [ka] (In the formula, Z is -O-, -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR L45 -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C6 Alkyl and C 3 ~C 8 cycloalkyl); and X is a bond, triazolyl or -CH 2 -triazolyl-, X is R 2 or R 3 (connected to or a spacer moiety having the structure (ii) L 4 and L 5 is, independently, [ka] (In the formula, Z is -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NR L45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is -CH 2 -Triazolyl-C1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n where each n is independently 1, 2, or 3; X is R 2 or R 3 (connected to or a pharma- ceutically acceptable salt thereof according to any one of embodiments 5 to 27b, wherein the spacer moiety has the structure:

[0318] Embodiment 29. Z is -O-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH- or -CH 2 X is a bond, triazolyl or -CH 2 -triazolyl-; and R L45 is, at each occurrence, independently H or C 1 ~C 329. The compound according to embodiment 28, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl.

[0319] Embodiment 30.L 4 and L 5 are each independently [ka] (In the formula, L 4 Or L 5 @ indicates the direct point of attachment to the phenyl group, and L 4 Or L 5 @@ is R 2 or R 3 (Indicates the direct attachment point to 30. The compound or pharma- ceutically acceptable salt according to any one of embodiments 5 to 29, wherein the spacer moiety is selected from the group consisting of:

[0320] Embodiment 31.R 2 and R 3 Each of the hydrophilic groups represented by the formula (I) is independently selected from polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 [ka] C replaced with 2 ~C 6 Alkyl or -OC(=O)NHS(O) 2 NHCH 2 CH 2 OCH 3 , -NHC(=O)C 1 ~C 4 Alkylene-P(O)(OCH 2 CH 3 ) 2 and C substituted with 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 The compound according to any one of embodiments 5 to 30, or a pharma- ceutically acceptable salt thereof, comprising alkyl.

[0321] Embodiment 32.R 2or / and R 3 are each independently [ka] (wherein n is an integer of 1 to 6). [ka] or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 5 to 30, selected from the group consisting of:

[0322] Embodiment 33.R 2 or / and R 3 is, independently, (i) the following part: [ka] (In the formula, f is an integer from 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) Polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by The compound or pharma- ceutically acceptable salt according to any one of embodiments 5 to 30, comprising:

[0323] Embodiment 33a.R 2 or R 3 Each hydrophilic group represented by the formula: (i) the following part: [ka] (wherein f is an integer of 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) or polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by The compound or pharma- ceutically acceptable salt according to any one of embodiments 5 to 30, comprising:

[0324] Embodiment 34.R 2 or / and R 3 are each independently [ka] (In the formula, g and h are independently an integer of 20 to 30 (e.g., 23 or 24). A compound or a pharma- ceutically acceptable salt according to any one of embodiments 5 to 30, selected from the group consisting of:

[0325] Embodiment 35.R 2 or / and R 3 teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0326] Embodiment 35a.R 2 and R 3 are each independently represented by the formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or a pharma- ceutically acceptable salt thereof.

[0327] Embodiment 36.D 1 and D. 2 is the same.

[0328] Embodiment 37.D 1 and D. 2 is different, a compound or a pharma- ceutically acceptable salt according to any one of embodiments 1 to 35a.

[0329] Embodiment 38.D 1 and D. 2 or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments, wherein each of the following is independently selected from a cytotoxic drug, a cytostatic agent, and an immunosuppressant.

[0330] Embodiment 39.D 1 and D. 2 or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-37, wherein each of the formulas (I) and (II) is independently selected from an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, a taxane, a benzodiazepine or a benzodiazepine-containing drug (e.g., a pyrrolo[1,4]-benzodiazepine (PBD), an indolinobenzodiazepine, and an oxazolidinobenzodiazepine), and a vinca alkaloid.

[0331] Embodiment 39a.D 1 and D. 2 are each independently [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-37.

[0332] Embodiment 39b.i)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iv) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; v)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; viii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; x)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xi) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvi)D1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xli)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; il)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; l)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; li)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxiii)D 1 teeth, [ka] and D 2 teeth, [ka] or lxiv)D 1 teeth, [ka] and D 2 teeth, [ka] A compound or a pharma- ceutically acceptable salt according to embodiment 39a, wherein: and * indicates the point of attachment to the rest of the molecule.

[0333] Embodiment 39c.i)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iv) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; v)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; viii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ix) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; x)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiv)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xl)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xli)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] Is it; xlii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; l)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; li)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxiii)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] or lxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] and * indicates the point of attachment to the rest of the molecule.

[0334] Embodiment 40.D 1 and / or D. 2 The compound or pharma- ceutically acceptable salt according to any one of embodiments 1-37, wherein is an auristatin.

[0335] Embodiment 40a.D 1 and D. 2 or a pharma- ceutically acceptable salt thereof according to embodiment 40, wherein both of

[0336] Embodiment 40b.D 1 and / or D. 2 The compound or pharma- ceutically acceptable salt according to any one of embodiments 1-37, wherein is a topoisomerase 1 inhibitor.

[0337] Embodiment 40c.D 1 and D. 2 or a pharma- ceutically acceptable salt thereof according to embodiment 40b, wherein both of are topoisomerase 1 inhibitors.

[0338] Embodiment 40d.D 1 and D. 2 is an auristatin and D 1 and D. 2The compound or pharma- ceutically acceptable salt according to any one of embodiments 1 to 37, wherein the other is a topoisomerase 1 inhibitor.

[0339] Embodiment 40e.D 1 is an auristatin, and D 2 The compound or pharma- ceutically acceptable salt according to embodiment 40d, wherein is a topoisomerase 1 inhibitor.

[0340] Embodiment 40f.D 1 is a topoisomerase 1 inhibitor, and D 2 The compound or pharma- ceutically acceptable salt according to embodiment 40d, wherein is an auristatin.

[0341] Embodiment 41.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments, selected from the group consisting of:

[0342] Embodiment 41a.D 1 and D. 2 is, independently, [ka] 42. A compound according to embodiment 41, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

[0343] Embodiment 41b.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0344] Embodiment 41c.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0345] Embodiment 42.D 1 and D. 2 or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-37, wherein each of the is independently selected from an antitubulin agent, a tubulin inhibitor, a DNA minor groove binder, a DNA replication inhibitor, an alkylating agent, an antibiotic, an antifolate, an antimetabolite, a chemotherapeutic sensitizer, a topoisomerase inhibitor, and / or a vinca alkaloid.

[0346] Embodiment 43.D 1 and D. 2 are each independently 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 maytansinoid, MetAP (methionine aminopeptidase), an inhibitor of nuclear export of protein CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reaction in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, a HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA interfering agent, a DNA minor groove binder, an RNA polymerase inhibitor, an amanitin, a spliceosome inhibitor, a topoisomerase inhibitor, a DHFR inhibitor, or a proapoptotic agent; 1 Also D 238. The compound or pharma- ceutically acceptable salt according to any one of embodiments 1-37, provided that said compound or pharma- ceutically acceptable salt is not a BH3 mimetic.

[0347] EMBODIMENT 44. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments, selected from the group consisting of:

[0348] Embodiment 44a. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments, selected from the group consisting of:

[0349] EMBODIMENT 45. [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of the preceding embodiments, selected from the group consisting of:

[0350] Embodiment 45a. [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-45, selected from the group consisting of:

[0351] Embodiment 45b. [ka] [ka] or a pharma- ceutically acceptable salt thereof. A compound according to embodiment 45a, selected from the group consisting of:

[0352] Embodiment 45c. [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-43, wherein the compound or a pharma- ceutically acceptable salt thereof is selected from:

[0353] Embodiment 45d. [ka] [ka] or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-43, wherein the compound or a pharma- ceutically acceptable salt thereof is selected from:

[0354] Embodiment 45e. [ka] or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-43, wherein the compound or a pharma- ceutically acceptable salt thereof is selected from:

[0355] Embodiment 45f. [ka] or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1-43, wherein the compound or a pharma- ceutically acceptable salt thereof is selected from:

[0356] Embodiment 46. A conjugate comprising an antibody or antigen-binding fragment thereof covalently linked to two pharmaceutically active drugs via a dual linker, the dual linker having one point of attachment attached to the antibody and two points of attachment to the two pharmaceutically active drugs, provided that neither of the pharmaceutically active drugs is a BH3 mimetic.

[0357] Embodiment 46a. A conjugate according to embodiment 46, wherein the two pharma- ceutical active drugs are the same or different.

[0358] Embodiment 46b. A conjugate according to embodiment 46 or 46a, wherein the pharma- ceutically active drug is selected from cytotoxic drugs, cytostatic drugs and immunosuppressants.

[0359] Embodiment 46c. A conjugate according to any one of embodiments 46-46b, wherein the pharma- ceutically active drug is selected from auristatins, camptothecins, duocarmycins, etoposide, maytansine, maytansinoids, taxanes, benzodiazepines or benzodiazepine-containing drugs (e.g., pyrrolo[1,4]-benzodiazepines (PBDs), indolinobenzodiazepines and oxazolidinobenzodiazepines) and vinca alkaloids.

[0360] Embodiment 46d. A conjugate according to embodiment 46c, wherein the pharma- ceutically active drug is an auristatin.

