Linkers, drug linkers and their conjugates, and methods of using them

Abstract

Polar units, linker intermediates, linkers, drug-linkers and conjugates thereof are provided.SOLUTION: Linkers are provided that have hydrophilic properties that maintain the inherent properties of the antibody conjugated to the linker and the drug. In particular, the linker helps to maintain the hydrophilicity of the antibody at higher drug loadings and / or when conjugated to hydrophobic drugs and other agents. Also provided are conjugates comprising the drug-linkers and linkers, and methods of using such conjugates for the treatment of cancer and other diseases.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Reference to the electronic sequence list The contents of the electronic sequence listing (760270_40201WO_SEQUENCE_LISTING.xml; size: 40657 bytes; created June 30, 2022) are incorporated herein by reference in their entirety. [Background technology]

[0002] The use of monoclonal antibodies (mAbs) for targeted delivery of cytotoxic agents to disease-associated cells, such as cancer cells and other cells, in the form of antibody-drug conjugates (or ADCs) is of great interest. Designing antibody-drug conjugates, typically by conjugating cytotoxic agents, immunomodulators, or other drugs (collectively, "drugs") to antibodies via linkers, involves consideration of various factors. These factors include the identity and position of the chemical group for drug binding, the mechanism of drug release, the structural elements (if any) that provide drug release, and, if any, the structural modifications of the released free drug. If the drug is released in an extracellular environment, the drug release form must be able to reach its target. If the drug is released after antibody internalization, the structural elements and mechanism of drug release must be consistent with the intracellular transport of the conjugate.

[0003] Another important factor in the design of antibody-drug conjugates is the amount of drug that can be delivered per targeting agent (i.e., the number of drugs bound to each targeting agent (e.g., antibody), referred to as drug load or drug loading). Historically, there was an assumption that higher drug loads were superior to lower loads (e.g., 8 loads vs. 4 loads). The rationale was that conjugates with higher drug loads would deliver more drugs (e.g., cytotoxic agents) to target cells. This rationale was supported by the observation that conjugates with higher drug loads were more active against cell lines in vitro. However, certain subsequent studies have shown that this assumption was not confirmed in animal models. Conjugates with drug loads of 4 or 8 of a particular auristatin were observed to have similar activity in mouse models. See, for example, Hamblett et al., Clinical Cancer Res. 10:7063-70 (2004). Hamblett et al. further reported that higher-loading ADCs were more rapidly removed from circulation in animal models. This faster clearance suggested that higher-loading ADCs were responsible for PK compared to lower-loading ADCs. See Hamblett et al. In addition, higher-loading conjugates had a lower maximum tolerated dose (MTD) in mice, resulting in a narrower reported therapeutic index. Ibid. In contrast, ADCs with a drug loading of 2 at the manipulated site of the monoclonal antibody have been reported to have the same or better PK and therapeutic index compared to certain 4-loading ADCs. See, for example, Junutula et al., Clinical Cancer Res. 16:4769 (2010). Therefore, the recent trend is to develop ADCs with lower drug loadings.

[0004] Therefore, there is a need for antibody-drug conjugate forms (and more generally, other conjugate forms) that allow for higher drug loading while maintaining other properties of lower-loading conjugates, such as preferred PK properties. Surprisingly, the present invention addresses these needs. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hamblett et al.,Clinical Cancer Res.10:7063-70(2004) [Non-Patent Document 2] Junutula et al.,Clinical Cancer Res.16:4769(2010) [Overview of the project] [Problems that the invention aims to solve]

[0006] This specification provides linkers having hydrophilic properties that maintain the intrinsic properties of the antibody conjugated with the drug. In particular, the linker helps maintain the hydrophilicity of the antibody at higher drug loads and / or when conjugated with hydrophobic drugs and other agents. Drug-linkers and conjugates containing the linker, as well as methods for using such conjugates for the treatment of cancer and other diseases, are also provided. [Means for solving the problem]

[0007] In some embodiments, the following equation (V): [ka] (In the formula, AA is an amino acid unit having 1 to 12 amino acid subunits; s is either 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for drug units; Each dashed line (~) indicates a joint for a stretcher unit, and a double dashed line ( [ka] ) is a linker intermediate having a binding site for a drug unit (or a salt thereof), A linker intermediate is provided in which at least one polar unit is present within an amino acid unit, a linker subunit, or both, and the polar unit is selected from a sugar unit, a PEG unit, a carboxyl unit, and combinations thereof.

[0008] In some embodiments, the following equation (I): [ka] (In the formula, L1 is a stretcher unit having a binding site for the targeting unit; AA is an amino acid unit having 1 to 12 subunits; s is either 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for drug units; A dashed line (~) indicates a binding site for a targeting unit, and a double dashed line ( [ka] ) indicates a binding site for a drug unit) or a linker having a salt thereof, A linker is provided in which at least one polar unit is present within an amino acid unit, a linker subunit, or both, and the polar unit is selected from a sugar unit, a PEG unit, a carboxyl unit, and combinations thereof.

[0009] In some embodiments, the following equation (I): [ka] (In the formula, L1 is a stretcher unit having a binding site for the targeting unit; AA is an amino acid unit having 1 to 12 subunits; s is either 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for drug units; A dashed line (~) indicates a binding site for a targeting unit, and a double dashed line ( [ka] ) indicates a binding site for a drug unit) or a linker having a salt thereof, A linker is provided in which at least one polar unit is present within an amino acid unit, a linker subunit, a stretcher unit, or a combination thereof, and the polar unit is selected from sugar units, PEG units, carboxyl units, and combinations thereof.

[0010] sugar units In some embodiments, the sugar unit is expressed by the following formula: L3-**N(CH2-(CH(XR)) k -X1(X2))2 (X) (In the formula, each X is selected independently from NH or O; Each R is independently selected from hydrogen, acetyl, monosaccharides, disaccharides, and polysaccharides; Each X1 is selected independently from CH2 and C(O); Each X2 is independently selected from H, OH, and OR; k is between 1 and 10; L3 is given by the following general formula (XI): L3a | *-NH-(CH2) p -CH-(CH2) o -C(O)-# (XI) (In the formula, L3a is C1-C 10 Selected from alkylene and polyethylene glycol having 1 to 24 ethylene glycol subunits; p and o are independently between 0 and 2; each * and each # represent a binding site for another subunit of an amino acid unit (AA), a linker subunit L2 or a stretcher unit (L1); L3a is covalently bonded to the N atom marked with a** in formula (X)) or a salt thereof, or there is provided a linker intermediate or a linker having a salt thereof.

[0011] In some embodiments, the linker intermediate or the linker is a formula selected from:

Chemical Formula

Chemical Formula

[0012] PEG unit In some embodiments, the linker intermediate or the linker is a formula selected from: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (wherein R 20 is a functional group for binding to a subunit of an amino acid unit or a part of a linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene; R24 and R 25 These are, respectively: H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 is independently selected from (the sugar unit of formula (XII) or (XIII); or -NR 24 R 25 These are formed from the C3-C8 heteroalgebra; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1-26) or its salt, or (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 21 and R 22 These are, independently, any selected C1-C3 alkylene; R 24 and R 25 One of them is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 R is selected from the sugar units of formula (XII) or (XIII); R 24 and R 25 The other is optionally polyethylene glycol having 1 to 24 ethylene glycol subunits; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1-26 ;) or its salts, or (c) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXI) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; R 26 and R 27 Each of these is optional, C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)- and -C(O)-C1-C 12 Selected independently from alkylene-NH-; R 24 and R 25One of them is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 R is selected from the sugar units of formula (XII) or (XIII); R 24 and R 25 The other side is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 is a sugar unit of formula (XII) or (XIII); and optionally selected from polyethylene glycol having 1 to 24 ethylene glycol subunits; or -NR 24 R 25 These are formed from the C3-C8 heteroalgebra; Each R 29 This is optional and can be independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH-, -C1-C6 alkenylene-C(O)-, -NH(CO)NH- and triazole; The wavy line (~) represents R 20 Shows the binding site to; n20 is between 1 and 26; n21 is 1-4; n27 is 1-4;) or contains PEG units having a salt thereof.

[0013] In some embodiments, R in PEG units 24 and R 25 A linker intermediate or linker is provided in which both are not H. In some embodiments, the PEG unit R 24 and R 25 Each of these provides a linker intermediate or linker independently selected from H and a polyhydroxyl group, however, R 24 and R 25 The condition is that neither of them is H.

[0014] In some embodiments, linker intermediates or linkers are provided in which the polyhydroxyl group is optionally a linear monosaccharide selected from C6 or C5 sugars, sugar acids or amino sugars. The C6 or C5 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, growth, idosterose, aldose, and ketose; The sugar acid is selected from gluconic acid, aldonic acid, uronic acid, and uronic acid; or The linker intermediate or linker is provided, in which the amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0015] In some embodiments, linker intermediates or linkers or salts thereof are provided, in which PEG units are selected from the following: [ka] (In the formula, R 39 (These are selected from H, linear monosaccharides, and optionally polyethylene glycol having 1 to 24 ethylene glycol subunits; the wavy line on the left indicates the binding site to a subunit or part of a linker subunit of an amino acid unit.)

[0016] In some embodiments, R in PEG units24 and R 25 provided is a linker intermediate or a linker, wherein one of the groups is a linear monosaccharide and the other is a cyclic monosaccharide.

[0017] In some embodiments, provided is a linker intermediate or a linker, or a salt thereof, wherein the PEG unit is selected from the group consisting of:

Chemical Structure

[0018] In some embodiments, R in the PEG unit 24 and R 25 provided is a linker intermediate or a linker, wherein the R groups are each independently selected from the group consisting of cyclic monosaccharides, disaccharides and polysaccharides. In some embodiments, provided is a linker intermediate or a linker, or a salt thereof, wherein the PEG unit is selected from the group consisting of:

Chemical Structure

Chemical Structure

[0019] In some embodiments, R in the PEG unit 24 and R 25 provided is a linker intermediate or a linker, wherein the R groups are each independently selected from linear monosaccharides and substituted linear monosaccharides, and the substituted linear monosaccharide is substituted with a monosaccharide, a disaccharide or a polysaccharide. In some embodiments, provided is a linker intermediate or a linker, or a salt thereof, wherein the PEG unit is selected from the group consisting of:

Chem.

[0020] In some embodiments, R 24 and R 25 of the PEG unit are independently selected from linear monosaccharides and substituted linear monosaccharides, wherein the substituted linear monosaccharide is substituted with one or more substituents selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester or amide, and optionally further substituted with a monosaccharide, disaccharide or polysaccharide, a linker intermediate or a linker is provided. In some embodiments, there is provided a linker intermediate or a linker, or a salt thereof, wherein the PEG unit is selected from:

Chem.

Chem.

[0021] In some embodiments, one of R 24 and R 25 of the PEG unit is a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group, and R 24 and R 25A linker intermediate or linker is provided in which the other is H, -C(O)-polyhydroxyl group, substituted -C(O)-polyhydroxyl group, polyhydroxyl group or substituted polyhydroxyl group, wherein the substituted -C(O)-polyhydroxyl group and polyhydroxyl group are substituted with monosaccharides, disaccharides, polysaccharides, alkyl, -O-alkyl, aryl, carboxyl, ester or amide. In some embodiments, a linker intermediate or linker or a salt thereof is provided in which the PEG unit is selected from the following: [ka] or [ka] (In the formula, the wavy line on the left indicates the binding site to a subunit of the amino acid unit or part of the linker subunit.)

[0022] In some embodiments, R in PEG units 24 and R 25 However, H is independently selected from substituted-C1-C8 alkyl, substituted-C1-C4 alkyl, or substituted-C1-C3 alkyl, provided that R 24 and R 25 Provided that both are not H, linker intermediates or linkers are provided in which the substituted -C1-C8 alkyl, -C1-C4 alkyl, and -C1-C3 alkyl are substituted with hydroxyl and / or carboxyl. In some embodiments, linker intermediates or linkers or salts thereof are provided in which the PEG units are selected from the following: [ka] or [ka] (In the formula, R 48(These are selected from -C1-C6 alkyl groups substituted with H, OH, CH2OH, COOH, or hydroxyl or carboxyl; the wavy line on the left indicates a binding site to a subunit of the amino acid unit or part of the linker subunit).

[0023] In some embodiments, R in PEG units 24 and R 25 One of them is selected from H, substituted-C(O)-C1-C8 alkyl, substituted-C(O)-C1-C4 alkyl, and substituted-C(O)-C1-C3 alkyl, R 24 and R 25 The other is selected from substituted-C(O)-C1-C8 alkyl, substituted-C(O)-C1-C4 alkyl, substituted-C(O)-C1-C3 alkyl, substituted-C1-C8 alkyl, substituted-C1-C4 alkyl, and substituted-C1-C3 alkyl, where substituted-C(O)-C1-C8 alkyl, substituted-C(O)-C1-C4 alkyl, substituted-C(O)-C1-C3 alkyl, substituted-C1-C8 alkyl, -C1-C4 alkyl, and -C1-C3 alkyl are substituted with hydroxyl and / or carboxyl. In some embodiments, linker intermediates or linkers or salts thereof are provided in which the PEG units are selected from the following: [ka] or [ka] (In the formula, the wavy line on the left indicates the binding site to a subunit of the amino acid unit or part of the linker subunit.)

[0024] In some embodiments, R in PEG units 24 and R 25 However, H and optionally selected from the substitution aryls, but R 24 and R 25Provided that both are not H, and the optional substituent is as defined herein, for example, in some embodiments, linker intermediates or linkers are provided in which the optional substituent is a halo such as F, Cl or Br. In some embodiments, linker intermediates or linkers or salts thereof are provided in which the PEG units are selected from the following: [ka] or [ka] (In the formula, the wavy line on the left indicates the binding site to a subunit of the amino acid unit or part of the linker subunit.)

[0025] In some embodiments, R 24 and R 25 These combine to form an optionally substituted C3-C8 heterocycle or heteroaryl, and in some embodiments, a linker intermediate or linker is provided in which the C3-C8 heterocycle or heteroaryl is unsubstituted. In some embodiments, the PEG units are: [ka] A linker intermediate or linker, which is a salt thereof, is provided.

[0026] In some embodiments, R in PEG units 24 and R 25 However, H and the chelating agent are selected independently, and the chelating agent is determined by alkylene, arylene, carbocyclo, heteroarylene or heterocarbocyclo-NR 24 R 25 It is optionally bonded to the nitrogen, however, R 24 and R 25A linker intermediate or linker is provided, provided that both are not H. In some embodiments, a linker intermediate or linker is provided, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), benzyl-DOTA, 1,4,7-triazacyclododecane-N,N',N''-triacetic acid (NOTA), benzyl-NOTA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), and N,N'-dialkylsubstituted piperazines. In some embodiments, a linker intermediate or linker or a salt thereof is provided, wherein the PEG unit is selected from the following: [ka] or [ka] (In the formula, the wavy line on the left indicates the binding site to a subunit of the amino acid unit or part of the linker subunit.)

[0027] In some embodiments, each monosaccharide of a sugar unit or PEG unit is provided as a linker intermediate or linker independently selected from the following: C5 or C6 sugars selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, growth, idostalose, aldose, ketose, glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine; Sugar acids selected from gluconic acid, aldonic acid, uronic acid, and urosonic acid; or The amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0028] In some embodiments, R 20 However, linker intermediates or linkers are provided, selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or protected forms thereof.

[0029] In some embodiments, R 20 However, linker intermediates or linkers are provided, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or protected forms thereof.

[0030] In some embodiments, the PEG unit is selected from the following formulas: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -R 30 (XXX) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit (if present) and / or part of the linker subunit L2; R 21 and R 22 Each of these is optional and, if present, independently a C1-C3 alkylene group; R 30 C3-C, which was replaced by optional substitution. 10Carbocyclic; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfamide; alkylsulfamide; acylsulfamide, optionally substituted alkylsulfamide; optionally substituted acylsulfamide; sulfonamide; optionally substituted sulfonamide; guanidine (including alkyl and arylguanidine); phosphoramide; or optionally substituted phosphoramide; or R 30 These include azide, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, and -NH-C(O)-alkynyl-R 65 ;Cyclooctin; Selected from -NH-cyclooctin, -NH-C(O)-cyclooctin or -NH-(cyclooctin)2;R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1-26 ;) or its salts, (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit (if present) or to a part of the linker subunit L2; R 21 and R 22 Each of these is independently an optional C1-C3 alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 35These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1-26 ;) or its salts, (c) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit (if present) or to a part of the linker subunit L2; R 21 and R 22 Each of these is an optional choice and independently a C1-C3 alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch independently has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyls, optionally substituted alkenyls, optionally substituted alkynyls, optionally substituted carbocyclics, optionally substituted aryls, optionally substituted heterocarbocyclics, and optionally substituted heteroaryls; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1 to 26;) or its salts, as (d) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit (if present) or to a part of the linker subunit L2; R 21 and R 22 Each of these is an optional choice and is a C1-C3 alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 33 These are C1-C3 alkylene, C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene, or -C(O)-C1-C3 alkylene-C(O); R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 Shows the binding site to; A linker intermediate or linker is provided having n20 being 1 to 26;) or a salt thereof.

[0031] In some embodiments, a linker intermediate or linker or salt thereof is provided in which the PEG unit has a formula selected from the following: ~R20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII) or ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII); (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit (if present) or to a part of the linker subunit L2; 21 and R 22 Each is optional and is a C1-C3 alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 It has; R 33 These are C1-C3 alkylene, -C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene, or -C(O)-C1-C3 alkylene-C(O); R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; the tilde (~) indicates R 20The binding site is shown to the PEG unit; n20 is 1 to 26). In some embodiments, a linker intermediate or linker is provided, selected from the following: [ka] (In the formula, R 65 The group is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocarbocyclic, or optionally substituted heteroaryl; the wavy line on the left indicates a binding site to a subunit or part of a linker subunit of the amino acid unit.

[0032] In some embodiments, R 20 However, linker intermediates or linkers are provided, selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or protected forms thereof.

[0033] In some embodiments, R 20 However, linker intermediates or linkers are provided, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or protected forms thereof.

[0034] In some embodiments, the following formulas are selected: ~R 40 -(R 43 -R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 )n42 (XL) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C6 alkylenes; Each R 43 It is either independent, does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene-C1-C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0035] In some embodiments, the following formulas are selected: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C6 alkylenes; R 43 It does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene, heteroaryl-C1-C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0036] In some embodiments, the following formulas are selected: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C3 alkylenes; R 43 It does not exist, or C1-C6 alkylene, -NH-C1-C 12 Alkylene, -C1-C6alkylene-NH-, -C(O)-C1-C6alkylene, -C1-C6alkylene-C(O)-, -NH-C1-C6alkylene-C(O)-, -C(O)-C1-C6alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C6alkylene, -C(O)-NH-C1-C 12Alkylene, -heteroarylene, heteroaryl-C1-C6 alkylene, heteroaryl-C1-C6 alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C6 alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-16; n41 is 1-4; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 4) or a salt thereof.

[0037] In some embodiments, R 40 A linker intermediate or linker is provided, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or their protected forms.

[0038] In some embodiments, R 40 However, it is one of the following structures: [ka] or [ka] (In the formula, R = H or C1-6 alkyl; and n = 0 to 12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The binding site is shown, ( [ka] ) is R for the remainder of the PEG unit 40 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0039] In some embodiments, R 40 However, it is one of the following structures: [ka] or [ka] (In the formula, n=0~12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The binding site is shown, ( [ka] ) is R for the remainder of the PEG unit 40 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0040] In some embodiments, R 43 -(NR 44 R 45 ) n41 However, R 43 When exists, one of the following structures: [ka] or [ka] (In the formula, R=H, C1-6 Alkyl, polyhydroxyl, or substituted polyhydroxyl ( [ka] ) is R for the remainder of the PEG unit 43 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0041] In some embodiments, R 43 -(NR 44 R 45 ) n41 However, R 43 When exists, one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is R for the remainder of the PEG unit 43 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0042] In some embodiments, -NR 44 R 45 However, it is one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is -NR for the remainder of the PEG unit 44 R 45A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0043] In some embodiments, a linker intermediate or linker having one of the following structures is provided before the PEG unit binds to an amino acid unit or part of the linker subunit L2: [ka] [ka] [ka] [ka] or [ka] (In the formula, R is H or alkyl, and n is 1 to 12).

[0044] In some embodiments, the following formulas are selected: ~R 40 -(R 43 -R 41 -[O-CH2-CH2] n40 -R 46 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLIII) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They either do not exist, or each is independently a C1-C6 alkylene; Each R 43It is either independent, does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene-C1-C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; R 46 It is selected from amino, amino-alkyl-amino, or -NH-C(O)-NH-S(O)2-NH-; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0045] In some embodiments, a linker intermediate or linker having one of the following structures is provided before the PEG unit binds to an amino acid unit or part of the linker subunit L2: [ka] (In the formula, R is H or alkyl, and n is 1 to 12).

[0046] In some embodiments, the following formulas are selected: [ka] or [ka] (In the formula, each Y is independently R 76 or [ka] and Each R 76 These are independently H, acetyl, -P(=O)(OH)2, or -(CH2) v -OS(=O)2(OH) is; Each R a and R b is independently H or R a and R b They, together with the carbon atoms to which they are bonded, form an oxo group; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; Each * indicates a linker intermediate or linker comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1) (or a salt thereof).

[0047] In some embodiments, the following formulas are selected: [ka] or [ka] (In the formula, each R 76 These are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v S(=O)2(OH) is; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; Each * indicates a linker intermediate or linker comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1) (or a salt thereof).

[0048] In some embodiments, linker intermediates or linkers are provided that include PEG units having a formula or salt thereof selected from the following: [ka] or [ka] (In the formula, Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each * indicates a binding site for an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1).

[0049] In some embodiments, Y is R 76 A linker intermediate or linker is provided.

[0050] In some embodiments, Y is [ka] A linker intermediate or linker is provided.

[0051] Several embodiments, each R a and R b However, a linker intermediate or linker that is independently H is provided.

[0052] In some embodiments, R a and R b However, these linkers, together with the carbon atoms to which they are bonded, provide linker intermediates or linkers that form oxo groups.

[0053] In some embodiments, linker intermediates or linkers are provided in which q is 10 to 20.

[0054] In some embodiments, a linker intermediate or linker is provided in which q is 12.

[0055] In some embodiments, linker intermediates or linkers or salts thereof are provided, in which PEG units are selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] (In the formula, each Z is joined by * and selected individually from the following: [ka] , and [ka] each [ka] (This indicates a binding site for an amino acid unit (AA), a linker subunit L2, or another subunit of the stretcher unit (L1).)

[0056] Carboxylate unit In some embodiments, linker intermediates or linkers are provided in which the carboxyl unit has the following formula or a salt thereof: R 70 | L 70 | ~NH-(CH2) p1 -CH-(CH2) o1 -C(O)~ (XXXX) (In the formula, (a) L70 This is selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene-, and -C(O)-C1-C8 alkylene-C(O)-; R 70 is, ~NR 71 (R 72 -R 73 ) and in the formula, R 71 H, C1-C 12 Alkyl, substituted C1-C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 72 R is selected from non-existent or optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted aryls, or optionally substituted heteroaryls. 73 A carboxyl is a carboxyl or polycarboxyl, where a polycarboxyl contains 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, and the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide groups; Each dash (~) indicates a binding site for an amino acid unit (AA), linker subunit L2, or another subunit of the stretcher unit (L1); Each of p1 and o1 is independently selected from 0 to 2; or (b) L 70 This is selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene-, and -C(O)-C1-C8 alkylene-C(O)-; R 70 is, ~NR 71 (R 75 -(R 73 )2) and in the formula, R71 H, C1-C 12 Alkyl, substituted C1-C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 75 These are branched, optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted aryls, or optionally substituted heteroaryls, and each R 73 These are independently carboxyls or polycarboxyls, where a polycarboxyl contains 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, and the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide groups; Each dash (~) indicates a binding site for an amino acid unit (AA), linker subunit L2, or another subunit of the stretcher unit (L1); Each of p1 and o1 is independently selected from 0 to 2; or (c) L 70 This is selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene-, and -C(O)-C1-C8 alkylene-C(O)-; R 70 It is approximately N(R 74 -R 73 )(R 72 -R 73 ) and in the formula, R 72 and R 74Each of these is independently selected from optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted aryls, or optionally substituted heteroaryls, and each R 73 These are independently carboxyl or polycarboxyl, comprising 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, the carboxyl groups being interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkyl, heteroalkylene, amino and / or amide groups; Each dash (~) indicates a binding site for an amino acid unit (AA), linker subunit L2, or another subunit of the stretcher unit (L1); (Each of p1 and o1 is independently selected from 0 to 2).

[0057] In some embodiments, a linker intermediate or linker comprising at least one sugar unit is provided. In some embodiments, a linker intermediate or linker comprising at least one PEG unit is provided. In some embodiments, a linker intermediate or linker comprising at least one carboxyl unit is provided. In some embodiments, a linker intermediate or linker comprising at least two polar units is provided, each polar unit being selected from a sugar unit, a PEG unit, and a carboxyl unit. In some embodiments, a linker intermediate or linker comprising at least one sugar unit and a PEG unit or a carboxyl unit is provided. In some embodiments, a linker intermediate or linker comprising at least one carboxyl unit and a PEG unit is provided.

[0058] In some embodiments, linker intermediates or linkers are provided in which amino acid units (AA) are present (s=1). In some embodiments, linker intermediates or linkers are provided in which the amino acid units include at least one polar unit.

[0059] In some embodiments, a linker intermediate or linker is provided in which L2 or AA-L2 has one of the following structures: [ka] or [ka] (In the formula, the wavy line on the amino group indicates the binding site for the stretcher unit, and the drug unit is bound to the benzyl alcohol.)

[0060] In some embodiments, a linker intermediate or linker is provided in which ~AA-L2~ has a formula selected from the following: [ka] , [ka] ,or [ka] (In the formula, square brackets indicate amino acid units, each aa is an optional subunit of AA, L2 is a linker subunit, and each tilde (~) indicates a binding site for a stretcher unit; aa1(PEG) is a PEG unit bound to an amino acid subunit of AA, SU is a sugar unit bound to a subunit or L2 of AA, and CU is a carboxyl unit bound to a subunit or L2 of AA; double tilde ( [ka] ) indicates a binding site for the drug unit, where aa and aa1 are independently selected from alpha, beta, and gamma amino acids and their derivatives).

[0061] In some embodiments, a linker intermediate or linker is provided in which ~AA-L2~ has a formula selected from the following: [ka] [ka] ,or [ka] (In the formula, square brackets indicate amino acid units, each aa is an amino acid subunit of AA, L2 is a linker subunit attached to the side chain of aa, and a tilde (~) indicates a binding site for a stretcher unit; aa1(PEG) is a PEG unit attached to aa, SU is a sugar unit attached to aa, CU is a carboxyl unit attached to aa, and a double tilde ( [ka] ) indicates the binding site for the drug unit; aa and aa1 are independently selected from alpha, beta, and gamma amino acids and their derivatives).

[0062] In some embodiments, a linker intermediate or linker is provided in which the amino acid unit comprises at least two polar units.

[0063] In some embodiments, a linker intermediate or linker is provided in which ~AA-L2~ has a formula selected from the following: [ka] , [ka] ,or [ka] (In the formula, square brackets indicate amino acid units, aa is an optional subunit of AA, L2 is a linker subunit, and a tilde (~) indicates a binding site for a stretcher unit; aa1(PEG) and aa2(PEG) are each PEG units bound to aa or other PEG units; each SU is a sugar unit bound to aa or other sugar unit, and each CU is a carboxyl unit bound to aa or other carboxyl unit, and a double tilde ( [ka] ) indicates a binding site for the drug unit; aa, aa1, and aa2 are independently selected from alpha, beta, and gamma amino acids and their derivatives).

