Chemotherapeutic compounds and methods of use

Abstract

The present disclosure describes novel compounds, drug-linker compounds, and ligand-drug conjugate molecules thereof. Pharmaceutical compositions of the compounds and drug conjugates is also described. The disclosure also provides methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compounds or ligand-drug conjugate molecule of the present disclosure to the subject. The compounds have following Formula I:

Description

[0001] PC073265A

[0002] CHEMOTHERAPEUTIC COMPOUNDS AND METHODS OF USE

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit under 35 U. S. C. § 119(e) of U. S. Provisional Patent 5 Application Serial No. 63 / 791,164, filed April 18, 2025, and U. S. Provisional Patent Application Serial No. 64 / 014,488, filed March 23, 2026, the disclosures of which are hereby incorporated by reference in their entirety.

[0005] SEQUENCE LISTING

[0006] This application is being filed electronically via Patent Center and includes an 0 electronically submitted sequence listing in.xml format. The.xml file contains a sequence listing entitled “PC073265A_Sequence_Listing_ST26.xml” created on March 24, 2026, and having a size of 943 KB. The sequence listing contained in this.xml file is part of the specification and is hereby incorporated herein by reference in its entirety.

[0007] BACKGROUND

[0008] Cancer is the second leading cause of death globally. While cancer treatment options have progressed in recent decades, many forms of cancer exhibit degrees of recalcitrance which render these treatment options ineffective. As many cancers are capable of rapid mutation, proliferation, and immune modulation, cancer treatment often requires near complete cancer cell 0 clearance to prevent recurrence. Nonetheless, many available cancer treatments are dose-limited by high systemic toxicities, rendering them incapable of achieving sufficient cancer clearance to prevent its spread.

[0009] Accordingly, there remains a need for improved cancer treatments with high potencies and target specificities.

[0010] SUMMARY

[0011] The present disclosure provides compounds of Formula I and Formula II, and their pharmaceutically acceptable salts thereof. Also provided in the present disclosure are liganddrug conjugate molecules of Formula III. Such compounds and molecules may be useful in affecting immune stimulation and treating cancer. Also provided are pharmaceutical

[0012] 0 compositions comprising the compounds or pharmaceutically acceptable salt thereof, and the molecules or pharmaceutically acceptable salt thereof as described in the present disclosure, alone or in combination with additional therapeutic agents. The present disclosure also provides methods of preparing such compounds, molecules, pharmaceutically acceptable salts thereof, and compositions comprising the compounds and molecules of the present disclosure, andmethods of using the same. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter According to an embodiment of the present disclosure, there is provided a compound of Formula I:

[0013]

[0014] Formula I

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] X is N or C(R7);

[0017] Y is O or S;

[0018] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0019] R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0020] R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0021] R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0022] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;

[0023] each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0024] 3- to 10-membered heterocycloalkyl,

[0025]

[0026] or

[0027]

[0028] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0029] R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0030] R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0031] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0032] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0033] R11is hydrogen, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0034] and

[0035] n is 0, 1, 2, 3, 4, or 5.

[0036] In another embodiment of the present disclosure, there is provided a drug-linker compound of Formula II:

[0037] Q-D

[0038] Formula II

[0039] or a pharmaceutically acceptable salt thereof, wherein:

[0040] Q is a Linker Unit selected from:

[0041]

[0042]

[0043] wherein:

[0044] R14, R15, R16, and R17are each independently hydrogen, Ci-Ce alkyl, or C3-C8 cycloalkyl; and

[0045] D is a compound of Formula I:

[0046]

[0047] Formula I

[0048] or a pharmaceutically acceptable salt thereof, wherein:

[0049] X is N or C(R7);

[0050] Y is O or S;

[0051] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0052] R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0053] R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0054] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;

[0055] each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0056] R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0057] 3- to 10-membered heterocycloalkyl,

[0058]

[0059]

[0060] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0061] R10A, R10B, R10C

[0062]

[0063] independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0064] R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0065] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0066] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- Cio aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0067] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0068] and

[0069] n is 0, 1, 2, 3, 4, or 5.

