Drug conjugates and uses thereof

Abstract

Provided herein is a Drug-Linker of Formula (X): or a pharmaceutically acceptable salt thereof, wherein M1 is a group which can react with a ligand to form a connector unit, K1 is a peptide unit comprising at least one amino acid selected from glutamic acid and aspartic acid, and the further variables are as defined in the application. Such compounds can be useful as anti-cancer agents.

Description

CONJUGATES AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 707,680 filed on October 15, 2024, and U.S. Provisional Patent Application No. 63 / 824,676 filed on June 16, 2025, the entire contents of each of which are incorporated herein by reference. BACKGROUND

[0002] Currently, small cytotoxic molecules for antibody drug conjugates can include camptothecin derivatives, which have antitumor effects by inhibiting topoisomerase I. Camptothecin derivatives can be used in antibody drug conjugates (ADC). However, there is still a need for further development of camptothecin derivatives and ADC drugs with better efficacy and / or safety. SUMMARY OF THE INVENTION

[0003] In an aspect, the present disclosure provides a Drug-Linker of Formula (X):, or a pharmaceutically acceptable salt thereof, wherein: D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

[0004] In an aspect, the present disclosure provides a conjugate of the Formula (XX):Formula (XX), or a pharmaceutically acceptable salt thereof, wherein: D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is peptide cleavable unit; L is a Targeting Unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and(iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M2is a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0005] In one aspect, the present disclosure provides a method of treating a subject with a disease or disorder comprising administering to a subject in need thereof a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), or a pharmaceutical composition of any one thereof. INCORPORATION BY REFERENCE

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will beobtained by reference to the following detailed description that sets forth illustrativeembodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:

[0008] FIG.1 illustrates the median fluorescence intensity (MFI) of different ROR2 ADCs binding in a LCLC-103H cell model;

[0009] FIG.2 illustrates the percentage of inhibition of binding of different ROR2 ADCs in a LCLC-103H cell model;

[0010] FIG.3 illustrates the percentage of internalization of different ROR2 ADCs in a LCLC-103H cell model;

[0011] FIG.4 illustrates the percentage of inhibition of binding of different ROR2 ADCs in a LCLC-103H cell model;

[0012] FIG.5 illustrates the MFI of different 5T4 ADCs binding in a H520 cell model;

[0013] FIG.6 illustrates the percentage of inhibition of binding of different 5T4 ADCs in a H520 cell model;

[0014] FIG.7 illustrates the internalization of different 5T4 ADCs in a H520 internalization assay;

[0015] FIG.8 illustrates the percentage inhibition of different 5T4 ADCs in a H520 cell binding assay;

[0016] FIG. 9 illustrates the percentage inhibition of different 5T4 ADCs in a MDA-MB-468 binding assay;

[0017] FIG.10 shows in vivo antitumor activity of different ROR2 ADCs in a LCLC-103H xenograft model;

[0018] FIG.11 shows retention times for various drug-linkers;

[0019] FIG.12 shows log scores for various drug-linkers; and

[0020] FIG.13 shows log scores for various drug-linkers. DETAILED DESCRIPTION OF THE INVENTION

[0021] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intendedas a limitation on the scope of the present disclosure, but is instead provided as a desc ription ofexemplary embodiments.

[0022] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the disclosure may be practiced without these details. Definitions

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0024] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1- C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0025] The terms “Cx-y” and “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the terms “C1-6alkyl” or “C1-C6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The terms –Cx-yalkylene- or –Cx-Cyalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6alkylene- or –C1-C6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0026] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula –O- alkyl, where alkyl is an alkyl chain as defined above.

[0027] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4alkenyl). The alkenylis attached to the rest of the molecule by a single bond, for example, ethenyl ( i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0028] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0029] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0030] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon andhydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms,for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, analkylene comprises one to ten carbon atoms (i.e., C1-C8alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5alkylene).

[0031] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5alkenylene).

[0032] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of thealkynylene chain to the rest of the molecule and to the radical group may be through an y twocarbons within the chain. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-C10alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5alkynylene). In other embodiments, an alkynylene comprises twoto four carbon atoms (i.e., C2-C4alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene).

[0033] “Aryl” refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0034] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like.

[0035] “Aralkenyl” refers to a radical of the formula –Rd-aryl where Rdis an alkenylene chain as defined above.

[0036] “Aralkynyl” refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0037] “Activated group” refers to a cyclic alkyne which is highly reactive due to ring strain towards azide group to form a triazole.

[0038] “Activated disulfide group” refers to a disulfide which is capable to react with a thiol to form a new disulfide bond.

[0039] “Carbocycle” refers to a saturated, unsaturated , or aromatic rings in which each atomof the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicycliccarbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0040] “Carbocyclene” refers to a divalent carbocycle linking the rest of the molecule to a radical group.

[0041] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0042] “Cycloalkyl” refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0043] “Cycloalkenyl” refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, a cycloalkenyl comprises five to seven carbon atoms. The cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0044] “Cycloalkylalkyl” refers to a radical of the formula –Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0045] “Cycloalkylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0046] “Halo” or “halogen” refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.

[0047] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2- haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinationsof alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.

[0048] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0049] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4- triamine and the like.

[0050] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0051] “Alkoxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1- methoxypropane, 2-ethoxypentane, and the like.

[0052] “Cyanoalkyl” as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.

[0053] “Heterocycle” refers to a saturated or unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated,unsaturated, and aromatic rings. Bicyclic heterocycles may be fused, bridged or spiro -ringsystems. In some cases, spiro-ring heterocycles have at least two molecular rings with only one common atom. The spiro-ring heterocycle includes at least one heteroatom.

[0054] “Heterocyclene” refers to a divalent heterocycle linking the rest of the molecule to a radical group.

[0055] “Heteroaryl” or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through anyatom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.

[0056] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0057] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0058] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.

[0059] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N- H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen,haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N-NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0060] As used in the specification and claims, the singular form “a”, “an” and “the”includes plural references unless the context clearly dictates otherwise.

[0061] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0062] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0063] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0064] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” as used herein means a pharmaceutically acceptable material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0065] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0066] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0067] The term “ligand” generally refers to a macromolecular compound capable of recognizing and binding to an antigen or receptor associated with a target cell. The ligand can be used to bring the drug to the target cell population that binds to the ligand, including but not limited to protein hormones, lectins, growth factors, antibodies, or others that can bind to cells, receptors and / or antigens molecule. The ligand can be an antibody. The ligand can be an antigen binding fragment.

[0068] The term “targeting moiety” or “Targeting Unit” refers to a structure that has a selective affinity for a target molecule relative to other non-target molecules. The targeting moiety binds to a target molecule. A Targeting Unit may include, for example, an antibody, a peptide, a ligand, a receptor, or a binding portion thereof. The target biological molecule maybe a biological receptor or other structure of a cell such as a tumor antigen.

[0069] The term “antibody” means whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chain variants thereof. A whole antibody is a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (VH) and a heavy chain constant region comprising three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (VL or Vk) and a light chain constant region comprising one single domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from amino- to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions contain a binding domain that interacts with an antigen. The constant regions may mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. An antibody is said to “specifically bind” to an antigen X if the antibody binds to antigen X with a KD of 1 x 10-7M or less, 5×10−8M or less, more preferably 1×10−8M or less, more preferably 6×10−9M or less, more preferably 3×10−9M or less, even more preferably 2×10−9M or less. The antibody can be chimeric, humanized, or, preferably, human. The heavy chain constant region can be engineered to affect glycosylation type or extent, to extend antibody half-life, to enhance or reduce inter-actions with effector cells or the complement system, or to modulate some other property. The engineering can be accomplishedby replacement, addition, or deletion of one or more amino acids or by replacement of a domainwith a domain from another immunoglobulin type, or a combination of the foregoing.

[0070] The term “antigen binding fragment” and “antigen binding portion” of an antibody (or simply “antibody portion” or “antibody fragment”) mean one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody, such as (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab’)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fab’ fragment, which is essentially an Fab withpart of the hinge region (see, for example, Abbas et al., Cellular and Molecular Immunology, 6 thEd., Saunders Elsevier 2007); (iv) a Fd fragment consisting of the VH and CH1 domains; (v) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (vi) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; (vii) an isolated complementarity determining region (CDR); and (viii) a nanobody, a heavy chain variable region containing a single variable domain and two constant domains. Preferred antigen binding fragments are Fab, F(ab’)2, Fab’, Fv, and Fd fragments. Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv, or scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also encompassed within the term “antigen-binding portion” of an antibody.

[0071] The term “isolated antibody” means an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds antigen X is substantially free of antibodies that specifically bind antigens other thanantigen X). An isolated antibody that specifically binds antigen X may, however, have cross -reactivity to other antigens, such as antigen X molecules from other species. In certain embodiments, an isolated antibody specifically binds to human antigen X and does not cross- react with other (non-human) antigen X antigens. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0072] The term “monoclonal antibody” or “monoclonal antibody composition” means a preparation of antibody molecules of single molecular composition, which displays a single binding specificity and affinity for a particular epitope.

[0073] The term “human antibody” means an antibody having variable regions in which both the framework and CDR regions (and the constant region, if present) are derived fromhuman germline immunoglobulin sequences. Human antibodies may include later modifications, including natural or synthetic modifications. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, “human antibody” does not include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0074] The term “human monoclonal antibody” means an antibody displaying a binding specificity, which has variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. In one embodiment, human monoclonal antibodies are produced by a hybridoma that includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a humanheavy chain transgene and a light chain transgene fused to an immortalized cell.The term “epitope” refers to the amino acids conventionally bound by an immunoglobulin VH / VL pair, such as the antibodies, antigen binding portions thereof and other binding agents described herein. Other binding agents comprise non-antibody scaffolds. An epitope can be formed on a polypeptide from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, and more usually, at least 5, about 9, or about 8-10 amino acids in a unique spatial conformation. An epitope defines the minimum binding site for an antibody, antigen binding portions thereof and other binding agent, and thus represents the target of specificity of an antibody, antigen binding portion thereof or other immunoglobulin-based binding agent. In the case of a single domain antibody, an epitope represents the unit of structure bound by a variable domain in isolation. An epitope may include non-amino acid components, such as glycan structures.

[0075] The assignment of amino acid numbers, and of FR and CDR regions, in the heavy or light chain may be in accordance with IMGT®definitions (Lefranc et al., Dev Comp Immunol. (2003) 27(1):55-77); or the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J Mol Biol. (1987) 196:901-17; Chothia et al., Nature (1989) 342:878-83; Abhinandan et al., Molecular Immunology (2008) 45(14):3832-39; MacCallum et al., J Mol Biol. (1996) 262:732- 45; or Honegger and Plückthun, J Mol Biol. (2001) 309(3):657-70. The CDR boundaries of various schemes are illustrated below, where the amino acid numbers are Kabat numbers unless otherwise indicated.CDR Delineations According to Various Schemes

[0076] The term “specifically binds” refers to the ability of a molecule (e.g., an antibody or antigen binding portion thereof or non-antibody scaffold) described herein to bind to a target with a KD of 10-5M (10000 nM) or less, e.g., 10-6M, 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, 10-12M, or less. Specific binding can be influenced by, for example, the affinity and avidity of the antibody, antigen binding portion or other binding agent and the concentration of target polypeptide.

[0077] The term “about” when used in connection with percentages can mean + / -1%.

[0078] The term “cleavable unit” refers to a chemical group that may be cleaved by action of an internal or external, preferably external, stimulus. The stimulus triggering the cleavage of the cleavable unit may be for instance pH or temperature conditions, or the presence of an enzyme.Cleavage of the cleavable unit preferably triggers self -immolation of the phenyl-comprisinglinker of the compounds of the invention, and release of the active agent D.

[0079] The term “cleavable sugar unit” or “sugar cleavable unit” can refer to a sugar moiety, preferably a glucuronide or a galactoside.

[0080] The term “peptide cleavable unit” can refer to a polypeptide, preferably a dipeptide or a tripeptide.

[0081] The term “cleavable unit” refers to a chemical group that may be cleaved by action of an internal or external, preferably external, stimulus. The stimulus triggering the cleavage of the cleavable unit may be for instance pH or temperature conditions, or the presence of an enzyme. Linkers, Drug-Linkers and Conjugates of the Disclosure

[0082] In an aspect, the present disclosure provides a Drug-Linker of Formula (X*):Formula (X*), or a pharmaceutically acceptable salt thereof, wherein: R40is selected fromalkylene, wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN;(ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

[0083] In some embodiments, the Drug-Linker of Formula (X*) is represented by Formula (X). In some cases, the Drug-Linker of Formula (B-4) is represented by Formula (X-4). In some cases, the Drug-Linker further comprises a Targeting unit, wherein M1reacts with the Targeting unit and forms M2.

[0084] In an aspect, the present disclosure provides a Drug-Linker of Formula (X):Formula (X), or a pharmaceutically acceptable salt thereof, wherein:D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit;K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

[0085] In some embodiments, Formula (X*) or Formula (X) is represented by the structure of Formula (X-I)Formula (X-I), or a pharmaceutically acceptable salt thereof.

[0086] In an aspect, the present disclosure provides a conjugate of the Formula (XX*):Formula (XX*), or a pharmaceutically acceptable salt thereof, wherein: R40is selected fromalkylene, wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit;T2is peptide cleavable unit; L is a Targeting Unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M2is a connector unit; K1is selected from:(i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

[0087] In some embodiments, Formula (XX*) is represented by Formula (XX). In some cases, Formula (XX*) or Formula (XX) is represented by Formula (XX-I).

[0088] In an aspect, the present disclosure provides a conjugate of the Formula (XX):Formula (XX), or a pharmaceutically acceptable salt thereof, wherein; D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is peptide cleavable unit; L is a Targeting Unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M2is a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

[0089] In some embodiments, Formula (XX) is represented aspharmaceutically acceptable salt thereof. wherein DAR is selected from 1 to 10.

[0090] In some embodiments, Formula (XX*) or Formula (XX) is represented by the structure of Formula (XX-I)Formula (XX-I), or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, Formula (XX-I) is represented byor a pharmaceutically acceptable salt thereof , wherein DAR is selected from 1 to 10.

[0092] In some embodiments, Formula (XX*), Formula (XX) or Formula (XX-I) is represented by the structure of Formula (XX-II)Formula (XX-II),or a pharmaceutically acceptable salt thereof .

[0093] In some embodiments, Formula (XX-II) is represented by,or a pharmaceutically acceptable salt thereof , wherein DAR is selected from 1 to 10.

[0094] In some embodiments, Formula (XX-II) is represented by,or a pharmaceutically acceptable salt thereof , wherein DAR is selected from 1 to 10. In somecases, the DAR is 8.

[0095] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),S3is absent; Y1is absent or selected from a cleavable sugar and cleavable peptide (e.g., dipeptide);K1is selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; and

[0096] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),S3is absent; Y1is absent or selected from a cleavable sugar and cleavable peptide (e.g., dipeptide);K1is selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; and.

[0097] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),S1-S2-K1 is selected fromS2is selected fromS3is absent;K1is selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; and.

[0098] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),S3is absent;,

[0099] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),S1-S2-K1 is selected fromS2is selected fromS3is absent;

[0100] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I),.

