Conjugates and uses thereof

Abstract

Provided herein is method of treating a refractory cancer comprising administering to a subject in need thereof a conjugate of Formula (XX) or a pharmaceutically acceptable salt thereof, wherein L is a Targeting Unit and the rest of the variables of Formula (XX) are as defined in the application. Such compounds can be useful as anti-cancer agents.

Description

WSGR Docket No. 63125-728.601CONJUGATES AND USES THEREOF CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Patent Application No.63 / 760,033 filed on February 18, 2025; the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Refractory cancers (e.g., metaplastic breast cancer) are cancers that are resistant at the beginning of treatment, cancers that become resistant during treatment, and / or are cancers that reoccur. Metaplastic breast cancer (MBC) is a rare, aggressive form of breast cancer that is usually discovered as a fast-growing lump or mass in the breast and accounts for less than 1% of all breast cancers. MBC is typically diagnosed via a biopsy of the breast lump. Most metaplastic breast cancers have triple-negative receptor status, meaning MBC does not have high levels of the estrogen receptor, progesterone receptor, and HER2 gene / protein. Drugs that target these features of cancer cells do not work well against triple-negative cancers. Other treatment strategies are needed. The five-year survival rate of patients with metaplastic breast cancer is about 55%.SUMMARY OF THE INVENTION

[0003] There is a need for treating subjects having refractory cancers (e.g., metaplastic breast cancer). Provided herein are ADC conjugates that are effective in treating refractory cancers like metaplastic breast cancer.

[0004] In an aspect, the present disclosure provides a method of treating a refractory cancer comprising, administering a conjugate to a subject in need thereof, wherein the conjugate is represented by Formula (XX):MfS1DARFormula (XX) or a pharmaceutically acceptable salt thereof, wherein;L is a Targeting Unit;WSGR Docket No. 63125-728.601DAR is an integer from 1 to 20;D is a Drug unit;Y1is absent or selected from -O-T1and -NH-T2;T1is a sugar cleavable unit;T2is peptide cleavable unit;51is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-C30 alkenylene, wherein one or more alkenylene units of the C3- C30 alkenylene 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-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;52is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(0)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-;53is selected from a spacer, wherein S1is present or absent;wherein the optional substituents on M1, K1, S1, S2, and S1, 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, =0, =S, =N(R30), and -CN;(ii) Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle 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, -WSGR Docket No. 63125-728.601S(O)2R30, -P(O)(OR30)2, -OP(O)(OR30)2, -N02, =0, =S, =N(R30), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;M2is a connector unit;K1is selected from:(i) a peptide unit,(ii) an oligosaccharide; and(iii) a polyether;each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; andeach R30is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0005] In some embodiments, the refractory cancer is metaplastic breast cancer.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 be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “figure” and “FIG.” herein), of which:WSGR Docket No. 63125-728.601

[0008] FIG. 1 and FIG. 2 illustrate anti-tumor activity of ADC-1, ADC-2, and ADC-3 in metaplastic sub-type patient-derived xenograft (PDX) models;DETAILED DESCRIPTION OF THE INVENTION

[0009] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0010] 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

[0011] 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.

[0012] " 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 (z.e., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (z.e., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (z.e., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (z.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (z.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (z.e., Ci-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (z.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (z.e., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (z.e., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (z.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (z.e., C3-C5 alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl), 1 -methylpropyl ( ec-butyl), 2-m ethylpropyl (z.w-butyl),1,1 -dimethylethyl (tert-butyl), 1 -pentyl (zz-pentyl). The alkyl is attached to the rest of the molecule by a single bond.WSGR Docket No. 63125-728.601

[0013] The term “Cx-y” 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 term “Ci-ealkyl” 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 term -Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example -Ci-ealkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0014] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0015] " 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-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (z.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (z.e., C2-C6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (z.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0016] " 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 (z.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (z.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (z.e., C2-C6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (z.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0017] The terms “Cx-yalkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, 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-ealkenylene- 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 unsubstitutedWSGR Docket No. 63125-728.601alkynylene chain with from x to y carbons in the alkenylene chain. For example, -C2-ealkenylene- 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.

[0018] " 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 and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, zz-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, an alkylene comprises one to ten carbon atoms (i.e., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (z.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (z.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (z.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (z.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (z.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (z.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (z.e., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (z.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (z.e., C3-C5 alkylene).

[0019] " 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 (z.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (z.e., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (z.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (z.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (z.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenyleneWSGR Docket No. 63125-728.601comprises five to eight carbon atoms (z.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0020] " 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 the alkynylene 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 alkynylene comprises two to ten carbon atoms (z.e., C2-C10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (z.e., C2-C8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atom (z.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (z.e., Cs-Cs alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (z.e., C3-C5 alkynylene).

[0021] " 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, z.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel 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.

[0022] " 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.

[0023] " Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. " Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above.

[0024] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of 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,WSGR Docket No. 63125-728.601e.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 include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles 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.

[0025] “Carbocyclene” refers to a divalent carbocycle linking the rest of the molecule to a radical group.

[0026] 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.

[0027] " 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), norbomenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0028] " 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.

[0029] " Cycloalkylalkyl" refers to a radical of the formula -Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0030] " Cycloalkylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-cycloalkyl where Rcis an alkylene chain as described above.

[0031] Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro and iodo substituents.WSGR Docket No. 63125-728.601

[0032] 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, di chloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-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., tri chloromethane, 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 combinations of 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., l-chloro,2-fluoroethane.

[0033] " 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, l-fluoromethyl-2-fluoroethyl, and the like.

[0034] " Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-l-ol, butane- 1,4-diol, pentane- 1, 2, 4-triol, and the like.

[0035] " 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.

[0036] “Activatedc-cgroup” refers to a cyclic alkyne which is highly reactive due to ring strain towards azide group to form a triazole.

[0037] Activated disulfide group” refers to a disulfide which is capable to react with a thiol to form a new disulfide bond.

[0038] " 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.

[0039] “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-ringWSGR Docket No. 63125-728.601systems. 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.

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

[0041] " 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, / .<., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Hiickel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-WSGR Docket No. 63125-728.601aromatic 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 (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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(0)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 (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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(0)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 heteroaryl alkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N- NH2), -Rb-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)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(0)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.

[0046] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0047] 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 fromWSGR Docket No. 63125-728.601which 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, / ?-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.

[0048] 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.

[0049] 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.

[0050] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” 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)WSGR Docket No. 63125-728.601oils, 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.

[0051] 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.

[0052] 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 or condition, 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.

[0053] 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.

[0054] 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 may be a biological receptor or other structure of a cell such as a tumor antigen.

[0055] 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 chainWSGR Docket No. 63125-728.601constant region comprising three domains, CHI, 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. 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(l):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 Pltickthun, 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.

[0056] CDR Definitions from www.bioinf.org.uk / abs / info. html#cdrdef (Kabat numbering system for all, except Contact, which uses Chothia numbering system)CDR Kabat AbM Chothia Contact IMGT LI L24-L34 L24-L34 L26-L32 L30-L36 L27-L32 L2 L50-L56 L50-L56 L50-L52 L46-L55 L50-L51 L3 L89-L97 L89-L97 L91-L96 L89-L96 L89-L97 Hl H31-H35b H26-H35b H26-H32, H34 H30-H35b H26-H35b H2 H50-H65 H50-H58 H52-H56 H47-H58 H51-H56 H3 H95-H102 H95-H102 H96-H101 H93-H101 H93-H102

[0057] An antibody is said to “specifically bind” to an antigen X if the antibody binds to antigen X with a KD of 5 x 108M or less, more preferably 1 x 10-8M or less, more preferably 6x 109M or less, more preferably 3 109M or less, even more preferably 2x 109M 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 accomplished by replacement, addition, or deletion of one orWSGR Docket No. 63125-728.601more amino acids or by replacement of a domain with a domain from another immunoglobulin type, or a combination of the foregoing.

[0058] The terms “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 CHI 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 with part of the hinge region (see, for example, Abbas et al., Cellular and Molecular Immunology, 6th Ed., Saunders Elsevier 2007); (iv) a Fd fragment consisting of the VH and CHI 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.

[0059] 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 than antigen X). An isolated antibody that specifically binds antigen X may, however, have crossreactivity 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 crossreact with other (non-human) antigen X antigens. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0060] 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.WSGR Docket No. 63125-728.601

[0061] 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 from human 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.

[0062] The term “human monoclonal antibody” means an antibody displaying a single 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 human heavy chain transgene and a light chain transgene fused to an immortalized cell.

[0063] 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.

[0064] A “variant” antibody or antigen-binding portion has amino acid substitutions (which may be conservative or non-conservative) from a reference antibody or antigen-binding portion, but does not have substantially altered biologic activity from the reference antibody or antigenbinding portion. For example, the variant antibody or antigen-binding portion may retain at least 50%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the binding affinity of the referenceWSGR Docket No. 63125-728.601antibody or antigen-binding portion, or may exceed the binding affinity of the reference antibody or antigen-binding portion.

[0065] 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., IO’6M, IO’7M, IO’8M, IO’9M, IO’10M, 10’11M, IO’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.

[0066] As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

[0067] 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.

[0068] The term “cleavable sugar unit” or “sugar cleavable unit” can refer to a sugar moiety, preferably a glucuronide or a galactoside.

[0069] The term “peptide cleavable unit” can refer to a polypeptide, preferably a dipeptide or a tripeptide.

[0070] For preparation of suitable antibodies of the invention and for use according to the invention, e.g., recombinant, monoclonal, or polyclonal antibodies, many techniques known in the art can be used (see, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp. 77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies:Principles and Practice (2d ed. 1986)). The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (U. S. Patent 4,946,778, U. S. Patent No. 4,816,567) can be adapted toWSGR Docket No. 63125-728.601produce antibodies to polypeptides of this invention. Also, transgenic mice, or other organisms such as other mammals, may be used to express humanized or human antibodies (see, e.g., U. S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-13 (1994); Fishwild et al., Nature Biotechnology 14:845-51 (1996); Neuberger, Nature Biotechnology 14:826 (1996); and Lonberg & Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). Alternatively, phage display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779-783 (1992)). Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93 / 08829, Traunecker et al., EMBO J. 10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or immunotoxins (see, e.g., U. S. Patent No. 4,676,980, WO 91 / 00360; WO 92 / 200373; and EP 03089).

[0071] Methods for humanizing or primatizing non-human antibodies are well known in the art (e.g., U. S. Patent Nos. 4,816,567; 5,530,101; 5,859,205; 5,585,089; 5,693,761; 5,693,762; 5,777,085; 6,180,370; 6,210,671; and 6,329,511; WO 87 / 02671; EP Patent Application 0173494; Jones et al. (1986) Nature 321:522; and Verhoyen et al. (1988) Science 239:1534). Humanized antibodies are further described in, e.g., Winter and Milstein (1991) Nature 349:293. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as import residues, which are typically taken from an import variable domain. Humanization can be essentially performed following the method of Winter and co-workers (see, e.g., Morrison et al., PNAS USA, 81:6851- 6855 (1984), Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Morrison and Oi, Adv. Immunol., 44:65-92 (1988), Verhoeyen et al., Science 239: 1534- 1536 (1988) andPresta, Curr. Op. Struct. Biol. 2:593-596 (1992), Padlan, Molec. Immun, 28:489- 498 (1991); Padlan, Molec. Immun., 31 (3): 169-217 (1994)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such humanized antibodies are chimeric antibodies (U. S. Patent No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non- human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies. For example, polynucleotides comprising a first sequence coding for humanized immunoglobulin framework regions and aWSGR Docket No. 63125-728.601second sequence set coding for the desired immunoglobulin complementarity determining regions can be produced synthetically or by combining appropriate cDNA and genomic DNA segments. Human constant region DNA sequences can be isolated in accordance with well known procedures from a variety of human cells.Conjugates of the Disclosure

[0072] The following is a discussion of conjugates and salts thereof that can be used for treating a refractory cancer in a subject in need thereof.