[0070] In yet another embodiment of the present disclosure, there is provided a ligand-drug conjugate molecule of Formula III:

[0071] L-(Q-D)P

[0072] Formula III

[0073] or a pharmaceutically acceptable salt thereof, wherein:

[0074] L is a Ligand Unit;

[0075] p is an integer selected from 1 to 36;

[0076] Q is a linker unit selected from:

[0077]

[0078]

[0079] wherein:

[0080] * denotes the point of attachment to L;

[0081] R14, R15, R16, and R17are each independently hydrogen, Ci-Ce alkyl, or C3-C8 cycloalkyl; and

[0082] D is a compound of Formula I:

[0083]

[0084] Formula I

[0085] or a pharmaceutically acceptable salt thereof, wherein:

[0086] X is N or C(R7);

[0087] Y is O or S;

[0088] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0089] R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0090] R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0091] R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0092] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0093] R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0094] 3- to 10-membered heterocycloalkyl,

[0095]

[0096] or

[0097]

[0098] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0099] R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0100] R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0101] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0102] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0103] R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted orsubstituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0104] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl;

[0105] or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0106] and

[0107] n is 0, 1, 2, 3, 4, or 5.

[0108] Described below are embodiments of the disclosure, where for convenience embodiment 1 (El) is identical to the embodiment of Formula I as provided above, embodiment 28 (E28) is identical to the embodiment of Formula II as provided above, and embodiment 36 (E36) is identical to the embodiment of Formula III as provided above.

[0109] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the present disclosure as described.

[0110] INCORPORATION BY REFERENCE

[0111] 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.

[0112] DETAILED DESCRIPTION

[0113] The present disclosure may be understood more readily by reference to the following detailed description of the embodiments of the disclosure and the Examples included herein. It is to be understood that this disclosure is not limited to the specific synthetic methods of making that may vary. It is also to be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0114] El A compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined above.

[0115] E2 A compound of embodiment El, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogenE3 A compound of any one of embodiments El to E2, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0116] E4 A compound of any one of embodiments El to E3, or a pharmaceutically acceptable salt thereof, wherein R2is CH3.

[0117] E5 A compound of any one of embodiments El to E4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula la:

[0118]

[0119] Formula la

[0120] E6 A compound of any one of embodiments El to E5, or a pharmaceutically acceptable salt thereof, wherein R3is C(O)R10.

[0121] E7 A compound of any one of embodiments El to E6, or a pharmaceutically acceptable salt thereof, wherein R6Ais OH and R6Bis hydrogen.

[0122] E8 A compound of any one of embodiments El to E7, or a pharmaceutically acceptable salt thereof, wherein R10is C3-C8cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl.

[0123] E9 A compound of any one of embodiments El to E8, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:

[0124]

[0125]

[0126] E10 A compound of any one of embodiments El to E8, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I of la is a compound of Formula lb:

[0127]

[0128] Formula lb

[0129] or a pharmaceutically acceptable salt thereof,

[0130] wherein:

[0131] R13is hydrogen or C1-C3 alkyl; and

[0132] m is 0, 1, 2, or 3.

[0133] E11 A compound of any one of embodiments El to E7, or a pharmaceutically acceptable salt

[0134]

[0135] E12 A compound of any one of embodiments El to E7 or Ell, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:

[0136]

[0137]

[0138] E13 A compound of any one of embodiments El to E7 or Ell, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or la is a compound of Formula Ic:

[0139]

[0140] Formula Ic

[0141] E14 A compound of any one of embodiments El to E7 or Ell, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or la is a compound of Formula Id:

[0142]

[0143] Formula Id

[0144] El 5 A compound of embodiment E14, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3.E16 A compound of any one of embodiments E14 to E15, or a pharmaceutically acceptable

[0145]

[0146] E17 A compound of any one of embodiments El to E16, or a pharmaceutically acceptable salt thereof, wherein X is C(R7).

[0147] E18 A compound of any one of embodiments El to E17, or a pharmaceutically acceptable salt thereof, wherein R7is Ce-Cio aryl, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0148] E19 A compound of embodiment E18, or a pharmaceutically acceptable salt thereof, wherein R7is unsubstituted.