[0361] Embodiment 46e. A conjugate according to embodiment 46 or 46a, wherein the pharma- ceutically active drug is selected from antitubulin agents, tubulin inhibitors, DNA minor groove binders, DNA replication inhibitors, alkylating agents, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, topoisomerase inhibitors and / or vinca alkaloids.

[0362] Embodiment 46f. A conjugate according to embodiment 46 or 46a, wherein the pharma- ceutically active drug is selected from Eg5 inhibitors, V-ATPase inhibitors, HSP90 inhibitors, IAP inhibitors, mTor inhibitors, microtubule stabilizing agents, microtubule destabilizing agents, auristatins, dolastatins, maytansinoids, MetAP (methionine aminopeptidase), inhibitors of nuclear export of protein CRM1, DPPIV inhibitors, inhibitors of phosphoryl transfer reactions in mitochondria, protein synthesis inhibitors, kinase inhibitors, CDK2 inhibitors, CDK9 inhibitors, proteasome inhibitors, kinesin inhibitors, HDAC inhibitors, DNA damaging agents, DNA alkylating agents, DNA interfering agents, DNA minor groove binders, RNA polymerase inhibitors, amanitin, spliceosome inhibitors, topoisomerase inhibitors, DHFR inhibitors or proapoptotic agents.

[0363] Embodiment 46g. A conjugate according to embodiment 46 or 46a, wherein the pharma- ceutically active drug is selected from a topoisomerase 1 inhibitor or its enantiomer, diastereoisomer, atropisomer, deuterated derivative and / or addition salt with a pharma- ceutically acceptable acid or base.

[0364] Embodiment 46h. A conjugate according to embodiment 46g, wherein the pharma- ceutically active drug, topoisomerase 1 inhibitor, is selected from topotecan, exatecan, deruxtecan and SN-38.

[0365] Embodiment 46i. A conjugate according to embodiment 46 or 46a, wherein the pharma- ceutically active drug is selected from a mitotic inhibitor or its enantiomer, diastereoisomer, atropisomer, deuterated derivative and / or addition salt with a pharma- ceutically acceptable acid or base.

[0366] Embodiment 46j. A conjugate according to embodiment 46i, wherein the mitotic inhibitor is monomethyl auristatin E (MMAE) or a taxane.

[0367] Embodiment 46k. A conjugate according to embodiment 46j, wherein the taxane is selected from docetaxel, paclitaxel, or cabazitaxel.

[0368] Embodiment 46l. A conjugate according to embodiment 46, wherein the conjugate comprises a compound according to any one of embodiments 1 to 45f or a pharma- ceutically acceptable salt thereof.

[0369] Embodiment 46m. Formula (A-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is a branching moiety; L 2’ and L 3’ are each independently a linker; D 1 and D. 2 are each independently a pharma- ceutically active drug, but D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. Conjugate of.

[0370] Embodiment 47.L 2’ and L 3’ each of which comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0371] Embodiment 47a.L 2’ and L 3’ Each of the above comprises a peptide group and a self-immolative group.

[0372] Embodiment 47b.L 2’ and L 3’ each of which comprises a cleavable group, and optionally at least one cleavable group comprises a phosphate group, a pyrophosphate group, a sugar (e.g., glucuronamide) group, a peptide group, and / or a self-immolative group (e.g., a peptide group and a self-immolative group).

[0373] Embodiment 48. Formula (B-2): [ka] (In the formula, Ab is an antibody or fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently an enzyme cleavage element or a hydrophilic moiety (e.g., E 1 and E 2 are enzyme cleavage elements, respectively); V 1 and V 2 may independently comprise: i) a self-immolative group; ii) an enzymatic cleavage element (e.g., V 1 and V 2 are each independently a self-immolative group, or iii) comprises a self-immolative group and an enzymatic cleavage element; D 1 and D. 2 are each independently a pharma- ceutically active drug, but D 1 Also D 2 is not a BH3 mimetic; and a is an integer from 1 to 16. The conjugate according to embodiment 46m, embodiment 47 or embodiment 47a.

[0374] Embodiment 48aa.V 1 and V 2 are each 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,

[0375] Embodiment 48a. A conjugate according to embodiment 48 or embodiment 48aa, wherein W is N or CH.

[0376] Embodiment 48b.E 1 and E 2 A conjugate according to embodiment 48, embodiment 48aa or embodiment 48a, wherein each of

[0377] Embodiment 48c.V 1 and V 2 A conjugate according to embodiment 48, embodiment 48aa, embodiment 48a or embodiment 48b, wherein each is independently a self-immolative group.

[0378] Embodiment 49. A conjugate according to any one of embodiments 46m to 48c, wherein a is an integer from 1 to 8, 1 to 6, 1 to 4, or a is 1 or 2.

[0379] Embodiment 49a.a is a conjugate according to embodiments 46m to 49, as determined by liquid chromatography-mass spectrometry (LC-MS).

[0380] Embodiment 50. (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 is -CH 2 -O-, -NH-CH 2A conjugate according to any one of embodiments 46m to 49, comprising a self-immolative group comprising -, -C(=O)-, para-aminobenzyl-carbamate, para-aminobenzyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-ammonium.

[0381] Embodiment 50a. A conjugate according to embodiment 50, wherein W is N or CH.

[0382] Embodiment 50b.R 2 and R 3 A conjugate according to embodiment 50 or embodiment 50a, wherein each is a hydrophilic group.

[0383] Embodiment 51. Formula (C-2): [ka] (In the formula, Ab is an antibody or an antigen-binding fragment thereof; R 100 is a coupling group; L 1 is a bridging spacer; W is N or CR w and R w is H or C 1 ~C 6 is alkyl (e.g., R w is H); L 2 and L 3 are each independently a linking spacer; E 1 and E 2 are each independently a peptide group comprising 1 to 6 amino acids, said peptide group being optionally substituted with a hydrophilic group; A1 and A 2 are each independently a bond, -OC(=O)-*, [ka] -OC(=O)N(CH 3 )CH 2 CH 2 N(CH 3 )C(=O)-* or -OC(=O)N(CH 3 )C(R a ) 2 C(R a ) 2 N(CH 3 )C(=O)-*, Each R a are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl; A 1 Or A 2 * is D 1 Or D 2 Indicates the attachment point to; D 1 and D. 2 are each independently a pharma- ceutically active drug, but D 1 Also D 2 is not a BH3 mimetic; L 4 and L 5 are each independently a spacer moiety; R 2 and R 3 are each independently a hydrophilic group or an enzyme cleavage element (e.g., R 2 and R 3 are hydrophilic groups); and m and n are each independently 0 or 1. A conjugate according to any one of embodiments 46m to 50b.

[0384] Embodiment 52. Formula (D1-2), (D2-2) or (D3-2): [ka] The conjugate according to embodiment 51.

[0385] Embodiment 53. With respect to formula (D1-2), R 2 and R 3 are each independently a hydrophilic group, and in formula (D2-2), R 2 and R 3 are each independently an enzyme cleavage element; and with respect to formula (D3-2), R 2 is a hydrophilic group, and R 3 is an enzymatic cleavage element.

[0386] Embodiment 54.R 100 teeth, [ka] [ka] [ka] [ka] [ka] [ka] Disulfides (In the formula, R 16 , H, C 1 ~C 4 alkyl, phenyl, pyrimidine or pyridine; R 18 , H, C 1 ~C 6 C substituted with alkyl, phenyl or 1 to 3 -OH groups 1 ~C 4 is alkyl; Each R 15 are independently H, C 1 ~C 6Alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C substituted with -C(=O)OH 1 ~C 4 Alkoxy and -C(=O)OH substituted C 1 ~C 4 alkyl; R 17 is independently selected from H, phenyl and pyridine; q is 0, 1, 2 or 3; R 19 is H or methyl; and R 20 -H, -CH 3 or phenyl) A conjugate according to any one of embodiments 46m to 53, selected from the group consisting of:

[0387] Embodiment 55.R 100 teeth, [ka] (In the formula, R 100 (*** indicates the attachment point to Ab) A conjugate according to any one of embodiments 46m to 54, selected from the group consisting of:

[0388] Embodiment 56.R 100 teeth, [ka] (In the formula, R 100 (*** indicates the attachment point to Ab) 56. The conjugate according to embodiment 55, wherein

[0389] Embodiment 57.(1)L 1 teeth, [ka] or *-CH(OH)CH(OH)CH(OH)CH(OH)-** (wherein each n is an integer from 1 to 12). Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (2)L 1 teeth, [ka] and n is an integer from 1 to 12, or n is 1, or n is 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (3) L 1 teeth, [ka] and n is an integer from 1 to 12; L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; (4) L 1 teeth, [ka] Including L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicates a direct or indirect (e.g., direct) point of attachment to; or (5) L 1 is *-C(=O)(CH 2 ) m O(CH 2 ) m -**;*-C(=O)((CH 2 )m O) t (CH 2 ) n -**;*-C(=O)(CH 2 ) m -**;*-C(=O)NH((CH 2 ) m O) t (CH 2 ) n -**;*-C(=O)O(CH 2 ) m SSC(R L1 ) 2 (CH 2 ) m C(=O)NR L1 (CH 2 ) m NR L1 C(=O)(CH 2 ) m -**;*-C(=O)O(CH 2 ) m C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m NH(CH 2 ) n C(=O)-**;*-C(=O)(CH 2 ) m X 1 (CH 2 ) m -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) nNHC(=O)(CH 2 ) n -**;*-C(=O)(CH 2 ) m NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n NHC(=O)(CH 2 ) n X 1 (CH 2 ) n -**;*-C(=O)((CH 2 ) m O) t (CH 2 ) n C(=O)NH(CH 2 ) m -**;*-C(=O)(CH 2 ) m C(R L1 ) 2 -** or *-C(=O)(CH 2 ) m C(=O)NH(CH 2 ) m -** (In the formula, L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 indicating a direct or indirect (e.g., direct) point of attachment to; X 1 teeth, [ka] 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 are independently H and C 1 ~C 6 alkyl) The conjugate according to any one of embodiments 46m to 56, wherein the bridging spacer comprises:

[0390] Embodiment 58.L 1 teeth, [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8), and L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and L 1 The ** is R 1 (Indicating a direct or indirect point of attachment to A conjugate according to any one of embodiments 46m to 57, comprising a moiety represented by:

[0391] A conjugate according to embodiment 58, wherein n is an integer from 4 to 8.