[0073] In some embodiments, the conjugate is represented by Formula (C): / / Kk S22\ \L\ s3 r4° X / \0 / / OAR Formula (C)or a pharmaceutically acceptable salt thereof, wherein;R40is selected from VYv and C1-C30 alkylene, wherein one or more alkylene units of the C1-C30 alkylene 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-;L is a Targeting Unit;DAR is an integer from 1 to 20;D is a Drug unit;Y1is absent or selected from -O-T1and -NH-T2;T1is a sugar cleavable unit;T2is peptide cleavable unit;S1is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-C30 alkenylene, wherein one or more alkenylene units of the C3-C30 alkenylene 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)-,WSGR Docket No. 63125-728.601-S(0)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-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;52is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-;53is selected from a spacer, wherein S1is present or absent;wherein the optional substituents on M1, K1, S1, S2, and S1, 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, =0, =S, =N(R30), and -CN;(ii) Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle 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, =0, =S, =N(R30), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;M2is a connector unit;K1is selected from:(i) a peptide unit,(ii) an oligosaccharide; and(iii) a polyether;each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; andWSGR Docket No. 63125-728.601each R30is independently selected from hydrogen; and Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, 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(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0074] In some embodiments, the conjugate of Formula (C) is represented by Formula (XX). In some cases, Formula (C) is represented by Formula (A).

[0075] In some embodiments, the conjugate is represented by Formula (XX):I<s='s:Dor a pharmaceutically acceptable salt thereof, wherein;L is a Targeting Unit;DAR is an integer from 1 to 20;D is a Drug unit;Y1is absent or selected from -O-T1and -NH-T2;T1is a sugar cleavable unit;T2is peptide cleavable unit;51is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-C30 alkenylene, wherein one or more alkenylene units of the C3- C30 alkenylene 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-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;52is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-;WSGR Docket No. 63125-728.601S1is selected from a spacer, wherein S1is present or absent;wherein the optional substituents on M1, K1, S1, S2, and S1, 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, =0, =S, =N(R30), and -CN;(ii) Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, -N02, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle 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, -N02, =0, =S, =N(R30), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;M2is a connector unit;K1is selected from:(i) a peptide unit,(ii) an oligosaccharide; and(iii) a polyether;each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, Cs-12 carbocycle, and 3- to 12-membered heterocycle; andeach R30is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, Cs-12 carbocycle, and 3- to 12-membered heterocycle.

[0076] In some embodiments, Formula (XX) is represented byWSGR Docket No. 63125-728.601Formula (A) or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), K1is a hydrophilic spacer. In some cases, K1is selected from polyethylene glycol units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides and dendrimers. In some cases, K1is selected from polyamides, hydrophilic peptides, and polysaccharides. In some cases, K1is selected from hydrophilic peptides and polysaccharides. In some cases, K1is selected from hydrophilic peptides. In some cases, K1is selected from polysaccharides.

[0078] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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: (i) an optionally substituted Ce-Cio alkylene wherein one or more alkylene units of the Ce-C10 alkylene 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 Ci alkylene. In some cases, S1is an optionally substituted C2alkylene. In some cases, S1is an optionally substituted C3 alkylene. In some cases, S1is an optionally substituted C4 alkylene. In some cases, S1is an optionally substituted Cs alkylene. In some cases, S1is an optionally substituted Ce alkylene. In some cases, S1is an optionally substituted C7 alkylene. In some cases, S1is an optionally substituted Cs alkylene. In some cases, S1is an optionally substituted C9 alkylene. In some cases, S1is an optionally substituted C10 alkylene. In some cases, S1is an optionally substituted C11 alkylene. In some cases, S1is an optionally substituted C12 alkylene. In some cases, S1is an optionally substituted C13 alkylene. In some cases, S1is an optionally substituted C14 alkylene. In some cases, S1is an optionally substituted C15 alkylene. In some cases, S1is an optionally substituted Ci6 alkylene. In some cases, S1is an optionally substituted C17 alkylene. In some cases, S1is an optionally substituted Cis alkylene. In some cases, S1is an optionally substituted C19 alkylene. In some cases, S1is an optionally substituted C2o alkylene. In some cases, the one or more alkylene units of the alkylene of S1are optionally and independently replaced by -WSGR Docket No. 63125-728.601N(R20)-, -N(R20)C(O)-, -C(O)N(R20)-, -N(R20)S(O)2- - S(O)2N(R20)- -0-, -C(0)-, -0C(0)-, — C(0)0—, -S-, — S(0)—, -S(0)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 of the 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 heteroatomsWSGR Docket No. 63125-728.601can 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.

[0079] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is selected from: -N(R20)C(O)-CI-C3 alkylene-N(R20)C(O)-C1-C3 alkylene-N(R20)C(O)-Ci-C3 alkylene. In some cases, S1is selected from: -NHC(O)-Ci-C3 alkylene-NHC(O)-Ci-C3 alkylene-NHC(O)-Ci-C3 alkylene.

[0080] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the optional substituents on S1, 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, =0, =S, =N(R30), and -CN; (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle. In some cases, the optional substituents on S1, 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, =0, =S, =N(R30), and -CN. In some cases, the optional substituents on S1, are independently selected at each occurrence from: halogen, -OR30, -N(R30)2, =0, and -CN. In some cases, the optional substituents on S1, are independently selected at each occurrence from: =0. In some cases, the S1is unsubstituted.

[0081] In some embodiments for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the optionally substituted C1-C30 alkylene of S1is linear. In some cases, the optionally substituted C1-C30 alkylene of S1is a branched alkylene.

[0082] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(H)C(O)-.

[0083] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is selected from -NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-.WSGR Docket No. 63125-728.601

[0084] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is selected from -NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-, wherein - S2-I<1is bound to one of the alkylene. In somecases, S1is selected fromwherein - S2-I<1is bound to one of thealkylene. In some cases, S1is selected fromwherein -S2-I<1is bound to one of the alkylene, and wherein S2is -C(O)-.

[0085] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX),Formula (A), or Formula (A-l), -S^S^K1is selected fromsome cases, -S^S^K1is selected from

[0086] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX),Formula (A), or Formula (A-l), Y1is selected from, and K1is selected from a peptide unit. In some cases, the peptide unit is represented bym is selected from 1 to 3;n is selected from 1 to 30;each R5is independently selected from: hydrogen and Ci-6 alkyl;each R10is independently selected from: hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -WSGR Docket No. 63125-728.601CH2CH2CONH2, -CH2CH2COOH, -CH2CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, and; and / >n,0ANX^U, S'T is selected from -OH, -NH2 andH 0In some cases, each R10is selected from: hydrogen, and methyl. In some cases, the peptide unit is represented byIn some cases, each n is selected from 7 to 12. In some cases, each n is selected from 8 to 10. In some cases, each n is 8. In some cases, each n is 9. In some cases, n is 10. In some cases, each R10is hydrogen. In some cases, each R5is independently selected from: hydrogen and methyl. In

[0087] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S2is selected from an optionally substituted Ci-C3o alkylene wherein one or more alkylene units of the Ci-C3o alkylene 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 Ci-C3o alkylene wherein one or more alkylene units of the Ci-C3o alkylene 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 Ci-C3o alkylene wherein one or more alkylene units of the Ci-C3o alkylene 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 Ci-C3o alkylene wherein one or more alkylene units of the Ci-C3o alkylene 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 Ci-C3o alkylene wherein one or more alkylene units of the Ci-C3o alkylene are optionally and independentlyWSGR Docket No. 63125-728.601replaced by - S(O)2N(R20)-, -0-, -C(0)-, -0C(0)-, -C(0)0- -S-, -S(0)-, or -S(0)2-. In some embodiments, S2is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -0-, -C(0)-, — OC(O)—, — C(0)0—, -S-, — S(0)—, or -S(0)2- In some embodiments, S2is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -C(0)-, -0C(0)-, -C(0)0-, -S-, -S(0)-, or -S(0)2-.

[0088] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S2is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -C(O)-.

[0089] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S2is selected from an optionally substituted Ci-Ce alkylene wherein one or more alkylene units of the Ci-Ce alkylene are optionally and independently replaced by -C(O)-. In some cases, S2is selected from an optionally substituted Ci-C2alkylene wherein one or more alkylene units of the Ci-C2alkylene are optionally and independently Oreplaced by -C(O)-. In some cases,S2is.

[0090] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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)-.

[0091] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), -S^S^K1is represented by -S^ Oj-K1.

[0092] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S2is selected from -Ci-Ce alkylene-C(O)-. In some embodiments, S2is selected from -C1-C5 alkylene-C(O)-. In some embodiments, S2is selected from -Ci-C4alkylene-C(O)-. In some embodiments, S2is selected from -C1-C3 alkylene-C(O)-. In some embodiments, S2is selected from -Ci-C2alkylene-C(O)-. In some embodiments, S2is selected from -C2alkylene-C(O)-. In some embodiments, S2is selected from -Ci alkylene-C(O)-.WSGR Docket No. 63125-728.601

[0093] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX),O O N N HFormula (A), or Formula (A-l), -S^S^K1is

[0094] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX) or Formula (A), S1is present and is a phenylene.

[0095] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX) or Formula (A), S1is absent.

[0096] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the sugar cleavable unit can refer to a sugar moiety, preferably a glucuronide or a galactoside.

[0097] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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).

[0098] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the peptide cleavable unit can refer to a polypeptide, preferably a dipeptide or a tripeptide.

[0099] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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. In some cases, the P-glucuronidase enzyme in lysosomes or the tumor interstitium cleaves the drug-linker between the sugar and the oxygen bond, releasing the drug.

[0100] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX) orO OFormula (A), or Formula (A-l), Y1is. In some cases, Y1is a sugar moiety. In some cases, Y1is absent.

[0101] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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 P-Alanine. In someWSGR Docket No. 63125-728.601cases, 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 P-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, Vai-Ala and Phe-Lys. In some cases, Cathepsin B is a lysosomal cysteine protease that is highly up-regulated in malignant cells. In some cases, the peptide cleavable unit is cleaved by Cathepsin B.

[0102] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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 9 YHOz H Y T 'NAcas s t e a p n mIe, h c p i g oiety is '. In some cases, Y is °1.

[0103] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), K1is selected from a peptide unit. In some cases, the peptide unit is a residue.

[0104] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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 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 mostWSGR Docket No. 63125-728.60120 amino acids. In some cases, the peptide unit of K1has 20 amino acids. In some cases, the peptide unit of K1has at most 30 amino acids. In some cases, the peptide unit of K1has at least 30 amino acids. In some cases, the amino acids of K1are 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 P-Alanine. In some cases, the amino acids of K1are 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 P-Alanine. In some cases, the amino acids of K1are 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 P-Alanine. In some cases, the amino acids of K1are selected from a group consisting of glycine, sarcosine, proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1are selected from a group consisting of glycine, proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1are selected from a group consisting of glycine, proline, serine, alanine, and P-Alanine. In some cases, K1includes at least one glycine. In some cases, K1includes at least one proline. In some cases, K1includes at least one serine. In some cases, K1includes at least one alanine. In some cases, K1includes at least one P-Alanine. In some cases, K1is a polysarcosine. In some cases, K1is a polysarcosine with ten repeating sarcosine units.

[0105] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), K1is selected from a peptide unit, wherein the peptide unit has a terminal -NH2. In some cases, K1is selected from a peptide unit, wherein the peptide unit has a terminal -OH. In some cases, K1is selected from a peptide, wherein the peptide has a terminal -NH2. In some cases, K1is selected from a peptide, wherein the peptide has a terminal -OH.