[0101] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S1is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, – N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or – P(O)(R20)2. In some cases, S1is selected from an optionally substituted C6-C10alkylene wherein one or more alkylene units of the C6-C10alkylene are optionally and independently replaced by – N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, or –C(O)–. In some cases, S1is an optionally substituted C1alkylene. In some cases, S1is an optionally substituted C2alkylene. In some cases, S1is an optionally substituted C3alkylene. In some cases, S1is an optionally substituted C4alkylene. In some cases, S1is an optionally substituted C5alkylene. In some cases, S1is an optionally substituted C6alkylene. In some cases, S1is an optionally substituted C7alkylene. In some cases, S1is an optionally substituted C8alkylene. In some cases, S1is an optionally substituted C9alkylene. In some cases, S1is an optionally substituted C10alkylene. In some cases, S1is an optionally substituted C11alkylene. In some cases, S1is an optionally substituted C12alkylene. In some cases, S1is an optionally substituted C13alkylene. In some cases, S1is an optionally substituted C14alkylene. In some cases, S1is an optionally substituted C15alkylene. In some cases, S1is an optionally substituted C16alkylene. In some cases, S1is an optionally substituted C17alkylene. In some cases, S1is an optionally substituted C18alkylene. In some cases, S1is an optionally substituted C19alkylene. In some cases, S1is an optionally substituted C20alkylene. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, or –C(O)–. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –N(R20)–. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –N(R20)C(O)–. In some cases, the one or more alkylene units ofthe alkylene of S1are optionally and independently replaced by –C(O)N(R20)–. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –C(O)–. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by –O–. In some cases, if an alkylene unit of the alkylene is replaced, the alkylene may be referred to as a resulting alkylene. In some cases, if two or more of the alkylene units of S1are replaced, the replaced alkylene units are not adjacent alkylene units. In some cases, if two or more of the alkylene units of S1are replaced, the adjacent alkylene units of the resulting alkylene are not replaced. In some cases, if two or more of the alkylene units of S1are replaced, the resulting alkylene has no repeating heteroatoms of adjacent alkylene units. In some cases, if two or more of the alkylene units of S1are replaced, the resulting alkylene has no repeating of the same heteroatoms of adjacent alkylene units. In some cases, if two or more of the alkylene units of S1are replaced, the resulting alkylene unit has no - N-N- or -O-O-. In some cases, if two or more of the alkylene units of S1are replaced, the resulting alkylene unit is a stable alkylene. In some cases, if two or more of the alkylene units of S1are replaced, the resulting alkylene unit is an unreactive alkylene. In some cases, the resulting alkylene has only 1 heteroatom. In some cases, the resulting alkylene has only 2 heteroatoms, wherein the 2 heteroatoms are different from each other. In some cases, the resulting alkylene has only 2 heteroatoms, wherein the 2 heteroatoms are not adjacent to each other. In some cases, the resulting alkylene has only 3 heteroatoms, wherein the 3 heteroatoms are not adjacent to each other. In some cases, the alkylene has 0 replaced units. In some cases, the alkylene has 1 replaced unit. In some cases, the alkylene has 2 replaced units. In some cases, the alkylene has 3 replaced units. In some cases, the alkylene has 4 replaced units. In some cases, the alkylene has 5 replaced units. In some cases, the alkylene has 6 replaced units. In some cases, no adjacent alkylene units of the alkylene are replaced. In some cases, no adjacent alkylene units resulting in two or more adjacent heteroatoms are present in the resulting alkylene (e.g., adjacent – N(R20)S(O)2– and –N(R20)– are not allowed, but the singular –N(R20)S(O)2– is allowed). In some cases, two heteroatoms can be present in a resulting alkylene if they come from a singular replaced alkylene unit. In some cases, two heteroatoms can be present in a resulting alkylene if they come from a singular replaced alkylene unit. In some cases, a resulting alkylene has two heteroatoms, the two heteroatoms are from a singular replaced alkylene unit. In some cases, there are two heteroatoms in a resulting alkylene if they result from a singular replacement of an alkylene unit.

[0102] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S1is selected from –N(R20)C(O)–C1-C3alkylene–N(R20)C(O)–C1-C3alkylene–N(R20)C(O)–C1-C3alkylene. In some cases, S1is selected from –NHC(O)–C1-C3alkylene–NHC(O)–C1-C3alkylene–NHC(O)–C1-C3alkylene.

[0103] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), the optional substituents on S1are independently selected at each occurrence from halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, - C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, the optional substituents on S1are independently selected at each occurrence from halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN. In some cases, the optional substituents on S1are independently selected at each occurrence from: halogen, -OR30, - N(R30)2, =O, and -CN. In some cases, the optional substituents on S1are independently selected at each occurrence from =O. In some cases, the S1is unsubstituted.

[0104] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), the optionally substituted C1-C30alkylene of S1is linear. In some cases, the optionally substituted C1-C30alkylene of S1is a branched alkylene.

[0105] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S1is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(H)C(O)–.

[0106] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S1is selected from -NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-.

[0107] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugateor salt of Formula (XX*), Formula (XX), or Formula (XX-I), S1is selected from -NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-, wherein -S2-K1is bound to one of the alkylene. In some cases, S1is selected from, wherein -S2-K1is bound to one of the alkylene. In some cases, S1is selected from, wherein -S2-K1is bound to one of the alkylene, and wherein S2is -C(O)-.

[0108] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), -S1-S2-K1is selected from.

[0109] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S2is selected from an optionallysubstituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, – N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or –S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, or –S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or –S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, – C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or –S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or –S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or – S(O)2–. In some embodiments, S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, or –S(O)2–.

[0110] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –C(O)–.

[0111] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S2is selected from an optionally substituted C1-C6alkylene wherein one or more alkylene units of the C1-C6alkylene are optionally and independently replaced by –C(O)–. In some cases, S2is selected from an optionally substituted C1-C2alkylene wherein one or more alkylene units of the C1-C2alkylene are optionally and independently replaced by –C(O)–. In some cases, S2is .

[0112] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S2is selected from –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, and –P(O)(R20)2–. In some cases, S2is selected from –NH–, –NHC(O)–, –C(O)NH–, –NHS(O)2–, – S(O)2NH–, –O–, – C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, and – P(O)(R20)2–. In some cases, S2is selected from –NH–, –NHC(O)–, –C(O)NH–, and –C(O)–. In some cases, S2is selected from –NHC(O)–, –C(O)NH–, and –C(O)–. In some cases, S2is selected from –C(O)–.

[0113] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), -S1-S2-K1is represented by -S1- C(O)-K1.

[0114] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I),S2is selected from -C1-C6alkylene- C(O)-. In some embodiments, S2is selected from -C1-C5alkylene-C(O)-. In some cases, S2is selected from -C1-C4alkylene-C(O)-. In some cases, S2is selected from -C1-C3alkylene-C(O)-. In some cases, S2is selected from -C1-C2alkylene-C(O)-. In some cases, S2is selected from -C2alkylene-C(O)-. In some cases, S2is selected from -C1alkylene-C(O)-.

[0115] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), -S1-S2-K1is selected from.

[0116] In some embodiments, a Drug-Linker or salt of Formula (X*), Formula (X) or Formula (X-I) is represented by the structure of Formula (X-II):Formula (X-II). In some cases, D is exatecan. In some cases, D is MMAE. In some cases, D is MMAF. In some cases, D is SN-38. In some cases, Formula (X*), Formula (X), Formula (X-I) or Formula (X-II) is represented by the

[0117] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1includes at least one amino acid selected from glutamic acid and aspartic acid. In some cases, the peptide unit of K1includes a sarcosine. In some cases, the peptide unit of K1includes a glycine and two adjacent sarcosines. In some cases, the peptide unit of K1includes a glycine and three adjacent sarcosines. In some cases, the peptide unit of K1includes a glycine and four adjacent sarcosines. In some cases, the peptide unit of K 1 includes 4glycines and 7 sarcosines. In some cases, the peptide unit of K1includes 3 glycines and 7 sarcosines. In some cases, the peptide unit of K1includes 3 glycines and 6 sarcosines. In some cases, the peptide unit of K1includes 3 glycines and 5 sarcosines. In some cases, the peptide unit of K1includes 3 glycines and 4 sarcosines. In some cases, K1includes 3 glycines and 3 sarcosines. In some cases, K1includes 3 glycines and 9 sarcosines. In some cases, the peptide unit of K1includes 3 glycines and 10 sarcosines. In some cases, the peptide unit of K1includes 5 glycines and 5 sarcosines. In some cases, the peptide unit of K1includes 4 glycines and 4 sarcosines. In some cases, the peptide unit of K1includes 4 glycines and 5 sarcosines. In some cases, K1includes 5 glycines and 4 sarcosines. In some cases, K1has at most 9 sarcosines. In some cases, the peptide unit of K1has at most 8 sarcosines. In some cases, the peptide unit of K1has at most 7 sarcosines. In some cases, the peptide unit of K1has at most 6 sarcosines. In some cases, the peptide unit of K1has at most 5 sarcosines. In some cases, the peptide unit of K1has at most 4 sarcosines. In some cases, the peptide unit of K1has at most 3 sarcosines. In some cases, K1has at most 2 sarcosines. In some cases, K1has at most 1 sarcosine. In some cases, the peptide unit of K1has at most 9 glycines. In some cases, the peptide unit of K1has at most 8 glycines. In some cases, the peptide unit of K1has at most 7 glycines. In some cases, the peptide unit of K1has at most 6 glycines. In some cases, the peptide unit of K1has at most 5 glycines. In some cases, the peptide unit of K1has at most 4 glycines. In some cases, the peptide unit of K1has at most 3 glycines. In some cases, the peptide unit of K1has at most 2 glycines. In some cases, the peptide unit of K1has at most 1 glycine. In some cases, the peptide unit of K1has one glutamic acid. In some cases, the peptide unit of K1has two glutamic acids. In some cases, the peptide unit of K1has three glutamic acids. In some cases, the peptide unit of K1has four glutamic acids. In some cases, the peptide unit of K1has five glutamic acids. In some cases, the peptide unit of K1has six glutamic acids. In some cases, the peptide unit of K1has one aspartic acid. In some cases, the peptide unit of K1has two aspartic acids. In some cases, the peptide unit of K1has three aspartic acids. In some cases, the peptide unit of K1has four aspartic acids. In some cases, the peptide unit of K1has five aspartic acids. In some cases, the peptide unit of K1has aspartic acids. In some cases, the peptide unit of K1only includes sarcosine and aspartic amino acids. In some cases, the peptide unit of K1only includes sarcosine and glutamic amino acids. In some cases. In some cases, the peptide unit of K1includes at most 20 amino acids. In some cases, the peptide unit of K1includes at most 18 amino acids. In some cases, the peptide unit of K1includes at most 16 amino acids. In some cases, the peptide unit of K1includes at most 14 amino acids. In some cases, the peptide unit of K1includes at most 12 amino acids. In some cases, the peptide unit of K1includes at most 10 amino acids. In some cases, the peptideunit of K1has a terminus unit. In some cases, the terminus unit is represented by R6. In some cases, the terminus unit is selected from -OH, -NH2, and.

[0118] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1includes 1 aspartic acid and 8 sarcosines. In some cases, the peptide unit of K1includes 2 aspartic acids and 7 sarcosines. In some cases, the peptide unit of K1includes 3 aspartic acids and 6 sarcosines. In some cases, the peptide unit of K1includes 4 aspartic acids and 5 sarcosines. In some cases, the peptide unit of K1includes 5 aspartic acids and 4 sarcosines. In some cases, the peptide unit of K1includes 6 aspartic acids and 3 sarcosines. In some cases, the peptide unit of K1includes 7 aspartic acids and 2 sarcosines. In some cases, the peptide unit of K1includes 8 aspartic acids and 1 sarcosine. In some cases, the peptide unit of K1includes 1 glutamic acid and 8 sarcosines. In some cases, the peptide unit of K1includes 2 glutamic acids and 7 sarcosines. In some cases, the peptide unit of K1includes 3 glutamic acids and 6 sarcosines. In some cases, the peptide unit of K1includes 4 glutamic acids and 5 sarcosines. In some cases, the peptide unit of K1includes 5 glutamic acids and 4 sarcosines. In some cases, the peptide unit of K1includes 6 glutamic acids and 3 sarcosines. In some cases, the peptide unit of K1includes 7 glutamic acids and 2 sarcosines. In some cases, the peptide unit of K1includes 8 glutamic acids and 1 sarcosine. In some cases, the peptide unit of K1includes 1 aspartic acid and 9 sarcosines. In some cases, the peptide unit of K1includes 2 aspartic acids and 8 sarcosines. In some cases, the peptide unit of K1includes 3 aspartic acids and 7 sarcosines. In some cases, the peptide unit of K1includes 4 aspartic acids and 6 sarcosines. In some cases, the peptide unit of K1includes 5 aspartic acids and 5 sarcosines. In some cases, the peptide unit of K1includes 6 aspartic acids and 4 sarcosines. In some cases, the peptide unit of K1includes 7 aspartic acids and 3 sarcosines. In some cases, the peptide unit of K1includes 8 aspartic acids and 2 sarcosines. In some cases, the peptide unit of K1includes 9 aspartic acids and 1 sarcosine. In some cases, the peptide unit of K1includes 1 glutamic acid and 9 sarcosines. In some cases, the peptide unit of K1includes 2 glutamic acids and 8 sarcosines. In some cases, the peptide unit of K1includes 3 glutamic acids and 7 sarcosines. In some cases, the peptide unit of K1includes 4 glutamic acids and 6 sarcosines. In some cases, the peptide unit of K1includes 5 glutamic acids and 5 sarcosines. In some cases, the peptide unit of K1includes 6 glutamic acids and 4 sarcosines. In some cases, the peptide unit of K1includes 7 glutamic acids and 3 sarcosines. In some cases, the peptide unit of K1includes 8 glutamic acids and 2 sarcosines. In some cases, the peptide unit of K1includes 9 glutamic acids and 1 sarcosine. In some cases, the peptide unit ofK1has at most 12 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 11 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 10 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 9 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 8 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 7 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 6 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 5 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 4 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 3 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 2 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 1 sarcosines and at least one aspartic acid. In some cases, the peptide unit of K1has at most 12 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 11 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 10 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 9 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 8 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 7 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 6 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 5 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 4 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 3 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 2 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 1 sarcosines and at least one glutamic acid. In some cases, the peptide unit of K1has at most 12 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 11 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 10 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 9 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 8 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 7 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 6 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 5 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 4 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, thepeptide unit of K1has at most 3 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 2 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has at most 1 sarcosines, at least one aspartic acid, and at least one glutamic acid. In some cases, the peptide unit of K1has a terminus unit. In some cases, the terminus unit is represented by R6. In some cases, the terminus unit is selected from

[0119] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1comprises at least one amino acid selected from glutamic acid and aspartic acid. In some cases, the peptide unit of K1comprises at least one amino acid selected from glutamic acid. the peptide unit of K1comprises at least one amino acid selected from aspartic acid. In some cases, the peptide unit of K1has 1 to 50 amino acids. In some cases, the peptide unit of K1has 1 to 20 amino acids. In some cases, the peptide unit of K1has 1 to 10 amino acids. In some cases, the peptide unit of K1has 2 to 50 amino acids. In some cases, the peptide unit of K1has 2 to 40 amino acids. In some cases, the peptide unit of K1has 2 to 30 amino acids. In some cases, the peptide unit of K1has 2 to 20 amino acids. In some cases, the peptide unit of K1has 2 to 10 amino acids. In some cases, the peptide unit of K1has 5 to 10 amino acids. In some cases, the peptide unit of K1has at least 1 amino acid. In some cases, the peptide unit of K1has at least 2 amino acids. In some cases, the peptide unit of K1has at least 5 amino acids. In some cases, the peptide unit of K1has at least 8 amino acids. In some cases, the peptide unit of K1has at least 10 amino acids. In some cases, the peptide unit of K1has at most 10 amino acids. In some cases, the peptide unit of K1has 10 amino acids. In some cases, the peptide unit of K1has at least 12 amino acids. In some cases, the peptide unit of K1has at most 12 amino acids. In some cases, the peptide unit of K1has at least 20 amino acids. In some cases, the peptide unit of K1has at most 20 amino acids. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine ,serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine,asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, cysteine, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, sarcosine, aspartic acid, glutamic acid, proline, serine, alanine, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, sarcosine, aspartic acid, proline, serine, alanine, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, sarcosine, glutamic acid, proline, serine, alanine, and β- Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, proline, serine, aspartic acid, glutamic acid, alanine, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, proline, serine, glutamic acid, alanine, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of glycine, proline, serine, aspartic acid, alanine, and β-Alanine. In some cases, the peptide unit of K1has amino acids further selected from a group consisting of proline, serine, alanine, and β-Alanine. In some cases, thepeptide unit of K1has at least one glycine and at least one other amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one sarcosine and at least one other amino acid selected from aspartic acid and glutamic acid.. In some cases, the peptide unit of K1includes at least one glycine and at least one other amino acid selected from proline, serine, alanine, aspartic acid, glutamic acid, and β-Alanine. In some cases, the peptide unit of K1includes at least one glycine and at least one other amino acid selected from proline, serine, alanine, glutamic acid, and β-Alanine. In some cases, the peptide unit of K1includes at least one glycine and at least one other amino acid selected from proline, serine, alanine, glutamic acid, and β-Alanine. In some cases, the peptide unit of K1includes at least onesarcosine and at least one other amino acid selected from proline, serine, alanine, aspartic acid,glutamic acid, and β-Alanine. In some cases, the peptide unit of K1includes at least one sarcosine and at least one other amino acid selected from proline, serine, alanine, glutamic acid, and β-Alanine. In some cases, the peptide unit of K1includes at least one sarcosine and at leastone other amino acid selected from proline, serine, alanine, glutamic acid, and β-Alanine. Insome cases, the peptide unit of K1includes at least one glycine and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one glycine and at least one aspartic acid. In some cases, the peptide unit of K1includes at least one glycine and at least one glutamic acid. In some cases, the peptide unit of K1includes at least one sarcosine and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one sarcosine and at least one aspartic acid. In some cases, the peptide unit of K1includes at least one sarcosine and at least one glutamic acid. In some cases, the peptide unit of K1includes at least one proline and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one proline and at least one aspartic acid. In some cases, the peptide unit of K1includes at least one proline and at least one glutamic acid. In some cases, the peptide unit of K1includes at least one serine and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one serine and at least one aspartic acid. In some cases, the peptide unit of K1includes at least one serine and at least one glutamic acid. In some cases, the peptide unit of K1includes at least one alanine and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one alanine and at least one aspartic acid. In some cases, the peptide unit of K1includes at least one alanine and at least one glutamic acid. In some cases, the peptide unit of K1includes at least one β-Alanine and at least one amino acid selected from aspartic acid and glutamic acid. In some cases, the peptide unit of K1includes at least one β-Alanine and at least one aspartic acid.In some cases, the peptide unit of K1includes at least one β-Alanine and at least one glutamic acid.

