Linkers, drug linkers and conjugates thereof and methods of use thereof

Abstract

The present invention provides polar units, linker intermediates, linkers, drug-linkers and conjugates thereof.

Description

[Technical Field]

[0001] Electronic sequence listing reference 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-related cells, such as cancer cells and other cells, in the form of antibody-drug conjugates (or ADCs) is of great interest. The design of antibody-drug conjugates, typically by attaching a cytotoxic agent, immunomodulator, or other agent (collectively "drug") to an antibody via a linker, involves consideration of various factors. These factors include the identity and location of the chemical group for drug attachment, the mechanism of drug release, the structural elements (if any) that provide for drug release, and structural modifications of the released free drug, if any. If the drug is released in the extracellular environment, the released form of the drug 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 trafficking 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 attached to each targeting agent (e.g., antibody), referred to as drug load or drug loading). Historically, there was an assumption that higher drug loading was superior to lower drug loading (e.g., 8 loading vs. 4 loading). The rationale was that a more highly loaded conjugate would deliver more drug (e.g., cytotoxic agent) to the target cell. This rationale was supported by the observation that conjugates with higher drug loading were more active against cell lines in vitro. However, certain subsequent studies revealed that this assumption was not confirmed in animal models. Conjugates with drug loadings of 4 or 8 of a specific auristatin were observed to have similar activity in mouse models. See, e.g., Hamblett et al., Clinical Cancer Res. 10:7063-70 (2004). Hamblett et al. further reported that more highly loaded ADCs were cleared more rapidly from the circulation in animal models. This faster clearance suggested PK liability of the highly loaded species compared to the less loaded species. See Hamblett et al. In addition, the more highly loaded conjugates had a lower maximum tolerated dose (MTD) in mice and, consequently, a narrower reported therapeutic index. Ibid. In contrast, ADCs with a drug loading of 2 at an engineered site on a monoclonal antibody have been reported to have the same or better PK and therapeutic index compared to certain 4-loaded ADCs. See, e.g., Junutula et al., Clinical Cancer Res. 16:4769 (2010). Therefore, the recent trend is to develop ADCs with lower drug loading.

[0004] Thus, there is a need for antibody-drug conjugate formats (and other conjugate formats more generally) that allow for higher drug loading while maintaining other properties of lower-loading conjugates, such as favorable 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) Summary of the Invention [Problem to be solved by the invention]

[0006] Provided herein are linkers with hydrophilic properties that maintain the inherent properties of antibody conjugated with linkers and drugs.In particular, linkers help maintain the hydrophilicity of antibodies at higher drug loadings and / or when conjugated with hydrophobic drugs and other agents.Also provided are drug-linkers and conjugates comprising linkers, and methods for using such conjugates for the treatment of cancer and other diseases. [Means for solving the problem]

[0007] In some embodiments, the following formula (V): [ka] (wherein AA is an amino acid unit having 1 to 12 amino acid subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for Drug units; Each wavy line (~) indicates a binding site for a Stretcher unit, and a double wavy line ( [ka] ) indicates the attachment site for the Drug unit) or a salt thereof, Linker intermediates are 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 formula (I): [ka] where L1 is a Stretcher unit having a binding site for a Targeting unit; AA is an amino acid unit with 1 to 12 subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for Drug units; The wavy line (~) indicates the binding site for the targeting unit, and the double wavy line ( [ka] ) indicates an attachment site for a Drug unit) or a salt thereof, Linkers are 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 saccharide unit, a PEG unit, a carboxyl unit, and combinations thereof.

[0009] In some embodiments, the following formula (I): [ka] where L1 is a Stretcher unit having a binding site for a Targeting unit; AA is an amino acid unit with 1 to 12 subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for Drug units; The wavy line (~) indicates the binding site for the targeting unit, and the double wavy line ( [ka] ) indicates an attachment site for a Drug unit) or a salt thereof, Linkers are 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 a saccharide unit, a PEG unit, a carboxyl unit, and a combination thereof.

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

[0011] In some embodiments, the linker intermediate or linker has a formula selected from the following: [ka] or [ka] wherein each R is independently selected from hydrogen, monosaccharides, disaccharides, and polysaccharides; p and o are independently 0 to 2; m is 1 to 8; n is 0 to 4; Each * and each # indicates a binding site for another subunit of an amino acid unit (AA), linker subunit L2 or stretcher unit (L1), or a sugar unit having a salt thereof.

[0012] PEG units In some embodiments, the linker intermediate or linker has a formula selected from the following: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene; R24 and R 25 are respectively H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C1-C8 alkyl; Substituted -C(O)-C1-C8 alkyl; Chelating agent; -C(O)-R 28 (In the formula, R 28 are sugar units of formula (XII) or (XIII); or —NR 24 R 25 are joined together from C3-C8 heterocycles; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26) or a salt thereof. or (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene; R 24 and R 25 one of which is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; 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); R 24 and R 25 the other optionally is polyethylene glycol having 1 to 24 ethylene glycol subunits; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26;) or a salt thereof; 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 26 and R 27 are optional, and C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene -C(O)- and -C(O)-C-C 12 independently selected from alkylene-NH-; R 24 and R 25one of which is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; 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); R 24 and R 25 the other is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; 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 polyethylene glycol having 1 to 24 ethylene glycol subunits; or —NR 24 R 25 are joined together from C3-C8 heterocycles; Each R 29 is optional and independently selected from —C(O)—, —NH—, —C(O)—Ci-C6 alkenylene-, —NH—Ci-C6 alkenylene-, —Ci-C6 alkenylene-NH—, —Ci-C6 alkenylene-C(O)—, —NH(CO)NH—, and triazole; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26; n21 is 1 to 4; n27 is 1 to 4;) or a salt thereof.

[0013] In some embodiments, the R of the PEG unit 24 and R 25 and R are not both H. In some embodiments, the R of the PEG unit 24 and R 25 are each independently selected from H and a polyhydroxyl group, with the proviso that R 24 and R 25 and (b) are not H.

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

[0015] In some embodiments, a linker intermediate or linker, or a salt thereof, is provided, wherein the PEG unit is selected from the following: [ka] (In the formula, R 39 is selected from H, a linear monosaccharide, and optionally, a polyethylene glycol having 1 to 24 ethylene glycol subunits; the wavy line on the left indicates the site of attachment of an amino acid unit to the subunit or part of a linker subunit).

[0016] In some embodiments, the R of the PEG unit24 and R 25 In one embodiment, a linker intermediate or linker is provided, one of which is a linear monosaccharide and the other is a cyclic monosaccharide.

[0017] In some embodiments, a linker intermediate or linker, or a salt thereof, is provided, wherein the PEG unit is selected from the following: [ka] (In the formula, R 41 is a cyclic monosaccharide; the wavy line on the left indicates the site of attachment of an amino acid unit to a subunit or part of a linker subunit).

[0018] In some embodiments, the R of the PEG unit 24 and R 25 are independently selected from cyclic monosaccharides, disaccharides, and polysaccharides. In some embodiments, linker intermediates or linkers are provided wherein the PEG units are selected from the following, or salts thereof: [ka] or [ka] (In the formula, each R 45 is selected from H and a monosaccharide, a disaccharide, or a polysaccharide; R 46 is selected from cyclic monosaccharides, disaccharides, or polysaccharides; the wavy line on the right indicates the attachment site of an amino acid unit to a subunit or part of a linker subunit).

[0019] In some embodiments, the R of the PEG unit 24 and R 25 is independently selected from a linear monosaccharide and a substituted linear monosaccharide, and the substituted linear monosaccharide is replaced with a monosaccharide, a disaccharide, or a polysaccharide. In some embodiments, a linker intermediate or linker is provided in which the PEG unit is selected from the following, or a salt thereof: [ka] (In the formula, R 47 is a linear monosaccharide; each R 49 is selected from monosaccharides, disaccharides and polysaccharides; the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or part of the linker subunit).

[0020] In some embodiments, the R of the PEG unit 24 and R 25 are independently selected from a straight chain monosaccharide and a substituted monosaccharide, and the substituted straight chain 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. In some embodiments, a linker intermediate or linker is provided in which the PEG unit is selected from the following, or a salt thereof: [ka] or [ka] (In the formula, each R 42 are independently selected from linear monosaccharides and substituted linear monosaccharides; each R 43 are independently selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, and amide; the wavy line on the left indicates the site of attachment of an amino acid unit to a subunit or part of a linker subunit).

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

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

[0023] In some embodiments, the R of the PEG unit 24 and R 25 is selected from H, substituted —C(O)—C-C alkyl, substituted —C(O)—C-C alkyl, and substituted —C(O)—C-C alkyl; and R 24 and R 25 and 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, wherein the 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, a linker intermediate or linker, or a salt thereof, is provided wherein the PEG unit is selected from: [ka] or [ka] (where the wavy line on the left indicates the site of attachment of the amino acid unit to a subunit or part of a linker subunit).

[0024] In some embodiments, the R of the PEG unit 24 and R 25 is selected from H and optionally substituted aryl, with the proviso that R 24 and R 25and n are not H, and the optional substituents are as defined herein, for example, in some embodiments, the optional substituent is halo, such as F, Cl, or Br. In some embodiments, linker intermediates or linkers are provided in which the PEG unit is selected from the following, or a salt thereof: [ka] or [ka] (where the wavy line on the left indicates the site of attachment of the amino acid unit to a subunit or part of a linker subunit).

[0025] In some embodiments, R 24 and R 25 taken together form an optionally substituted C3-C8 heterocycle or heteroaryl, in some embodiments, the C3-C8 heterocycle or heteroaryl is unsubstituted. [ka] or a salt thereof.

[0026] In some embodiments, the R of the PEG unit 24 and R 25 is independently selected from H and a chelating agent, and the chelating agent is connected to —NR by an alkylene, arylene, carbocyclo, heteroarylene, or heterocarbocyclo; 24 R 25 optionally attached to the nitrogen of R 24 and R 25and N,N'-dialkyl-substituted piperazines are provided. In some embodiments, linker intermediates or linkers are provided wherein the chelator 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'-dialkyl-substituted piperazines. In some embodiments, linker intermediates or linkers are provided wherein the PEG unit is selected from the following, or a salt thereof: [ka] or [ka] (where the wavy line on the left indicates the site of attachment of the amino acid unit to a subunit or part of a linker subunit).

[0027] In some embodiments, linker intermediates or linkers are provided in which each monosaccharide of a sugar unit or PEG unit is independently selected from the following: a C5 or C6 sugar selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, gulose, idostulose, aldose, ketose, glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine; a sugar acid 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 is 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 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof.

[0030] In some embodiments, the PEG unit is a formula selected from: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -R 30 (XXX) (In the formula, R 20 is a functional group for attachment to a subunit of the amino acid unit (if present) and / or part of the linker subunit L2; R 21 and R 22 are each optional and, when present, are independently a C1-C3 alkylene group; R 30 is an optionally substituted C3-C 10selected from carbocycles; thioureas; optionally substituted thioureas; ureas; optionally substituted ureas; sulfamides; alkylsulfamides; acylsulfamides, optionally substituted alkylsulfamides; optionally substituted acylsulfamides; sulfonamides; optionally substituted sulfonamides; guanidines (including alkyl and aryl guanidines); phosphoramides; or optionally substituted phosphoramides; or R 30 represents azido, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, -NH-C(O)-alkynyl-R 65 cyclooctyne; selected from -NH-cyclooctyne, -NH-C(O)-cyclooctyne or -NH-(cyclooctyne)2; R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26;) or a salt thereof; (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) (In the formula, R 20 is a functional group for attachment to a subunit of an amino acid unit (if present) or part of the linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 having; R 35is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26;) or a salt thereof; (c) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII) (In the formula, R 20 is a functional group for attachment to a subunit of an amino acid unit (if present) or part of the linker subunit L2; R 21 and R 22 are each optional and independently a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch independently having 1 to 26 ethylene glycol subunits, and each branch has at its terminus R 35 having; R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, and optionally substituted heteroaryl; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26;) or a salt thereof, and (d) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII) (In the formula, R 20 is a functional group for attachment to a subunit of an amino acid unit (if present) or part of the linker subunit L2; R 21 and R 22 are each optional and are a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 having; R 33 is C1-C3 alkylene, C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene, or -C(O)-C1-C3 alkylene-C(O); R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26; or a salt thereof.

[0031] In some embodiments, a linker intermediate or linker is provided in which the PEG unit has a formula selected from the following, or a salt thereof: ~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 is a functional group for attachment to a subunit of an amino acid unit (if present) or part of the linker subunit L2; R 21 and R 22 are each optional and are a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 R 33 is C1-C3 alkylene, -C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene or -C(O)-C1-C3 alkylene-C(O); R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, or optionally substituted heteroaryl; the wavy line (~) represents R 20and n20 is 1-26). In some embodiments, a linker intermediate or linker is provided in which the PEG unit is selected from the following: [ka] (In the formula, R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; the wavy line on the left indicates the site of attachment to a subunit of an amino acid unit or part of a linker subunit).

[0032] In some embodiments, R 20 is 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 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof.

[0034] In some embodiments, the formula is selected from: ~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 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; Each R 43 independently, absent or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

[0035] In some embodiments, the formula is selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; R 43 does not exist or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

[0036] In some embodiments, the formula is selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) (In the formula, R 40 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C3 alkylene; R 43 is absent or C1-C6 alkylene, -NH-C1-C 12 Alkylene, -C1-C6 alkylene-NH-, -C(O)-C1-C6 alkylene, -C1-C6 alkylene-C(O)-, -NH-C1-C6 alkylene-C(O)-, -C(O)-C1-C6 alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C6 alkylene, -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 the groups is H or C1-C6 alkylene, and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1 to 16; n41 is 1 to 4; n42 is 1 to 4), or a salt thereof.

[0037] In some embodiments, R 40 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof.

[0038] In some embodiments, R 40 but one of the following structures: [ka] or [ka] (Wherein, R=H or C1-6 alkyl; and n=0~12 (*) indicates the R for a subunit of an amino acid unit or a part of the linker subunit L2. 40 indicates the binding site of ( [ka] ) is the R 40 or a stereoisomer thereof.

[0039] In some embodiments, R 40 but one of the following structures: [ka] or [ka] (In the formula, n=0~12 (*) indicates the R for a subunit of an amino acid unit or a part of the linker subunit L2. 40 indicates the binding site of ( [ka] ) is the R 40 or a stereoisomer thereof.

[0040] In some embodiments, R 43 -(NR 44 R 45 ) n41 But R 43 When present, one of the following structures: [ka] or [ka] (In the formula, R=H, C1-6 Alkyl, polyhydroxyl, or substituted polyhydroxyl ( [ka] ) is the R 43 or a stereoisomer thereof.

[0041] In some embodiments, R 43 -(NR 44 R 45 ) n41 But R 43 When present, one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is the R 43 or a stereoisomer thereof.

[0042] In some embodiments, —NR 44 R 45 but one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is the -NR 44 R 45or a stereoisomer thereof.

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

[0044] In some embodiments, the formula is selected from: ~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 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; Each R 43is independently absent or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; R 46 is selected from amino, amino-alkyl-amino, or —NH—C(O)—NH—S(O)2—NH—; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

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

[0046] In some embodiments, the formula is selected from: [ka] or [ka] wherein each Y is independently R 76 or [ka] and Each R 76 are independently H, acetyl, -P(=O)(OH)2, or -(CH2) v -OS(=O)2(OH); Each R a and R b are independently H or R a and R b together with the carbon to which they are attached to form an oxo group; each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; A linker intermediate or linker is provided that includes a PEG unit having an amino acid unit (AA), a linker subunit L2, or a Stretcher unit (L1) subunit (where each * indicates a binding site for the subunit), or a salt thereof.

[0047] In some embodiments, the formula is selected from: [ka] or [ka] (In the formula, each R 76 are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v S(=O)2(OH); each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; A linker intermediate or linker is provided that includes a PEG unit having an amino acid unit (AA), a linker subunit L2, or a Stretcher unit (L1) subunit (where each * indicates a binding site for the subunit), or a salt thereof.

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

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

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

[0051] In some embodiments, each R a and R b are independently H.

[0052] In some embodiments, R a and R b are provided which, together with the carbon to which they are attached, form an oxo group.

[0053] In some embodiments, a linker intermediate or linker is provided in which q is 10-20.

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

[0055] In some embodiments, a linker intermediate or linker, or a salt thereof, is provided, wherein the PEG unit is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] wherein each Z is joined by a * and is individually selected from: [ka] , and [ka] each [ka] indicates a binding site for another subunit of the amino acid unit (AA), linker subunit L2 or stretcher unit (L1).

[0056] Carboxyl 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 is selected from C-C alkylene, C-C alkylene-C(O)-, -C(O)-C-C alkylene- and -C(O)-C-C alkylene-C(O)-; R 70 is ~NR 71 (R 72 -R 73 ) where R 71 is H, C1-C 12 Alkyl, substituted C1-C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 72 is absent or selected from optionally substituted C1-C3 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 carbocycle, optionally substituted aryl or optionally substituted heteroaryl; R 73 is a carboxyl or polycarboxyl, wherein the 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 amido; Each wavy line (~) indicates a binding site for another subunit of the amino acid unit (AA), linker subunit L2, or stretcher unit (L1); each of p1 and o1 is independently selected from 0 to 2; or (b) L 70 is selected from C-C alkylene, C-C alkylene-C(O)-, -C(O)-C-C alkylene- and -C(O)-C-C alkylene-C(O)-; R 70 is ~NR 71 (R 75 -(R 73 )2), wherein R71 is H, C1-C 12 Alkyl, substituted C1-C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 75 is a branched optionally substituted C1-C3 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 carbocycle, optionally substituted aryl, or optionally substituted heteroaryl, and each R 73 is independently carboxyl or polycarboxyl, wherein the 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 amido; Each wavy line (~) indicates a binding site for another subunit of the amino acid unit (AA), linker subunit L2, or stretcher unit (L1); each of p1 and o1 is independently selected from 0 to 2; or (c) L 70 is selected from C-C alkylene, C-C alkylene-C(O)-, -C(O)-C-C alkylene- and -C(O)-C-C alkylene-C(O)-; R 70 is approximately N(R 74 -R 73 )(R 72 -R 73 ) where R 72 and R 74are each independently selected from optionally substituted C1-C3 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 carbocycle, optionally substituted aryl, or optionally substituted heteroaryl; and each R 73 is independently carboxyl or polycarboxyl and contains 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 amido; Each wavy line (~) indicates a binding site for another subunit of the amino acid unit (AA), linker subunit L2, or stretcher unit (L1); Each of p1 and o1 is independently selected from 0 to 2).

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

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

[0059] In some embodiments, linker intermediates or linkers are provided in which L2 or AA-L2 has one of the following structures: [ka] or [ka] (where the wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is attached to the benzyl alcohol).

[0060] In some embodiments, linker intermediates or linkers are provided in which ~AA-L2~ has a formula selected from the following: [ka] , [ka] ,or [ka] (wherein the square brackets indicate amino acid units, each aa is an optional subunit of AA, L2 is a linker subunit, and each wavy line (~) indicates a binding site for a Stretcher unit; aa1(PEG) is a PEG unit attached to an amino acid subunit of AA, SU is a sugar unit attached to a subunit of AA or L2, and CU is a carboxyl unit attached to a subunit of AA or L2; and the double wavy line ( [ka] ) indicates a binding site for a Drug unit, and aa and aa1 are independently selected from alpha, beta and gamma amino acids and derivatives thereof).

[0061] In some embodiments, linker intermediates or linkers are provided in which ~AA-L2~ has a formula selected from the following: [ka] [ka] ,or [ka] (wherein the 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, the wavy line (~) indicates the attachment site for the 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 the double wavy line ( [ka] ) indicates the attachment site for the Drug unit; aa and aa1 are independently selected from alpha, beta and gamma amino acids and derivatives thereof).

[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, linker intermediates or linkers are provided in which ~AA-L2~ has a formula selected from the following: [ka] , [ka] ,or [ka] (wherein the square brackets indicate amino acid units, aa is an optional subunit of AA, L2 is a linker subunit, the wavy line (~) indicates a binding site for a Stretcher unit; each of aa1(PEG) and aa2(PEG) is a PEG unit bound to aa or another PEG unit; each SU is a sugar unit bound to aa or another sugar unit, each CU is a carboxyl unit bound to aa or another carboxyl unit, and the double wavy line ( [ka] ) indicates the attachment site for the Drug unit; aa, aa1 and aa2 are independently selected from alpha, beta and gamma amino acids and derivatives thereof).