[0106] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), K1is selected from a peptide unit. 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 acids. In some cases, the peptide unit of K1has 1 amino acid. In some cases, theWSGR Docket No. 63125-728.601peptide 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 20 amino acids. In some cases, the peptide unit of K1has at most 30 amino acids. In some cases, the peptide unit of K1has at least 30 amino acids. In some cases, K1is a peptide unit selected from a glycine and two adjacent sarcosines. In some cases, K1is a peptide unit selected from a glycine and three adjacent sarcosines. In some cases, K1is a peptide unit selected from a glyicine and four adjacent sarcosines. In some cases, when a peptide unit includes adjacent sarcosines, there is at least one other amino acid present. In some cases, K1includes a glycine and two adjacent sarcosines. In some cases, K1includes a glycine and three adjacent sarcosines. In some cases, K1includes a glycine and four adjacent sarcosines. In some cases, K1is a peptide unit selected from a glycine and two adjacent sarcosines. In some cases, K1is a peptide unit selected from a glycine and three adjacent sarcosines. In some cases, K1is a peptide unit selected from a glyicine and four adjacent sarcosines. In some cases, K1includes 2 glycines and 8 sarcosines. In some cases, K1includes 3 glycines and 8 sarcosines. In some cases, K1includes 4 glycines and 7 sarcosines. In some cases, K1includes 3 glycines and 7 sarcosines. In some cases, K1includes 3 glycines and 6 sarcosines. In some cases, K1includes 3 glycines and 5 sarcosines. In some cases, 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, K1includes 3 glycines and 10 sarcosines. In some cases, K1includes 5 glycines and 5 sarcosines. In some cases, K1includes 4 glycines and 4 sarcosines. In some cases, 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, K1has at most 8 sarcosines. In some cases, K1has at most 7 sarcosines. In some cases, K1has at most 6 sarcosines. In some cases, K1has at most 5 sarcosines. In some cases, K1has at most 4 sarcosines. In some cases, K1has at most 3 sarcosines. In some cases, K1has at most 2 sarcosines. In some cases, K1has at most 1 sarcosine. In some cases, K1has at most 9 glycines. In some cases, K1has at most 8 glycines. In some cases, K1has at most 7 glycines. In some cases, K1has at most 6 glycines. In some cases, K1has at most 5 glycines. In some cases, K1has at most 4 glycines. In some cases, K1has at most 3 glycines. In some cases, K1has at most 2 glycines. In some cases, K1has at most 1 glycine. In some cases, the amino acids of K1isWSGR Docket No. 63125-728.601selected 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 P-Alanine. In some cases, the amino acids of K1is 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 P-Alanine. In some cases, the amino acids of K1is 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 P-Alanine. In some cases, the amino acids of K1is selected from a group consisting of glycine, sarcosine, proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1is selected from a group consisting of glycine, proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1is selected from a group consisting of proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1includes at least one glycine and at least one other amino acid. In some cases, the amino acids of K1includes at least one glycine and at least one sarcosine. In some cases, the amino acids of K1includes at least one glycine and at least one other amino acid selected from proline, serine, alanine, and P-Alanine. In some cases, the amino acids of K1is selected from a group consisting of glycine, proline, serine, alanine, and P-Alanine. In some cases, K1includes at least one glycine. In some cases, K1includes at least one proline. In some cases, K1includes at least one serine. In some cases, K1includes at least one alanine. In some cases, K1includes at least one P-Alanine.

[0107] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), K1includes PASylation. In some cases, PASylation is a peptide comprising proline, alanine, and serine. In some cases, PASylation is a peptide consisting of only proline, alanine, and serine. In some cases, K1includes PASylation of less than PAS 100. For example, PAS 100 refers to a peptide having 100 amino acids, wherein the amino acids are selected from proline, alanine, and serine. In some cases, K1includes PASylation of less than PAS50. In some cases, K1includes PASylation of less than PAS25. In some cases, K1includes PASylation of more than PAS5. In some cases, K1includes PASylation of more than PAS9. In some cases, K1includes PASylation of more than PAS15. In some cases, K1includes PASylation of PAS5 to PAS25. In some cases, K1includes PASylation of PAS 10 to PAS20. In some cases, K1includes PASylation of PAS 10. In some cases, K1includes PASylation of PAS20. In some cases, K1includes a beta-alanine that links the PASylation to the drug-linker. InWSGR Docket No. 63125-728.601some cases, PASylation is used to extend the plasma half-life. In some cases, PASylation is used to increase solubility. In some cases, PASylation is used to increase solubility without generating secondary structures. In some cases, PASylation issome cases, PASylation isPASylation isOHsome cases, PASylation is

[0108] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the peptide unit of K1has a terminus unit. In some cases, K1isR6selected fromwherein the terminus unit is represented by R6, and each j is selected from 1 to 30. In some cases, j is 1. In some cases, j is 3. In some cases, j is 5. In some cases, j is 10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or moreWSGR Docket No. 63125-728.601substituents 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, -NH2, and' / OH 6 6 6 °. In some cases, R is -OH. In some cases, R is -NH2. In some cases, R is AH 6' 'OH

[0109] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the peptide unit of K1has a terminus unit. In some cases, K1iswherein the terminus unit is represented by R6, and each j is selected from 1 to 30. In somecases, K1is selected fromOWSGR Docket No. 63125-728.601wherein the terminus unit is represented by R6, and each j is selected from 1 to 30. In some cases, j is 1. In some cases, j is 3. In some cases, j is 5. In some cases, j is 10. In some cases, j is 20. In some cases, R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle. In some cases, R6is selected from -OH, and -NH2. In some cases,Z '?' NR6is selected from -OH, -NH2, andH 0. In some cases, R6is -OH. In someN >'s°cases, R6is -NH2. In some cases,R6is H dOH

[0110] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX),Formula (A), or Formula (A-l), K1is selected fromWSGR Docket No. 63125-728.601some cases, K1is selected from In some cases, K1is selected fromIn some cases, K1is selected from. In some cases, K1is selected fromcases, K1is selected from. In some cases, K1is selected from

[0111] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l),WSGR Docket No. 63125-728.601K1is selected fromcases, K1is selected from

[0112] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), each K1is selected from: an oligosaccharide. In some cases,each K1is selected from:wherein k is selected from 2 to 10. In some cases, k is 2. In some cases, k is 3. In some cases, k is 4. In some cases, k is 5. In some cases, kis 6. In some cases, each K1is selected from:

[0113] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the Drug unit is selected from a cytotoxic agent, an immuneWSGR Docket No. 63125-728.601modulatory agent, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioactive isotope and a chelating ligand. In some cases, the Drug unit is selected from a cytotoxic agent.

[0114] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the Drug unit is selected from a cytotoxic agent, camptothecin derivative, and an immune modulatory agent. In some cases, the Drug unit is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE). 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, Drug unit 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 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 proteolysis targeted chimera (PROTAC).

[0115] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), S1is 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, S1is present. In some cases, S1is 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; Cs-Cs heterocyclo; C3-Cs carbocyclo; 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-Ci-C10 alkylene-, -C1-C10 heteroalkylene-, -Cs-Cs carbocyclo-, -O-(Ci Cs alkyl)-, -arylene-, -Ci-C10 alkylene-arylene-, -arylene-Ci-Cio alkylene-, -C1-C10 alkylene-(C3-Cs carbocyclo)-, - (C3-Cs carbocyclo)-Ci-Cio alkylene-, -C3-C8 heterocyclo-, -C1-C10 alkylene-(C3-Cs heterocyclo)-, -WSGR Docket No. 63125-728.601(C3-C8 heterocyclo)-Ci-Cio alkylene-, -C1-C10 alkylene-C(=O)-, -Ci- Cio heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(Ci-C8alkyl)-C(=O)-, - arylene-C(=O)-, -Ci-C10 alkylene-arylene-C(=O)-, -arylene-Ci-Cio alkylene-C(=O)-, -Ci- Cio alkylene-(C3-C8carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-Ci-Cio alkylene-C(=O)-, - C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-Ci-Cio alkylene-C(=O)-, -C1-C10 alkylene-NH-, -C1-C10 heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(Ci-Cs alkyl)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-Ci-Cio alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, - (C3-C8 carbocyclo)-Ci-Cio alkylene-NH-, -C3-Csheterocyclo-NH-, -C1-C10 alkylene-(C3- Cs heterocyclo)-NH-, -(C3-C8 heterocyclo)-Ci-C10 alkylene-NH-, -C1-C10 alkylene-S-, - C1-C10 heteroalkylene-S -, -Cs-Cscarbocyclo-S -, -O-(Ci-Cs alkyl)-)-S -, -arylene-S-, -Ci- Cio alkylene-arylene-S-, -arylene-Ci-Cio alkylene-S-, -Ci-C10 alkylene-(C3- Cs carbocyclo)-S-, -(C3-C8 carbocyclo)-Ci-Cio alkylene-S-, -C3- Cs heterocyclo-S-, -Ci- Cio alkylene-(C3-C8 heterocyclo)-S-, -(C3-C8 heterocyclo)-Ci-C10 alkylene-S-, -C1-C10 alkylene-O-C(=O)-, -C3-C8 carbocyclo-O-C(=O)-, -O-(Ci-C8alkyl)-O-C(=O)-, -arylene- O-C(=O)-, -C1-C10 alkylene-arylene-O-C(=O)-, -arylene-Ci-Cio alkylene-O-C(=O)-, -Ci- Cio alkylene-(C3-C8carbocyclo)-O-C(=O)-,-(C3-C8 carbocyclo)-Ci-Cio alkylene-O-C(=O)-, -C3-C8 heterocyclo-O-C(=O)-, -C1-C10 alkylene-(C3-C8heterocyclo)-O-C(=O)-, and -(C3-C8 heterocyclo)-Ci-Cio alkylene-O-C(=O)-. In some cases, S1is 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, =0, =S, =N(R30), and -CN; (ii) C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and (iii) C3-10 carbocycle 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, =0, =S, =N(R30), -CN, Ci-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, S1is 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, =0, =S, =N(R30), and -CN. In some cases, S1isWSGR Docket No. 63125-728.601unsubstituted. In some cases, S1is substituted. In some cases, S1is a phenylene. In some cases,

[0116] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), 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 can connect the Targeting Unit to S1(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., athiol group of an interchain disulfide bond). In some cases,M2is0. In some cases, M2N NN N 'N N N / . In some cases, M2is. In some cases, M2isOC(O)NH-. In some cases, M2is linked to the Targeting unit via a disulfide bond between a sulfuratom 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. In0H H N N Nsome cases, M2is selected from0, and °. In some OH H N Ncases, M2is. In some cases, M2is

[0117] In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), the L is modified with a group capable of reacting to form M2WSGR Docket No. 63125-728.601(e.g., to form). In some cases, Lis modified with a group / N 'N N ' N'Acapable of a click reaction to form M2(e.g., to form

[0118] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), L comprises 8 sulfur atoms that each can independently form a bond with about eight separate drug-linkers via each M2.