[0064] In some embodiments, a linker intermediate or linker is provided in which ~AA-L2~ has a formula selected from the following: [ka] [ka] ,or [ka] (In the formula, square brackets indicate amino acid units, aa is the amino acid subunit of AA, L2 is the linker subunit attached to the side chain of aa, each tilde (~) indicates a binding site for a stretcher unit; aa1(PEG) and aa2(PEG) are respectively PEG units attached to aa, each SU is a sugar unit attached to aa; each CU is a carboxyl unit attached to aa; double tilde ( [ka] ) indicates a binding site for the drug unit; each of aa, aa1, and aa2 is independently selected from alpha, beta, and gamma amino acids and their derivatives).

[0065] In some embodiments, a linker intermediate or linker is provided in which the linker subunit L2 is a cleavable linker unit. In some embodiments, a linker intermediate or linker is provided in which the linker subunit L2 comprises a peptide that can be cleaved by an intracellular protease. In some embodiments, a linker intermediate or linker is provided in which the cleavable peptide comprises a valine-citrulline peptide, a valine-alanine peptide, a valine-lysine peptide, a phenylalanine-lysine peptide, or a glycine-glycine-phenylalanine-glycine peptide.

[0066] In some embodiments, a linker intermediate or linker is provided in which the linker subunit L2 comprises at least one polar unit. In some embodiments, a linker intermediate or linker is provided in which the polar unit is a sugar unit (SU). In some embodiments, a linker intermediate or linker is provided in which the cleavable peptide comprises SU-valine-citrulline peptide, SU-valine-lysine peptide, SU-valine-alanine peptide, SU-phenylalanine-lysine peptide, or SU-glycine-glycine-phenylalanine-glycine peptide.

[0067] In some embodiments, linker intermediates or linkers are provided in which the polar unit is a carboxyl unit (CU). In some embodiments, linker intermediates or linkers are provided in which the cleavable peptide comprises a CU-valine-citrulline peptide, a CU-valine-lysine peptide, a valine-(CU-lysine) peptide, a CU-valine-alanine peptide, a CU-phenylalanine-lysine peptide, a phenylalanine-(CU-lysine) peptide, or a CU-glycine-glycine-phenylalanine-glycine peptide, and the CU-lysine is a carboxyl unit containing a lysine residue.

[0068] In some embodiments, linker intermediates or linkers are provided in which the polar unit is a PEG unit (PEG). In some embodiments, linker intermediates or linkers are provided in which the cleavable peptides include Lys(PEG)-valine-citrulline peptide, valine-Cit(PEG) peptide, Lys(PEG)-valine-lysine peptide, valine-lysine(PEG) peptide, Lys(PEG)-valine-alanine peptide, Lys(PEG)-phenylalanine-lysine peptide, phenylalanine-Lys(PEG) peptide, or Lys(PEG)-glycine-glycine-phenylalanine-glycine peptide, wherein Lys(PEG) and Cit(PEG) each contain a PEG unit attached to a lysine residue or a citrulline residue, respectively.

[0069] In some embodiments, a linker intermediate or linker is provided in which a cleavable peptide is bonded to a para-aminobenzyl alcohol self-sacrificing group (PABA).

[0070] In some embodiments, a linker intermediate or linker is provided in which ~AA-L2~ has one of the following structures: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] (In the formula, each Z is joined by * and selected individually from the following: [ka] , and [ka] The wavy lines on the amino group indicate the binding site for the stretcher unit, and the drug unit is bonded to the benzyl alcohol (i.e., the hydrogen atoms of the benzyl alcohol are replaced by the bond with the drug unit).

[0071] In some embodiments, a linker intermediate or linker is provided in which L2 is bonded to the side chain of the AA subunit. In some embodiments, [ka] However, a linker intermediate or linker having one of the following structures is provided: [ka] or [ka] (In the formula, the wavy line on the amino group indicates a binding site for the stretcher unit, and the drug unit is bound to the terminal acid group or benzyl alcohol (i.e., the H of the acid or benzyl alcohol is replaced by the bond with the drug unit), or the wavy line ( [ka] () indicates a binding site for the drug unit.

[0072] In some embodiments, linker intermediates or linkers are provided in which amino acid units are linked to linker subunit L2 by non-peptidic linking groups. In some embodiments, the non-peptidic linking groups are C1-C 10 Alkylene, C2-C 10 Alkenylene, C2-C 10 A linker intermediate or linker selected from alkylylene or polyethylene glycol is provided.

[0073] In some embodiments, a linker intermediate or linker is provided, further comprising stretcher units to a linker and stretcher units from a linker. In some embodiments, the stretcher units are selected from the following: [ka] [ka] ,or [ka] (In the formula, R 17 is -C1-C 10 Alkylene-,-C1-C 10 Heteroalkylene-,-C3-C8 carbocyclo-,-O-(C1-C8 alkylene)-,-(CH2-O-CH2) b -C1-C8 alkylene-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(where b is 1 to 26) -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene- (where b is 1 to 26), -arrine-, -C1-C 10 Alkilen-Arirene-,-Arirene-C1-C 10 Alkylene-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-,-C3-C8 heterocyclo-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-,-C1-C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene -C(=O)-, -C1-C8 alkylene-(CH2-O-CH2) b -C(=O)-(where b is between 1 and 26), -(CH2-O-CH2) b-C1-C8 alkylene-C(=O)-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)- (where b is 1 to 26), -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-,-arylene-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-NH-,-C1-C 10 Heteroalkylene-NH-,-C1-C8 alkylene-(CH2-O-CH2) b -NH-(where b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH-(where b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C(=O)-(where b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(where b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -NH-(where b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b-C1-C8 alkylene-NH- (where b is 1 to 26), -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkyl)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-,-arylene-C1-C 10 Alkylene-NH-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-NH-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-,-C3-C8 heterocyclo-NH-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-,-C1-C 10 Alkylene-S-,C1-C 10 Heteroalkylene-S-,-C3-C8carbocyclo-S-,-O-(C1-C8alkyl)-S-,-arylene-S-,-C1-C 10 Alkylene-Arirene-S-,-Arirene-C1-C 10 Alkylene-S-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-S-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-,-C3-C8 heterocyclo-S-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-S-, or-(C3-C8 heterocyclo)-C1-C 10 (It is alkylene-S-), or The stretcher unit is maleimide (C1-C 10 Alkylene-C(O)-, maleimide (CH2OCH2) p2 (C1-C 10 Alquiene)C(O)-, Maleimide(C1-C 10 Alkien (CH2OCH2) p2 Linkers are provided that include C(O)- (where p2 is 1 to 26) or their ring-opening forms.

[0074] In some embodiments, the stretcher unit is provided with a linker selected from the following: [ka] and [ka] (In the formula, the dashed line) [ka] (The symbol indicates the binding site of the stretcher unit to the amino acid unit, and the binding site to the target unit is located on a maleimide, primary amine, or alkyne functional group.)

[0075] In some embodiments, a linker having one of the following structures is provided: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] (In the formula, each Z is joined by * and selected individually from the following: [ka] , and [ka] The drug unit is optionally attached to a terminal acid group or benzyl alcohol, or has a wavy line ( [ka] () indicates a binding site for the drug unit.

[0076] In some embodiments, a linker is provided that further comprises at least one drug unit bound to linker subunit L2 to form a drug-linker. In some embodiments, a drug-linker is provided in which the drug unit is selected from cytotoxic agents, immunomodulators, nucleic acids, growth inhibitors, PROTACs, toxins, radioisotopes and chelated ligands. In some embodiments, a drug-linker is provided in which the drug unit is a cytotoxic agent. In some embodiments, a drug-linker is provided in which the cytotoxic agent is selected from the group consisting of auristatin, meitansinoids, camptothecin, duochamycin and calicheamycin. In some embodiments, a drug-linker is provided in which the cytotoxic agent is auristatin. In some embodiments, a drug-linker is provided in which the cytotoxic agent is MMAE or MMAF. In some embodiments, a drug-linker is provided in which the cytotoxic agent is camptothecin. In some embodiments, a drug-linker is provided in which the cytotoxic agent is exatecan or SN-38. In some embodiments, a drug-linker is provided in which the cytotoxic agent is exatecan. In some embodiments, a drug-linker is provided in which the cytotoxic agent is calicheamycin. In some embodiments, a drug-linker is provided in which the cytotoxic agent is a meitansinoid. In some embodiments, a drug-linker is provided in which the meitansinoid is meitansin, meitansinol, or ansamatosin-2.

[0077] In some embodiments, a drug-linker is provided in which the cytotoxic agent is calicheamycin. In some embodiments, a drug-linker is provided in which the cytotoxic agent is a meitansinoid. In some embodiments, a drug-linker is provided in which the meitansinoid is meitansin, meitansinol, or ansamatosin-2.

[0078] In some embodiments, a drug-linker is provided in which the drug unit is an immunomodulator. In some embodiments, a drug-linker is provided in which the immunomodulator is selected from a TRL7 agonist, a TLR8 agonist, a STING agonist, or a RIG-I agonist. In some embodiments, a drug-linker is provided in which the immunomodulator is a TLR7 agonist. In some embodiments, drug-linkers are provided in which the TLR7 agonist is imidazoquinoline, imidazoquinolineamine, thiazoquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazole-2-amine, tetrahydropyridopyrimidine, heteroalothiadiazide-2,2-dioxide, benzonaphthyridine, guanosine analog, adenosine analog, thymidine homopolymer, ssRNA, CpG-A, PolyG10, or PolyG3. In some embodiments, drug-linkers are provided in which the immunomodulator is a TLR8 agonist. In some embodiments, drug-linkers are provided in which the TLR8 agonist is selected from imidazoquinoline, thiazoloquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazole-2-amine, tetrahydropyridopyrimidine, or ssRNA. In some embodiments, drug-linkers are provided in which the immunomodulator is a STING agonist. In some embodiments, drug-linkers are provided in which the immunomodulator is a RIG-I agonist. In some embodiments, drug-linkers are provided in which the RIG-I agonist is selected from KIN1148, SB-9200, KIN700, KIN600, KIN500, KIN100, KIN101, KIN400, and KIN2000.

[0079] In some embodiments, drug-linkers are provided in which the drug unit is a chelating ligand. In some embodiments, drug-linkers are provided in which the chelating ligand is selected from radioisotopes such as platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti), or iridium (Ir); yttrium-88, yttrium-90, technetium-99, copper-67, rhenium-188, rhenium-186, gallium-66, gallium-67, indium-111, indium-114, indium-115, lutetium-177, strontium-89, salarium-153, and lead-212.

[0080] In some embodiments, a drug-linker having the following structure is provided: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0081] In some embodiments, a conjugate is provided comprising a targeting unit that binds to any of the drug-linkers described herein. In some embodiments, a conjugate is provided in which the targeting unit is selected from an antibody or its antigen-binding moiety. In some embodiments, a conjugate is provided in which the targeting unit is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-linked Fc, scFv, single-domain antibody, diabody, bispecific antibody, or multispecific antibody. In some embodiments, a conjugate is provided in which the targeting unit is a diabody, DART, antikalin, afibody, avimer, DARPin, or adonectin. In some embodiments, a conjugate is provided in which the targeting unit is monospecific. In some embodiments, a conjugate is provided in which the targeting unit is divalent. In some embodiments, a conjugate is provided in which the targeting unit is bispecific. In some embodiments, the mean drug load (p load A conjugate is provided in which the values ​​are approximately 1 to 8, 2, 4, 6, 8, 10, 12, 14, 16, 3 to 5, 6 to 8, or 8 to 16.

[0082] In some embodiments, a conjugate is provided which can be selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

[0083] In some embodiments, the above-mentioned conjugate is provided, in which the targeting unit binds to a target molecule such as CD19, CD20, CD30, CD33, CD70, LIV-1, or EGFRv3.

[0084] In some embodiments, the targeting units are selected from the above conjugates: scFv1-ScFv2, ScFv12-Fc-scFv22, IgG-scFv, DVD-Ig, triomab / quadroma, two-in-one IgG, scFv2-Fc, TandAb, and scFv-HSA-scFv.

[0085] In some embodiments, the targeting unit is cancer-related antigen, such as CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, JAK2, KDR(VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM 1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1 , STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4(TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6 The above conjugates are provided, which are CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4.

[0086] In some embodiments, the targeting unit is rituximab (Rituxan®), trastuzumab (Herceptin®), pertuzumab (Perjeta®), bevacizumab (Avastin®), ranibizumab (Lucentis®), cetuximab (Erbitux®), alemtuzumab (Campath®), panitumumab (Vectibix®) The above conjugates are provided, which include registered trademarks ()), ibritumomab tiuxetan (Zevalin®), tocitumomab (Bexxar®), ipilimumab, zaltumumab, darotuzumab, figtumumab, ramucirumab, gallium tuzumab, farletuzumab, ocrelizumab, ofatumumab (Arzerra®), tocitumumab, ibritumomab, CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 2C6, 11B8, B1, 2H7, LT20, 1FS or AT80, daclizumab (Zenapax®), or anti-LHRH receptor antibodies, such as clone A9E4, F1G4, AT2G7, GNRH03 or GNRHR2.

[0087] In some embodiments, the above conjugate is provided in which the targeting unit is antibody F131 and the drug-linker is LD038. In certain embodiments, the targeting unit is antibody F131 (VH SEQ ID NO: 26 and VL SEQ ID NO: 27).

[0088] In some embodiments, the above conjugate is provided in which the targeting unit is an antibody comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises complementarity-determining regions HCDR1, HCDR2, and HCDR3 arranged in the heavy chain variable region framework region, and the VL region comprises LCDR1, LCDR, and LCDR3 arranged in the light chain variable region framework region, and VH and VL The CDR has an amino acid sequence selected from a set of amino acid sequences represented by (a) SEQ ID NOs: 30, 31, 32, 33, 34, and 35, respectively; and (b) SEQ ID NOs: 36, 31, 37, 38, 39, and 40, respectively. In certain embodiments, the VH and VL regions have an amino acid sequence selected from a pair of amino acid sequences represented by the group SEQ ID NOs: 26 and 27, respectively; the heavy chain framework region and light chain framework region are optionally modified by substitutions, deletions, or insertions of 1 to 8 amino acids in the framework region. In certain embodiments, the antibody is F131 and the drug-linker is LD038.

[0089] In some embodiments, pharmaceutical compositions are provided that comprise one of the conjugates described herein and a pharmaceutically acceptable carrier.

[0090] In some embodiments, a method is provided for treating a subject in need thereof, comprising administering to the subject any of the conjugates or pharmaceutical compositions described herein, wherein the subject has cancer or an autoimmune disease, and the conjugate binds to a target antigen associated with cancer or an autoimmune disease.

[0091] [Invention 1001] The following equation (V): [C1] JPEG0007914997000222.jpg15170 (In the formula, AA is an amino acid unit having 1 to 12 amino acid subunits; s is either 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for drug units; Each dashed line (~) indicates a joint in a stretcher unit; Double wavy line ( [Case 2] JPEG0007914997000223.jpg6170 () indicates a binding site for the drug unit.) or a linker intermediate having a salt thereof, wherein at least one polar unit is present in the amino acid unit, the linker subunit, or both, and the polar unit is selected from a sugar unit, a PEG unit, a carboxyl unit, and combinations thereof. [Invention 1002] The following equation (I): [C3] JPEG0007914997000224.jpg15170 (In the formula, L1 is a stretcher unit having a binding site for the targeting unit; AA is an amino acid unit having 1 to 12 subunits; s is either 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for drug units; The dashed line (~) indicates the binding site for the targeting unit; Double wavy line ( [C4] JPEG0007914997000225.jpg6170 A linker having a binding site for a drug unit () or a salt thereof, wherein at least one polar unit is present within the amino acid unit, the linker subunit, the stretcher unit or a combination thereof, and the polar unit is selected from sugar units, PEG units, carboxyl units and combinations thereof. [Invention 1003] The aforementioned sugar unit is given by the following formula: L3-**N(CH 2 -(CH(XR)) k -X 1 (X 2 )) 2 (X) (In the formula, each X is selected independently from NH or O; Each R is independently selected from hydrogen, acetyl, monosaccharides, disaccharides, and polysaccharides; each X 1 CH 2 and selected independently of C(O); each X 2 It is selected independently from H, OH, and OR; k is between 1 and 10; L3 is given by the following general formula (XI): L3a | *-NH-(CH 2 ) p -CH-(CH 2 ) o -C(O)-# (XI) (In the formula, L3a is C 1 -C 10 Selected from alkylene and polyethylene glycol having 1 to 24 ethylene glycol subunits; p and o are independently between 0 and 2; Each * and each # indicates a binding site for an amino acid unit (AA), linker subunit L2, or another subunit of the stretcher unit (L1); L3a is a linker intermediate or linker of the present invention 1001 or 1002, having (or having a salt thereof) a N atom marked with ** in formula (X). [Invention 1004] The above sugar unit is selected from the following formulas: [5] JPEG0007914997000226.jpg64170 or [6] JPEG0007914997000227.jpg52170 (In the formula, each R is independently selected from hydrogen, monosaccharides, disaccharides, and polysaccharides; p and o are independently between 0 and 2; m is 1 to 8; n is between 0 and 4; Each * and each # indicates a binding site for the amino acid unit (AA), the linker subunit L2, or another subunit of the stretcher unit (L1) (or a salt thereof), a linker intermediate or linker of any of the present inventions 1001 to 1003. [Invention 1005] The PEG unit is selected from the following formulas: (a) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 This is a functional group for binding to a subunit of the amino acid unit or to a portion of the linker subunit L2; R 21 and R 22 Each of these is independently of the optional C. 1 -C 3 It is alkylene; R 24 and R 25 These are, respectively: H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C 3 -C 10 Carbon ring; C substituted by choice 1 -C 3 Alkilen C 3 -C 10 Carbohydrate; Optionally substituted heteroaryl; Optionally substituted carbohydrate; Substitution-C1 -C 8 Alkyl; substitution-C(O)-C 1 -C 8 Alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 is independently selected from (the sugar unit of formula (XII) or (XIII); or -NR 24 R 25 C 3 -C 8 They are joined together from complex algebras; The wavy line (~) represents R 20 Shows the binding site to; n20 is 1-26 ;) or its salts, or (b) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 21 and R 22 Each of these is independently of the optional C. 1 -C 3 It is alkylene; R 24 and R 25 One of them is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C 3 -C 10 Carbon ring; C substituted by choice 1 -C 3 Alkilen C 3 -C 10 Carbohydrate; Optionally substituted heteroaryl; Optionally substituted carbohydrate; Substitution-C 1 -C 8 Alkyl; substitution-C(O)-C 1 -C 8 Alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 R is selected from the sugar units of formula (XII) or (XIII); R24 and R 25 The other is optionally polyethylene glycol having 1 to 24 ethylene glycol subunits; The wavy line (~) represents R 20 The aforementioned bonding site is shown; n20 is 1-26 ;) or its salts, or (c) ~R 20 -[-R 26 -[R 29 -[O-CH 2 -CH 2 -] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXI) (In the formula, R 20 This is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; R 26 and R 27 Each of these is optional, and C 1 -C 12 Alkylene, -NH-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-NH-,-C(O)-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-C(O)-,-NH-C 1 -C 12 Alkylene-C(O)- and -C(O)-C 1 -C 12 Selected independently from alkylene-NH-; R 24 and R 25 One of them is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C 3-C 10 Carbon ring; C substituted by choice 1 -C 3 Alkilen C 3 -C 10 Carbohydrate; Optionally substituted heteroaryl; Optionally substituted carbohydrate; Substitution-C 1 -C 8 Alkyl; substitution-C(O)-C 1 -C 8 Alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 R is selected from the sugar units of formula (XII) or (XIII); R 24 and R 25 The other side is H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C 3 -C 10 Carbon ring; C substituted by choice 1 -C 3 Alkilen C 3 -C 10 Carbohydrate; Optionally substituted heteroaryl; Optionally substituted carbohydrate; Substitution-C 1 -C 8 Alkyl; substitution-C(O)-C 1 -C 8 Alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 is a sugar unit of formula (XII) or (XIII); and optionally selected from polyethylene glycol having 1 to 24 ethylene glycol subunits; or -NR 24 R 25 C 3 -C 8 They are joined together from complex algebras; Each R 29 The following are optional choices: -C(O)-, -NH-, -C(O)-C 1 -C 6 Alkenylene-,-NH-C 1 -C 6 Alkenylene-,-C 1 -C 6 Alkenylene-NH-,-C 1 -C 6 Independently selected from alkenylene-C(O)-, -NH(CO)NH-, and triazole; The wavy line (~) represents R 20 The aforementioned bonding site is shown; n20 is between 1 and 26; n21 is 1-4; A linker intermediate or linker of any of the present inventions 1001 to 1004, having n27 being 1 to 4;) or a salt thereof. [Invention 1006] R 24 and R 25 A linker intermediate or linker of the present invention 1005, wherein both are not H. [Invention 1007] R 24 and R 25 Each is independently selected from H and the polyhydroxyl group, however, R 24 and R 25 A linker intermediate or linker according to the present invention 1005 or 1006, provided that both are not H. [Invention 1008] A linker intermediate or linker according to any one of the present invention 1005 to 1007, wherein the polyhydroxyl group is optionally a linear monosaccharide selected from C6 or C5 sugars, sugar acids, or amino sugars. [Invention 1009] The C6 or C5 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, growth, idose, talose, aldose, and ketose; The aforementioned sugar acid is selected from gluconic acid, aldonic acid, uronic acid and uronic acid; or A linker intermediate or linker according to the present invention 1008, wherein the amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. [Invention 1010] The PEG unit is a linker intermediate or linker or salt thereof according to any of the present invention 1005 to 1009, selected from the following: [7] JPEG0007914997000228.jpg200170 (In the formula, R 39 (The ethylene glycol is selected from H, a linear monosaccharide, and optionally, polyethylene glycol having 1 to 24 ethylene glycol subunits; the wavy line on the left indicates the binding site of the amino acid unit to the subunit or the portion of the linker subunit). [Invention 1011] R 24 and R 25 A linker intermediate or linker according to the present invention 1005 or 1006, wherein one of the components is a linear monosaccharide and the other is a cyclic monosaccharide. [Invention 1012] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1011: [8] JPEG0007914997000229.jpg110170 (In the formula, R 41 (It is a cyclic monosaccharide; the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the part of the linker subunit). [Invention 1013] R 24 and R 25 However, a linker intermediate or linker of the present invention 1005 or 1006, independently selected from cyclic monosaccharides, disaccharides and polysaccharides. [Invention 1014] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1013: [9] JPEG0007914997000230.jpg132170 or [C10] JPEG0007914997000231.jpg61170 (In the formula, each R 45 R is selected from H and monosaccharides, disaccharides, or polysaccharides; 46 (These are selected from cyclic monosaccharides, disaccharides, or polysaccharides; the wavy line on the right indicates the binding site to the subunit of the amino acid unit or to the portion of the linker subunit). [Invention 1015] R 24 and R 25 A linker intermediate or linker of the present invention 1005 or 1006, wherein a linear monosaccharide and a substituted linear monosaccharide are independently selected, and the substituted linear monosaccharide is substituted with a monosaccharide, disaccharide or polysaccharide. [Invention 1016] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1015: [C11] JPEG0007914997000232.jpg169170 (In the formula, R 47 It is a linear monosaccharide; each R 49 (These are selected from monosaccharides, disaccharides, and polysaccharides; the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the portion of the linker subunit). [Invention 1017] R 24 and R 25 A linker intermediate or linker of the present invention 1005 or 1006, wherein a linear monosaccharide and a substituted monosaccharide are independently selected, and the substituted linear monosaccharide is substituted with one or more substituents selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester or amide, and optionally further substituted with a monosaccharide, disaccharide or polysaccharide. [Invention 1018] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1017: [C12] JPEG0007914997000233.jpg34170 or [C13] JPEG0007914997000234.jpg51170 (In the formula, each R 42 These are independently selected from linear monosaccharides and substituted linear monosaccharides; each R 43 (The elements are independently selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, and amide; the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the portion of the linker subunit). [Invention 1019] R 24 and R 25 One of them is a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group, R 24 and R 25 The other is H, -C(O)-polyhydroxyl group, substituted -C(O)-polyhydroxyl group, polyhydroxyl group or substituted polyhydroxyl group; the substituted -C(O)-polyhydroxyl group and polyhydroxyl group are substituted with a monosaccharide, disaccharide, polysaccharide, alkyl, -O-alkyl, aryl, carboxyl, ester or amide, linker intermediate or linker of the present invention 1005 or 1006. [Invention 1020] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1019: [C14] JPEG0007914997000235.jpg21170 or [C15] JPEG0007914997000236.jpg61170 (In the formula, the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the part of the linker subunit.) [Invention 1021] R 24 and R 25 However, H, substitution -C 1 -C 8 Alkyl, substituted-C 1 -C 4 Alkyl or substituted C 1 -C 3 It is selected independently of alkyl, however, R 24 and R 25 Provided that neither of them is H; substitution -C 1 -C 8 Alkyl, -C 1 -C 4 Alkyl and -C 1 -C 3 A linker intermediate or linker of the present invention 1005 or 1006, wherein the alkyl group is substituted with hydroxyl and / or carboxyl. [Invention 1022] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1021: [C16] JPEG0007914997000237.jpg196170 or [C17] JPEG0007914997000238.jpg31170 (In the formula, R 48 H, OH, CH 2 -C substituted with OH, COOH, or hydroxyl or carboxyl 1 -C 6 Selected from alkyl groups; the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the portion of the linker subunit). [Invention 1023] R 24 and R 25 One of them is H, substituted -C(O)-C 1 -C 8 Alkyl, substituted -C(O)-C 1 -C 4 Alkyl and substituted-C(O)-C 1 -C 3 Selected from alkyl, R 24 and R 25 The other is the substitution -C(O)-C 1 -C 8 Alkyl, substituted -C(O)-C 1 -C 4 Alkyl, substituted -C(O)-C 1-C 3 Alkyl, substituted-C 1 -C 8 Alkyl, substituted-C 1 -C 4 Alkyl and substituted C 1 -C 3 Selected from alkyl groups, substituted -C(O)-C 1 -C 8 Alkyl, substituted -C(O)-C 1 -C 4 Alkyl, substituted -C(O)-C 1 -C 3 Alkyl, substituted-C 1 -C 8 Alkyl, -C 1 -C 4 Alkyl and -C 1 -C 3 A linker intermediate or linker of the present invention 1005 or 1006, wherein the alkyl group is substituted with hydroxyl and / or carboxyl. [Invention 1024] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1023: [C18-1] JPEG0007914997000239.jpg182170 [C18-2] JPEG0007914997000240.jpg49170 or [C19] JPEG0007914997000241.jpg26170 (In the formula, the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the part of the linker subunit.) [Invention 1025] R 24 and R 25 However, it is selected from H and optionally replaced aryls, but R 24 and R 25 A linker intermediate or linker according to the present invention 1005 or 1006, provided that both are not H. [Invention 1026] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1025:

[20] JPEG0007914997000242.jpg47170 or

[21] JPEG0007914997000243.jpg20170 (In the formula, the wavy line on the left indicates the binding site of the subunit or part of the linker subunit of the amino acid unit.) [Invention 1027] R 24 and R25 However, together, C is replaced by arbitrary selection. 3 -C 8 A linker intermediate or linker according to invention 1005 or 1006, which forms a heterocyclic or heteroaryl ring. [Invention 1028] The aforementioned PEG unit is [C22] JPEG0007914997000244.jpg16170 ’ A linker intermediate or linker according to the present invention 1027, which is a salt thereof. [Invention 1029] R 24 and R 25 However, H and the chelating agent are selected independently, and the chelating agent is optionally alkylene, arylene, carbocyclo, heteroarylene or heterocarbocyclo-NR 24 R 25 It is bonded to the nitrogen, however, R 24 and R 25 A linker intermediate or linker according to the present invention 1005 or 1006, provided that both are not H. [Invention 1030] A linker intermediate or linker according to Invention 1029, wherein the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), benzyl-DOTA, 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), benzyl-NOTA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), and N,N'-dialkyl-substituted piperazine. [Invention 1031] The PEG unit is selected from the following to form a linker intermediate or linker or salt thereof of the present invention 1030:

[23] JPEG0007914997000245.jpg36170 or

[24] JPEG0007914997000246.jpg44170 (In the formula, the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the part of the linker subunit.) [Invention 1032] Each monosaccharide, C5 or C6 sugars selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, growth, idostalose, aldose, ketose, glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine; A sugar acid selected from gluconic acid, aldonic acid, uronic acid, and urosonic acid; independently selected from, or A linker intermediate or linker according to any of invention 1005 to 1019, wherein the amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. [Invention 1033] R 20 However, a linker intermediate or linker of any of the present invention 1005 to 1032, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl or a protected form thereof. [Invention 1034] The PEG unit is selected from the following formulas: (a) ~R20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -R 30 (XXX) (In the formula, R 20 This is a functional group for binding to a subunit of the amino acid unit (if present) and / or a portion of the linker subunit L2; R 21 and R 22 Each of these is optional, and if present, they are independent of C. 1 -C 3 It is an alkylene group; R 30 This is C, which has been replaced by an optional substitution. 3 -C 10 Carbocyclic; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfamide; alkylsulfamide; acylsulfamide, optionally substituted alkylsulfamide; optionally substituted acylsulfamide; sulfonamide; optionally substituted sulfonamide; guanidine (including alkyl and arylguanidine); phosphoramide; or optionally substituted phosphoramide; or R 30 These include azide, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, and -NH-C(O)-alkynyl-R 65 ;Cyclooctin;-NH-cyclooctin, -NH-C(O)-cyclooctin or -NH-(cyclooctin) 2 Selected from; R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 The aforementioned bonding site is shown; n20 is 1-26 ;) or its salts, (b) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NH-C(O)-R 31 (XXXI) (In the formula, R 20 This is a functional group for binding to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 Each of these is independently of the optional C. 1 -C 3 It is an alkylene group; R31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 The aforementioned bonding site is shown; n20 is 1-26 ;) or its salts, (c) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -C(O)NH-R 31 (XXXII) (In the formula, R 20 This is a functional group for binding to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 Each of these is an optional choice and is independent of C. 1 -C 3 It is an alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch independently has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyls, optionally substituted alkenyls, optionally substituted alkynyls, optionally substituted carbocyclics, optionally substituted aryls, optionally substituted heterocarbocyclics, and optionally substituted heteroaryls; The wavy line (~) represents R 20 The aforementioned bonding site is shown; n20 is 1 to 26;) or its salts, as (d) ~R 20 -R21 -[O-CH 2 -CH 2 ] n20 -R 22 -N-(R 33 -R 31 ) 2 (XXXIII) (In the formula, R 20 This is a functional group for binding to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 Each of these is optional, and C 1 -C 3 It is an alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 Having; R 33 C 1 -C 3 Alkylene, C 1 -C 3 Alkylene-C(O),-C(O)-C 1 -C 3 Alkylene or -C(O)-C 1 -C 3 It is alkylene-C(O); R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 This is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; The wavy line (~) represents R 20 The aforementioned bonding site is shown; A linker intermediate or linker of any of the present inventions 1001 to 1004, having n20 being 1 to 26;) or a salt thereof. [Invention 1035] The PEG unit is a linker intermediate or linker or salt thereof according to any of the present inventions 1001 to 1004, having a formula selected from the following: ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NH-C(O)-R31 (XXXI) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -C(O)NH-R 31 (XXXII) or ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -N-(R 33 -R 31 ) 2 (XXXIII); (In the formula, R 20 R is a functional group for binding to a subunit of the amino acid unit (if present) or to a part of the linker subunit L2; 21 and R 22 Each of these is optional, and C 1 -C 3 It is an alkylene group; R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 It has; R 33 C 1 -C 3 Alkylene, -C 1 -C 3 Alkylene-C(O),-C(O)-C 1 -C 3 Alkylene or -C(O)-C 1 -C 3 It is alkylene-C(O); R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; the tilde (~) indicates R 20 This shows the binding site to (n20 is 1-26). [Invention 1036] The PEG unit is selected from the following to form a linker intermediate or linker of the present invention 1035:

[25] JPEG0007914997000247.jpg216170 (In the formula, R 65 (These are selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocarbocyclic, or optionally substituted heteroaryl; the wavy line on the left indicates the binding site to the subunit of the amino acid unit or to the portion of the linker subunit). [Invention 1037] R 20 However, a linker intermediate or linker of any of the present invention 1034 to 1036, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl or a protected form thereof. [Invention 1038] The following expressions can be selected: ~R 40 -(R 43 -R 41 -[O-CH 2 -CH 2 ] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XL) (In the formula, R 40 This is a functional group for binding to a subunit of the amino acid unit or to a portion of the linker subunit L2; R 41 and R 42 They either do not exist, or each exists independently, C 1 -C 6 It is alkylene; Each R 43 It is either independent, does not exist, or C 1 -C 12 Alkylene, -NH-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-NH-,-C(O)-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-C(O)-,-NH-C 1 -C 12Alkylene-C(O)-,-C(O)-C 1 -C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C 1 -C 12 Alkylene, -C(O)-NH-C 1 -C 12 Alkylene, -heteroarylene, heteroaryl-C 1 -C 12 Alkylene-C 1 -C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C 1 -C 12 It is alkylene, and the other is C 1 -C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 The aforementioned bonding site is shown; n40 is 1-26; n41 is 1 to 6; Linker intermediates or linkers of the present invention 1001 to 1004, comprising PEG units having n42 (1 to 6) or a salt thereof. [Invention 1039] The following expressions can be selected: ~R 40 -(R 41 -[O-CH 2 -CH 2 ] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 This is a functional group for binding to a subunit of the amino acid unit or to a portion of the linker subunit L2; R 41 and R 42 They either do not exist, or each exists independently, C 1 -C 6 It is alkylene; R 43 It does not exist, or C 1 -C 12 Alkylene, -NH-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-NH-,-C(O)-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-C(O)-,-NH-C 1 -C 12 Alkylene-C(O)-,-C(O)-C 1 -C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C 1 -C 12 Alkylene, C(O)-NH-C 1 -C 12 Alkylene, -heteroarylene, heteroaryl-C 1 -C 12 Alkylene, heteroaryl-C 1 -C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C 1 -C 12 It is alkylene, and the other is C 1 -C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 The aforementioned bonding site is shown; n40 is 1-26; n41 is 1 to 6; Linker intermediates or linkers of the present invention 1001 to 1004, comprising PEG units having n42 (1 to 6) or a salt thereof. [Invention 1040] The following expressions can be selected: ~R 40 -(R 41 -[O-CH 2 -CH 2 ] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) (In the formula, R 40 This is a functional group for binding to a subunit of the amino acid unit or to a portion of the linker subunit L2; R 41 and R 42 They either do not exist, or each exists independently, C 1 -C 3 It is alkylene; R 43 It does not exist, or C 1 -C 6 Alkylene, -NH-C 1 -C 12 Alkylene, -C 1 -C 6 Alkylene-NH-,-C(O)-C 1 -C 6 Alkylene, -C 1 -C 6 Alkylene-C(O)-,-NH-C 1 -C 6 Alkylene-C(O)-,-C(O)-C 1 -C 6 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C 1 -C 6 Alkylene, -C(O)-NH-C 1 -C 12 Alkylene, -heteroarylene, heteroaryl-C 1 -C 6 Alkylene, heteroaryl-C 1 -C 6 Alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C 1-C 6 It is alkylene, and the other is C 1 -C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 The aforementioned bonding site is shown; n40 is 1-16; n41 is 1-4; Linker intermediates or linkers of the present invention 1001 to 1004, comprising PEG units having n42 (1 to 4) or a salt thereof. [Invention 1041] R 40 A linker intermediate or linker of any of the present invention 1038 to 1040, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or a protected form thereof. [Invention 1042] R 40 However, it is one of the following structures:

[26] JPEG0007914997000248.jpg183170 or

[27] JPEG0007914997000249.jpg29170 (In the formula, R = H or C 1-6 alkyl; and n=0~12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The aforementioned bonding site is shown, (

[28] JPEG0007914997000250.jpg5170 ) is R for the remainder of the PEG unit. 40 A linker intermediate or linker according to any one of the present invention 1038 to 1040, having the aforementioned bonding site or a stereoisomer thereof. [Invention 1043] R 40 However, it is one of the following structures: [C29] JPEG0007914997000251.jpg184170 or

[30] JPEG0007914997000252.jpg29170 (In the formula, n=0~12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The aforementioned bonding site is shown, (

[31] JPEG0007914997000253.jpg5170 ) is R for the remainder of the PEG unit. 40 A linker intermediate or linker of the present invention 1042, having the aforementioned bonding site (or a stereoisomer thereof). [Invention 1044] R 43 -(NR 44 R 45 ) n41 However, NR 43 If present, one of the following structures:

[32] JPEG0007914997000254.jpg55170 or

[33] JPEG0007914997000255.jpg22170 (In the formula, R=H, C 1-6 Alkyl, polyhydroxyl, or substituted polyhydroxyl (

[34] JPEG0007914997000256.jpg5170 ) is R for the remainder of the PEG unit. 43 Linker intermediates or linkers according to the present invention 1038 to 1040, having the aforementioned bonding site or a stereoisomer thereof. [Invention 1045] R 43 -(NR 44 R 45 ) n41 However, NR 43 If present, one of the following structures:

[35] JPEG0007914997000257.jpg55170 or

[36] JPEG0007914997000258.jpg22170 (In the formula, (

[37] JPEG0007914997000259.jpg5170 ) is R for the remainder of the PEG unit. 43 A linker intermediate or linker of the present invention 1044, having the aforementioned bonding site (or a stereoisomer thereof). [Invention 1046] -NR 44 R 45 However, it is one of the following structures:

[38] JPEG0007914997000260.jpg175170 or

[39] JPEG0007914997000261.jpg78170 (In the formula, (

[40] JPEG0007914997000262.jpg5170 ) is -NR for the remainder of the PEG unit. 44 R 45 A linker intermediate or linker according to any one of the present invention 1038 to 1040, having the aforementioned bonding site or a stereoisomer thereof. [Invention 1047] Before the PEG unit binds to the amino acid unit or a portion of the linker subunit L2, a linker intermediate or linker according to any of the present invention 1001 to 1046 has one of the following structures: [C41-1] JPEG0007914997000263.jpg175170 [C41-2] JPEG0007914997000264.jpg175170 [C41-3] JPEG0007914997000265.jpg175170 [C41-4] JPEG0007914997000266.jpg117170 or

[42] JPEG0007914997000267.jpg47170 (In the formula, R is H or alkyl, and n is 1 to 12). [Invention 1048] The following expressions can be selected: ~R 40 -(R 43 -R 41 --[O-CH 2 -CH 2 ] n40 -R 46 -[O-CH 2 -CH 2 ] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLIII) (In the formula, R 40 This is a functional group for binding to a subunit of the amino acid unit or to a portion of the linker subunit L2; R 41 and R 42 They either do not exist, or each exists independently, C 1 -C 6 It is alkylene; Each R 43 It is either independent, does not exist, or C 1 -C 12 Alkylene, -NH-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-NH-,-C(O)-C 1 -C 12 Alkylene, -C 1 -C 12 Alkylene-C(O)-,-NH-C 1 -C 12 Alkylene-C(O)-,-C(O)-C 1 -C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C 1 -C 12 Alkylene, -C(O)-NH-C 1 -C 12 Alkylene, -heteroarylene, heteroaryl-C 1 -C 12 Alkylene-C 1 -C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C 1 -C 12 It is alkylene, and the other is C 1 -C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; R 46 These are amino, amino-alkyl-amino, or -NH-C(O)-NH-S(O) 2 Selected from -NH-; The wavy line (~) represents R 40 The aforementioned bonding site is shown; n40 is 1-26; n41 is 1 to 6; Linker intermediates or linkers of the present invention 1001 to 1004, comprising PEG units having n42 (1 to 6) or a salt thereof. [Invention 1049] Before the PEG unit binds to the amino acid unit or a portion of the linker subunit L2, the linker intermediate or linker of the present invention 1048 has one of the following structures:

[43] JPEG0007914997000268.jpg54170 (In the formula, R is H or alkyl, and n is 1 to 12). [Invention 1050] The following expressions can be selected:

[44] JPEG0007914997000269.jpg133170 or

[45] JPEG0007914997000270.jpg102170 (In the formula, each Y is independently R 76 or

[46] JPEG0007914997000271.jpg24170 and Each R76 These are independently H, acetyl, and -P(=O)(OH) 2 , or -(CH 2 ) v -OS(=O) 2 (OH) is; Each R a and R b is independently H or R a and R b They, together with the carbon atoms to which they are bonded, form an oxo group; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; Each * represents a linker intermediate or linker of the present invention 1001 to 1004, comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a subunit of the stretcher unit (L1) (or a salt thereof). [Invention 1051] The following expressions can be selected:

[47] JPEG0007914997000272.jpg127170 or

[48] JPEG0007914997000273.jpg104170 (In the formula, each R 76 These are independently H, acetyl, and -P(=O)(OH) 2 or -(CH 2 ) v S(=O) 2 (OH) is; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; Each * represents a linker intermediate or linker of the present invention 1050, comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a subunit of the stretcher unit (L1) (or a salt thereof). [Invention 1052] The following expressions can be selected:

[49] JPEG0007914997000274.jpg136170 or

[50] JPEG0007914997000275.jpg107170 (In the formula, each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each * represents a linker intermediate or linker of the present invention 1050 or 1051, comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a subunit of the stretcher unit (L1) (or a salt thereof). [Invention 1053] Y is R 76 The linker intermediate or linker of the present invention 1050. [Invention 1054] Y

[51] JPEG0007914997000276.jpg22170 The linker intermediate or linker of the present invention 1050. [Invention 1055] Each R a and R b However, the linker intermediate or linker of the present invention 1050 is independently H. [Invention 1056] R a and R b However, these together with the carbon atoms to which they are bonded form an oxo group, which is a linker intermediate or linker of the present invention 1050. [Invention 1057] A linker intermediate or linker according to any of invention 1050 to 1052, wherein q is 10 to 20. [Invention 1058] A linker intermediate or linker according to any of inventions 1050 to 1052, wherein q is 12. [Invention 1059] The PEG unit is a linker intermediate or linker or salt thereof of any of the following: 1001 to 1004, 1038 to 1040, or 1050 to 1052 of the present invention: [C52-1] JPEG0007914997000277.jpg200170 [C52-2] JPEG0007914997000278.jpg192170 [C52-3] JPEG0007914997000279.jpg157170 [C52-4] JPEG0007914997000280.jpg214170 [C52-5] JPEG0007914997000281.jpg181170 [C52-6] JPEG0007914997000282.jpg206170 [C52-7] JPEG0007914997000283.jpg204170 [C52-8] JPEG0007914997000284.jpg193170 [C52-9] JPEG0007914997000285.jpg208170 [C52-10] JPEG0007914997000286.jpg190170 [C52-11] JPEG0007914997000287.jpg159170 [C52-12] JPEG0007914997000288.jpg123170 and

[53] JPEG0007914997000289.jpg41170 (In the formula, each Z is joined by * and selected individually from the following:

[54] JPEG0007914997000290.jpg76170 and

[55] JPEG0007914997000291.jpg55170 each

[56] JPEG0007914997000292.jpg5170 (This indicates a binding site for the amino acid unit (AA), the linker subunit L2, or another subunit of the stretcher unit (L1).) [Invention 1060] The carboxyl unit has the following formula or a salt thereof, and is a linker intermediate or linker according to any of the present inventions 1001 to 1004: R 70 | L 70 | ~NH-(CH 2 ) p1 -CH-(CH 2 ) o1 -C(O)~ (XXXX) (In the formula, (a) L 70 C 1 -C 8 Alkylene, C 1 -C 8 Alkylene-C(O)-,-C(O)-C 1 -C 8 Alkylene- and -C(O)-C 1 -C 8 Selected from alkylene-C(O)-; R 70 is, ~NR 71 (R 72 -R 73 ) and in the formula, R 71 H, C 1 -C 12 Alkyl, substituted C 1 -C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 72 C is either non-existent or optionally replaced. 1 -C 3 Selected from alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted aryls, or optionally substituted heteroaryls, R 73 is a carboxyl or polycarboxyl, wherein the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, and the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide; Each dash (~) indicates a binding site for an amino acid unit (AA), the linker subunit L2, or another subunit of the stretcher unit (L1); Each of p1 and o1 is independently selected from 0 to 2; or (b) L 70 C 1 -C 8 Alkylene, C 1 -C 8 Alkylene-C(O)-,-C(O)-C 1 -C 8 Alkylene- and -C(O)-C 1 -C 8 Selected from alkylene-C(O)-; R 70 is, ~NR 71 (R 75 -(R 73 ) 2 ) and in the formula, R 71 H, C 1 -C12 Alkyl, substituted C 1 -C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 75 This is C replaced by a branched arbitrary choice. 1 -C 3 Alkylene, optionally substituted ether, optionally substituted thioether, optionally substituted ketone, optionally substituted amide, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic ring, optionally substituted aryl or optionally substituted heteroaryl, and each R 73 Each independently comprises a carboxyl or a polycarboxyl, where the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, and the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide groups; Each dash (~) indicates a binding site for an amino acid unit (AA), the linker subunit L2, or another subunit of the stretcher unit (L1); Each of p1 and o1 is independently selected from 0 to 2; or (c) L 70 C 1 -C 8 Alkylene, C 1 -C 8 Alkylene-C(O)-,-C(O)-C 1 -C 8 Alkylene- and -C(O)-C 1 -C 8 Selected from alkylene-C(O)-; R 70 is, ~N(R 74 -R 73 )(R 72 -R 73 ) and in the formula, R 72 and R 74 Each of these is independently replaced by C by choice. 1 -C 3 Selected from alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted aryls, or optionally substituted heteroaryls, each R 73 Each is independently a carboxyl group or polycarboxyl, comprising 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkyl, heteroalkylene, amino and / or amide; Each dash (~) indicates a binding site for an amino acid unit (AA), the linker subunit L2, or another subunit of the stretcher unit (L1); (Each of p1 and o1 is independently selected from 0 to 2). [Invention 1061] A linker intermediate or linker according to any of the present inventions 1001 to 1060, comprising at least one sugar unit. [Invention 1062] A linker intermediate or linker according to any one of the present inventions 1001 to 1060, comprising at least one PEG unit. [Invention 1063] A linker intermediate or linker according to any one of the present inventions 1001 to 1060, comprising at least one carboxyl unit. [Invention 1064] A linker intermediate or linker according to any of the present inventions 1001 to 1060, comprising at least two polar units, each polar unit selected from a sugar unit, a PEG unit, and a carboxyl unit. [Invention 1065] A linker intermediate or linker according to any of the present invention 1001 to 1060, comprising at least one sugar unit and a PEG unit or carboxyl unit. [Invention 1066] A linker intermediate or linker according to any one of the present inventions 1001 to 1060, comprising at least one carboxyl unit and a PEG unit. [Invention 1067] A linker intermediate or linker according to any of the present invention 1001 to 1060, wherein the aforementioned amino acid unit (AA) is present (s=1). [Invention 1068] A linker intermediate or linker according to any one of the present invention 1001 to 1067, wherein the amino acid unit comprises at least one polar unit. [Invention 1069] L2 or AA-L2 is a linker intermediate or linker according to any of the following inventions 1001 to 1068, having one of the following structures:

[57] JPEG0007914997000293.jpg141170 or

[58] JPEG0007914997000294.jpg47170 (In the formula, the wavy line on the amino group indicates a binding site for the stretcher unit, and the drug unit is bound to benzyl alcohol.) [Invention 1070] ~AA-L2~ is a linker intermediate or linker according to any of the present inventions 1001 to 1067, having a formula selected from the following:

[59] JPEG0007914997000295.jpg8170 、

[60] JPEG0007914997000296.jpg8170 ,or

[61] JPEG0007914997000297.jpg8170 (In the formula, square brackets indicate the amino acid units, each aa is an optional subunit of AA, L2 is the linker subunit, and each tilde (~) indicates a binding site for the stretcher unit; aa 1 (PEG) is a PEG unit bound to the amino acid subunit of AA, SU is a sugar unit bound to the subunit or L2 of AA, and CU is a carboxyl unit bound to the subunit or L2 of AA; double tilde (

[62] JPEG0007914997000298.jpg6170 ) indicates the binding site for the drug unit, and aa and aa 1 (These are independently selected from alpha, beta, and gamma amino acids and their derivatives). [Invention 1071] ~AA-L2~ is a linker intermediate or linker according to any of the present inventions 1001 to 1067, having a formula selected from the following:

[63] JPEG0007914997000299.jpg48170 ,or

[64] JPEG0007914997000300.jpg21170 (In the formula, square brackets indicate the amino acid units, each aa is an amino acid subunit of AA, L2 is the linker subunit attached to the side chain of aa, and a dash (~) indicates a binding site for the stretcher unit; aa 1 (PEG) is a PEG unit bound to aa, SU is a sugar unit bound to aa, CU is a carboxyl unit bound to aa, and the double tilde (

[65] JPEG0007914997000301.jpg6170 ) indicates the binding site for the drug unit; aa and aa 1 (These are independently selected from alpha, beta, and gamma amino acids and their derivatives). [Invention 1072] A linker intermediate or linker according to any one of the present invention 1001 to 1068, wherein the amino acid unit comprises at least two polar units. [Invention 1073] ~AA-L2~ is a linker intermediate or linker of the present invention 1072 having a formula selected from the following:

[66] JPEG0007914997000302.jpg8170 、

[67] JPEG0007914997000303.jpg8170 ,or

[68] JPEG0007914997000304.jpg8170 (In the formula, square brackets indicate the amino acid unit, aa is an optional subunit of AA, L2 is the linker subunit, and a dash (~) indicates the binding site for the stretcher unit; aa 1 (PEG) and aa 2 Each (PEG) is a PEG unit bonded to aa or other PEG unit; each SU is a sugar unit bonded to aa or other sugar unit, and each CU is a carboxyl unit bonded to aa or other carboxyl unit, with a double tilde (

[69] JPEG0007914997000305.jpg6170 ) indicates the binding site for the drug unit; aa, aa 1 and aa 2 (These are independently selected from alpha, beta, and gamma amino acids and their derivatives). [Invention 1074] ~AA-L2~ is a linker intermediate or linker of the present invention 1072 having a formula selected from the following:

[70] JPEG0007914997000306.jpg47170 ,or

[71] JPEG0007914997000307.jpg21170 (In the formula, square brackets indicate the amino acid unit, aa is the amino acid subunit of AA, L2 is the linker subunit attached to the side chain of aa, and each tilde (~) indicates the binding site for the stretcher unit; aa 1 (PEG) and aa 2 Each of (PEG) is a PEG unit bonded to aa, SU is a sugar unit bonded to aa; each CU is a carboxyl unit bonded to aa; double tilde (

[72] JPEG0007914997000308.jpg6170 ) indicates the binding site for the drug unit; aa, aa 1 and aa 2 Each of these is independently selected from alpha, beta, and gamma amino acids and their derivatives. [Invention 1075] A linker intermediate or linker according to any of the present invention 1001 to 1074, wherein the linker subunit L2 is a severable linker unit. [Invention 1076] A linker intermediate or linker according to the present invention 1075, wherein the linker subunit L2 contains a peptide that can be cleaved by an intracellular protease. [Invention 1077] A linker intermediate or linker according to the present invention 1076, wherein the cleavable peptide comprises a valine-citrulline peptide, a valine-alanine peptide, a valine-lysine peptide, a phenylalanine-lysine peptide, or a glycine-glycine-phenylalanine-glycine peptide. [Invention 1078] A linker intermediate or linker according to any of the present inventions 1001 to 1077, wherein the linker subunit L2 includes at least one polarity unit. [Invention 1079] A linker intermediate or linker according to any of the present invention 1001 to 1078, wherein the polarity unit is a sugar unit (SU). [Invention 1080] A linker intermediate or linker according to the present invention 1079, wherein the cleavable peptide comprises SU-valine-citrulline peptide, SU-valine-lysine peptide, SU-valine-alanine peptide, SU-phenylalanine-lysine peptide, or SU-glycine-glycine-phenylalanine-glycine peptide. [Invention 1081] A linker intermediate or linker according to the present invention 1078, wherein the polarity unit is a carboxyl unit (CU). [Invention 1082] The linker intermediate or linker of the present invention 1081, wherein the cleavable peptide comprises CU-valine-citrulline peptide, CU-valine-lysine peptide, valine-(CU-lysine) peptide, CU-valine-alanine peptide, CU-phenylalanine-lysine peptide, phenylalanine-(CU-lysine) peptide, or CU-glycine-glycine-phenylalanine-glycine peptide, and CU-lysine is a carboxyl unit containing a lysine residue. [Invention 1083] A linker intermediate or linker according to the present invention 1078, wherein the polarity unit is a PEG unit (PEG). [Invention 1084] The linker intermediate or linker of the present invention 1083, wherein the cleavable peptide comprises Lys(PEG)-valine-citrulline peptide, valine-Cit(PEG) peptide, Lys(PEG)-valine-lysine peptide, valine-lysine(PEG) peptide, Lys(PEG)-valine-alanine peptide, Lys(PEG)-phenylalanine-lysine peptide, phenylalanine-Lys(PEG) peptide, or Lys(PEG)-glycine-glycine-phenylalanine-glycine peptide, wherein Lys(PEG) and Cit(PEG) each contain a PEG unit attached to a lysine residue or a citrulline residue. [Invention 1085] A linker intermediate or linker according to any of the present invention 1075 to 1084, wherein the cleavable peptide is bonded to a para-aminobenzyl alcohol self-sacrificing group (PABA). [Invention 1086]

[73] JPEG0007914997000309.jpg7170 However, the linker intermediate or linker of the present invention 1085 having one of the following structures: [C74-1] JPEG0007914997000310.jpg227170 [C74-2] JPEG0007914997000311.jpg215170 [C74-3] JPEG0007914997000312.jpg110170 (In the formula, the wavy line on the amino group indicates a binding site for the stretcher unit, and the drug unit is bound to benzyl alcohol.) [Invention 1087] ~AA-L2~ is a linker intermediate or linker of the present invention 1001 or 1002 having one of the following structures: [C75-1] JPEG0007914997000313.jpg189170 [C75-2] JPEG0007914997000314.jpg191170 [C75-3] JPEG0007914997000315.jpg179170 [C75-4] JPEG0007914997000316.jpg149170 [C75-5] JPEG0007914997000317.jpg199170 [C75-6] JPEG0007914997000318.jpg142170 [C75-7] JPEG0007914997000319.jpg155170 [C75-8] JPEG0007914997000320.jpg151170 [C75-9] JPEG0007914997000321.jpg206170 [C75-10] JPEG0007914997000322.jpg177170 [C75-11] JPEG0007914997000323.jpg158170 [C75-12] JPEG0007914997000324.jpg215170 [C75-13] JPEG0007914997000325.jpg205170 [C75-14] JPEG0007914997000326.jpg190170 [C75-15] JPEG0007914997000327.jpg155170 [C75-16] JPEG0007914997000328.jpg160170 [75-17] JPEG0007914997000329.jpg211170 [C75-18] JPEG0007914997000330.jpg173170 [C75-19] JPEG0007914997000331.jpg176170 [75-20] JPEG0007914997000332.jpg85170 or