[0064] In some embodiments, linker intermediates or linkers are provided in which ~AA-L2~ has a formula selected from the following: [ka] [ka] ,or [ka] (wherein the square brackets represent amino acid units, aa is an amino acid subunit of AA, L2 is a linker subunit attached to the side chain of aa, each wavy line (~) represents a binding site for a Stretcher unit; each of aa1(PEG) and aa2(PEG) is a PEG unit attached to aa, each SU is a sugar unit attached to aa; each CU is a carboxyl unit attached to aa; and the double wavy line ( [ka] ) indicates a binding site for a Drug unit; each of aa, aa1 and aa2 is independently selected from alpha, beta and gamma amino acids and derivatives thereof).

[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 cleavable 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 a SU-valine-citrulline peptide, a SU-valine-lysine peptide, a SU-valine-alanine peptide, a SU-phenylalanine-lysine peptide, or a SU-glycine-glycine-phenylalanine-glycine peptide.

[0067] In some embodiments, a linker intermediate or linker is provided in which the polar unit is a carboxyl unit (CU). In some embodiments, 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, wherein the CU-lysine is a carboxyl unit comprising a lysine residue.

[0068] In some embodiments, a linker intermediate or linker is provided in which the polar unit is a PEG unit (PEG). In some embodiments, a linker intermediate or linker is provided in which the cleavable peptide comprises a Lys(PEG)-valine-citrulline peptide, a valine-Cit(PEG) peptide, a Lys(PEG)-valine-lysine peptide, a valine-lysine(PEG) peptide, a Lys(PEG)-valine-alanine peptide, a Lys(PEG)-phenylalanine-lysine peptide, a phenylalanine-Lys(PEG) peptide, or a Lys(PEG)-glycine-glycine-phenylalanine-glycine peptide, wherein Lys(PEG) and Cit(PEG) comprise PEG units attached to lysine or citrulline residues, respectively.

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

[0070] In some embodiments, linker intermediates or linkers are 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] wherein each Z is joined by a * and is individually selected from: [ka] , and [ka] The wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is attached to the benzyl alcohol (i.e., the H of the benzyl alcohol is replaced by a bond with the Drug unit).

[0071] In some embodiments, a linker intermediate or linker is provided in which L2 is attached to a side chain of an AA subunit. [ka] However, a linker intermediate or linker having one of the following structures is provided: [ka] or [ka] where the wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is either attached to the terminal acid group or the benzyl alcohol (i.e., an H of the acid or benzyl alcohol is replaced by a bond to the Drug unit), or is attached to the wavy line ( [ka] ) indicates the binding site for the Drug unit).

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

[0073] In some embodiments, a linker intermediate or linker is provided that further comprises a Stretcher unit to or from the linker. In some embodiments, the Stretcher unit is selected from: [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- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene- (wherein b is 1 to 26), -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-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)- (wherein b is 1 to 26), -(CH2-O-CH2) b-C1-C8 alkylene-C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)- (wherein 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- (wherein b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -NH- (wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b-C1-C8 alkylene-NH- (wherein 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-C8 carbocyclo-S-, -O-(C1-C8 alkyl)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-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 alkylene-S-), or The stretcher unit is maleimide (C1-C 10 Alkylene-C(O)-, maleimide (CH2OCH2) p2 (C1-C 10 Alkyne) C(O)-, Maleimide (C1-C 10 Alkyne) (CH2OCH2) p2 Linkers are provided that include C(O)-, where p2 is 1-26, or open forms thereof.

[0074] In some embodiments, a linker is provided wherein the Stretcher unit is selected from: [ka] and [ka] (wherein, wavy line [ka] indicates the attachment site of the Stretcher unit to the Amino Acid unit, and the attachment site to the Targeting unit is on the maleimide, primary amine or alkyne functional group).

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

[0076] In some embodiments, linkers are provided that further comprise at least one drug unit attached to the linker subunit L2 to form the drug linker. In some embodiments, drug linkers are provided wherein the drug unit is selected from a cytotoxic agent, an immunomodulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioisotope, and a chelating ligand. In some embodiments, drug linkers are provided wherein the drug unit is a cytotoxic agent. In some embodiments, drug linkers are provided wherein the cytotoxic agent is selected from the group consisting of an auristatin, a maytansinoid, a camptothecin, a duocarmycin, and a calicheamicin. In some embodiments, drug linkers are provided wherein the cytotoxic agent is an auristatin. In some embodiments, drug linkers are provided wherein the cytotoxic agent is MMAE or MMAF. In some embodiments, drug linkers are provided wherein the cytotoxic agent is a camptothecin. In some embodiments, drug linkers are provided wherein the cytotoxic agent is exatecan or SN-38. In some embodiments, drug linkers are provided wherein the cytotoxic agent is exatecan. In some embodiments, Drug-Linkers are provided wherein the cytotoxic agent is calicheamicin. In some embodiments, Drug-Linkers are provided wherein the cytotoxic agent is a maytansinoid. In some embodiments, Drug-Linkers are provided wherein the maytansinoid is maytansine, maytansinol, or ansamatocin-2.

[0077] In some embodiments, Drug-Linkers are provided wherein the cytotoxic agent is calicheamicin. In some embodiments, Drug-Linkers are provided wherein the cytotoxic agent is a maytansinoid. In some embodiments, Drug-Linkers are provided wherein the maytansinoid is maytansine, maytansinol, or ansamatocin-2.

[0078] In some embodiments, a Drug-Linker is provided in which the Drug unit is an immunomodulatory agent. In some embodiments, a Drug-Linker is provided in which the immunomodulatory agent 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 immunomodulatory agent is a TLR7 agonist. In some embodiments, a Drug-Linker is provided in which the TLR7 agonist is an imidazoquinoline, imidazoquinoline amine, thiazoquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazol-2-amine, tetrahydropyridopyrimidine, heteroaromatic thiol azide-2,2-dioxide, benzonaphthyridine, guanosine analog, adenosine analog, thymidine homopolymer, ssRNA, CpG-A, PolyG10, or PolyG3. In some embodiments, a Drug-Linker is provided in which the immunomodulatory agent is a TLR8 agonist. In some embodiments, a drug-linker is 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-benzimidazol-2-amine, tetrahydropyridopyrimidine, or ssRNA. In some embodiments, a drug-linker is provided in which the immunomodulatory agent is a STING agonist. In some embodiments, a drug-linker is provided in which the immunomodulatory agent is a RIG-I agonist. In some embodiments, a drug-linker is 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, a Drug-Linker is provided in which the Drug unit is a chelating ligand. In some embodiments, the chelating ligand is selected from platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti), or iridium (Ir); or a radioactive isotope such as 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]

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[0081] In some embodiments, a conjugate is provided that includes a targeting unit attached to any of the drug-linkers described herein. In some embodiments, a conjugate is provided wherein the targeting unit is selected from an antibody or an antigen-binding portion thereof. In some embodiments, a conjugate is provided wherein 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 wherein the targeting unit is a diabody, DART, anticalin, affibody, avimer, DARPin, or adnectin. In some embodiments, a conjugate is provided wherein the targeting unit is monospecific. In some embodiments, a conjugate is provided wherein the targeting unit is bivalent. In some embodiments, a conjugate is provided wherein the targeting unit is bispecific. In some embodiments, a conjugate is provided wherein the average drug loading (p load ) is about 1 to about 8, about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 3 to about 5, about 6 to about 8, or about 8 to about 16.

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

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[0083] In some embodiments, the above conjugates are provided, wherein the targeting unit binds to a target molecule such as CD19, CD20, CD30, CD33, CD70, LIV-1, or EGFRv3.

[0084] In some embodiments, the above conjugate is provided, 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.

[0085] In some embodiments, the targeting unit is selected from the group consisting of cancer-associated antigens, 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 , 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 selected from the group consisting of rituximab (Rituxan®), trastuzumab (Herceptin®), pertuzumab (Perjeta®), bevacizumab (Avastin®), ranibizumab (Lucentis®), cetuximab (Erbitux®), alemtuzumab (Campath®), panitumumab (Vectibix®), and ribozyme (Ribozyme®).

[0033] Provided are conjugates as described above that are selected from the group consisting of ibritumomab, ibritumomab tiuxetan (Zevalin®), tositumomab (Bexxar®), ipilimumab, zalutumumab, dalotuzumab, figitumumab, ramucirumab, galiumtuzumab, farletuzumab, ocrelizumab, ofatumumab (Arzerra®), tositumumab, ibritumomab, CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 2C6, 11B8, B1, 2H7, LT20, 1FS or AT80, daclizumab (Zenapax®), or an anti-LHRH receptor antibody, e.g., clones A9E4, F1G4, AT2G7, GNRH03 or GNRHR2.

[0087] In some embodiments, the above conjugate is provided, wherein 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, wherein 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 the VH and VL CDRs have an amino acid sequence selected from the set of amino acid sequences set forth in the group consisting of: (a) SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35, respectively; and (b) 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, respectively. In certain embodiments, the VH and VL regions have an amino acid sequence selected from the pair of amino acid sequences set forth in the group consisting of SEQ ID NO:26 and SEQ ID NO:27, respectively; and the heavy chain framework region and the light chain framework region are optionally modified with substitution, deletion, or insertion of 1 to 8 amino acids in the framework region. In a specific embodiment, the antibody is F131 and the drug-linker is LD038.

[0089] In some embodiments, a pharmaceutical composition is provided comprising any of the conjugates described herein and a pharmaceutically acceptable carrier.

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

[0091] [The present invention 1001] Formula (V): [C1] JPEG0007735526000222.jpg15170 (wherein AA is an amino acid unit having 1 to 12 amino acid subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for Drug units; Each wavy line (~) indicates a binding site for a Stretcher unit; Double wavy line ( [C2] JPEG0007735526000223.jpg6170 ) indicates the binding site for the Drug unit) or a salt thereof, wherein at least one polar unit is present within the amino acid unit, the linker subunit, or both, and the polar unit is selected from a saccharide unit, a PEG unit, a carboxyl unit, and combinations thereof. [The present invention 1002] Formula (I): [C3] JPEG0007735526000224.jpg15170 where L1 is a Stretcher unit having a binding site for a Targeting unit; AA is an amino acid unit with 1 to 12 subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 binding sites for Drug units; The wavy line (~) indicates the binding site for the targeting unit; Double wavy line ( [C4] JPEG0007735526000225.jpg6170 ) indicates an attachment 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 a saccharide unit, a PEG unit, a carboxyl unit, and a combination thereof. [The present invention 1003] The sugar units have the following formula: L3-**N(CH 2 -(CH(XR)) k -X 1 (X 2 )) 2 (X) wherein each X is independently selected from NH or O; each R is independently selected from hydrogen, acetyl, monosaccharides, disaccharides, and polysaccharides; each X 1 is CH 2 and C(O); each X 2 are independently selected from H, OH, and OR; k is 1 to 10; L3 is represented by the following general formula (XI): L3a | *-NH-(CH 2 ) p -CH-(CH 2 ) o -C(O)-# (XI) (Wherein, L3a is C 1 -C 10 selected from alkylene and polyethylene glycol having 1 to 24 ethylene glycol subunits; p and o are independently 0 to 2; Each * and each # indicates a binding site for another subunit of the amino acid unit (AA), linker subunit L2 or stretcher unit (L1); L3a is a linker intermediate or linker of the present invention 1001 or 1002, having a group covalently bonded to the N atom marked with ** in formula (X)) or a salt thereof) or a salt thereof. [The present invention 1004] The sugar unit is selected from the following formula: [5] JPEG0007735526000226.jpg64170 or [6] JPEG0007735526000227.jpg52170 wherein each R is independently selected from hydrogen, monosaccharides, disaccharides, and polysaccharides; p and o are independently 0 to 2; m is 1 to 8; n is 0 to 4; 1006. The linker intermediate or linker of any of claims 1001 to 1003, wherein each * and each # indicates a binding site for another subunit of the amino acid unit (AA), the linker subunit L2 or the stretcher unit (L1), or a salt thereof. [The present invention 1005] The PEG unit is selected from the following formula: (a) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 is a functional group for binding to a subunit of the amino acid unit or a portion of the linker subunit L2; R 21 and R 22 are each independently an optional C 1 -C 3 is alkylene; R 24 and R 25 are respectively H; polyhydroxyl group; substituted polyhydroxyl group; -C(O)-polyhydroxyl group; substituted -C(O)-polyhydroxyl group; optionally substituted C 3 -C 10 Carbocyclic ring; optionally substituted C 1 -C 3 Alkylene C 3 -C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C 1 -C 8 Alkyl; Substituted -C(O)-C 1 -C 8 Alkyl; Chelating agent; -C(O)-R 28 (In the formula, R 28 are sugar units of formula (XII) or (XIII); or —NR 24 R 25 C 3 -C 8 Composed of heterocycles; The wavy line (~) is R 20 indicates the binding site for; n20 is 1 to 26;) or a salt thereof; or (b) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NR 24 R 25 (XX) (In the formula, R 20 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 21 and R 22 are each independently an optional C 1 -C 3 is alkylene; R 24 and R 25 one of which is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C 3 -C 10 Carbocyclic ring; optionally substituted C1 -C 3 Alkylene C 3 -C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C 1 -C 8 Alkyl; Substituted -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); R 24 and R 25 the other optionally is polyethylene glycol having 1 to 24 ethylene glycol subunits; The wavy line (~) is R 20 indicating the binding site to n20 is 1 to 26;) or a salt thereof; 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 26 and R 27 are 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 independently selected from alkylene-NH-; R 24 and R 25 one of which is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C 3 -C 10 Carbocyclic ring; optionally substituted C 1 -C 3 Alkylene C 3 -C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C 1 -C 8 Alkyl; Substituted -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); R 24 and R 25 the other of which is H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C 3 -C 10 Carbocyclic ring; optionally substituted C 1 -C 3 Alkylene C 3 -C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C 1 -C 8 Alkyl; Substituted -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 polyethylene glycol having 1 to 24 ethylene glycol subunits; or —NR 24 R 25 C 3 -C 8 Composed of heterocycles; Each R 29 is optional, -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 (~) is R 20 indicating the binding site to n20 is 1 to 26; n21 is 1 to 4; n27 is 1 to 4; or a salt thereof. [The present invention 1006] R 24 and R 25 and n is 0 or 1. The linker intermediate or linker of the present invention 1005, wherein both of [The present invention 1007] R 24 and R 25 are each independently selected from H and a polyhydroxyl group, with the proviso that R 24 and R 25 1005 or 1006, a linker intermediate or linker of the present invention, provided that both of [The present invention 1008] 1008. The linker intermediate or linker of any of claims 1005 to 1007, wherein said polyhydroxyl group is optionally a straight chain monosaccharide selected from a C6 or C5 sugar, a sugar acid, or an amino sugar. [The present invention 1009] the C6 or C5 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idose, talose, aldose, and ketose; the sugar acid is selected from gluconic acid, aldonic acid, uronic acid, and uronic acid; or 1008. The linker intermediate or linker of the present invention, wherein said amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine and N-acetylgalactosamine. [The present invention 1010] 1009. The linker intermediate or linker of any one of claims 1005 to 1009, wherein said PEG unit is selected from the following, or a salt thereof: [7] JPEG0007735526000228.jpg200170 (In the formula, R 39 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 site of attachment of the amino acid unit to the subunit or to the portion of the linker subunit). [The present invention 1011] R 24 and R 25 The linker intermediate or linker of the present invention 1005 or 1006, wherein one of the sugars is a linear monosaccharide and the other is a cyclic monosaccharide. [The present invention 1012] The linker intermediate or linker of the present invention, wherein the PEG unit is selected from the following: [8] JPEG0007735526000229.jpg110170 (In the formula, R 41 is a cyclic monosaccharide; the wavy line on the left indicates the site of attachment of the amino acid unit to the subunit or to the portion of the linker subunit). [The present invention 1013] R 24 and R 25 is independently selected from cyclic monosaccharides, disaccharides and polysaccharides. [The present invention 1014] The linker intermediate or linker of the present invention 1013, wherein the PEG unit is selected from the following, or a salt thereof: [9] JPEG0007735526000230.jpg132170 or [C10] JPEG0007735526000231.jpg61170 (In the formula, each R 45 is selected from H and a monosaccharide, a disaccharide, or a polysaccharide; R 46 is selected from a cyclic monosaccharide, disaccharide, or polysaccharide; the wavy line on the right indicates the attachment site of the amino acid unit to the subunit or the portion of the linker subunit). [The present invention 1015] R 24 and R 25 is independently selected from a linear monosaccharide and a substituted linear monosaccharide, and said substituted linear monosaccharide is substituted with a monosaccharide, a disaccharide, or a polysaccharide. [The present invention 1016] The linker intermediate or linker of the present invention 1015, wherein the PEG unit is selected from the following, or a salt thereof: [C11] JPEG0007735526000232.jpg169170 (In the formula, R 47 is a linear monosaccharide; each R 49 is selected from monosaccharides, disaccharides and polysaccharides; the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or to the portion of the linker subunit). [The present invention 1017] R 24 and R 25 are independently selected from linear monosaccharides and substituted monosaccharides, said substituted linear monosaccharides being 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. [The present invention 1018] The linker intermediate or linker of the present invention 1017, wherein the PEG unit is selected from the following, or a salt thereof: [C12] JPEG0007735526000233.jpg34170 or [C13] JPEG0007735526000234.jpg51170 (In the formula, each R 42 are independently selected from linear monosaccharides and substituted linear monosaccharides; each R 43 are independently selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, and amide; the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or the portion of the linker subunit). [The present invention 1019] R 24 and R 25 is a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group, and R<h2 style=";text-align:left;direction:ltr"> 24 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 25 <h2 style=";text-align:left;direction:ltr"> the other is H, a -C(O)-polyhydroxyl group, a substituted -C(O)-polyhydroxyl group, a polyhydroxyl group or a substituted polyhydroxyl group; and said substituted -C(O)-polyhydroxyl group and polyhydroxyl group are substituted with a monosaccharide, a disaccharide, a polysaccharide, an alkyl, an -O-alkyl, an aryl, a carboxyl, an ester or an amide. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1020] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The linker intermediate or linker of the present invention 1019, wherein the PEG unit is selected from the following, or a salt thereof: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [C14] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000235.jpg21170<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [C15] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000236.jpg61170<h2 style=";text-align:left;direction:ltr"> (wherein the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or the portion of the linker subunit). <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1021] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 24 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 25 <h2 style=";text-align:left;direction:ltr"> H, substituted -C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 8<h2 style=";text-align:left;direction:ltr"> Alkyl, substituted -C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 4<h2 style=";text-align:left;direction:ltr"> Alkyl or substituted -C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 3<h2 style=";text-align:left;direction:ltr"> alkyl, with the proviso that R <h2 style=";text-align:left;direction:ltr"> 24 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 25 <h2 style=";text-align:left;direction:ltr"> and -C are not H; <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 8<h2 style=";text-align:left;direction:ltr"> Alkyl, -C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 4<h2 style=";text-align:left;direction:ltr"> Alkyl and -C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 3<h2 style=";text-align:left;direction:ltr"> The linker intermediate or linker of 1005 or 1006, wherein the alkyl is substituted with hydroxyl and / or carboxyl. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1022] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The linker intermediate or linker of the present invention 1021, wherein the PEG unit is selected from the following, or a salt thereof: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [C16] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000237.jpg196170<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [C17] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000238.jpg31170<h2 style=";text-align:left;direction:ltr"> (In the formula, R <h2 style=";text-align:left;direction:ltr"> 48 <h2 style=";text-align:left;direction:ltr"> are H, OH, and CH <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> -C substituted with OH, COOH, or hydroxyl or carboxyl <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 6<h2 style=";text-align:left;direction:ltr"> alkyl; the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or the portion of the linker subunit). <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1023] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 24 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 25 <h2 style=";text-align:left;direction:ltr"> One of the groups is H, substituted -C(O)-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 8 Alkyl, substituted -C(O)-C 1 -C 4 Alkyl and substituted -C(O)-C 1 -C 3 alkyl, and R 24 and R 25 The other is a 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, substituted -C 1 -C 4 Alkyl and Substituted-C 1 -C 3 alkyl, 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 The linker intermediate or linker of 1005 or 1006, wherein the alkyl is substituted with hydroxyl and / or carboxyl. [The present invention 1024] The linker intermediate or linker of the present invention 1023, wherein the PEG unit is selected from the following, or a salt thereof: [C18-1] JPEG0007735526000239.jpg182170 [C18-2] JPEG0007735526000240.jpg49170 or [C19] JPEG0007735526000241.jpg26170 (wherein the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or to the portion of the linker subunit). [The present invention 1025] R 24 and R 25 is selected from H and optionally substituted aryl, with the proviso that R 24 and R 25 1005 or 1006, a linker intermediate or linker of the present invention, provided that both of [The present invention 1026] The linker intermediate or linker of the present invention 1025, wherein the PEG unit is selected from the following, or a salt thereof:

[20] JPEG0007735526000242.jpg47170 or

[21] JPEG0007735526000243.jpg20170 (wherein the wavy line on the left indicates the binding site of the subunit of the amino acid unit or the portion of the linker subunit). [The present invention 1027] R 24 and R 25 together with an optionally substituted C 3 -C 8 A linker intermediate or linker of the present invention 1005 or 1006, which forms a heterocycle or heteroaryl. [The present invention 1028] The PEG units are [C22] JPEG0007735526000244.jpg16170 ’ or a salt thereof. [The present invention 1029] R 24 and R 25 is independently selected from H and a chelator, and said chelator is optionally connected to —NR by alkylene, arylene, carbocyclo, heteroarylene, or heterocarbocyclo. 24 R 25 is bonded to the nitrogen of R 24 and R 25 1005 or 1006, a linker intermediate or linker of the present invention, provided that both of [The present invention 1030] 1029. A linker intermediate or linker according to the present invention, 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 piperazines. [The present invention 1031] The linker intermediate or linker of the present invention 1030, wherein the PEG unit is selected from the following, or a salt thereof:

[23] JPEG0007735526000245.jpg36170 or

[24] JPEG0007735526000246.jpg44170 (wherein the wavy line on the left indicates the attachment site of the amino acid unit to the subunit or the portion of the linker subunit). [The present invention 1032] Each monosaccharide is a C5 or C6 sugar selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, gulose, idostulose, aldose, ketose, glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine; sugar acids selected from gluconic acid, aldonic acid, uronic acid, and urosonic acid; or 1020. The linker intermediate or linker of any of claims 1005 to 1019, wherein the amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. [The present invention 1033] R 20 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or a protected form thereof. [The present invention 1034] The PEG unit is selected from the following formula: (a) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -R 30 (XXX) (In the formula, R 20 is a functional group for attachment to a subunit of said amino acid unit (if present) and / or a portion of the linker subunit L2; R 21 and R 22 are each optional and, if present, independently 1 -C 3 is an alkylene group; R 30 is an optionally substituted C 3 -C 10 carbocycle; 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 aryl guanidine); phosphoramide; or optionally substituted phosphoramide; or R 30 represents azido, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, -NH-C(O)-alkynyl-R 65 ;Cyclooctyne;-NH-cyclooctyne, -NH-C(O)-cyclooctyne or -NH-(cyclooctyne) 2 Selected from; R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicating the binding site to n20 is 1 to 26;) or a salt thereof; (b) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NH-C(O)-R 31 (XXXI) (In the formula, R 20 is a functional group for attachment to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 are each independently an optional C 1 -C 3 is an alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 having; R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicating the binding site to n20 is 1 to 26;) or a salt thereof; (c) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -C(O)NH-R 31 (XXXII) (In the formula, R 20 is a functional group for attachment to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 are each optional and independently 1 -C 3 is an alkylene group; R 31 is a branched polyethylene glycol chain, each branch independently having 1 to 26 ethylene glycol subunits, and each branch has at its terminus R 35 having; R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, and optionally substituted heteroaryl; The wavy line (~) is R 20 indicating the binding site to n20 is 1 to 26;) or a salt thereof, and (d) ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -N-(R 33 -R 31 ) 2 (XXXIII) (In the formula, R 20 is a functional group for attachment to a subunit of the amino acid unit (if present) or to a portion of the linker subunit L2; R 21 and R 22 are optional, and C 1 -C 3 is an alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 having; R 33 is 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 alkylene-C(O); R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) is R 20 indicating the binding site to n20 is 1 to 26; or a salt thereof. [This invention 1035] 1005. The linker intermediate or linker of any of claims 1001 to 1004, wherein said PEG unit has a formula selected from the following: ~R 20 -R 21 -[O-CH 2 -CH 2 ] n20 -R 22 -NH-C(O)-R 31 (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 is a functional group for binding to a subunit of the amino acid unit (if present) or a portion of the linker subunit L2; R 21 and R 22 are optional, and C 1 -C 3 is an alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 R 33 is 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 alkylene-C(O); R35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, or optionally substituted heteroaryl; the wavy line (~) represents R 20 n20 is 1 to 26). [The present invention 1036] The linker intermediate or linker of the present invention 1035, wherein said PEG unit is selected from the following:

[25] JPEG0007735526000247.jpg216170 (In the formula, R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; the wavy line on the left indicates the site of attachment of the amino acid unit to the subunit or to the portion of the linker subunit). [This invention 1037] R 20 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or a protected form thereof. [The present invention 1038] An expression selected from the following: ~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 is a functional group for binding to a subunit of the amino acid unit or a portion of the linker subunit L2; R 41 and R 42 are absent or, independently, C 1 -C 6 is alkylene; Each R 43 is independently absent 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 the two is H or C 1 -C 12 alkylene and the other is C 1 -C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicating the binding site to n40 is 1-26; n41 is 1-6; 1001 to 1004. A linker intermediate or linker according to the present invention, comprising a PEG unit having n42 is 1 to 6) or a salt thereof. [This invention 1039] An expression selected from the following: ~R 40 -(R 41 -[O-CH 2 -CH 2 ] n40 -R 42 -R43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 is a functional group for binding to a subunit of the amino acid unit or a portion of the linker subunit L2; R 41 and R 42 are absent or, independently, C 1 -C 6 is alkylene; R 43 does not exist or is 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 the two is H or C 1 -C 12 alkylene and the other is C 1 -C 12 is alkylene; R44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicating the binding site to n40 is 1-26; n41 is 1-6; 1001 to 1004. A linker intermediate or linker according to the present invention, comprising a PEG unit having n42 is 1 to 6) or a salt thereof. [The present invention 1040] An expression selected from the following: ~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 is a functional group for binding to a subunit of the amino acid unit or a portion of the linker subunit L2; R 41 and R 42 are absent or, independently, C 1 -C 3 is alkylene; R 43 does not exist or is 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 -C12 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 the two is H or C 1 -C 6 alkylene and the other is C 1 -C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicating the binding site to n40 is 1 to 16; n41 is 1 to 4; 1001 to 1004. A linker intermediate or linker according to the present invention, comprising a PEG unit having n42 is 1 to 4) or a salt thereof. [This invention 1041] R 40 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or a protected form thereof. [The present invention 1042] R 40 but one of the following structures:

[26] JPEG0007735526000248.jpg183170 or

[27] JPEG0007735526000249.jpg29170 (Wherein, R=H or C 1-6 alkyl; and n=0~12 (*) indicates the R 40 and (

[28] JPEG0007735526000250.jpg5170 ) is the R 40 1040. A linker intermediate or linker according to any one of claims 1038 to 1040, having the binding site shown in Figure 1040 or a stereoisomer thereof. [This invention 1043] R 40 but one of the following structures: [C29] JPEG0007735526000251.jpg184170 or

[30] JPEG0007735526000252.jpg29170 (In the formula, n=0~12 (*) indicates the R 40 and (

[31] JPEG0007735526000253.jpg5170 ) is the R 40 1042. A linker intermediate or linker of the present invention having the above-mentioned binding site (representing the above-mentioned binding site) or a stereoisomer thereof. [This invention 1044] R 43 -(NR 44 R 45 ) n41 But NR 43 If present, one of the following structures:

[32] JPEG0007735526000254.jpg55170 or

[33] JPEG0007735526000255.jpg22170 (In the formula, R=H, C 1-6 Alkyl, polyhydroxyl, or substituted polyhydroxyl (

[34] JPEG0007735526000256.jpg5170 ) is the R 43 1038 to 1040, a linker intermediate or linker of the present invention, having the above-mentioned binding site (representing the above-mentioned binding site) or a stereoisomer thereof. [This invention 1045] R 43 -(NR 44 R45 ) n41 But NR 43 If present, one of the following structures:

[35] JPEG0007735526000257.jpg55170 or

[36] JPEG0007735526000258.jpg22170 (In the formula, (

[37] JPEG0007735526000259.jpg5170 ) is the R 43 1044 linker intermediate or linker of the present invention having the above-mentioned binding site (showing the above-mentioned binding site) or a stereoisomer thereof. [The present invention 1046] -NR 44 R 45 but one of the following structures:

[38] JPEG0007735526000260.jpg175170 or

[39] JPEG0007735526000261.jpg78170 (In the formula, (

[40] JPEG0007735526000262.jpg5170 ) is -NR to the remainder of the PEG unit 44 R 45 1040. A linker intermediate or linker according to any one of claims 1038 to 1040, having the binding site shown in Figure 1040 or a stereoisomer thereof. [This invention 1047] 1047. The linker intermediate or linker of any of claims 1001 to 1046, wherein the PEG unit, prior to attachment to the amino acid unit or portion of the linker subunit L2, has one of the following structures: [C41-1] JPEG0007735526000263.jpg175170 [C41-2] JPEG0007735526000264.jpg175170 [C41-3] JPEG0007735526000265.jpg175170 [C41-4] JPEG0007735526000266.jpg117170 or

[42] JPEG0007735526000267.jpg47170 (wherein R is H or alkyl and n is 1 to 12). [This invention 1048] An expression selected from the following: ~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 is a functional group for binding to a subunit of the amino acid unit or a portion of the linker subunit L2; R 41 and R 42 are absent or, independently, C 1 -C 6 is alkylene; Each R 43 is independently absent 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<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene-C(O)-, -C(O)-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene, -C(O)-NH-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene, -heteroarylene, heteroaryl-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene-C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> Alkylene- or -C(O)NR <h2 style=";text-align:left;direction:ltr"> 46 <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 47 <h2 style=";text-align:left;direction:ltr"> Selected from R <h2 style=";text-align:left;direction:ltr"> 46 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 47 <h2 style=";text-align:left;direction:ltr"> One of the two is H or C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> alkylene and the other is C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 12 <h2 style=";text-align:left;direction:ltr"> is alkylene; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 44 <h2 style=";text-align:left;direction:ltr"> and R <h2 style=";text-align:left;direction:ltr"> 45 <h2 style=";text-align:left;direction:ltr"> are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 46 <h2 style=";text-align:left;direction:ltr"> is amino, amino-alkyl-amino, or -NH-C(O)-NH-S(O) <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> -NH-; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The wavy line (~) is R <h2 style=";text-align:left;direction:ltr"> 40 <h2 style=";text-align:left;direction:ltr"> indicating the binding site to <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> n40 is 1-26; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> n41 is 1-6; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1001 to 1004. A linker intermediate or linker according to the present invention, comprising a PEG unit having n42 is 1 to 6) or a salt thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1049] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The linker intermediate or linker of the present invention 1048, wherein said PEG unit has one of the following structures before being attached to said amino acid unit or portion of said linker subunit L2: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[43] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000268.jpg54170<h2 style=";text-align:left;direction:ltr"> (wherein R is H or alkyl and n is 1 to 12). <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1050] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> An expression selected from the following: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[44] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000269.jpg133170<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[45] <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000270.jpg102170 wherein each Y is independently R 76 or

[46] JPEG0007735526000271.jpg24170 and Each R 76 are independently H, acetyl, -P(=O)(OH) 2 , or -(CH 2 ) v -OS(=O) 2 (OH); Each R a and R b are independently H or R a and R b together with the carbon to which they are attached to form an oxo group; each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; 1001 to 1004. A linker intermediate or linker of any one of claims 1001 to 1004, comprising a PEG unit having a PEG group having a PEG group (or a salt thereof) in which each * indicates a binding site for said amino acid unit (AA), said linker subunit L2, or a subunit of said stretcher unit (L1). [This invention 1051] An expression selected from the following:

[47] JPEG0007735526000272.jpg127170 or

[48] JPEG0007735526000273.jpg104170 (In the formula, each R 76 are independently H, acetyl, -P(=O)(OH) 2 or -(CH 2 ) v S(=O) 2 (OH); each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; A linker intermediate or linker of the present invention 1050, comprising a PEG unit having a PEG group having a PEG group (where each * indicates a binding site for the amino acid unit (AA), the linker subunit L2, or a subunit of the stretcher unit (L1)) or a salt thereof. [This invention 1052] An expression selected from the following:

[49] JPEG0007735526000274.jpg136170 or

[50] JPEG0007735526000275.jpg107170 (wherein each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; A linker intermediate or linker of the present invention 1050 or 1051, comprising a PEG unit having a PEG group having a PEG group (where each * indicates a binding site for the amino acid unit (AA), the linker subunit L2, or a subunit of the stretcher unit (L1)) or a salt thereof. [This invention 1053] Y is R 76 1050. A linker intermediate or linker of the present invention, [This invention 1054] Y is

[51] JPEG0007735526000276.jpg22170 1050. A linker intermediate or linker of the present invention, [This invention 1055] Each R a and R b is independently H. [This invention 1056] R a and R b taken together with the carbon to which they are attached to form an oxo group. [This invention 1057] The linker intermediate or linker of any one of 1050 to 1052, wherein q is 10 to 20. [This invention 1058] The linker intermediate or linker of any of 1050 to 1052, wherein q is 12. [This invention 1059] The linker intermediate or linker of any of claims 1001 to 1004, 1038 to 1040 or 1050 to 1052, or a salt thereof, wherein said PEG unit is selected from the following: [C52-1] JPEG0007735526000277.jpg200170 [C52-2] JPEG0007735526000278.jpg192170 [C52-3] JPEG0007735526000279.jpg157170 [C52-4] JPEG0007735526000280.jpg214170 [C52-5] JPEG0007735526000281.jpg181170 [C52-6] JPEG0007735526000282.jpg206170 [C52-7] JPEG0007735526000283.jpg204170 [C52-8] JPEG0007735526000284.jpg193170 [C52-9] JPEG0007735526000285.jpg208170 [C52-10] JPEG0007735526000286.jpg190170 [C52-11] JPEG0007735526000287.jpg159170 [C52-12] JPEG0007735526000288.jpg123170 and

[53] JPEG0007735526000289.jpg41170 wherein each Z is joined by a * and is individually selected from:

[54] JPEG0007735526000290.jpg76170 and

[55] JPEG0007735526000291.jpg55170 each

[56] JPEG0007735526000292.jpg5170 indicates a binding site for the amino acid unit (AA), the linker subunit L2 or another subunit of the stretcher unit (L1). [The present invention 1060] 5. The linker intermediate or linker of any of claims 1001 to 1004, wherein said carboxyl unit has the formula: R 70 | L 70 | ~NH-(CH 2 ) p1 -CH-(CH 2 ) o1 -C(O)~ (XXXX) (In the formula, (a) L 70 is 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 alkylene-C(O)-; R 70 is ~NR 71 (R 72 -R 73 ) where R 71 is H, C 1 -C 12 Alkyl, substituted C 1 -C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 72 is absent or optionally replaced by C 1 -C 3 selected from 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 carbocycle, optionally substituted aryl or optionally substituted heteroaryl; R 73 is a carboxyl or polycarboxyl, wherein the 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 amido; Each wavy line (~) 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 is 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 alkylene-C(O)-; R 70 is ~NR 71 (R 75 -(R 73 ) 2 ) where R 71 is H, C 1 -C 12 Alkyl, substituted C 1 -C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 75 is a branched, optionally substituted C 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 carbocycle, optionally substituted aryl, or optionally substituted heteroaryl, and each R 73 independently comprise carboxyl or polycarboxyl, wherein the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, said carboxyl groups being interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amido; Each wavy line (~) 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 is 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 alkylene-C(O)-; R 70 is ~N(R 74 -R 73 )(R 72 -R 73 ) where R 72 and R 74 each independently represents an optionally substituted C 1 -C 3 selected from 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 carbocycle, optionally substituted aryl or optionally substituted heteroaryl, and each R 73 are independently carboxyl or polycarboxyl and contain 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, said carboxyl groups being interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkyl, heteroalkylene, amino and / or amido; Each wavy line (~) 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). [The present invention 1061] The linker intermediate or linker of any of claims 1001 to 1060, comprising at least one sugar unit. [The present invention 1062] The linker intermediate or linker of any of claims 1001 to 1060, comprising at least one PEG unit. [The present invention 1063] The linker intermediate or linker of any of claims 1001 to 1060, comprising at least one carboxyl unit. [The present invention 1064] 1060. The linker intermediate or linker of any of claims 1001 to 1060, comprising at least two polar units, each polar unit selected from a saccharide unit, a PEG unit, and a carboxyl unit. [This invention 1065] The linker intermediate or linker of any of claims 1001 to 1060, comprising at least one sugar unit and a PEG unit or a carboxyl unit. [The present invention 1066] The linker intermediate or linker of any of claims 1001 to 1060, comprising at least one carboxyl unit and a PEG unit. [This invention 1067] 1060. The linker intermediate or linker of any one of claims 1001 to 1060, wherein said amino acid unit (AA) is present (s=1). [The present invention 1068] 1068. The linker intermediate or linker of any one of claims 1001 to 1067, wherein said amino acid unit comprises at least one polar unit. [This invention 1069] The linker intermediate or linker of any of claims 1001 to 1068, wherein L2 or AA-L2 has one of the following structures:

[57] JPEG0007735526000293.jpg141170 or

[58] JPEG0007735526000294.jpg47170 where the wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is attached to the benzyl alcohol. [The present invention 1070] 1068. The linker intermediate or linker of any of claims 1001 to 1067, wherein ~AA-L2~ has a formula selected from:

[59] JPEG0007735526000295.jpg8170 、

[60] JPEG0007735526000296.jpg8170 ,or

[61] JPEG0007735526000297.jpg8170 (wherein the square brackets represent the amino acid units, each aa is an optional subunit of AA, L2 is the linker subunit, and each wavy line (~) represents a binding site for a Stretcher unit; aa 1 (PEG) is a PEG unit attached to an amino acid subunit of AA, SU is a sugar unit attached to a subunit of AA or L2, and CU is a carboxyl unit attached to a subunit of AA or L2;

[62] JPEG0007735526000298.jpg6170 ) indicates the binding site for the drug unit, and aa and aa 1 are independently selected from alpha, beta and gamma amino acids and derivatives thereof). [This invention 1071] 1068. The linker intermediate or linker of any of claims 1001 to 1067, wherein ~AA-L2~ has a formula selected from:

[63] JPEG0007735526000299.jpg48170 ,or

[64] JPEG0007735526000300.jpg21170 (wherein the square brackets represent 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 the wavy line (~) represents the attachment site for the Stretcher unit; aa 1 (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 the double wavy line (

[65] JPEG0007735526000301.jpg6170 ) indicates the binding site for the drug unit; aa and aa 1 are independently selected from alpha, beta and gamma amino acids and derivatives thereof). [This invention 1072] 1068. The linker intermediate or linker of any of claims 1001 to 1068, wherein said amino acid unit comprises at least two polar units. [This invention 1073] The linker intermediate or linker of the present invention 1072, wherein ~AA-L2~ has a formula selected from the following:

[66] JPEG0007735526000302.jpg8170 、

[67] JPEG0007735526000303.jpg8170 ,or

[68] JPEG0007735526000304.jpg8170 (wherein the square brackets represent the amino acid units, aa is an optional subunit of AA, L2 is the linker subunit, and the wavy line (~) represents the attachment site for the Stretcher unit; aa 1 (PEG) and aa 2 Each of the (PEG)s is a PEG unit bonded to an aa or other PEG unit; each SU is a saccharide unit bonded to an aa or other saccharide unit; each CU is a carboxyl unit bonded to an aa or other carboxyl unit, and is represented by a double wavy line (

[69] JPEG0007735526000305.jpg6170 ) indicates the binding site for the drug unit; aa, aa 1 and aa 2 are independently selected from alpha, beta and gamma amino acids and derivatives thereof). [This invention 1074] The linker intermediate or linker of the present invention 1072, wherein ~AA-L2~ has a formula selected from the following:

[70] JPEG0007735526000306.jpg47170 ,or

[71] JPEG0007735526000307.jpg21170 (wherein the square brackets represent the amino acid units, aa is an amino acid subunit of AA, L2 is a linker subunit attached to the side chain of aa, and each wavy line (~) represents a binding site for a Stretcher unit; aa 1 (PEG) and aa 2 Each of (PEG) is a PEG unit attached to aa, SU is a sugar unit attached to aa; each CU is a carboxyl unit attached to aa;