[0120] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1has a terminus unit. In some cases, K1is selected fromselected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is selected from,, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In some cases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases, R6is.

[0121] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), orFormula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1has a terminus unit. In some cases, K1is selected fromwherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In somecases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases, R6is.

[0122] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), orFormula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of K1has a terminus unit. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is selected fromterminus unit is represented by R6. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j isselected from 1 to 10. In some cases, the terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In some cases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases, R6is.

[0123] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), K1is selected from. some cases, K1is selected from. some cases, K1is selected fromselected from -OH, -NH2, and. In some cases, R6is -OH. In some cases, R6is -NH2. In some cases,.

[0124] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), K1is selected fromIn some cases, K1is selected fromselected from -OH, -NH2, and. In some cases, R6is -OH. In some cases, R6is -NH2. In some cases,.

[0125] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), K1is selected fromIn some cases, K1is selected fromselected from. In some cases, R6is selected from -OH, -NH2, . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases, R6.

[0126] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I),or Formula (XX-II), K1is selected from,,, ,Ksome cases, K1is selected from. In some cases, K1. cases, K1is.

[0127] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I),or Formula (XX-II), K1is selected from,some cases, K1is selected from. cases, K1is selected fromIn some cases, K1is selected fromIn some cases,. some cases, K1is. some cases, K1is.

[0128] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I),or Formula (XX-II), K1is selected from ,,,. In some cases, K1is selected from. In some cases, K1is selected from. In some cases, K1is selected fromIn some cases, K1is selected from. some cases, K1is.

[0129] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I),or Formula (XX-II), the peptide unit of K1has a terminal -NH2. In some cases, the peptide unit of K1has a terminal -OH. In some cases, the peptide unit of K1has a terminal.

[0130] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), orFormula (XX-II), Y1 is selected fromselected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid. In some cases,selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid. In some cases, K1is selected fromselected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In some cases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, - S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases,.

[0131] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), orFormula (XX-II), Y1 is selected fromselected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid. In some cases,selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is selected from, wherein the terminus unit is represented byR6, and each j is selected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In some cases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and . In some cases, R6is -OH. In some cases, R6is -NH2. In some cases, R6is.

[0132] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), orFormulaselected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from aspartic acid. In some cases,selected from a peptide unit, wherein the peptide unit comprises at least one amino acid selected from aspartic acid. In some cases, K1is selected from,, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, K1is, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 10. In some cases, terminus unit is represented by R6, and each j is selected from 2 to 5. In some cases, j is 1. In some cases, j is 2. In some cases, j is 3. In some cases, j is 4. In some cases, j is 5. In some cases, j is 6. In some cases, j is 7. In some cases, j is 8. In some cases, j is 9. In some cases, j is10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, - OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, - S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, - NH2, and. In some cases, R6is -OH. In some cases, R6is -NH2. In some cases,.

[0133] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S3is selected from a spacer. In some cases, the spacer is a divalent moiety that covalently binds two components of the conjugate or Drug-Linker. In some cases, S3is present. In some cases, S3is absent. In some cases, the spacer is selected from: alkylene, heteroalkylene (an alkylene having one or more alkylene units replaced by at least one heteroatom selected from Si, N, O and S, with the appropriate valency); alkoxy; polyether such as polyalkylene glycol and typically polyethylene glycol; one or more natural or non-natural aminoacids such as glycine, alanine, proline, valine, N-methylglycine; C3-C8heterocyclo; C3-C8carbocyclo; arylene, and any combination thereof. In some cases, a spacer is a divalent linear alkylene group. In some cases, the spacer can be selected from the group consisting of –C1-C10alkylene-, –C1-C10heteroalkylene-, -C3- C8carbocyclo-, -O-(C1C8alkyl)-, -arylene-, –C1-C10alkylene-arylene-, -arylene-C1- C10alkylene-, –C1-C10alkylene-(C3-C8carbocyclo)-, - (C3-C8carbocyclo)-C1-C10alkylene-, -C3- C8heterocyclo-, –C1-C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)–C1-C10alkylene-, –C1-C10alkylene-C(=O)-, –C1- C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1- C8alkyl)-C(=O)-, - arylene-C(=O)-, -C1-C10alkylene-arylene-C(=O)-, -arylene-C1-C10alkylene- C(=O)-, -C1- C10alkylene-(C3-C8carbocyclo)-C(=O)-, -(C3-C8carbocyclo)-C1-C10alkylene- C(=O)-, - C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, -(C3- C8heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, -C1-C10heteroalkylene-NH-, - C3-C8carbocyclo-NH-, -O-(C1-C8alkyl)-NH-, -arylene-NH-, -C1-C10alkylene- arylene-NH-, - arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)-NH-, - (C3-C8carbocyclo)- C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3- C8heterocyclo)-NH-, -(C3- C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, - C1-C10heteroalkylene-S -, -C3- C8carbocyclo-S -, -O-(C1-C8alkyl)-)-S -, -arylene-S-, -C1- C10alkylene-arylene-S-, -arylene-C1- C10alkylene-S-, -C1-C10alkylene-(C3- C8carbocyclo)-S-, -(C3-C8carbocyclo)-C1-C10alkylene- S-, -C3-C8heterocyclo-S-, -C1- C10alkylene-(C3-C8heterocyclo)-S-, -(C3-C8heterocyclo)-C1- C10alkylene-S-, –C1-C10alkylene-O-C(=O)-, -C3-C8carbocyclo-O-C(=O)-, -O-(C1-C8alkyl)-O- C(=O)-, -arylene- O-C(=O)-, -C1-C10alkylene-arylene-O-C(=O)-, -arylene-C1-C10alkylene-O- C(=O)-, -C1- C10alkylene-(C3-C8carbocyclo)-O-C(=O)-,-(C3-C8carbocyclo)-C1-C10alkylene-O- C(=O)-, -C3-C8heterocyclo-O-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-O-C(=O)-, and - (C3-C8heterocyclo)-C1-C10alkylene-O-C(=O)-. In some cases, S3is optionally substituted with one or more of the substituents selected from (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, - C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -O-S(O)2R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, - OC(O)R30, -S(O)R30, -S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, S3is optionally substituted with one or more of the substituents selected from (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -O-S(O)2R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN. In some cases, S3is unsubstituted. In some cases, S3is substituted. In some cases, S3is a phenylene. In some cases,.

[0134] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S3is present and is a phenylene.

[0135] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), or Formula (X-I), or for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), S3is absent.

[0136] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the sugar cleavable unit can refer to a sugar moiety, preferably a glucuronide or a galactoside. In some cases, the sugar cleavable unit is glucuronide or a glucuronide derivative. In some cases, the sugar cleavable unit is glucuronide. In some cases, the sugar cleavable unit is galactoside or a galactoside derivative. In some cases, the sugar cleavable unit is galactoside.

[0137] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), orFormula (XX-II), cleavage of the cleavable unit triggers self -immolation of the phenyl-comprising linker of the compounds of the invention, and release of the Drug unit (D).

[0138] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide cleavable unit can refer to a polypeptide, preferably a dipeptide or a tripeptide. In some cases, the peptide cleavable unit is selected from dipeptide. In some cases, the peptide cleavable unit is selected from a tripeptide. In some cases, the peptide cleavable unit is selected from a tetrapeptide.

[0139] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the sugar cleavable unit of T1includes a sugar. In some cases, the sugar is glucuronide. In some cases, the sugar is selected from fructose, galactose glucose, xylose and ribose. In some cases, the sugar is a monosaccharide. In some cases, the sugar is a disaccharide.

[0140] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (some cases, Y1is a sugar moiety. In some cases, Y1is absent.

[0141] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of T2includes one or more amino acids selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of T2includes one or more amino acids selected from a group consisting of alanine, arginine, asparagine, aspartic acid, glutamine, glycine, lysine, methionine, phenylalanine, proline, serine, valine, citrulline, and β-Alanine. In some cases, the peptide unit of T2includes a dipeptide or tripeptide. In some cases, the peptide unit of T2includes a dipeptide. In some cases, the dipeptide is selected from Val-Cit, Val-Ala and Phe-Lys.

[0142] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), orFormula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of T2includes a capping moiety. In some cases, the capping moiety is a moiety capable of reacting with an amine of the peptide of to form an amide, carbamate or sulfonamide. In some cases, the capping moiety is a moiety which results from reacting with an amine to form an amide, carbamate or sulfonamide. In some cases, the capping moiety is a moiety which results from reacting with an amine to form an amide. In some cases, the capping moiety is a moiety which caps the end of an peptide / amino acid. In some cases, the capping moiety is. , .

[0143] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the peptide unit of T2includes a capping moiety. In some cases, the capping moiety is a moiety capable of reacting with an amine of the peptide to form an amide, carbamate or sulfonamide. In some cases, the capping moiety is a moiety which results from reacting with an amine to form an amide, carbamate or sulfonamide. In some cases, the capping moiety is a moiety which results from reacting with an amine to form an amide. In some cases, the capping moiety is a moiety which caps the end of an peptide / amino acid. In some cases, the capping moiety is an acyl moiety. In some cases, the capping moiety is, wherein R* is selected from C1-6alkyl. In some cases, the capping moiety is. In some cases, Y1is.

[0144] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III), M1is a group which can react with a Targeting Unit to form a connector unit. In some cases, a group that can react with a Targeting Unit to form a connector unit refers to any chemical moiety that is being reactive for covalently binding a Targeting Unit (e.g., antibody, ligand, antigen-binding fragment). In some cases, it may react with a thiol group present on aTargeting Unit. In some cases, it may react with a thiol group present on an antibody or antigen -binding fragment thereof. In some cases, it may react with a thiol group present on a ligand. In some cases, the chemical moieties that are being reactive for covalently binding a ligand includes: carboxylic acid; primary amine; secondary amine; tertiary amine; hydroxyl; halogen; activated ester such as N-hydroxysuccinimide ester, perfluorinated esters, nitrophenyl esters, aza-benzotriazole and benzotriazole activated ester, acylureas; alkynyl; alkenyl; azide; isocyanate; isothiocyanate; aldehyde; thiol- reactive moieties such as maleimide, halomaleimides, haloacetyls, pyridyl disulfides; thiol; acrylate; mesylate; tosylate; triflate, hydroxylamine; chlorosulfonyl; boronic acid - B(OR’)2derivatives wherein R’ is hydrogen or alkyl group. In some cases, M1is selected from maleimide, halogen,, azide, , activated group ,, OH, SH, activated disulfide group, -NH2, and -ONH2. In some cases, M1is maleimide. In some cases, M1is halogen. In some cases, M1isCOOH. In some cases,some cases, M1 is azide. In some cases, M1 is. In some cases, the activated group of M1is selected from,cases,. some cases, M1is OH. In some cases, M1is SH. In some cases, the activated disulfide group of M1is selected fromand. , . In some cases, M1is NH2. In some cases, M1is -ONH2. In some cases, M1is suitable for click reaction (e.g., cyclic alkyne, azide). In some cases,.

[0145] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), or Formula (X-II), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), D is drug unit. In some cases, D includes a spacer. In some cases, the spacer is a divalent moiety that covalently attaches the drug to the linker. In some cases, the spacer is a divalent moiety that covalently attaches the drug to the rest of the molecule. In some cases, D does not include a spacer. In some cases, the spacer can be selected from the group consisting of –C1-C10alkylene-, –C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O-(C1C8alkyl)-, -arylene-, –C1-C10alkylene- arylene-, -arylene-C1-C10alkylene-, –C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)- C1-C10alkylene-, -C3-C8heterocyclo-, –C1-C10alkylene-(C3-C8heterocyclo)-, -(C3- C8heterocyclo)–C1-C10alkylene-, –C1-C10alkylene-C(=O)-, –C1-C10heteroalkylene-C(=O)-, - C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C10alkylene-arylene- C(=O)-, -arylene-C1-C10alkylene-C(=O)-, -C1- C10alkylene-(C3-C8carbocyclo)-C(=O)-, -(C3- C8carbocyclo)-C1-C10alkylene-C(=O)-, - C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3- C8heterocyclo)-C(=O)-, -(C3-C8heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, - C1-C10heteroalkylene-NH-, -C3-C8carbocyclo-NH-, -O-(C1-C8alkyl)-NH-, -arylene-NH-, -C1- C10alkylene- arylene-NH-, -arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)- NH-, - (C3-C8carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3- C8heterocyclo)-NH-, -(C3-C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, - C1- C10heteroalkylene-S -, -C3-C8carbocyclo-S -, -O-(C1-C8alkyl)-)-S-, -arylene-S-, -C1- C10alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3- C8carbocyclo)-S-, - (C3-C8carbocyclo)-C1-C10alkylene-S-, -C3-C8heterocyclo-S-, -C1- C10alkylene-(C3- C8heterocyclo)-S-, -(C3-C8heterocyclo)-C1-C10alkylene-S-, –C1-C10alkylene-O-C(=O)-, -C3- C8carbocyclo-O-C(=O)-, -O-(C1-C8alkyl)-O-C(=O)-, -arylene- O-C(=O)-, -C1-C10alkylene- arylene-O-C(=O)-, -arylene-C1-C10alkylene-O-C(=O)-, -C1- C10alkylene-(C3-C8carbocyclo)-O- C(=O)-,-(C3-C8carbocyclo)-C1-C10alkylene-O-C(=O)-, -C3-C8heterocyclo-O-C(=O)-, -C1- C10alkylene-(C3-C8heterocyclo)-O-C(=O)-, and -(C3-C8heterocyclo)-C1-C10alkylene-O-C(=O)-. In some cases, the spacer can be selected from the group consisting of –C1-C10alkylene-, and - C1-C10alkylene-NH-. In some cases, the drug unit is only a drug.

[0146] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), or Formula (X-II), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), D is selected from a Drug unit. In some cases, the Drug unit comprises a drug. In some cases, the Drug unit is a drug. In some cases, the Drug unit is a drug and a spacer. In some cases, D is selected from a drug. In some cases, D is a selected from a cytotoxic agent, an immune modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope and a chelating ligand. In some cases, D is a selected from a cytotoxic agent, and an immune modulatory agent. In some cases, D is selected from exatecan and monomethyl auristatin E (MMAE). In some cases, D is a camptothecin. In some cases, D is exatecan. In some cases,. some cases, D is SN-38. In some cases, D is selected from MMAF and MMAE. In some cases, the cytotoxic agent is selected from the group consisting of an auristatin, a maytansinoid, a camptothecin, a duocarmycin, and a calicheamicin. In some cases, a cytotoxic agent is an agent that has a cytotoxic effect on a cell. In some cases, cytotoxic agents include, for example, tubulin disrupting agents, topoisomerase inhibitors, DNA minor groove binders, and DNA alkylating agents. In some cases, tubulin disrupting agents include, for example, auristatins, dolastatins, tubulysins, colchicines, vinca alkaloids, taxanes, cryptophycins, maytansinoids, hemiasterlins, as well as other tubulin disrupting agents. In some cases, auristatins are derivatives of the natural product dolastatin 10. In some cases, auristatins are selected from MMAE (N-methylvaline-valine-dolaisoleuine-dolaproine-norephedrine), MMAF (N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine) and AFP. In some cases, a cytsotoxic agent can be a topoisomerase inhibitor. In some cases, a drug is an immune modulatory agent, such as a TLR7 and / or TLR8 agonist. In some cases, an immune modulatory agent is a STING agonist. In some cases, a drug is a radioactive atom. In some cases, a drug is a proteolysis targeted chimera (PROTAC). In some cases, the drug is selected from exatecan, MMAE, MMAF, duocarmycin, SN-38, and dxd. In some cases, the drug is selected from MMAE, MMAF, duocarmycin, SN-38, and dxd. In some cases, the drug is.