[76] JPEG0007914997000333.jpg69170 (In the formula, each Z is joined by * and selected individually from the following:

[77] JPEG0007914997000334.jpg79170 and

[78] JPEG0007914997000335.jpg60170 The wavy lines on the amino group indicate the binding site for the stretcher unit, and the drug unit is bound to the benzyl alcohol (i.e., the hydrogen atoms of the benzyl alcohol are replaced by the bond with the drug unit). [Invention 1088] A linker intermediate or linker according to any of invention 1075 to 1085, wherein L2 is bonded to the side chain of the AA subunit. [Invention 1089]

[79] JPEG0007914997000336.jpg7170 However, the linker intermediate or linker of the present invention 1088 having one of the following structures:

[80] JPEG0007914997000337.jpg143170 or

[81] JPEG0007914997000338.jpg77170 (In the formula, the wavy line on the amino group indicates a binding site for the stretcher unit, and the drug unit is bound to the terminal acid group, benzyl alcohol, or the wavy line(

[82] JPEG0007914997000339.jpg6170 ) indicates the binding site for the drug unit. [Invention 1090] A linker intermediate or linker according to any of the present invention 1001 to 1085, wherein the aforementioned amino acid units are linked to the linker subunit L2 by a non-peptidic linking group. [Invention 1091] The non-peptidic linking group is C 1 -C 10 Alkylene, C 2 -C 10 Alkenylene, C 2 -C 10 A linker intermediate or linker of the present invention 1090, selected from alkylylene or polyethylene glycol. [Invention 1092] A linker intermediate or linker according to any one of the invention 1001 to 1091, further comprising stretcher units. [Invention 1093] The stretcher unit is selected from the following: [C83-1] JPEG0007914997000340.jpg181170 [C83-2] JPEG0007914997000341.jpg155170 or

[84] JPEG0007914997000342.jpg29170 (In the formula, R 17 is -C 1 -C 10 Alkylene-,-C 1 -C 10 Heteroalkylene-,-C 3 -C 8 Carbocyclo-,-O-(C 1 -C 8 Alkylene)-,-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-(where b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -(where b is between 1 and 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-(where b is 1 to 26), -arrine-, -C 1 -C 10 Alkilen-Arirene-, -Arirene-C 1 -C 10 Alkylene-,-C 1 -C 10 Alkylene-(C) 3 -C 8 Carbocyclo)-,-(C 3 -C 8 Carbocyclo)-C 1 -C 10 Alkylene-,-C 3 -C 8 Heterocyclo-, -C 1 -C 10 Alkylene-(C) 3 -C 8 Heterocyclo)-,-(C 3 -C 8 Heterocyclo)-C 1 -C 10 Alkylene-,-C 1 -C 10 Alkylene-C(=O)-, C 1 -C 10 Heteroalkylenes -C(=O)-, -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C(=O)-(where b is 1 to 26), -(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-C(=O)-(where b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-C(=O)-(where b is 1 to 26), -C 3 -C 8 Carbocyclo-C(=O)-,-O-(C 1 -C 8 Alkyl)-C(=O)-,-Arylene-C(=O)-,-C 1 -C 10 Alkylene-arirene-C(=O)-, -arirene-C 1 -C 10 Alkylene -C(=O)-, -C 1 -C 10 Alkylene-(C) 3 -C 8 Carbocyclo)-C(=O)-,-(C 3 -C 8 Carbocyclo)-C 1 -C 10 Alkylene -C(=O)-, -C 3 -C 8 Heterocyclo-C(=O)-, -C 1 -C 10 Alkylene-(C) 3 -C 8 Heterocyclo)-C(=O)-,-(C 3 -C 8 Heterocyclo)-C 1 -C 10 Alkylene -C(=O)-, -C 1 -C 10 Alkylene-NH-,-C 1 -C 10 Heteroalkylene -NH-, -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -NH-(where b is 1 to 26), -(CH 2 -O-CH 2 )b -C 1 -C 8 Alkylene-NH-(where b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-NH-(where b is 1 to 26), -C 1 -C 8 Alkylene-(C(=O))-NH-(CH 2 -O-CH 2 ) b -C(=O)-(where b is 1 to 26), -C 1 -C 8 Alkylene-(C(=O))-NH-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-C(=O)-(where b is 1 to 26), -C 1 -C 8 Alkylene-NH-(C(=O))-(CH 2 -O-CH 2 ) b -NH-(where b is 1 to 26), -C 1 -C 8 Alkylene-NH-(C(=O))-(CH 2 -O-CH 2 ) b -C 1 -C 8 Alkylene-NH-(where b is 1 to 26), -C 3 -C 8 Carbocyclo-NH-,-O-(C 1 -C 8 Alkyl)-NH-,-Arylene-NH-,-C 1 -C 10 Alkylene-arylene-NH-,-arylene-C 1 -C 10 Alkylene-NH-,-C 1 -C 10 Alkylene-(C) 3 -C 8 Carbocyclo)-NH-,-(C 3 -C 8 Carbocyclo)-C 1 -C 10 Alkylene-NH-,-C 3 -C 8 Heterocyclo-NH-,-C 1 -C 10 Alkylene-(C) 3 -C 8 Heterocyclo)-NH-,-(C 3 -C 8 Heterocyclo)-C 1 -C 10 Alkylene-NH-,-C 1 -C10 Alkylene-S-,C 1 -C 10 Heteroalkylene -S-, -C 3 -C 8 Carbocyclo-S-,-O-(C 1 -C 8 Alkyl)-S-,-Arylene-S-,-C 1 -C 10 Alkilen-Arirene-S-,-Arirene-C 1 -C 10 Alkylene-S-,-C 1 -C 10 Alkylene-(C) 3 -C 8 Carbocyclo)-S-,-(C 3 -C 8 Carbocyclo)-C 1 -C 10 Alkylene-S-,-C 3 -C 8 Heterocyclo-S-,-C 1 -C 10 Alkylene-(C) 3 -C 8 Heterocyclo)-S-, or -(C 3 -C 8 Heterocyclo)-C 1 -C 10 (It is alkylene-S-) or The stretcher unit is maleimide (C 1 -C 10 Alkylene-C(O)-, Maleimide(CH 2 OCH 2 ) p2 (C 1 -C 10 Alquiene)C(O)-, Maleimide(C 1 -C 10 Alkien) (CH 2 OCH 2 ) p2 A linker according to the present invention 1092, comprising C(O)- (wherein p2 is 1 to 26) or their ring-opened forms. [Invention 1094] The stretcher unit is selected from the following linker intermediate or linker of the present invention 1092:

[85] JPEG0007914997000343.jpg113170 and

[86] JPEG0007914997000344.jpg24170 (In the formula, the dashed line)

[87] JPEG0007914997000345.jpg5170 (This indicates a binding site for the stretcher unit to an amino acid unit, and the binding site for the targeting unit is located on a maleimide, primary amine, or alkyne functional group.) [Invention 1095] A linker of the present invention 1093 having one of the following structures: [C88-1] JPEG0007914997000346.jpg207170 [C88-2] JPEG0007914997000347.jpg200170 [C88-3] JPEG0007914997000348.jpg213170 [C88-4] JPEG0007914997000349.jpg125170 (In the formula, the drug unit is bonded to a terminal acid group, benzyl alcohol, or a wavy line.)

[89] JPEG0007914997000350.jpg6170 ) indicates the binding site for the drug unit. [Invention 1096] A linker of the present invention 1092 having one of the following structures: [C90-1] JPEG0007914997000351.jpg213170 [C90-2] JPEG0007914997000352.jpg213170 [C90-3] JPEG0007914997000353.jpg216170 [C90-4] JPEG0007914997000354.jpg221170 [C90-5] JPEG0007914997000355.jpg186170 [C90-6] JPEG0007914997000356.jpg198170 [C90-7] JPEG0007914997000357.jpg147170 [90-8] JPEG0007914997000358.jpg150170 [90-9] JPEG0007914997000359.jpg219170 [90-10] JPEG0007914997000360.jpg135170 [90-11] JPEG0007914997000361.jpg181170 [90-12] JPEG0007914997000362.jpg158170 [C90-13] JPEG0007914997000363.jpg215170 [90-14] JPEG0007914997000364.jpg205170 [90-15] JPEG0007914997000365.jpg190170 [90-16] JPEG0007914997000366.jpg155170 [90-17] JPEG0007914997000367.jpg160170 [90-18] JPEG0007914997000368.jpg213170 [90-19] JPEG0007914997000369.jpg156170 [90-20] JPEG0007914997000370.jpg164170 [90-21] JPEG0007914997000371.jpg168170 or

[91] JPEG0007914997000372.jpg69170 (In the formula, each Z is joined by * and selected individually from the following:

[92] JPEG0007914997000373.jpg82170 and

[93] JPEG0007914997000374.jpg60170 The drug unit is optionally attached to a terminal acid group, benzyl alcohol, or a wavy line.

[94] JPEG0007914997000375.jpg6170 ) indicates the binding site for the drug unit. [Invention 1097] A linker according to any one of the inventions 1001 to 1096, further comprising at least one drug unit bonded to a linker subunit L2 to form a drug-linker. [Invention 1098] The drug-linker of the present invention 1097, wherein the drug unit is selected from cytotoxic agents, immunomodulators, nucleic acids, proliferation inhibitors, PROTACs, toxins, radioisotopes, and chelated ligands. [Invention 1099] The drug-linker of the present invention 1098, wherein the drug unit is a cytotoxic agent. [Invention 1100] The drug-linker of the present invention 1099, wherein the cytotoxic agent is selected from the group consisting of auristatin, meitansinoid, camptothecin, duocalmycin, and calicheamycin. [Invention 1101] The drug-linker of the present invention 1100, wherein the cytotoxic agent is auristatin. [Invention 1102] The drug-linker of the present invention 1101, wherein the cytotoxic agent is MMAE or MMAF. [Invention 1103] The drug-linker of the present invention 1100, wherein the cytotoxic agent is camptothecin. [Invention 1104] The drug-linker of the present invention 1103, wherein the cytotoxic agent is exatecan or SN-38. [Invention 1105] The drug-linker of the present invention 1104, wherein the cytotoxic agent is exatecan. [Invention 1106] The drug-linker of the present invention 1099, wherein the cytotoxic agent is calicheamicin. [Invention 1107] The drug-linker of the present invention 1099, wherein the cytotoxic agent is a meitansinoid. [Invention 1108] The drug-linker of the present invention 1107, wherein the meitansinoid is meitansin, meitansinol, or ansamatosin-2. [Invention 1109] The drug-linker of the present invention 1098, wherein the drug unit is an immunomodulator. [Invention 1110] The drug-linker of the present invention 1109, wherein the immunomodulator is selected from a TRL7 agonist, a TLR8 agonist, a STING agonist, or a RIG-I agonist. [Invention 1111] The drug-linker of the present invention 1110, wherein the immunomodulator is a TLR7 agonist. [Invention 1112] The drug-linker of the present invention 1111, wherein the TLR7 agonist is imidazoquinoline, imidazoquinolineamine, thiazoquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazole-2-amine, tetrahydropyridopyrimidine, heteroalothiadiazide-2,2-dioxide, benzonaphthyridine, guanosine analog, adenosine analog, thymidine homopolymer, ssRNA, CpG-A, PolyG10, or PolyG3. [Invention 1113] The drug-linker of the present invention 1110, wherein the immunomodulator is a TLR8 agonist. [Invention 1114] The drug-linker of the present invention 1113, wherein the TLR8 agonist is selected from imidazoquinoline, thiazoloquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazole-2-amine, tetrahydropyridopyrimidine, or ssRNA. [Invention 1115] The drug-linker of the present invention 1110, wherein the immunomodulator is a STING agonist. [Invention 1116] The drug-linker of the present invention 1110, wherein the immunomodulator is a RIG-I agonist. [Invention 1117] The drug-linker of the present invention 1116, wherein the RIG-I agonist is selected from KIN1148, SB-9200, KIN700, KIN600, KIN500, KIN100, KIN101, KIN400 and KIN2000. [Invention 1118] A drug-linker according to the present invention 1098, wherein the drug unit is a chelated ligand. [Invention 1119] The drug-linker of the present invention 1118, wherein the chelating ligand is selected from radioactive isotopes such as platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti), or iridium (Ir); yttrium-88, yttrium-90, technetium-99, copper-67, rhenium-188, rhenium-186, gallium-66, gallium-67, indium-111, indium-114, indium-115, lutetium-177, strontium-89, salarium-153, and lead-212. [Invention 1120] The drug-linker of the present invention 1097 having the following structure: [C95-1] JPEG0007914997000376.jpg175170 [C95-2] JPEG0007914997000377.jpg202170 [C95-3] JPEG0007914997000378.jpg145170 [C95-4] JPEG0007914997000379.jpg160170 [C95-5] JPEG0007914997000380.jpg200170 [C95-6] JPEG0007914997000381.jpg199170 [95-7] JPEG0007914997000382.jpg193170 [95-8] JPEG0007914997000383.jpg208170 [95-9] JPEG0007914997000384.jpg138170 [95-10] JPEG0007914997000385.jpg218170 [95-11] JPEG0007914997000386.jpg161170 [95-12] JPEG0007914997000387.jpg158170 [95-13] JPEG0007914997000388.jpg156170 [95-14] JPEG0007914997000389.jpg148170 [95-15] JPEG0007914997000390.jpg153170 [95-16] JPEG0007914997000391.jpg155170 [95-17] JPEG0007914997000392.jpg156170 [95-18] JPEG0007914997000393.jpg209170 [95-19] JPEG0007914997000394.jpg148170 [95-20] JPEG0007914997000395.jpg180170 [95-21] JPEG0007914997000396.jpg185170 [95-22] JPEG0007914997000397.jpg166170 [95-23] JPEG0007914997000398.jpg189170 [95-24] JPEG0007914997000399.jpg210170 [95-25] JPEG0007914997000400.jpg160170 [95-26] JPEG0007914997000401.jpg148170 [95-27] JPEG0007914997000402.jpg157170 [95-28] JPEG0007914997000403.jpg169170 [95-29] JPEG0007914997000404.jpg170170 [95-30] JPEG0007914997000405.jpg166170 [95-31] JPEG0007914997000406.jpg159170 [95-32] JPEG0007914997000407.jpg170170 [95-33] JPEG0007914997000408.jpg193170 [95-34] JPEG0007914997000409.jpg168170 [95-35] JPEG0007914997000410.jpg182170 [95-36] JPEG0007914997000411.jpg153170 (In the formula, each Z is joined by * and selected individually from the following:

[96] JPEG0007914997000412.jpg86170 and

[97] JPEG0007914997000413.jpg60170 or

[98] JPEG0007914997000414.jpg76170 (In the formula, each Z is joined by * and selected individually from the following:)

[99] JPEG0007914997000415.jpg82170 and

[100] JPEG0007914997000416.jpg59170 )。 [Invention 1121] A conjugate comprising a targeted unit bound to any of the drug-linkers of the present invention 1097 to 1120. [Invention 1122] The conjugate of the present invention 1121, wherein the targeting unit is selected from an antibody or its antigen-binding portion. [Invention 1123] The conjugate of the present invention 1122, wherein the targeting unit is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-bonded Fc, scFv, single-domain antibody, diabody, bispecific antibody, or multispecific antibody. [Invention 1124] The conjugate of the present invention 1121, wherein the targeting unit is a diabody, DART, antikalin, aphibody, avimer, DARPin, or adnectin. [Invention 1125] A conjugate according to any one of the present invention 1121 to 1124, wherein the targeting unit is single-specific. [Invention 1126] A conjugate according to any one of the present invention 1121 to 1125, wherein the targeting unit is divalent. [Invention 1127] The conjugate according to any one of the present invention 1121 to 1124, wherein the targeting unit is bispecific. [Invention 1128] The average drug load of the conjugate (p load A conjugate of any of the present inventions 1121 to 1127, wherein the values ​​are approximately 1 to approximately 8, approximately 2, approximately 4, approximately 6, approximately 8, approximately 10, approximately 12, approximately 14, approximately 16, approximately 3 to approximately 5, approximately 6 to approximately 8, or approximately 8 to approximately 16. [Invention 1129] A conjugate selected from any of the following, 1121 to 1128 of the present invention: [Case 101-1] JPEG0007914997000417.jpg160170 [Case 101-2] JPEG0007914997000418.jpg140170 [Case 101-3] JPEG0007914997000419.jpg184170 [Case 101-4] JPEG0007914997000420.jpg187170 [Case 101-5] JPEG0007914997000421.jpg174170 [Case 101-6] JPEG0007914997000422.jpg178170 [Case 101-7] JPEG0007914997000423.jpg180170 [Case 101-8] JPEG0007914997000424.jpg190170 [Case 101-9] JPEG0007914997000425.jpg143170 [C101-10] JPEG0007914997000426.jpg204170 [Case 101-11] JPEG0007914997000427.jpg144170 [Case 101-12] JPEG0007914997000428.jpg153170 [C101-13] JPEG0007914997000429.jpg154170 [Case 101-14] JPEG0007914997000430.jpg149170 [Case 101-15] JPEG0007914997000431.jpg146170 [Case 101-16] JPEG0007914997000432.jpg205170 [Case 101-17] JPEG0007914997000433.jpg149170 [Case 101-18] JPEG0007914997000434.jpg151170 [Case 101-19] JPEG0007914997000435.jpg205170 [C101-20] JPEG0007914997000436.jpg139170 [Case 101-21] JPEG0007914997000437.jpg170170 [Case 101-22] JPEG0007914997000438.jpg177170 [C101-23] JPEG0007914997000439.jpg148170 [Case 101-24] JPEG0007914997000440.jpg162170 [Case 101-25] JPEG0007914997000441.jpg203170 [C101-26] JPEG0007914997000442.jpg217170 [C101-27] JPEG0007914997000443.jpg216170 [C101-28] JPEG0007914997000444.jpg167170 [C101-29] JPEG0007914997000445.jpg170170 [C101-30] JPEG0007914997000446.jpg211170 [Case 101-31] JPEG0007914997000447.jpg181170 [Case 101-32] JPEG0007914997000448.jpg150170 [C101-33] JPEG0007914997000449.jpg175170 [Case 101-34] JPEG0007914997000450.jpg164170 [Case 101-35] JPEG0007914997000451.jpg159170 [C101-36] JPEG0007914997000452.jpg65170 (In the formula, each Z is joined by * and selected individually from the following: [C102] JPEG0007914997000453.jpg83170 and [C103] JPEG0007914997000454.jpg57170 or [C104] JPEG0007914997000455.jpg78170 (In the formula, each Z is joined by * and selected individually from the following:) [C105] JPEG0007914997000456.jpg83170 and [C106] JPEG0007914997000457.jpg58170 Ab is the targeting unit, and n is p load (That is.) [Invention 1130] A conjugate according to any one of the present invention 1121, 1128, or 1129, wherein the targeting unit is bound to a target molecule. [Invention 1131] The conjugate of the present invention 1130, wherein the target molecule is CD19, CD20, CD30, CD33, CD70, LIV-1, or EGFRv3. [Invention 1132] A conjugate according to any of the present inventions 1121, 1128, or 1129, wherein the targeting unit is selected from scFv1-ScFv2, ScFv12-Fc-scFv22, IgG-scFv, DVD-Ig, triomab / quadroma, two-in-one IgG, scFv2-Fc, TandAb, and scFv-HSA-scFv. [Invention 1133] A conjugate according to any one of the present invention 1121, 1128, or 1129, wherein the targeting unit is a cancer-related antigen. [Invention 1134] The targeting units are CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, ABL1, AKT1, A LK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, JA K2, KDR(VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1, STK1, MLH1, MSH2, M SH6, PMS2, ROS1, ERCC1, 5T4(TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6, CLDN6, CLDN18.2, C A conjugate according to any of Invention 1121, 1128, or 1129, which is LEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4. [Invention 1135] The aforementioned targeting units are Rituximab (Rituxan®), Trastuzumab (Herceptin®), Pertuzumab (Perjeta®), Bevacizumab (Avastin®), Ranibizumab (Lucentis®), Cetuximab (Erbitux®), Alemtuzumab (Campath®), and Panitumumab (Vectibix®). ), ibritumomab tiuxetan (Zevalin®), tocitumomab (Bexxar®), ipilimumab, zaltumumab, darotuzumab, figtumumab, ramucirumab, gallium tuzumab, farletuzumab, ocrelizumab, ofatumumab (Arzerra®), tocitumumab, ibritumomab, CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 A conjugate of any of the inventions 1121, 1128, or 1129, which is an antibody or fragment thereof, comprising an anti-LHRH receptor antibody including 2C6, 11B8, B1, 2H7, LT20, 1FS, or AT80, daclizumab (Zenapax®), or clone A9E4, F1G4, AT2G7, GNRH03, or GNRHR2. [Invention 1136] The conjugate of the present invention 1121, wherein the targeting unit is antibody F131 and the drug-linker is LD038. [Invention 1137] The aforementioned targeting unit is The VH region includes a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region includes complementarity determination regions HCDR1, HCDR2, and HCDR3 located in the heavy chain variable region framework region, and the VL region includes LCDR1, LCDR, and LCDR3 located in the light chain variable region framework region, and the VH and VL CDRs are (a) Sequence IDs 30, 31, 32, 33, 34, and 35, respectively; and (b) A conjugate of any of the present invention 1121, 1128, or 1129, having an amino acid sequence selected from the set of amino acid sequences represented by the group consisting of SEQ ID NO: 36, SEQ ID NO: 31, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, and SEQ ID NO: 40. [Invention 1138] The VH region and the VL region are Each has an amino acid sequence selected from the pair of amino acid sequences represented by the group consisting of Sequence ID No. 26 and Sequence ID No. 27; The conjugate of the present invention 1137, wherein the heavy chain framework region and the light chain framework region are optionally modified by substitution, deletion, or insertion of 1 to 8 amino acids within the framework region. [Invention 1139] The conjugate of the present invention 1137, wherein the antibody is F131 and the drug-linker is LD038. [Invention 1140] A conjugate comprising a targeting unit bound to the drug-linker, wherein the targeting unit is antibody F131 and the drug-linker is LD038. [Invention 1141] A pharmaceutical composition comprising any conjugate of Invention 1121 to 1140 and a pharmaceutically acceptable carrier. [Invention 1142] A method for treating a subject requiring such treatment, comprising the step of administering to the subject any conjugate of the present invention 1121 to 1140 or a pharmaceutical composition of the present invention 1141, wherein the subject has cancer or an autoimmune disease, and the conjugate binds to a target antigen associated with the cancer or autoimmune disease. These and other aspects of the present invention can be better understood by referring to the following detailed description, non-limiting examples of specific embodiments, and the accompanying drawings. [Brief explanation of the drawing]

[0092] [Figure 1A] This figure shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against OV90 cells. [Figure 1B] This figure shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against OVCAR-3 cells. [Figure 1C] This figure shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against NCI-H292 cells. [Figure 2]This figure shows the in vivo activity of the human anti-huFOLR1 antibody PA038 conjugate. Mice with established OV90 xenografts of approximately 117 mm³ were administered 5 mg / kg of the conjugate or PBS intravenously over two weeks, starting 8 days after tumor cell inoculation. The mean tumor volume (mm³) versus time after cell inoculation (days) is plotted. (N=6, mean ± SEM) [Figure 3] This figure shows the in vivo activity of the human anti-huFOLR1 antibody PA038 conjugate. Mice with established NCI-H292 xenografts of approximately 123 mm³ were administered 5 mg / kg of the conjugate or PBS intravenously over two weeks, starting 11 days after cell inoculation. The mean tumor volume (mm³) versus time after cell inoculation (days) is plotted. (N=6, mean ± SEM) [Figure 4] This figure shows the in vivo activity of the human anti-huFOLR1 antibody PA038 conjugate. Mice with established OV90 xenografts of approximately 110 mm³ were administered 5 mg / kg of the conjugate or PBS intravenously over two weeks, starting 13 days after cell inoculation. The mean tumor volume (mm³) versus time after cell inoculation (days) is plotted. (N=6, mean ± SEM) [Figure 5] This figure shows the PK profiles of anti-huFOLR-1 conjugate F131-LD038 and unadulterated Ab F131 evaluated at 3 mg / kg (N=3; mean ± SD). [Figure 6] This figure shows a comparison of anti-FOLR1 antibody binding to Hela cells. [Figure 7] This figure shows a comparison of the binding ability of anti-FOLR1 antibodies to RPTEC / TERT1 cells. [Figure 8] This figure shows the dose-dependent binding of anti-FOLR1 antibodies to Hela cells. [Figure 9] This figure shows the dose-dependent binding of anti-FOLR1 antibody to RPTEC / TERT1 cells. [Figure 10] This figure shows the internalization of anti-FOLR1 antibodies into Hela cells. [Figure 11] This figure shows the internalization of anti-FOLR1 antibodies into RPTEC / TERT1 cells. [Figure 12A] This figure shows the internalization of F131 in tumor cell lines. [Figure 12B] This figure shows the internalization of F131-LD038 in tumor cell lines. [Figure 13A] This figure shows the in vitro cytotoxicity of KB. [Figure 13B] This figure shows the in vitro cytotoxicity of OVCAR3. [Figure 13C] This figure shows the in vitro cell cytotoxicity of JEG-3. [Figure 14A] This figure shows the in vivo efficacy of F131 and F131-LD038 in CDX against OVCAR-3. [Figure 14B] This figure shows the in vivo efficacy of F131 and F131-LD038 in CDX against KB. [Figure 14C] This figure shows the in vivo efficacy of F131 and F131-LD038 in CDX against HCC827. [Figure 14D] This figure shows the in vivo efficacy of F131 and F131-LD038 in CDX on H441. [Figure 14E] This figure shows the in vivo efficacy of F131 and F131-LD038 in CDX against OV90. [Figure 15A] This figure shows the in vivo efficacy of F131-038 and other conjugates in CDX against KB. [Figure 15B] This figure shows the in vivo effectiveness of the F131 conjugate in CDX against KB. [Figure 16A] This figure shows PK studies in rat models of F131 and its conjugate. [Figure 16B] This figure shows PK studies in rat models of F131 and its conjugate. [Figure 16C]This figure shows PK studies in rat models of F131 and its conjugate. [Figure 17A] This figure shows the tolerance levels of F131-deluctecan and F131-LD038 in pilot cynomolgus monkey toxicity tests. [Figure 17B] This figure shows the tolerance levels of F131-deluctecan and F131-LD038 in pilot cynomolgus monkey toxicity studies. [Figure 18] This figure shows the toxicity of F131-deluctecan and F131-LD038 PK in pilot cynomolgus monkey toxicity studies. [Modes for carrying out the invention]

[0093] definition For convenience, specific terms in this specification, examples, and claims are defined herein. Unless otherwise stated or implied by the context, the following terms and phrases have the meanings provided below. The definitions are provided to aid in the description of specific embodiments and are not intended to limit the invention described in the claims, as the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains.

[0094] Where used herein, unless otherwise indicated, the terms “a” and “an” shall mean “one,” “at least one,” or “one or more.” Unless otherwise required by context, singular terms as used herein shall include the plural form, and plural terms shall include the singular form.

[0095] Unless the context requires otherwise, words such as “comprise” and “comprising” throughout the specification and claims should be interpreted in a comprehensive rather than exclusive or exhaustive sense, meaning “including, but not limited to, the following.”

[0096] The terms “decrease,” “reduce,” “reduced,” “reduce,” “decrease,” and “suppress” are all used herein to generally mean a decrease of a statistically significant amount relative to a standard.

[0097] The terms “increased,” “enhance,” “improve,” or “activate” are all used in the specification to generally mean an increase of a statically significant amount relative to the standard.