[0119] In some embodiments, the conjugate of Formula (XX) is represented byDFormula (A), wherein the DAR is a drug to antibody (L) ratio. In some cases, the DAR is about 1 to about 10. In some cases, the DAR is about 2 to about 10. In some cases, the DAR is about 4. In some cases, the DAR is about 8. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0120] In some embodiments, the conjugate of Formula (XX) is represented by0^DFormula (A),wherein the DAR is a drug to antibody (L) ratio. In some cases, the DAR is about 1 to about 10. In some cases, the DAR is about 2 to about 10. In some cases, the DAR is about 4. In someWSGR Docket No. 63125-728.601cases, the DAR is about 8. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0121] In some embodiments, the conjugate of Formula (XX) is represented byFormula (A-l), wherein the DAR is a drug to antibody (L) ratio. In some cases, the DAR is about 1 to about 10. In some cases, the DAR is about 4. In some cases, the DAR is about 8. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0122] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedby the structure of wherein:Ris selected from:NH OWSGR Docket No. 63125-728.601Ris selected from:HOWSGR Docket No. 63125-728.601WSGR Docket No. 63125-728.601Ris selected from:wherein L is an antibody or an antigen-binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. InWSGR Docket No. 63125-728.601some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0123] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedby the structure of wherein:Ris selected from:WSGR Docket No. 63125-728.601wherein L is an antibody or antigen binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.WSGR Docket No. 63125-728.601

[0124] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedby the structure of wherein:Ris selected from:wherein L is an antibody or antigen binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10WSGR Docket No. 63125-728.601In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In some cases, the drug of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0125] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedwherein:Ris selected from:NH OWSGR Docket No. 63125-728.601Ris selected from:HOHOWSGR Docket No. 63125-728.601WSGR Docket No. 63125-728.601Ris selected from:wherein L is an antibody or antigen binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the DAR is from about 6 to about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In someWSGR Docket No. 63125-728.601cases, the drug of the DAR is exatecan. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4.

[0126] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedby the structure of wherein:Ris selected from:WSGR Docket No. 63125-728.601wherein L is an antibody or antigen binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In some cases, the drug of the DAR is exatecan. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4. In some cases, L is selected from Abl,WSGR Docket No. 63125-728.601

[0127] In some embodiments, a conjugate of Formula (XX) or Formula (A), is representedwherein L is an antibody or antigen binding portion thereof; D is a Drug unit; and DAR is a drug to antibody ratio. In some cases, the DAR is determined using RP-HPLC. In some cases, the DAR is at most about 16. In some cases, the DAR is about 8. In some cases, the DAR is most about 10. In some cases, the DAR is at least about 1. In some cases, the DAR is at least about 2. In some cases, the DAR is at least about 4. In some cases, the DAR is at least about 8. In some cases, the DAR is at most about 8. In some cases, the DAR is from about 1 to about 16. In some cases, the DAR is from about 4 to about 12. In some cases, the DAR is from about 6 to about 10. In some cases, the DAR is from about 7 to about 9. In some cases, the DAR is from about 8 to about 10. In some cases, the DAR is from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DARWSGR Docket No. 63125-728.601is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DT< oA=R is about 8. In some cases, DAR is a drug (D) to antibody (L) ratio. In some cases, the ZIDrug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38. In some cases, the dru IZg of the DAR is exatecan. In some cases, the drug of the DAR is exatecan. In some cases, the conj4ug □at ZIes have the same stereochemistry as the drug-linkers in example 1.IZTable AA-1: Specific Co4n □jugates of the DisclosureZIko IZ o4 □ ZI IZ5 °IZ rZI IZ5 °4 □ ZI?° U zZI I M _ _IZ5 °ZI5 ° R LIZL is 1) Abl; 2) Ab2;ZI r5 ° H3) Ab3 or 4) Ab4;> IxO=ZL is 1) Abl; 2) Ab2;3) Ab3 or 4) Ab4;L is 1) Abl; 2) Ab2; / 'NH 0Q3) Ab3 or 4) Ab4;H 00HZNH L is 1) Abl; 2) Ab2;0 |H3) Ab3 or 4) Ab4;H 0 >0r N H o 1o1H J LNHHOWSGR Docket No. 63125-728.601R LL is 1) Abl; 2) Ab2; / NH 0 IH3) Ab3 or 4) Ab4; H o >0( N H 0 | rNo1H J kH00, H0HO HO H n L is 1) Abl; 2) Ab2; o 7NTN3) Ab3 or 4) Ab4;0AH0 1 H HNn'uH 0 >°nfN H 0 1 rA \-NyOA ofVwA0A AH X XH°OU L yA y 9 1 oHN^( )HO7H2N H r"\ L is 1) Abl; 2) Ab2;0JNYN3) Ab3 or 4) Ab4;0°^Q / SH9 1 H HNA‘AW y Z-ZOH 0 Z=° / 1 ~f~N H 0 | r\AVm AHVU° 0 0^0 oNOy-" i 9 i Ly oHNy=oH0HO. L is 1) Abl; 2) Ab2;HOJV^OH» V-HM x ^Sn9 3) Ab3 or 4) Ab4;\-NH X)--. / / HO^A / ^OH / \°AcHN VQH<\Xy°H / \°AcHN VoHO^AAOH / \°AcHN VQ\WSGR Docket No. 63125-728.601R Li 9 | 9 1 9 1 9 1 9 L is 1) Abl; 2) Ab2;o 1 g I o I o I o13) Ab3 or 4) Ab4;| O I O | O | O | O L is 1) Abl; 2) Ab2;5 1 g I o I o I od3) Ab3 or 4) Ab4;^NH i ° i 9 I 9 1 9 I 9 L is 1) Abl; 2) Ab2;g H g H QHg Ho°5) Ab3 or 4) Ab4;^NH I O I o I O I o I O L is 1) Abl; 2) Ab2;gHgHgHO O n^) Ab3 or 4) Ab4;L is 1) Abl; 2) Ab2;'V 1 9 H 9 1 9 1 9 H 913) Ab3 or 4) Ab4;g 1 g 1 gHg 1 gL is 1) Abl; 2) Ab2;L N 1 A 9. H N A 9k N i A 9-. N i A 9 H N A 9^o II 11o II 11o II H o II 11o IId53) Ab3 or 4) Ab4;L is 1) Abl; 2) Ab2;^NH | 0 | 0 | 0 | 03) Ab3 or 4) Ab4;01oHO10HoL is 1) Abl; 2) Ab2;■^NH | 0 | 0 | 0 | 0‘=3) Ab3 or 4) Ab4;01oH01oH0In some embodiments, the conjugates of Table AA-1 have a DAR selected from about 1 to about 8. In some cases, the DAR is selected from about 2 to about 8. In some cases, the DAR is selected from about 4 to about 8. In some cases, the DAR is selected from about 2 to about 6. In some cases, the DAR is selected from about 2 to about 4. In some cases, the DAR is selected from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the conjugates have the same stereochemistry as the drug-linkers in example 1.WSGR Docket No. 63125-728.601Table AA-2: Specific Conjugates of the Disclosureq eIZf°R ZI L$0=Z I L is 1) Abl; 2) XNHHO H ° H O H O H Or°ZI Ab2; 3) Ab3 or 4) Ab4;Z IL is 1) Abl; 2) rZIAb2; 3) Ab3 or 5 °IZ 4) Ab4;r°ZI L is 1) Abl; 2) ^NH 0Q5 ° Ab2; 3) Ab3 or IZ> Io H 00H4) Ab4;L is 1) Abl; 2) / NH O 1HAb2; 3) Ab3 or 4) Ab4;01H 0 J-NH° nHOWSGR Docket No. 63125-728.601R LL is 1) Abl; 2) / NH 0 IHAb2; 3) Ab3 or H 0 >o4) Ab4;01H on<^NH° I LoHOL is 1) Abl; 2) Ab2; 3) Ab3 or ° °" x° 4) Ab4;9 1 H HN Y■" NJZNCn0H,... ^O°HH 0n / --N H01 r\ VN^J.0AH°U?0x w X Cro | M oHNro m VyNJHOH2NHr\ L is 1) Abl; 2) O\N / NZAb2; 3) Ab3 or °<yc°4) Ab4;AH9 1 H HN \UA Hv 0 < >°™ X° / -NH0 I r"\ f VN \ XnXNAY? ^NH%-UoHo Qu^NH B rk / O o^r'\huk'( / y o | LJ oHN^oHOWSGR Docket No. 63125-728.601R L HO. L is 1) Abl; 2)HOXA / ^OHIHAb2; 3) Ab3 or VN / VYNH \K 4) Ab4; / / HO. A / OH / t°AcHN VQHO^\A°H / K°AcHN \QHO^X / ^OHA°AcHN \Q\L is 1) Abl; 2) 1 ° 1 ° i ff i ff i ff ^N^N^N^N-^N^N'^|fN^AN^YN^<OH Ab2; 3) Ab3 or J 1 A I o I o1o4) Ab4;L is 1) Abl; 2) i ff i ff i ff i ff i ff ^N^N^N^N'^N^N^YN^XN^YN^XANH2Ab2; 3) Ab3 or o I o I o I o I o4) Ab4;L is 1) Abl; 2) ANH 1 ° 1 ° i ff i ff i ffAb2; 3) Ab3 or 4) Ab4;L is 1) Abl; 2) ANH. O I o I O I o I OAb2; 3) Ab3 or 4) Ab4;L is 1) Abl; 2) ^7H1 ff H ff I ff I ff H ffLYN^N-VN^N^N^N^TN^N^YN'^OH Ab2; 3) Ab3 or o 1 O I oHO I o4) Ab4;L is 1) Abl; 2) / <TH1 ff H ff I ff I ff H ffNNNNNNNNNN H2Ab2; 3) Ab3 or O 1 O 1 OHO I o4) Ab4;L is 1) Abl; 2) ■^NH | O | O | O | OAb2; 3) Ab3 or NN^N^N^N^N^N'*YN-AN'~YOH01oH01oH0 4) Ab4;L is 1) Abl; 2) ^NH | O | O | O | OAb2; 3) Ab3 or O 1 0 0 1 0 0 4) Ab4;WSGR Docket No. 63125-728.601

[0128] In some embodiments, the conjugates of Table AA-2 have a DAR selected from about 1 to about 8. In some cases, the DAR is selected from about 2 to about 8. In some cases, the DAR is selected from about 4 to about 8. In some cases, the DAR is selected from about 2 to about 6. In some cases, the DAR is selected from about 2 to about 4. In some cases, the DAR is selected from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the conjugates have the same stereochemistry as the drug-linkers in example 1.

[0129] In some embodiments, the conjugate is represented by Formula (D):L— TA— w— Y -D)Formula (D),or a pharmaceutically acceptable salt thereof, wherein:L is a Targeting Unit;each Y is independently a Spacer unit;y is selected from 0, 1, and 2;each D is a Drug unit;p is an integer from 1 to 20;each W is independently an Amino Acid unit;w is 0 to 12;each A is independently a Stretcher unit; anda is 0 or 1.

[0130] In some embodiments, for a conjugate or salt of Formula (D), a is 1.

[0131] In some embodiments, for a conjugate or salt of Formula (D), A is0 0, and R30is selected from -Ci-Cio alkylene-, -Cs-Cs carbocyclo-, -O-(C3- Cs alkyl)-, -arylene-, -Ci-Cio alkylene-arylene-, -arylene-Ci-Cio alkylene-, -Ci-Cio alkylene-(C3-Cs carbocyclo)-, -(Cs-Cs carbocyclo)-Ci-Cio alkylene-, -Cs-Cs heterocyclo-, -Ci-Cio alkylene-(Cs-Cs heterocyclo)-, -(C3-C8 heterocyclo)-Ci-Cio alkylene-, -(CH2CH2O)r-, and -(CH2CH2O)r-CH2-, and each r is independently selected from an integer from 1 to 10.

[0132] In some embodiments, for a conjugate or salt of Formula (D), the Spacer unit (-Y-), when present, links an Amino Acid unit to the Drug moiety when an Amino Acid unit is present. Alternately, the Spacer unit links the Stretcher unit to the Drug moiety when the Amino AcidWSGR Docket No. 63125-728.601unit is absent. The Spacer unit also links the Drug moiety to the Ligand unit when both the Amino Acid unit and Stretcher unit are absent.