[0147] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), or Formula (X-II), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Drug unit (D) is selected from an alkylating agent, a cytotoxic agent, an immune modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope, a chelating ligand, and a chelating ligand comprising a radioactive isotope. In some cases, the Drug unit is selected from a cytotoxic agent. In some cases, the Drug unit is selected from an alkylating agent, a cytotoxic agent, an immune modulatory agent, a growth inhibitory agent. In some cases, each Drug unit is independently selected from an alkylating agent, a cytotoxic agent, an immune modulatory agent, a growth inhibitory agent. In some cases, the Drug unit is selected from an alkylating agent. In some cases, the Drug unit is selected from an alkylating agent. In some cases, the Drug unit is selected from a cytotoxic agent. In some cases, the Drug unit is selected from an immune modulatory agent. In some cases, the Drug unit is selected from a growth inhibitory agent. In some cases, the agent is a small molecule agent. In some cases, the agent is a peptide-based agent. In some cases, the agent is a small molecule agent, a peptide- based agent, or a combination thereof. In some cases, each Drug unit is independently selectedfrom an alkylating agent. In some cases, each Drug unit is independently selected from a cytotoxic agent. In some cases, the Drug unit is selected from an immune modulatory agent. Insome cases, each Drug unit is independently selected from a growth inhib itory agent. In somecases, each agent is independently a small molecule agent. In some cases, each agent is independently a peptide-based agent. In some cases, each agent is independently a small molecule agent, a peptide-based agent, or a combination thereof.

[0148] In some embodiments, for a Linker or salt of Formula (XXX) or Formula (XXX-I), or for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), or Formula (X-II), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I),or Formula (XX-II), the Drug unit (D) is selected from an alkylating agent, a bizelesin derivative, a cytotoxic agent, camptothecin derivative, a growth inhibitory agent, a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like) and an immune modulatory agent. In some cases, each Drug unit (D) is independently selected from an alkylating agent, a bizelesin derivative, a cytotoxic agent, camptothecin derivative, a growth inhibitory agent, a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like) and an immune modulatory agent. In some cases, the Drug unit is selected from a bizelesin derivative, camptothecin derivative, and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, each Drug unit is independently selected from a bizelesin derivative, camptothecin derivative, and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, the Drug unit is selected from analkylating agent, a bizelesin derivative, a cytotoxic agent, camptothecin derivative, a growthinhibitory agent, and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, each Drug unit is independently selected from an alkylating agent, a bizelesin derivative, a cytotoxic agent, camptothecin derivative, a growth inhibitory agent, and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, the Drug unit is selected from an alkylating agent and a bizelesin derivative. In some cases, each Drug unit is independently selected from an alkylating agent and a bizelesin derivative. In some cases,the Drug unit is selected from a cytotoxic agent and camptothecin derivative. In some cases,each Drug unit is independently selected from a cytotoxic agent and camptothecin derivative. In some cases, the Drug unit is selected from camptothecin derivative and a growth inhibitory agent. In some cases, each Drug unit is independently selected from camptothecin derivative and a growth inhibitory agent. In some cases, the Drug unit is selected from a growth inhibitory agent and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, each Drug unit is independently selected from a growth inhibitory agent and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, the Drug unit is selected from an immune modulatory agent. In some cases, the agent is a small moleculeagent. In some cases, the agent is a peptide-based agent. In some cases, the agent is a small molecule agent, a peptide-based agent, or a combination thereof. In some cases, the Drug unit is selected from exatecan, SN-38, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and bizelesin. In some cases, each Drug unit is independently selected from exatecan, SN-38, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and bizelesin. In some cases, the Drug unit is selected from a camptothecin derivative, a bizelesin derivative, and a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, Drug unit is a camptothecin derivative. In some cases, Drug unit is exatecan. In some cases, Drug unit is SN-38. In some cases, the Drug unit is a bizelesin derivative. In some cases, the Drug unit is bizelesin. In some cases, the Drug unit is a monomethyl auristatin derivative (e.g. MMAE, MMAF, and the like). In some cases, Drug unit is selected from MMAF and MMAE. In some cases, the Drug unit is selected from exatecan, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and bizelesin. In some cases, the Drug unit is selected form exatecan, monomethyl auristatin E (MMAE), and bizelesin. In some cases, the Drug unit is selected from monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and bizelesin. In some cases, the Drug unit is selected from exatecan, SN-38, and bizelesin. In some cases, the Drug unit is exatecan. In some cases, the Drug unit is SN-38. In some cases, the Drug unit is monomethyl auristatin E (MMAE). In some cases, the Drug unit is monomethyl auristatin F (MMAF). In some cases, the Drug unit is bizelesin. In some cases, the cytotoxic agent is selected from an auristatin, a maytansinoid, a camptothecin, a duocarmycin, and a calicheamicin. In some cases, a cytotoxic agent is an agent that has a cytotoxic effect on a cell. In some cases, cytotoxic agents include, for example, tubulin disrupting agents, topoisomerase inhibitors, DNA minor groove binders, and DNA alkylating agents. In some cases, an alkylating agent is a DNA alkylating agent. In some cases, the DNA alkylating is selected from a bizelesin derivative. In some cases, the DNA alkylating is bizelesin. In some cases, tubulin disrupting agents include, for example, auristatins, dolastatins, tubulysins, colchicines, vinca alkaloids, taxanes, cryptophycins, maytansinoids, hemiasterlins, as well as other tubulin disrupting agents. In some cases, auristatins are derivatives of the natural product dolastatin 10. In some cases, auristatins are selected from MMAE (N-methylvaline-valine-dolaisoleuine-dolaproine- norephedrine), MMAF (N-methylvaline-valine-dolaisoleuine-dolaproine-phenylalanine) and AFP. In some cases, a cytotoxic agent can be a topoisomerase inhibitor. In some cases, a drug is an immune modulatory agent, such as a TLR7 and / or TLR8 agonist. In some cases, an immune modulatory agent is a STING agonist. In some cases, a drug is a radioactive atom. In some cases, a drug is a chelate, wherein the chelate comprises a radioactive atom. In some cases, a drug is a proteolysis targeted chimera (PROTAC). In some cases, D is selected from.

[0149] In some embodiments, for a Drug-Linker or salt of Formula (B-4), Formula (X-4), Formula (I-4), or Formula (I-A-4), further includes attaching a Targeting Unit to M1to form a conjugate, wherein M1of the Drug-Linker reacts and forms a covalent bond to the TargetingUnit. In some cases, the Targeting unit is selected from an antibody or an antigen -bindingportion thereof. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1 to 10. In some cases, the Targeting unit is selected from an antibody or an antigen-binding portion thereof. In some cases, the conjugate has an average ratio of Drug- Linker to Targeting unit of about 1 to 10. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1 to 5. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10. In some cases, the conjugate has an average ratio of Drug-Linker to Targeting unit (DAR) of about 8.

[0150] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), or Formula (XX-I), M2is a connector unit. In some cases, the connector unit refers to a component that connects different parts of the conjugate together. In some cases, the connector unit canconnect the Targeting Unit to S3(if present) or to S1. In some cases, the connector unit forms a bond with a sulfur atom of a Targeting unit. In some cases, the connector unit forms a bond with a sulfur atom of a Targeting unit via a maleimide group. In some cases, the sulfur atom can be derived from, for example, a sulfhydryl group of a Targeting unit (e.g., a thiol group of aninterchain disulfide bond). In some cases,some cases, M2 is. In, . In some cases,. In somecases, M2is -CH2-C(O)NH-. In some cases, M2is linked to the Targeting unit via a disulfide bond between a sulfur atom of M2and a sulfur atom of the Targeting unit. In some cases, M2is . In some cases, the connector unit forms a bond with a primary or secondary amino group of a Targeting unit. In some cases, M2is selected from.

[0151] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; andIn some cases, the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; andwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; andIn some cases, the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; andIn some cases, the conjugate is selected from.

[0152] In an aspect, the present disclosure provides a Linker of Formula (XXX):, or a pharmaceutically acceptable salt thereof, wherein: Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent;wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and R50 is selected from a substituent capable of reacting with a nucleophilic group on a Drug.

[0153] In some embodiments, a linker of Formula (XXX) is represented by the structure of Formula (XXX-I), or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, for a linker of Formula (XXX) or Formula (XXX-I), R50is selected from a substituent capable of reacting with a nucleophilic group on a Drug. In some cases, R50is -OH. In some cases, R50is. In some cases,. some cases,. cases, R50is -NH2. Table A-P. Exemplary Drug LinkersTable A-G. Exemplary Drug LinkersTable AA-P. Exemplary Conjugates

[0155] For the Table AA-P, L is an antibody or antigen-binding portion thereof.

[0156] In some embodiments, the exemplary conjugates of Table AA-P have a DAR of at most about 16. In some cases, the exemplary conjugates of Table AA-P have a DAR about 8. In some cases, the exemplary conjugates of Table AA-P have a DAR about 10. In some cases, the exemplary conjugates of Table AA-P have a DAR of at least about 1. In some cases, the exemplary conjugates of Table AA-P have a DAR at least about 2. In some cases, the exemplary conjugates of Table AA-P have a DAR at least about 4. In some cases, the exemplary conjugates of Table AA-P have a DAR at least about 8. In some cases, the exemplary conjugates of Table AA-P have a DAR at most about 8. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 1 to about 16. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 4 to about 12. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 6 to about 10. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 7 to about 9. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 8 to about 10. In some cases, the exemplary conjugates of Table AA-P have a DAR from about 6 to about 8. In some embodiments, the exemplary conjugates of Table AA-P, L is selected from Table A. In some embodiments, the exemplary conjugates of Table AA-P, L is selected from Table B. In some embodiments, the exemplary conjugates of Table AA-P, L is Ab1. In some embodiments, the exemplary conjugates of Table AA-P, L is Ab2. In some embodiments, the exemplary conjugates of Table AA-P, L is Ab3. In some embodiments, the exemplary conjugates of Table AA-P, L is Ab4. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-7EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-9. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-9EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-1EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-2EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-3EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-3EL-VL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4- 4EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-5EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-5EL-VH. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-6EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-10EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-8EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-11EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-12EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4- 13EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-14EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-15EL. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-16. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-17. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-18. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-19. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-20. In some embodiments, the exemplary conjugates of Table AA-P, L is 5T4-21. Table AA-G. Exemplary Conjugates

[0157] For the Table AA-G, L is an antibody or antigen-binding portion thereof.

[0158] In some embodiments, the exemplary conjugates of Table AA-G have a DAR of at most about 16. In some cases, the exemplary conjugates of Table AA-G have a DAR about 8. In some cases, the exemplary conjugates of Table AA-G have a DAR about 10. In some cases, the exemplary conjugates of Table AA-G have a DAR of at least about 1. In some cases, the exemplary conjugates of Table AA-G have a DAR at least about 2. In some cases, the exemplary conjugates of Table AA-G have a DAR at least about 4. In some cases, the exemplary conjugates of Table AA-G have a DAR at least about 8. In some cases, the exemplary conjugates of Table AA-G have a DAR at most about 8. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 1 to about 16. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 4 to about 12. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 6 to about 10. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 7 to about 9. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 8 to about 10. In some cases, the exemplary conjugates of Table AA-G have a DAR from about 6 to about 8. In some embodiments, the exemplary conjugates of Table AA-G, L is selected from Table A. In some embodiments, the exemplary conjugates of Table AA-G, L is selected from Table B. In some embodiments, the exemplary conjugates of Table AA-G, L is Ab1. In some embodiments, the exemplary conjugates of Table AA-G, L is Ab2. In some embodiments, the exemplary conjugates of Table AA-G, L is Ab3. In some embodiments, the exemplary conjugates of Table AA-G, L is Ab4. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4- 7EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-9. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-9EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-1EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-2EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-3EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-3EL-VL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4- 4EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-5EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-5EL-VH. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-6EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-10EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-8EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-11EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-12EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4- 13EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-14EL. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-15EL. In someembodiments, the exemplary conjugates of Table AA-G, L is 5T4-16. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-17. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-18. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-19. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-20. In some embodiments, the exemplary conjugates of Table AA-G, L is 5T4-21.

[0159] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0160] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0161] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:.

[0162] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0163] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0164] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, thecompounds may be labeled with isotopes, such as for example , deuterium (2H), tritium (3H),iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0165] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0166] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0167] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0168] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs,and amorphous forms of the compounds, as well as mixtures thereof.

[0169] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, orchromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samue l H. Wilen,“Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0170] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0171] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0172] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0173] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administrationwhereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0174] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series;and Edward B. Roche, Bioreversible Carriers in Drug Design , American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0175] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Targeting Unit (L)

[0176] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), L is a Targeting Unit. In some cases, the Targeting Unit is selected from an antibody or an antigen-binding fragment thereof. In some cases, the Targeting unit is an antibody. In some cases, the Targeting unit is an antigen-binding fragment. In some cases, the Targeting unit is a nanobody.

[0177] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting Unit is selected from an antibody or an antigen-binding fragment thereof. In some cases, the Targeting Unit is selected from a group consisting of chimeric antibodies,humanized antibodies, and human antibodies. In some cases, the Targeting Unit, performs a targeting function. In some cases, a Targeting unit specifically binds to a target molecule. In some cases, specifically binds refers to the ability of a Targeting unit (e.g., an antibody orportion thereof) described herein to bind to a target with a KD 10 -5 M (10000 nM) or less, e.g.,10-6M, 10-7M, 10-8M, 10-9M, 10-10M, 10-11M, 10-12M, or less. In some cases, a Targeting unit is said to specifically bind to its target when it preferentially recognizes its target in a complex mixture of proteins and / or macromolecules. In some cases, the antibody is a monoclonal antibody.

[0178] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting unit is an antibody or antigen binding portion thereof is a bispecific or multispecific binding agent. Bispecific and multi-specific antibodies include the following: an scFv1-ScFv2, an ScFv12-Fc-scFv22, an IgG-scFv, a DVD-Ig, a triomab / quadroma, a two-in- one IgG, a scFv2-Fc, a TandAb, and an scFv-HSA-scFv. In some embodiments, an IgG-scFv is an IgG (H) -scFv, scFv-(H) IgG, IgG (L) -scFv, svFc- (L) IgG, 2scFV-IgG or IgG-2scFv.

[0179] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting unit (L) includes at least one amino acid. In some cases, the Targeting unit is one or more amino acids. In some cases, the Targeting unit includes one or more natural amino acids. In some cases, the Targeting unit includes one or more unnatural amino acids. In some cases, unnatural amino acids (p-acetylphenylalanine or pAcF and p-azidomethyl-L- phenylalanine or pAMF), or short peptide tags. In some cases, the Targeting unit includes a cysteine. In some cases, the Targeting unit includes a glutamine. In some cases, the Targeting unit is a peptide having less than 50 amino acids. In some cases, the Targeting unit is a peptide having less than 40 amino acids. In some cases, the Targeting unit is a peptide having less than 30 amino acids. In some cases, the Targeting unit is a peptide having less than 20 amino acids. In some cases, the Targeting unit is a peptide having more than 50 amino acids. In some cases, the Targeting unit is a peptide having more than 40 amino acids. In some cases, the Targeting unit is a peptide having more than 30 amino acids. In some cases, the Targeting unit is a peptide having more than 20 amino acids. In some cases, the Targeting unit is a peptide having more than 10 amino acids. In some cases, the Targeting unit is a peptide having more than 5 amino acids. In some cases, the Targeting unit is a peptide having about 1 to about 50 amino acids. In some cases, the Targeting unit is a peptide having about 2 to about 30 amino acids. In somecases, the Targeting unit is a peptide having about 3 to about 15 amino acids. In some cases, theTargeting unit includes a cyclic peptide. In some cases, the Targeting unit is a linear peptide.

[0180] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting unit has at least one sulfur atom. In some cases, the Targeting unit has at least one sulfur atom from a cysteine residue. In some cases, the Targeting unit has at least one sulfur atom from a reduced cysteine residue.