[72] JPEG0007735526000308.jpg6170 ) indicates the binding site for the drug unit; aa, aa 1 and aa 2 are independently selected from alpha, beta and gamma amino acids and derivatives thereof). [This invention 1075] 1075. The linker intermediate or linker of any one of claims 1001 to 1074, wherein the linker subunit L2 is a cleavable linker unit. [This invention 1076] 1075. A linker intermediate or linker of the present invention, wherein the linker subunit L2 comprises a peptide cleavable by an intracellular protease. [This invention 1077] 1076. The linker intermediate or linker of the present invention, wherein said 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. [This invention 1078] 1078. The linker intermediate or linker of any of claims 1001 to 1077, wherein the linker subunit L2 comprises at least one polar unit. [This invention 1079] 1078. The linker intermediate or linker of any one of claims 1001 to 1078, wherein the polar unit is a sugar unit (SU). [The present invention 1080] 1079. The linker intermediate or linker of the present invention, wherein said cleavable peptide comprises a SU-valine-citrulline peptide, a SU-valine-lysine peptide, a SU-valine-alanine peptide, a SU-phenylalanine-lysine peptide, or a SU-glycine-glycine-phenylalanine-glycine peptide. [This invention 1081] 1078. A linker intermediate or linker according to the present invention, wherein said polar unit is a carboxyl unit (CU). [This invention 1082] 1081. A linker intermediate or linker according to the present invention, wherein 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, wherein CU-lysine is a carboxyl unit comprising a lysine residue. [This invention 1083] 1078. A linker intermediate or linker according to the present invention, wherein said polar unit is a PEG unit (PEG). [This invention 1084] 1083. A linker intermediate or linker according to the present invention, wherein the cleavable peptide comprises a Lys(PEG)-valine-citrulline peptide, a valine-Cit(PEG) peptide, a Lys(PEG)-valine-lysine peptide, a valine-lysine(PEG) peptide, a Lys(PEG)-valine-alanine peptide, a Lys(PEG)-phenylalanine-lysine peptide, a phenylalanine-Lys(PEG) peptide or a Lys(PEG)-glycine-glycine-phenylalanine-glycine peptide, wherein Lys(PEG) and Cit(PEG) comprise PEG units attached to a lysine residue or a citrulline residue, respectively. [This invention 1085] The linker intermediate or linker of any of claims 1075 to 1084, wherein the cleavable peptide is attached to a para-aminobenzyl alcohol self-immolative group (PABA). [The present invention 1086]

[73] JPEG0007735526000309.jpg7170 a linker intermediate or linker of the present invention 1085 having one of the following structures: [C74-1] JPEG0007735526000310.jpg227170 [C74-2] JPEG0007735526000311.jpg215170 [C74-3] JPEG0007735526000312.jpg110170 where the wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is attached to the benzyl alcohol. [This invention 1087] The linker intermediate or linker of invention 1001 or 1002, wherein ~AA-L2~ has one of the following structures: [C75-1] JPEG0007735526000313.jpg189170 [C75-2] JPEG0007735526000314.jpg191170 [C75-3] JPEG0007735526000315.jpg179170 [C75-4] JPEG0007735526000316.jpg149170 [C75-5] JPEG0007735526000317.jpg199170 [C75-6] JPEG0007735526000318.jpg142170 [C75-7] JPEG0007735526000319.jpg155170 [C75-8] JPEG0007735526000320.jpg151170 [C75-9] JPEG0007735526000321.jpg206170 [C75-10] JPEG0007735526000322.jpg177170 [C75-11] JPEG0007735526000323.jpg158170 [C75-12] JPEG0007735526000324.jpg215170 [C75-13] JPEG0007735526000325.jpg205170 [C75-14] JPEG0007735526000326.jpg190170 [C75-15] JPEG0007735526000327.jpg155170 [C75-16] JPEG0007735526000328.jpg160170 [75-17] JPEG0007735526000329.jpg211170 [C75-18] <h2 style=";text-align:left;direction:ltr">JPEG0007735526000330.jpg173170<h2 style=";text-align:left;direction:ltr"> [C75-19] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000331.jpg176170<h2 style=";text-align:left;direction:ltr"> [75-20] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000332.jpg85170<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[76] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000333.jpg69170<h2 style=";text-align:left;direction:ltr"> wherein each Z is joined by a * and is individually selected from: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[77] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000334.jpg79170<h2 style=";text-align:left;direction:ltr"> and <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[78] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000335.jpg60170<h2 style=";text-align:left;direction:ltr"> The wavy line over the amino group indicates the attachment site for a Stretcher unit, and the Drug unit is attached to the benzyl alcohol (i.e., the H of the benzyl alcohol is replaced by a bond with the Drug unit). <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1088] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The linker intermediate or linker of any of claims 1075 to 1085, wherein L2 is attached to a side chain of an AA subunit. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1089] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[79] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000336.jpg7170<h2 style=";text-align:left;direction:ltr"> a linker intermediate or linker of the present invention 1088 having one of the following structures: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[80] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000337.jpg143170<h2 style=";text-align:left;direction:ltr"> or <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[81] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000338.jpg77170<h2 style=";text-align:left;direction:ltr"> where the wavy line over the amino group indicates the attachment site for a Stretcher unit, and the Drug unit is attached to the terminal acid group, the benzyl alcohol, or the wavy line ( <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[82] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JPEG0007735526000339.jpg6170<h2 style=";text-align:left;direction:ltr"> ) indicates the binding site for the Drug unit). <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1090] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1086. The linker intermediate or linker of any one of claims 1001 to 1085, wherein said amino acid unit is linked to linker subunit L2 by a non-peptide linking group. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [This invention 1091] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The non-peptidic linking group is C <h2 style=";text-align:left;direction:ltr"> 1<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 10 <h2 style=";text-align:left;direction:ltr"> Alkylene, C <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> -C <h2 style=";text-align:left;direction:ltr"> 10 <h2 style=";text-align:left;direction:ltr"> Alkenylene, C <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> -C10 A linker intermediate or linker of the present invention 1090 selected from alkynylene or polyethylene glycol. [This invention 1092] The linker intermediate or linker of any one of claims 1001 to 1091, further comprising a Stretcher unit. [This invention 1093] The stretcher unit is selected from the following: [C83-1] JPEG0007735526000340.jpg181170 [C83-2] JPEG0007735526000341.jpg155170 or

[84] JPEG0007735526000342.jpg29170 (In the formula, R 17 -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- (wherein b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b - (wherein b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 alkylene- (wherein b is 1 to 26), -arylene-, -C 1 -C 10 Alkylene-arylene-, -arylene-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 Heteroalkylene -C(=O)-, -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C(=O)- (wherein b is 1 to 26), -(CH 2 -O-CH 2 ) b -C 1 -C 8 alkylene-C(=O)- (wherein b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 alkylene-C(=O)- (wherein 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-arylene-C(=O)-, -arylene-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- (wherein b is 1 to 26), -(CH 2 -O-CH 2 ) b -C 1 -C 8 alkylene-NH- (wherein b is 1 to 26), -C 1 -C 8 Alkylene-(CH 2 -O-CH 2 ) b -C 1 -C 8 alkylene-NH- (wherein b is 1 to 26), -C 1 -C 8 Alkylene-(C(=O))-NH-(CH 2 -O-CH 2 ) b -C(=O)- (wherein 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)- (wherein b is 1 to 26), -C 1 -C 8 Alkylene-NH-(C(=O))-(CH 2 -O-CH 2 ) b -NH- (wherein 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- (wherein 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 -C 10 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 Alkylene-arylene-S-, -arylene-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 alkylene-S-) or The stretcher unit is a maleimide (C 1 -C 10 Alkylene-C(O)-, maleimide (CH 2 OCH 2 ) p2 (C 1 -C 10 Alkyne)C(O)-, Maleimide (C 1 -C 10 Alkyen) (CH 2 OCH 2 ) p2 1092. A linker of the present invention, comprising C(O)-, where p2 is 1-26, or an open ring form thereof. [This invention 1094] The linker intermediate or linker of the present invention 1092, wherein said Stretcher unit is selected from:

[85] JPEG0007735526000343.jpg113170 and

[86] JPEG0007735526000344.jpg24170 (wherein, wavy line

[87] JPEG0007735526000345.jpg5170 indicates the attachment site for the Stretcher unit to an Amino Acid unit, and the attachment site for the Targeting unit is on a maleimide, primary amine, or alkyne functional group). [This invention 1095] A linker of the present invention 1093 having one of the following structures: [C88-1] JPEG0007735526000346.jpg207170 [C88-2] JPEG0007735526000347.jpg200170 [C88-3] JPEG0007735526000348.jpg213170 [C88-4] JPEG0007735526000349.jpg125170 wherein the Drug unit is attached to a terminal acid group, a benzyl alcohol, or is represented by a wavy line (

[89] JPEG0007735526000350.jpg6170 ) indicates the binding site for the Drug unit). [This invention 1096] A linker of the present invention 1092 having one of the following structures: [C90-1] JPEG0007735526000351.jpg213170 [C90-2] JPEG0007735526000352.jpg213170 [C90-3] JPEG0007735526000353.jpg216170 [C90-4] JPEG0007735526000354.jpg221170 [C90-5] JPEG0007735526000355.jpg186170 [C90-6] JPEG0007735526000356.jpg198170 [C90-7] JPEG0007735526000357.jpg147170 [90-8] JPEG0007735526000358.jpg150170 [90-9] JPEG0007735526000359.jpg219170 [90-10] JPEG0007735526000360.jpg135170 [90-11] JPEG0007735526000361.jpg181170 [C90-12] JPEG0007735526000362.jpg158170 [C90-13] JPEG0007735526000363.jpg215170 [90-14] JPEG0007735526000364.jpg205170 [90-15] JPEG0007735526000365.jpg190170 [90-16] JPEG0007735526000366.jpg155170 [90-17] JPEG0007735526000367.jpg160170 [90-18] JPEG0007735526000368.jpg213170 [90-19] JPEG0007735526000369.jpg156170 [90-20] JPEG0007735526000370.jpg164170 [90-21] JPEG0007735526000371.jpg168170 or

[91] JPEG0007735526000372.jpg69170 wherein each Z is joined by a * and is individually selected from:

[92] JPEG0007735526000373.jpg82170 and

[93] JPEG0007735526000374.jpg60170 The Drug unit is optionally attached to a terminal acid group, a benzyl alcohol, or a wavy line (

[94] JPEG0007735526000375.jpg6170 ) indicates the binding site for the Drug unit). [This invention 1097] The linker of any of claims 1001 to 1096, further comprising at least one drug unit attached to linker subunit L2 to form a drug-linker. [This invention 1098] The Drug-Linker of the present invention 1097, wherein said Drug unit is selected from a cytotoxic agent, an immunomodulator, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioisotope, and a chelating ligand. [This invention 1099] The Drug-Linker of the present invention, wherein the Drug unit is a cytotoxic agent. [The present invention 1100] The drug-linker of claim 1099, wherein said cytotoxic agent is selected from the group consisting of an auristatin, a maytansinoid, a camptothecin, a duocarmycin, and a calicheamicin. [The present invention 1101] The drug-linker of claim 1100, wherein said cytotoxic agent is an auristatin. [The present invention 1102] The drug-linker of the present invention 1101, wherein said cytotoxic agent is MMAE or MMAF. [The present invention 1103] The drug-linker of claim 1100, wherein said cytotoxic agent is camptothecin. [The present invention 1104] The drug-linker of invention 1103, wherein said cytotoxic agent is exatecan or SN-38. [This invention 1105] The drug-linker of the present invention 1104, wherein said cytotoxic agent is exatecan. [The present invention 1106] The drug-linker of the present invention, wherein the cytotoxic agent is calicheamicin. [This invention 1107] The drug-linker of the present invention, wherein the cytotoxic agent is a maytansinoid. [This invention 1108] The drug-linker of the present invention 1107, wherein said maytansinoid is maytansine, maytansinol or ansamatocin-2. [This invention 1109] The Drug-Linker of the present invention 1098, wherein the Drug unit is an immunomodulatory agent. [The present invention 1110] The drug-linker of the present invention 1109, wherein said immunomodulatory agent is selected from a TRL7 agonist, a TLR8 agonist, a STING agonist, or a RIG-I agonist. [The present invention 1111] The drug-linker of the present invention 1110, wherein said immunomodulatory agent is a TLR7 agonist. [The present invention 1112] The drug-linker of the present invention, wherein the TLR7 agonist is imidazoquinoline, imidazoquinoline amine, thiazoquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazol-2-amine, tetrahydropyridopyrimidine, heteroaromatic thiol azide-2,2-dioxide, benzonaphthyridine, guanosine analogue, adenosine analogue, thymidine homopolymer, ssRNA, CpG-A, PolyG10 or PolyG3. [The present invention 1113] The drug-linker of the present invention 1110, wherein said immunomodulatory agent is a TLR8 agonist. [This 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-benzimidazol-2-amine, tetrahydropyridopyrimidine or ssRNA. [This invention 1115] The drug-linker of the present invention 1110, wherein the immunomodulatory agent is a STING agonist. [The present invention 1116] The drug-linker of the present invention 1110, wherein said immunomodulatory agent is a RIG-I agonist. [This invention 1117] The drug-linker of the present invention 1116, wherein said RIG-I agonist is selected from KIN1148, SB-9200, KIN700, KIN600, KIN500, KIN100, KIN101, KIN400 and KIN2000. [This invention 1118] The Drug-Linker of the present invention 1098, wherein said Drug unit is a chelating ligand. [This invention 1119] The drug-linker of the present invention 1118, wherein the chelating ligand is selected from platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti), or iridium (Ir); a radioactive isotope such as 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. [The present invention 1120] The drug-linker of the present invention has the following structure: [C95-1] JPEG0007735526000376.jpg175170 [C95-2] JPEG0007735526000377.jpg202170 [C95-3] JPEG0007735526000378.jpg145170 [C95-4] JPEG0007735526000379.jpg160170 [C95-5] JPEG0007735526000380.jpg200170 [C95-6] JPEG0007735526000381.jpg199170 [95-7] JPEG0007735526000382.jpg193170 [95-8] JPEG0007735526000383.jpg208170 [95-9] JPEG0007735526000384.jpg138170 [95-10] JPEG0007735526000385.jpg218170 [95-11] JPEG0007735526000386.jpg161170 [95-12] JPEG0007735526000387.jpg158170 [95-13] JPEG0007735526000388.jpg156170 [95-14] JPEG0007735526000389.jpg148170 [95-15] JPEG0007735526000390.jpg153170 [95-16] JPEG0007735526000391.jpg155170 [95-17] JPEG0007735526000392.jpg156170 [95-18] JPEG0007735526000393.jpg209170 [95-19] JPEG0007735526000394.jpg148170 [95-20] JPEG0007735526000395.jpg180170 [95-21] JPEG0007735526000396.jpg185170 [95-22] JPEG0007735526000397.jpg166170 [95-23] JPEG0007735526000398.jpg189170 [95-24] JPEG0007735526000399.jpg210170 [95-25] JPEG0007735526000400.jpg160170 [95-26] JPEG0007735526000401.jpg148170 [95-27] JPEG0007735526000402.jpg157170 [95-28] JPEG0007735526000403.jpg169170 [95-29] JPEG0007735526000404.jpg170170 [95-30] JPEG0007735526000405.jpg166170 [95-31] JPEG0007735526000406.jpg159170 [95-32] JPEG0007735526000407.jpg170170 [95-33] JPEG0007735526000408.jpg193170 [95-34] JPEG0007735526000409.jpg168170 [95-35] JPEG0007735526000410.jpg182170 [95-36] JPEG0007735526000411.jpg153170 wherein each Z is joined by a * and is individually selected from:

[96] JPEG0007735526000412.jpg86170 and

[97] JPEG0007735526000413.jpg60170 or

[98] JPEG0007735526000414.jpg76170 wherein each Z is joined by a * and is individually selected from the following:

[99] JPEG0007735526000415.jpg82170 and

[100] JPEG0007735526000416.jpg59170 )。 [This invention 1121] A conjugate comprising a targeting unit attached to a drug-linker of any of claims 1097 to 1120. [This invention 1122] The conjugate of the present invention 1121, wherein said targeting unit is selected from an antibody or an antigen-binding portion thereof. [This invention 1123] 1122. The conjugate of the present invention, wherein said targeting unit is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-linked Fc, scFv, single domain antibody, diabody, bispecific antibody or multispecific antibody. [This invention 1124] 1121. A conjugate according to the invention, wherein said targeting unit is a diabody, a DART, an anticalin, an affibody, an avimer, a DARPin or an adnectin. [Invention 1125] The conjugate of any of claims 1121 to 1124, wherein said targeting unit is monospecific. [The present invention 1126] 1126. The conjugate of any of claims 1121 to 1125, wherein said targeting unit is bivalent. [This invention 1127] 1125. The conjugate of any of claims 1121 to 1124, wherein said targeting unit is bispecific. [This invention 1128] The average drug loading of the conjugate (p load ) is about 1 to about 8, about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 3 to about 5, about 6 to about 8, or about 8 to about 16. [This invention 1129] A conjugate of any of claims 1121 to 1128 selected from: [Case 101-1] JPEG0007735526000417.jpg160170 [Case 101-2] JPEG0007735526000418.jpg140170 [Case 101-3] JPEG0007735526000419.jpg184170 [Case 101-4] JPEG0007735526000420.jpg187170 [Case 101-5] JPEG0007735526000421.jpg174170 [Case 101-6] JPEG0007735526000422.jpg178170 [Case 101-7] JPEG0007735526000423.jpg180170 [Case 101-8] JPEG0007735526000424.jpg190170 [Case 101-9] JPEG0007735526000425.jpg143170 [C101-10] JPEG0007735526000426.jpg204170 [Case 101-11] JPEG0007735526000427.jpg144170 [Case 101-12] JPEG0007735526000428.jpg153170 [C101-13] JPEG0007735526000429.jpg154170 [Case 101-14] JPEG0007735526000430.jpg149170 [Case 101-15] JPEG0007735526000431.jpg146170 [Case 101-16] JPEG0007735526000432.jpg205170 [Case 101-17] JPEG0007735526000433.jpg149170 [Case 101-18] JPEG0007735526000434.jpg151170 [Case 101-19] JPEG0007735526000435.jpg205170 [C101-20] JPEG0007735526000436.jpg139170 [Case 101-21] JPEG0007735526000437.jpg170170 [Case 101-22] JPEG0007735526000438.jpg177170 [C101-23] JPEG0007735526000439.jpg148170 [Case 101-24] JPEG0007735526000440.jpg162170 [Case 101-25] JPEG0007735526000441.jpg203170 [C101-26] JPEG0007735526000442.jpg217170 [C101-27] JPEG0007735526000443.jpg216170 [C101-28] JPEG0007735526000444.jpg167170 [C101-29] JPEG0007735526000445.jpg170170 [C101-30] JPEG0007735526000446.jpg211170 [Case 101-31] JPEG0007735526000447.jpg181170 [Case 101-32] JPEG0007735526000448.jpg150170 [C101-33] JPEG0007735526000449.jpg175170 [Case 101-34] JPEG0007735526000450.jpg164170 [Case 101-35] JPEG0007735526000451.jpg159170 [C101-36] JPEG0007735526000452.jpg65170 wherein each Z is joined by a * and is individually selected from: [C102] JPEG0007735526000453.jpg83170 and [C103] JPEG0007735526000454.jpg57170 or [C104] JPEG0007735526000455.jpg78170 wherein each Z is joined by a * and is individually selected from the following: [C105] JPEG0007735526000456.jpg83170 and [C106] JPEG0007735526000457.jpg58170 Ab is the targeting unit and n is p load (It is). [The present invention 1130] 1129. The conjugate of any of claims 1121, 1128 or 1129, wherein said targeting unit is bound to a target molecule. [This invention 1131] The conjugate of the present invention 1130, wherein said target molecule is CD19, CD20, CD30, CD33, CD70, LIV-1 or EGFRv3. [This invention 1132] 1129. The conjugate of any of claims 1121, 1128 or 1129, wherein said 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. [This invention 1133] The conjugate of any of claims 1121, 1128 or 1129, wherein said targeting unit is a cancer-associated antigen. [This invention 1134] The targeting unit is selected from the group consisting of 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 The conjugate of any of the inventions 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. [This invention 1135] The targeting unit may be selected from the group consisting of rituximab (Rituxan®), trastuzumab (Herceptin®), pertuzumab (Perjeta®), bevacizumab (Avastin®), ranibizumab (Lucentis®), cetuximab (Erbitux®), alemtuzumab (Campath®), panitumumab (Vectibix®), ), ibritumomab tiuxetan (Zevalin®), tositumomab (Bexxar®), ipilimumab, zalutumumab, dalotuzumab, figitumumab, ramucirumab, galiumtuzumab, farletuzumab, ocrelizumab, ofatumumab (Arzerra®), tositumumab, 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 clones A9E4, F1G4, AT2G7, GNRH03 or GNRHR2. [This invention 1136] The conjugate of the present invention 1121, wherein said targeting unit is antibody F131 and said drug-linker is LD038. [This invention 1137] The targeting unit comprises: The antibody comprises 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 heavy chain variable region framework regions, and the VL region comprises LCDR1, LCDR, and LCDR3 arranged in light chain variable region framework regions, and the VH and VL CDRs are (a) SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, and SEQ ID NO:35, respectively; and (b) A conjugate of any of 1121, 1128 or 1129 of the present invention, having an amino acid sequence selected from the set of amino acid sequences shown in 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, respectively. [This invention 1138] the VH region and the VL region having an amino acid sequence selected from the pair of amino acid sequences set forth in the group consisting of SEQ ID NO:26 and SEQ ID NO:27, respectively; 1137. The conjugate of the present invention, wherein said heavy chain framework regions and said light chain framework regions are optionally modified by substitution, deletion or insertion of 1 to 8 amino acids within said framework regions. [This invention 1139] The conjugate of the present invention 1137, wherein the antibody is F131 and the drug-linker is LD038. [The present invention 1140] A conjugate comprising a targeting unit attached to said drug-linker, wherein said targeting unit is antibody F131 and said drug-linker is LD038. [This invention 1141] A pharmaceutical composition comprising a conjugate of any of 1121 to 1140 of the present invention and a pharmaceutically acceptable carrier. [This invention 1142] A method of treating a subject in need thereof, comprising the step of administering to the subject a conjugate of any of inventions 1121 to 1140 or a pharmaceutical composition of 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 more fully understood by reference to the following detailed description, non-limiting examples of specific embodiments, and the accompanying drawings. [Brief explanation of the drawings]