[0098] As used herein, the terms “protein” and “polypeptide” are used interchangeably to refer to a set of amino acid residues, respectively, linked to one another by peptide bonds between the alpha-amino and carboxyl groups of adjacent residues. The terms “protein” and “polypeptide” also refer to polymers of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of their size or function. While “protein” and “polypeptide” are often used in reference to relatively large polypeptides, the term “peptide” is often used in reference to small polypeptides, but the use of these terms in the art is overlapping. The terms “protein” and “polypeptide” are used interchangeably herein when referring to encoded gene products and their fragments. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologues, paralogs, fragments, and other equivalents, variants, fragments, and analogs of the foregoing.

[0099] As used herein, “epitope” refers to amino acids conventionally bound by immunoglobulin VH / VL pairs, such as antibodies, their antigen-binding moieties, and other binders as described herein. Other binders include non-antibody scaffolds. Epitopes can be formed on polypeptides from juxtaposed consecutive or discontinuous amino acids by tertiary folding of the protein. Epitopes formed from consecutive amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon processing with denaturing solvents. Epitopes typically contain at least three, more commonly at least five, about nine, or about eight to ten amino acids in their unique spatial conformation. Epitopes define the minimum binding sites for antibodies, their antigen-binding moieties, and other binders, and thus represent the targets of the specificity of antibodies, their antigen-binding moieties, or other immunoglobulin binders. In the case of single-domain antibodies, the epitope represents the structural unit to which the variable domain binds alone.

[0100] As used herein, “specifically binds” means that the binder described herein (e.g., an antibody or its antigen-binding portion) binds to 10 -5 M (10000 nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 This refers to the ability to bind to a target with a KD of M or less. "Specifically binding" as used herein also means that the molecule described herein (e.g., an antibody or its antigen-binding moiety or a non-antibody scaffold) binds to the target in a specific manner. -5 M (10000 nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12This refers to the ability to bind to a target with a KD of M or less. Specific binding may be influenced, for example, by the affinity and binding activity of the antibody, antigen-binding moiety, or other binder, as well as the concentration of the target polypeptide. Those skilled in the art can determine the appropriate conditions for the selective binding of the antibodies, antigen-binding moieties, and other binders described herein to the target molecule using any suitable method, such as titration of the antibody or binder in a suitable cell-binding assay. A binder that specifically binds to a target molecule cannot be replaced by a dissimilar competitor. In certain embodiments, an antibody or its antigen-binding moiety or other binder is said to bind specifically to a target molecule if it preferentially recognizes its target molecule in a complex mixture of proteins and / or macromolecules. Specific binding may be influenced, for example, by the affinity and binding activity of the antibody, antigen-binding moiety, or non-antibody scaffold, as well as the concentration of the target polypeptide. Those skilled in the art can determine the appropriate conditions for the selective binding of the antibodies, antigen-binding moieties, and non-antibody scaffolds described herein to the target molecule using any suitable method, such as titration of the antibody or non-antibody scaffold in a suitable cell-binding assay. A molecule that specifically binds to a target molecule cannot be replaced by a dissimilar competitor. In certain embodiments, an antibody or its antigen-binding moiety or non-antibody scaffold is said to bind specifically to a target molecule if it preferentially recognizes that target molecule in a complex mixture of proteins and / or macromolecules.

[0101] Unless otherwise indicated, the term "alkyl" refers to the number of carbon atoms indicated by the given number, either by itself or as part of another term (e.g., "-C1-C5 alkyl", "-C1-C8 alkyl", or "-C1-C 10Alkyl refers to a substituted or unsubstituted linear or branched saturated hydrocarbon having an alkyl group having 1 to 5, 1 to 8, or 1 to 10 carbon atoms, respectively. Examples include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl, -CH(CH 3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-butyl, -C(CH3)3), 1-pentyl(n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(--CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1- Butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(C Examples include H3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3).

[0102] Unless otherwise indicated, “alkenyl” means, by itself or as part of another term, at least one unsaturated site (i.e., carbon-carbon, sp). 2This refers to straight-chain or branched C2-C8 substituted or unsubstituted hydrocarbons having a double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0103] Unless otherwise indicated, “alkynyl” means, by itself or as part of another term, a substituted or unsubstituted straight-chain or branched C2-C8 hydrocarbon having at least one unsaturated site (i.e., a carbon-carbon, sp triple bond). Examples include, but are not limited to, acetylene and propargyl.

[0104] Unless otherwise specified, "alkylene" refers to a saturated, branched, or linear hydrocarbon radical of 1 to 8 carbon atoms, which has two monovalent radical centers induced by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,2-ethyl (-CH2CH2-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0105] Unless otherwise specified, "alkenylene" refers to an unsaturated, branched, or linear hydrocarbon radical of 2 to 8 carbon atoms, which has two monovalent radical centers induced by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0106] Unless otherwise specified, "alkynylene" refers to an unsaturated, branched, linear, or cyclic hydrocarbon radical consisting of 2 to 8 carbon atoms, which has two monovalent radical centers induced by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene, propargyl, and 4-pentinyl.

[0107] Unless otherwise indicated, the term “heteroalkyl” means, by itself or in combination with another term, a substituted or unsubstituted stable linear or branched hydrocarbon, or a combination thereof, which is saturated and comprises 1 to 10, preferably 1 to 3, heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be located at any internal position of the heteroalkyl group (i.e., as part of the main chain) or at a position where the alkyl group is bonded to the remainder of the molecule. The heteroatom Si may be located at any position of the heteroalkyl group, including a position where the alkyl group is bonded to the remainder of the molecule. Examples of heteroalkyl groups include -CH2CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3)CH3, -CH2SCH2CH3, CH2CH2S(O)CH3, -CH2CH2S(O)2CH3, and -Si(CH3)3-. For example, up to two heteroatoms, such as -CH2NHOCH3 and CH2OSi(CH3)3, may be consecutive. In some embodiments, C1-C4 heteroalkyls have 1-4 carbon atoms and 1 or 2 heteroatoms, and C1-C3 heteroalkyls have 1-3 carbon atoms and 1 or 2 heteroatoms.

[0108] Unless otherwise indicated, the terms “heteroalkenyl” and “heteroalkynyl,” used alone or in combination with other terms, refer to a substituted or unsubstituted stable linear or branched alkenyl or alkynyl having 1 to 10, preferably 1 to 3, heteroatoms selected from the group consisting of O, N, Si, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N, and S may be located at any internal position of the heteroalkenyl or heteroalkynyl group (i.e., as part of the main chain) or at positions where the alkyl group is bonded to the remainder of the molecule. The heteroatom Si may be located at any position of the heteroalkenyl or heteroalkynyl group, including positions where the alkyl group is bonded to the remainder of the molecule.

[0109] Unless otherwise indicated, the term “heteroalkylene” refers to substituted or unsubstituted divalent groups derived from heteroalkyls, such as those exemplified by -CH2CH2SCH2CH2- and -CH2SCH2CH2NHCH2-, either by themselves or as part of another substituent (as discussed above). In some embodiments, C1-C4 heteroalkylenes have 1-4 carbon atoms and 1 or 2 heteroatoms, and C1-C3 heteroalkylenes have 1-3 carbon atoms and 1 or 2 heteroatoms. In the case of heteroalkylene groups, the heteroatoms can also occupy either or both of the chain ends. Furthermore, in the case of alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied.

[0110] Unless otherwise indicated, the terms “heteroalkenylene” and “heteroalkynylene” refer to substituted or unsubstituted divalent groups derived from heteroalkenyl or heteroalkynyl, either by themselves or as part of another substituent (as discussed above). In some embodiments, C2-C4 heteroalkenylene or heteroalkynylene has 1-4 carbon atoms. For heteroalkenylene and heteroalkynylene groups, the heteroatoms can also occupy either or both of the chain ends. Furthermore, for alkylene and heteroalkenylene and heteroalkynylene linking groups, the orientation of the linking group is not implied.

[0111] Unless otherwise indicated, “C3-C8 carbocyclic ring” refers, by itself or as part of another term, to a substituted or unsubstituted 3, 4, 5, 6, 7, or 8-membered monovalent substituted or unsubstituted saturated or unsaturated non-aromatic monocyclic or bicyclic carbocyclic ring derived by removing one hydrogen atom from a ring atom of the parent ring system. Representative C3-C8 carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrielinyl, cyclooctyl, and cyclooctadienyl.

[0112] Unless otherwise indicated, “C3-C8 carbocyclo” refers, by itself or as part of another term, to a substituted or unsubstituted C3-C8 carbocyclic group, where another hydrogen atom of the carbocyclic group is replaced by a bond (i.e., it is divalent).

[0113] Unless otherwise specified, "C3-C 10A "carbocyclic ring" refers, either by itself or as part of another term, to a substituted or unsubstituted 3, 4, 5, 6, 7, 8, 9, or 10-membered monovalent substituted or unsubstituted saturated or unsaturated non-aromatic monocyclic, bicyclic, or tricyclic carbocyclic ring, which is induced by removing one hydrogen atom from the ring atom of the parent ring system. A typical example is -C3-C 10 Examples of carbocyclic compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrielinyl, cyclooctyl, and cyclooctadienyl. -C3-C 10 The carbocyclic rings may further include condensed cyclooctinate carbocyclic rings such as condensed cyclooctinate compounds disclosed in International Publication No. 2011 / 136645 (the disclosure of which is incorporated herein by reference), including BCN (bicyclo[6.1.0]nonine) and DBCO (dibenzocyclooctin).

[0114] Unless otherwise specified, “C3-C8 heterocycle” refers, by itself or as part of another term, to a monocyclic or bicyclic ring system having 3 to 8 carbon atoms (also called ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P, or S, which is substituted or unsubstituted monovalent substituted or unsubstituted aromatic or unaromatic monocyclic or bicyclic ring system induced by removing one hydrogen atom from the ring atoms of the parent ring system. One or more N, C, or S atoms in the heterocycle can be oxidized. Rings containing heteroatoms can be aromatic or unaromatic. Unless otherwise specified, the heterocycle is bonded to its pendant group by any heteroatom or carbon atom that results in a stable structure. Representative examples of C3-C8 heterocycles include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridadinyl, isothiazolyl, and isoxazolyl. Unless otherwise indicated, the term “heterocarbon ring” is synonymous with the terms “heterocycle” or “heterocyclo” as used herein.

[0115] Unless otherwise indicated, “C3-C8 heterocyclo” refers, by itself or as part of another term, to a substituted or unsubstituted C3-C8 heterocyclic group defined as one of the hydrogen atoms of the heterocyclic group being replaced by a bond (i.e., it is divalent).

[0116] Unless otherwise indicated, “aryl” means, by itself or as part of another term, a substituted or unsubstituted monovalent carbocyclic aromatic hydrocarbon radical of 6 to 20 carbon atoms (preferably 6 to 14 carbon atoms) derived by removing one hydrogen atom from a single carbon atom of an aromatic ring system. Some aryl groups are represented as “Ar” in exemplary structures. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzenes, naphthalenes, anthracenes, biphenyls, and others. An exemplary aryl group is the phenyl group.

[0117] Unless otherwise indicated, “arylene” is defined, either by itself or as part of another term, as an unsubstituted or substituted aryl group in which one of the hydrogen atoms of the aryl group is replaced by a bond (i.e., it is divalent) and which can be ortho, meta, or para oriented.

[0118] Unless otherwise specified, “heteroaryl” refers to a ring system in which one or more ring atoms are heteroatoms, such as nitrogen, oxygen, and sulfur. Heterocyclic radicals contain 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. Heterocyclic rings can be monocyclic rings with 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or dicyclic rings with 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S), such as bicyclo[4,5], [5,5], [5,6], or [6,6] systems.

[0119] Unless otherwise indicated, “heteroarylene” is defined, either by itself or as part of another term, as an unsubstituted or substituted heteroaryl group on which one of the hydrogen atoms of the heteroaryl group is replaced by a bond (i.e., it is divalent).

[0120] Unless otherwise specified, "carboxyl" is COOH or COO - M + It refers to M+ is a cation.

[0121] Unless otherwise specified, "oxo" refers to (C=O).

[0122] Unless otherwise specified, "substituted alkyl" and "substituted aryl" refer to alkyl and aryl, respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Exemplary substituents include, but are not limited to, -X, -R 10 , -O - , -OR 10 , -SR 10 , -S - , -NR 10 2, -NR 10 3, =NR 10 , -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, -NR 10 C(=O)R 10 , -C(=O)R 10 , -C(=O)NR 10 2, -SO3 - , -SO3H, -S(=O)2R 10 , -OS(=O)2OR 10 , -S(=O)2NR 10 , -S(=O)R 10 , -OP(=O)(OR 10 )2, -P(=O)(OR 10 )2, -PO - 3, -PO3H2, -AsO2H2, -C(=O)R 10 , -C(=O)X, -C(=S)R 10 , -CO2R 10 , -CO2 - , -C(=S)OR 10 , C(=O)SR 10 , C(=S)SR 10 , C(=O)NR 10 2, C(=S)NR 10 2 or C(=NR 10 )NR 10 2, without being limited thereto, each X is independently halogen: -F, -Cl, -Br or -I; each R 10 is independently -H, -C1-C20 Alkyl, -C6-C 20 Ariel, -C3-C 14 These are heterocyclic rings, protecting groups, or prodrug moieties. Typical substituents include (=O). The alkylene, carbocyclic, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocyclic, and heterocyclo groups mentioned above may also be substituted in the same manner.

[0123] Unless otherwise specified, “polyhydroxyl group” refers to an alkyl, alkylene, carbocyclic, or carbocyclo group comprising two or more or three or more hydroxyl group substitutions on hydrogen atoms on carbon atoms of a carbon chain. In some embodiments, the polyhydroxyl group comprises at least three hydroxyl groups. In some embodiments, the polyhydroxyl group comprises carbon atoms containing only one hydroxyl group per carbon atom. The polyhydroxyl group may contain one or more carbon atoms that are not substituted with hydroxyl. The polyhydroxyl group may have each carbon atom substituted with a hydroxyl group. Examples of polyhydroxyl groups include linear (acyclic) or cyclic forms of monosaccharides such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, glucose, idose, talose, aldose, and ketose; sugar acids such as gluconic acid, aldonic acid, uronic acid, or uronic acid; and amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. In some embodiments, the polyhydroxyl group includes linear or cyclic forms of disaccharides and polysaccharides.

[0124] Unless otherwise indicated by context, “optionally substituted” means alkyl, alkenyl, alkynyl, alkylaryl, arylalkyl heterocycle, aryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, or other substituents, moieties, or groups defined or disclosed herein in which a hydrogen atom of the substituent, moiety, or group is optionally replaced by a different moiety or group, or an alicyclic carbon chain containing one of those substituents, moieties, or groups is interrupted by replacing a carbon atom of the chain with a different moiety or group. In some embodiments, unless the radical carbon of the alkyl moiety is replaced, the alkene functional group replaces two consecutive sp3 carbon atoms of the alkyl substituent, and as a result the optionally substituted alkyl is an unsaturated alkyl substituent.

[0125] The optional substituents that replace any one hydrogen of the aforementioned substituents, parts, or groups are independently selected from the group consisting of aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, cyano, halogen, nitro, fluoroalkoxy, and amino (including monosubstituted, disubstituted, and trisubstituted amino groups) and their protected derivatives, or -X, -OR', -SR', -NH2, -N(R')(R''), -N(R'')3, =NR, -CX3, -CN, -NO2, -NR'C(=O)H, -NR'C(=O)R, -NR'C(=O)R'', -C(=O)R', -C(=O)NH2, -C(=O)N(R')R'', -S(=O)2R'', -S(=O)2N H2, -S(=O)2N(R')R'', -S(=O)2NH2, -S(=O)2N(R')R'', -S(=O)2OR', -S(=O)R'', -OP(=O) (OR')(OR''), -OP(OH)3, -P(=O)(OR')(OR''), -PO3H2, -C(=O)R', -C(=S)R'', -CO2R', -C( -C(=O)OR'', -C(=S)SR', -C(=S)SR', -C(=S)NH2, -C(=S)N(R')(R'')2, -C(=NR')NH2, -C(=NR')N(R')R'' and their salts are selected, and each X is independently selected from the group consisting of halogens: -F, -CI, -Br and -I; each R'' is C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkinyl, C6-C 24 Ariel, C3-C 24 Heterocycline (C5-C 24 R'' is independently selected from the group consisting of a protecting group and a prodrug moiety (including heteroaryl groups), or two R''s together with the heteroatom to which they are bonded define a heterocycline; R' is hydrogen or R'', and R'' is C1-C 20 Alkyl, C6-C 24 Ariel, C3-C 24 Heterocycline (C5-C 24 Selected from the group consisting of heteroaryl groups and protecting groups.

[0126] Typically, optional substituents include -X, -OH, -OR'', -SH, -SR'', -NH2, -NH(R''), -NR'(R'')2, -N(R'')3, =NH, =NR'', -CX3, -CN, -N O2, -NR'C(=O)H, NR'C(=O)R'', -CO2H, -C(=O)H, -C(=O)R'', -C(=O)NH2, -C(=O)NR'R''--S(=O)2R'', -S(=O)2NH2, The group is selected from -S(=O)2N(R')R'', -S(=O)2NH2, -S(=O)2N(R')(R''), -S(=O)2OR', -S(=O)R'', -C(=S)R'', -C(=S)NH2, -C(=S)N(R')R'', -C(=NR')N(R'')2 and their salts, where each X is independently selected from the group consisting of -F and -Cl, and R'' is typically C1-C6 alkyl, C6-C 10 Ariel, C3-C 10 Heterocyclyl (C5-C 10 R' is selected from the group consisting of heteroaryl groups and protecting groups; R' is independently hydrogen, C1-C6 alkyl, C6-C 10 Ariel, C3-C 10 Heterocyclyl (C5-C 10 A protecting group that is independently selected from (including heteroaryls) and R''. More typically, substituents are selected from the group consisting of -X, -R'', -OH, -OR'', -NH2, -NH(R''), -N(R'')2, -N(R'')3, -CX3, -NO2, -NHC(=O)H, -NHC(=O)R'', -C(=O)NH2, -C(=O)NHR'', -C(=O)N(R'')2, -CO2H, -CO2R'', -C(=O)H, -C(=O)R'', -C(=O)NH2, -C(=O)NH(R'''), -C(=O)N(R'')2, -C(=')NH2, -C(=NR')NH(R''), -C(=NR')N(R'')2, protecting groups and their salts, where each X is -F and R'' is C1-C6 alkyl, C6-C 10 Aryl, C5-C 10 R' is independently selected from the group consisting of heteroaryls and protecting groups; R' is independently selected from the group consisting of hydrogen, C1-C6 alkyls and R'' protecting groups.

[0127] The term "pharmaceutically acceptable salt," as used herein, refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a linker, drug linker, or conjugate). The compound typically contains at least one amino group, and therefore can form an acid addition salt with this amino group. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbicates, succinates, linoleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may involve the inclusion of other molecules such as acetate ions, succinate ions, or other counterions. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have two or more charged atoms in its structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0128] As used herein, the term "essentially consisting of" refers to elements necessary for a given embodiment. This term allows for the presence of elements that do not substantially affect the basic and novel or functional characteristics of that embodiment.

[0129] As used herein, the term "consisting of" refers to the compositions, methods, and their respective components described herein, excluding any elements not described in the description of the embodiments.

[0130] Except in the examples or unless otherwise indicated, all figures representing amounts of components or reaction conditions used herein should be understood to be modified in all cases by the term “approximately.” When used in relation to percentages, the term “approximately” may mean + / - 1%.

[0131] The terms "statistically significant" or "significant" refer to statistical significance, which generally means a difference of two standard deviations (2SD) above or below a baseline value.

[0132] Other terms are defined herein within the scope of describing various aspects of the present invention.

[0133] Linkers comprising polar units such as sugar units, PEG units, and / or carboxyl units are provided herein. Targeted unit-linkers, drug linkers, and their conjugates comprising drug units such as cytotoxic agents or immunomodulators are also provided herein, as further described herein.

[0134] In some embodiments, the linker comprises a stretcher unit (L1) attached directly or via an optional amino acid unit (AA) to a linker subunit (L2) as shown in the following formula (I): [ka] (In the formula, s is 0 or 1, and the dashed line is ( [ka] The linker has a binding site for a targeting unit (L) or a drug unit (D), or a salt thereof. The linker contains at least one polar unit within an amino acid unit, a linker subunit L2, or both. Each polar unit may be a sugar unit, a PEG unit, or a carboxyl unit. The linker may contain at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 may have 1 to 4 binding sites for the drug unit. In some embodiments, the linker subunit L2 has one binding site for the drug unit. In some embodiments, the linker subunit L2 has two binding sites for the drug unit.

[0135] A linker conjugate is also provided, comprising a targeting unit (L) bound to at least one linker, as shown in the following formula (II), where each linker is bound to at least one drug unit (D): L-[[L1-AA s -L2]-D t ] pload (II) (In the formula, L1, AA and L2 include linkers, as described above with respect to formula (I), s is 0 or 1, t is 1 to 4, p load (The value is 1 to 20). The linker contains at least one polar unit within the amino acid unit, the linker subunit L2, or both. Each polar unit may be a sugar unit, a PEG unit, or a carboxyl unit. The linker may contain at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 may have 1 to 4 binding sites for the drug unit. In some embodiments, the linker subunit L2 has one binding site for the drug unit. In some embodiments, the linker subunit L2 has two binding sites for the drug unit.

[0136] The following equation (III) ~[L1-AAs -L2]-D t (III) Drug-linkers represented by formulas (wherein L1, AA, L2, and D comprise the linker, as described above with respect to formula (II), where s is 0 or 1, t is 1 to 4, and the dashed line indicates a binding site for the targeting unit) or by salts thereof are also provided. The linker comprises at least one polar unit within an amino acid unit, linker subunit L2, or both. Each polar unit may be a sugar unit, a PEG unit, or a carboxyl unit. The linker may contain at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 may have 1 to 4 binding sites for the drug unit. In some embodiments, the linker subunit L2 has one binding site for the drug unit. In some embodiments, the linker subunit L2 has two binding sites for the drug unit.

[0137] The following equation (IV): [ka] (In the formula, L1, AA and L2 include linkers, L, L1, AA and L2 are as above with respect to formula (I), s is 0 or 1, d is 1 to 20, and double dashes ( [ka] Further provided are intermediates of a targeted unit-linker, indicated by a binding site for a drug unit (L2) or a salt thereof. The linker contains at least one polar unit within an amino acid unit, a linker subunit L2, or both. Each polar unit may be a sugar unit, a PEG unit, or a carboxyl unit. The linker may contain at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 may have 1 to 4 binding sites for a drug unit. In some embodiments, the linker subunit L2 has one binding site for a drug unit. In some embodiments, the linker subunit L2 has two binding sites for a drug unit.

[0138] Polarity unit The polar units (PUs) provided herein include sugar units, PEG units, and carboxyl units, as further described herein.

[0139] Sugar unit (SU) In some embodiments, the sugar unit (SU) is represented by the general formula (X): L3-**N(CH2-(CH(XR)) k -X1(X2))2 (X) (wherein each X is independently selected from NH or O, each R is independently selected from hydrogen, acetyl, monosaccharide, disaccharide and polysaccharide, each X1 is independently selected from CH2 and C(O), each X2 is independently selected from H, OH and OR, and k is 1 to 10) or a salt thereof. In some embodiments, each (CH2-(CH(XR)) k-X1(X2)) is a monosaccharide. In some embodiments, the monosaccharide is a C6 or C5 sugar, such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, glucose, idostalose, aldose, ketose, sugar acids, such as gluconic acid, aldonic acid, uronic acid or urosonic acid, or amino sugars, such as glucosamine, N-acetylglucosamine, galactosamine and N-acetylgalactosamine. Preferred disaccharides include sucrose, lactose and maltose. Preferred polysaccharides include maltotriose, raffinose, kestose, starch, cellulose and glycogen. The stereochemistry at the anomeric C-1 position can be either alpha or beta.

[0140] L3 has the following general formula (XI): L3a | *-NH-(CH2) p -CH-(CH2) o -C(O)-# (XI) (In the formula, L3a is C1-C 10 Selected from alkylenes and polyethylene glycol (having 1 to 26 ethylene glycol units), where p and o are independently 0 to 2, and L3a is covalently bonded to the N atom marked a** in formula (X). Each * and each # indicates a binding site for an amino acid unit (AA) or linker subunit (L2), stretcher unit (L1), or another subunit of another component of the linker, as described herein.

[0141] In some embodiments, the sugar unit has the following formula (XII): [ka] (In the formula, R, p, and o are as described above, n is between 0 and 4, and each m is independently between 1 and 4).

[0142] In some embodiments, the sugar unit has the following formula (XIII): [ka] (In the formula, n is between 0 and 4, and each m is independently between 1 and 4).

[0143] PEG units In some embodiments, the linker includes a PEG unit. The PEG unit may be bound to a subunit of an amino acid unit or to a portion of the linker subunit L2. The subunit of the amino acid unit may be, for example, an alpha, beta, or gamma amino acid or a derivative thereof. In some embodiments, the PEG unit may be bound to a stretcher unit.

[0144] In some embodiments, the PEG unit is represented by the following general formula -(CH2CH2O) n20 -R 24 It has, in the formula, R 24 is H or C1-C6 alkyl, and n20 is 1-26. In some cases, n20 is 12, and R 24 It is methyl.

[0145] In some embodiments, the PEG unit is given by the following general formula (XX): ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 21 and R 22 These are, independently, anyly selected C1-C3 alkylenes; R 24 and R 25The following is shown; the dashed line (~) indicates the bonding site; n20 is 1 to 26) or has a salt thereof. In some embodiments, R 20 The protecting group is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0146] In some embodiments, the PEG unit is given by the following general formula (XX): ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 21 and R 22 These are, independently, anyly selected C1-C3 alkylenes; R 24 and R 25 The following is shown; the dashed line (~) indicates the bonding site; n20 is 1 to 26) or has a salt thereof. In some embodiments, R 20 The protecting group is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0147] In some embodiments, the PEG unit is given by the following general formula (XXI): ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXI) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 26 and R 27 These are C1-C, each an optional choice. 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)- or -C(O)-C1-C 12 It is alkylene-NH-;R 24 and R 25 The following applies to each R: 29 is optional and independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH- and -C1-C6 alkenylene-C(O)-; the dashed line (~) indicates the binding site; n20 is 1-26; n21 is 1-4; n27 is 1-3) or a salt thereof. In some embodiments, R 20 The protecting group is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0148] In some embodiments, the PEG unit is given by the following general formula (XXI): ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXI) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 26 and R 27 These are C1-C, each an optional choice. 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)- or -C(O)-C1-C 12 It is alkylene-NH-;R 24 and R 25 The following applies to each R: 29 is optional and independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH-, -C1-C6 alkenylene-C(O)-, -NH(CO)NH- and triazole; the dash (~) indicates the binding site; n20 is 1-26; n21 is 1-4; n27 is 1-3) or a salt thereof. In some embodiments, R 20 The protecting group is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0149] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 These are, respectively, H and polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; and optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 (is a sugar unit of formula (XII) or (XIII)) is selected independently of or -NR 24 R 25 These are linked from the C3-C8 complex algebra.

[0150] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 One of them is H and polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C3-C 10 Carbon ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocyclic; optionally substituted heteroaryl; optionally substituted carbocyclic; substituted-C1-C8 alkyl; substituted-C(O)-C1-C8 alkyl; chelating agent; -C(O)-R 28 (In the formula, R 28 is selected from the sugar units of formula (XII) or (XIII), and R 24 and R 25 The other is optionally polyethylene glycol having 1 to 24 ethylene glycol subunits.

[0151] In some embodiments of the PEG units of formula (XX) or (XXI), R 24 and R 25Neither of them is H. In some embodiments of the PEG unit of formula (XX) or (XXI), R 24 and R 25 One of them is H.