[0392] Embodiment 58b.n is a conjugate according to embodiment 58a, wherein n is 4 or 8.

[0393] Embodiment 59.L 1 is the formula [ka] (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, for example, 4 or 8); x is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); y is 0 or 1; z is an integer from 0 to 6 (e.g., 0 to 4, for example, 0 to 2, for example, 0 or 2); u is 0 or 1; L 1 The * in indicates the direct point of attachment to W, and L 1 The ** is R 1 (Indicates the direct attachment point to A conjugate according to any one of embodiments 46m to 58b, represented by:

[0394] A conjugate according to embodiment 59, wherein n is an integer from 4 to 8.

[0395] Embodiment 59b.n is a conjugate according to embodiment 59a, wherein n is 4 or 8.

[0396] Embodiment 59c. A conjugate according to embodiment 59, embodiment 59a or embodiment 59b, wherein x is an integer from 0 to 2.

[0397] Embodiment 59d. A conjugate according to embodiment 59c, wherein x is 0 or 2.

[0398] Embodiment 59e.z is a conjugate according to embodiment 59, embodiment 59a, embodiment 59b, embodiment 59c or embodiment 59d, wherein R is an integer from 0 to 2.

[0399] Embodiment 59f. A conjugate according to embodiment 59e, wherein z is 0 or 2.

[0400] Embodiment 60.L 1 teeth, [ka] A conjugate according to any one of embodiments 46m to 59f, selected from the group consisting of:

[0401] Embodiment 61.L 2 and L 3 are each independently [ka] (In the formula, 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; L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 (## indicates the direct or indirect point of attachment to W) A conjugate according to any one of embodiments 48 to 60, wherein the linking spacer comprises a moiety represented by:

[0402] Embodiment 62.L 2 and L 3 are each independently [ka] [ka] (In the formula, k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R L23 is hydrogen or C 1 ~C 6 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2and L 2 Or L 3 ## indicates the direct point of attachment to W; If W is N, then L 2 and L 3 (provided that it is not (L2c), (L2d), (L2f) or (L2k)) The conjugate according to any one of embodiments 48 to 60, wherein the linking spacer is selected from the group consisting of:

[0403] Embodiment 63.L 2 and L 3 are each independently [ka] [ka] (In the formula, k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1 ~C 3 is alkyl; R L is hydrogen or -C(O)-R H and; R H is a hydrophilic group; and L 2 Or L 3 # is E 1 Or E 2 and L 2 Or L 3 ## indicates the direct point of attachment to W; if W is N, then L 2 and L 3 (provided that it is not (L2FF), (L2MM), (L2NN), (L2OO) or (L2PP)) 63. The conjugate according to embodiment 62, wherein the linking spacer is selected from the group consisting of:

[0404] Embodiment 64.L 2 and L 3 is, independently, [ka] [ka] (In the formula, L 2 Or L 3 # is E 1 Or E 2 indicates the direct attachment point to L 2 Or L 3 ## indicates the direct attachment point to W; R L is hydrogen or -C(O)-R H and R H teeth, [ka] and d is an integer from 20 to 30 (e.g., 25). The conjugate according to any one of embodiments 48 to 63, wherein the linking spacer is selected from the group consisting of:

[0405] Embodiment 64a.d is a conjugate according to embodiment 64, which is 25.

[0406] Embodiment 65. A conjugate according to any one of embodiments 51 to 64a, wherein each peptide group independently comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues.

[0407] Embodiment 65a. A conjugate according to embodiment 65, wherein each peptide group independently comprises two amino acid residues.

[0408] Embodiment 66. A conjugate according to embodiment 65 or embodiment 65a, wherein each amino acid residue is independently selected from glycine (Gly), L-valine (Val), L-citrulline (Cit), L-cysteic acid (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).

[0409] Embodiment 67. A conjugate according to any one of embodiments 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 Sulfo-Ala-Val-Ala.

[0410] Embodiment 68.E 1 and / or E 2 are each independently [ka] (Wherein, E1-1 or E1-2 is V in formula (B) 1 Or V 2 or the direct point of attachment to the -NH- group in formulas (C) and (D); and E1-1 or E1-2 ^^ respectively represent L 2 Or L 3 indicates the direct point of attachment to 1 and E 2 are peptide groups independently selected from (E1-1) and (E1-2). 66. The conjugate according to any one of embodiments 48 to 65, wherein the peptide group is selected from the group consisting of:

[0411] Embodiment 68a.E 1 and E 2is a peptide group independently selected from (E1-1) and (E1-2), or a pharma- ceutically acceptable salt thereof.

[0412] Embodiment 69.E 1 and / or E 2 are each independently [ka] (In the formula, R E is a hydrophilic group R H is) The conjugate according to any one of embodiments 48 to 65, wherein the peptide group is represented by:

[0413] Hydrophilic group R in embodiment 70 (E1-3) H teeth, [ka] (wherein e is an integer of 20 to 30 (e.g., 25)) 70. The conjugate according to embodiment 69, wherein

[0414] Embodiment 70a.e is a conjugate according to embodiment 70, which is 25.

[0415] Embodiment 71.E 1 and E 2 are respectively [ka] 69. The conjugate according to embodiment 68, wherein

[0416] Embodiment 72.A 1 and A 2 are independently a bond and -OC(=O)-* (wherein * represents D 1 Or D 2 The conjugate according to any one of embodiments 51 to 71, wherein the conjugate is selected from the group consisting of:

[0417] Embodiment 72a.A 1 and A 2 are independent, combined, [ka] and -OC(=O)-* (wherein * represents D 1 Or D 2 The conjugate according to any one of embodiments 51 to 71, wherein the conjugate is selected from the group consisting of:

[0418] Embodiment 73.A 1 and A 2 The conjugate according to embodiment 72, wherein is a bond.

[0419] Embodiment 73a.A 1 and A 2 A conjugate according to embodiment 72, wherein both are -OC(=O)-*.

[0420] Embodiment 73b.A 1 and A 2 One of the groups is OC(=O)-* and A 1 and A 2 The conjugate according to embodiment 72, wherein the other is a bond.

[0421] Embodiment 73c.A 1 and A 2 is independently a bond, or [ka] (In the formula, * represents D 1 Or D 2 (Indicates the attachment point to The conjugate according to embodiment 72a,

[0422] Embodiment 73d.A 1 and A 2 On the other hand, [ka] And A 1 and A2 The conjugate according to embodiment 72a, wherein the other is a bond.

[0423] Embodiment 73e.A 1 and A 2 Both [ka] The conjugate according to embodiment 72a,

[0424] Embodiment 73f.A 1 and A 2 On the other hand, [ka] And A 1 and A 2 The conjugate according to embodiment 72a, wherein the other is OC(=O)-*.

[0425] Embodiment 73g.A 1 and A 2 is -OC(=O)-*; (ii)A 1 and A 2 teeth, [ka] or (iii)A 1 is -OC(=O)-*, and A 2 is a bond or (iv)A 1 is -OC(=O)-*, and A 2 teeth, [ka] or (v)A 1 is a bond, and A 2 teeth, [ka] or (vi) A 1 is a bond, and A 2 is -OC(=O)-* (wherein * is D 1 Or D 2 A conjugate according to embodiment 72a, wherein

[0426] Embodiment 74.i)L 4 and L 5 are each independently [ka] (In the formula, D 1 and D. 2 is independently selected from the group consisting of: X is a bond, triazolyl or -CH 2 -triazolyl-, X is R 2 or R 3 (connected to or a spacer moiety having the structure (ii) L 4 and L 5 is, independently, [ka] (In the formula, Z is -CH 2 -, -CH 2 O-, -CH 2 N(R L45 )C(=O)O-, -NHC(=O)C(R L45 ) 2 NHC(=O)O-, -NHC(=O)C(R L45 ) 2 NH-, -NHC(=O)C(R L45 ) 2 NHC(=O)-, -C(=O)NR b -, -C(=O)NH-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH-, -CH 2 NRL45 C(=O)NR L45 -, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, -OC(=O)NH-, -S(O) 2 NH-, -NHS(O) 2 -, -C(=O)-, -C(=O)O-, or -NH- (wherein each R L45 are independently H, C 1 ~C 6 Alkyl and C 3 ~C 8 cycloalkyl); and X is -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-, -(CH 2 CH 2 O) n -C(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -CH 2 -Triazolyl-C 1 ~C 4 Alkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n -, -C 4 ~C 6 Cycloalkylene-OC(O)NHS(O) 2 NH-(CH 2 CH 2 O) n where each n is independently 1, 2, or 3; X is R 2 or R 3 (connected to A conjugate according to any one of embodiments 51 to 73b, wherein the spacer moiety has the structure:

[0427] In embodiment 75, Z is -O-, -CH 2 NR L45 C(=O)-, -CH 2 NR L45 C(=O)NH- or -CH 2 X is a bond, triazolyl or -CH 2 -triazolyl-; and R L45 is, at each occurrence, independently H or C 1 ~C 3 The conjugate according to embodiment 74, wherein said alkyl is aryl.