[0181] In some embodiments, for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting unit, such as an antibody or antigen-binding portion thereof or other Targeting unit, has an antibody constant region(s). In some cases, the constant region is a fully human constant region(s). In some cases, the constant region is a humanized constant region(s). In some cases, the constant region is a non-human constant region(s). In some cases, an immunoglobulin constant region refers to a heavy or light chain constant region. A constant region can be of any suitable type, which can be selected from the classes of immunoglobulins, IgA, IgD, IgE, IgG, and IgM. Several immunoglobulin classes can be further divided into isotypes, e.g., IgG1, IgG2, IgG3, IgG4, or IgAl, and IgA2. The heavy-chain constant regions (Fc) that correspond to the different classes of immunoglobulins can be α, δ, ε, γ, and μ,respectively. The light chains can be one of either kappa (κ) and lambda (λ).

[0182] In some embodiments, a constant region can have an IgG isotype. In some embodiments, a constant region can have an IgG1 isotype. In some embodiments, a constant region can have an IgG2 isotype. In some embodiments, a constant region can have an IgG3isotype. In some embodiments, a constant region can have an IgG4 isotype. In someembodiments, a constant region can have a hybrid isotype comprising constant regions from two or more isotypes. In some embodiments, an immunoglobulin constant region can be an IgG1 or IgG4 constant region.

[0183] In some cases, L is a 5T4 antibody. In some cases, L is Ab6. In some cases, the heavy chain variable region further comprises a heavy chain constant region. In some cases, the heavy chain constant region is of the IgG isotype. In some cases, the heavy chain constant region is an IgG1 constant region. In some cases, the heavy chain constant region is an IgG4 constant region.

[0184] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the Targeting unit is capable of binding the extracellular domain of 5T4.

[0185] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chain CDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:86, 91, 96, 78, 81, and 84, respectively.

[0186] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chain CDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:88, 93, 97, 78, 81, and 84, respectively.

[0187] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) comprising SEQ ID NOs:20 and 21, respectively.

[0188] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VHand the VLcomprise: SEQ ID NOs:4 and 5, respectively; SEQ ID NOs:6 and 7, respectively; SEQ ID NOs:8 and 9, respectively; SEQ ID NOs:10 and 11, respectively; SEQ ID NOs:10 and 12, respectively; SEQ ID NOs:13 and 14, respectively; SEQ ID NOs:15 and 17, respectively; SEQ ID NOs:16 and 17, respectively; SEQ ID NOs:18 and 19, respectively; SEQ ID NOs:20 and 21, respectively; SEQ ID NOs:22 and 23, respectively; SEQ ID NOs:24 and 25, respectively; SEQ ID NOs:26 and 27, respectively; SEQ ID NOs:28 and 29, respectively; SEQ ID NOs:30 and 31, respectively; SEQ ID NOs:32 and 33, respectively;SEQ ID NOs:34 and 35, respectively; SEQ ID NOs:36 and 37, respectively; SEQ ID NOs:38 and 39, respectively; SEQ ID NOs:40 and 41, respectively; SEQ ID NOs:42 and 43, respectively; SEQ ID NOs:44 and 45, respectively; or SEQ ID NOs:46 and 47, respectively.

[0189] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody comprises a human IgG1 constant region.

[0190] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the human IgG1 constant region comprises SEQ ID NO:1, optionally without the C-terminal lysine.

[0191] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the human IgG1 constant region comprises SEQ ID NO:2, optionally without the C-terminal lysine.

[0192] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX),Formula (XX-I), or Formula (XX-II), the antibody comprises a human light chain constant region that comprises SEQ ID NO:3.

[0193] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody is selected from 5T4-1EL, 5T4-2EL, 5T4- 3EL, 5T4-3EL-VL, 5T4-4EL, 5T4-5EL, 5T4-5EL-VH, 5T4-6EL, 5T4-7EL, 5T4-8EL, 5T4-9, 5T4-9EL, 5T4-10EL, 5T4-11EL, 5T4-12EL, 5T4-13EL, 5T4-14EL, 5T4-15EL, 5T4-16, 5T4-17, 5T4-18, 5T4-19, 5T4-20, and 5T4-21.

[0194] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or antigen-binding portion comprises a heavy (HC) and a light chain (LC) comprising SEQ ID NOs:1 and 3, respectively or SEQ ID NOs:2 and 3, respectively.

[0195] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX),Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chain CDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:86, 91, 96, 78, 81, and 84, respectively.

[0196] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), the antibody or portion thereof comprises a heavy chainCDR (HCDR) 1-3 and a light chain CDR (LCDR) 1-3 comprising SEQ ID NOs:88, 93, 97, 78, 81, and 84, respectively.

[0197] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX),Formula (XX-I), or Formula (XX-II), the anti-5T4 antibody or antigen-binding portion comprises the HCDR1-3 and LCDR1-3 amino acid sequences of any one of the antibodies exemplified herein. The assignment of CDR regions may be in accordance with any method known in the art, such as IMGT®, Kabat, Chothia, Martin, Contact, or AHo definitions, or any combination of any of these definitions (Kabat plus Chothia, for example). Examples of CDR definitions under different methods are shown below for SLX-2079 (SEQ: SEQ ID NO): SLX-2079 HCDRsSLX-2079 LCDRs

[0198] Thus, for example, the SLX-2079 IMGT®-defined HCDR1-3 and LCDR1-3 sequences of SEQ ID NOs:86, 91, 96, 78, 81, and 84, respectively, may be replaced in any embodiment described herein by SEQ ID NOs:87, 92, 97, 79, 82, and 84, respectively; SEQ ID NOs:88, 93, 97, 79, 82, and 84, respectively; SEQ ID NOs:89, 94, 97, 79, 82, and 84, respectively; or SEQ ID NOs:90, 95, 98, 80, 83, and 85, respectively.

[0199] Also contemplated is a set of SLX-2079 CDRs wherein each of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 may individually be specified according to any of the methods for defining SLX-2079 CDRs as shown above (e.g., HCDR1 specified by the Kabat definition, HCDR2 specified by the Chothia definition, etc.). The same means for defining SLX-2079 CDRs are contemplated for any of the exemplified antibodies herein.

[0200] In some embodiments, for a conjugate or salt of Formula (XX*), Formula (XX),Formula (XX-I), or Formula (XX-II), the anti-5T4 antibody of the present disclosure can be an IgG, an IgM, an IgE, an IgA, or an IgD molecule, but is typically of the IgG isotype, e.g., of IgG subclass IgG1, IgG2, IgG3 or IgG4. In some embodiments, the antibody is of the isotype subclass IgG1. Pharmaceutical Formulations

[0201] Provided herein, in certain embodiments, are pharmaceutical compositions comprising a therapeutically effective amount of a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II) (also referred to herein as “a pharmaceutical agent”).

[0202] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0203] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration,particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can alsobe present in a solution suitable for topical administration, such as an eye drop.

[0204] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0205] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinklecapsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongu e;absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0206] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to anamount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0207] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0208] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0209] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0210] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: AComprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and in Remington: TheScience and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0211] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferablysterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0212] For oral formulations, at least one of the pharmaceutical agents described herein canbe used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0213] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, andthe nature of the condition, disease or disorder to be treated or prevented.

[0214] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodiumpropionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cety lpyridiniumchloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0215] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oilypharmaceutically approved excipients. Suitable surf actants include, but are not limited to,anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0216] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated withan aqueous or oily base and will in general also contain one or more emulsifyin g agents,stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0217] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0218] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^L. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0219] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized drypowder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^L. Predominantly in this application means that atleast 70% but preferably more than 90% of all generated aerosol particles are within 1 -5 ^Lrange. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb^^ and AeroDose^^ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC^ and Pari LC Star^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic^^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0220] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0221] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow the desired release of the compound.

[0222] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with waterinsoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0223] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0224] A polymer formulation can also be utilized to provide controlled or sustained release.Bioadhesive polymers described in the art may be used. By way of example, a sustained -releasegel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying,solvent extraction and other methods known to those skilled in the art.

[0225] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. Methods of Treatment

[0226] In an aspect, the present disclosure provides a method of treating a subject with a disease or disorder comprising administering to a subject in need thereof a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), or a pharmaceutical composition of any one thereof. In some cases, the disease or disorder is cancer. In some cases, the disease or disorder is a tumor. In some cases, the tumor is associated with a cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers. In some cases, the cancer is selected from cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, andparagangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma;intestinal cancers, particularly colorectal cancer; ovarian cancer; small cell and non -small celllung cancer (SCLC and NSCLC); breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomysosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; leukemias such as acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML); neoplasms of the central nervous systems, particularly brain cancer; multiple myeloma (MM), lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma. In some cases, cancer is selected from melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngealcancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non -small cell lungcancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV- associated T cell leukemia / lymphoma), and mesothelioma. In some cases, the cancer is selectedfrom head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In some cases, the cancer is selected from of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft-tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma. In some cases, the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer. In some cases, the cancer is cell lymphoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is large-cell lung cancer. In some cases, the cancer is breast cancer. In some cases, the cancer is small-cell lung cancer.

[0227] In an aspect, the present disclosure provides a use of a pharmaceutical composition for a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), in the preparation of a medicament for treating a disease or disorder. In some cases, the disease or disorder is cancer. In some cases, the disease or disorder is a tumor. In some cases, the tumor is associated with a cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovariancancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers. In somecases, the cancer is selected from cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma; intestinal cancers, particularly colorectal cancer; ovarian cancer; small cell and non-small cell lung cancer (SCLC and NSCLC); breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomysosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; leukemias such as acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML); neoplasms of the central nervous systems, particularly brain cancer; multiple myeloma (MM), lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B- lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma. Insome cases, cancer is selected from melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngeal cancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tractcancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervicalcancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV-associated T cell leukemia / lymphoma), and mesothelioma. In some cases, the cancer is selected from head and neck cancer, bone cancer (e.g., osteosarcoma), Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In some cases, the cancer is selected from of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft- tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma. In some cases, the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer. In some cases, the cancer is cell lymphoma. In some cases,the cancer is non-small cell lung cancer. In some cases, the cancer is large-cell lung cancer. In some cases, the cancer is breast cancer. In some cases, the cancer is small-cell lung cancer.

[0228] In an aspect, the present disclosure provides a method of treating a subject with a cancer. In some cases, the treatment of a subject with a cancer includes administering to a subject in need thereof a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), or a pharmaceutical composition of any one thereof. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers.

[0229] In an aspect, the present disclosure provides a method of treating a subject with a tumor. In some cases, the treatment of a subject with the tumor includes administering to a subject in need thereof a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), or a pharmaceutical composition of any one thereof. In some cases, the tumor is associated with a cancer. In some cases, the cancer is selected from the group consisting of lung cancer, kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic, breast, melanoma, liver, bladder, stomach, and esophageal cancers.

[0230] In some embodiments, conjugates or salts described herein are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating cancer in a patient.

[0231] The conjugates provide conjugation-specific tumor or cancer targeting, thus reducing general toxicity of these compounds. The linker stabilizes the conjugates in blood, yet is cleavable by enzymes within the cell (e.g., lysosomal enzymes), liberating the Drug(s).

[0232] In some embodiments, conjugates or salts described herein (e.g., Formula (XX*), Formula (XX), Formula (XX-I), Formula (XX-II), Table AA-P, or Table AA-G) can be used for treating diseases such as, but not limited to, hyperproliferative diseases, including: cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma;intestinal cancers, particularly colorectal cancer; ovarian cancer; small cell and non -small celllung cancer (SCLC and NSCLC); breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomysosarcoma, neurofibrosarcoma,osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; leukemias such as acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML); neoplasms of the central nervous systems, particularly brain cancer; multiple myeloma (MM), lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma. Clinically, practice of the methods and use of compositions described herein will result in a reduction in the size or number of the cancerous growth and / or a reduction in associated symptoms (where applicable). Pathologically, practice of the method and use of compositions described herein will produce a pathologically relevant response, such as: inhibition of cancer cell proliferation, reduction in the size of the cancer or tumor, prevention of further metastasis, and inhibition of tumor angiogenesis. The method of treating such diseases comprises administering a therapeutically effective amount of an inventive combination to a subject. The method may be repeated as necessary. The cancer can be renal, lung, gastric, or ovarian cancer. In some cases, the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer. In some cases, the cancer is cell lymphoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is large-cell lung cancer. In some cases, the cancer is breast cancer. In some cases, the cancer is small-cell lung cancer.

[0233] In some embodiments, the cancer treated by the ADCs or salts of the present disclosure (e.g., Formula (XX*), Formula (XX), Formula (XX-I), Formula (XX-II), Table AA- P, or Table AA-G) may be a solid tumor or a hematopoietic cancer. The cancer may be, e.g., melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck,nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx , larynx, hypopharynx,and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngealcancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non -small cell lungcancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma, kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer, fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma,osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer,multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acu telymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV- associated T cell leukemia / lymphoma), or mesothelioma. In certain embodiments, the cancer isselected from the group consisting of head and neck cancer, bone cancer (e.g. , osteosarcoma),Ewing sarcoma, squamous cell carcinoma, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, urethral cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, cervical cancer, pancreatic cancer, breast cancer (e.g., triple negative breast cancer), melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and chronic myelogenous leukemia. In particular embodiments, the cancer is selected from the group consisting of head and neck cancer, non-small cell lung cancer, esophageal cancer, gastric cancer, hepatic cancer, pancreatic cancer, colorectal cancer, breast cancer, endometrial cancer, ovarian cancer, soft-tissue sarcoma, bladder cancer, prostate cancer, renal cancer, and melanoma. The cancer may be, e.g., at an early, intermediate, late, locally advanced, or metastatic stage, and may be relapsed or refractory to other therapeutics, or there may be no standard therapy available. In some cases, the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer. In some cases, the cancer is cell lymphoma. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is large-cell lung cancer. In some cases, the cancer is breast cancer. In some cases, the cancer is small-cell lung cancer.

[0234] In some embodiments, therapeutic use of an ADC or salts described herein (e.g., Formula (XX*), Formula (XX), Formula (XX-I), Formula (XX-II), Table AA-P, or Table AA- G) will result in delayed tumor growth, elimination of cancer cells, tumor shrinkage / regression, increased survival, slowed or decreased metastasis, or other clinical endpoints desired byhealthcare professionals. In certain embodiments, therapeutic use of an ADC described hereininhibits tumor growth by at least 10, 20, 30, 40, 50, 60, 70, 80 , 90, or 100%. In certainembodiments, therapeutic use of an ADC described herein provides partial tumor regression ofat least 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or complete tumor regression.

[0235] In some embodiments, the ADCs or salts of the present disclosure may be administered without additional therapeutic treatments, i.e., as a stand-alone therapy (monotherapy). Alternatively, treatment with the ADCs of the present disclosure may include at least one additional therapeutic treatment (combination therapy), e.g., an immunomodulatory agent, an anti-cancer agent (such as a chemotherapeutic agent, an anti-neoplastic agent, or an anti-angiogenic agent), a vaccine (such as a tumor vaccine), or radiation therapy.

[0236] In some embodiments, the additional therapeutic treatment may comprise an anti- cancer agent such as, for example, an agent selected from the group consisting of alkylating agents (e.g., platinum derivatives such as cisplatin, carboplatin and / or oxaliplatin); plant alkoids (e.g., paclitaxel, docetaxel and / or irinotecan); antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, idarubicin mitoxantrone, dactinomycin, bleomycin, actinomycin, luteomycin, and / or mitomycin); topoisomerase inhibitors (e.g., topotecan); antimetabolites (e.g., fluorouracil and / or other fluoropyrimidines); kinase inhibitors such as tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, imatinib, sorafenib, lapatinib, etc.); or any combination thereof.

[0237] In some embodiments, the additional therapeutic treatment may comprise an agent that modulates immune system activation, including, but not limited to, an agent that modulates the expression or activity of A2AR, A1AR, A2BR, A3AR, ADA, ALP, AXL, BTLA, B7-H3, B7-H4, CD116, CD123, CD27, CD28, CD39, CD40, CD47, CD55, CD73, CD122, CD137, CD160, CGEN-15049, CHK1, CHK2, CTLA-3, CTLA-4, CEACAM (e.g., CEACAM-1 and / or CEACAM-5), EGFR, FLT3, HER2, NKG2A, NKG2AL, GAL9, GITR, HVEM, LAG-3, LILRB1, LY108, LAIR1, MET, NKG2A, ICOS, IDO, IL2R, IL4R, KIR, LAIR1, PAP, PD- 1 / PD-L1 / PD-L2, OX40, STING, TIGIT, TIM-3, TGFR-beta, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9 and TLR10, TNFR2, VEGFR, VEGF, VISTA, LILRB2, CMTM6 and / or 2B4. In certain embodiments, the agent is a small molecule inhibitor, an antisense oligonucleotide, a small interfering RNA, an aptamer, a peptide, or an antibody or an antigen-binding fragment thereof that binds to one of the above molecules.