[0152] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 Each is independently selected from H and polyhydroxyl groups, however, R 24 and R 25 Provided that neither of the atoms is H. The polyhydroxyl group can be linear or branched. In some embodiments, the polyhydroxyl group comprises at least three hydroxyl groups. In some embodiments, the polyhydroxyl group is a linear monosaccharide. As used herein, linear monosaccharide refers to the ring-opened form of a monosaccharide. In some embodiments, the linear monosaccharide is the linear form of a C6 or C5 sugar such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, growth, idostalose, aldose, and ketose. In some embodiments, the linear monosaccharide may further comprise sugar acids such as gluconic acid, aldonic acid, uronic acid, or urosonic acid. In some embodiments, the linear monosaccharide may further comprise amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0153] Examples of PEG units containing linear monosaccharides include: [ka] [ka] (In the formula, R 39(The PEG is selected from H, linear monosaccharides, and polyethylene glycol). In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or a portion of linker subunit L2, it is deprotected as necessary, and a bond is formed between the carboxyl or hydroxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or a portion of linker subunit L2.

[0154] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 Each is independently selected from H and polyhydroxyl groups, however, R 24 and R 25 Provided that neither of them is H. In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 One of the components is selected from polyhydroxyl groups, and the other is polyethylene glycol. In some embodiments, each polyhydroxyl group contains at least three hydroxyl groups. The polyhydroxyl groups can be linear, branched, or cyclic. In some embodiments, R 24 and R 25 One is a linear monosaccharide, and the other is a cyclic monosaccharide. In some embodiments, R 24 and R 25One is a cyclic monosaccharide, and the other is a linear or cyclic monosaccharide. In some embodiments, the linear monosaccharide is a linear (acyclic) form of C6 or C5 sugars such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, allulose, glucose, idostalose, aldose, and ketose. In some embodiments, the linear monosaccharide may further include sugar acids such as gluconic acid, aldonic acid, uronic acid, or urosonic acid. In some embodiments, the linear monosaccharide may further include amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. In some embodiments, the cyclic monosaccharide is a cyclic form of C6 or C5 sugars such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, glucose, idose, talose, aldose, and ketose. In some embodiments, the cyclic monosaccharide may further contain sugar acids such as gluconic acid, aldonic acid, uronic acid, or urosonic acid. In some embodiments, the cyclic monosaccharide may further contain amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. The stereochemistry at the anomeric C-1 position may be either alpha or beta.

[0155] Examples of PEG units include: [ka] (In the formula, R 41 (These are linear monosaccharides, cyclic monosaccharides, or polyethylene glycol). In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or a portion of linker subunit L2, it is deprotected as necessary, and a bond is formed between the carboxyl or hydroxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or a portion of linker subunit L2.

[0156] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 Each is independently selected from H and polyhydroxyl groups, however, R 24 and R 25 The condition is that neither of them is H. In some embodiments, R 24 and R 25 Each of these is a cyclic monosaccharide, disaccharide, or polysaccharide. In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 One of them is selected from cyclic monosaccharides, disaccharides, or polysaccharides, R 24 and R 25 The other is polyethylene glycol. In some embodiments, the cyclic monosaccharide is a cyclic form of a C6 or C5 sugar such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, glucose, idose, talose, aldose, and ketose. In some embodiments, the cyclic monosaccharide may further contain sugar acids such as gluconic acid, aldonic acid, uronic acid, or urosonic acid. In some embodiments, the cyclic monosaccharide may further contain amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. The stereochemistry at the anomeric C-1 position may be either alpha or beta.

[0157] In some embodiments, disaccharides include those containing any of the monosaccharides described above. The term disaccharide may include linear, cyclic, and linear-cyclic forms of disaccharides. Exemplary disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, and cellobiose. In some embodiments, polysaccharides include those containing any of the monosaccharides described above. The term polysaccharide may include linear, cyclic, and linear-cyclic forms of polysaccharides. Exemplary polysaccharides include, but are not limited to, maltotriose, raffinose, kestose, starch, cellulose, and glycogen.

[0158] In exemplary embodiments, PEG units having a cyclic monosaccharide, disaccharide, or polysaccharide include: [ka]

[0159] In each of these examples, each R 45 H is selected from a polysaccharide containing a monosaccharide, disaccharide, or any of these amino sugars, and R 46- This is selected from H, or a polysaccharide containing a monosaccharide, disaccharide, or any of these amino sugars, and polyethylene glycol. In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected as necessary to form a bond between the carboxyl group at the right end (first four examples) or left end (last example) of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0160] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 Each is independently selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide. In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25One of them is selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide, R 24 and R 25 The other is polyethylene glycol. In some embodiments, the linear monosaccharide is a linear form of C6 or C5 sugar such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gros, idostalose, aldose, and ketose. In some embodiments, the linear monosaccharide may further include sugar acids such as gluconic acid, aldonic acid, uronic acid, or urosonic acid. In some embodiments, the linear monosaccharide may further include amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0161] In some embodiments, the substituted linear monosaccharide may be substituted with a monosaccharide, disaccharide, or polysaccharide, which in any case may be linear or cyclic. In some embodiments, the disaccharide may contain any of the monosaccharides described above. The term disaccharide may include the linear, cyclic, and linear-cyclic forms of the disaccharide. Exemplary disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, and cellobiose. In some embodiments, the polysaccharide may contain any of the monosaccharides described above. The term polysaccharide may include the linear, cyclic, and linear-cyclic forms of the polysaccharide. Exemplary polysaccharides include, but are not limited to, maltotriose, raffinose, kestose, starch, cellulose, and glycogen.

[0162] Examples of PEG units containing linear monosaccharides optionally substituted with sugars include: [ka] (In the formula, R 47 R is selected from H, linear monosaccharides and polyethylene glycol, and each R 49(These are selected from monosaccharides, disaccharides, and polysaccharides). In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or a portion of the linker subunit L2, it is deprotected as necessary, and a bond is formed between the carboxyl or hydroxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or a portion of the linker subunit L2.

[0163] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 Each is independently selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide, and the substituted linear monosaccharide is substituted with one or more substituents such as alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, or amide. In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 One of the groups is selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide, and the substituted linear monosaccharide is substituted with one or more substituents such as alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester or amide, R 24 and R 25 The other is polyethylene glycol. Such substituted polyhydroxyl groups may optionally be further substituted with monosaccharides, disaccharides, or polysaccharides.

[0164] In exemplary embodiments, a PEG unit having a polyhydroxyl group, including a linear monosaccharide or a substituted linear monosaccharide, includes: [ka]

[0165] In each of these examples, each R 42 H is independently selected from monosaccharides, disaccharides or polysaccharides as described herein, or polyethylene glycol, and each R 43The group is selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, or amide. In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0166] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 At least one of them is a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group, R 24 and R 25 The other is a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group, a polyhydroxyl group, or a substituted polyhydroxyl group. In some embodiments, the substituted -C(O)-polyhydroxyl group and the polyhydroxyl group may be substituted with monosaccharides, disaccharides, or polysaccharides (either linear or cyclic in any case); alkyl; O-alkyl; aryl; carboxyl; ester; or amide. In some embodiments, disaccharides include those containing any of the above monosaccharides. The term disaccharide may include the linear, cyclic, and linear-cyclic forms of disaccharides. Exemplary disaccharides include, but are not limited to, sucrose, lactose, maltose, trehalose, and cellobiose. In some embodiments, polysaccharides include those containing any of the above monosaccharides. The term polysaccharide may include the linear, cyclic, and linear-cyclic forms of polysaccharides. Exemplary polysaccharides include, but are not limited to, maltotriose, raffinose, kestose, starch, cellulose, and glycogen.

[0167] In exemplary embodiments, PEG units having a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group include: [ka]

[0168] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0169] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 is selected independently of H and substituted C1-C8 alkyl, however, R 24 and R 25 The condition is that neither of them is H. In some embodiments, R 24 and R 25 is independently selected from H and substituted C1-C4 alkyl groups, however, R 24 and R 25 The condition is that neither of them is H. In some embodiments, R 24 and R 25 is independently selected from H and substituted C1-C3 alkyl groups, however, R 24 and R 25 The condition is that neither of them is H. The alkyl moieties of substituted -C1-C8, -C1-C4, and -C1-C3 alkyls can be linear or branched.

[0170] Substituting -C1-C8, -C1-C4, or -C1-C3 alkyls can be substituted with hydroxyl or carboxyl. In some embodiments, each carbon atom of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl is substituted with hydroxyl or carboxyl. In some embodiments, each carbon atom of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl is substituted with carboxyl. In some embodiments, one or two carbon atoms of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl are substituted with hydroxyl or carboxyl. In some embodiments, one or two carbon atoms of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl are substituted with carboxyl. In some embodiments, the terminal carbon atoms of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl are substituted with carboxyl. In some embodiments, the terminal carbon atoms of substituted -C1-C8, -C1-C4, or -C1-C3 alkyl groups are substituted with hydroxyls.

[0171] Exemplary embodiments of PEG units having substituted -C1-C8, -C1-C4, or -C1-C3 alkyl groups are as follows: [ka] [ka] (In the formula, R 48 (The group can be H, OH, CH2OH, COOH, or a C1-C6 alkyl group substituted with hydroxyl and / or carboxyl). In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0172] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25One of them is selected from H and substituted-C(O)-C1-C8 alkyl, R 24 and R 25 The other is selected from substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl and -C(O)-C1-C3 alkyl, as well as substituted -C1-C8 alkyl, -C1-C4 alkyl and -C1-C3 alkyl (as described above). In some embodiments, R 24 and R 25 One of them is independently selected from H and substituted-C(O)-C1-C4 alkyl, and R 24 and R 25 The other is selected from substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl and -C(O)-C1-C3 alkyl, as well as substituted -C1-C8 alkyl, -C1-C4 alkyl and -C1-C3 alkyl (as described above). In some embodiments, R 24 and R 25 One of them is selected from H and substituted-C(O)-C1-C3 alkyl, R 24 and R 25 The other is selected from substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl and -C(O)-C1-C3 alkyl, as well as substituted -C1-C8 alkyl, -C1-C4 alkyl and -C1-C3 alkyl (as described above). The alkyl in substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C8 alkyl and -C(O)-C1-C8 alkyl can be linear or branched. The alkyl portion of substituted -C1-C8, -C1-C4 and -C1-C3 alkyl can be linear or branched.

[0173] Substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C3 alkyl can be substituted with hydroxyl or carboxyl. In some embodiments, each carbon atom of the substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C4 alkyl is substituted with hydroxyl or carboxyl. In some embodiments, one or two carbon atoms of the substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C3 alkyl are substituted with hydroxyl or carboxyl. In some embodiments, one or two carbon atoms of the substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C3 alkyl are substituted with carboxyl. In some embodiments, the terminal carbon atoms of substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C3 alkyl are substituted with carboxyls. In some embodiments, the terminal carbon atoms of substituted -C(O)-C1-C8 alkyl, -C(O)-C1-C4 alkyl, and -C(O)-C1-C3 alkyl are substituted with hydroxyls.

[0174] Exemplary embodiments of such PEG units include: [ka] [ka]

[0175] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0176] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25is selected from H and optionally substituted aryls, however R 24 and R 25 The condition is that neither of them is H. In some embodiments, the substituted aryl includes aryls substituted with halogens (such as chloro, fluoro, and bromo).

[0177] In exemplary embodiments, the PEG unit containing the substituted aryl includes: [ka]

[0178] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0179] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 These combine to form an optionally substituted C3-C8 heterocycle or heteroaryl. In some embodiments, the optionally substituted substituents include halogen-substituted heterocycles or aryls (such as chloro, fluoro, and bromo).

[0180] In exemplary embodiments, a PEG unit containing an optionally substituted C3-C8 heterocycle includes: [ka]

[0181] In this exemplary embodiment, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0182] In some embodiments of the PEG units of formulas (XX) and (XXI), R 24 and R 25 The is selected independently of H and the chelating agent, however, R 24 and R 25 The condition is that neither of them is H. In some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-,N,N',N'',N'''-tetraacetic acid (DOTA), benzyl-DOTA,1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), benzyl-NOTA,1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), and N,N'-dialkylsubstituted piperazines. In some embodiments, the chelating agent is -NR 24 R 25 It is directly bonded to the nitrogen. In some embodiments, the chelating agent is bonded via alkylene, arylene, carbocyclo, heteroarylene, or heterocarbocyclo (either substituted or unsubstituted in any case).

[0183] In some exemplary embodiments, the PEG unit containing a chelating agent includes: [ka]

[0184] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0185] In some embodiments of the PEG units of formulas (XX), (XXI), (XXX), (XXXI), (XXXII), and (XXXIII), the chelating agent is R as described herein. 24 , R 25 and / or R 30 It can be added to any of the groups. In some embodiments, the chelating agent is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-,N,N',N'',N'''-tetraacetic acid (DOTA), benzyl-DOTA, 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA), benzyl-NOTA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), and N,N'-dialkyl-substituted piperazines. In some embodiments, the chelating agent is R as described herein. 24 , R 25 or R 30 It is directly bonded to the base. In some embodiments, the chelating agent is bonded via alkylene, arylene, carbocyclic, heteroaryl, or heterocarbosyl (either substituted or unsubstituted in any case).

[0186] In some embodiments, the PEG unit has the following general formula (XXX): ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -R 30 (XXX) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 21 and R 22 These are each of any selected C1-C3 alkylene groups; R 30 C3-C, which was replaced by optional substitution. 10Carbocyclic; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfamide; alkylsulfamide; acylsulfamide, optionally substituted alkylsulfamide; optionally substituted acylsulfamide; sulfonamide; optionally substituted sulfonamide; guanidine (including alkyl and arylguanidine); phosphoramide; or optionally substituted phosphoramide (selected from these); tildes (~) indicate binding sites; n20 is 1-26). In some embodiments, R 20 The protecting group is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0187] In some embodiments, the PEG unit has the following general formula (XXX): ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -R 30 (XXX) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit and / or part of the linker subunit L2; 21 and R 22 These are each of any choice of C1-C3 alkylene groups; R 30 C3-C, which was replaced by optional substitution. 10Carbocyclic; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfamide; alkylsulfamide; acylsulfamide, optionally substituted alkylsulfamide; optionally substituted acylsulfamide; sulfonamide; optionally substituted sulfonamide; guanidine (including alkyl and arylguanidine); phosphoramide; or optionally substituted phosphoramide; the dash (~) indicates the binding site; n20 is 1 to 26). In some embodiments, R 20 The protecting group is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0188] In some embodiments of the PEG units of formula (XXX), R 30 C3-C, which was replaced by optional substitution. 10 It is a carbon ring. In some embodiments, it is optionally substituted with C3-C 10 The carbocyclic compounds are condensed cyclooctin compounds disclosed in International Publication No. 2011 / 136645 (the disclosure of which is incorporated herein by reference). Exemplary PEG units having condensed cyclooctin are shown below. [ka]

[0189] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected as necessary, and a bond is formed between the carboxyl group or amino group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or portion of linker subunit L2.

[0190] As those skilled in the art will understand, the above compounds and other compounds disclosed in International Publication No. 2011 / 136645 can be used as intermediates for click chemistry for the linking of further compounds. In some embodiments, the further compounds are drug units. In some embodiments, the further compounds are linker subunits L2 as described herein.

[0191] In some embodiments of the PEG units of formula (XXX), R 30 This is thiourea; substituted thiourea, urea, or substituted urea. The thiourea and urea groups may be substituted, for example, with optionally substituted alkyl groups, optionally substituted carbocyclic groups, or optionally substituted aryl groups.

[0192] Exemplary PEG units containing thiourea; substituted thiourea; urea; or substituted urea include: [ka]

[0193] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0194] In some embodiments of the PEG units of formula (XXX), R 30 These are sulfamides; alkylsulfamides; acylsulfamides, optionally substituted alkylsulfamides; optionally substituted acylsulfamides; sulfonamides; or optionally substituted sulfonamides. Optionally substituted alkylsulfamides; optionally substituted acylsulfamides; and optionally substituted sulfonamides may be substituted with additional groups, such as linkers, drug or other compound binding groups, to enhance solubility or, in other embodiments, with further groups.

[0195] Examples of PEG units including sulfamides; alkylsulfamides; acylsulfamides, optionally substituted alkylsulfamides; optionally substituted acylsulfamides; sulfonamides; or optionally substituted sulfonamides include: [ka]

[0196] In these examples, R 50 These can be, for example, optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl groups. In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0197] In some embodiments of the PEG units of formula (XXX), R 30 This is guanidine or optionally substituted guanidine. Optionally substituted guanidine can be substituted with optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl atoms.

[0198] Exemplary PEG units containing guanidine or optionally substituted guanidine include: [ka]

[0199] In these examples, R 55These can be, for example, optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl groups. In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected as necessary, and a bond is formed between the leftmost carboxyl group of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0200] In some embodiments of the PEG units of formula (XXX), R 30 This is a phosphoramide or an optionally substituted phosphoramide. The optionally substituted phosphoramide may be substituted with optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl atoms.

[0201] Exemplary PEG units containing phosphoramide or optionally substituted phosphoramide include: [ka] In these examples, R 60 This can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl. 61 These can be, for example, optionally substituted alkyl, alkenyl, alkynyl, carbocyclic, aryl, heterocarbocyclic, or heteroaryl groups. In these exemplary embodiments, if the PEG unit is bonded to a subunit of the amino acid unit or part of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or part of linker subunit L2.

[0202] In some embodiments of the PEG unit of formula (XXX), the PEG unit includes a functional group for attaching further parts. In some embodiments of the PEG unit of formula (XXX), R 30These include azide, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, and -NH-C(O)-alkynyl-R 65 ;Cyclooctin; Selected from -NH-cyclooctin, -NH-C(O)-cyclooctin or -NH-(cyclooctin)2;R 65 The PEG unit is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted aryl, optionally substituted heterocarbocyclic, or optionally substituted heteroaryl. In some embodiments, such PEG units can be used as intermediates for click chemistry to link further compounds. In some embodiments, the further compound is a drug unit. In some embodiments, the further compound is a linker subunit L2 as described herein. In some embodiments, the further compound is another linker or drug linker.

[0203] Exemplary PEG units containing azide, alkynyl, or cyclooctin groups include: [ka] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0204] In some embodiments, the PEG unit is given by the following formula: ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) ~R 20 -R 21 -[O-CH2-CH2] n20 -R22 -C(O)NH-R 31 (XXXII) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NC(O)-R 31 (XXXIV) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -C(O)NH-R 31 (XXXV) or ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXXVI) (In the formula, R 20 R is a functional group for binding to a subunit of an amino acid unit or part of the linker subunit L2; 21 and R 22 These are each of any choice of C1-C3 alkylene groups; R 26 and R 27 These are C1-C, each an optional choice. 12 Alkylene, -NH-C1-C 12Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)- or -C(O)-C1-C 12 It is alkylene-NH-;R 31 This is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 It has; R 33 These are C1-C3 alkylene, C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene, or -C(O)-C1-C3 alkylene-C(O); each R 29 This is optional and can be independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH- and -C1-C6 alkenylene-C(O)-; R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; the dash (~) indicates a bonding site; n20 is 1-26; n21 is 1-4; n27 is 1-4) or has salts thereof. In some embodiments, R 20 The protecting group is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0205] In some embodiments, the PEG unit is given by the following formula: ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NC(O)-R 31 (XXXIV) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -C(O)NH-R 31 (XXXV) or ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXXVI) (In the formula, R 20R is a functional group for binding to a subunit of an amino acid unit or part of the linker subunit L2; 21 and R 22 These are each of any choice of C1-C3 alkylene groups; R 26 and R 27 These are C1-C, each an optional choice. 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)- or -C(O)-C1-C 12 It is alkylene-NH-;R 31 It is a branched polyethylene glycol chain, where each branch has 1 to 26 ethylene glycol subunits, and each branch has R at its end. 35 It has; R 33 These are C1-C3 alkylene, C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene, or -C(O)-C1-C3 alkylene-C(O); each R 29 This is optional and can be independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH-, -C1-C6 alkenylene-C(O)-, -NH(CO)NH- and triazole; R 35 These are azid, alkinyl, and alkinyl-R 65 , cyclooctin or cyclooctin-R 65 And R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbon ring, optionally substituted aryl, optionally substituted heterocarbon ring, or optionally substituted heteroaryl; the dash (~) indicates a binding site; n20 is 1-26; n21 is 1-4; n27 is 1-4) or a salt thereof. In some embodiments, R 20The protecting group is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonic acid triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or their protected forms. Preferred protecting groups include carboxylic acid protecting groups, amine protecting groups, and sulfonyl protecting groups, which are typically used in the art.

[0206] As will be understood by those skilled in the art, such PEG units can be used for the binding of further compounds. In some embodiments, the further compound is a drug unit. In some embodiments, the further compound is a linker subunit L2 as described herein. In some embodiments, the further compound is a linker or a drug linker.

[0207] Exemplary PEG units containing branched polyethylene glycol chains include: [ka] [ka] In these exemplary embodiments, if a PEG unit is bound to a subunit of an amino acid unit or a portion of linker subunit L2, it is deprotected and a bond is formed between the carboxyl group at the left end of the PEG unit and the reactive group of the subunit of the amino acid unit or the portion of linker subunit L2.

[0208] In some embodiments, the following formulas are selected: ~R 40 -(R 43 -R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XL) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C6 alkylenes; Each R 43 It is either independent, does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene-C1-C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and any substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0209] In some embodiments, the following formulas are selected: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C6 alkylenes; R 43 It does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene, heteroaryl-C1-C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0210] In some embodiments, the following formulas are selected: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C3 alkylenes; R 43 It does not exist, or C1-C6 alkylene, -NH-C1-C 12 Alkylene, -C1-C6alkylene-NH-, -C(O)-C1-C6alkylene, -C1-C6alkylene-C(O)-, -NH-C1-C6alkylene-C(O)-, -C(O)-C1-C6alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C6alkylene, -C(O)-NH-C1-C 12Alkylene, -heteroarylene, heteroaryl-C1-C6 alkylene, heteroaryl-C1-C6 alkylene-C(O)- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C6 alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-16; n41 is 1-4; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 4) or a salt thereof.

[0211] In some embodiments, R 40 A linker intermediate or linker is provided, selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctin, hydrazine, carbonylalkyl heteroaryl, or their protected forms.

[0212] In some embodiments, R 40 However, it is one of the following structures: [ka] or [ka] (In the formula, R = H or C1-6 alkyl; and n = 0 to 12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The binding site is shown, ( [ka] ) is R for the remainder of the PEG unit 40 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0213] In some embodiments, R 40 It is one of the following structures: [ka] or [ka] (In the formula, n=0~12 (*) indicates R for a subunit of the amino acid unit or a part of the linker subunit L2. 40 The binding site is shown, ( [ka] ) is R for the remainder of the PEG unit 40 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0214] In some embodiments, R 43 -(NR 44 R 45 ) n41 However, R 43 When exists, one of the following structures: [ka] or [ka] (In the formula, R=H, C1-6 Alkyl, polyhydroxyl, or substituted polyhydroxyl, ( [ka] ) is R for the remainder of the PEG unit 43 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0215] In some embodiments, R 43 -(NR 44 R 45 ) n41 However, R 43 When exists, one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is R for the remainder of the PEG unit 43 A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0216] In some embodiments, -NR 44 R 45 However, it is one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is -NR for the remainder of the PEG unit 44 R 45A linker intermediate or linker is provided that has a bonding site (showing the linker) or a stereoisomer thereof.

[0217] In some embodiments, a linker intermediate or linker having one of the following structures is provided before the PEG unit binds to an amino acid unit or part of the linker subunit L2: [ka] [ka] [ka] [ka] or [ka] (In the formula, R is H or alkyl, and n is 1 to 12).

[0218] In some embodiments, the following formulas are selected: ~R 40 -(R 43 -R 41 -[O-CH2-CH2] n40 -R 46 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLIII) (In the formula, R 40 This is a functional group for binding to a subunit of an amino acid unit or to a part of the linker subunit L2; R 41 and R 42 They are either nonexistent or, independently, C1-C6 alkylenes; Each R 43It is either independent, does not exist, or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-,-C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-,-NH-C1-C 12 Alkylene-C(O)-,-C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene-C1-C 12 Alkylene- or -C(O)NR 46 R 47 Selected from, R 46 and R 47 One of them is H or C1-C 12 It is alkylene, and the other is C1-C 12 It is alkylene; R 44 and R 45 Each of these is independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a -C(O)-polyhydroxyl group, or a substituted -C(O)-polyhydroxyl group, and the optional substituent is selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; R 46 It is selected from amino, amino-alkyl-amino, or -NH-C(O)-NH-S(O)2-NH-; The wavy line (~) represents R 40 Shows the binding site to; n40 is 1-26; n41 is 1 to 6; A linker intermediate or linker is provided that contains a PEG unit having n42 (where n42 is 1 to 6) or a salt thereof.

[0219] In some embodiments, a linker intermediate or linker having one of the following structures is provided before the PEG unit binds to an amino acid unit or part of the linker subunit L2: [ka] (In the formula, R is H or alkyl, and n is 1 to 12).

[0220] In some embodiments, the following formulas are selected: [ka] or [ka] (In the formula, each Y is independently R 76 or [ka] And, Each R 76 These are independently H, acetyl, -P(=O)(OH)2, or -(CH2) v -OS(=O)2(OH) is; Each R a and R b is independently H or R a and R b They, together with the carbon atoms to which they are bonded, form an oxo group; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; and Each * indicates a linker intermediate or linker comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1) (or a salt thereof).

[0221] In some embodiments, the following formulas are selected: [ka] or [ka] (In the formula, each R 76 These are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v S(=O)2(OH) is; Each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each v is independently 1 to 6; Each * indicates a linker intermediate or linker comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1) (or a salt thereof).

[0222] In some embodiments, the following formulas are selected: [ka] or [ka] (In the formula, each q is independently between 1 and 26; Each m is independently 1 to 4; Each n is independently 1 to 4; Each * indicates a linker intermediate or linker comprising a PEG unit having an amino acid unit (AA), a linker subunit L2, or a stretcher unit (L1) (or a salt thereof).

[0223] In some embodiments, Y is R 76 A linker intermediate or linker is provided.

[0224] In some embodiments, Y is [ka] A linker intermediate or linker is provided.

[0225] Several embodiments, each R a and R b However, a linker intermediate or linker that is independently H is provided.

[0226] In some embodiments, R a and R b However, these linkers, together with the carbon atoms to which they are bonded, provide linker intermediates or linkers that form oxo groups.

[0227] In some embodiments, linker intermediates or linkers are provided in which q is 10 to 20.

[0228] In some embodiments, a linker intermediate or linker is provided in which q is 12.

[0229] In some embodiments, PEG units are provided as linker intermediates or linkers selected from the following, or salts thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] (In the formula, each Z is joined by * and selected individually from the following: [ka] , and [ka] each [ka] (This indicates a subunit of an amino acid unit (AA), part of the linker subunit L2, or a binding site to a stretcher unit (L1).)

[0230] Carboxylate unit In some embodiments, the linker includes a carboxyl unit. The carboxyl unit may be a subunit of an amino acid unit or may be bonded to a portion of the linker subunit L2. In some embodiments, the carboxyl unit is represented by the following general formula (XXXX): R 70 | L 70 | ~NH-(CH2) p1 -CH-(CH2) o1 -C(O)~ (XXXX) (In the formula, L 70This is selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene-, and -C(O)-C1-C8 alkylene-C(O)-; R 70 is, ~NR 71 (R 72 R 73 ) and R 71 H, C1-C 12 Alkyl, substituted C1-C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 72 This is selected from non-existent or optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted arylenes, or optionally substituted heteroarylenes; R 73 The carboxyl group is a carboxyl or polycarboxyl group; each of p1 and o1 is independently selected from 0 to 2) or a salt thereof. As used herein, the term "polycarboxyl" refers to a group comprising 1 to 10, 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino, and / or amide groups. As used herein, polycarboxyl includes carboxylate forms.