[0149] E20 A compound of embodiment El 8, or a pharmaceutically acceptable salt thereof, wherein R7is substituted with 1 to 3 instances of R8.

[0150] E21 A compound of embodiment 18, or a pharmaceutically acceptable salt thereof, wherein R7is selected from phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, CF3, and CHF2.

[0151] E22 A compound of any one of embodiments El to E16, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0152] E23 A compound of any one of embodiments El to E22, or a pharmaceutically acceptable salt thereof, wherein R1is Ce-Cio aryl, Ci-Ce alkyl, or C3-C8 cycloalkyl.

[0153] E24 A compound of embodiment E23, or a pharmaceutically acceptable salt thereof, wherein R1is unsubstituted.

[0154] E25 A compound of embodiment E23, or a pharmaceutically acceptable salt thereof, wherein R1is substituted with 1 to 3 instances of R8.

[0155] E26 A compound of embodiment E23, wherein R1is selected from phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, CF3, and CHF2.

[0156] E27 A compound of any one of embodiments E1-E26, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1.

[0157] E28 A drug-linker compound of Formula II, or a pharmaceutically acceptable salt thereof, as defined above.

[0158] E29 A drug-linker compound of embodiment E28, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula la, lb, Ic, or Id:

[0159]

[0160] Formula Ic Formula Id

[0161] , or

[0162] wherein R13is hydrogen or C1-C3 alkyl and m is 0, 1, 2, or 3.

[0163] E30 A drug-linker compound of any one of embodiments E28 to E29, or a pharmaceutically acceptable salt thereof, wherein the linker unit is

[0164]

[0165] E31 A drug-linker compound of any one of embodiments E28 to E30, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula Ila or a compound of Formula lib:

[0166]

[0167] wherein each instance of D is independently a compound of Formula I.E32 A drug-linker compound of any one of embodiments E28 to E31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula lie or a compound of Formula lid:

[0168]

[0169] wherein:

[0170] X is N or C(R7);

[0171] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0172] R8is independently halogen, OR9, or C1-C6 alkyl;

[0173] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0174] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0175] R13is hydrogen or C1-C3 alkyl; and

[0176] m is 0, 1, 2, or 3.

[0177] E33 A drug-linker compound of any one of embodiments E28 to E31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula lie:

[0178]

[0179] wherein:

[0180] X is N or C(R7);

[0181] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0182] R8is independently halogen, OR9, or C1-C6 alkyl;

[0183] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0184] R10Aand R10Bare each independently hydrogen, halogen, or C1-C6alkyl, wherein C1-C6alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0185] R10Lis hydrogen or C1-C12 alkyl, wherein the C1-C12 alkyl is unsubstituted or substituted with 1 to 3 instances ofR12; and

[0186] each instance ofR12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

[0187] E34 A drug-linker compound of any one of embodiments E28 to E31, or a pharmaceutically acceptable salt thereof 28-31, wherein the compound of Formula II is a compound of Formula Ilf:

[0188]

[0189] wherein:

[0190] X is N or C(R7);

[0191] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0192] R8is independently halogen, OR9, or C1-C6 alkyl;

[0193] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0194] R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, and wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen; and

[0195] n is 0, 1, 2, 3, 4, or 5.

[0196] E35 A drug-linker compound of any one of embodiments E28 to E34, or a pharmaceutically acceptable salt thereof, wherein the drug-linker compound is selected from Table 3. E36 A ligand-drug conjugate molecule of Formula III, or a pharmaceutically acceptable salt thereof, as defined above.

[0197] E37 A ligand-drug conjugate molecule of embodiment E36, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula la, lb, Ic, or Id:

[0198]

[0199] Formula Ic Formula Id

[0200] , or

[0201] or a pharmaceutically acceptable salt thereof.