[0238] In some embodiments, the treatment of tumor-bearing subjects inhibits tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. A therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject, which is typically a human but can be another mammal. In some cases, the subject is a human. In some cases, the subject is a mammal.

[0239] In some embodiments, compositions described herein can be administered in combination with other therapeutic agents, including antibodies, alkylating agents, angiogenesisinhibitors, antimetabolites, DNA cleavers, DNA crosslinkers, DNA intercalators, DNA minor groove binders, enediynes, heat shock protein 90 inhibitors, histone deacetylase inhibitors, immunomodulators, microtubule stabilizers, nucleoside (purine or pyrimidine) analogs, nuclear export inhibitors, proteasome inhibitors, topoisomerase (I or II) inhibitors, tyrosine kinase inhibitors, and serine / threonine kinase inhibitors. Specific therapeutic agents include adalimumab, ansamitocin P3, auristatin, bendamustine, bevacizumab, bicalutamide, bleomycin, bortezomib, busulfan, callistatin A, camptothecin, capecitabine, carboplatin, carmustine, cetuximab, cisplatin, cladribin, cytarabin, cryptophycins, dacarbazine, dasatinib, daunorubicin, docetaxel, doxorubicin, duocarmycin, dynemycin A, epothilones, etoposide, floxuridine, fludarabine, 5-fluorouracil, gefitinib, gemcitabine, ipilimumab, hydroxyurea, imatinib, infliximab, interferons, interleukins, β-lapachone, lenalidomide, irinotecan, maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mitomycin C, nilotinib, oxaliplatin, paclitaxel, procarbazine, suberoylanilide hydroxamic acid (SAHA), 6-thioguanidine, thiotepa, teniposide, topotecan, trastuzumab, trichostatin A, vinblastine, vincristine, and vindesine.

[0240] In some embodiments, a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0241] In some embodiments, a Drug-Linker or salt of Formula (X*), Formula (X), Formula (X-I), Formula (X-II), or Formula (X-III) (each of which further comprises a targeting unit), or a conjugate or salt of Formula (XX*), Formula (XX), Formula (XX-I), or Formula (XX-II), described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0242] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease,disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0243] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for anextended period of time, including throughout the duration of the patient’s life in order toameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0244] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.

[0245] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0246] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation isdivided into unit doses containing appropriate quantities of one or more compound. Th e unitdosage may be in the form of a package containing discrete quantities of the formulation. Non -limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0247] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxicand therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage may vary within thisrange depending upon the dosage form employed and the route of administration utilized.In certain embodiments, the invention provides a method of treating or preventing a disease, state, or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. Preparation of Drug-Linkers and Conjugates of the Disclosure

[0248] The Linkers, Drug-Linkers and conjugates of the present disclosure can generally beprepared in a number of ways well known to those skilled in the art of organic synthesis.

[0249] In some embodiments, Linkers, Drug-Linkers and conjugates of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. In some embodiments, a conjugate may be prepared by several routes employing organic chemistry reactions, conditions, and reagents known to those skilled in the art, including: (1) reaction of a nucleophilic group of a Targeting unit (e.g., an antibody or antigen binding portion thereof or non-antibody protein scaffold) with a bivalent Linker to form a Targeting unit-Linker intermediate via a covalent bond, followed by reaction with a Drug; and (2) reaction of a nucleophilic group of a Drug with a bivalent Linker, to form Drug-Linker, via a covalent bond, followed by reaction with a nucleophilic group of a Targeting unit.

[0250] In some embodiments, techniques for attaching a drug to Targeting units (such as antibodies or antigen binding portions thereof or non-antibody scaffolds) via linkers may be used. In some cases, a Linker is first attached to a Drug (e.g., a cytotoxic agent (s), immune modulatory agent or other agent) and then the Drug-Linker (s) is attached to the Targeting unit (e.g., an antibody or antigen binding portion thereof or non-antibody protein scaffold). In some cases, a Linker is first attached to a Targeting unit (e.g., an antibody or antigen binding portionthereof or non-antibody protein scaffold), and then a Drug is attached to a Linker.

[0251] In some embodiments, a Drug is attached to a Targeting unit via a Linker in a manner that reduces the activity of the Drug until it is released from the conjugate (e.g., by hydrolysis, by proteolytic degradation or by a cleaving agent.

[0252] In some embodiments, nucleophilic groups on Targeting units such as antibodies, antigen binding portions and other binding agents (including non-antibody scaffolds) include, but are not limited to: (i) N-terminal amine groups, (ii) side chain amine groups, e.g. lysine, (iii) side chain thiol groups, e.g. cysteine, and (iv) sugar hydroxyl or amino groups where the antibody is glycosylated. Amine, thiol, and hydroxyl groups are nucleophilic and capable of reacting to form covalent bonds with electrophilic groups on Linkers including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; and (iii) aldehydes, ketones, carboxyl, and maleimide groups. In some cases, targeting units, such as antibodies (and antigen binding portions and other binding agents(including non-antibody scaffolds)) have reducible interchain disulfides, i.e., cysteine bridges. Insome cases, antibodies (and antigen binding portions and other binding agents (including non- antibody scaffolds)) may be made reactive for conjugation with Linkers or Drug-Linkers by treatment with a reducing agent such as DTT (dithiothreitol) or tricarbonylethylphosphine (TCEP), such that the antibody is fully or partially reduced. In some cases, each cysteine bridge will thus form, theoretically, two reactive thiol nucleophiles. In some cases, additional nucleophilic groups can be introduced into Targeting units such as antibodies (and antigen binding portions and other binding agents (including non-antibody scaffolds)) throughmodification of lysine residues, e.g., by reacting lysine residues with 2 -iminothiolane (Traut'sreagent), resulting in conversion of an amine into a thiol. In some cases, reactive thiol groups may also be introduced into a Targeting unit (such as an antibody and antigen binding portions and other binding agents (including non-antibody scaffolds)) by introducing one, two, three, four, or more cysteine residues (e.g., by preparing antibodies, antigen binding portions and other binding agents (including non-antibody scaffolds) comprising one or more non-native cysteine amino acid residues).

[0253] In some embodiments, conjugates may also be produced by reaction between an electrophilic group on a Targeting unit, such as an aldehyde or ketone carbonyl group, with a nucleophilic group on a Linker or Drug-Linker. In some cases, useful nucleophilic groups on a linker reagent include, but are not limited to, hydrazide, oxime, amino, hydrazine, thiosemicarbazone, hydrazine carboxyl, and arylhydrazide. In some cases, an antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)) is modified to introduce electrophilic moieties that are capable of reacting with nucleophilic substituents on a Linker or Drug-Linker. In some cases, the sugars of glycosylated antibodiesmay be oxidized, e.g. with periodate oxidizing reagents, to form aldehyde or ketone groups which may react with the amine group of a Linker or Drug-Linker. In some cases, the resulting imine Schiff base groups may form a stable linkage, or may be reduced, e.g., by borohydride reagents to form stable amine linkages. In some cases, reaction of the carbohydrate portion of a glycosylated antibody with either galactose oxidase or sodium meta-periodate may yield carbonyl (aldehyde and ketone) groups in the antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)) that can react with appropriate groups on the Linker or Drug-Linker (see, e.g., Hermanson, Bioconjugate Techniques).

[0254] In some embodiments, exemplary nucleophilic groups on a Drug, such as a cytotoxic agent, include, but are not limited to: amine, thiol, hydroxyl, hydrazide, oxime, hydrazine, thiosemicarbazone, hydrazine carboxyl, and arylhydrazide groups capable of reacting to form covalent bonds with electrophilic groups on a Linker including: (i) active esters such as NHS esters, HOBt esters, haloformates, and acid halides; (ii) alkyl and benzyl halides such as haloacetamides; (iii) aldehydes, ketones, carboxyl, and maleimide groups, ultimately forming a Drug-Linker or a conjugate.

[0255] In some embodiments, a Linker or Drug-Linker is attached to an interchain cysteine residue(s) of an antibody (or antigen binding portion thereof or other binding agent (including non-antibody scaffolds)). In some cases, the Linker or Drug-Linker typically comprises a maleimide group for attachment to the cysteine residues of an interchain disulfide. In some cases, a Linker or Drug-Linker is attached to a cysteine residue(s) of an antibody or antigen binding portion thereof.

[0256] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein.

[0257] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. The drug-linkers in the example section can be conjugated to an antibody to form an antibody-drug-conjugate (i.e., conjugate) EXAMPLES

[0258] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors orsynthesized according to sources known to those skilled in the art or prepared as described herein. Preparation of Drug Linkers Example 1A: Synthesis of compound A (Fmoc-Asp-Sar-(Asp(OAll)-Sar)4-NH2)

[0259] Compound A was prepared as shown in scheme 1A. Scheme 1A

[0260] To a solution of Fmoc-Asp(OAll)-OH (1-A, 1.2 g, 3 mmol) in anhydrous DMF (10 mL) was added TSTU (0.91 g, 3 mmol), followed by DIEA (1.05 mL). The mixture was stirred at room temperature for 10 min. A solution of Sarcosine (0.36 g) in acetonitrile / water (1 / 1, 3 mL) was added, followed by DIEA (0.7 mL). The reaction mixture was stirred at room temperature for 30 min, and the crude product was purified directly by RP-HPLC to give compound 2-A as a white powder (1.2 g) after lyophilization.

[0261] To a solution of Fmoc-Asp(OtBu)-OH (3-A, 0.41 g, 1 mmol) in anhydrous DMF (3 mL) was added TSTU (0.31 g, 1 mmol), followed by DIEA (0.35 mL). The mixture was stirred at room temperature for 10 min. A solution of Sarcosine (0.1 g) in acetonitrile / water (1 / 1, 1 mL) was added, followed by DIEA (0.2 mL). The reaction mixture was stirred at room temperature for 30 min, and the crude product was purified directly by RP-HPLC to give compound 4-A as a white powder (0.42 g) after lyophilization.

[0262] The resin bound peptide 6-A was synthesized on a Fmoc-Rink Amide MBHA resin (5-A, 0.7 mmol / g, 0.3 g) following the standard Fmoc SPPS strategy using compound 2-A and compound 4-A as building blocks. The resin bound compound 6-A was treated with neat TFA at room temperature for 30 min. The polymer was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by RP-HPLC to give compound A as a white powder (0.15 g). Example 2A: Synthesis of compound B (Fmoc-Glu-Sar-(Glu(OAll)-Sar)4-NH2)

[0263] Compound B was prepared as shown in scheme 2. Scheme 2A

[0264] To a solution of Fmoc-Glu(OAll)-OH (1-B, 1.23 g, 3 mmol) in anhydrous DMF (10 mL) was added TSTU (0.91 g, 3 mmol), followed by DIEA (1.05 mL). The mixture was stirred at room temperature for 10 min. A solution of Sarcosine (0.36 g) in acetonitrile / water (1 / 1, 3 mL) was added, followed by DIEA (0.7 mL). The reaction mixture was stirred at room temperature for 30 min, and the crude product was purified directly by RP-HPLC to give compound 2-B as a white powder (1.26 g) after lyophilization.

[0265] To a solution of Fmoc-Glu(OtBu)-OH (3-B, 0.43 g, 1 mmol) in anhydrous DMF (3 mL) was added TSTU (0.31 g, 1 mmol), followed by DIEA (0.35 mL). The mixture was stirred at room temperature for 10 min. A solution of Sarcosine (0.1 g) in acetonitrile / water (1 / 1, 1 mL) was added, followed by DIEA (0.2 mL). The reaction mixture was stirred at room temperature for 30 min, and the crude product was purified directly by RP-HPLC to give compound 4-B as a white powder (0.44 g) after lyophilization.

[0266] The resin bound peptide 5-B was synthesized on a Fmoc-Rink Amide MBHA resin (5-A, 0.7 mmol / g, 0.3 g) following the standard Fmoc SPPS strategy using compound 2-B and compound 4-B as building blocks. The resin bound compound 5-B was treated with neat TFA at room temperature for 30 min. The polymer was filtered off and the filtrate was concentratedunder reduced pressure. The residue was purified by RP-HPLC to give compound B as a white powder (0.14 g). Example 1B: Synthesis of Drug-Linker compound 1

[0267] Drug-Linker compound 1 scheme 1B. Scheme 1B

[0268] To a solution of compound 1-1 (TFA salt, 19 mg, 19 umol) in anhydrous DMF (1 mL) was added compound A (25 mg, 19 umol), PyAOP (10 mg, 19 umol) and DIEA (13 uL). The mixture was stirred at room temperature for a period of 10 min. Then piperidine (80 uL) was added and the stirring continued for an additional 10 min. Then the mixture was purified directly by RP-HPLC to give compound 1-2 as a TFA salt which was dissolved in DMF (1 mL). To this solution, pyrrolidine (15 mg) was added, followed by Pd(PPh3)4(2 mg), and the mixture was stirred under Argon atmosphere. After 15 mins, the mixture was purified directly by RP- HPLC to give compound 1-3 as a yellow solid.

[0269] To a solution of compound 1-3 (TFA salt, 29 mg, 15 umol) in anhydrous DMF (1 mL) was added compound 1-4 (6 mg, 18 umol) and DIEA (15 uL). The mixture was stirred at room temperature for a period of 10 min. Then the mixture was purified directly by RP-HPLC to give Drug-Linker compound 1 as a pale-yellow solid. Example 2B: Synthesis of Drug-Linker compound 2

[0270] Drug-Linker compound 2 scheme 2B.Scheme 2B

[0271] To a solution of compound 1-1 (TFA salt, 19 mg, 19 umol) in anhydrous DMF (1 mL) was added compound B (27 mg, 19 umol), PyAOP (10 mg, 19 umol) and DIEA (13 uL). The mixture was stirred at room temperature for a period of 10 min. Then piperidine (80 uL)was added and the stirring continued for an additional 10 min. Then the mixture was purified directly by RP-HPLC to give compound 2-1 as a TFA salt To this solution, pyrrolidine (15 mg) was added, followed by Pd(PPh3)4(2 mg), and the mixture was stirred under Argon atmosphere. After 15 mins, the mixture was purified directly by RP-HPLC to give compound 2-2 as a yellow solid.

[0272] To a solution of compound 2-2 (TFA salt, 28 mg, 14 umol) in anhydrous DMF (1 mL) was added compound 1-4 (6 mg, 18 umol) and DIEA (15 uL). The mixture was stirred at room temperature for a period of 10 min. Then the mixture was purified directly by RP-HPLC to give Drug-Linker compound 2 as a pale-yellow solid.

[0273] Drug-Linker 3Example 2C: Synthesis of Drug-Linker 3

[0274] Compound 3-1:

[0275] To a solution of compound 1-1 (TFA salt, 30 mg, 30 umol) in anhydrous DMF (2 mL) was added compound C (35 mg, 30 umol), PyAOP (16 mg, 30 umol) and DIEA (22 uL). The mixture was stirred at room temperature for a period of 10 min. Then piperidine (100 uL) was added and the stirring continued for an additional 10 min. Then Pd(PPh3)4 (8 mg, 7 umol) was added and the mixture was stirred for another 10 min. Then the mixture was purified directly by RP-HPLC to give compound 3-1as a TFA salt (37 mg, 67%).

[0276] Compound 3

[0277] To a solution of compound 3-1 (TFA salt, 37 mg, 20 umol) in anhydrous DMF (2 mL) was added compound 1-4 (7 mg, 20 umol) and DIEA (17 uL). The mixture was stirred at room temperature for a period of 20 min. Then the mixture was purified directly by RP-HPLC to give compound 3 as a pale-yellow solid (26 mg, 69%). Example 2D: Synthesis of Drug-Linker 4

[0278] Compound 4-1: To a solution of compound 1-1 (TFA salt, 30 mg, 30 umol) in anhydrous DMF (2 mL) was added compound D (37 mg, 30 umol), PyAOP (16 mg, 30 umol) and DIEA (22 uL). The mixture was stirred at room temperature for a period of 10 min. Then piperidine (100 uL) was added and the stirring continued for an additional 10 min. Then Pd(PPh3)4 (8 mg, 7 umol) was added and the mixture was stirred for another 10 min. Then the mixture was purified directly by RP-HPLC to give compound 4-1 as a TFA salt (41 mg, 73%).