[0231] In some embodiments, R 70 is, ~NR 71 (R 75 -(R 73 )2) and in the formula, R 71 H, C1-C 12 Alkyl, substituted C1-C 12 Selected from alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 75The components are branched and optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbon rings, optionally substituted arylenes, or optionally substituted heteroarylenes, and each R 73 is a carboxyl or polycarboxyl, and each of p1 and o1 is independently selected from 0 to 2.

[0232] In some embodiments, R 70 is, ~N(R 74 -R 73 )(R 72 -R 73 ) and in the formula, R 72 and R 74 Each R is independently selected from optionally substituted C1-C3 alkylenes, optionally substituted ethers, optionally substituted thioethers, optionally substituted ketones, optionally substituted amides, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocyclic rings, optionally substituted arylenes, or optionally substituted heteroarylenes, and each R 73 These are independently carboxyl or polycarboxyl, and each of p1 and o1 is independently selected from 0 to 2.

[0233] In some of the above embodiments, R 73 You can choose from the following: [ka] and ~COOH; (In the formula, the dashed line represents R 72 , R 74 or R 75 (This indicates a connection to the specified target.)

[0234] Linker subunit L2 The linker comprises at least one linker subunit L2, each linker subunit L2 having a binding site for at least one drug unit (D), as further described herein. In some embodiments, the drug unit (D) binds to each binding site for the drug unit on the linker subunit L2. In various embodiments, the linker subunit L2 may be a cleavable or incleavable linker subunit. The linker subunit L2 also has a binding site for an amino acid unit (AA) or a stretcher unit (L1).

[0235] In some embodiments, the linker subunit L2 includes polar units such as sugar units, PEG units, or carboxyl units. In some embodiments, the linker subunit L2 does not include polar units, while the amino acid units do. In some embodiments, both the linker subunit L2 and the amino acid units (if present) include polar units.

[0236] In some embodiments, the linker subunit L2 is a cleavable linker subunit. As used herein, the term “cleavable” refers to a metabolic process or reaction in the intracellular or extracellular environment in which a covalent bond between a drug unit (e.g., a cytotoxic agent) and the linker subunit L2 or a portion thereof is cleaved, resulting in a free drug unit or other metabolites of the linker subunit L2 drug unit dissociated from the remainder of the linker subunit L2.

[0237] In some embodiments, the linker subunit L2 is a protease-cleavable linker subunit, an acid-cleavable linker subunit, a disulfide linker subunit, a disulfide-containing linker subunit, or a disulfide-containing linker subunit having a dimethyl group adjacent to a disulfide bond (e.g., SPDB linker) (see, for example, Jain et al., Pharm. Res. 32:3526-3540 (2015); Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020), a cleavable self-stabilizing linker (see, for example, International Publication No. 2018 / 031690 and International Publication No. 2015 / 095755 and Jain et al. See al., Pharm.Res.32:3526-3540 (2015), and / or include a severable hydrophilic linker (see, for example, International Publication No. 2015 / 123679). In some embodiments, the linker subunit L2 includes a photosensitive linker subunit. In some embodiments, the linker subunit L2 has a non-severable linker unit (see, for example, International Publication No. 2007 / 008603).

[0238] In some embodiments, linker subunit L2 is a cleavable linker that can be cleaved under intracellular conditions such that cleavage of linker subunit L2 or cleavage within linker subunit L2 releases drug units from linker subunit L2 or the remainder of linker subunit L2 in the intracellular environment. For example, in some embodiments, linker subunit L2 can be cleaved by cleaving agents present in the intracellular environment (e.g., within lysosomes or endosomes or caveolae). As used herein, the terms “cleavable under intracellular conditions,” “intracellular cleavage,” and “intracellular cleavage” refer to intracellular metabolic processes or reactions in which a covalent bond between a drug unit (e.g., a cytotoxic agent) and linker subunit L2 or a portion thereof is cleaved, resulting in free drug units or other metabolites of the linker subunit L2 drug unit dissociated from the remainder of linker subunit L2 inside the cell. Thus, the cleaved portion of the conjugate is an intracellular metabolite.

[0239] In some embodiments, the linkage between the linker subunit L2 and the drug unit can be enzymatically cleaved by one or more enzymes, including tumor-associated proteases, to release the drug unit (D). The linker subunit L2 may be a peptidyl linker that is cleaved by intracellular peptidase or protease enzymes, including, but not limited to, lysosome or endosomal proteases (see, for example, International Publication 2004 / 010957, U.S. Patent Application Publication 20150297748, U.S. Patent Application Publication 2008 / 0166363, U.S. Patent Application Publication 20120328564, and U.S. Patent Application Publication 20200347075). Examples of intracellular cleavage agents include cathepsin B, C, and D, as well as plasmin, all of which are known to hydrolyze dipeptide drug derivatives, leading to the release of active drugs within target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). Peptidyl linkers may be cleavable by enzymes present in target antigen-expressing cells. For example, peptidyl linker subunits cleavable by the thiol-dependent protease cathepsin B, which is highly expressed in cancerous tissues, can be used (e.g., those having Phe-Leu, Val-Ala, Val-Cit, or Gly-Phe-Leu-Gly peptides).

[0240] Typically, peptidyl linkers are at least one amino acid long or at least two amino acid long. In certain embodiments, the peptidyl linker is a dipeptide, tripeptide, tetrapeptide, or pentapeptide. In certain embodiments, the peptidyl linker subunit may contain only native amino acids. In some embodiments, for example, the peptidyl linker subunit may have Phe-Leu, Val-Ala, Val-Cit, or Gly-Phe-Leu-Gly peptides. Other such cleavable linkers are described, for example, in U.S. Patent No. 6,214,345. In certain embodiments, peptidyl linkers cleavable by intracellular proteases include Val-Cit peptides or Phe-Lys peptides (see, for example, U.S. Patent No. 6,214,345) or Gly-Gly-Phe-Gly linkers (see, for example, U.S. Patent Application Publication No. 2015 / 0297748). One advantage of using intracellular proteolytic release of drug units is that the activity of the drug units is typically weakened when conjugated, and the serum stability of the conjugate is typically high. See also U.S. Patent No. 9,345,785.

[0241] In some embodiments, the peptidyl linker subunit may contain only non-natural amino acids. In some embodiments, the peptidyl linker subunit may contain a natural amino acid linked to a non-natural amino acid. In some embodiments, the peptidyl linker subunit may contain a natural amino acid linked to a D-isomer of a natural amino acid. In some embodiments, at least one amino acid of the peptidyl linker subunit is an L-amino acid. In some embodiments, at least one amino acid is a D-amino acid.

[0242] In some embodiments, the peptidyl linker subunit contains one or more of the following glycine and / or L-amino acids, e.g., arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units (including PEG units bound to glycine or L-amino acids). In some embodiments, the peptidyl linker subunit contains one or more of the following glycine and / or D-amino acids, e.g., arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units (including PEG units bound to glycine or D-amino acids). In some embodiments, the peptidyl linker subunit contains one or more of the following: glycine and / or mixtures of L-amino acids and D-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units (including PEG units bound to glycine or amino acids).

[0243] In some embodiments, the peptidyl linker subunit contains one or more of the following glycine and / or natural L-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit bound to glycine or an L-amino acid. In some embodiments, the peptidyl linker subunit contains the following glycine and / or D-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as at least one polar unit, such as a sugar unit, or one or more carboxyl units or PEG units bound to glycine or a D-amino acid.

[0244] In some embodiments, the amino acids of the peptidyl linker subunit have the following formula in square brackets: [ka] (In the formula, R 190 Hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH-CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-ρpyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, [ka] )

[0245] In some embodiments, the peptidyl linker subunit comprises the following L-(natural) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine; and at least one polar unit, such as a sugar unit, or one or more carboxyl units or PEG units bonded to glycine or a natural amino acid.

[0246] In some embodiments, the peptidyl linker subunit does not contain cysteine. In some embodiments, the peptidyl linker does not contain proline.

[0247] In some embodiments, the peptidyl linker subunit comprises D-isomers of the following natural amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine; and at least one polar unit, such as a sugar unit, or one or more carboxyl units or PEG units bonded to glycine or a D-amino acid.

[0248] In some embodiments, the peptidyl linker subunit comprises the following amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, ornithine, penicillamine, β-alanine, aminoalkanoic acid, aminoalkynic acid, aminoalkanedioic acid, aminobenzoic acid, aminoheterocycloalkanoic acid, heterocyclocarboxylic acid, citrulline, statin, diaminoalkanoic acid, and their derivatives; as well as at least one polar unit, e.g., a sugar unit, or one or more carboxyl units or PEG units attached to an amino acid. Examples of such amino acid derivatives are shown below in the section describing the amino acid subunits.

[0249] In some embodiments, the peptidyl linker subunit contains a sugar unit as part of the cleavable peptide. For example, the sugar unit contains lysine or citrulline as part of the cleavable peptide. In some embodiments, the peptidyl linker subunit contains a carboxyl unit as part of the cleavable peptide. For example, the carboxyl unit contains lysine or citrulline as part of the cleavable peptide.

[0250] In some embodiments, the cleavable linker subunit is pH-sensitive, i.e., susceptible to hydrolysis at a specific pH value. Typically, pH-sensitive linker subunits are hydrolyzable under acidic conditions. For example, acid-unstable linker subunits that are hydrolyzable in lysosomes (e.g., hydrazones, semicarbazones, thiosemicarbazones, cis-aconitamides, orthoesters, acetals, ketals, etc.) can be used. (See, for example, U.S. Patent No. 5,122,368; No. 5,824,805; and No. 5,622,929; Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such linker subunits are relatively stable under neutral pH conditions, for example in blood, but unstable below pH 5.5 or 5.0, which is the approximate pH of lysosomes. In certain embodiments, the hydrolyzable linker unit is a thioether linker (e.g., a thioether bound to a drug unit via an acylhydrazone linkage (see, for example, U.S. Patent No. 5,622,929)).

[0251] In some embodiments, the linker subunit L2 is cleavable under reducing conditions (e.g., a disulfide linker subunit). Various disulfide linkers are known, including those that can be formed using SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate), and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)toluene), SPDB, and SMPT (e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In lmmunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (CWVogel ed., Oxford)). See U.S. Press, 1987. Also see U.S. Patent No. 4,880,935.

[0252] In some embodiments, the linker subunit L2 is a malonic acid linker (Johnson et al. These include the maleimido-benzoyl linker (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1299-1304) or a 3'-N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10):1305-12). In some embodiments, the linker subunit L2 is not cleavable, such as the maleimido-caproyl linker, and the drug unit is released by metabolic degradation of the drug-linker. (See, for example, U.S. Patent Application Publication No. 2005 / 0238649.)

[0253] In some embodiments, linker subunit L2 is substantially insensitive to the extracellular environment. As used herein, “substantially insensitive to the extracellular environment” in the context of linker subunit L2 means that when the conjugate is present in an extracellular environment (e.g., plasma), about 20% or less, typically about 15% or less, more typically about 10% or less, and even more typically about 5% or less, about 3% or less, or about 1% or less of the linker subunit L2 in the sample of the conjugate is cleaved. Whether linker subunit L2 is substantially insensitive to the extracellular environment can be determined, for example, by incubating both (a) the conjugate ("conjugate sample") and (b) an equal molar amount of unconjugated targeted units or drug units ("control sample") independently of plasma for a predetermined period (e.g., 2, 4, 8, 16, or 24 hours), and then comparing the amount of unconjugated targeted units or drug units present in the conjugate sample with that present in the control sample, as measured, for example, by high-performance liquid chromatography.

[0254] In some embodiments, the linker or linker subunit L2 promotes intracellular integration. In some embodiments, the linker or linker subunit L2 promotes intracellular integration when conjugated to a drug unit such as a cytotoxic agent (i.e., in the environment of the linker-drug unit portion of the conjugate described herein). In yet other embodiments, the linker or linker subunit L2 promotes intracellular integration when conjugated to both the drug unit and the targeting unit (i.e., in the environment of the conjugate described herein).

[0255] Various linker subunits L2 that can be used with the compositions and methods of the present invention are described, for example, in International Publication No. 2004010957. In some embodiments, linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive spacer and a dipeptide (e.g., maleimidylcaproylvalinealanine). In some embodiments, linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive maleimidolcaproyl spacer, an amino acid or peptide and a self-sacrificing group. In some embodiments, linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive maleimidolcaproyl spacer, a valine-citrulline dipeptide and a p-aminobenzyloxycarbonyl self-sacrificing group.

[0256] In some embodiments, the linker subunit L2 includes an acid-cleavable linker such as a hydrazine linker or a quaternary ammonium linker (see, for example, International Publication No. 2017 / 096311 and International Publication No. 2016 / 040684).

[0257] In some embodiments, the linker subunit L2 includes a self-stabilizing moiety containing a maleimide group, as described in International Publication No. 2013 / 173337.

[0258] In some embodiments, the linker subunit L2 includes hydrophilic linkers such as the hydrophilic peptide disclosed in International Publication No. 2015 / 123679 and the sugar alcohol polymer-based linkers disclosed in International Publication Nos. 2013 / 012961 and International Publication No. 2019 / 213046.

[0259] In other embodiments, the linker subunit L2 may be prepared using various bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxyl (SMCC), iminothiolane (IT), difunctional derivatives of imide esters (e.g., dimethyladipimidate HCl), active esters (e.g., disuccinimidylsberate), aldehydes (e.g., glutaraldehyde), bis-azide compounds (e.g., bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (e.g., bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). Chelating agents for the conjugation of radioactive nucleotides are described, for example, in International Publication No. 94 / 11026.

[0260] In some embodiments, the linker subunit L2 can be prepared using commercially available crosslinking agents (e.g., Pierce Biotechnology, Inc. (Rockford, IL, USA)) such as BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, as well as SVSB (succinimidyl-(4-vinylsulfone)benzoate).

[0261] amino acid (AA) units The linker optionally contains an amino acid unit (AA). If present in the linker, the amino acid unit connects a stretcher unit (L1) to linker subunit L2. If 's' of AA is 0, the amino acid unit is absent (e.g., any of formulas I-IV). In some embodiments, the amino acid unit contains 0 to 12 subunits. Each subunit of the amino acid unit is selected from natural or unnatural alpha, beta, or gamma amino acids or polar units, such as sugar units (SU), or carboxyl units or PEG units attached to the subunits of the amino acid unit.

[0262] In some embodiments, the amino acid unit is an amino acid or a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide, or dodecapeptide, and one or more of the subunits are optionally modified to form polar units, such as sugar units, PEG units, or carboxyl units.

[0263] In some embodiments, the subunit of the amino acid unit is selected from glycine and / or L-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units (including PEG units bound to glycine or L-amino acids). In some embodiments, the subunit of the amino acid unit is selected from glycine and / or D-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units. In some embodiments, the subunits of the amino acid unit are selected from glycine and / or mixtures of L-amino acids and D-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as polar units (including PEG units bound to glycine or D-amino acids).

[0264] In some embodiments, the subunit of the amino acid unit is selected from glycine and / or natural L-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit bound to glycine or an L-amino acid. In some embodiments, the subunit of the amino acid unit is selected from glycine and / or D-amino acids, such as arginine, glutamine, phenylalanine, tyrosine, tryptophan, lysine, alanine, histidine, serine, proline, glutamic acid, aspartic acid, threonine, cysteine, methionine, leucine, asparagine, isoleucine, and valine, as well as at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit bound to glycine or an L-amino acid.

[0265] In some embodiments, the subunits of the amino acid unit independently have the following formula in square brackets: [ka] (In the formula, R 190 Hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH-CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-ρpyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, [ka] )

[0266] In some embodiments, each subunit of an amino acid unit is independently selected from the group consisting of the following L-(natural) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine; and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit attached to a natural amino acid.

[0267] In some embodiments, the amino acid subunit is not cysteine. In some embodiments, the amino acid subunit is not proline.

[0268] In some embodiments, each subunit of an amino acid unit is independently selected from the group consisting of the following D-isomers of these native amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan, and valine; and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit bonded to glycine or an L-amino acid.

[0269] In some embodiments, each subunit of an amino acid unit is independently selected from alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, ornithine, penicillamine, β-alanine, aminoalkanoic acid, aminoalkinoic acid, aminoalkanedioic acid, aminobenzoic acid, aminoheterocycloalkanoic acid, heterocyclocarboxylic acid, citrulline, statin, diaminoalkanoic acid and its derivatives; as well as at least one polar unit, for example, a sugar unit, or a carboxyl unit or PEG unit attached to one of the subunits.

[0270] Examples of alanine and its derivatives include alanine (Ala), N-alkyl-alanine, dehydro-alanine, 4-thiazolyl-alanine, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, β-(l-naphthyl)-alanine, β-(2-naphthyl)-alanine, α-aminobutyric acid, β-chloro-alanine, β-cyano-alanine, β-cyclopentyl-alanine, β-cyclohexyl-alanine, β-iodo-alanine, β-cyclopentenyl- Examples include, but are not limited to, alanine, β-tBu-alanine, β-cyclopropyl-alanine, β-diphenyl-alanine, β-fluoro-alanine, β-piperazine-alanine with or without protected piperazine ring, β-(2-quinolyl)-alanine, β-(l,2,4-triazole-l-yi)-alanine, β-ureido-alanine, H-β-(3-benzothienyl)-Ala-OH, and H-β-(2-thienyl)~Ala-OH.

[0271] Examples of arginine and its derivatives include, but are not limited to, arginine (Arg), N-alkyl-arginine, H-Arg(Me)-OH, H-Arg(NH2)-OH, H-Arg(NO2)-OH, H-Arg(Ac)2-OH, H-Arg(Me)2-OH (asymmetric), H-Arg(Me)2-OH (symmetric), 2-amino-4-(2'-hydroxyguanidino)-butyric acid (N-ω-hydroxy-nor-arginine), and homoarginine.

[0272] Examples of aspartic acid and its derivatives include, but are not limited to, aspartic acid (Asp), N-alkyl-aspartic acid, and H-Asp(OtBu)-OH.

[0273] Examples of asparagine and its derivatives include, but are not limited to, asparagine (Asn), N-alkyl-asparagine, and isoasparagine (H-Asp-NH2).

[0274] Examples of cysteine ​​(Cys) derivatives (that do not contain a free SH group) include, but are not limited to, H-Cys(Acm)-OH, H-Cys(Trt)-OH, H-Cys(tBu)-OH, H-Cys(Bzl)-OH, H-Cys(Et)-OH, H-Cys(SO3H)-OH, H-Cys(aminoethyl)-OH, H-Cys(carbamoyl)-OH, H-Cys(phenyl)-OH, H-Cys(Boc)-OH, and H-Cys(hydroxyethyl)-OH.

[0275] Examples of histidine and its derivatives include, but are not limited to, histidine (His), N-alkyl-histidine, H-His(Boc)-OH, H-His(Bzl)-OH, H-HBs(I-Me)-OH, H-His(l-Tos)-OH, H-2,5-diiodo-His-OH, and H-His(3-Me)-OH.

[0276] Examples of glycine and its derivatives include glycine (GIy), N-alkyl-glycine, H-propargylglycine ( [ka] CH); α Examples include, but are not limited to, aminoglycines (protected or unprotected), β-cyclopropylglycine, cyclopentylglycine, cyclohexylglycine, α-allylglycine, t-butylglycine, neopentylglycine, and phenylglycine.

[0277] Examples of glutamic acid and its derivatives include, but are not limited to, glutamic acid (GIu), N-alkyl glutamic acid, H-GIu(OtBu)-OH, H-γ-hydroxy-Glu-OH, H-γ-methylene-Glu-OH, H-γ-carboxy-Glu(OtBu)2-OH, and pyroglutamic acid.

[0278] Examples of glutamine and its derivatives include, but are not limited to, glutamine (GIn), N-alkyl-glutamine, isoglutamine (H-GIu-NH2), H-GIn(Trt)-OH, and H-Gln(isopropyl)-OH.

[0279] Examples of phenylalanine and its derivatives include, but are not limited to, phenylalanine (Phe), N-alkyl-phenylalanine, Hp-amino-Phe-OH, Hp-amino-Phe(Z)-OH, Hp-bromo-Phe-OH, Hp-benzyl-Phe-OH, Hp-tBu-Phe-OH, Hp-carboxy-Phe(OtBu)-OH, Hp-carboxy-Phe-OH, Hp-cyano-Phe-OH, Hp-fluoro-Phe-OH, H-3,4-dichloro-Phe-OH, Hp-iodo-Phe-OH, Hp-nitro-Phe-OH, Hp-methyl-Phe-OH, H-pentafluoro-Phe-OH, Hm-fluoro-Phe-OH, H-α-Me-Phe-OH, H-4-phenyl-Phe-OH, homoalanine, chloro-phenylalanine, and β-homophenylalanine.

[0280] Examples of lysine and its derivatives include lysine (Lys), N-alkyl-lysine, H-Lys(Boc)-OH, H-Lys(Ac)-OH, H-Lys(formyl)-OH, H-Lys(Me)2-OH, H-Lys(nicotinoyl)-OH, H-Lys(Me)3-OH, H-trans-4,5-dehydro-Lys-OH, H-Lys(Aloc)-OH, HH-δ-hydroxy-Lys-OH, H-δ- Examples of leucine and its derivatives include, but are not limited to, hydroxy-Lys(Boc)-OH, H-Lys(acetamidoyl)-OH, and H-Lys(isopropyl)-OH, as well as leucine (Leu), N-alkyl-leucine, 4,5-dehydroleucine-leucine, H-α-Me-Leu-OH, homoleucine, norleucine, and t-leucine.

[0281] Examples of methionine and its derivatives include, but are not limited to, methionine (Met), H-Met(O)-OH, and H-Met(O)2-OH.

[0282] Examples of serine and its derivatives include, but are not limited to, serine (Ser), N-alkyl-serine, H-Ser(Ac)-OH, H-Ser(tBu)-OH, H-Ser(Bzl)-OH, H-Ser(ρ-chloro-Bzl)-OH, H-β-(3,4-dihydroxyphenyl)-Ser-OH, H-β-(2-thienyl)-Ser-OH, isoserine, N-alkyl-isoserine, and 3-phenylisoserine.

[0283] Examples of tyrosine and its derivatives include, but are not limited to, tyrosine (Tyr), N-alkyl-tyrosine, H-3,5-dinitro-Tyr-OH, H-3-amino-Tyr-OH, H-3,5-dibromo-Tyr-OH, H-3,5-diiodo-Tyr-OH, H-Tyr(Me)-OH, H-Tyr(tBu)-OH, H-Tyr(Boc)-OH, H-Tyr(Bzl)-OH, H-Tyr(Et)-OH, H-3-iodo-Tyr-OH, and H-3-nitro-Tyr-OH.

[0284] Examples of threonine and its derivatives include, but are not limited to, threonine (Thr), N-alkyl-threonine, allo-threonine, H-Thr(Ac)-OH, H-Thr(tBu)-OH, and H-Thr(Bzl)-OH.

[0285] Examples of isoleucine and its derivatives include, but are not limited to, isoleucine (He), N-alkyl-isoleucine, allo-isoleucine, and norleucine.

[0286] Examples of tryptophan and its derivatives include, but are not limited to, tryptophan (Tip), N-alkyl-tryptophan, H-5-Me-Trp-OH, H-5-hydroxy-Trρ-OH, H-4-Me-Trp-OH, H-α-Me-Trp-OH, H-Trp(Boc)-OH, H-Trp(formyl)-OH, and H-Trp(mesitylene-2-sulfonyl)-OH.

[0287] Examples of proline and its derivatives include, but are not limited to, proline (Pro), N-alkyl-proline, homoproline, thioproline, hydroxyproline (H-Hyp-OH), H-Hyp(tBu)-OH, H-Hyp(Bzl)-OH, H-3,4-dehydro-Pro-OH, 4-keto-proline, α-Me-Pro-OH, and H-4-fluoro-Pro-OH.

[0288] Examples of valine and its derivatives include, but are not limited to, valine (VaI), N-alkyl-valine, H-α-Me-Val-OH, and norvaline.

[0289] Examples of ornithine and its derivatives include, but are not limited to, ornithine, N-alkyl-ornithine, H-0rn(Boc)-OH, H-0m(Z)-OH, H-α-difluoro-Me-Orn-OH (eflornithine), and H-Orn(Aloc)-OH.

[0290] Examples of penicillamines and their derivatives include, but are not limited to, penicillamine, H-penicillam(Acm)-OH(H-β,β-dimethylcyz(Acm)-OH), and N-alkyl-penicillamines.

[0291] Examples of β-alanine and its derivatives include, but are not limited to, β-alanine, N-alkyl-β-alanine, and dehydro-alanine.

[0292] Examples of aminoalkanoic acids and their derivatives include, but are not limited to, N-alkylaminoalkanoic acid, aminobutyric acid, 4-(neopentyloxysulfonyl)-aminobutyric acid, ε-aminocaproic acid, α-aminoisobutyric acid, piperidylacetic acid, 3-amurnopropionic acid, 3-amino-3-(3-pyridyl)-propionic acid, and 5-aminopentanioic acid (aminovaleric acid).

[0293] Examples of aminoalkynic acids and their derivatives include, but are not limited to, N-alkylaminoalkynic acids, 6-amino-4-hexic acid, and 6-(Boc-amino)-4-hexic acid.

[0294] Examples of aminoalkanediols and their derivatives include, but are not limited to, N-alkylaminoalkanediols, 2-aminohexanediols, 2-aminoheptanediols, and 2-aminooctanedioic acid (H-Asu-OH).

[0295] Examples of aminobenzoic acids and their derivatives include, but are not limited to, N-alkylaminobenzoic acid, 2-aminobenzoic acid, 3-aminobenzoic acid, and 4-aminobenzoic acid.

[0296] Examples of amino-heterocycloalkanoates and their derivatives include, but are not limited to, N-alkylamino-heterocycloalkanoates, 4-amino-1-methyl-1H-imidazole-2-carboxylic acid, 4-amino-1-methyl-1H-pyrrole-2-carboxylic acid, 4-amino-piperidine-4-carboxylic acid (H-pipe-OH; 1-protected or unprotected), and 3-amino-3-(3-pyridyl)-propionic acid.

[0297] Examples of heterocyclocarboxylic acids and their derivatives include, but are not limited to, azetidine-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-4-carboxylic acid, and thiazolidined-4-carboxylic acid.

[0298] Examples of citrulline and its derivatives include, but are not limited to, citrulline (cit), N-alkyl-citrulline, thiocitrulline, S-methyl-thiocitrulline, and homocitrulline.

[0299] Examples of statins and their derivatives include, but are not limited to, statins, N-alkyl statins, cyclohexyl statins, and phenyl statins.

[0300] Examples of diaminoalkanoic acid (Dab) and its derivatives include, but are not limited to, N-alkyl-diaminoalkanoic acid, N,N-dialkylaminoalkanoic acid, α,γ-diaminobutyric acid (H-Dab-OH), H-Dab(Aloc)-OH, H-Dab(Boc)-OH, H-Dab(Z)-OH, α,β-diaminopropionic acid and its side-chain protected versions.

[0301] In some embodiments, amino acid units may be terminated with capping groups, such as linear or branched alkyl groups, or polyethylene chains (1 to 30 subunits) or PEG units.

[0302] Exemplary embodiments of amino acid units include the following, where SU is a sugar unit, PEG is a PEG unit, and CU is a carboxyl unit:

[0303] In some embodiments, the amino acid unit includes SU.