[0092] [Figure 1A] FIG. 1 shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against OV90 cells. [Figure 1B] FIG. 1 shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against OVCAR-3 cells. [Figure 1C]FIG. 1 shows the in vitro cytotoxicity of anti-huFOLR-1 conjugates against NCI-H292 cells. [Figure 2] The in vivo activity of the PA038 conjugate of human anti-huFOLR1 antibody was tested. Mice bearing established OV90 xenografts of approximately 117 mm were treated with 5 mg / kg of conjugate or PBS intravenously four times over two weeks, starting on day 8 after tumor cell inoculation. The mean tumor volume (mm) versus time (days) after cell inoculation is plotted. (N=6, mean ± SEM) [Figure 3] The in vivo activity of the PA038 conjugate of human anti-huFOLR1 antibody was tested. Mice bearing established NCI-H292 xenografts of approximately 123 mm were treated with 5 mg / kg of conjugate or PBS intravenously four times over two weeks, starting 11 days after cell inoculation. The mean tumor volume (mm) versus time (days) after cell inoculation is plotted. (N=6, mean ± SEM) [Figure 4] Figure 1 shows the in vivo activity of the PA038 conjugate of human anti-huFOLR1 antibody. Mice bearing established OV90 xenografts of approximately 110 mm were treated with 5 mg / kg of conjugate or PBS intravenously four times over two weeks, starting 13 days after cell inoculation. The mean tumor volume (mm) versus time (days) after cell inoculation is plotted. (N=6, mean ± SEM) [Figure 5] FIG. 1 shows the PK profiles of anti-huFOLR-1 conjugate F131-LD038 and naked Ab F131 evaluated at 3 mg / kg (N=3; mean±SD). [Figure 6] FIG. 1 shows a comparison of anti-FOLR1 antibody binding to Hela cells. [Figure 7] FIG. 1 shows a comparison of the binding ability of anti-FOLR1 antibodies to RPTEC / TERT1 cells. [Figure 8] FIG. 1 shows dose-dependent binding of anti-FOLR1 antibodies to Hela cells. [Figure 9] FIG. 1 shows dose-dependent binding of anti-FOLR1 antibodies to RPTEC / TERT1 cells. [Figure 10] FIG. 1 shows the internalization of anti-FOLR1 antibodies into Hela cells. [Figure 11] FIG. 1 shows the internalization of anti-FOLR1 antibodies into RPTEC / TERT1 cells. [Figure 12A] FIG. 1 shows F131 internalization in tumor cell lines. [Figure 12B] FIG. 1 shows F131-LD038 internalization in tumor cell lines. [Figure 13A] FIG. 1 shows in vitro cell cytotoxicity against KB. [Figure 13B] FIG. 1 shows in vitro cell cytotoxicity against OVCAR3. [Figure 13C] FIG. 1 shows in vitro cell cytotoxicity against JEG-3. [Figure 14A] FIG. 1 shows the in vivo efficacy of F131 and F131-LD038 in CDX against OVCAR-3. [Figure 14B] FIG. 1 shows the in vivo efficacy of F131 and F131-LD038 in CDX against KB. [Figure 14C] FIG. 1 shows the in vivo efficacy of F131 and F131-LD038 in CDX against HCC827. [Figure 14D] FIG. 1 shows the in vivo efficacy of F131 and F131-LD038 in CDX on H441. [Figure 14E] FIG. 1 shows the in vivo efficacy of F131 and F131-LD038 in CDX against OV90. [Figure 15A] FIG. 1 shows the in vivo efficacy of F131-038 and other conjugates in CDX against KB. [Figure 15B] FIG. 1 shows the in vivo efficacy of F131 conjugates in CDX against KB. [Figure 16A] FIG. 1 shows PK studies of F131 and conjugates in a rat model. [Figure 16B]FIG. 1 shows PK studies of F131 and conjugates in a rat model. [Figure 16C] FIG. 1 shows PK studies of F131 and conjugates in a rat model. [Figure 17A] FIG. 1 shows the tolerability of F131-deluktecan and F131-LD038 in a pilot cynomolgus monkey toxicity study. [Figure 17B] FIG. 1 shows the tolerability of F131-deluktecan and F131-LD038 in a pilot cynomolgus monkey toxicity study. [Figure 18] FIG. 1 shows F131-deluktecan and F131-LD038 PK in a pilot cynomolgus monkey toxicity study. DETAILED DESCRIPTION OF THE INVENTION

[0093] definition For convenience, certain terms in the specification, examples, and claims are defined here. Unless otherwise specified or implied from context, the following terms and phrases have the meanings provided below. The definitions are provided to aid in the description of particular embodiments and are not intended to limit the claimed invention, 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 one of ordinary skill in the art to which this invention belongs.

[0094] As used herein, unless otherwise indicated, the terms "a" and "an" shall be construed to mean "one," "at least one," or "one or more." Unless otherwise required by context, singular terms used herein shall include plurals and plural terms shall include the singular.

[0095] Unless the context requires otherwise, throughout the specification and claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense rather than an exclusive or exhaustive sense, i.e., meaning "including but not limited to".

[0096] The terms "reduce," "reduce," "reduced," "reduce," "reduce," and "inhibit" are all used generally herein to mean a decrease by a statistically significant amount relative to a reference.

[0097] The terms "increased," "increase," or "enhance," or "activate" are all used herein to generally mean an increase of a statically significant amount relative to a baseline.

[0098] As used herein, the terms "protein" and "polypeptide" are used interchangeably to refer to a series of amino acid residues connected to each other by peptide bonds between the alpha-amino and carboxyl groups of adjacent residues. The terms "protein" and "polypeptide" also refer to a polymer of amino acids, including modified amino acids (e.g., phosphorylated, glycated, glycosylated, etc.) and amino acid analogs, regardless of their size or function. Although "protein" and "polypeptide" are often used in reference to relatively large polypeptides, while the term "peptide" is often used in reference to small polypeptides, the use of these terms in the art overlaps. The terms "protein" and "polypeptide" are used interchangeably herein to refer to encoded gene products and fragments thereof. Thus, exemplary polypeptides or proteins include gene products, naturally occurring proteins, homologs, orthologs, paralogs, fragments, and other equivalents, variants, fragments, and analogs of the foregoing.

[0099] As used herein, "epitope" refers to amino acids conventionally bound by an immunoglobulin VH / VL pair, e.g., antibodies, their antigen-binding portions, and other binding agents described herein. Other binding agents include non-antibody scaffolds. Epitopes can be formed on polypeptides from contiguous or noncontiguous amino acids juxtaposed by tertiary folding of the protein. Epitopes formed from contiguous amino acids are typically retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. An epitope typically comprises at least three, more usually at least five, about nine, or about eight to ten amino acids in a unique spatial conformation. An epitope defines the minimal binding site of an antibody, its antigen-binding portion, and other binding agent and thus represents the target of specificity of the antibody, its antigen-binding portion, or other immunoglobulin-based binding agent. In the case of a single-domain antibody, an epitope represents the structural unit bound by the variable domain alone.

[0100] As used herein, "specifically binds" means that a binding agent (e.g., an antibody or antigen-binding portion thereof) described herein specifically binds to a target molecule. -5 M (10000nM) or less, e.g., 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 As used herein, "specifically binds" also refers to the ability of a molecule described herein (e.g., an antibody or antigen-binding portion thereof, or a non-antibody scaffold) to bind to a target with a KD of 10 or less. -5 M (10000nM) or less, e.g., 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12Specific binding refers to the ability to bind to a target with a KD of M or less. Specific binding can be influenced, for example, by the affinity and avidity of the antibody, antigen-binding portion, or other binding agent, as well as the concentration of the target polypeptide. One skilled in the art can determine appropriate conditions under which the antibodies, antigen-binding portions, and other binding agents described herein selectively bind to a target molecule using any suitable method, such as titrating the antibody or binding agent in a suitable cell-binding assay. A binding agent that specifically binds to a target molecule is not displaced by a dissimilar competitor. In certain embodiments, an antibody or antigen-binding portion thereof, or other binding agent, is said to specifically bind to a target molecule if it preferentially recognizes its target molecule in a complex mixture of proteins and / or macromolecules. Specific binding can be influenced, for example, by the affinity and avidity of the antibody, antigen-binding portion, or non-antibody scaffold, as well as the concentration of the target polypeptide. One skilled in the art can determine appropriate conditions under which the antibodies, antigen-binding portions, and non-antibody scaffolds described herein selectively bind to a target molecule using any suitable method, such as titrating the antibody or non-antibody scaffold in a suitable cell-binding assay. A molecule that specifically binds to a target molecule is not displaced by a dissimilar competitor. In certain embodiments, an antibody or antigen-binding portion thereof, or a non-antibody scaffold is said to specifically bind to a target molecule if it preferentially recognizes its target molecule in a complex mixture of proteins and / or macromolecules.

[0101] Unless otherwise indicated, the term "alkyl," by itself or as part of another term, refers to an alkyl group having the indicated number of carbon atoms (e.g., "-C1-C5 alkyl," "-C1-C8 alkyl," or "-C1-C 10"Alkyl" refers to a substituted or unsubstituted, straight or branched, saturated hydrocarbon having alkyl groups 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), 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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(C 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," by itself or as part of another term, refers to an alkyl group having at least one site of unsaturation (i.e., carbon-carbon, sp 2"C" refers to a C2-C8 substituted or unsubstituted straight or branched chain hydrocarbon 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 stated, "alkynyl," by itself or as part of another term, refers to a substituted or unsubstituted, straight or branched chain C2-C8 hydrocarbon having at least one site of unsaturation (i.e., a carbon-carbon, sp triple bond). Examples include, but are not limited to, acetylene and propargyl.

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

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

[0106] Unless otherwise indicated, "alkynylene" refers to an unsaturated, branched or straight-chain or cyclic hydrocarbon radical of 2 to 8 carbon atoms having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene, propargyl, and 4-pentynyl.

[0107] Unless otherwise indicated, the term "heteroalkyl," by itself or in combination with another term, refers to a substituted or unsubstituted, stable, straight- or branched-chain hydrocarbon, or combinations thereof, saturated and containing from 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 are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. The O, N, and S heteroatoms may be placed at any interior position of the heteroalkyl group (i.e., as part of the backbone) or at the position at which the alkyl group is attached to the remainder of the molecule. The Si heteroatom may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples of heteroalkyl groups include the following: -CHCHOCH, -CHCHNHCH, -CHCHN(CH)CH, -CHSCHCH, CHCHS(O)CH, -CHCHS(O)CH, and -Si(CH)-. For example, up to two heteroatoms may be consecutive, such as -CH2NHOCH3 and CH2OSi(CH3)3. In some embodiments, a C1-C4 heteroalkyl has 1-4 carbon atoms and 1 or 2 heteroatoms, and a C1-C3 heteroalkyl has 1-3 carbon atoms and 1 or 2 heteroatoms.

[0108] Unless otherwise indicated, the terms "heteroalkenyl" and "heteroalkynyl," alone or in combination with another term, refer to a substituted or unsubstituted, stable, straight- or branched-chain 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 are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The O, N, and S heteroatoms may be placed at any interior position of the heteroalkenyl or heteroalkynyl group (i.e., as part of the backbone) or at the position at which the alkyl group is attached to the remainder of the molecule. The Si heteroatom may be placed at any position of the heteroalkenyl or heteroalkynyl group, including the position at which the alkyl group is attached to the remainder of the molecule.

[0109] Unless otherwise stated, the term "heteroalkylene," by itself or as part of another substituent, refers to a substituted or unsubstituted divalent group derived from heteroalkyl, as exemplified by -CH2CH2SCH2CH2- and -CH2SCH2CH2NHCH2- (as discussed above). In some embodiments, a C1-C4 heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms, and a C1-C3 heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

[0110] Unless otherwise stated, the terms "heteroalkenylene" and "heteroalkynylene," by themselves or as part of another substituent, refer to a substituted or unsubstituted divalent group derived from heteroalkenyl or heteroalkynyl (as discussed above). In some embodiments, a C2-C4 heteroalkenylene or heteroalkynylene has 1 to 4 carbon atoms. For heteroalkenylene and heteroalkynylene groups, heteroatoms can also occupy either or both of the chain termini. Additionally, for alkylene and heteroalkenylene and heteroalkynylene linking groups, no orientation of the linking group is implied.

[0111] Unless otherwise indicated, "C3-C8 carbocycle," by itself or as part of another term, refers 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 carbocycle derived by removing one hydrogen atom from a ring atom of a parent ring system. Representative -C3-C8 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.

[0112] Unless otherwise indicated, "C3-C8 carbocyclo," by itself or as part of another term, refers to a substituted or unsubstituted C3-C8 carbocyclic group as defined above in which one or more of the carbocyclic group's hydrogen atoms have been replaced with a bond (i.e., it is divalent).

[0113] Unless otherwise indicated, "C3-C 10"Carbocycle," by itself or as part of another term, refers 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 derived by the removal of one hydrogen atom from a ring atom of a parent ring system. Representative -C3-C 10 Carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl. 10 Carbocycles can further include fused cyclooctyne carbocycles, such as the fused cyclooctyne compounds disclosed in WO 2011 / 136645 (the disclosure of which is incorporated herein by reference), including BCN (bicyclo[6.1.0]nonyne) and DBCO (dibenzocyclooctyne).

[0114] Unless otherwise indicated, "C3-C8 heterocycle," by itself or as part of another term, refers to a substituted or unsubstituted, monovalent, substituted or unsubstituted, aromatic or non-aromatic monocyclic or bicyclic ring system having 3 to 8 carbon atoms (also referred to as ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P, or S, derived by removing one hydrogen atom from a ring atom of the parent ring system. One or more N, C, or S atoms in the heterocycle can be oxidized. A ring containing a heteroatom can be aromatic or non-aromatic. Unless otherwise specified, a heterocycle is attached to its pendant group at 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, pyridazinyl, isothiazolyl, and isoxazolyl. Unless otherwise specified, the term "heterocarbocycle" is synonymous with the term "heterocycle" or "heterocyclo" as used herein.

[0115] Unless otherwise indicated, "C3-C8 heterocyclo" by itself or as part of another term refers to a substituted or unsubstituted C3-C8 heterocyclic group as defined above in which one of the heterocyclic group's hydrogen atoms has been replaced with a bond (i.e., it is divalent).

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

[0117] Unless otherwise indicated, an "arylene," by itself or as part of another term, is an unsubstituted or substituted aryl group, as defined above, in which one of the aryl group's hydrogen atoms has been replaced with a bond (i.e., it is divalent), and which may be in the ortho, meta, or para orientation.

[0118] Unless otherwise indicated, "heteroaryl" refers to a ring system in which one or more ring atoms is a heteroatom, such as nitrogen, oxygen, and sulfur. The heterocyclic radical contains 1 to 20 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S. The heterocyclic ring can be a monocyclic ring (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) having 3 to 7 ring members or a bicyclic ring (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) having 7 to 10 ring members, such as a bicyclo[4,5], [5,5], [5,6], or [6,6] system.

[0119] Unless otherwise indicated, a "heteroarylene," by itself or as part of another term, is an unsubstituted or substituted heteroaryl group, as defined above, in which one of the heteroaryl group's hydrogen atoms has been replaced with a bond (i.e., it is divalent).

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

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

[0122] Unless otherwise indicated, "substituted alkyl" and "substituted aryl" refer to alkyl and aryl, respectively, in which one or more hydrogen atoms have each been independently replaced with a substituent. Exemplary substituents include -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, where each X is independently a halogen: -F, -Cl, -Br, or -I; 10 are independently -H, -C1-C20 Alkyl, -C6-C 20 Aryl, -C3-C 14 Heterocycle, protecting group or prodrug moiety. Typical substituents also include (=O). The above alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle and heterocyclo groups may also be similarly substituted.

[0123] Unless otherwise specified, a "polyhydroxyl group" refers to an alkyl, alkylene, carbocyclic, or carbocyclo group containing two or more or three or more hydroxyl groups substituted for hydrogen on carbon atoms of a carbon chain. In some embodiments, a polyhydroxyl group contains at least three hydroxyl groups. In some embodiments, a polyhydroxyl group contains carbon atoms containing only one hydroxyl group per carbon atom. A polyhydroxyl group may contain one or more carbon atoms that are not substituted with hydroxyl. A 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 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, sugar acids such as gluconic acid, aldonic acid, uronic acid, and amino sugars such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. In some embodiments, polyhydroxyl groups include linear or cyclic forms of disaccharides and polysaccharides.

[0124] Unless otherwise indicated by context, "optionally substituted" refers to an alkyl, alkenyl, alkynyl, alkylaryl, arylalkylheterocycle, aryl, heteroaryl, alkylheteroaryl, heteroarylalkyl, or other substituent, moiety, or group as defined or disclosed herein, in which a hydrogen atom of the substituent, moiety, or group is optionally replaced with a different moiety or group, or an alicyclic carbon chain comprising one of the substituents, moieties, or groups is interrupted by replacing a carbon atom of the chain with a different moiety or group. In some embodiments, an alkene functional group replaces two consecutive sp3 carbon atoms of an alkyl substituent, so long as the radical carbon of the alkyl moiety is not replaced, and thus the optionally substituted alkyl is an unsaturated alkyl substituent.

[0125] The optional substituents replacing a hydrogen on any one of the foregoing substituents, moieties, or groups are independently selected from the group consisting of aryl, heteroaryl, hydroxyl, alkoxy, aryloxy, cyano, halogen, nitro, fluoroalkoxy, and amino (including mono-, di-, and tri-substituted amino groups), and protected derivatives thereof, 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( and salts thereof, wherein each X is independently selected from the group consisting of halogens: -F, -CI, -Br, and -I; and each R" is selected from C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C6-C 24 Aryl, C3-C 24 Heterocyclyl (C5-C 24 or two of R" together with the heteroatom to which they are attached define a heterocyclyl; R' is hydrogen or R" and R" is C-C 20 Alkyl, C6-C 24 Aryl, C3-C 24 Heterocyclyl (C5-C 24 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, and salts thereof, each X is independently selected from the group consisting of -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 salts thereof, wherein each X is independently selected from the group consisting of -F and -Cl, and R'' is typically C1-C6 alkyl, C6-C 10 Aryl, C3-C 10 Heterocyclyl (C5-C 10 R' is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C6 ... 10 Aryl, C3-C 10 Heterocyclyl (C5-C 10 is a protecting group independently selected from R″ (including heteroaryl) and R″. More typically, the substituents are selected from the group consisting of -X, -R", -OH, -OR", -NH, -NH(R"), -N(R"), -N(R"), -CX, -NO, -NHC(=O)H, -NHC(=O)R", -C(=O)NH, -C(=O)NHR", -C(=O)N(R"), -COH, -COR", -C(=O)H, -C(=O)R", -C(=O)NH, -C(=O)NH(R'"), -C(=O)N(R"), -C(=')NH, -C(=NR')NH(R"), -C(=NR')N(R"), protecting groups and salts thereof, wherein each X is -F and R" is C-C alkyl, C-C 10 Aryl, C5-C 10 is independently selected from the group consisting of heteroaryl and a protecting group; R' is selected from the group consisting of hydrogen, C1-C6 alkyl, and a protecting group independently selected from R''.