[0279] Compound 4:

[0280] To a solution of compound 4-1 (TFA salt, 38 mg, 20 umol) in anhydrous DMF (2 mL) was added compound 1-4 (7 mg, 20 umol) and DIEA (17 uL). The mixture was stirred atroom temperature for a period of 20 min. Then the mixture was purified directly by RP-HPLC to give compound 4 as a pale-yellow solid (27 mg, 71%).

[0281] Drug-Linker 5

[0284] Drug-Linker 7 was prepared as described in PCT / US2024 / 036950.

[0285] GGFG-ExaPreparation of Antibodies Example 2: 5T4 Antibodies

[0286] The 5T4 antibody is a human IgG1 / kappa antibody. The 5T4 antibod ies wereexpressed transiently in CHO-K1 cells and was purified in a single step using protein A chromatography resin and the final buffer composition was 20 mM histidine, 150 mM sodiumchloride, pH 5.5 (WuXi Biologics). The heavy chain and light chain sequences o f various 5T4antibodies are shown below. Table A. Antibodies and Corresponding SequencesExample 3: ROR2 Antibodies

[0287] The ROR2 described herein (e.g., Table B) are described and prepared as described PCT / US2024 / 036950. Table B. Antibodies and Corresponding SequencesExample 4: Preparation of Antibody-Drug-Conjugates

[0288] The conjugates are prepared using the followed conditions using the appropriate Drug-Linker and antibody (e.g., ROR2 antibody or 5T4 antibody).

[0289] 50 mg of mAb(s) for conjugation in various formulations were pH adjusted or buffer exchanged into 5% (v / v) 0.5 M Tris, 0.025 M EDTA, pH 8.5 formulations for reduction. The addition of 0.025 M EDTA in the formulation buffer is added to prevent metal-catalysed disulphide reoxidation.10 mM TCEP (7 M eq.) is added to reduce a target number of interchain disulphide bonds and generate the desired average number of free thiols per mAb for 90 min at 25 °C. The free thiols are conjugated with an excess of maleimide (MC) containing toxin linker dissolved in a water miscible solvent (12 eq. of 20 mM MC-linker in 10% DMA) for 60 min at 25 °C. Extra solvent is added prior to toxin linker to maintain solubility of the toxin linker upon addition and mixing is performed utilizing stir flasks. Conjugation is ended by the addition of anexcess of NAC (110 mM) and further stirred for 30 min to quench unreacted maleimide. Excess quenched toxin linker is removed by incubation with activated carbon for 60 min at room temperature at 15 rpm and / or diafiltration. Conjugates (yields, 93-97%) are exchanged into the final formulation buffer (0.1 M Arg / PBS, pH 7.4) and filtered through 0.22 μm PES before aliquoting and storage at ≤ -60 °C. Example 5: Antibody Drug Conjugates Preparation of ADC-1 using Drug-linker 2 and 5T4-7EL Antibody

[0290] ADC-1 was synthesized using Drug-linker 1 in combination with 5T4-7EL antibody.; wherein the DAR value as determined by RP-HPLC was 8. Preparation of ADC-2 using Drug-linker 2 and 5T4-7EL Antibody

[0291] ADC-2 was synthesized using Drug-linker 2 in combination with 5T4-7EL antibody using example 4.; wherein the DAR value as determined by RP-HPLC was 8.Preparation of ADC-3 using Drug-linker 3 and Ab1 (ROR2) Antibody

[0292] ADC-3 was synthesized using Drug-linker 3 in combination with Ab1 (ROR2) antibody using example 4.wherein the DAR value as determined by RP-HPLC was 8 and wherein ROR2 is Ab1. Preparation of ADC-4 using Drug-linker 4 and Ab1 (ROR2) Antibody

[0293] ADC-4 was synthesized using Drug-linker 4 in combination with Ab1 (ROR2) antibody using example 4.; wherein the DAR value as determined by RP-HPLC was 8. Preparation of ADC-R using Drug-Linker 7 and Ab1 (ROR2) Antibody

[0294] ADC-R was synthesized using Drug-Linker 7 in combination with Ab1 (ROR2) antibody using example 4.; wherein the DAR value as determined by RP-HPLC was 8. Preparation of ADC-T using Drug-Linker 7 and 5T4-7EL Antibody

[0295] ADC-T was synthesized using Drug-Linker 7 in combination with 5T4-7EL antibody using example 4.; wherein the DAR value as determined by RP-HPLC was 8. Example 6: DAR by RP-HPLC

[0296] RP-HPLC of the ADCs is used to determine the drug to antibody ratio (DAR) of each ADC. Fig.11 shows the retention time of various drug-linkers. The retention times show the relative hydrophobicity of the various drug-linkers. The hydrophobicity increases as follows: 1 < 2< GGFG-Exa.

[0297] RP-HPLC conditions: Column – Phenomenex Kinetex 100 Å, 50 x 4.6 mm, 2.6 µm, Part Number: PL1912-1502. MPA – 0.1% TFA / H20, MPB – 0.1% TFA / CAN.

[0298] Method: Flow rate – 1 mL / min, Gradient – see Table C. Column temp. – 50 C.

[0299] Sample temp – RT. DAD 214 nm, BW 16 nm; Reference 440 nm, BW 80 nm; Peak width > 0.4 min (8 s response time (0.62 Hz); Spectrum: 200 – 600 nm, step 1.2 nm, slit 8 nm.

[0300] Sample – neat injection, ~ 5 μg. Table C: RP-HPLC Method Flow rate GradientExample 7: Cellular Binding

[0301] The ability of various ROR2 ADCs to bind to LCLC-103H cells and 5T4 ADCs to bind to H520 cells were measured using in vitro cellular binding assay.

[0302] For each LCLC-103H cell line, 0.5 million cells were plated in 50 µL on each well of a 96-well deep-well plate (Thermo Scientific #249946). A 1:3 dilution series of primary antibody was made starting with 1-µg / mL starting stock. Thereafter, 50 μL of different concentrations of primary antibody (from 17 pg / mL to 1000 ng / mL final concentration) were placed over the 50 µL containing the cells. Cells and antibodies were mixed and incubated on ice for 20 minutes. For the first wash, 300 µL of FACS buffer was added and cells were centrifuged at 500 × g for 5 minutes at 4 ºC. The supernatant was discarded, and cells were resuspended in 400 µL of FACS buffer for an additional wash. After the second wash, cells were resuspended in 100 µL of goat anti-human IgG secondary phycoerythrin (PE) antibodies (ThermoFisher Scientific #12-4998-82) at 1 µg / mL final concentration and incubated on ice (in the dark) for 20 minutes. Cells were washed twice as described previously and analyzed on the BD FACSVerse with Flowjo software, Version 10. The percentage of maximal binding relativeto the highest concentration was graphed and half -maximal effective concentrations (EC50)values were determined using GraphPad Prism Version 7 and shown in Table D and binding percentage of each ADC plotted in FIG.2 and FIG.6. FIG.1 and FIG.5 shows the mean fluorescence intensity of each ADC. Table D.Example 8: Cytotoxicity measurement

[0303] The ability of various ROR2 conjugates and 5T4 conjugates to inhibit cell growth was measured using an in vitro cytotoxicity assay.

[0304] LCLC-103H cells, H520 cells, and MDA-MB-468 were cultured in log phase growth and split into 96-well plates. Each cell-line was plated at a slightly different concentration but ranged from 5x103to 50x104cells / well. Cells, in duplicate, were incubated with 3-fold serial dilution of a particular immunoconjugate starting at 3000 or 1000 nanomolar (3000, 1000, 333, 111, 37, 12.3, 4.1, 1.37, 0.46, 0.15 nanomolar) for 72 hours at 37° C and 5% CO2. After treatment the cells were incubated with an equal volume of CellTiter-Glo® reagent (Promega Inc.) for 15 minutes at room temperature, and viability was determined by a luminometer. EC50 values were shown in Table E and percentage of inhibition plotted in FIG.4 (LCLC-103H), FIG.8 (H520), and FIG.9 (MDA-MB-468). Table E.Example 9: Internalization

[0305] LCLC-103H cells and H520 cells were harvested, washed with cold PBS and resuspended at a concentration of 1 × 107cells / mL in cold FACS buffer comprising PBS and 2% FBS. Aliquots of 1 × 106cells were added to microcentrifuge tubes or wells. Primary antibodywas diluted to create 10× stock solutions of 300 µg / mL or 1 mg / mL to allow addition of 10 µl of each solution to the appropriate tubes.

[0306] Control groups comprised of unstained and secondary antibody only (goat anti- human IgG-PE, Fc-gamma specific) (ThermoFisher Scientific #12-4998-82). Test groups comprised cells subjected to the following conditions with evaluation at 30 µg / mL (203 nM) or 100 µg / mL (676 nM) of primary antibody depending upon the experiment: Cells were kept on ice for 20 minutes in addition to controls centrifuged at 300 × g for 4 minutes, washed twice with 200 µl FACS buffer, resuspended in 100 µl of FACS buffer, and incubated at 37°C for 30, 60, 120, or 240 minutes. After incubation, cells were centrifuged at 250 × g and washed twicewith FACS buffer and resuspended in 100 µl of FACS buffer. A 10× stock of the secondaryantibody was diluted 1:2000 in FACS buffer and 10 µl per tube was added to the appropriate tubes. Cells were incubated on ice for 20 minutes, washed twice with FACS buffer and resuspended in 100 µl of fixation buffer (4% paraformaldehyde in PBS). FACS analysis was then performed, assessing median fluorescence intensity (MFI). The relative magnitude of primary antibody internalization was determined by comparing MFI values for each timepoint with that for the primary antibody control at Time 0 are shown in FIG.3 (LCLC-103H) and FIG.7 (H520). Example 10: In Vivo efficacy

[0307] The antitumor activity of ADCs was evaluated in the xenograft models of LCLC- 103H (NSCLC). The tumor bearing mice were randomized based on their individual tumor and given iv injection dose. As shown in FIG.10, at 5 mg / kg, once weekly iv injection dose for 3 weeks (days 0, 8, 16), ADCs were shown to have antitumor activity in LCLC-103H model.SEQUENCES

[0308] The table below shows sequences described herein (SEQ: SEQ ID NO). Table S

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A Drug-Linker of Formula (X):or a pharmaceutically acceptable salt thereof, wherein: D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

2. The Drug-Linker or salt of claim 1, wherein Formula (X) is represented by the structure of Formula (X-I)Formula (X-I), or a pharmaceutically acceptable salt thereof.

3. The Drug-Linker of claim 1 or claim 2, wherein the optionally substituted C1-C30alkylene of S1is linear.

4. The Drug-Linker of any one of claims 1 to 3, wherein S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(H)C(O)–.

5. The Drug-Linker of any one of claims 1 to 4, wherein S1is selected from -NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-.

6. The Drug-Linker of any one of claims 1 to 5, wherein S1is selected from -NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-, and wherein S2is bound to one of the alkylene.

7. The Drug-Linker of any one of claims 1 to 6, wherein S1-S2-K1is.

8. The Drug-Linker of any one of claims 1 to 7, wherein S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –C(O)–.

9. The Drug-Linker of any one of claims 1 to 8, wherein S2is selected from an optionally substituted C1-C6alkylene wherein one or more alkylene units of the C1-C6alkylene are optionally and independently replaced by –C(O)–.

10. The Drug-Linker of any one of claims 1 to 9, wherein S2 is.

11. The Drug-Linker of any one of claims 1 to 10, wherein S1-S2-K1is.

12. The Drug-Linker of any one of claims 1 to 11, wherein Formula (X) or Formula (X-I) is represented by the structure of Formula (X-II)Formula (X-II), or a pharmaceutically acceptable salt thereof.

13. The Drug-Linker or salt of any one of claims 1 to 12, wherein the sugar cleavable unit of T1includes a sugar.

14. The Drug-Linker or salt of any one of claims 1 to 13, wherein the sugar is glucuronide.

15. The Drug-Linker or salt of any one of claims 1 to 14, wherein.

16. The Drug-Linker or salt of any one of claims 1 to 12, wherein the peptide unit of T2includes one or more amino acids selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine.

17. The Drug-Linker or salt of any one of claims 1 to 12 or 16, wherein the peptide unit of T2includes a dipeptide or tripeptide.

18. The Drug-Linker or salt of any one of claims 1 to 12, 16, or 17, wherein the peptide unit of T2includes a dipeptide.

19. The Drug-Linker or salt of any one of claims 1 to 12 or 16 to 18, wherein the dipeptide is selected from Val-Cit, Val-Ala, and Phe-Lys.

20. The Drug-Linker or salt of any one of claims 1 to 12 or 16 to 19, wherein the peptide unit of T2includes a capping moiety.

21. The Drug-Linker or salt of claim 20, wherein the capping moiety is.

22. The Drug-Linker or salt of any one of claims 1 to 12 or 16 to 21, wherein Y1is.

23. The Drug-Linker or salt of any one of claims 1 to 11, wherein Y1is absent.

24. The Drug-Linker or salt of any one of claims 1 to 23, wherein the peptide unit of K1comprises at least one amino acid selected from glutamic acid, or wherein the peptide unit of K1comprises at least one amino acid selected from aspartic acid.

25. The Drug-Linker or salt of any one of claims 1 to 24, wherein the peptide unit of K1comprises at least one amino acid selected from glutamic acid.

26. The Drug-Linker or salt of any one of claims 1 to 24, wherein the peptide unit of K1comprises at least one amino acid selected from aspartic acid.

27. The Drug-Linker or salt of any one of claims 24 to 26, wherein the peptide unit has 1 to 20 amino acids.

28. The Drug-Linker or salt of claim 27, wherein the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine,glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine.

29. The Drug-Linker or salt of claim 28, wherein the peptide unit of K1has amino acids further selected from the group consisting of glycine, sarcosine, glutamic acid and aspartic acid.

30. The Drug-Linker or salt of any one of claims 1 to 29, wherein the peptide unit of K1has a terminus unit.

31. The Drug-Linker or salt of any one of claims 1 to 30, wherein K1is selected fromselected from 1 to 10.

32. The Drug-Linker or salt of any one of claims 1 to 31, wherein K1is selected from,wherein the terminus unit is represented by R6, and each j is selected from 1 to 10.

33. The Drug-Linker or salt of any one of claims 1 to 31, wherein K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10.

34. The Drug-Linker or salt of any one of claims 31 to 33, wherein R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, - OC(O)R30, -S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle.

35. The Drug-Linker or salt of any one of claims 31 to 34, wherein R6is selected from -OH,36. The Drug-Linker or salt of any one of claims 1 to 35, wherein K1is selected from ,,37. The Drug-Linker or salt of any one of claims 1 to 36, wherein K1is selected from , ,38. The Drug-Linker or salt of any one of claims 1 to 36, wherein K1is selected from ,,,39. The Drug-Linker or salt of any one of claims 1 to 36, wherein K1is selected from ,40. The Drug-Linker or salt of any one of claims 1 to 36, wherein K1is selected from,41. The Drug-Linker or salt of any one of claims 1 to 34, 37, or 40, wherein K1is selected.

42. The Drug-Linker or salt of any one of claims 1 to 34, 37, or 39, wherein K1is selected f.

43. The Drug-Linker or salt of any one of claims 1 to 34, 38, or 40, wherein K1is selected.

44. The Drug-Linker or salt of any one of claims 1 to 34, 38, or 39, wherein K1is selected.

45. The Drug-Linker or salt of any one of claims 1 to 30, wherein each K1is selected fromselected from 2 to 5.

46. The Drug-Linker or salt of any one of claims 1 to 30 or 45, wherein each K1is selected fwherein the terminus unit is represented by R6, and each j is selected from 2 to 5.

47. The Drug-Linker or salt of any one of claims 1 to 30 or 45, wherein each K1is selected, wherein the terminus unit is represented by R6, and each j is selected from 2 to 5.

48. The Drug-Linker or salt of any one of claims 45 to 47, wherein each R6is selected from -49. The Drug-Linker or salt of claim 48, wherein R6is -OH.

50. The Drug-Linker or salt of claim 48, wherein R6is -NH2.

51. The Drug-Linker or salt of any one of claims 1 to 50, wherein M1is selected from maleimide, halogen, COOH,, azide, , activated group,, OH, SH, activated disulfide group, NH2, and -ONH2, preferably .