[0304] In some embodiments, the amino acid unit includes SU-Lys-SU.

[0305] In some embodiments, the amino acid unit includes SU-Lys-SU-tert-butyl.

[0306] In some embodiments, the amino acid unit includes SU-Lys.

[0307] In some embodiments, the amino acid unit includes Lys-SU.

[0308] In some embodiments, the amino acid unit includes Lys-SU-Lys(PEG).

[0309] In some embodiments, the amino acid unit includes SU-Lys(PEG)-SU.

[0310] In some embodiments, the amino acid unit includes SU-Glu-SU.

[0311] In some embodiments, the amino acid unit includes Lys(PEG).

[0312] In some embodiments, the amino acid unit includes Lys(PEG)-Lys(PEG).

[0313] In some embodiments, the amino acid unit includes CU.

[0314] In some embodiments, the amino acid unit includes CU-CU.

[0315] In some embodiments, an amino acid unit is present and linked to the peptide of linker subunit L2 via a peptide bond. In some embodiments, such amino acid unit-linker subunit L2 comprises SU-Val-Cit~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises SU-Val-Ala~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises SU-Val-Lys~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises SU-Gly-Gly-Phe-Gly~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit.

[0316] In some embodiments, such amino acid unit-linker subunit L2 comprises Val-Lys(PEG)~, and the wavy line indicates the remainder of linker subunit L2 or binding to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises Val-Cit(PEG)~, and the wavy line indicates the remainder of linker subunit L2 or binding to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises Lys(PEG)-Val-Cit~, and the wavy line indicates the remainder of linker subunit L2 or binding to a drug unit. In some embodiments, such amino acid unit-linker subunit L2 comprises Lys(PEG)-Gly-Gly-Phe-Gly~, and the wavy line indicates the remainder of linker subunit L2 or binding to a drug unit.

[0317] In some embodiments, such an amino acid unit-linker subunit L2 comprises CU-Val-Cit~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such an amino acid unit-linker subunit L2 comprises CU-Val-Lys~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such an amino acid unit-linker subunit L2 comprises CU-Val-Ala~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit. In some embodiments, such an amino acid unit-linker subunit L2 comprises Val-CU~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit, where CU comprises a lysine residue. In some embodiments, such an amino acid unit-linker subunit L2 comprises CU-Gly-Gly-Phe-Gly~, where the wavy line indicates binding to the remainder of linker subunit L2 or to a drug unit.

[0318] In some embodiments, amino acid units are present and are linked to linker subunit L2 by non-peptidic bonds. In some embodiments, the amino acid units are C1-C 10Alkylene, C2-C 10 Alkenylene, C2-C 10 It is linked to the linker subunit L2 by a peptidic linking group such as alkylylene or polyethylene glycol.

[0319] In some embodiments, a linker intermediate or linker is provided in which L2 or AA-L2 has one of the following structures: [ka] or [ka] (In the formula, the wavy line on the amino group indicates the binding site for the stretcher unit, and the drug unit is bound to the benzyl alcohol.)

[0320] Stretcher unit (L1) A stretcher unit (L1) can link a targeting unit to an amino acid unit (AA) or a linker subunit L2. The stretcher unit has a functional group that can form a bond with the functional group of the targeting unit. In some embodiments of the linker, the stretcher unit is bonded to an amino acid unit which is bonded to a linker subunit L2 (i.e., when s of AA is 1, see, for example, formulas (I) to (IV)). In some embodiments, the stretcher unit is bonded to a linker subunit L2 (i.e., when s of AA is 0, see, for example, formulas (I) to (IV)). In some embodiments, the stretcher unit is bonded to an amino acid unit-linker subunit L2 after the amino acid unit-linker subunit L2 has been formed. In some embodiments, the stretcher unit is bonded to an amino acid unit-linker subunit L2-drug unit after the amino acid unit-linker subunit L2-drug unit has been formed. In some embodiments, the stretcher unit binds to the linker subunit L2-drug unit after the linker subunit L2-drug unit has been formed.

[0321] The functional groups of the stretcher units for binding to the targeting units may include, for example, maleimides, haloacetamides, sulfhydryl groups, NHS esters, aldehydes, ketones, carbonyls, hydrazides, hydroxylamines, amines, aminos, hydrazines, thiosemicarbazones, hydrazine carboxyls, or aryl hydrazides.

[0322] Functional groups that may be present on the targeting unit, either naturally or through chemical manipulation, include, but are not limited to, sulfhydryl (-SH), amino, hydroxyl, carboxyl, anomeric hydroxyl, and carboxyl groups of carbohydrates. In one embodiment, the functional groups of the targeting unit are sulfhydryl and amino. Sulfhydryl groups can be generated by reduction of intramolecular disulfide bonds in the targeting unit. Alternatively, sulfhydryl groups can be generated by reaction of the amino group of the lysine moiety of the targeting unit using 2-iminothiolane (Trout's reagent) or another sulfhydryl-generating reagent.

[0323] In some embodiments, the stretcher unit forms a bond with the sulfur atom of the targeting unit via the maleimide group of the stretcher unit. The sulfur atom may originate from, for example, the sulfhydryl group of the targeting unit (e.g., the thiol group of the interchain disulfide bond). Representative stretcher units of this embodiment are shown in the following formulas 100 and 101, where L is the targeting unit and the dashed line indicates the binding site for the amino acid unit or linker subunit L2: [ka]

[0324] In some embodiments, the stretcher unit is provided with a linker selected from the following: [ka] and [ka] (In the formula, the dashed line) [ka] (This indicates the binding site of the stretcher unit to the amino acid unit.)

[0325] In equations 100 and 101, R 17 is -C1-C 10 Alkylene-,-C1-C 10 Heteroalkylene-,-C3-C8 carbocyclo-,-O-(C1-C8 alkylene)-,-(CH2-O-CH2) b -C1-C8 alkylene-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(where b is 1 to 26) -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene- (where b is 1 to 26), -arrine-, -C1-C 10 Alkilen-Arirene-,-Arirene-C1-C 10 Alkylene-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-,-C3-C8 heterocyclo-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-,-C1-C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene -C(=O)-, -C1-C8 alkylene-(CH2-O-CH2) b -C(=O)-(where b is between 1 and 26), -(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b-C1-C8 alkylene-C(=O)- (where b is 1 to 26), -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C 10 Alkylene-arylene-C(=O)-,-arylene-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocyclo)-C(=O)-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene -C(=O)-, -C1-C 10 Alkylene-NH-,-C1-C 10 Heteroalkylene-NH-,-C1-C8 alkylene-(CH2-O-CH2) b -NH-(where b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH-(where b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C(=O)-(where b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(where b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -NH-(where b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -C1-C8 alkylene-NH- (where b is 1 to 26), -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkyl)-NH-, -arylene-NH-, -C1-C 10 Alkylene-arylene-NH-,-arylene-C1-C 10Alkylene-NH-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-NH-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-NH-,-C3-C8 heterocyclo-NH-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-NH-,-(C3-C8 heterocyclo)-C1-C 10 Alkylene-NH-,-C1-C 10 Alkylene-S-,-C1-C 10 Heteroalkylene-S-,-C3-C8carbocyclo-S-,-O-(C1-C8alkyl)-S-,-arylene-S-,-C1-C 10 Alkylene-Arirene-S-,-Arirene-C1-C 10 Alkylene-S-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-S-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-S-,-C3-C8 heterocyclo-S-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-S- or-(C3-C8 heterocyclo)-C1-C 10 It is alkylene-S-. 17 Any substituent may be substituted or unsubstituted (also called unsubstituted). In some embodiments, R 17 The substituents are unsubstituted. In some embodiments, R 17 The substituents are optionally substituted. In some embodiments, for example, -(CH2) x NH2, -(CH2) x NHR a and -(CH2) x NR a R such as 2 17 Based on the formula (see, for example, International Publication No. 2013 / 173337), in the formula, x is an integer from 1 to 4, and each R a The R is independently selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl, or two R a The groups, when combined with the nitrogen to which they are bonded, form azetidinyl, pyrrolidinyl, or piperidinyl groups.

[0326] In some embodiments of formula 100, R 17 This is -C1-C6 alkylene (C=O)-. In some embodiments, R 17 This is -C1 alkylene-C(=O)-.

[0327] In some embodiments of formula 100, R 17 is -(CH2-O-CH2) b -C1-C8 alkylene-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(where b is 1 to 26) -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C(=O), -(where b is between 1 and 26), -(CH2-O-CH2) b -C1-C8 alkylene-C(=O), -(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-C(=O), -(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -NH-(where b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH-(where b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH- (where b is 1 to 26), -C1-C8 alkylene-(C(=O)), -NH-(CH2-O-CH2) b -C(=O), -(where b is 1 to 26), -C1-C8 alkylene-(C(=O)), -NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O), -(where b is 1 to 26), -C1-C8 alkylene-NH-(C(=O)), -(CH2-O-CH2) b -NH- (where b is 1 to 26), or -C1-C8 alkylene-NH-(C(=O)), -(CH2-O-CH2) b-C1-C8 alkylene-NH- (where b is 1 to 26).

[0328] In other embodiments, the stretcher unit is linked to the targeting unit via a disulfide bond between the sulfur atom of the stretcher unit and the sulfur atom of the targeting unit. A typical stretcher unit in this embodiment is shown in formula 102 below, where L is the targeting unit, the dashed line indicates a binding site for an amino acid unit or linker subunit, and L2 and R 17 The results for equations 100 and 101 are as stated above. [ka]

[0329] In yet another embodiment, the reactive group of the stretcher unit contains a reactive site that can form a bond with a primary or secondary amino group of the targeting unit. Examples of these reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Representative stretcher units of this embodiment are shown in formulas 103, 104, and 105, where L is the targeting unit, the dashed line indicates a binding site for an amino acid unit or linker subunit, and L2 and R 17 The same applies to equations 100 and 101 as described above: [ka]

[0330] In yet another embodiment, the reactive group of the stretcher unit contains a reactive site that is reactive to a modified carbohydrate (-CHO) group that may be present on the targeting unit. For example, the carbohydrate can be mildly oxidized using a reagent such as sodium periodate, and the resulting (-CHO) unit of the oxidized carbohydrate can be condensed with a stretcher unit containing a functional group such as a hydrazide, oxime, primary or secondary amine, hydrazine, thiosemicarbazone, hydrazine carboxyl, or arylhydrazide (as described by Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41). Representative stretcher units of this embodiment are shown in the following formulas 106, 107, and 108, where L is the targeting unit, the dashed line indicates a binding site for an amino acid unit or linker subunit, and L2 and R 17 The same applies to equations 100 and 101 as described above: [ka]

[0331] In some embodiments, it may be desirable to extend the length of the stretcher unit. Therefore, the stretcher unit may contain further components. A typical stretcher unit of this embodiment is shown in the following formula 109, where L is a targeting unit, the dashed line indicates a binding site for an amino acid unit or linker subunit, and L2 and R 17 The same applies to equations 100 and 101 as described above: [ka]

[0332] In some aspects of this embodiment, R 17 This is -C1-C5 alkylene-C(=O)-. 13 -C1-C6 alkylene-, -(CH2-O-CH2) b-(wherein b is 1 to 26), -C3-C8 carbocyclo-,-arylene-,-C1-C 10 Heteroalkylene-,-C3-C8 heterocyclo-,-C1-C 10 Alkilen-Arirene-,-Arirene-C1-C 10 Alkylene-,-C1-C 10 Alkylene-(C3-C8 carbocyclo)-,-(C3-C8 carbocyclo)-C1-C 10 Alkylene-,-C1-C 10 Alkylene-(C3-C8 heterocyclo)-or-(C3-C8 heterocyclo)-C1-C 10 It is alkylene-. In a preferred embodiment, R 13 is -(CH2-O-CH2) b - and b is between 1 and 26.

[0333] Target unit In some embodiments, the linker binds to the targeting unit to form a targeting unit-linker. In some embodiments, the linker binds to the targeting unit via a stretcher unit (L1) and to the drug unit via a linker subunit L2 to form a conjugate. In some embodiments, the linker binds to the targeting unit via a stretcher unit (L1) and to the drug unit via a linker subunit L2 to form a conjugate. The targeting unit may be an antibody, its antigen-binding moiety, or a non-antibody targeting unit. A non-antibody targeting unit may also be referred to as a non-antibody scaffold.

[0334] In some embodiments, the targeting unit specifically binds to a target molecule. As used herein, “specifically binds” means that the targeting unit described herein (e.g., an antibody or a portion thereof) binds to a target molecule. -5 M (10000 nM) or less, for example, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12This refers to the ability to bind to a target with a KD of M or less. Specific binding may be influenced, for example, by the affinity and binding activity of the targeting unit and the concentration of the target polypeptide. Those skilled in the art can determine the appropriate conditions for the selective binding of the antibodies, antibody-binding moieties, and non-antibody scaffolds described herein to a target using any suitable method, such as titration of the binding agent in a suitable cell binding assay. A targeting unit that is specifically bound to its target cannot be replaced by a dissimilar competitor. In certain embodiments, a targeting unit is said to bind specifically to its target if it preferentially recognizes its target in a complex mixture of proteins and / or macromolecules.

[0335] As used herein, the term “antibody” refers to an immunoglobulin molecule and a molecule containing an immunoactive portion of an immunoglobulin molecule, i.e., an antigen-binding site that specifically binds to a target antigen. The term generally refers to an antibody composed of two immunoglobulin heavy chain variable regions and two immunoglobulin light chain variable regions, including a full-length antibody (having a heavy chain constant region and a light chain constant region).

[0336] Each heavy chain typically consists of a variable region (abbreviated as the VH region) and a constant region. The heavy chain constant region may contain three domains CH1, CH2, and CH3, and optionally a fourth domain CH4. Each light chain consists of a variable region (abbreviated as the VL region) and a constant region. The light chain constant region is the CL domain. The VH and VL regions are further divided into hypervariable regions called complementarity-determining regions (CDRs), and conserved regions called framework regions (FRs) may be scattered throughout. Thus, each VH and VL region contains three CDRs and four FRs arranged from the N-terminus to the C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. This structure is well known to those skilled in the art.

[0337] As used herein, the “antigen-binding region” of an antibody refers to the portion of the antibody having the VH and / or VL sequences or the CDR, which specifically binds to a target antigen. Examples of antigen-binding regions include Fab, Fab', F(ab')2, Fv, scFv, disulfide-bonded Fv, single-domain antibodies (also referred to as VHH, VNAR, sdAb, or nanobody), or diabody (see, for example, Huston et al., Proc. Natl. Acad. Sci. USA, 85, 5879-5883 (1988) and Bird et al., Science 242, 423-426 (1988), which are incorporated herein by reference). As used herein, the terms Fab, F(ab')2, and Fv mean: (i) Fab is a monovalent fragment comprising VL, VH, CL, and CH1 domains; (ii) F(ab')2 is a bivalent fragment comprising two Fab fragments linked to each other within a hinge region via disulfide crosslinks; and (iii) Fv is composed of a VL domain and a VH domain. The two domains of the Fv fragment, namely VL and VH, are encoded by separate coding regions, but they are linked by a synthetic linker, e.g., a polyG4S amino acid sequence (disclosed as SEQ ID NO: 1, "(G4S) nThey may be further linked together using (where n=1 to 5) to allow them to be prepared as a single protein chain with VL and VH regions bound to form a monovalent molecule (known as single-chain Fv or scFv). The term “antigen-binding site” of an antibody is also intended to include such single-chain antibodies. Other forms of single-chain antibodies, such as “diabodies,” are also included here. Diabody is a bivalent, bispecific antibody in which the VH and VL regions are expressed on a single polypeptide chain, but a linker is used to connect the VH and VL regions, which are too short to bind on the same chain, thereby pairing the VH and VL regions with complementary regions (VL and VH, respectively) on different chains, forming two antigen-binding sites (see, for example, Holliger, R, et al. (1993) Proc. Natl. Acad. Sci. USA 90:64446448; Poljak, RJ, et al. (1994) Structure 2:1121-1123).

[0338] A single-domain antibody is an antibody whose antigen-binding portion contains a single monomeric variable antibody region. Single-domain antibodies can originate from the variable region of antibody heavy chains from camelids (e.g., nanobody or VHH moiety). Furthermore, the term single-domain antibody includes autonomous human heavy chain variable domains (aVH) or VNAR moieties derived from sharks (see, for example, Hasler et al., Mol.Immunol. 75:28-37, 2016).

[0339] Techniques for producing single-domain antibodies (e.g., DAB or VHH) are known in the art, as disclosed, for example, in Cossins et al. (2006, Prot Express Purif 51:253-259) and Li et al. (Immunol. Lett. 188:89-95, 2017). Single-domain antibodies can be obtained, for example, from camels, alpacas, or llamas by standard immunization techniques. (See, for example, Muyldermans et al., TIBS 26:230-235, 2001; Yau et al., J Immunol Methods 281:161-75, 2003; and Maass et al., J Immunol Methods 324:13-25, 2007.) VHH may possess potent antigen-binding ability and may interact with novel epitopes inaccessible to conventional VH-VL pairs (see, for example, Muyldermans et al., 2001). Alpaca serum IgG contains approximately 50% IgG antibodies (HCAbs) consisting solely of camel heavy chain (see, for example, Maass et al., 2007). Alpacas can be immunized with antigens, and VHH that binds to and neutralizes target antigens can be isolated (see, for example, Maass et al., 2007). PCR primers for amplifying the alpaca VHH coding sequence have been identified and can be used to construct an alpaca VHH phage display library, which can then be used for isolation of antibody fragments by standard biopanning techniques well known in the art (see, e.g., Maass et al., 2007).

[0340] In some embodiments, the targeting unit is an antibody, or its antigen-binding portion is a bispecific or multispecific binder. Examples of bispecific and multispecific antibodies include scFv1-ScFv2, ScFv12-Fc-scFv22, IgG-scFv, DVD-Ig, triomab / quadroma, two-in-one IgG, scFv2-Fc, TandAb, and scFv-HSA-scFv. In some embodiments, IgG-scFv is IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, svFc-(L)IgG, 2scFV-IgG, or IgG-2scFv. For example, Brinkmann and Kontermann, MAbs 9(2):182-212(2017); Wang et al., Antibodies, 2019, 8, 43; Dong et al., 2011, MAbs 3:273-88; Natsume et al., J. Biochem. 140(3):359-368, 2006; Cheal et al., Mol. Cancer Ther. 13(7):1803-1812, 2014; and Bates See and Power, Antibodies, 2019, 8, 28.

[0341] In some embodiments, the targeting unit is cancer-related antigen, such as CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, and IL-13R-α2. , GD2, 1p19q, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNA Q, GNAS, HRAS, IDH1, IDH2, JAK2, KDR(VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTE N, RET, RRM1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SM AD4, SMARCB1, STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4(TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD These are 71, CD79b, CDH6, CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4. According to the present invention, the terms "cancer-related antigen," "tumor antigen," "tumor expression antigen," "cancer antigen," "cancer-related antigen," and "cancer expression antigen" are equivalent and are used interchangeably herein.

[0342] In some embodiments, the targeting unit specifically binds to a target such as CD19, CD20, CD30, CD33, CD70, LIV-1, or EGFRv3.

[0343] In some embodiments, the targeting unit is an antibody (or fragment thereof) that binds to a target having a sequence disclosed in Leuschner et al., U.S. Patent Application Publication No. 2022 / 0048951 and / or Lerchen et al., U.S. Patent Application Publication No. 2022 / 0016258. Non-limiting examples of monoclonal antibodies include rituximab (Rituxan®), trastuzumab (Herceptin®), pertuzumab (Perjeta®), bevacizumab (Avastin®), ranibizumab (Lucentis®), cetuximab (Erbitux®), alemtuzumab (Campath®), and panibizumab. Tummumab (Vectibix®), ibritumomab (Zevalin®), tositumomab (Bexxar®), ipilimumab, zaltumumab, darotuzumab, figtumumab, ramucirumab, galiximab, farletuzumab, oclezumab, ofatumumab (Arzerra®), CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 Examples include 2C6, 11B8, B1, 2H7, LT20, 1FS or AT80 (see Teeling et al., J.Immunol. 177:362-371 (2006)), daclizumab (Zenapax®), and anti-LHRH receptor antibodies, such as clones A9E4, F1G4, AT2G7, GNRH03, and GNRHR2, which can be used in combination with the conjugate according to the present invention.

[0344] In some embodiments, FOLR1 antibodies, their antigen-binding moieties and other binders, as well as conjugates of such antibodies, antigen-binding moieties and other binders, are provided. Methods of using FOLR1 antibodies, antigen-binding moieties and other binders and their conjugates for the treatment of cancer and other diseases are also provided. The present invention disclosed herein is partially based on FOLR1 antibodies, their antigen-binding moieties and other binders, and their conjugates that specifically bind to FOLR1 and exhibit improved properties. FOLR1 is an important and advantageous therapeutic target for the treatment of certain cancers. FOLR1 antibodies, their antigen-binding moieties, other binders and their conjugates provide compositions and methods based on the use of such antibodies, antigen-binding moieties and associated binders, and their conjugates in the treatment of FOLR1+ cancer and other diseases.

[0345] In some embodiments, the targeting unit is a non-antibody scaffold. In some embodiments, the targeting unit is a non-antibody protein scaffold. Examples of such non-antibody scaffolds include afibodies, affilins, antikalins, atrimers, avimers, bicyclic peptides, Cys-knots, DARPins, FN3 scaffolds (e.g., adnectin, centinline, pronectin, and Tn3), finomers, Knitz domains, and O bodies. (See, for example, Vazquez-Lombardi et al., Drug Discovery Today 20(10):1271 (2015) and the references cited therein.) Examples of such non-antibody protein scaffolds include afibodies, affilins, antikalins, atrimers, avimers, bicyclic peptides, Cys-knots, DARPins, FN3 scaffolds (e.g., adnectin, centinline, pronectin, and Tn3), finomers, Knitz domains, and O bodies. (See, for example, Vazquez-Lombardi et al., Drug Discovery Today 20(10):1271(2015) and the references cited therein.) Non-antibody scaffolds can be thought of as being classified into two structural categories: domain-sized constructs (ranging from 6 to 20 kDa) and restrictive peptides (ranging from 2 to 4 kDa). Examples of domain-sized non-antibody scaffolds include, but are not limited to, afibodies, affilins, antikalins, atrimers, DARPin, FN3 scaffolds (such as adonectin and centinlin), finomers, Knitz domains, pronectin, and O bodies. Examples of peptide-sized non-antibody scaffolds include avimers, bicyclic peptides, and cysteine ​​knots. Non-antibody protein scaffolds can be thought of as being classified into two structural categories: domain-sized constructs (ranging from 6 to 20 kDa) and restrictive peptides (ranging from 2 to 4 kDa). Domain-sized non-antibody scaffolds include, but are not limited to, afibodies, affilins, antikalins, atrimers, DARPin, FN3 scaffolds (such as adonectin and centinlin), finomers, Knitz domains, pronectin, and O bodies.Examples of peptide-sized non-antibody scaffolds include avimers, bicyclic peptides, and cysteine ​​knots. These non-antibody scaffolds and the underlying proteins or peptides on which they are based or from which they are derived are outlined, for example, by Simeon and Chen, Protein Cell 9(1):3-14(2018); Vazquez-Lombardi et al., Drug Discovery Today 20:1271-1283(2015); and Binz et al., Nature Biotechnol. 23:1257-1268(2005), the contents of which are incorporated herein by reference in their entirety.

[0346] Advantages of using non-antibody scaffolds include increased affinity, target neutralization, and stability. Various non-antibody scaffolds can also overcome some of the limitations of antibody scaffolds, for example, with respect to tissue penetration, smaller size, and thermal stability. Some non-antibody scaffolds can also en...

Claims

1. The following structure: A drug containing a linker or a pharmaceutically acceptable salt thereof.

2. The following formula: A conjugate represented by, Ab is the antibody or its antigen-binding portion, and n is the mean drug load (p load ) The aforementioned conjugate.

3. The conjugate according to claim 2, wherein the antibody or its antigen-binding portion is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-bonded Fc, scFv, single-domain antibody, diabody, bispecific antibody, or multispecific antibody.

4. The conjugate according to claim 2, wherein the antibody or its antigen-binding portion is monospecific.

5. The conjugate according to claim 2, wherein the antibody or its antigen-binding portion is divalent.

6. The conjugate according to claim 2, wherein the antibody or its antigen-binding portion is bispecific.

7. A conjugate comprising a drug-linker or a pharmaceutically acceptable salt thereof, and an antibody or its antigen-binding moiety conjugated thereto, The drug-linker has the following structure The aforementioned conjugate.

8. The conjugate according to claim 7, wherein the antibody or its antigen-binding portion is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-linked Fc, scFv, single-domain antibody, diabody, bispecific antibody, or multispecific antibody.

9. The conjugate according to claim 7, wherein the antibody or its antigen-binding portion is monospecific.

10. The conjugate according to claim 7, wherein the antibody or its antigen-binding portion is bivalent.

11. The conjugate according to claim 7, wherein the antibody or its antigen-binding portion is bispecific.

12. The conjugate according to claim 2, wherein the antibody includes a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

13. The conjugate according to claim 4, wherein the antibody includes a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

14. The conjugate according to claim 5, wherein the antibody includes a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

15. The conjugate according to claim 6, wherein the antibody includes a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

16. The conjugate according to claim 7, wherein the antibody comprises a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

17. The conjugate according to claim 9, wherein the antibody comprises a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

18. The conjugate according to claim 10, wherein the antibody comprises a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

19. The conjugate according to claim 11, wherein the antibody comprises a heavy chain constant region, and the heavy chain constant region is an IgG isotype.

20. The conjugate according to claim 2, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

21. The conjugate according to claim 4, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

22. The conjugate according to claim 5, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

23. The conjugate according to claim 6, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

24. The conjugate according to claim 7, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

25. The conjugate according to claim 9, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

26. The conjugate according to claim 10, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

27. ​​The conjugate according to claim 11, wherein the antibody comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being an IgG isotype, and the light chain constant region being a kappa isotype.

28. The conjugate according to any one of claims 2 to 27, having an average drug load (p load) of about 1 to about 8.

29. The conjugate according to any one of claims 2 to 27, wherein the antibody or its antigen-binding portion binds to a cancer-related antigen.

30. The conjugate according to claim 28, wherein the antibody or its antigen-binding portion binds to a cancer-related antigen.

31. The antibody or its antigen-binding moiety is CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, ABL1 , AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, JAK2, KDR (VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1, SMO, SPARC , TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1, STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4 (TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6, CLDN6, CLDN 18.2 A conjugate according to any one of claims 2 to 27, which binds to CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4.

32. The antibody or its antigen-binding moiety is CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate-specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma-associated antigen (HMW-MAA), MAGE-A1, IL-13R-a2, GD2, 1p19q, AB L1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA11, GNAQ, GNAS, HRAS, ID H1, IDH2, JAK2, KDR (VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, PR, PTEN, RET, RRM1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1, STK1 , MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4 (TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, CD70, CD71, CD79b, CDH6, CLD The conjugate according to claim 28, which binds to N6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), nectin-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2, or B7-H4.

33. A pharmaceutical composition comprising a conjugate according to any one of claims 2 to 27 and a pharmaceutically acceptable excipient.

34. A pharmaceutical composition comprising the conjugate described in claim 28 and a pharmaceutically acceptable excipient.

35. A pharmaceutical composition comprising the conjugate described in Claim 29 and a pharmaceutically acceptable excipient.

36. A pharmaceutical composition comprising the conjugate described in claim 30 and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition comprising the conjugate described in claim 31 and a pharmaceutically acceptable excipient.

38. A pharmaceutical composition comprising the conjugate described in claim 32 and a pharmaceutically acceptable excipient.

Images