[0428] Embodiment 76.L 4 and L 5 are each independently [ka] (In the formula, L 4 Or L 5 @ indicates the direct point of attachment to the phenyl group, and L 4 Or L 5 @@ is R 2 or R 3 (Indicates the direct attachment point to The conjugate according to any one of embodiments 51 to 75, wherein the spacer moiety is selected from the group consisting of:

[0429] Embodiment 77.R 2 and R 3 Each of the hydrophilic groups represented by the formula (I) is independently selected from polyethylene glycol, polyalkylene glycol, polyol, polysarcosine, sugar, oligosaccharide, polypeptide, 1 to 3 [ka] C replaced with 2 ~C 6 Alkyl or -OC(=O)NHS(O) 2 NHCH 2 CH2 OCH 3 , -NHC(=O)C 1 ~C 4 Alkylene-P(O)(OCH 2 CH 3 ) 2 and C substituted with 1 to 2 substituents independently selected from -COOH groups. 2 ~C 6 The conjugate according to any one of embodiments 51 to 76, comprising an alkyl.

[0430] Embodiment 78.R 2 or / and R 3 are each independently [ka] (wherein n is an integer of 1 to 6). [ka] The conjugate according to any one of embodiments 51 to 76, selected from the group consisting of:

[0431] Embodiment 79.R 2 or / and R 3 are each independently (i) the following part: [ka] (In the formula, f is an integer from 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) Polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by The conjugate according to any one of embodiments 51 to 76, comprising:

[0432] Embodiment 79a.R 2 or R 3 Each hydrophilic group represented by the formula: (i) the following part: [ka] (wherein f is an integer of 3 to 25; and R 23 -H, -CH 3 or -CH 2 CH 2 C(=O)OH) or polysarcosine having (ii) Formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) or (iii) [ka] The part represented by The conjugate according to any one of embodiments 51 to 76, comprising:

[0433] Embodiment 80.R 2 and R 3 are each independently [ka] (In the formula, g and h are independently an integer of 20 to 30 (e.g., 23 or 24). The conjugate according to any one of embodiments 51 to 76, selected from the group consisting of:

[0434] Embodiment 81.R 2 or / and R 3 teeth, [ka] The conjugate according to embodiment 80, comprising:

[0435] Embodiment 81a.R 2 and R 3 are each independently represented by the formula: [ka] (In the formula, g and h are independently an integer of 2 to 30.) The conjugate according to embodiment 80, comprising a polyethylene glycol of

[0436] Embodiment 82.D 1 and D. 2 A conjugate according to any one of embodiments 46m to 81a, wherein:

[0437] Embodiment 83.D 1 and D. 2 is different, a conjugate according to any one of embodiments 46m to 81a.

[0438] Embodiment 84.D 1 and D. 2 The conjugate according to any one of embodiments 46m to 83, wherein each of the above is independently selected from a cytotoxic drug, a cytostatic drug, and an immunosuppressant.

[0439] Embodiment 85.D 1 and D. 2 The conjugate according to any one of embodiments 46m to 83, wherein each of said groups is independently selected from an auristatin, a camptothecin, a duocarmycin, an etoposide, a maytansine, a maytansinoid, a taxane, a benzodiazepine or a benzodiazepine-containing drug (e.g., a pyrrolo[1,4]-benzodiazepine (PBD), an indolinobenzodiazepine, and an oxazolidinobenzodiazepine), and a vinca alkaloid.

[0440] Embodiment 85a.D 1 and D. 2 is, independently, [ka] [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0441] Embodiment 85b.i)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iii) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; iv) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; v)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; viii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; ix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; x)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xi) D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxiv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xxxix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xli)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xliv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; vl)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; xlviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; il)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; l)D 1teeth, [ka] and D 2 teeth, [ka] Is it; li)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; liv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lv)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lvii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lviii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lix)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lx)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxi)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxii)D 1 teeth, [ka] and D 2 teeth, [ka] Is it; lxiii)D 1 teeth, [ka] and D 2 teeth, [ka] or lxiv)D 1 teeth, [ka] and D 2 teeth, [ka] A conjugate according to embodiment 85a, wherein * indicates the point of attachment to the rest of the molecule.

[0442] Embodiment 85c.i)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; iv) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; v)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; vii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; viii) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; ix) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; x)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xi) A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiii)A1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xxxix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xl)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] Is it; xli)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xliv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; xlix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; l)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; li)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; liv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lvii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lviii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lix)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lx)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxi)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] Is it; lxii)A 1 -D 1 teeth, [ka] and A 2 -D2 teeth, [ka] Is it; lxiii)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] or lxiv)A 1 -D 1 teeth, [ka] and A 2 -D 2 teeth, [ka] A conjugate according to any one of embodiments 46 to 85b, wherein * indicates the point of attachment to the rest of the molecule.

[0443] Embodiment 86.D 1 and / or D. 2 The conjugate according to any one of embodiments 46m to 83, wherein is an auristatin.

[0444] Embodiment 86a.D 1 and D. 2 The conjugate according to embodiment 86, wherein both of are auristatins.

[0445] Embodiment 86b.D 1 and / or D. 2 The conjugate according to any one of embodiments 46m to 83, wherein is a topoisomerase 1 inhibitor.

[0446] Embodiment 86c.D1 and D. 2 The conjugate according to embodiment 86b, wherein both of said compounds are topoisomerase 1 inhibitors.

[0447] Embodiment 86d.D 1 and D. 2 one of which is an auristatin and D 1 and D. 2 The conjugate according to any one of embodiments 46m to 83, wherein the other is a topoisomerase 1 inhibitor.

[0448] Embodiment 86e.D 1 is an auristatin, and D 2 The conjugate according to embodiment 86d, wherein is a topoisomerase 1 inhibitor.

[0449] Embodiment 86f.D 1 is a topoisomerase 1 inhibitor, and D 2 The conjugate according to embodiment 86d, wherein is an auristatin.

[0450] Embodiment 87.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to The conjugate according to embodiment 86, selected from the group consisting of:

[0451] Embodiment 87a.D 1 and D. 2 is, independently, [ka] 88. The conjugate according to embodiment 87, selected from the group consisting of:

[0452] Embodiment 87b.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0453] Embodiment 87c.D 1 and D. 2 is, independently, [ka] (In the formula, * represents A 1 Or A 2 (Indicates the attachment point to or a pharma- ceutically acceptable salt thereof.

[0454] Embodiment 88.D 1 and D. 2 The conjugate according to any one of embodiments 46m to 83, wherein each of said groups is independently selected from an antitubulin agent, a tubulin inhibitor, a DNA minor groove binder, a DNA replication inhibitor, an alkylating agent, an antibiotic, an antifolate, an antimetabolite, a chemotherapeutic sensitizer, a topoisomerase inhibitor, and / or a vinca alkaloid.

[0455] Embodiment 89.D 1 and D. 2are each independently 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 maytansinoid, MetAP (methionine aminopeptidase), an inhibitor of nuclear export of protein CRM1, a DPPIV inhibitor, an inhibitor of phosphoryl transfer reaction in mitochondria, a protein synthesis inhibitor, a kinase inhibitor, a CDK2 inhibitor, a CDK9 inhibitor, a proteasome inhibitor, a kinesin inhibitor, a HDAC inhibitor, a DNA damaging agent, a DNA alkylating agent, a DNA interfering agent, a DNA minor groove binder, an RNA polymerase inhibitor, an amanitin, a spliceosome inhibitor, a topoisomerase inhibitor, a DHFR inhibitor, or a proapoptotic agent; 1 Also D 2 A conjugate according to any one of embodiments 46m to 83, with the proviso that neither is a BH3 mimetic.

[0456] Embodiment 90. A conjugate comprising an antibody or antigen-binding fragment bound to one or more (e.g., 1-16, such as 1-4) compounds independently selected from embodiment 44 or embodiment 45.

[0457] Embodiment 91. A conjugate according to any one of embodiments 46m to 90, wherein the antibody or antigen-binding fragment binds to a target antigen on a cancer cell.

[0458] Embodiment 92. (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 conjugate according to embodiment 91, wherein the target antigen is selected from PCAD, CD48, CD74, EphA2, TROP2, B7-H3, 5T4, and HER2.

[0459] Embodiment 92a. The conjugate of embodiment 91 or 92, wherein the antibody or antigen-binding fragment thereof is selected from Table D1.

[0460] Embodiment 93. A conjugate according to any one of embodiments 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) a heavy chain variable region sequence and a light chain variable region sequence selected from Tables D2 and D8, or iii) a heavy chain sequence and a light chain sequence selected from Tables D4, D5 and D7.