[0127] The phrase "pharmaceutically acceptable salt," as used herein, refers to a pharmaceutically acceptable organic or inorganic salt of a compound (e.g., a linker, a drug linker, or a 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, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, linoleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate, succinate, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have two or more charged atoms in its structure. When multiple charged atoms are part of a pharmaceutically acceptable salt, it may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions.

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

[0129] As used herein, the term "consisting of" refers to compositions, methods, and their respective components described herein, excluding any element not recited in that description of an embodiment.

[0130] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood to be modified in all instances by the term "about." When used in connection with percentages, the term "about" can mean + / - 1%.

[0131] The term "statistically significant" or "significant" refers to statistical significance, generally meaning a difference of 2 standard deviations (2SD) above or below a reference value.

[0132] Other terms are defined herein within the context of the description of various aspects of the invention.

[0133] Provided herein are linkers comprising polar units, such as saccharide units, PEG units, and / or carboxyl units. Also provided are targeting unit-linkers, drug linkers, and conjugates thereof, comprising drug units, such as cytotoxic agents or immunomodulatory agents, as further described herein.

[0134] In some embodiments, the linker has the general formula (I) comprising a stretcher unit (L1) attached directly or via an optional amino acid unit (AA) to a linker subunit (L2), as shown in formula (I) below: [ka] (where s is 0 or 1, and the wavy line ( [ka] ) indicates a binding site for a targeting unit (L) or a drug unit (D) or a salt thereof. The linker includes at least one polar unit within the amino acid unit, the linker subunit L2, or both. Each polar unit can be a sugar unit, a PEG unit, or a carboxyl unit. The linker can include at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 can 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.

[0135] Also provided are linker conjugates comprising a targeting unit (L) attached to at least one linker, each linker being attached to at least one drug unit (D), as shown in formula (II) below: L-[[L1-AA s -L2]-D t ] pload (II) wherein L1, AA, and L2 comprise a linker and are as described above for formula (I), s is 0 or 1, t is 1 to 4, and p load is 1 to 20). The linker includes at least one polar unit in the amino acid unit, the linker subunit L2, or both. Each polar unit can be a saccharide unit, a PEG unit, or a carboxyl unit. The linker can include at least one saccharide unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 can have 1 to 4 attachment sites for the Drug unit. In some embodiments, the linker subunit L2 has one attachment site for the Drug unit. In some embodiments, the linker subunit L2 has two attachment sites for the Drug unit.

[0136] The following formula (III) ~[L1-AAs -L2]-D t (III) Also provided are drug-linkers represented by the formula: (wherein L1, AA, L2, and D comprise a linker and are as described above with respect to Formula (II), s is 0 or 1, t is 1 to 4, and the wavy line represents a binding site for a targeting unit), or a salt thereof. The linker comprises at least one polar unit within the amino acid unit, the linker subunit L2, or both. Each polar unit can be a sugar unit, a PEG unit, or a carboxyl unit. The linker can comprise at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 can 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.

[0137] Formula (IV): [ka] wherein L, L, AA, and L comprise a linker, L, L, AA, and L are as described above for formula (I), s is 0 or 1, d is 1 to 20, and the double wavy line ( [ka] Further provided are targeting unit-linker intermediates represented by the formula (I) or a salt thereof, wherein L2 denotes a binding site for a Drug unit. The linker comprises at least one polar unit within the amino acid unit, the linker subunit L2, or both. Each polar unit can be a sugar unit, a PEG unit, or a carboxyl unit. The linker can comprise at least one sugar unit, at least one PEG unit, at least one carboxyl unit, or a combination thereof. The linker subunit L2 can 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] Polar Units The polar units (PU) provided herein include saccharide units, PEG units, and carboxyl units, as further described herein.

[0139] Sugar Unit (SU) In some embodiments, the sugar unit (SU) has 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, monosaccharides, disaccharides, and polysaccharides; each X is independently selected from CH and C(O); each X is independently selected from H, OH, and OR; and k is 1 to 10, or a salt thereof. In some embodiments, each (CH—(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, idustalose, aldose, ketose, a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid, or an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. Suitable disaccharides include sucrose, lactose, and maltose. Suitable 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) (Wherein, L3a is C1-C 10 and L3a is covalently bonded to the N atom marked with a** in formula (X). Each * and each # indicates a binding site for another subunit of an amino acid unit (AA) or linker subunit (L2), a Stretcher unit (L1), or other component of a linker, as described herein.

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

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

[0143] PEG units In some embodiments, the linker comprises a PEG unit. The PEG unit may be attached to a subunit of an amino acid unit or a portion of the linker subunit L2. The subunit of an 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 attached to a stretcher unit.

[0144] In some embodiments, the PEG unit has the general formula: -(CHCHO) n20 -R 24 wherein R 24 is H or C1-C6 alkyl and n20 is 1 to 26. In some, n20 is 12 and R 24 is methyl.

[0145] In some embodiments, the PEG unit has 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene; R 24 and R 25is as shown below; the wavy line (~) indicates the binding site; n20 is 1 to 26) or a salt thereof. In some embodiments, R 20 is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0146] In some embodiments, the PEG unit has 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 21 and R 22 are each independently an optional C1-C3 alkylene; R 24 and R 25 is as shown below; the wavy line (~) indicates the binding site; n20 is 1 to 26) or a salt thereof. In some embodiments, R 20 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0147] In some embodiments, the PEG unit has 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 26 and R 27 are optional C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene -C(O)- or -C(O)-C-C 12 alkylene-NH-; R 24 and R 25 are as shown below; each R 29 is optional and independently selected from -C(O)-, -NH-, -C(O)-C-C alkenylene-, -NH-C-C alkenylene-, -C-C alkenylene-NH-, and -C-C alkenylene-C(O)-; a wavy line (~) indicates the site of attachment; n20 is 1 to 26; n21 is 1 to 4; and n27 is 1 to 3) or a salt thereof. In some embodiments, R 20 is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0148] In some embodiments, the PEG unit has 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 26 and R 27 are optional C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene -C(O)- or -C(O)-C-C 12 alkylene-NH-; R 24 and R 25 are as shown below; each R 29 is optional and independently selected from —C(O)—, —NH—, —C(O)—Ci-C6 alkenylene-, —NH—Ci-C6 alkenylene-, —Ci-C6 alkenylene-NH—, —Ci-C6 alkenylene-C(O)—, —NH(CO)NH—, and triazole; a wavy line (~) indicates the site of attachment; n20 is 1 to 26; n21 is 1 to 4; and n27 is 1 to 3) or a salt thereof. In some embodiments, R 20 is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0149] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are, respectively, H and a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; Substituted -C1-C8 alkyl; Substituted -C(O)-C1-C8 alkyl; Chelating agent; -C(O)-R 28 (In the formula, R 28 are sugar units of formula (XII) or (XIII), or —NR 24 R 25 are formed from C3-C8 heterocycles.

[0150] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 one of which is H and a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 Carbocycle; Optionally substituted heteroaryl; Optionally substituted carbocycle; 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 R 24 and R 25 The other is optionally a polyethylene glycol having 1 to 24 ethylene glycol subunits.

[0151] In some embodiments of the PEG unit of formula (XX) or (XXI), R 24 and R 25and R are not H. In some embodiments of PEG units of formula (XX) or (XXI), R 24 and R 25 One of them is H.

[0152] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are each independently selected from H and a polyhydroxyl group, with the proviso that R 24 and R 25 provided that both are not H. The polyhydroxyl group can be linear or branched. In some embodiments, the polyhydroxyl group contains at least three hydroxyl groups. In some embodiments, the polyhydroxyl group is a linear monosaccharide. As used herein, a linear monosaccharide refers to the open-ring form of a monosaccharide. In some embodiments, a linear monosaccharide is a linear form of a C6 or C5 sugar, such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altose, gulose, idostulose, aldose, and ketose. In some embodiments, the linear monosaccharide can further comprise a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid. In some embodiments, the linear monosaccharide can further comprise an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0153] Examples of PEG units with linear monosaccharides include: [ka] [ka] (In the formula, R 39is selected from H, a linear monosaccharide, and polyethylene glycol). In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is optionally deprotected to form a bond between the left-most carboxyl or hydroxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or a portion of a linker subunit L2.

[0154] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are each independently selected from H and a polyhydroxyl group, with the proviso that R 24 and R 25 and (XXI) are not H. In some embodiments of PEG units of formula (XX) and (XXI), R 24 and R 25 One of R is selected from a polyhydroxyl group and the other is polyethylene glycol. In some embodiments, each polyhydroxyl group contains at least three hydroxyl groups. The polyhydroxyl group can be linear, branched, or cyclic. In some embodiments, R 24 and R 25 One of R is a linear monosaccharide and the other is a cyclic monosaccharide. 24 and R 25One of the monosaccharides 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 a C6 or C5 sugar, such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, allulose, glucose, idostulose, aldose, and ketose. In some embodiments, the linear monosaccharide can further comprise a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid. In some embodiments, the linear monosaccharide can further comprise an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. 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 can further comprise a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid. In some embodiments, the cyclic monosaccharide can further comprise an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. The stereochemistry at the anomeric C-1 position can be either alpha or beta.

[0155] Examples of PEG units include: [ka] (In the formula, R 41 is a linear monosaccharide, a cyclic monosaccharide, or polyethylene glycol). In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is optionally deprotected, and a bond is formed between the left-most carboxyl or hydroxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or a portion of a linker subunit L2.

[0156] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are each independently selected from H and a polyhydroxyl group, with the proviso that R 24 and R 25 and R are not H. In some embodiments, R 24 and R 25 Each of R is a cyclic monosaccharide, disaccharide, or polysaccharide. In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 one of R is selected from a cyclic monosaccharide, disaccharide, or polysaccharide; 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 can further comprise a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid. In some embodiments, the cyclic monosaccharide can further comprise an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine. The stereochemistry at the anomeric C-1 position can be either alpha or beta.

[0157] In some embodiments, disaccharides include those containing any of the above monosaccharides. 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 above monosaccharides. 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 an exemplary embodiment, the PEG unit having a cyclic monosaccharide, disaccharide, or polysaccharide comprises: [ka]

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

[0160] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are each independently selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide. In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25one of R is selected from a polyhydroxyl group that is a linear monosaccharide or a substituted linear monosaccharide; 24 and R 25 The other is polyethylene glycol. In some embodiments, the linear monosaccharide is a linear form of a C6 or C5 sugar, such as glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idostulose, aldose, and ketose. In some embodiments, the linear monosaccharide can further comprise a sugar acid, such as gluconic acid, aldonic acid, uronic acid, or ulosonic acid. In some embodiments, the linear monosaccharide can further comprise an amino sugar, such as glucosamine, N-acetylglucosamine, galactosamine, and N-acetylgalactosamine.

[0161] In some embodiments, the substituted linear monosaccharide may be replaced with a monosaccharide, disaccharide, or polysaccharide, in either case, linear or cyclic. In some embodiments, disaccharides include those containing any of the above monosaccharides. 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 above monosaccharides. 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.

[0162] Examples of PEG units containing linear monosaccharides optionally substituted with saccharides include: [ka] (In the formula, R 47 is selected from H, a linear monosaccharide, and a polyethylene glycol, and each R 49is selected from monosaccharides, disaccharides, and polysaccharides. In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is optionally deprotected to form a bond between the left-most carboxyl or hydroxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or a portion of a linker subunit L2.

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

[0164] In an exemplary embodiment, the PEG unit having a polyhydroxyl group comprising a linear or substituted linear monosaccharide comprises: [ka]

[0165] In each of these examples, each R 42 is independently selected from H, a monosaccharide, disaccharide, or polysaccharide as described herein, or polyethylene glycol; and each R 43is selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester, or amide. In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or a portion of a linker subunit L2.

[0166] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 at least one of R is a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group; 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 can be substituted with a monosaccharide, disaccharide, or polysaccharide (in each case, either linear or cyclic); an alkyl; an O-alkyl; an aryl; a carboxyl; an ester; or an amide. In some embodiments, disaccharides include those containing any of the above monosaccharides. The term disaccharide can 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 above monosaccharides. The term polysaccharide can include 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 an exemplary embodiment, the PEG unit having a -C(O)-polyhydroxyl group or a substituted -C(O)-polyhydroxyl group comprises: [ka]

[0168] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0169] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are independently selected from H and substituted -C1-C8 alkyl, with the proviso that R 24 and R 25 and R are not H. In some embodiments, R 24 and R 25 are independently selected from H and substituted -C1-C4 alkyl, with the proviso that R 24 and R 25 and R are not H. In some embodiments, R 24 and R 25 are independently selected from H and substituted -C1-C3 alkyl, with the proviso that R 24 and R 25 are not both H. The alkyl portion of the substituted -C1-C8, -C1-C4 and -C1-C3 alkyl can be linear or branched.

[0170] The substituted -C1-C8, -C1-C4, or -C1-C3 alkyl may 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 atom of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl is substituted with carboxyl. In some embodiments, the terminal carbon atom of the substituted -C1-C8, -C1-C4, or -C1-C3 alkyl is substituted with hydroxyl.

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

[0172] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25is selected from H and substituted —C(O)—C-C alkyl; 24 and R 25 and the other is selected from substituted —C(O)—C-C alkyl, —C(O)—C-C alkyl, and —C(O)—C-C alkyl, and substituted —C-C alkyl, —C-C alkyl, and —C-C alkyl (as described above). 24 and R 25 is independently selected from H and substituted —C(O)—C-C alkyl; 24 and R 25 and the other is selected from substituted —C(O)—C-C alkyl, —C(O)—C-C alkyl, and —C(O)—C-C alkyl, and substituted —C-C alkyl, —C-C alkyl, and —C-C alkyl (as described above). 24 and R 25 is selected from H and substituted —C(O)—C1-C3 alkyl, and R 24 and R 25 is selected from substituted -C(O)-C-C alkyl, -C(O)-C-C alkyl, and -C(O)-C-C alkyl, and substituted -C-C alkyl, -C-C alkyl, and -C-C alkyl (as described above). The alkyl of the substituted -C(O)-C-C alkyl, -C(O)-C-C alkyl, and -C(O)-C-C alkyl can be linear or branched. The alkyl moiety of the substituted -C-C, -C-C, and -C-C alkyl can be linear or branched.

[0173] The 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 atom of the substituted -C(O)-C-C alkyl, -C(O)-C-C alkyl, and -C(O)-C-C alkyl is substituted with carboxyl. In some embodiments, the terminal carbon atom of the substituted -C(O)-C-C alkyl, -C(O)-C-C alkyl, and -C(O)-C-C alkyl is substituted with hydroxyl.

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

[0175] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0176] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25is selected from H and optionally substituted aryl, with the proviso that R 24 and R 25 and R are not H. In some embodiments, substituted aryl includes aryl substituted with halogen (such as chloro, fluoro, and bromo).

[0177] In an exemplary embodiment, the substituted aryl-containing PEG unit comprises: [ka]

[0178] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0179] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are taken together to form an optionally substituted C-C heterocycle or heteroaryl. In some embodiments, the optional substituents include a heterocycle or aryl substituted with a halogen (such as chloro, fluoro, and bromo).

[0180] In an exemplary embodiment, the PEG unit comprising an optionally substituted C3-C8 heterocycle comprises: [ka]

[0181] In this exemplary embodiment, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0182] In some embodiments of the PEG units of formula (XX) and (XXI), R 24 and R 25 are independently selected from H and chelators, with the proviso that R 24 and R 25 and N,N'-dialkyl-substituted piperazines. In some embodiments, the chelator 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 chelator is selected from -NR 24 R 25 In some embodiments, the chelator is attached via an alkylene, arylene, carbocyclo, heteroarylene, or heterocarbocyclo (in each case either substituted or unsubstituted).

[0183] In some exemplary embodiments, the PEG unit comprising the chelator comprises: [ka]

[0184] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0185] In some embodiments of the PEG units of formula (XX), (XXI), (XXX), (XXXI), (XXXII), and (XXXIII), the chelator may be an R 24 , R 25 and / or R 30 The chelator can be attached to any of the R groups described herein. In some embodiments, the chelator 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 ... 24 , R 25 or R 30 In some embodiments, the chelator is attached via an alkylene, arylene, carbocycle, heteroaryl, or heterocarbosyl (in each case, either substituted or unsubstituted).

[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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 21 and R 22 are each an optional C1-C3 alkylene group; R 30 is an optionally substituted C3-C 10In some embodiments, R is selected from a carbocycle; a thiourea; an optionally substituted thiourea; a urea; an optionally substituted urea; a sulfamide; an alkylsulfamide; an acylsulfamide, an optionally substituted alkylsulfamide; an optionally substituted acylsulfamide; a sulfonamide; an optionally substituted sulfonamide; a guanidine (including alkyl and aryl guanidines); a phosphoramide; or an optionally substituted phosphoramide; a wavy line (~) indicates the site of attachment; and n20 is 1 to 26. 20 is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups 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 is a functional group for binding to a subunit of an amino acid unit and / or a portion of the linker subunit L2; R 21 and R 22 are each an optional C1-C3 alkylene group; R 30 is an optionally substituted C3-C 10In some embodiments, R is selected from a carbocycle; a thiourea; an optionally substituted thiourea; a urea; an optionally substituted urea; a sulfamide; an alkylsulfamide; an acylsulfamide, an optionally substituted alkylsulfamide; an optionally substituted acylsulfamide; a sulfonamide; an optionally substituted sulfonamide; a guanidine (including alkyl and aryl guanidines); a phosphoramide; or an optionally substituted phosphoramide; a wavy line (~) indicates the site of attachment; and n20 is 1 to 26. 20 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0188] In some embodiments of the PEG unit of formula (XXX), R 30 is an optionally substituted C3-C 10 In some embodiments, an optionally substituted C-C 10 The carbocycle is a fused cyclooctyne compound as disclosed in WO 2011 / 136645, the disclosure of which is incorporated herein by reference. An exemplary PEG unit having a fused cyclooctyne is shown below: [ka]

[0189] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is optionally deprotected to form a bond between the left-most carboxyl or amino group of the PEG unit and a reactive group on the subunit of an amino acid unit or a portion of a linker subunit L2.

[0190] As will be understood by those skilled in the art, the above compounds and other compounds disclosed in WO 2011 / 136645 can be used as intermediates for click chemistry to attach additional compounds. In some embodiments, the additional compound is a drug unit. In some embodiments, the additional compound is a linker subunit L2 as described herein.

[0191] In some embodiments of the PEG unit of formula (XXX), R 30 is a thiourea; a substituted thiourea, a urea, or a substituted urea. The thiourea and urea groups can be substituted, for example, with an optionally substituted alkyl, an optionally substituted carbocycle, or an optionally substituted aryl.

[0192] Exemplary PEG units comprising thiourea; substituted thiourea; urea; or substituted urea include the following: [ka]

[0193] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0194] In some embodiments of the PEG unit of formula (XXX), R 30 is sulfamide, alkylsulfamide, acylsulfamide, optionally substituted alkylsulfamide, optionally substituted acylsulfamide, sulfonamide, or optionally substituted sulfonamide. The optionally substituted alkylsulfamide, optionally substituted acylsulfamide, and optionally substituted sulfonamide may be substituted with additional groups, such as linkers, groups for attaching drugs or other compounds, to enhance solubility or in other embodiments.

[0195] Exemplary PEG units comprising a sulfamide; an alkylsulfamide; an acylsulfamide, an optionally substituted alkylsulfamide; an optionally substituted acylsulfamide; a sulfonamide; or an optionally substituted sulfonamide include the following: [ka]

[0196] In these examples, R 50 can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocarbocycle, or heteroaryl. In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of a subunit of an amino acid unit or a portion of a linker subunit L2.