[0133] In some embodiments, for a conjugate or salt of Formula (D), the Spacer units are of two general types: self-immolative and non self-immolative. A non self-immolative Spacer unit is one in which part or all of the Spacer unit remains bound to the Drug moiety after cleavage, particularly enzymatic, of an Amino Acid unit from the Drug-Linker-Ligand Conjugate or the Drug-Linker Compound. Examples of a non self-immolative Spacer unit include, but are not limited to a (glycineglycine) Spacer unit and a glycine Spacer unit. When Drug-linker or conjugate containing a glycine-glycine Spacer unit or a glycine Spacer unit undergoes enzymatic cleavage via a tumor-cell associated-protease, a cancer-cell associated protease or a lymphocyte-associated protease, a glycine-glycine-Drug moiety or a glycine-Drug moiety is cleaved from L-Aa-Ww. In some cases, an independent hydrolysis reaction takes place within the target cell, cleaving the glycine Drug moiety bond and liberating the Drug.

[0134] In some embodiments, for a conjugate or salt of Formula (D), -Yy- is a p-aminobenzyl alcohol (PAB) unit whose phenylene portion is substituted with Qm:wherein Q is selected from -Ci-Cs alkyl, -O-(Ci-Cs alkyl), halogen, nitro, and cyano; and m is an integer selected from 0 to 4.In some embodiments, for a conjugate or salt of Formula (D), -Yy- is

[0135] In some embodiments, for a conjugate or salt of Formula (D), a non self-immolative Spacer unit (-Y-) is -Gly-Gly-. In some cases, a non self-immolative the Spacer unit (-Y-) is -Gly-.

[0136] In some embodiments, for a conjugate or salt of Formula (D), the Spacer unit is absent (y = 0), or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, for a conjugate or salt of Formula (D), a conjugate containing a self-immolative Spacer unit can release -D without the need for a separate hydrolysis step. InWSGR Docket No. 63125-728.601some cases, -Y- is a PAB group that is linked to -Ww- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate, carbamate or ether group:wherein Q is selected from -Ci-Cs alkyl, -O-(Ci-Cs alkyl), halogen, nitro, and cyano; m is an integer selected from 0 to 4; and p is from 1 to 20.

[0138] In some embodiments, for a conjugate or salt of Formula (D), other examples of self-immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group such as 2-aminoimidazol-5-methanol derivatives and ortho or paraaminobenzyl acetals. In some cases, the self-immolative spacer is para-aminobenzyl carbamate (PABC). Spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides, appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems, and 2-aminophenylpropionic acid amides.Elimination of amine-containing drugs that are substituted at the a-position of glycine are also examples of self-immolative spacer useful in a Drug-Linker or a conjugate.

[0139] In some embodiments, for a conjugate or salt of Formula (D), Spacer units (-Yy-) are represented by Formulas (X)-(XII):OG"1Formula Xwherein Q is selected from -Ci-Cs alkyl, -O-(Ci-Cs alkyl), halogen, nitro, and cyano; m is an integer from 0 to 4;H\O Formula XIandFormula XII.WSGR Docket No. 63125-728.601

[0140] In some embodiments, for a conjugate or salt of Formula (D), y is 1.

[0141] In some embodiments, for a conjugate or salt of Formula (D), Y is selected from

[0142] In some embodiments, for a conjugate or salt of Formula (D), Y is selected from

[0143] In some embodiments, for a conjugate or salt of Formula (D), y is 0 and Y is absent.

[0144] In some embodiments, for a conjugate or salt of Formula (D), the Amino Acid unit (- W-), when present, links the Stretcher unit to the Spacer unit if the Spacer unit is present, links the Stretcher unit to the Drug moiety if the Spacer unit is absent, and links the Ligand unit to the Drug unit if the Stretcher unit and Spacer unit are absent.

[0145] In some embodiments, for a conjugate or salt of Formula (D), Ww is a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit. Each -W- unit independently is selected from the formulae denoted below in the square brackets, and w is an integer from 0 to 12:wherein R31is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2CO2H, -CH2CH2CONH2, -CH2CH2CO2H, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,WSGR Docket No. 63125-728.601, and

[0146] In some embodiments, for a conjugate or salt of Formula (D), useful -Ww- units can be designed and optimized in their selectivity for enzymatic cleavage by a particular enzymes, for example, a tumor-associated protease. In some cases, -Ww- unit is that whose cleavage is catalyzed by cathepsin B, C and D, or a plasmin protease. In some cases, -Ww- is a dipeptide, tripeptide, tetrapeptide or pentapeptide. In some cases, when R31, R32, R33, R34, or R35is other than hydrogen, the carbon atom to which R31, R32, R33, R34, or R35is attached is chiral. In some cases, each carbon atom to which R31, R32, R33, R34, or R35is attached is independently in the (S) or (R) configuration.

[0147] In some embodiments, for a conjugate or salt of Formula (D), the Amino Acid unit is valine-citrulline. In some cases, the Amino Acid unit is phenylalanine-lysine (i.e. fk). In some cases, the Amino Acid unit is N-methylvaline-citrulline. In some cases, the Amino Acid unit is 5-aminovaleric acid, homo phenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalanine lysine, isonepecotic acid lysine, beta-alanine lysine, glycine, serine, valine, glutamine, and isonepecotic acid. In some cases, the Amino Acid unit can comprise natural amino acids.

[0148] In some embodiments, for a conjugate or salt of Formula (D), Ww is -Val-Cit-. InH HA. Nsome cases, Ww is O NH2

[0149] In some embodiments, for a conjugate or salt of Formula (D), the Amino Acid unit can comprise non-natural amino acids.WSGR Docket No. 63125-728.601

[0150] In some embodiments, for a conjugate or salt of Formula (D), the Amino Acid unit is

[0151] In some embodiments, for a conjugate or salt of Formula (D), w is 1.

[0152] In some embodiments, for a conjugate or salt of Formula (D), W is independentlyselected from

[0153] In some embodiments, for a conjugate or salt of Formula (D), W is

[0154] In some embodiments, for a conjugate or salt of Formula (D), A is selected fromWSGR Docket No. 63125-728.601

[0155] In some embodiments, for a conjugate or salt of Formula (D), AO

[0156] In some embodiments, for a conjugate or salt of Formula (D), the Drug unit is selected from a cytotoxic agent, camptothecin derivative, and an immune modulatory agent. In some cases, the Drug unit is selected from exatecan, SN-38, and monomethyl auristatin E (MMAE). 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, Drug unit 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 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 proteolysis targeted chimera (PROTAC). In some cases, the Drug unit (D) is exatecan. In some cases, D is MMAE. In some cases, D is SN-38.

[0157] In some embodiments, for a conjugate or salt of Formula (D), D isWSGR Docket No. 63125-728.601

[0158] In some embodiments, for a conjugate or salt of Formula (D), D is

[0159] In some embodiments, the conjugate or salt of Formula (D) isDAR In some cases, the DAR is selected from about 2 to about 8. In some cases, the DAR is selected from about 4 to about 8. In some cases, the DAR is selected from about 2 to about 6. In some cases, the DAR is selected from about 2 to about 4. In some cases, the DAR is selected from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the conjugates have the same stereochemistry as the drug-linkers in example 1. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4. In some cases, L is Abl.

[0160] In some embodiments, the conjugate or salt of Formula (D) isWSGR Docket No. 63125-728.601DAR. In some cases, the DAR is selected from about 2 to about 8. In some cases, the DAR is selected from about 4 to about 8. In some cases, the DAR is selected from about 2 to about 6. In some cases, the DAR is selected from about 2 to about 4. In some cases, the DAR is selected from about 6 to about 8. In some cases, the DAR is about 2. In some cases, the DAR is about 3. In some cases, the DAR is about 4. In some cases, the DAR is about 5. In some cases, the DAR is about 6. In some cases, the DAR is about 7. In some cases, the DAR is about 8. In some cases, the conjugates have the same stereochemistry as the drug-linkers in example 1. In some cases, L is an anti-ROR2 antibody. In some cases, L is selected from Abl, Ab2, Ab3, and Ab4. In some cases, L is selected from Abl.

[0161] 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.

[0162] 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.

[0163] 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 onWSGR Docket No. 63125-728.601several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:OH OH H H OH NHN N NHH

[0164] 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.

[0165] 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.

[0166] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds 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,35C1,37C1,79Br,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.

[0167] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compoundsWSGR Docket No. 63125-728.601are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel 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.

[0172] 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.WSGR Docket No. 63125-728.601

[0173] 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.

[0174] 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.

[0175] 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 administration whereas 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.

[0176] 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 Pharmaceutical Association 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.WSGR Docket No. 63125-728.601

[0177] 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 Fie ser ’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).Targeting Unit / Anti-ROR2 Antibodies (L)

[0178] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), L is a Targeting Unit. In some cases, the Targeting Unit is selected from an antibody or an antigen-binding fragment thereof.

[0179] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), 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 or portion thereof) described herein to bind to a target with a KD 10'5M (10000 nM) or less, e.g., 10’6M, 10’7M, IO’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.

[0180] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), the Targeting unit 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. InWSGR Docket No. 63125-728.601some 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 some cases, the Targeting unit is a peptide having about 3 to about 15 amino acids. In some cases, the Targeting unit includes a cyclic peptide.

[0181] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), 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.

[0182] In some embodiments, for a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), 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., IgGl, IgG2, IgG3, IgG4, or IgAl, and IgA2. The heavychain constant regions (Fc) that correspond to the different classes of immunoglobulins can be a, 8, a, y, and p, respectively. The light chains can be one of either kappa (K) and lambda (λ).

[0183] In some embodiments, a constant region can have an IgG isotype. In some embodiments, a constant region can have an IgGl isotype. In some embodiments, a constant region can have an IgG2 isotype. In some embodiments, a constant region can have an IgG3 isotype. In some embodiments, a constant region can have an IgG4 isotype. In some embodiments, 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 IgGl or IgG4 constant region.In some embodiments, for a conjugate or salt of Formula (C), Formula (XX), Formula (A), or Formula (A-l), L is a Receptor tyrosine kinase-like orphan receptor 2 (ROR2) antibody. In some cases, the ROR2 antibody is Abl. In some cases, the ROR2 antibody is Ab2. In some cases, the ROR2 antibody is Ab 3.WSGR Docket No. 63125-728.601

[0184] An ADC (e.g., Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l)) of the invention comprises an antibody or an antigen-binding portion thereof that specifically binds to ROR2. In some cases, an ADC (e.g., Formula (C), Formula (XX), Formula (A), or Formula (A-l)) of the invention comprises an antibody or an antigen-binding portion thereof that specifically binds to ROR2. Unless otherwise stated, “ROR2” refers to human ROR2. A human ROR2 polypeptide sequence is available under UniProt Accession No.Q01974 (R0R2_HUMAN), as shown below:1 MARGSALPRR PLLCIPAVWA AAALLLSVSR TSGEVEVLDP NDPLGPLDGQ51 DGPIPTLKGY FLNFLEPVNN ITIVQGQTAI LHCKVAGNPP PNVRWLKNDA101 PVVQEPRRII IRKTEYGSRL RIQDLDTTDT GYYQCVATNG MKTITATGVL151 FVRLGPTHSP NHNFQDDYHE DGFCQPYRGI ACARFIGNRT IYVDSLQMQG201 EIENRITAAF TMIGTSTHLS DQCSQFAIPS FCHFVFPLCD ARSRTPKPRE251 LCRDECEVLE SDLCRQEYTI ARSNPLILMR LQLPKCEALP MPESPDAANC301 MRIGIPAERL GRYHQCYNGS GMDYRGTAST TKSGHQCQPW ALQHPHSHHL351 SSTDFPELGG GHAYCRNPGG QMEGPWCFTQ NKNVRMELCD VPSCSPRDSS401 KMGILYILVP SIAILPVIAC LFFLVCMCRN KQKASASTPQ RRQLMASPSQ451 DMEMPLINQH KQAKLKEISL SAVRFMEELG EDRFGKVYKG HLFGPAPGEQ501 TQAVAIKTLK DKAEGPLREE FRHEAMLRAR LQHPNIVWCLL GWTKDQPLS551 MIFSYCSHGD LHEFLVMRSP HSDVGSTDDD RTVKSALEPP DFVHLVAQIA601 AGMEYLSSHH VVHKDLATRN VLVYDKLNVK ISDLGLFREV YAADYYKLLG651 NSLLPIRWMA PEAIMYGKFS IDSDIWSYGV VLWEVFSYGL QPYCGYSNQD701 VVEMIRNRQV LPCPDDCPAW VYALMIECWN EFPSRRPRFK DIHSRLRAWG751 NLSNYNSSAQ TSGASNTTQT SSLSTSPVSN VSNARYVGPK QKAPPFPQPQ801 FIPMKGQIRP MVPPPQLYVP VNGYQPVPAY GAYLPNFYPV QIPMQMAPQQ851 VPPQMVPKPS SHHSGSGSTS TGYVTTAPSN TSMADRAALL SEGADDTQNA901 PEDGAQSTVQ EAEEEEEGSV PETELLGDCD TLQVDEAQVQ LEA( SEQ ID NO: 38 )In the above sequence, the extracellular domain spans amino acids 34-403. The anti-ROR2 antibodies herein bind to an epitope in the extracellular domain.