[0461] Embodiment 94. The antibody or antigen-binding fragment comprises: 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, 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, 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) 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: 172, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 173, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; 5) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 256, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 257, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 171; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 263, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 265; 6) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 258, 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; 7) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 259, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 260, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 261; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 215, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 264, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 174; and 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 92. The conjugate of embodiment 91, which is an anti-CD74 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0462] Embodiment 95. The conjugate of embodiment 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.

[0463] Embodiment 96. The antibody or antigen-binding fragment comprises: (a) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; (b) a heavy chain amino acid sequence of SEQ ID NO: 236, or a sequence at least 95% identical to SEQ ID NO: 236, and a light chain amino acid sequence of SEQ ID NO: 237, or a sequence at least 95% identical to SEQ ID NO: 237; or (c) a heavy chain amino acid sequence of SEQ ID NO: 118, or a sequence at least 95% identical to SEQ ID NO: 118, and a light chain amino acid sequence of SEQ ID NO: 239, or a sequence at least 95% identical to SEQ ID NO: 239. 92. The conjugate of embodiment 91, wherein the anti-CD74 antibody comprises

[0464] Embodiment 97. The antibody or antigen-binding fragment comprises: 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, 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, 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, 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) 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 92. The conjugate of embodiment 91, which is an anti-CD48 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0465] Embodiment 98. The conjugate of embodiment 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.

[0466] Embodiment 99. The conjugate of embodiment 91, 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 that is at least 95% identical to SEQ ID NO: 240 and a light chain amino acid sequence of SEQ ID NO: 243 or a sequence that is 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 that is at least 95% identical to SEQ ID NO: 242 and a light chain amino acid sequence of SEQ ID NO: 243 or a sequence that is at least 95% identical to SEQ ID NO: 243; c) a heavy chain amino acid sequence of SEQ ID NO: 240 or a sequence that is at least 95% identical to SEQ ID NO: 240 and a light chain amino acid sequence of SEQ ID NO: 69 or a sequence that is at least 95% identical to SEQ ID NO: 70.

[0467] Embodiment 100. The antibody or antigen-binding fragment comprises: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 289, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 290, 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, 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, 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) 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 92. The conjugate of embodiment 91, which is an anti-Her2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0468] Embodiment 101. The conjugate of embodiment 91, 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.

[0469] Embodiment 102. The conjugate of embodiment 91, 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.

[0470] Embodiment 103. The antibody or antigen-binding fragment comprises: 1) a heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 304, a heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 305, 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, 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, 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) 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 92. The conjugate of embodiment 91, which is an anti-PCAD antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0471] Embodiment 104. The conjugate of embodiment 91, 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.

[0472] Embodiment 105. The conjugate of embodiment 91, 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.

[0473] Embodiment 106. The antibody or antigen-binding fragment comprises: 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, 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, 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) heavy chain CDR1 (HCDR1) consisting of SEQ ID NO: 328, heavy chain CDR2 (HCDR2) consisting of SEQ ID NO: 323, heavy chain CDR3 (HCDR3) consisting of SEQ ID NO: 321; light chain CDR1 (LCDR1) consisting of SEQ ID NO: 333, light chain CDR2 (LCDR2) consisting of SEQ ID NO: 334, and light chain CDR3 (LCDR3) consisting of SEQ ID NO: 335 92. The conjugate of embodiment 91, which is an anti-EphA2 antibody comprising three heavy chain CDRs and three light chain CDRs selected from the group consisting of:

[0474] Embodiment 107. The conjugate of embodiment 91, 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.

[0475] Embodiment 108. The conjugate of embodiment 91, 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.

[0476] Embodiment 109. The conjugate of any one of embodiments 94 to 108, wherein the antibody or antigen-binding fragment thereof comprises one or more cysteine ​​substitutions selected from E152C, S375C or both E152C and S375C in the heavy chain of the antibody or antigen-binding fragment thereof, wherein the positions are numbered according to the EU system.

[0477] Embodiment 110. The conjugate of any one of embodiments 94 to 108, wherein the antibody or antigen-binding fragment thereof comprises one or more Fc-silencing mutations.

[0478] Embodiment 111. A composition comprising multiple copies of any one of embodiments 46m to 110, wherein the average a of the conjugate in the composition is from about 1 to about 8, for example from about 1 to about 6, from about 1 to about 4, or from about 1 to about 2.

[0479] Embodiment 112. A compound of the formula: [ka] [ka] [ka] [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., from 2 to 5); and n is an integer from 1 to 12 (e.g., 2 to 5). or a pharma- ceutically acceptable salt thereof.

[0480] Embodiment 112a.A 1 and A 2 each independently represents a bond and OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 or a pharma- ceutically acceptable salt thereof.

[0481] Embodiment 113. A compound of the formula: [ka] [ka] [ka] [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., from 2 to 5); n is an integer from 1 to 12 (e.g., from 2 to 5); and **--- indicates the attachment point to Ab) The conjugate according to any one of embodiments 46m to 110, represented by any one of:

[0482] Embodiment 113a.A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 The conjugate according to embodiment 113, wherein the conjugate is selected from the group consisting of:

[0483] Embodiment 114. Formula (D5a-1): [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); and n is an integer from 1 to 12 (e.g., 5 to 10). 44. A compound according to any one of embodiments 1 to 43, or a pharma- ceutically acceptable salt thereof.

[0484] Embodiment 114a.A 1 and A 2each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 or a pharma- ceutically acceptable salt thereof.

[0485] Embodiment 115. Formula (D5a-2): [ka] (In the formula, A 1 and A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 (indicating the point of attachment to the); g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); n is an integer from 1 to 12 (e.g., 5 to 10); and **--- indicates the attachment point to Ab) The conjugate according to any one of embodiments 46m to 110.

[0486] Embodiment 115a.A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 The conjugate according to embodiment 115, wherein the conjugate is selected from the group consisting of:

[0487] Embodiment 116. A compound of the formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, A 1 Or A 2 are each independently a bond, [ka] and -OC(=O)-* (wherein * is D 1 Or D 2 **--- indicates point of attachment to Ab; and [ka] D 1 Or D 2 (Indicates a direct attachment point to The conjugate according to any one of embodiments 46m to 110, represented by:

[0488] Embodiment 116a.A 1 and A 2 each independently represents a bond and -OC(=O)-* (wherein A 1 and A 2 The * in D 1 Or D 2 The conjugate according to embodiment 116, wherein the conjugate is selected from the group consisting of:

[0489] Embodiment 117. A pharmaceutical composition comprising the conjugate of any one of embodiments 46 to 110, 113, 115 and 116 and a pharma- ceutically acceptable carrier.

[0490] Embodiment 118. A method for treating a subject having or suspected of having cancer, comprising administering to the subject a therapeutically effective amount of a conjugate of any one of embodiments 46 to 110, 113, 115 and 116, or a pharmaceutical composition of embodiment 117.

[0491] Embodiment 119. The method of embodiment 118, wherein the cancer expresses the target antigen.

[0492] Embodiment 120. The method of embodiment 118 or embodiment 119, wherein the cancer is a tumor or blood cancer, optionally wherein 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 neoplasms 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.

[0493] Embodiment 121. A method for reducing or inhibiting tumor growth in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate of any one of embodiments 46 to 110, 113, 115 and 116, or a pharmaceutical composition of embodiment 117.

[0494] Embodiment 122. The method of embodiment 121, wherein the tumor expresses the target antigen.

[0495] Embodiment 123. The method of embodiment 121 or embodiment 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, splenic cancer, pancreatic cancer, stomach cancer, colon cancer or head and neck cancer.

[0496] Embodiment 124. A method for reducing or inhibiting a hematological cancer in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate of any one of embodiments 46 to 110, 113, 115 and 116, or a pharmaceutical composition of embodiment 117.

[0497] Embodiment 125. The method of embodiment 124, wherein the hematological cancer expresses the target antigen.

[0498] Embodiment 126. The method of embodiment 124 or embodiment 125, 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 myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non-Hodgkin's lymphoma or myelodysplastic syndrome (MDS).

[0499] Embodiment 127. The method of any one of embodiments 121-126, 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%.

[0500] Embodiment 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 a conjugate of any one of embodiments 46 to 110, 113, 115 and 116, or a pharmaceutical composition of embodiment 117.

[0501] Embodiment 129. The method of embodiment 128, wherein the cancer cell population expresses a target antigen.

[0502] Embodiment 130. The method of embodiment 128 or embodiment 129, wherein the cancer cell population is derived from a tumor or blood cancer, and optionally the cancer cell population is derived 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 neoplasms 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, splenic cancer, pancreatic cancer, gastric cancer, colon cancer or head and neck cancer.

[0503] Embodiment 131. The method of any one of embodiments 128-130, 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%.

[0504] Embodiment 132. The method of any one of embodiments 118 to 131, wherein the conjugate is administered as monotherapy.

[0505] Embodiment 133. The method of any one of embodiments 118 to 131, wherein the conjugate is administered concomitantly with another therapeutic agent or radiation therapy.

[0506] Embodiment 134. The method of embodiment 133, wherein the conjugate is administered in an amount effective to sensitize tumor cells to one or more additional therapeutic agents and / or radiation therapy.

[0507] Embodiment 135. The method of any one of embodiments 118 to 131, further comprising administering at least one additional therapeutic agent to a subject in need thereof.

[0508] Embodiment 136. The method of embodiment 135, wherein one additional therapeutic agent is a taxane, a vinca alkaloid, a MEK inhibitor, an ERK inhibitor, a topoisomerase inhibitor, or a RAF inhibitor.