[0197] In some embodiments of the PEG unit of formula (XXX), R 30 is guanidine or an optionally substituted guanidine. The optionally substituted guanidine may be substituted with an optionally substituted alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocarbocycle, or heteroaryl.

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

[0199] In these examples, R 55can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocarbocycle, or heteroaryl. In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is optionally deprotected to form a bond between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or a portion of a linker subunit L2.

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

[0201] Exemplary PEG units that contain a phosphoramide or an optionally substituted phosphoramide include the following: [ka] In these examples, R 60 R can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocarbocycle, or heteroaryl. 61 can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocarbocycle, or heteroaryl. In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or a portion of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of a subunit of an amino acid unit or a portion of a linker subunit L2.

[0202] In some embodiments of PEG units of formula (XXX), the PEG unit comprises a functional group for attaching additional moieties. In some embodiments of PEG units of formula (XXX), R 30represents azido, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, -NH-C(O)-alkynyl-R 65 cyclooctyne; selected from -NH-cyclooctyne, -NH-C(O)-cyclooctyne or -NH-(cyclooctyne)2; R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, or optionally substituted heteroaryl. In some embodiments, such PEG units can be used as intermediates for click chemistry to attach additional compounds. In some embodiments, the additional compound is a drug unit. In some embodiments, the additional compound is a linker subunit L2 as described herein. In some embodiments, the additional compound is another linker or a drug linker.

[0203] Exemplary PEG units containing an azide, alkynyl, or cyclooctyne group include the following: [ka] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0204] In some embodiments, the PEG unit has 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 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 21 and R 22 are each an optional C1-C3 alkylene group; R 26 and R 27 are optional C1-C 12 Alkylene, -NH-C1-C 12Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene -C(O)- or -C(O)-C-C 12 alkylene-NH-; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having at its end R 35 R 33 is C-C alkylene, C-C alkylene-C(O), -C(O)-C-C alkylene, or -C(O)-C-C alkylene-C(O); each R 29 is optional and independently selected from —C(O)—, —NH—, —C(O)—C-C alkenylene-, —NH—C-C alkenylene-, —C-C alkenylene-NH—, and —C-C alkenylene-C(O)—; R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, or optionally substituted heteroaryl; the wavy line (~) indicates the point of attachment; n20 is 1 to 26; n21 is 1 to 4; and n27 is 1 to 4) or a salt thereof. In some embodiments, R 20 is selected from carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, or a protected form thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

[0205] In some embodiments, the PEG unit has 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 20is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 21 and R 22 are each an optional C1-C3 alkylene group; R 26 and R 27 are optional C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene -C(O)- or -C(O)-C-C 12 alkylene-NH-; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having an R 35 R 33 is C-C alkylene, C-C alkylene-C(O), -C(O)-C-C alkylene, or -C(O)-C-C alkylene-C(O); each R 29 is optional and independently selected from —C(O)—, —NH—, —C(O)—C-C alkenylene-, —NH—C-C alkenylene-, —C-C alkenylene-NH—, —C-C alkenylene-C(O)—, —NH(CO)NH—, and triazole; R 35 is azide, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 and R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, or optionally substituted heteroaryl; the wavy line (~) indicates the point of attachment; n20 is 1 to 26; n21 is 1 to 4; and n27 is 1 to 4), or a salt thereof. In some embodiments, R 20is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof. Suitable protecting groups include carboxylic acid, amine, and sulfonyl protecting groups typically used in the art.

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

[0207] Exemplary PEG units comprising branched polyethylene glycol chains include: [ka] [ka] In these exemplary embodiments, when the PEG unit is attached to a subunit of an amino acid unit or part of a linker subunit L2, it is deprotected and a bond is formed between the left-most carboxyl group of the PEG unit and a reactive group of the subunit of an amino acid unit or part of a linker subunit L2.

[0208] In some embodiments, the formula is selected from: ~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 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; Each R 43 is independently absent or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene, and the other is C-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

[0209] In some embodiments, the formula is selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) (In the formula, R 40 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; R 43 does not exist or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

[0210] In some embodiments, the formula is selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) (In the formula, R 40 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C3 alkylene; R 43 is absent or C1-C6 alkylene, -NH-C1-C 12 Alkylene, -C1-C6 alkylene-NH-, -C(O)-C1-C6 alkylene, -C1-C6 alkylene-C(O)-, -NH-C1-C6 alkylene-C(O)-, -C(O)-C1-C6 alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C6 alkylene, -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 the groups is H or C1-C6 alkylene, and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; The wavy line (~) is R 40 indicates the binding site for; n40 is 1 to 16; n41 is 1 to 4; n42 is 1 to 4), or a salt thereof.

[0211] In some embodiments, R 40 is selected from halo, aldehyde, carboxyl, amino, alkynyl, azide, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl, or protected forms thereof.

[0212] In some embodiments, R 40 but one of the following structures: [ka] or [ka] (Wherein, R=H or C1-6 alkyl; and n=0~12 (*) indicates the R for a subunit of an amino acid unit or a part of the linker subunit L2. 40 indicates the binding site of ( [ka] ) is the R 40 or a stereoisomer thereof.

[0213] In some embodiments, R 40 is one of the following structures: [ka] or [ka] (In the formula, n=0~12 (*) indicates the R for a subunit of an amino acid unit or a part of the linker subunit L2. 40 indicates the binding site of ( [ka] ) is the R 40 or a stereoisomer thereof.

[0214] In some embodiments, R 43 -(NR 44 R 45 ) n41 But R 43 When present, one of the following structures: [ka] or [ka] (In the formula, R=H, C1-6 alkyl, polyhydroxyl or substituted polyhydroxyl; ( [ka] ) is the R 43 or a stereoisomer thereof.

[0215] In some embodiments, R 43 -(NR 44 R 45 ) n41 But R 43 When present, one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is the R 43 or a stereoisomer thereof.

[0216] In some embodiments, —NR 44 R 45 but one of the following structures: [ka] or [ka] (In the formula, ( [ka] ) is the -NR 44 R 45or a stereoisomer thereof.

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

[0218] In some embodiments, the formula is selected from: ~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 is a functional group for binding to a subunit of an amino acid unit or a part of the linker subunit L2; R 41 and R 42 are absent or each independently C1-C6 alkylene; Each R 43is independently absent or C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C-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 the two is H or C1-C 12 alkylene and the other is C1-C 12 is alkylene; R 44 and R 45 are each independently H, a polyhydroxyl group, a substituted polyhydroxyl group, a —C(O)-polyhydroxyl group, or a substituted —C(O)-polyhydroxyl group, wherein the optional substituents are selected from sulfate, phosphate, alkyl sulfate, and alkyl phosphate; R 46 is selected from amino, amino-alkyl-amino, or —NH—C(O)—NH—S(O)2—NH—; The wavy line (~) is R 40 indicates the binding site for; n40 is 1-26; n41 is 1-6; n42 is 1 to 6), or a salt thereof.

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

[0220] In some embodiments, the formula is selected from: [ka] or [ka] (wherein each Y is independently R 76 or [ka] and Each R 76 are independently H, acetyl, -P(=O)(OH)2, or -(CH2) v -OS(=O)2(OH); Each R a and R b are independently H or R a and R b together with the carbon to which they are attached to form an oxo group; each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; and A linker intermediate or linker is provided that includes a PEG unit having an amino acid unit (AA), a linker subunit L2, or a Stretcher unit (L1) subunit (where each * indicates a binding site for the subunit), or a salt thereof.

[0221] In some embodiments, the formula is selected from: [ka] or [ka] (In the formula, each R 76 are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v S(=O)2(OH); each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; each v is independently 1 to 6; A linker intermediate or linker is provided that includes a PEG unit having an amino acid unit (AA), a linker subunit L2, or a Stretcher unit (L1) subunit (where each * indicates a binding site for the subunit), or a salt thereof.

[0222] In some embodiments, the formula is selected from: [ka] or [ka] (wherein each q is independently 1 to 26; each m is independently 1 to 4; each n is independently 1 to 4; A linker intermediate or linker is provided that includes a PEG unit having an amino acid unit (AA), a linker subunit L2, or a Stretcher unit (L1) subunit (where each * indicates a binding site for the subunit), or a salt thereof.

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

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

[0225] In some embodiments, each R a and R b are independently H.

[0226] In some embodiments, R a and R b are provided which, together with the carbon to which they are attached, form an oxo group.

[0227] In some embodiments, a linker intermediate or linker is provided in which q is 10-20.

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

[0229] In some embodiments, a linker intermediate or linker is provided in which the PEG unit is selected from the following, or a salt thereof: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka] wherein each Z is joined by a * and is individually selected from: [ka] , and [ka] each [ka] indicates the subunit of the amino acid unit (AA), part of the linker subunit L2 or the binding site to the stretcher unit (L1).

[0230] Carboxyl Unit In some embodiments, the linker comprises a carboxyl unit. The carboxyl unit may be a subunit of an amino acid unit or may be attached to a portion of the linker subunit L2. In some embodiments, the carboxyl unit has the following general formula (XXXX): R 70 | L 70 | ~NH-(CH2) p1 -CH-(CH2) o1 -C(O)~ (XXXX) (In the formula, L 70is selected from C-C alkylene, C-C alkylene-C(O)-, -C(O)-C-C alkylene- and -C(O)-C-C alkylene-C(O)-; R 70 is ~NR 71 (R 72 R 73 ) and R 71 is H, C1-C 12 Alkyl, substituted C1-C 12 alkyl, or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 72 is absent or selected from optionally substituted C1-C3 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 carbocycle, optionally substituted arylene, or optionally substituted heteroarylene; R 73 is carboxyl or polycarboxyl; 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 containing 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, where the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino, and / or amido. As used herein, polycarboxyl includes carboxylate forms.

[0231] In some embodiments, R 70 is ~NR 71 (R 75 -(R 73 )2), wherein R 71 is H, C1-C 12 Alkyl, substituted C1-C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits); R 75is a branched, optionally substituted C1-C3 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 carbocycle, optionally substituted arylene, or optionally substituted heteroarylene; and each R 73 is 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 ) where R 72 and R 74 are each independently selected from optionally substituted C1-C3 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 carbocycle, optionally substituted arylene, or optionally substituted heteroarylene; and each R 73 is 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 can be selected from: [ka] and ~COOH; (In the formula, the wavy line represents R 72 , R 74 or R 75 (showing the bond to

[0234] Linker subunit L2 The linker comprises at least one linker subunit L2, each of which has a binding site for at least one Drug unit (D), as further described herein. In some embodiments, a Drug unit (D) binds to each binding site for a Drug unit on the linker subunit L2. In various embodiments, the linker subunit L2 can be a cleavable or non-cleavable 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 comprises a polar unit such as a sugar unit, a PEG unit, or a carboxyl unit. In some embodiments, the linker subunit L2 does not comprise a polar unit, and the amino acid unit comprises a polar unit. In some embodiments, both the linker subunit L2 and the amino acid unit (if present) comprise a polar unit.

[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 within a cell or extracellular environment in which the covalent bond between the 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 metabolic product 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 the disulfide bond (e.g., an SPDB linker) (see, e.g., Jain et al., Pharm. Res. 32:3526-3540 (2015); Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020), a cleavable self-stabilizing linker (see, e.g., WO 2018 / 031690 and WO 2015 / 095755 and Jain et al. al., Pharm. Res. 32:3526-3540 (2015)), and / or a cleavable hydrophilic linker (see, e.g., WO 2015 / 123679). In some embodiments, the linker subunit L2 comprises a photolabile linker subunit. In some embodiments, the linker subunit L2 has a non-cleavable linker unit (see, e.g., WO 2007 / 008603).

[0238] In some embodiments, the linker subunit L2 is a cleavable linker that is cleavable under intracellular conditions such that cleavage of or within the linker subunit L2 releases the drug unit from the linker subunit L2 or the remainder of the linker subunit L2 in the intracellular environment. For example, in some embodiments, the linker subunit L2 is cleavable by a cleaving agent present in the intracellular environment (e.g., within a lysosome, endosome, or caveolae). As used herein, the terms "cleavable under intracellular conditions," "cleaved intracellularly," and "intracellular cleavage" refer to a metabolic process or reaction within a cell in which the covalent bond between the 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 metabolic product of the linker subunit L2 drug unit dissociated from the remainder of the linker subunit L2 within the cell. Thus, the cleaved portion of the conjugate is an intracellular metabolic product.

[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). Linker subunit L2 can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease (see, e.g., WO 2004 / 010957, U.S. Patent Application Publication No. 20150297748, U.S. Patent Application Publication No. 2008 / 0166363, U.S. Patent Application Publication No. 20120328564, and U.S. Patent Application Publication No. 20200347075). Intracellular cleavage agents may include cathepsins B, C, and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives, resulting in the release of active drugs inside target cells (see, for example, Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123). The peptidyl linker may be cleavable by enzymes present in target antigen-expressing cells. For example, a peptidyl linker subunit that can be cleaved by the thiol-dependent protease cathepsin B, which is highly expressed in cancerous tissues, may be used (e.g., having a Phe-Leu, Val-Ala, Val-Cit, or Gly-Phe-Leu-Gly peptide).

[0240] Typically, the peptidyl linker is at least one amino acid long or at least two amino acids long. In certain embodiments, the peptidyl linker is a dipeptide, tripeptide, tetrapeptide, or pentapeptide. In certain embodiments, the peptidyl linker subunit can contain only natural amino acids. In some embodiments, for example, the peptidyl linker subunit can have a Phe-Leu, Val-Ala, Val-Cit, or Gly-Phe-Leu-Gly peptide. Other such cleavable linkers are described, for example, in U.S. Pat. No. 6,214,345. In certain embodiments, the peptidyl linker cleavable by an intracellular protease comprises a Val-Cit peptide or a Phe-Lys peptide (see, e.g., U.S. Pat. No. 6,214,345) or a Gly-Gly-Phe-Gly linker (see, e.g., U.S. Patent Application Publication No. 2015 / 0297748). One advantage of using intracellular proteolytic release of the Drug unit is that the activity of the Drug unit is typically attenuated 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, a peptidyl linker subunit can comprise only unnatural amino acids. In some embodiments, a peptidyl linker subunit can comprise a natural amino acid linked to an unnatural amino acid. In some embodiments, a peptidyl linker subunit can comprise a natural amino acid linked to a D-isomer of the natural amino acid. In some embodiments, at least one amino acid of a 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 subunits contain one or more of the following 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, and polar units (including PEG units attached to glycine or L-amino acids). In some embodiments, the peptidyl linker subunits contain one or more of 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, and polar units (including PEG units attached to glycine or D-amino acids). In some embodiments, the peptidyl linker subunits contain one or more of the following: glycine and / or a mixture of L- 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, and a polar unit (including a PEG unit attached to a glycine or amino acid).

[0243] In some embodiments, the peptidyl linker subunit contains one or more of the following glycine and / or naturally occurring 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, and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit attached to the glycine or L-amino acid. In some embodiments, the peptidyl linker subunits contain one or more of 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, and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit attached to the glycine or D-amino acid.

[0244] In some embodiments, the amino acids of the peptidyl linker subunit have the formula shown below within the brackets: [ka] (In the formula, R 190 is 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 one or more 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, e.g., a sugar unit, or a carboxyl unit or PEG unit attached to the glycine or natural amino acid.

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

[0247] In some embodiments, the peptidyl linker subunit comprises one or more of the following D-isomers of these naturally occurring 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, e.g., a sugar unit, or a carboxyl unit or PEG unit attached to the glycine or D-amino acid.

[0248] In some embodiments, peptidyl linker subunit comprises the following amino acid: 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, aminoalkanoic acid, aminoalkane diacid, aminobenzoic acid, amino-heterocycloalkanoic acid, heterocyclocarboxylic acid, citrulline, statin, diaminoalkanoic acid, and derivatives thereof; and at least one polar unit, for example, a sugar unit, or one or more of a carboxyl unit or PEG unit bonded to amino acid.Illustrative examples of such amino acid derivatives are shown below in the section describing amino acid subunit.

[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., sensitive to hydrolysis at a specific pH value.Typically, the pH-sensitive linker subunit is hydrolyzable under acidic conditions.For example, acid-labile linker subunits (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic acid amide, orthoester, acetal, ketal, etc.) that can be hydrolyzed in lysosomes can be used. (See, e.g., U.S. Pat. Nos. 5,122,368; 5,824,805; and 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, e.g., in blood, but are unstable below pH 5.5 or 5.0, the approximate pH of lysosomes. In certain embodiments, the hydrolyzable linker unit is a thioether linker, such as a thioether attached to the drug unit via an acylhydrazone bond (see, e.g., U.S. Pat. No. 5,622,929).

[0251] In some embodiments, the linker subunit L2 is cleavable under reducing conditions (e.g., a disulfide linker subunit). For example, a variety of 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-pyridyl-dithio)toluene)-, SPDB, and SMPT (see, e.g., Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In Immunoconjugates: Antibody Conjugates in Radioimagery and Therapy of Cancer (C.W. Vogel ed., Oxford U.S. Press, 1987. See also U.S. Pat. No. 4,880,935.

[0252] In some embodiments, the linker subunit L2 is a malonic acid linker (Johnson et al., 1995, Anticancer Res. 15:1387-93), a maleimidobenzoyl 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 a maleimidocaproyl linker, and the drug unit is released by metabolic degradation of the drug-linker. (See, e.g., U.S. Patent Application Publication No. 2005 / 0238649.)

[0253] In some embodiments, the linker subunit L2 is substantially insensitive to the extracellular environment. As used herein, "substantially insensitive to the extracellular environment" in the context of the linker subunit L2 means that when the conjugate is present in an extracellular environment (e.g., in 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 a sample of the conjugate is cleaved. Whether the 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 targeting unit or drug unit ("control sample") independently with plasma for a predetermined period of time (e.g., 2, 4, 8, 16, or 24 hours), and then comparing the amount of unconjugated targeting unit or drug unit 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 cellular internalization. In some embodiments, the linker or linker subunit L2 promotes cellular internalization when conjugated to a drug unit, such as a cytotoxic agent (i.e., in the context of the linker-drug unit portion of a conjugate described herein). In yet other embodiments, the linker or linker subunit L2 promotes cellular internalization when conjugated to both a drug unit and a targeting unit (i.e., in the context of a 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 WO2004010957. In some embodiments, the linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive spacer and a dipeptide (e.g., maleimidyl caproyl valine alanine). In some embodiments, the linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive maleimidocaproyl spacer, an amino acid or peptide, and a self-immolative group. In some embodiments, the linker subunit L2 comprises a protease-cleavable linker comprising a thiol-reactive maleimidocaproyl spacer, a valine-citrulline dipeptide, and a p-aminobenzyloxycarbonyl self-immolative group.

[0256] In some embodiments, the linker subunit L2 comprises an acid-cleavable linker such as a hydrazine linker or a quaternary ammonium linker (see, e.g., WO 2017 / 096311 and WO 2016 / 040684).

[0257] In some embodiments, the linker subunit L2 comprises a self-stabilizing moiety comprising a maleimide group as described in WO 2013 / 173337.

[0258] In some embodiments, the linker subunit L2 comprises a hydrophilic linker, such as, for example, the hydrophilic peptides of WO 2015 / 123679 and the sugar alcohol polymer-based linkers disclosed in WO 2013 / 012961 and WO 2019 / 213046.

[0259] In other embodiments, the linker subunit L2 can be generated using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxyl (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Chelating agents for the conjugation of radionucleotides are described, for example, in WO 94 / 11026.

[0260] In some embodiments, linker subunit L2 can be prepared using cross-linkers including, but not limited to, commercially available (e.g., Pierce Biotechnology, Inc. (Rockford, IL, USA)) 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, and SVSB (succinimidyl-(4-vinylsulfone)benzoate).

[0261] Amino acid (AA) units The linker optionally comprises an amino acid unit (AA). When present in the linker, the amino acid unit connects the stretcher unit (L1) to the linker subunit L2. When s in AA is 0, the amino acid unit is absent (e.g., any of Formulas I-IV). In some embodiments, the amino acid unit comprises 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 is optionally modified to form a polar unit, such as a sugar unit, a PEG unit, or a carboxyl unit.

[0263] In some embodiments, the subunits of the amino acid unit are 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, and polar units (including PEG units attached to glycine or L-amino acids). In some embodiments, the subunits of the amino acid unit are 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, and polar units. In some embodiments, the subunits of the amino acid unit are selected from glycine and / or a mixture of L- 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, and polar units (including PEG units attached to glycine or D-amino acids).