52. The Drug-Linker or salt of claim 51, wherein the activated group is selected from53. The Drug-Linker or salt of claim 51, wherein the activated disulfide group is selected.

54. The Drug-Linker or salt of any one of claims 1 to 53, wherein the D is selected from a cytotoxic agent, an immune modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope and a chelating ligand.

55. The Drug-Linker or salt of any one of claims 1 to 54, wherein the D is selected from acytotoxic agent, camptothecin derivative, and an immune modulatory agent.

56. The Drug-Linker or salt of any one of claims 1 to 55, wherein the Drug unit is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE).

57. The Drug-Linker or salt of any one of claims 1 to 56, wherein D is.

58. A conjugate comprising a Drug-Linker or salt of any one of claims 1 to 57, and a Targeting Unit, wherein M1of the Drug-Linker reacts and forms a covalent bond to the Targeting Unit.

59. The conjugate of claim 58, wherein the Targeting unit is selected from an antibody or an antigen-binding portion thereof.

60. The conjugate of claim 58 or claim 59, having an average ratio of Drug-Linker to Targeting unit of about 1 to 10.

61. A pharmaceutical composition comprising a conjugate of any one of claims 58 to 60 and a pharmaceutically acceptable excipient.

62. A method of treating a subject with a cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 58 to 60 or the pharmaceutical composition of claim 61.

63. A conjugate of the Formula (XX):Formula (XX), or a pharmaceutically acceptable salt thereof, wherein: D is a Drug unit; Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit;T2is peptide cleavable unit; L is a Targeting Unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, – C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M2, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M2is a connector unit; K1is selected from:(i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle.

64. The conjugate or salt of claim 63, wherein Formula (XX) is represented by the structure of Formula (XX-I)Formula (XX-I), or a pharmaceutically acceptable salt thereof.

65. The conjugate or salt of claim 63 or claim 64, wherein S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(H)C(O)–.

66. The conjugate or salt of any one of claims 63 to 65, wherein S1is selected from -NH- C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-.

67. The conjugate or salt of any one of claims 63 to 66, wherein S1is selected from -NH- C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-NH-C(O)-C1-C6alkylene-, and wherein S2is bound to one of the alkylene.

68. The conjugate or salt of any one of claims 63 to 67, wherein S1-S2-K1is selected from.

69. The conjugate or salt of any one of claims 63 to 68, wherein S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –C(O)–.

70. The conjugate or salt of any one of claims 63 to 69, wherein S2is selected from an optionally substituted C1-C6alkylene wherein one or more alkylene units of the C1-C6alkylene are optionally and independently replaced by –C(O)–.

71. The conjugate or salt of any one of claims 63 to 70, wherein S2.

72. The conjugate or salt of any one of claims 63 to 71, wherein S1-S2-K1is.

73. The conjugate or salt of claim 63 or claim 64, wherein Formula (XX) or Formula (XX-I) is represented by the structure of Formula (XX-II)Formula (XX-II), or a pharmaceutically acceptable salt thereof.

74. The conjugate or salt of any one of claims 63 to 73, wherein the sugar cleavable unit of T1includes a sugar.

75. The conjugate or salt of any one of claims 63 to 74, wherein the sugar is glucuronide.

76. The conjugate or salt of any one of claims 63 to 75, wherein.

77. The conjugate or salt of any one of claims 63 to 73, wherein the peptide unit of T2includes one or more amino acids selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine.

78. The conjugate or salt of any one of claims 63 to 73 or 77, wherein the peptide unit of T2includes a dipeptide or tripeptide.

79. The conjugate or salt of any one of claims 63 to 73, 77, or 78, wherein the peptide unit of T2includes a dipeptide.

80. The conjugate or salt of any one of claims 63 to 73 or 77 to 79, wherein the dipeptide is selected from Val-Cit, Val-Ala, and Phe-Lys.

81. The conjugate or salt of any one of claims 63 to 73 or 77 to 80, wherein the peptide unit of T2includes a capping moiety.

82. The conjugate or salt of claim 81, wherein the capping moiety is.

83. The conjugate or salt of any one of claims 63 to 73 or 77 to 82, wherein Y1is.

84. The conjugate or salt of any one of claims 63 to 73, wherein Y1is absent.

85. The conjugate or salt of any one of claims 63 to 84, wherein the peptide unit of K1comprises at least one amino acid selected from glutamic acid, or wherein the peptide unit of K1comprises at least one amino acid selected from aspartic acid.

86. The conjugate or salt of any one of claims 63 to 85, wherein the peptide unit of K1comprises at least one amino acid selected from glutamic acid.

87. The conjugate or salt of any one of claims 63 to 85, wherein the peptide unit of K1comprises at least one amino acid selected from aspartic acid.

88. The conjugate or salt of any one of claims 85 to 87, wherein the peptide unit of K1has 1 to 20 amino acids.

89. The conjugate or salt of claim 88, wherein the peptide unit of K1has amino acids further selected from a group consisting of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, sarcosine, serine, threonine, tryptophan, tyrosine, valine, citrulline, and β-Alanine.

90. The conjugate or salt of claim 89, wherein the peptide unit of K1has amino acids further selected from the group consisting of glycine, sarcosine, proline, glutamic acid and aspartic acid.

91. The conjugate or salt of any one of claims 63 to 90, wherein the peptide unit of K1has a terminus unit.

92. The conjugate or salt of any one of claims 63 to 91, wherein K1is selected from,, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10.

93. The conjugate or salt of any one of claims 63 to 92, wherein K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10.

94. The conjugate or salt of any one of claims 63 to 92, wherein K1is selected from,, wherein the terminus unit is represented by R6, and each j is selected from 1 to 10.

95. The conjugate or salt of any one of claims 92 to 94, wherein R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, - OC(O)R30, -S(O)R30, -S(O)2R30, -O-S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle.

96. The conjugate or salt of claims 92 to 95, wherein R6is selected from -OH, -NH2, and.

97. The conjugate or salt of any one of claims 63 to 96, wherein K1is selected from ,,98. The conjugate or salt of any one of claims 63 to 97, wherein each K1is selected from99. The conjugate or salt of any one of claims 63 to 97, wherein each K1is selected from , ,100. The conjugate or salt of any one of claims 63 to 97, wherein K1is selected from , ,101. The conjugate or salt of any one of claims 63 to 97, wherein K1is selected from,,102. The conjugate or salt of any one of claims 63 to 97, 98, or 101, wherein K1is selected.

103. The conjugate or salt of any one of claims 63 to 97, 98, or 100, wherein K1is selected.

104. The conjugate or salt of any one of claims 63 to 97, 99, or 101, wherein K1is selected.

105. The conjugate or salt of any one of claims 63 to 97, 99, or 100, wherein K1is selected.

106. The conjugate or salt of any one of claims 63 to 91, wherein each K1is selected from ,,selected from 2 to 5.

107. The conjugate or salt of any one of claims 63 to 91 or 106, wherein each K1is selected, wherein the terminus unit is represented by R6, and each j is selected from 2 to 5.

108. The Drug-Linker or salt of any one of claims 63 to 91 or 106, wherein each K1is, wherein the terminus unit is represented by R6, and each j is selected from 2 to 5.

109. The conjugate or salt of any one of claims 106 to 108, wherein each R6is selected from -110. The conjugate or salt of claim 109, wherein R6is -OH.

111. The conjugate or salt of claim 109, wherein R6is -NH2.

112. The conjugate or salt of any one of claims 63 to 111, wherein M2is selected from.

113. The conjugate or salt of any one of claims 63 to 112, wherein.

114. The conjugate or salt of claims 63 to 113, wherein the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; and.

115. The conjugate or salt of claims 63 to 114, wherein the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; and.

116. The conjugate or salt of claims 63 to 114, wherein the conjugate is selected fromwherein L is the Targeting Unit; and DAR is a drug to Targeting Unit ratio; and.

117. The conjugate or salt of any one of claims 114 to 116, wherein the conjugate is selected from.

118. The conjugate or salt of any one of claims 63 to 117, wherein the Targeting unit is selected from an antibody or an antigen-binding portion thereof.

119. The conjugate of any one of claims 63 to 118, wherein the Targeting unit is a monoclonal antibody.

120. The conjugate of claim 118 or claim 119, wherein the antibody is an anti-5T4 antibody.

121. The conjugate of claim 120, wherein the anti-5T4 antibody is selected from 5T4-1EL, 5T4-2EL, 5T4-3EL, 5T4-3EL-VL, 5T4-4EL, 5T4-5EL, 5T4-5EL-VH, 5T4-6EL, 5T4-7EL, 5T4- 8EL, 5T4-9, 5T4-9EL, 5T4-10EL, 5T4-11EL, 5T4-12EL, 5T4-13EL, 5T4-14EL, 5T4-15EL, 5T4-16, 5T4-17, 5T4-18, 5T4-19, 5T4-20, and 5T4-21.

122. The conjugate of claim 120 or claim 121, wherein the anti-5T4 antibody is 5T4-7EL.

123. The conjugate of claim 118 or claim 119, wherein the antibody is an anti-ROR2 antibody.

124. The conjugate of claim 123, wherein the anti-ROR2 antibody is selected from Ab1, Ab2, Ab3, and Ab4.

125. The conjugate of claim 123 or claim 124, wherein the anti-ROR2 antibody is Ab1.

126. The conjugate or salt of any one of claims 63 to 125, having an average ratio of Drug- Linker to Targeting unit (DAR) of about 1 to about 10.

127. The conjugate or salt of any one of claims 63 to 126, having an average ratio of Drug- Linker to Targeting unit (DAR) of about 2 to about 8.

128. The conjugate or salt of any one of claims 63 to 127, having an average ratio of Drug- Linker to Targeting unit (DAR) of about 8.

129. A Conjugate selected from Table AA-P and Table AA-G.

130. A Conjugate selected from Table AA-P.

131. A Conjugate selected from Table AA-G.

132. A pharmaceutical composition comprising a conjugate of any one of claims 63 to 131 and a pharmaceutically acceptable excipient.

133. A method of treating a subject with a disease or disorder, comprising administering to the subject in need thereof a therapeutically effective amount of a conjugate of any one of claims 63 to 131 or a pharmaceutical composition of claim 132.

134. The method of claim 133, wherein the disease or disorder is a cancer.

135. A method of treating a subject with a cancer, comprising administering to the subject in need thereof a conjugate of any one of claims 63 to 131 or a pharmaceutical composition of claim 132.

136. A method of treating a subject with a tumor, comprising administering to the subject in need thereof a conjugate of any one of claims 63 to 131 or a pharmaceutical composition of claim 132.

137. The method of claim 136, wherein the tumor is associated with a cancer.

138. Use of a conjugate, for treating a subject with a disease or disorder, comprising administering to the subject in need thereof a conjugate of any one of claims 63 to 131 or a pharmaceutical composition of claim 132.

139. The use of claim 138, wherein the disease or disorder is a cancer.

140. The method of any one of claims 134 to 139, wherein the cancer is selected from: cancers of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas; cancers of the liver and biliary tree, particularly hepatocellular carcinoma;intestinal cancers, particularly colorectal cancer; ovarian cancer; small cell and non -small celllung cancer (SCLC and NSCLC); breast cancer sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomysosarcoma, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma; leukemias such as acute promyelocytic leukemia (APL), acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML); neoplasms of the central nervous systems, particularly brain cancer; multiple myeloma (MM), lymphomas such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma.

141. The method of any one of claims 134 to 140, wherein the cancer is selected from melanoma, skin basal cell cancer, glioblastoma, glioma, gliosarcoma, astrocytoma, meningioma, neuroblastoma, adrenocortical cancer, head and neck cancer (e.g., cancer of the head, neck,nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx,and / or salivary glands, and paragangliomas), oral cancer, salivary gland cancer, nasopharyngealcancer, breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non -small cell lungcancer (NSCLC), small cell lung cancer, or squamous cell lung cancer), esophageal cancer, gastroesophageal junction cancer, gastric cancer, gastrointestinal cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, rectal cancer, colorectal carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, upper urinary tract cancer, urothelial cancer, renal cell carcinoma,kidney cancer, genitourinary cancer, cervical cancer, testicular cancer, prostate cancer,fibrosarcoma, liposarcoma, rhabdomyosarcoma (e.g., embryonal rhabdomyosarcoma), leiomyosarcoma, neurofibrosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, osteosarcoma, histiocytoma (e.g., malignant fibrous histiocytoma), pancreatic cancer, endometrial cancer, cancer of the appendix, thyroid cancer, advanced Merkel cell cancer, multiple myeloma, sarcomas, choriocarcinoma, leukemia (e.g., erythroleukemia, acutelymphoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, chronic myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or mast cell leukemia), lymphoma (e.g., small lymphocytic lymphoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, diffuse large B cell lymphoma, lymphoplasmacytoid lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, T-cell anaplastic large cell lymphoma, follicular lymphoma, monocytic lymphoma, or HTLV- associated T cell leukemia / lymphoma), and mesothelioma.

142. The method of any one of claims 134 to 141, wherein the cancer is selected from cell lymphoma, non-small cell lung cancer, large-cell lung cancer, breast cancer, and small-cell lung cancer.

143. The method of any one of claims 134 to 141, wherein the cancer is cell lymphoma.

144. The method of any one of claims 134 to 141, wherein the cancer is non-small cell lung cancer.

145. The method of any one of claims 134 to 141, wherein the cancer is large-cell lung cancer.

146. The method of any one of claims 134 to 141, wherein the cancer is breast cancer.

147. The method of any one of claims 134 to 141, wherein the cancer is small-cell lung cancer.

148. A Linker of Formula (XXX):Formula (XXX) or a pharmaceutically acceptable salt thereof, wherein: Y1is absent or selected from -O-T1and -NH-T2; T1is a sugar cleavable unit; T2is a peptide cleavable unit; S1is selected from: (i) an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; (ii) optionally substituted C3-C30alkenylene, wherein one or more alkenylene units of the C3- C30alkenylene are optionally and independently replaced by –N(R20)–, –N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, –C(O)O–, –S–, –S(O)–, –S(O)2–, or –P(O)(R20)2; (iii) one or more amino acid(s); (iv) one or more N-substituted amino acid(s); (v) optionally substituted polyether; (vi) optionally substituted C3-C10carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene; S2is selected from an optionally substituted C1-C30alkylene wherein one or more alkylene units of the C1-C30alkylene are optionally and independently replaced by –N(R20)–, – N(R20)C(O)–, –C(O)N(R20)–, –N(R20)S(O)2–, – S(O)2N(R20)–, –O–, –C(O)–, –OC(O)–, – C(O)O–, –S–, –S(O)–, –S(O)2–, 5- to 6-membered heterocyclene, or –P(O)(R20)2–; S3is selected from a spacer, wherein S3is present or absent; wherein the optional substituents on M1, K1, S1, S2, and S3, are independently selected at each occurrence from: (i) halogen, -OR30, -N(R30)2, -SR30, -N(R30)2, -C(O)R30, -C(O)N(R30)2, - N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), and -CN; (ii) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, -N(R30)2, -C(O)R30, - C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, -S(O)2R30, -O- S(O)2OR30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C3-10carbocycle and 3- to 10-membered heterocycle; and (iii) C3-10carbocycle and 3- to 10-membered heterocycle each of which is optionally substituted with one or more substituents independently selected from halogen, -OR30, -SR30, - N(R30)2, -C(O)R30, -C(O)N(R30)2, -N(R30)C(O)R30,-C(O)OR30, -OC(O)R30, -S(O)R30, - S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -NO2, =O, =S, =N(R30), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; M1is a group which can react with a ligand to form a connector unit; K1is selected from: (i) a peptide unit, wherein the peptide unit comprises at least one amino acid selected from glutamic acid and aspartic acid; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycle; and each R30is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substitutedwith one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12- membered heterocycles; and R50is selected from hydroxy or a substituent capable of reacting with a nucleophilic group on a Drug.

149. The Linker or salt of claim 148, wherein Formula (XXX) is represented by the structure of Formula (XXX-I)Formula (XXX-I), or a pharmaceutically acceptable salt thereof.

150. The linker or salt of claim 148 or claim 149, wherein R50is.

151. The linker or salt of claims 148 or 149, wherein.

152. The linker of salt of claims 148 or 149, wherein R50is -NH2.

153. A Drug-Linker selected from Table A-P and Table A-G.

154. A Drug-Linker selected from Table A-P.

155. A Drug-Linker selected from Table A-G.

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