[0509] Embodiment 137. Use of a conjugate of any one of embodiments 46 to 110, 113, 115 and 116, or a pharmaceutical composition of embodiment 117, for the manufacture 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 hematological cancer in a subject, or (iv) reducing or slowing the expansion of a cancer cell population in a subject.

[0510] Embodiment 138. A conjugate of any one of embodiments 46 to 113, 110, 115 and 116, or a pharmaceutical composition of embodiment 117, 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.

[0511] definition Various terms relating to aspects of the present specification are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise specified. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein.

[0512] As used herein, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise. The terms "is," "includes," and "containing," such as in "comprising," "having," and "is of the formula," should be considered open terms (i.e., meaning "including, but not limited to") unless otherwise noted. Furthermore, whenever "comprising" or another open-ended term is used in an embodiment, it should be understood that the same embodiment may be more narrowly claimed using the intermediate term "consisting essentially of" or the limiting term "consisting of."

[0513] The term "about" or "approximately," when used in connection with numerical values ​​and ranges, refers to a value or range that is close to or near the recited value or range, such that an embodiment may be performed as intended, as would be apparent to one of ordinary skill in the art from the teachings contained herein. In some embodiments, about means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of a quantity. In one embodiment, the term "about" refers to a set of numerical values ​​that are greater than or less than 10% of a particular numerical value. In another embodiment, the term "about" refers to a set of numerical values ​​that are greater than or less than 5% of a particular numerical value. In another embodiment, the term "about" refers to a set of numerical values ​​that are greater than or less than 1% of a particular numerical value.

[0514] The terms "antibody drug conjugate," "antibody conjugate," "conjugate," "immunoconjugate," and "ADC" are used interchangeably and refer to one or more therapeutic compounds (not BH3 mimetics) linked to one or more antibodies or antigen-binding fragments. In some embodiments, an ADC has the general formula: [ka] (Formula 1), where Ab=antibody or antigen-binding fragment, L=dual linker moiety, and D 1 and D. 2 = a drug moiety that is not a BH3 mimetic, and A = D bound to each antibody or antigen-binding fragment. 1 and D.2 is the number of dual linker moieties having

[0515] The term "antibody" is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the above, through at least one antigen recognition site in the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain or intact immunoglobulins, and can be from natural or recombinant sources. An "intact" antibody is a glycoprotein that typically comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region contains three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs arranged from amino to carboxyl termini in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody may mediate the binding of the immunoglobulin to host tissues or to various cells of the immune system (e.g., effector cells) and factors including the first component (C1q) of the classical complement system. The antibody may be a monoclonal antibody, a human antibody, a humanized antibody, a camelized antibody, or a chimeric antibody. The antibody can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. The antibody can be an intact antibody or an antigen-binding fragment thereof.

[0516] In some embodiments, the antibody or antibody fragment disclosed herein comprises modified or engineered amino acid residues, such as one or more cysteine ​​residues, as sites for conjugation to a drug moiety (Junutula JR, et al., Nat Biotechnol 2008,26:925-932). In one embodiment, the present disclosure provides modified antibodies or antibody fragments comprising substitutions of one or more amino acids with cysteine ​​at the positions described herein. The sites for cysteine ​​substitutions are in the constant region of the antibody or antibody fragment, and are therefore applicable to a variety of antibodies or antibody fragments, with the sites being selected to provide stable and uniform conjugates. The modified antibody or fragment can have one, two or more cysteine ​​substitutions, and these substitutions can be used in combination with other modification and conjugation methods as described herein. Methods for inserting cysteines at specific positions in an antibody are known in the art, see, e.g., Lyons et al, (1990) Protein Eng., 3:703-708, WO 2011 / 005481, WO 2014 / 124316, WO 2015 / 138615. In certain embodiments, the modified antibody comprises a substitution of one or more amino acids in its constant region selected from 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 of the heavy chain of the antibody, wherein positions are numbered according to the EU system.In some embodiments, the modified antibody or antibody fragment comprises a substitution by cysteine ​​of one or more amino acids in its constant region 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, positions numbered according to the EU system, and the light chain is a human kappa light chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitution by cysteine ​​of two or more amino acids in its constant region, positions numbered according to the EU system, including substitution 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, positions numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid by cysteine ​​in its constant region, which substitution is at position 375 of the antibody heavy chain, at position 152 of the antibody heavy chain, at position 360 of the antibody heavy chain, at position 107 of the antibody light chain, at position 165 of the antibody light chain or at position 159 of the antibody light chain, positions numbered according to the EU system, and the light chain is a kappa chain. In certain embodiments, the modified antibody or antibody fragment thereof comprises a combination of substitutions of two amino acids by cysteine ​​in its constant region, which combination comprises a substitution at position 375 of the antibody heavy chain and at position 152 of the antibody heavy chain, positions numbered according to the EU system. In certain embodiments, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid by cysteine ​​at position 360 of the antibody heavy chain, positions numbered according to the EU system. In another particular embodiment, the modified antibody or antibody fragment thereof comprises a substitution of one amino acid at position 107 of the antibody light chain with a cysteine, where positions are numbered according to the EU system, and the light chain is a kappa chain.

[0517] The term "antibody fragment" or "antigen-binding fragment" or "functional antibody fragment" as used herein refers to at least a portion of an antibody that retains the ability to specifically interact with an epitope of an antigen (e.g., PCAD, HER2, CD48, CD74, EphA2, TROP2, B7-H3 or 5T4) (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution). Antigen-binding fragments may also retain the ability to be internalized into antigen-expressing cells. In some embodiments, antigen-binding fragments also retain immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, and the like are intended to encompass the use of binding domains derived 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 the full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), Fd fragments consisting of VH and CH1 domains, linear antibodies, single domain antibodies (either VL or VH) such as sdAb, camelid VHH domains, multispecific antibodies formed from antibody fragments such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, bispecific or multispecific antibody constructs, ADCs, v-NARs, and bis-scFvs (e.g., Holliger and Hudson (2005) Nat Biotechnol. 23(9):1126-36). Antigen-binding fragments can also be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see US Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies).The term "scFv" refers to a fusion protein comprising at least one antigen-binding fragment comprising a variable region of a light chain and at least one antigen-binding fragment comprising a variable region of a heavy chain, where the light chain variable region and the heavy chain variable region are closely linked, for example, via a synthetic linker, e.g., a short flexible polypeptide linker, and can be expressed as a single-chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. Unless otherwise specified, an scFv can have the VL and VH variable regions in any order, e.g., relative to the N-terminus and C-terminus of the polypeptide, and the scFv can comprise VL-linker-VH or VH-linker-VL. Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as intact antibodies. Antigen-binding fragments can be prepared, for example, by cleavage of the intact protein, e.g., by protease or chemical cleavage.

[0518] As used herein, the term "complementarity determining region" or "CDR" refers to a sequence of amino acids in an antibody variable region that confers antigen specificity and binding affinity. For example, typically, there are three CDRs in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3). The exact amino acid sequence boundaries of a given CDR may be determined using any of a number of well-known schemes, including those described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. 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. 27(1):55-77) ("IMGT" numbering scheme); or a combination thereof. In a combination of the Kabat and Chothia numbering schemes for a given CDR region (e.g., HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, or LC CDR3), in some embodiments, the CDRs correspond to the amino acid residues defined as part of the Kabat CDRs along with the amino acid residues defined as part of the Chothia CDRs. As used herein, CDRs defined according to the "Chothia" numbering scheme are sometimes referred to as "hypervariable loops."

[0519] In some embodiments, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31 to 35 (HCDR1) (e.g., an insertion after position 35), 50 to 65 (HCDR2), and 95 to 102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24 to 34 (LCDR1) (e.g., an insertion after position 27), 50 to 56 (LCDR2), and 89 to 97 (LCDR3). In some embodiments, under Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1) (e.g., insertion after position 31), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1) (e.g., insertion after position 30), 50-52 (LCDR2), and 91-96 (LCDR3). Combining the CDR definitions of both Kabat and Chothia, in some embodiments, the CDRs comprise or consist of, 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. In some embodiments, under IMGT, the CDR amino acid residues in VH are numbered from about 26-35 (CDR1), 51-57 (CDR2), and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered from about 27-32 (CDR1), 50-52 (CDR2), and 89-97 (CDR3). In some embodiments, under IMGT, the CDR regions of an antibody may be determined using the program IMGT / DomainGap Align.

[0520] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical except for naturally occurring variants that may be present in minor amounts. Monoclonal antibodies are highly specific and directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations usually contain a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be produced by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using, for example, the 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 preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0521] The monoclonal antibodies described herein may be non-human, human, or humanized. The term specifically includes "chimeric" antibodies in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chains are identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind to the target antigen and / or exhibit the desired biological activity.