[0185] Amino acid sequences of exemplary anti-ROR2 antibodies used in the ADCs of the invention are shown in Table Z below.Table Z. SEQ ID NOs of Exemplary Anti-ROR2 Antibodies Ab HC LC VH VL HCDR1 HCDR2 HCDR3 LCDR1 LCDR2 LCDR3 1 1 2 3 4 5 6 7 8 9 10 2 11 2 12 4 13 6 14 8 9 10 3 15 16 17 18 19 6 20 8 9 10WSGR Docket No. 63125-728.6014 21 16 17 18 19 6 20 8 9 10

[0186] Abl and Ab2 are humanized, effectorless versions of murine anti-ROR2 antibody 6E6 (see, e.g., PCT Patent Publication WO 2021 / 102055 and PCT Patent Application PCT / US2023 / 086552). Ab3 is a chimeric version of 6E6. Ab4 is a chimeric, effectorless version of 6E6.

[0187] In some embodiments, an anti-ROR2 antibody or antigen-binding portion thereof used in an ADC of the present disclosure (e.g., Formula (C), Formula (XX), Formula (A), or Formula (A-l)) competes or cross-competes for binding to human ROR2 with, or binds to the same epitope of human ROR2 as, an antibody comprising:a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 2;b) an HC comprising the amino acid sequence of SEQ ID NO: 11 and an LC comprising the amino acid sequence of SEQ ID NO: 2;c) an HC comprising the amino acid sequence of SEQ ID NO: 15 and an LC comprising the amino acid sequence of SEQ ID NO: 16; ord) an HC comprising the amino acid sequence of SEQ ID NO: 21 and an LC comprising the amino acid sequence of SEQ ID NO: 16.

[0188] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has HCDR1-3 comprising the amino acid sequences ofSEQ ID NOs: 5, 6, and 7, respectively;SEQ ID NOs: 13, 6, and 14, respectively; orSEQ ID NOs: 19, 6, and 20, respectively.

[0189] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has a heavy chain variable domain (VH) amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3, 12, or 17.

[0190] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has a VH comprising the amino acid sequence of SEQ ID NO: 3, 12, or 17.

[0191] In some embodiments, the anti-ROR2 antibody has an HC amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1, 11, 15, or 21, or said sequence without the C-terminal lysine.WSGR Docket No. 63125-728.601

[0192] In some embodiments, the anti-ROR2 antibody comprises an HC amino acid sequence of SEQ ID NO: 1, 11, 15, or 21, or said sequence without the C-terminal lysine.

[0193] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has LCDR1-3 comprising the amino acid sequences of SEQ ID NOs: 8-10, respectively.

[0194] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has a light chain variable domain (VL) amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 or 18.

[0195] In some embodiments, the anti-ROR2 antibody or antigen-binding portion has a VL comprising the amino acid sequence of SEQ ID NO: 4 or 18.

[0196] In some embodiments, the anti-ROR2 antibody has an LC amino acid sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 or 16.

[0197] In some embodiments, the anti-ROR2 antibody comprises an LC amino acid sequence of SEQ ID NO: 2 or 16.

[0198] In certain embodiments, the anti-ROR2 antibody or antigen-binding portion comprises any of the above-described heavy chain sequences paired with any one of the abovedescribed light chain sequences.

[0199] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises the HCDR1-3 and LCDR1-3 amino acid sequences of:a) SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively;b) SEQ ID NOs: 13, 6, 14, 8, 9, and 10, respectively; orc) SEQ ID NOs: 19, 6, 20, 8, 9, and 10, respectively.

[0200] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical (e.g., at least 90% identical) to the amino acid sequences of:a) SEQ ID NOs: 3 and 4, respectively;b) SEQ ID NOs: 12 and 4, respectively; orc) SEQ ID NOs: 17 and 18, respectively.

[0201] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that comprise the amino acid sequences of: a) SEQ ID NOs: 3 and 4, respectively;b) SEQ ID NOs: 12 and 4, respectively; orWSGR Docket No. 63125-728.601c) SEQ ID NOs: 17 and 18, respectively.

[0202] In some embodiments, the anti-ROR2 antibody of the present disclosure comprises an HC and an LC that comprise the amino acid sequences of:a) SEQ ID NOs: 1 and 2, respectively;b) SEQ ID NOs: 11 and 2, respectively;c) SEQ ID NOs: 15 and 16, respectively; ord) SEQ ID NOs: 21 and 16, respectively;optionally wherein the HC amino acid sequence is without the C-terminal lysine.

[0203] The present disclosure also provides an anti-ROR2 antibody or an antigen-binding portion thereof that competes or cross-competes for binding to human ROR2 with, or binds to the same epitope of human ROR2 as, any one of Abl-Ab4.

[0204] In some embodiments, the anti-ROR2 antibody or antigen-binding portion comprises HCDR1 comprising the amino acid sequence TY;HCDR2 comprising the amino acid sequence SSGGGY (SEQ ID NO: 27); andHCDR3 comprising the amino acid sequence HPRDFSYALDY (SEQ ID NO: 24);and / orLCDR1 comprising the amino acid sequence GHY;LCDR2 comprising the amino acid sequence WAS (SEQ ID NO: 9); andLCDR3 comprising the amino acid sequence QQYNIYPW (SEQ ID NO: 28).

[0205] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises the HCDR1-3 and LCDR1-3 amino acid sequences of any one of Abl-Ab4. 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 the IMGT® and Kabat methods is shown below for Abl (SEQ: SEQ ID NO):Abl HCDRsDefinition HCDR1 SEQ HCDR2 SEQ HCDR3 SEQ IMGT® GFTFSTYG 5 ISSGGGYT 6 ARHPRDFSYALDY 7 Kabat TYGVS 22 TISSGGGYTHYAGSVKG 23 HPRDFSYALDY 24Abl LCDRsDefinition LCDR1 SEQ LCDR2 SEQ LCDR3 SEQ IMGT® QDVGHY 8 WAS 9 QQYNIYPWT 10 Kabat RASQDVGHYLA 25 WAS T RAT 26 QQYNIYPWT 10WSGR Docket No. 63125-728.601

[0206] Thus, for example, the Abl IMGT®-defined HCDR1-3 and LCDR1-3 sequences of SEQ ID NOs: 5-10, respectively, may be replaced in any embodiment described herein by SEQ ID NOs: 22, 23, 24, 25, 26, and 10, respectively.

[0207] Also contemplated is a set of Abl CDRs wherein each of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 may individually be specified according to any of the methods for defining Abl CDRs as shown above (e.g., HCDR1 specified by the Kabat definition, HCDR2 specified by the IMGT® definition, etc.). The same means for defining Abl CDRs are contemplated for any of Ab2-Ab4.

[0208] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical in amino acid sequence to the VH and VL, respectively, of any one of Abl-Ab4.

[0209] In some embodiments, the anti-ROR2 antibody or antigen-binding portion of the present disclosure comprises a VH and a VL that are the VH and VL, respectively, of any one of Abl-Ab4.

[0210] In some embodiments, the anti-ROR2 antibody is any one of Abl-Ab4, or an antibody with the same amino acid sequences as said antibody.

[0211] In some embodiments, the Targeting unit of Formula (C), Formula (XX), Formula (A), or Formula (A-l) is an anti-ROR2 antibody or antigen-binding portion is a variant antibody or antigen-binding portion.

[0212] In some embodiments, the anti-ROR2 antibody or antigen-binding portion is a variant antibody or antigen-binding portion. In some embodiments, a variant antibody or an antigen-binding portion thereof may have mutations, e.g., that increase its half-life, alter its immunogenicity, provide a site for covalent or non-covalent binding to another molecule, etc. In certain embodiments, the variant antibody or antigen-binding portion thereof may have mutations in its FRs (e.g., in one, two, three, four, five, six, seven, or eight of its FRs). In certain embodiments, the variant antibody or antigen-binding portion thereof may have mutations in its CDRs (e.g., in one, two, three, four, five, or six of its CDRs). In certain embodiments, the variant antibody or antigen-binding potion thereof may have mutations in its constant regions.

[0213] The class of an anti-ROR2 antibody described herein may be changed or switched with another class or subclass. For example, an anti-ROR2 antibody that was originally IgM may be class switched to IgG. Further, the class switching may be used to convert one IgG subclass to another, e.g., from IgGi to IgG2. A K light chain constant region can be changed, e.g., to a light chain constant region, or vice-versa.WSGR Docket No. 63125-728.601

[0214] The anti-ROR2 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 IgGi, IgG2a or IgG2b, IgGs or IgG4.

[0215] In some embodiments, the anti-ROR2 antibody may comprise at least one mutation in the Fc region. A number of different Fc mutations are known, where these mutations alter, e.g., the antibody’s effector functions or half-life. For example, in some embodiments, the anti-ROR2 antibody comprises at least one mutation in the Fc region that reduces or eliminates effector function. In certain embodiments, the anti-ROR2 antibody may comprise, e.g., L234A, L235A, and / or P329A mutations (Eu numbering), wherein the mutations may appear alone or in any combination. In particular embodiments, the anti-ROR2 antibody may comprise an Fc region with all three mutations.

[0216] In some embodiments, the Targeting Unit of Formula (C), Formula (XX), Formula (A), or Formula (A-l), comprise antibodies or portions thereof that are specific for human ROR2 (“ROR2 ADCs”) and thus can serve as excellent targeting moieties for delivering the conjugated payloads to ROR2-positive cancer cells. It is understood that where the present disclosure refers to an anti-ROR2 antibody or an antigen-binding portion thereof, any moiety that serves as a means for binding to ROR2 may be used.Pharmaceutical Formulations / Compositions

[0217] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a conjugate or salt of Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l) (also referred to herein as “a pharmaceutical agent”).

[0218] 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).

[0219] 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,WSGR Docket No. 63125-728.601or 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 also be present in a solution suitable for topical administration, such as an eye drop.

[0220] 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.

[0221] 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 sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously,WSGR Docket No. 63125-728.601subcutaneously 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.

[0222] 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 an amount 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.

[0223] 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.