[0264] In some embodiments, the subunits of the amino acid unit are 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, and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit, attached to glycine or an L-amino acid. In some embodiments, the subunits of the amino acid unit are 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, and at least one polar unit, such as a sugar unit, or a carboxyl unit or PEG unit, attached to glycine or an D-amino acid.

[0265] In some embodiments, the subunits of the amino acid unit independently have the formula shown below in square brackets: [ka] (In the formula, R 190 is 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 the amino acid unit is independently selected from the group consisting of the following L-(naturally occurring) 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, e.g., a sugar unit, or a carboxyl unit or PEG unit attached to a natural amino acid.

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

[0268] In some embodiments, each subunit of the amino acid unit is independently selected from the group consisting of the following D-isomers of these naturally occurring 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, e.g., a sugar unit, or a carboxyl unit or PEG unit attached to glycine or an L-amino acid.

[0269] In some embodiments, each subunit of the 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, aminoalkanoic acid, aminoalkanedioic acid, aminobenzoic acid, amino-heterocycloalkanoic acid, heterocyclocarboxylic acid, citrulline, statin, diaminoalkanoic acid, and derivatives thereof; and at least one polar unit, for example, a sugar unit, or a carboxyl unit or PEG unit attached to one of the subunits.

[0270] Illustrative examples of alanine and its derivatives include alanine (Ala), N-alkyl-alanine, dehydro-alanine, 4-thiazolylalanine, 2-pyridylalanine, 3-pyridylalanine, 4-pyridylalanine, β-(1-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- These 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 a protected piperazine ring, β-(2-quinolyl)-alanine, β-(1,2,4-triazole-1-yi)-alanine, β-ureido-alanine, H-β-(3-benzothienyl)-Ala-OH, and H-β-(2-thienyl)~Ala-OH.

[0271] Illustrative examples of arginine and its derivatives include, but are not limited to, arginine (Arg), N-alkyl-arginine, H-Arg(Me)-OH, H-Arg(NH)-OH, H-Arg(NO)-OH, H-Arg(Ac)-OH, H-Arg(Me)-OH (asymmetric), H-Arg(Me)-OH (symmetric), 2-amino-4-(2'-hydroxyguanidino)-butyric acid (N-ω-hydroxy-nor-arginine), and homoarginine.

[0272] Illustrative 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] Illustrative examples of asparagine and its derivatives include, but are not limited to, asparagine (Asn), N-alkyl-asparagine, and isoasparagine (H-Asp-NH2).

[0274] Illustrative examples of cysteine ​​(Cys) derivatives (not containing 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(SOH)-OH, H-Cys(aminoethyl)-OH, H-Cys(carbamoyl)-OH, H-Cys(phenyl)-OH, H-Cys(Boc)-OH, and H-Cys(hydroxyethyl)-OH.

[0275] Illustrative 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] Illustrative examples of glycine and its derivatives include glycine (GIy), N-alkyl-glycines, H-propargylglycine ( [ka] CH); α These include, but are not limited to, aminoglycine (protected or unprotected), β-cyclopropyl-glycine, cyclopentyl-glycine, cyclohexyl-glycine, α-allylglycine, t-butyl-glycine, neopentylglycine and phenylglycine.

[0277] Illustrative 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] Illustrative 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] Illustrative 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] Illustrative 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)-OH, H-Lys(nicotinoyl)-OH, H-Lys(Me)-OH, H-trans-4,5-dehydro-Lys-OH, H-Lys(Aloc)-OH, HH-δ-hydroxy-Lys-OH, H-δ- Illustrative examples of leucine and its derivatives include, but are not limited to, leucine (Leu), N-alkyl-leucine, 4,5-dehydroleucine-leucine, H-α-Me-Leu-OH, homoleucine, norleucine, and t-leucine, including, but not limited to, hydroxy-Lys(Boc)-OH, H-Lys(acetamidoyl)-OH, and H-Lys(isopropyl)-OH.

[0281] Illustrative 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] Illustrative 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] Illustrative 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] Illustrative 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] Illustrative examples of isoleucine and its derivatives include, but are not limited to, isoleucine (He), N-alkyl-isoleucine, allo-isoleucine, and norleucine.

[0286] Illustrative 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] Illustrative 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] Illustrative examples of valine and its derivatives include, but are not limited to, valine (Val), N-alkyl-valine, H-α-Me-Val-OH, and norvaline.

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

[0290] Illustrative examples of penicillamine and its derivatives include, but are not limited to, penicillamine, H-penicillum(Acm)-OH (H-β,β-dimethylbis(Acm)-OH), and N-alkyl-penicillamine.

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

[0292] Illustrative examples of aminoalkanoic acids and derivatives thereof include, but are not limited to, N-alkylaminoalkanoic acids, 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] Illustrative examples of aminoalkynoic acids and derivatives thereof include, but are not limited to, N-alkylaminoalkynoic acids, 6-amino-4-hexynoic acid, 6-(Boc-amino)-4-hexynoic acid.

[0294] Illustrative examples of aminoalkanedioic acids and derivatives thereof include, but are not limited to, N-alkylaminoalkanedioic acids, 2-aminohexanedioic acid, 2-aminoheptanedioic acid, 2-aminooctanedioic acid (H-Asu-OH).

[0295] Illustrative examples of aminobenzoic acids and derivatives thereof include, but are not limited to, N-alkylaminobenzoic acids, 2-aminobenzoic acids, 3-aminobenzoic acids, and 4-aminobenzoic acids.

[0296] Illustrative examples of amino-heterocycloalkanoic acids and derivatives thereof include, but are not limited to, N-alkylamino-heterocycloalkanoic acids, 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), 3-amino-3-(3-pyridyl)-propionic acid.

[0297] Illustrative examples of heterocyclocarboxylic acids and derivatives thereof include, but are not limited to, azetidine-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-4-carboxylic acid, and thiazolidine-4-carboxylic acid.

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

[0299] Illustrative examples of statins and derivatives thereof include, but are not limited to, statins, N-alkyl-statins, cyclohexylstatins, and phenylstatins.

[0300] Illustrative examples of diaminoalkanoic acids (Dab) and derivatives thereof include, but are not limited to, N-alkyl-diamino-alkanoic acids, N,N-dialkylamino-alkanoic acids, α,γ-diaminobutyric acid (H-Dab-OH), H-Dab(Aloc)-OH, H-Dab(Boc)-OH, H-Dab(Z)-OH, α,β-diaminopropionic acid and side chain protected versions thereof.

[0301] In some embodiments, the amino acid unit may be terminated with a capping group, such as a straight or branched alkyl group, or a polyethylene chain (1-30 subunits) or PEG unit.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0318] In some embodiments, the amino acid unit is present and is attached to the linker subunit L2 by a non-peptide bond. In some embodiments, the amino acid unit is C1-C 10Alkylene, C2-C 10 Alkenylene, C2-C 10 It is connected to the linker subunit L2 by a peptidic linking group such as alkynylene or polyethylene glycol.

[0319] In some embodiments, linker intermediates or linkers are provided in which L2 or AA-L2 has one of the following structures: [ka] or [ka] (where the wavy line over the amino group indicates the attachment site for the Stretcher unit, and the Drug unit is attached to the benzyl alcohol).

[0320] Stretcher unit (L1) The 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 a functional group of a targeting unit. In some embodiments of the linker, the Stretcher unit is attached to an amino acid unit that is attached to a linker subunit L2 (i.e., when s of AA is 1, see e.g., Formulas (I)-(IV)). In some embodiments, the Stretcher unit is attached to a linker subunit L2 (i.e., when s of AA is 0, see e.g., Formulas (I)-(IV)). In some embodiments, the Stretcher unit is attached to an amino acid unit-linker subunit L2 after the amino acid unit-linker subunit L2 bond is formed. In some embodiments, the Stretcher unit is attached to an amino acid unit-linker subunit L2-drug unit after the amino acid unit-linker subunit L2-drug unit bond is formed. In some embodiments, the Stretcher unit is attached to the linker-subunit L2-Drug unit after the linker-subunit L2-Drug unit has been formed.

[0321] The functional group of the Stretcher unit for attachment to the targeting unit can include, for example, a maleimide, a haloacetamide, a sulfhydryl group, an NHS ester, an aldehyde, a ketone, a carbonyl, a hydrazide, a hydroxylamine, an amine, an amino, a hydrazine, a thiosemicarbazone, a hydrazine carboxyl, or an aryl hydrazide.

[0322] Functional groups that may be present on a targeting unit, either naturally or through chemical manipulation, include, but are not limited to, sulfhydryl (-SH), amino, hydroxyl, carboxy, anomeric hydroxyl groups of carbohydrates, and carboxyl groups. In one embodiment, the functional groups of a targeting unit are sulfhydryl and amino. Sulfhydryl groups can be generated by reduction of intramolecular disulfide bonds of a targeting unit. Alternatively, sulfhydryl groups can be generated by reaction of the amino groups of lysine moieties of a targeting unit with 2-iminothiolane (Traut'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 can be, for example, derived from a sulfhydryl group of the targeting unit (e.g., a thiol group of an interchain disulfide bond). Representative Stretcher units of this embodiment are shown in Formulas 100 and 101 below, where L is a targeting unit and the wavy line indicates the binding site for an amino acid unit or linker subunit L2: [ka]

[0324] In some embodiments, a linker is provided wherein the Stretcher unit is selected from: [ka] and [ka] (wherein, wavy line [ka] indicates the binding site of the Stretcher unit to the amino acid unit).

[0325] In Equation 100 and Equation 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- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene- (wherein b is 1 to 26), -arylene-, -C1-C 10 Alkylene-arylene-, -arylene-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)- (wherein b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b-C1-C8 alkylene-C(=O)- (wherein 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- (wherein b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)- (wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -NH- (wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein 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-C8 carbocyclo-S-, -O-(C1-C8 alkyl)-S-, -arylene-S-, -C1-C 10 Alkylene-arylene-S-, -arylene-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 of the substituents can be substituted or unsubstituted (also referred to as unsubstituted). In some embodiments, R 17 The substituent is unsubstituted. In some embodiments, R 17 The substituents are optionally substituted. In some embodiments, for example, -(CH) x NH2, -(CH2) x NHR a and -(CH2) x NR a R such as 2 17 group (see, for example, WO 2013 / 173337), where x is an integer from 1 to 4, and each R a are independently selected from the group consisting of C-C alkyl and C-C haloalkyl, or two R a The groups, taken together with the nitrogen to which they are attached, form an azetidinyl, pyrrolidinyl, or piperidinyl group.

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

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

[0328] In other embodiments, the Stretcher unit is linked to the targeting unit via a disulfide bond between a sulfur atom of the Stretcher unit and a sulfur atom of the targeting unit. A representative Stretcher unit of this embodiment is shown in Formula 102 below, where L is a targeting unit, the wavy line indicates the attachment site for an amino acid unit or linker subunit, and L and R 17 is as described above for Equation 100 and Equation 101. [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 a targeting unit, the wavy line indicates the attachment site for an amino acid unit or linker subunit, and L and R 17 is as above for equations 100 and 101: [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 hydrazide, oxime, primary or secondary amine, hydrazine, thiosemicarbazone, hydrazine carboxyl, or arylhydrazide (such as those described by Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41). Representative Stretcher units of this embodiment are shown in Formulas 106, 107, and 108 below, where L is a targeting unit, the wavy line indicates the attachment site for an amino acid unit or linker subunit, and L and R 17 is as above for Equation 100 and Equation 101: [ka]

[0331] In some embodiments, it may be desirable to extend the length of the Stretcher unit. Thus, the Stretcher unit may include additional components. A representative Stretcher unit of this embodiment is shown in Formula 109 below, where L is a targeting unit, the wavy line indicates a binding site for an amino acid unit or linker subunit, and L and R 17 is as above for equations 100 and 101: [ka]

[0332] In some aspects of this embodiment, R 17 is -C1-C5 alkylene-C(=O)-. R 13 is -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 Alkylene-arylene-, -arylene-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 In a preferred embodiment, R 13 is -(CH2-O-CH2) b - and b is 1 to 26.

[0333] Target Unit In some embodiments, the linker is attached to the targeting unit to form a targeting unit-linker. In some embodiments, the linker is attached 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 is attached 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 can be an antibody, an antigen-binding portion thereof, or a non-antibody targeting unit. A non-antibody targeting unit can 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" refers to a targeting unit (e.g., an antibody or portion thereof) described herein specifically binds to a target molecule. -5 M (10000nM) or less, e.g., 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12Specific binding refers to the ability to bind to a target with a KD of M or less. Specific binding can be affected, for example, by the affinity and avidity of the targeting unit and the concentration of the target polypeptide. Those skilled in the art can determine the appropriate conditions under which the antibodies, antibody-binding moieties, and non-antibody scaffolds described herein selectively bind to a target using any suitable method, for example, titration of the binding agent in a suitable cell binding assay. A targeting unit that specifically binds to its target is not displaced by a dissimilar competitor. In certain embodiments, a targeting unit is said to specifically bind to a 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 immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds to a target antigen. The term generally refers to antibodies composed of two immunoglobulin heavy chain variable regions and two immunoglobulin light chain variable regions, including full-length antibodies (having heavy and light chain constant regions).

[0336] Each heavy chain is typically composed of a variable region (abbreviated as VH region) and a constant region. The heavy chain constant region may include three domains, CH1, CH2, and CH3, and optionally a fourth domain, CH4. Each light chain is composed of a variable region (abbreviated as VL region) and a constant region. The light chain constant region is a CL domain. The VH and VL regions are further divided into hypervariable regions called complementarity-determining regions (CDRs), and may be interspersed with conserved regions called framework regions (FRs). Thus, each VH and VL region includes 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 portion" of an antibody refers to the portion of an antibody that has the VH and / or VL sequence or the CDR of the antibody and specifically binds to a target antigen. Examples of antigen-binding portions include Fab, Fab', F(ab')2, Fv, scFv, disulfide-linked Fv, single domain antibodies (also referred to as VHH, VNAR, sdAb or nanobody) or diabodies (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 refer to the following: (i) Fab is a monovalent fragment composed of the VL, VH, CL, and CH1 domains; (ii) F(ab')2 is a bivalent fragment comprising two Fab fragments linked together in the hinge region via disulfide bridges; and (iii) Fv is composed of the VL and VH domains. The two domains of the Fv fragment, i.e., VL and VH, are encoded by separate coding regions, but they may be separated by a synthetic linker, such as the poly G4S amino acid sequence ("(G4S)" disclosed as SEQ ID NO: 1). n(where n=1-5)), allowing them to be prepared as a single protein chain in which the VL and VH regions combine to form monovalent molecules (known as single-chain Fvs or scFvs). The term "antigen-binding portion" of an antibody is also intended to include such single-chain antibodies. Other forms of single-chain antibodies, such as "diabodies," are also included herein. Diabodies are bivalent, bispecific antibodies in which the VH and VL regions are expressed on a single polypeptide chain, but the VH and VL regions are allowed to pair with complementary regions (VL and VH, respectively) on different chains to form two antigen-binding sites, using a linker connecting the VH and VL regions that is too short to allow the two regions to be combined on the same chain (see, e.g., 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 antigen-binding portion of an antibody that contains a single monomeric variable antibody region. A single domain antibody can be derived from the variable region of an antibody heavy chain from a camelid (e.g., a nanobody or VHH portion). Furthermore, the term single domain antibody includes an autonomous human heavy chain variable domain (aVH) or VNAR portion derived from a shark (see, for example, Hasler et al., Mol. Immunol. 75:28-37, 2016).

[0339] Techniques for producing single domain antibodies (e.g., DABs or VHHs) 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, e.g., 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.) VHHs can have strong antigen-binding ability and can interact with novel epitopes that are inaccessible to conventional VH-VL pairs (see, e.g., Muyldermans et al., 2001). Alpaca serum IgG contains approximately 50% camel heavy chain-only IgG antibodies (HCAbs) (see, e.g., Maass et al., 2007). Alpacas can be immunized with antigens, and VHHs that bind to and neutralize the target antigen can be isolated (see, e.g., Maass et al., 2007). PCR primers that amplify alpaca VHH coding sequences have been identified and can be used to construct alpaca VHH phage display libraries, which can be used to isolate 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 binding agent. Bispecific and multispecific antibodies include the following: 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, the IgG-scFv is IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, svFc-(L)IgG, 2scFV-IgG, or IgG-2scFv. See, 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 and Power, Antibodies, 2019, 8, 28.

[0341] In some embodiments, the targeting unit is a cancer-associated antigen, e.g., 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, 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 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-associated antigen," "tumor antigen," "tumor-expressed antigen," "cancer antigen," "cancer-associated antigen," and "cancer-expressed 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®), pancreatic cancer (PMC), erythromycin (Protein® ... Tumumab (Vectibix®), ibritumomab (Zevalin®), tositumomab (Bexxar®), ipilimumab, zalutumumab, dalotuzumab, figitumumab, ramucirumab, galiximab, farletuzumab, oclezumab, ofatumumab (Arzerra®), CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG1 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, GNRHR2, among others, which can be used in combination with the co...

Claims

1. A conjugate comprising an anti-FOLR1 antibody or an antigen-binding portion thereof conjugated to a drug-linker or a pharmaceutically acceptable salt thereof, the anti-FOLR1 antibody or antigen-binding portion thereof, a heavy chain variable (VH) region comprising a heavy chain complementarity determining region (HCDR) 1 comprising the amino acid sequence set forth in SEQ ID NO: 30, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32; and a light chain variable (VL) region comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence set forth in SEQ ID NO: 33, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; Including, the drug-linker The conjugate,

2. Average drug load (p load 2. The conjugate of claim 1, having

3. The following formula: A conjugate of the formula: The Ab is an anti-FOLR1 antibody or antigen-binding portion thereof, comprising a heavy chain variable (VH) region comprising a heavy chain complementarity determining region (HCDR) 1 comprising the amino acid sequence set forth in SEQ ID NO: 30, an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31, and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a light chain variable (VL) region comprising a light chain complementarity determining region (LCDR) 1 comprising the amino acid sequence set forth in SEQ ID NO: 33, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 35; and n is p load That is, The conjugate.

4. The conjugate described in claim 3, having an average drug loading (p load) of about 1 to about 8.

5. The conjugate described in claim 1, wherein the VH and VL regions comprise the amino acid sequences shown in SEQ ID NO: 26 and SEQ ID NO: 27, respectively.

6. The conjugate described in claim 3, wherein the VH and VL regions comprise the amino acid sequences shown in SEQ ID NO: 26 and SEQ ID NO: 27, respectively.

7. A conjugate comprising an anti-FOLR1 antibody, or an antigen-binding portion thereof, linked to a drug-linker, or a pharmaceutically acceptable salt thereof, the anti-FOLR1 antibody or antigen-binding portion thereof, a heavy chain variable (VH) region comprising the amino acid sequence set forth in SEQ ID NO: 26; and A light chain variable (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 27 Including, the drug-linker The conjugate,

8. The conjugate described in claim 7, having an average drug loading (p load) of about 1 to about 8.

9. The formula: A conjugate of the formula: The Ab is an anti-FOLR1 antibody or antigen-binding portion thereof, comprising a heavy chain variable (VH) region comprising the amino acid sequence set forth in SEQ ID NO: 26 and a light chain variable (VL) region comprising the amino acid sequence set forth in SEQ ID NO: 27; and n is p load, The conjugate.

10. The conjugate of claim 9, having an average drug loading (p load) of about 1 to about 8.

11. The conjugate of claim 3 having an average drug loading (p load) of about 8.

12. The conjugate of claim 7, having an average drug loading (p load) of about 8.

13. The conjugate of claim 9, having an average drug loading (p load) of about 8.

14. The conjugate of claim 1 , wherein the antibody further comprises a heavy chain constant region, the heavy chain constant region being of the IgG isotype.

15. The conjugate of claim 3, wherein the antibody further comprises a heavy chain constant region, the heavy chain constant region being of the IgG isotype.

16. The conjugate of claim 7, wherein the antibody further comprises a heavy chain constant region, the heavy chain constant region being of the IgG isotype.

17. The conjugate of claim 9, wherein the antibody further comprises a heavy chain constant region, the heavy chain constant region being of the IgG isotype.

18. The conjugate of claim 3, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

19. The conjugate of claim 7, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

20. The conjugate of claim 9, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

21. The conjugate of claim 10, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

22. The conjugate of claim 11, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

23. The conjugate of claim 12, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

24. The conjugate of claim 13, wherein the antibody further comprises a heavy chain constant region and a light chain constant region, the heavy chain constant region being of the IgG isotype, and the light chain constant region being of the kappa isotype.

25. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

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