[0522] The term "human antibody" as used herein refers to an antibody produced by a human or an antibody having the amino acid sequence of an antibody produced by a human. This term includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region is also derived from such a human sequence, e.g., a human germline sequence or a variant of a human germline sequence, or an antibody containing a consensus framework sequence derived from human framework sequence analysis, e.g., as described in Knappik, et al. ((2000) J Mol Biol. 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 the ImMunoGenTics (IMGT) numbering. The human antibodies of the invention may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo, or conservative substitutions to facilitate stability or manufacturing). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0523] As used herein, the term "recombinant human antibody" refers to a human antibody that is made, expressed, created or isolated by recombinant means, such as an antibody isolated from an animal (e.g., a mouse) transgenic or transchromosomal for human immunoglobulin genes or from a hybridoma made therefrom, an antibody isolated from a host cell transformed to express a human antibody, e.g., from a transfectoma, an antibody isolated from a recombinant combinatorial human antibody library, and an antibody made, expressed, created or isolated by any other means including splicing all or a portion of a human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally exist within the human antibody germline repertoire in vivo.

[0524] The term "chimeric antibody" as used herein refers to an antibody in which the amino acid sequences of the immunoglobulin molecules are derived from two or more species. In some instances, the variable regions of both the heavy and light chains correspond to the variable regions of an antibody derived from one species having the desired specificity, affinity, and activity, while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize the immune response in the latter species.

[0525] As used herein, the term "humanized antibody" refers to a form of an antibody that contains sequences derived from a non-human (e.g., murine) antibody and a human antibody. Such antibodies are a type of chimeric antibody that contains minimal sequences derived from a non-human immunoglobulin. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are from human immunoglobulin sequences. A humanized antibody will optionally contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. A humanized antibody can be further modifi...

Claims

1. Formula (C-1): 【Chemistry 1】 (In the formula, R １ is a linking group; L １ is a bridging spacer; W is N or CR ｗ and R ｗ is H or C １ ~C ６ alkyl (e.g., R ｗ teeth , H); L ２ and L ３ are each independently a linking spacer; E １ and E ２ are each independently a peptide group containing 1 to 6 amino acids, The peptide group is optionally substituted with a hydrophilic group; A １ and A ２ each independently represents a bond, —OC(═O)—*, 【Chemistry 2】 , -OC(=O)N(CH ３ )CH ２ CH ２ N(CH ３ )C(=O)- * or -OC(= O)N(CH ３ ) C (R ａ ) ２ C (R ａ ) ２ N (CH ３ )C(=O)-*, Each R ａ are independently H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl Re, A １ or A ２ The * is D １ or D ２ indicates the point of attachment to D １ and D ２ are each independently a pharmaceutically active drug, and optionally, D １ Also D ２ is not a BH3 mimetic; L ４ and L ５ are each independently a spacer moiety; R ２ and R ３ are each independently (i) the following part: 【Transformation 3】 (In the formula, f is an integer from 3 to 25; and R 23 is H, —CH 3 or —CH 2 CH 2 C(═O)OH. and polysarcosine having the formula: (ii) Formula: 【Chemistry 4】 (wherein g and h are independently integers from 2 to 30). of polyethylene glycol and is selected from: m and n are each independently 1. or a pharmaceutically acceptable salt thereof.

2. The compound represented by formula (D1-1): 【Transformation 5】 2. The compound of claim 1, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

3. R １ teeth, 【Transformation 6】 -ONG ２ 、-NH ２ 、 【Transformation 7】 -N ３ 、 【Transformation 8】 、-SH、-SR １１ 、-SSR １２ 、-S(=O) ２ (CH=CH ２ )、-(CH ２ ) ２ S(=O) ２ (CH=CH ２ )、-NHS(=O) ２ (CH=CH ２ )、-NR １１ C (=O)CH ２ Br, for example -NHC(=O)CH ２ Br, -NR １１ C(=O)CH ２ I, for example, —NHC(═O)CH ２ I, 【Chemistry 9】 -C(O)NHNH ２ 、 【Chemistry 10】 (In the formula, Each R １１ are independently H and C １ ~C ６ alkyl; Each R １２ is 2-pyridyl or 4-pyridyl; Each R １３ are independently H, C １ ~C ６ selected from alkyl, F, Cl, and —OH; Each R １４ are independently H, C １ ~C ６ Alkyl, F, Cl, —NH ２ , -OCH ３ ,- OCH ２ CH ３ , -N(CH ３ ) ２ , -CN, -NO ２ and —OH; and Each R １５ are independently H, C １ ~C ６ Substituted with alkyl, fluoro, -C(=O)OH benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH C １ ~C ４ C substituted with alkoxy and —C(═O)OH １ ~C ４ From alkyl selected) is selected from the group consisting of Preferably, R 1 is 【Chemistry 11】 -ONH2, 【Chemistry 12】 selected from the group consisting of -NHC(=O)CH 2 Br and -NHC(=O)CH 2 I; Most preferably, R 1 is 【Chemistry 13】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. (1) L １ teeth, 【Chemistry 14】 or *-CH(OH)CH(OH)CH(OH)CH(OH)-** wherein each n is an integer from 1 to 12. Including L １ * indicates a direct or indirect (e.g., direct) point of attachment to W. , and L １ ** is R １ indicates the direct or indirect (e.g., direct) point of attachment to Suka; (2) L １ teeth, 【Chemistry 15】 and n is an integer from 1 to 12, or n is 1, or n is 12 Yes, L １ * indicates a direct or indirect (e.g., direct) point of attachment to W; and L １ ** is R １ indicates a direct or indirect (e.g., direct) point of attachment to mosquito; (3) L １ teeth, 【Chemistry 16】 and n is an integer from 1 to 12, and L １ * indicates direct or indirect support for W indicates a point of attachment (e.g., direct), and L １ ** is R １ Directly or indirectly against whether the bond indicates a direct (e.g., direct) point of attachment; (4) L １ teeth, 【Chemistry 17】 Including L １ * indicates a direct or indirect (e.g., direct) point of attachment to W. , and L １ ** is R １ indicates the direct or indirect (e.g., direct) point of attachment to Suka; or (5)L １ は、*-C(=O)(CH ２ ) ｍ O(CH ２ ) ｍ -**;*-C(=O)(( CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ -**;*-C(= O)NH((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ -**;*-C(=O)O(CH ２ ) ｍ SS C(R Ｌ１ ) ２ (CH ２ ) ｍ C(=O)NR Ｌ１ (CH ２ ) ｍ NR Ｌ１ C(=O)(CH ２ ) ｍ -**;*-C(=O)O(CH ２ ) ｍ C(=0)NH(CH ２ ) ｍ -**;*- C(=0)(CH ２ ) ｍ NH(CH) ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ NH(C) H ２ ) ｎ C(=O)-**;*-C(=O)(CH ２ ) ｍ X １ (CH ２ ) ｍ -**;*- C(=O)((CH ２ ) ｍ O) ｔ (CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O) (CH) ２ ) ｍ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ NHC(=0)(CH ２ ) ｎ -**;*-C(=O)(CH ２ ) ｍ NHC( =O)(CH ２ ) ｎ X １ (CH ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (C H ２ ) ｎ NHC(=0)(CH ２ ) ｎ X １ (CH) ２ ) ｎ -**;*-C(=O)((CH ２ ) ｍ O) ｔ (CH) ２ ) ｎ C(=0)NH(CH ２ ) ｍ -**;*-C(=O)(CH ２ ) ｍ C (R Ｌ１ ) ２ -** or *-C(=O)(CH ２ ) ｍ C(=O)NH(CH ２ ) ｍ - is a bridging spacer containing **, and L １ * indicates direct or indirect (e.g. indicates the point of attachment (e.g., direct), and L １ ** is R １ Direct or indirect (e.g. indicating points of attachment (e.g., direct); X １ teeth, [Chemistry 18] and 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1 ４、１５、１６、１７、１８、１９、２０、２１、２２、２３、２４、２５、２６、２７ , 28, 29 and 30; and Each R Ｌ１ are independently H and C １ ~C ６ alkyl, Preferably, L 1 is 【Chemistry 19】 (wherein n is an integer of 1 to 12 (for example, 4 to 8, for example, 4 or 8), and * of L 1 indicates a direct or indirect (e.g., direct) point of attachment to W, and ** of L 1 . indicates the direct or indirect point of attachment to R 1 ) including the portion represented by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. L １ is the expression 【Chemistry 20】 (In the formula, n is an integer from 1 to 12 (e.g., 4 to 8, e.g., 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; L １ * indicates the direct point of attachment to W, and L １ ** is R １ Direct to (indicating the most suitable attachment point) 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

6. L １ teeth, 【Chemistry 21】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

7. L ２ and L ３ are each independently 【Chemistry 22】 (In the formula, 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; L ２ or L ３ The # of each is E １ or E ２ indicates a direct or indirect point of attachment to and L ２ or L ３ ## indicates the direct or indirect point of attachment to W) The compound of claim 1 or a pharmaceutical composition thereof, wherein the compound is a linking spacer comprising a moiety represented by A physiologically acceptable salt.