[0224] 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 relevantWSGR Docket No. 63125-728.601art. 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 1000 mg / 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.

[0225] 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.

[0226] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science 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.WSGR Docket No. 63125-728.601

[0227] 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 preferably sterile. 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.

[0228] For oral formulations, at least one of the pharmaceutical agents described herein can be 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.

[0229] 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, and the nature of the condition, disease or disorder to be treated or prevented.

[0230] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. TheWSGR Docket No. 63125-728.601compositions 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, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0231] 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 oily pharmaceutically approved excipients. Suitable surfactants 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.

[0232] 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 with an aqueous or oily base and will in general also contain one or more emulsifying 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.

[0233] 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. LiquidWSGR Docket No. 63125-728.601aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0234] 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 p. 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.

[0235] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 p. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 p range. 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, AeroNebTM and AeroDoseTM 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 AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0236] 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 (hydrophobic lipophilic balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.WSGR Docket No. 63125-728.601

[0237] 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.

[0238] 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 water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0239] 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.

[0240] 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-release gel 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.

[0241] 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.WSGR Docket No. 63125-728.601Methods of Treatment

[0242] In an aspect, the present disclosure provides a method of treating a refractory cancer includes administering a conjugate to a subject in need thereof. In some cases, the conjugate incudes an antibody or antigen binding portion thereof and a drug-linker. In some cases, the antibody is an anti-ROR2 antibody. In some cases, the drug-linker is Mal-C5-GGFG-Exatecan. In some cases, the drug-linker is Mal-C5-GGFG-Dxd. In some cases, the conjugate is represented by Formula (D) Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), or a salt of any one thereof or a pharmaceutical composition of any one thereof.

[0243] In an aspect, the present disclosure provides a method of treating a refractory cancer includes administering a conjugate to a subject in need thereof, wherein the conjugate is represented by Formula (C), Formula (D), Formula (XX), Formula (A), or Formula (A-l), or a salt of any one thereof or a pharmaceutical composition of any one thereof. In some cases, the refractory cancer is a metaplastic cancer. In some cases, the refractory cancer is metaplastic breast cancer. In some cases, the cancer is a relapsed cancer. In some cases, the refractory cancer is a ROR2-positive cancer.

[0244] 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 conjugate 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

[0245] The Linkers, Drug-Linkers and conjugates of the present disclosure can generally be prepared in a number of ways well known to those skilled in the art of organic synthesis.

[0246] 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.WSGR Docket No. 63125-728.601

[0247] 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 portion thereof or non-antibody protein scaffold), and then a Drug is attached to a Linker.

[0248] 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.

[0249] 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. In some cases, antibodies (and antigen binding portions and other binding agents (including nonantibody 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)) through modification of lysine residues, e.g., by reacting lysine residues with 2-iminothiolane (Traut's reagent), 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).WSGR Docket No. 63125-728.601

[0250] 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 antibodies may 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).

[0251] 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.

[0252] 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.

[0253] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein.

[0254] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.WSGR Docket No. 63125-728.601EXAMPLES

[0255] 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 or synthesized according to sources known to those skilled in the art or prepared as described herein. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN acetonitrile°C degrees Celsiusδn chemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH₂Cl₂)DIAD diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethylg gram(s)h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometryp microm multiplet (spectral); meter(s); milliM molarWSGR Docket No. 63125-728.601M+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertzmin minute(s)mol mole(s); molecular (as in mol wt)mL milliliterMS mass spectrometrynm nanometer(s)NMR nuclear magnetic resonancepH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperatures singlet (spectral)d doublet (spectral)t triplet (spectral)m multiplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTfOH trifluoromethanesulfonic acidTHF tetrahydrofuranTPP TriphenylphosphineEDC N-(Dimethylaminopropyl)-N’-ethyl-carbodiimideHO At l-Hydroxy-7-azabenzotriazoleTSTU N’-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate AOP (7-Azabenzotriazol-l-yl)oxytris(dimethylamino) phosphoniumHexafluorophosphatePyAOP (7- Azabenzotri azol- 1 -yloxy)tripyrrolidinophosphoniumhexafluorophosphateWSGR Docket No. 63125-728.601EEDQ 2-Ethoxy- 1 -ethoxy carbonyl- 1,2-dihydroquinolinePfp PentafluorophenylNAC N-Acetyl CysteineNIS N-IodosuccinimideNMM N-MethylmorpholinePreparation of Drug LinkersExample 1: Synthesis of Drug-Linkers

[0256] Drug-Linkers in Table 1 are prepared as described in PCT / US2024 / 036950, which is which is incorporated herein by reference in its entirety.Table 1: Drug-linkersWSGR Docket No. 63125-728.601WSGR Docket No. 63125-728.601WSGR Docket No. 63125-728.601Mal-C5- GGFG-DxdMal-C5- GGFG- AExatecanOZI /

[0257] Other drug-linkers described elsewhere herein can be prepared as described in PCT / US2024 / 036950 using the appropriate reagents and conditions.Preparation of ROR2 antibodiesExample 2: ROR2 antibodies

[0258] R0R2 antibodies were prepared as described in PCT / US2024 / 030085 and PCT7US2024 / 036950. The sequences of 4 different R0R2 antibodies (e.g., Abl, Ab2, Ab3, and Ab4) are shown below.Table 1. Antibodies and Corresponding SequencesHeavy ChainVLVHLight Chain ConstantName Target SEQ ID SEQ ID Constant Region Region SEQ IDNO NO SEQ ID NO NOAbl R0R2 4 3 1 2 Ab2 R0R2 4 12 11 2 Ab3 R0R2 18 17 15 16 Ab4 R0R2 18 17 21 16WSGR Docket No. 63125-728.601Example 3: Preparation of ROR2 Antibody-Drug-Conjugates

[0259] ROR2 conjugates were prepared as similarly described in PCT / US2024 / 036950 using the appropriate drug linker and R0R2 antibody.WSGR Docket No. 63125-728.601Activity of ROR2 ConjugatesExample 4: In Vivo efficacy of ADCs in Various Xenograft Models

[0260] The in vivo efficacy of the ADCs was evaluated in the TNBC (metaplastic sub-type) patient-derived xenograft (PDX) models. Cells (~1 x 106 / mouse) were resuspended in PBS and mixed 50 / 50% with Matrigel and subsequently engrafted in the mammary fat pads of female NSG mice. Once tumors had reached a mean volume of -150 mm3 treatment was initiated with IV infusions of vehicle QW x 3 (n=5) and ADC at 5 or 10 mg / kg QW x 3 (n=5). Animals were weighed two times per week, and body weights were recorded. Tumors were measured by length and width in millimeters two times per week. Tumor volumes were calculated using the formula V = L x W x W / 2. FIG. 1 shows anti-tumor activity in metaplastic sub-type PDX models after administering ADC-1, ADC-2, or ADC-3 once weekly for 3 weeks (QWx3). FIG.2 shows anti -tumor activity in metaplastic sub-type PDX models after administering ADC-1, ADC-2, or ADC-3 once weekly for 5 weeks (QWx5).WSGR Docket No. 63125-728.601SEQUENCES

[0261] The table below shows sequences described herein (SEQ: SEQ ID NO).Table SSEQ ID Name of Sequence SequenceNO:1 Abl HC EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGVSW VRQAPGKGLEWVSTISSGGGYTHYAGSVKGRFTISR DNAKNSL YLQMNSLRAEDT AVYYC ARHPRDF S Y A L DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK2 Abl / Ab2 LC EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWY QQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKAD YEKHKVYACEVTHQGLS SP VTKSFNRGEC3 Abl VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYGVSW VRQAPGKGLEWVSTISSGGGYTHYAGSVKGRFTISR DNAKNSL YLQMNSLRAEDT AVYYC ARHPRDF S YAL DYWGQGTTVTVSS4 Abl / Ab2 VL EIVMTQSPATLSVSPGERATLSCRASQDVGHYLAWY QQKPGQAPRLLIYWASTRATGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYNIYPWTFGQGTKVEIK5 Abl HCDR1 (IMGT) GFTFSTYG6 Abl / Ab2 / Ab3 / Ab4 ISSGGGYTHCDR2 (IMGT)7 Abl HCDR3 (IMGT) ARHPRDF SYALDY8 Abl / Ab2 / Ab3 / Ab4 QDVGHYLCDR1 (IMGT)9 Abl / Ab2 / Ab3 / Ab4 WASLCDR2 (IMGT)WSGR Docket No. 63125-728.601SEQ ID Name of Sequence SequenceNO:10 Abl / Ab2 / Ab3 / Ab4 QQYNIYPWTLCDR3(IMGT / Kabat)11 Ab2 HC EVQLVESGGGLVKPGGSLRLSCAASGFTFSQYGHSW VRQAPGKGLEWVSTISSGGGYTHYAHSVKGRFTISR DNAKNSL YLQMNSLRAEDT AVYYC ARHPRDF S YAN DYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK12 Ab2 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSQYGHSW VRQAPGKGLEWVSTISSGGGYTHYAHSVKGRFTISR DNAKNSL YLQMNSLRAEDT AVYYC ARHPRDF S YAN DYWGQGTTVTVSS13 Ab2 HCDR1 (IMGT) GFTFSQYG14 Ab2 HCDR3 (IMGT) ARHPRDF SY AN DY15 Ab3 HC EVQLVESGGDLVKPGGSLKLSCAASGFTFSNYGMSW VRQTPDKRLEWVATIS SGGGYTHYVD SVKGRFTISR DNANHILYLQMS SLNSEDTAMYYC ARHPRDF S YAM DYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK16 Ab3 / Ab4 LC DIVMTQSHKFMSTSIGDRVSITCKASQDVGHYVAWY QQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTL TISNVQSEDLADYFCQQYNIYPWTFGGGSKLAIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SP VTKSFNRGECWSGR Docket No. 63125-728.601SEQ ID Name of Sequence SequenceNO:17 Ab3 / Ab4 VH EVQLVESGGDLVKPGGSLKLSCAASGFTFSNYGMSW VRQTPDKRLEWVATIS SGGGYTHYVD SVKGRFTISR DNANHILYLQMS SLNSEDT AMYYC ARHPRDF S YAM DYWGQGTSVTVSS18 Ab3 / Ab4 VL DIVMTQSHKFMSTSIGDRVSITCKASQDVGHYVAWY QQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTL TISNVQSEDLADYFCQQYNIYPWTFGGGSKLAIK19 Ab3 / Ab4 HCDR1 GFTFSNYG(IMGT)20 Ab3 / Ab4 HCDR3 ARHPRDF SYAMDY(IMGT)21 Ab4 HC EVQLVESGGDLVKPGGSLKLSCAASGFTFSNYGMSW VRQTPDKRLEWVATIS SGGGYTHYVD SVKGRFTISR DNANHILYLQMS SLNSEDT AMYYC ARHPRDF S YAM DYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALAAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK22 Abl HCDR1 (Kabat) TYGVS23 Abl HCDR2 (Kabat) TIS SGGGYTHYAGS VKG24 Abl HCDR3 (Kabat) HPRDFSYALDY25 Abl LCDR1 (Kabat) RASQDVGHYLA26 Abl LCDR2 (Kabat) WASTRAT27 Abl HCDR2 SSGGGY(Chothia)WSGR Docket No. 63125-728.601SEQ ID Name of Sequence SequenceNO:28 Abl LCDR3 QQYNIYPW(Chothia)38 Human ROR2 MARGSALPRRPLLCIPAVWAAAALLLSVSRTSGEVE VLDPNDPLGPLDGQDGPIPTLKGYFLNFLEPVNNITIV QGQTAILHCKVAGNPPPNVRWLKNDAPVVQEPRRIII RKTEYGSRLRIQDLDTTDTGYYQCVATNGMKTITAT GVLFVRLGPTHSPNHNFQDDYHEDGFCQPYRGIACA RFIGNRTIYVDSLQMQGEIENRITAAFTMIGTSTHLSD QCSQFAIPSFCHFVFPLCDARSRTPKPRELCRDECEVL ESDLCRQEYTIARSNPLILMRLQLPKCEALPMPESPDA ANCMRIGIPAERLGRYHQCYNGSGMDYRGTASTTKS GHQCQPWALQHPHSHHLS STDFPELGGGHAYCRNPG GQMEGPWCFTQNKNVRMELCDVPSCSPRDSSKMGIL YILVPSIAIPLVIACLFFLVCMCRNKQKASASTPQRRQ LMASPSQDMEMPLINQHKQAKLKEISLSAVRFMEEL GEDRFGKVYKGHLFGPAPGEQTQAVAIKTLKDKAEG PLREEFRHEAMLRARLQHPNVVCLLGVVTKDQPLSM IFSYCSHGDLHEFLVMRSPHSDVGSTDDDRTVKSALE PPDFVHLVAQIAAGMEYLSSHHVVHKDLATRNVLVY DKLNVKISDLGLFREVYAADYYKLLGNSLLPIRWMA PEAIMYGKFSIDSDIWSYGVVLWEVFSYGLQPYCGYS NQDVVEMIRNRQVLPCPDDCPAWVYALMIECWNEF PSRRPRFKDIHSRLRAWGNLSNYNSSAQTSGASNTTQ TSSLSTSPVSNVSNARYVGPKQKAPPFPQPQFIPMKG QIRPMVPPPQLYVPVNGYQPVPAYGAYLPNFYPVQIP MQMAPQQVPPQMVPKPSSHHSGSGSTSTGYVTTAPS NTSMADRAALLSEGADDTQNAPEDGAQSTVQEAEEEEEGSVPETELLGDCDTLQVDEAQVQLEA

Claims

WSGR Docket No. 63125-728.601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a refractory cancer comprising, administering a conjugate to a subject in need thereof, wherein the conjugate is represented by Formula (XX): / Kks2Dor a pharmaceutically acceptable salt thereof, wherein;L is a Targeting Unit;DAR is an integer from 1 to 20;D is a Drug unit;Y1is absent or selected from -O-T1and -NH-T2;T1is a sugar cleavable unit;T2is peptide cleavable unit;51is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-C30 alkenylene, wherein one or more alkenylene units of the C3- C30 alkenylene 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-C10 carbocyclene; (vii) optionally substituted 5- to 10-membered heterocyclene;52is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene 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-;53is selected from a spacer, wherein S1is present or absent;wherein the optional substituents on M2, K1, S1, S2, and S1, are independently selected at each occurrence from:WSGR Docket No. 63125-728.601(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, =0, =S, =N(R30), and -CN;(ii) Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, 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, -N02, =0, =S, =N(R30), -CN, C3-10 carbocycle and 3-to 10-membered heterocycle; and(iii) C3-10 carbocycle 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, -N02, =0, =S, =N(R30), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;M2is a connector unit;K1is selected from:(i) a peptide unit,(ii) an oligosaccharide; and(iii) a polyether;each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, Cs-12 carbocycle, and 3- to 12-membered heterocycle; andeach R30is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -N02, -NH2, -N(CI-6 alkyl)2, C1-10 alkyl, -Ci-iohaloalkyl, -O-Ci-10 alkyl, oxo, Cs-12 carbocycle, and 3- to 12-membered heterocycle.

2. The method of claim 1, wherein Formula (XX) is represented byFormula (A)WSGR Docket No. 63125-728.601or a pharmaceutically acceptable salt thereof.

3. The method of claims 1 or 2, wherein S1is selected from: (i) an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -N(H)C(O)-.

4. The method of any one of claims 1 to 3, wherein S1is selected from -NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-.

5. The method of any one of claims 1 to 4, wherein S1is selected from -NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-NH-C(O)-Ci-Ce alkylene-, and wherein S2is bound to one of the alkylene.

6. The method of any one of claims 1 to 5, wherein S1is7. The method of any one of claims 1 to 6, wherein S1is selected from8. The method of any one of claims 1 to 7, wherein S2is selected from an optionally substituted C1-C30 alkylene wherein one or more alkylene units of the C1-C30 alkylene are optionally and independently replaced by -C(O)-.

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

10. The method of any one of claims 1 to 9, whereinS2is11. The method of any one of claims 1 to 6 or 8 to 10, wherein S^S^K1is12. The method of any one of claims 1 to 11, wherein S^S^K1is13. The method of claim 2, wherein Formula (A) is represented byWSGR Docket No. 63125-728.601Formula (A-l) or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1 to 13, wherein the sugar cleavable unit of T1includes a sugar.

15. The method of any one of claims 1 to 14, wherein the sugar is glucuronide.CK ^OHH° I016. The method of any one of claims 1 to 15, whereinY1is OH17. The method of any one of claims 1 to 15, 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 P-Alanine.

18. The method of any one of claims 1 to 15, wherein the peptide unit of T2includes a dipeptide or tripeptide.

19. The method of any one of claims 1 to 15, 17, or 18, wherein the peptide unit of T2includes a dipeptide.

20. The method of claim 18 or claim 19, wherein the dipeptide is selected from Val-Cit, Val-Ala and Phe-Lys.

21. The method of any one of claims 1 to 15 or 17 to 20, wherein the peptide unit of T2includes a capping moiety.

22. The method of claim 21, wherein the capping moiety is23. The method of any one of claims 1 to 15 or 17 to 22, wherein Y1is24. The method of any one of claims 1 to 13, wherein Y1is absent.WSGR Docket No. 63125-728.60125. The method of any one of claims 1 to 24, wherein each K1is selected from a peptide unit.

26. The method of any one of claims 1 to 25, wherein the peptide unit of K1has 1 to 50 amino acids.

27. The method of claim 26, wherein the amino acids of K1is selected from the 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 P-Alanine.

28. The method of claim 26 or claim 27, wherein the amino acids of K1is selected from the group consisting of glycine, sarcosine, proline, serine, and P-Alanine.

29. The method of any one of claims 1 to 26, wherein the peptide unit of K1has a terminus unit.

30. The method of any one of claims 1 to 29, wherein K1is selected fromJ, and, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.WSGR Docket No. 63125-728.60131. The method of any one of claims 1 to 30, wherein K1is selected from, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30., and, wherein the terminus unit is represented by R6, and each j is selected from 1 to 30.WSGR Docket No. 63125-728.60134. The method of any one of claims 1 to 33, wherein K1is selected fromJ I_I O | oJ, and J, wherein each j is selected from 3 to 20.

35. The method of any one of claims 1 to 34, wherein K1is selected fromJwherein j is selected from 5 to 15.

36. The method of any one of claims 1 to 34, wherein K1is selected fromJ, wherein j is selected from 3 to 8.

37. The method of any one of claims 1 to 34, wherein K1is selected fromI ° xJ, wherein j is selected from 3 to 8.

38. The method of any one of claims 30 to 37, wherein R6is selected from -OR7and -NHR7, wherein R7is selected from hydrogen; Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, --Ill-WSGR Docket No. 63125-728.601OR30, -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, =0, =s,=N(R30), -CN, C3-10 carbocycle and 3- to 10-membered heterocycle.

39. The method of any one of claims 30 to 38, wherein R6is selected from -OH, -NH2, andN >~s°H 6'OH40. The method of any one of claims 30 to 39, wherein R6is -OH.

41. The method of any one of claims 30 to 39, wherein R6is -NH2.>~s°42. The method of any one of claims 30 to 39, wherein R6is6’OH43. The method of any one of claims 1 to 30, wherein K1is selected fromWSGR Docket No. 63125-728.601WSGR Docket No. 63125-728.60145. The method of any one of claims 1 to 30, 43, or 44, wherein K1is'S'H II r> OH / 'OH46. The method of any one of claims 1 to 30 or 43, wherein K1is selected from47. The method of any one of claims 1 to 30, 43, 44, or 46, wherein K1is48. The method of any one of claims 1 to 30, 43, or 46, wherein K1is49. The method of any one of claims 1 to 30 or 43, wherein K1is selected from50. The method of any one of claims 1 to 30, 43, or 49, wherein K1is551. The method of any one of claims 1 to 30, 43, 44, or 49, wherein K1isWSGR Docket No. 63125-728.60152. The method of any one of claims 1 to 30 or 43, wherein K1is selected from53.The method of any one of claims 1 to 30, 43, or 52, wherein K1is54. The method of any one of claims 1 to 30, 43, 44, or 52, wherein K1is55. The method of any one of claims 1 to 30 or 43, wherein K1is56. The method of any one of claims 1 to 30, 43, or 44, wherein K1is57. The method of any one of claims 1 to 30, 43, or 44, wherein K1is58. The method of any one of claims 1 to 30 or 43, wherein K1is59. The method of any one of claims 1 to 30, 43, or 44, wherein K1is60. The method of any one of claims 1 to 30 or 43, wherein K1isWSGR Docket No. 63125-728.60161. The method of any one of claims 1 to 24, wherein each K1is selected from: an oligosaccharide.

62. The method of any one of claims 1 to 24 or 61, wherein each K1is selected from:, wherein k is selected from 2 to 10.

63. The method of claim 62, wherein each K1is selected from:

64. The method of any one of claims 1 to 63, wherein M2is selected from 0,, NVN 'N65. The method of any one of claims 1 to 64, wherein M2is selected fromWSGR Docket No. 63125-728.601O. / \NU 66. The method of any one of claims 1 to 64, wherein M2is selected from O, O / YL°HOH \ H V0, and0°\ 7^67. The method of any one of claims 1 to 64 or 66, whereinM2is 0OP^-OHH Vj yN68. The method of any one of claims 1 to 64 or 66, whereinM2is 0O i_i y\69. The method of any one of claims 1 to 64 or 66, whereinM2is ° 70. The method of claim 1, wherein the conjugate is selected from Table AA-1 and Table AA-2.

71. The method of claim 1, wherein the conjugate is selected from Table AA-1.

72. The method of any one of claims 1 to 71, having a DAR (drug to antibody ratio) of about 1 to about 10.

73. The method of any one of claims 1 to 72, having a DAR of about 2 to about 8.

74. The method of any one of claims 1 to 72, having a DAR of about 3 to about 8.

75. The method of any one of claims 1 to 73, having a DAR of about 2, about 3, about 4, about 5, about 6, about 7, or about 8.

76. The method of any one of claims 1 to 74, having a DAR of about 8.

77. The method of any one of claims 1 to 76, wherein the Targeting unit is selected from an antibody or an antigen-binding portion thereof.

78. The method of claim 77, wherein the Targeting unit is a monoclonal antibody.

79. The method of any one of claims 77 to 78, wherein the antibody is an anti-ROR2 antibody.WSGR Docket No. 63125-728.60180. The method of any one of claims 1 to 79, further comprising administering a pharmaceutical composition comprising the conjugate of any one of claims 1 to 79 and a pharmaceutically acceptable excipient.

81. The method of any one of claims 1 to 80, wherein the refractory cancer is a metaplastic cancer.

82. The method of claim 81, wherein the refractory cancer is metaplastic breast cancer.

83. The method of any one of claims 1 to 82, wherein the cancer is a relapsed cancer.

84. Use of a conjugate, for treating a subject with a refractory cancer comprising, administering the conjugate of any one of claims 1 to 79 to the subject in need thereof, or a pharmaceutical composition comprising the conjugate of any one of claims 1 and 79 and a pharmaceutically acceptable excipient.

85. The use of claim 84, wherein the refractory cancer is metaplastic breast cancer.

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