8. L ２ and L ３ are each independently 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 (In the formula, k in each occurrence is independently an integer from 0 to 4; r in each occurrence is independently 0 or 1; o in each occurrence is independently an integer from 0 to 10; p in each occurrence is independently an integer from 0 to 4; R Ｌ２３ is hydrogen or C １ ~C ６ is alkyl; R Ｌ is hydrogen or —C(O)—R Ｈ and R Ｈ is a hydrophilic group; and L ２ or L ３ The # of each is E １ or E ２ and L ２ also Is L ３ ## indicates the direct point of attachment to W; When W is N, L ２ and L ３ is (L2c), (L2d), (L2f) or (L2k ) is a linking spacer selected from the group consisting of: Preferably, L 2 and L 3 are each independently 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 (In the formula, k in each occurrence is independently an integer from 1 to 3; o in each occurrence is independently an integer from 1 to 9; p in each occurrence is independently an integer from 1 to 3; R L23 is hydrogen or C 1 -C 3 alkyl; R L is hydrogen or —C(O)—R H ; R H is a hydrophilic group; and The # in L 2 or L 3 indicates the direct point of attachment to E 1 or E 2 , respectively, and the # in L 2 or L 3 indicates the direct point of attachment to E 1 or E 2 , respectively. The ## in L 3 indicates the direct point of attachment to W; when W is N, L 2 and L 3 are , (L2FF), (L2MM), (L2NN), (L2OO) or (L2PP) (Condition: is a linking spacer selected from the group consisting of:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. L ２ and L ３ is, independently, 【Chemistry 29】 【Transformation 30】 (In the formula, L ２ or L ３ The # of each is E １ or E ２ indicates the direct point of attachment to L ２ or L ３ ## indicates the direct point of attachment to W; R Ｌ is hydrogen or —C(O)— R Ｈ and R Ｈ teeth, 【Chemistry 31】 and d is an integer from 20 to 30 (e.g., 25). The compound according to claim 1 or a pharmaceutical composition thereof, wherein the linking spacer is selected from the group consisting of A commercially acceptable salt.

10. each peptide group independently comprises 1 to 4, 1 to 3, or 1 to 2 amino acid residues; Preferably, each amino acid residue is independently glycine (Gly), L-valine (Val), , L-citrulline (Cit), L-cysteic acid (Sulfo-Ala), L-lysine (Ly s), L-isoleucine (Ile), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline (Pro), L-alanine (A Ia), L-leucine (Leu), L-tryptophan (Trp), L-tyrosine (Ty r) and β-alanine (β-Ala), or Pharmaceutically acceptable salts.

11. Each peptide group is independently Val-Cit, Phe-Lys, Val-Ala, Va l-Lys, Leu-Cit, Cit-(β-Ala), Gly-Gly-Gly, Gl γ-Gly-Phe-Gly and Sulfo-Ala-Val-Ala. Item 1. The compound or a pharmaceutically acceptable salt thereof according to Item 1.

12. E １ and / or E ２ are each independently 【Chemistry 32】 (wherein E1-1 or E1-2 represents V in formula (B) １ Or V ２ Direct to indicates a point of attachment to the -NH- group in formulas (C) and (D); and E1-1 or E1-2 ^ are L ２ or L ３ Show the direct attachment point for (e.g., E １ and E ２ are each independently selected from (E1-1) and (E1-2) (If the peptide group is 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a peptide group selected from the group consisting of Salt to be used.

13. E １ and / or E ２ are each independently 【Transformation 33】 (In the formula, R Ｅ is a hydrophilic group R Ｈ is) The compound of claim 1 or a pharmaceutically acceptable salt thereof, Salt.

14. The hydrophilic group R in (E1-3) Ｈ teeth, 【Transformation 34】 (wherein e is an integer of 20 to 30 (e.g., 25)) 14. The compound of claim 13, wherein:

15. A １ and A ２ are independent, combined, 【Chemistry 35】 and -OC(=O)-* (where * represents D １ or D ２ (indicating the point of attachment to 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. i) L ４ and L ５ are each independently 【Transformation 36】 (In the formula, Zは、-O-、-CH ２ -、-CH ２ O-、-CH ２ N(R Ｌ４５ )C(=O)O-、- NHC(=O)C(R Ｌ４５ ) ２ NHC(=O)O-、-NHC(=O)C(R Ｌ４５ ) ２ NH-,-NHC(=0)C(R Ｌ４５ ) ２ NHC(=0)-,-C(=0)NR Ｌ４ ５ -、-C(=O)NH-、-CH ２ NR Ｌ４５ C(=O)-、-CH ２ NR Ｌ４５ C( =O)NH-、-CH ２ NR Ｌ４５ C(=0)NR Ｌ４５ -、-NHCC(=O)-、-N HC(=O)O-、-NHC(=O)NH-、-OC(=O)NH-、-S(O) ２ NH -, -NHS(O) ２ -, -C(=O)-, -C(=O)O- or -NH- (wherein each R Ｌ４５ are independently H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl and X is a bond, triazolyl, or —CH ２ -triazolyl-, X is R ２ or R ３ (connected to or a spacer moiety having the structure (ii) L ４ and L ５ is, independently, 【Chemistry 37】 (In the formula, Zは、-CH ２ -、-CH ２ O-、-CH ２ N(R Ｌ４５ )C(=O)O-、-NHC( =O)C(R Ｌ４５ ) ２ NHC(=O)O-、-NHC(=O)C(R Ｌ４５ ) ２ NH- 、-NHC(=O)C(R Ｌ４５ ) ２ [HC(=O)-、-C(=O)NR ｂ -、-C( =O)NH-、-CH ２ NR Ｌ４５ C(=O)-、-CH ２ NR Ｌ４５ C(=0)NH- 、-CH ２ NR Ｌ４５ C(=0)NR Ｌ４５ -、-NHC(=O)-、-NHC(=O) O-,-NHC(=0)NH-,-OC(=0)NH-,-S(O) ２ NH-NHS (O) ２ -, -C(=O)-, -C(=O)O- or -NH- (wherein each R Ｌ４５ is German Stand up, H, C １ ~C ６ Alkyl and C ３ ~C ８ cycloalkyl) and X is -CH ２ -Triazolyl-C １ ~C ４ Alkylene-OC(O)NHS(O) ２ NH -, -C ４ ~C ６ Cycloalkylene-OC(O)NHS(O) ２ NH-, -(CH ２ CH ２ O) ｎ -C(O)NHS(O) ２ NH-、-(CH ２ CH ２ O) ｎ -C(O)NHS( O) ２ NH-(CH ２ CH ２ O) ｎ -, -CH ２ -Triazolyl-C １ ~C ４ Alkylene -OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ -, -C ４ ~C ６ Cycloalkane Ren-OC(O)NHS(O) ２ NH-(CH ２ CH ２ O) ｎ - (wherein each n is independently and X is R ２ or R ３ (connected to is a spacer moiety having the structure Preferably, L 4 and L 5 are each independently 【Transformation 38】 (wherein @ of L 4 or L 5 indicates the direct point of attachment to the phenyl group, and The @@ in L 5 represents the direct point of attachment to R 2 or R 3 . is a spacer moiety selected from the group consisting of:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. R ２ and R ３ are each independently represented by the formula: 【Chemistry 39】 (wherein g and h are independently integers from 2 to 30). The compound of claim 1 or a pharmaceutically acceptable salt thereof, salt.

18. An antibody or antibody thereof covalently linked to two pharmaceutically active drugs via a dual linker wherein the dual linker is attached to the antibody. and two points of attachment to the two pharmaceutically active drugs, provided that neither pharmaceutically active drug is a BH3 mimetic, A conjugate comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. 20. A composition comprising multiple copies of the antibody drug conjugate of claim 18, wherein the The average a of the antibody drug conjugates in the composition is from about 1 to about 8, for example, from about 1 to about 6; The composition is from about 1 to about 4 or from about 1 to about 2.

20. The following formula: 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 (In the formula, A １ and A ２ are each independently a bond, 【Chemistry 44】 and —O—C(═O)—* (wherein A １ and A ２ * in the above indicates D １ or D ２ Attachment point to (representing the same) g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., from 2 to 5); and n is an integer from 1 to 12 (e.g., 2 to 5). or a pharmaceutically acceptable salt thereof, salt.

21. The following formula: 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 (In the formula, A １ and A ２ are each independently a bond, 【Chemistry 49】 and —O—C(═O)—* (wherein A １ and A ２ * in the above indicates D １ or D ２ Attachment point to (representing the same) g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., from 2 to 5); n is an integer from 1 to 12 (e.g., from 2 to 5); and **--- indicates the binding point to Ab) 19. The conjugate of claim 18, represented by any one of:

22. Formula (D5a-1): [Transformation 50] (In the formula, A １ and A ２ are each independently a bond, 【Chemistry 51】 and —O—C(═O)—* (wherein A １ and A ２ * in the above indicates D １ or D ２ Attachment point to (representing the same) g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); and n is an integer from 1 to 12 (e.g., 5 to 10).

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

23. Formula (D5a-2): 【Chemistry 52】 (In the formula, A １ and A ２ are each independently a bond, 【Chemistry 53】 and —O—C(═O)—* (wherein A １ and A ２ * in the above indicates D １ or D ２ Attachment point to (representing the same) g for each occurrence is independently an integer from 20 to 30 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30); o for each occurrence is independently an integer from 1 to 9 (e.g., 1 to 3); n is an integer from 1 to 12 (e.g., 5 to 10); and **--- indicates the binding point to Ab) a conjugate of The following formula: 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 (wherein A 1 and A 2 each independently represent a bond, 【Chemical Formula 66】 and —OC(═O)—*, where * indicates the point of attachment to D 1 or D 2 ; **--- indicates the point of attachment to Ab; and 【Transformation 67】 indicates the direct point of attachment to D 1 or D 2 ) is a conjugate represented by 19. The conjugate of claim 18.

24. A pharmaceutical composition comprising the conjugate of claim 18 or 23 and a pharmaceutically acceptable carrier. Finished product.

Images