[0202] E38 A ligand-drug conjugate molecule of any one of embodiments E36 to E37, or a pharmaceutically acceptable salt thereof, wherein the linker unit is

[0203]

[0204] E39 A ligand-drug conjugate molecule of any one of embodiments E36 to E38, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug conjugate molecule of Formula Illa:

[0205]

[0206] wherein:

[0207] L is a Ligand Unit;

[0208] p is an integer selected from 1 to 36; and

[0209] D is a compound of Formula I.E40 A ligand-drug conjugate molecule of any one of embodiments E36 to E38, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug conjugate molecule of Formula Illb:

[0210]

[0211] Formula Illb

[0212] wherein:

[0213] L is a Ligand Unit

[0214] p is an integer selected from 1 to 36; and

[0215] D is a compound of Formula I.

[0216] E41 A ligand-drug conjugate molecule of any one of embodiments E36 to E39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula IIIc:

[0217]

[0218] wherein:

[0219] L is a Ligand Unit;

[0220] p is an integer selected from 1 to 36;

[0221] X is N or C(R7);

[0222] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0223] R8is independently halogen, OR9, or C1-C6 alkyl;

[0224] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

[0225] E42 A ligand-drug conjugate molecule of any one of embodiments E36 to E38 or E40 or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula Hid:

[0226]

[0227] wherein:

[0228] L is a Ligand Unit;

[0229] p is an integer selected from 1 to 36;

[0230] X is N or C(R7);

[0231] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0232] R8is independently halogen, OR9, or C1-C6 alkyl;

[0233] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0234] R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0235] R13is hydrogen or C1-C3 alkyl; and

[0236] m is 0, 1, 2, or 3.E43 A ligand-drug conjugate molecule of any one of embodiments E36 to E39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula Ille:

[0237]

[0238] wherein:

[0239] L is a Ligand Unit;

[0240] p is an integer selected from 1 to 36;

[0241] X is N or C(R7);

[0242] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0243] R8is independently halogen, OR9, or C1-C6 alkyl;

[0244] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0245] R10Aand R10Bare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, RIOB, R10CR1OD, R1OE, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances ofR12;

[0246] R10Lis hydrogen or C1-C12 alkyl, wherein the C1-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0247] each instance of R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.E44 A ligand-drug conjugate molecule of any one of embodiments E36 to E39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula IIIf:

[0248]

[0249] wherein:

[0250] L is a Ligand Unit;

[0251] p is an integer selected from 1 to 36;

[0252] X is N or C(R7);

[0253] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0254] R8is independently halogen, OR9, or C1-C6 alkyl;

[0255] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0256] R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, and wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen; and

[0257] n is 0, 1, 2, 3, 4, or 5.

[0258] E45 A ligand-drug conjugate molecule of any one of embodiments E36 to E44, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule is selected from Table 5.

[0259] E46 A ligand-drug conjugate molecule of any one of embodiments E36 to E45, or a pharmaceutically acceptable salt thereof, wherein p is an integer selected 2 to 4, 2 to 8, 2 to 16, 1 to 32, 4 to 8, 4 to 16, 4 to 32, 8 to 32, or 16 to 32.

[0260] E47 A ligand-drug conjugate molecule of any one of embodiments E36 to E46, or a pharmaceutically acceptable salt thereof, wherein L comprises a protein, a nucleic acid, asaccharide, a polyketide, a nanoparticle, a microparticle, a polymer, a hydrogel, or a combination thereof.

[0261] E48 A ligand-drug conjugate molecule of any one of embodiments E36 to E47, or a pharmaceutically acceptable salt thereof, wherein L comprises a protein or is a protein. E49 A ligand-drug conjugate molecule of embodiment E48, or a pharmaceutically acceptable salt thereof, 48, wherein the protein is an antibody, a fragment antigen binding (Fab), a heavy chain variable domain, a nanobody, a diabody, a triabody, or a minibody, a F(ab')₂ fragment, a Fab fragment, a single chain variable fragment (scFv), or a single domain antibody (sdAb).

[0262] E50 A ligand-drug conjugate molecule of any one of embodiments E48 to E49, or a pharmaceutically acceptable salt thereof, wherein the protein is an antibody.

[0263] E51 A ligand-drug conjugate molecule of any one of embodiments 48-50, or a pharmaceutically acceptable salt thereof, wherein the protein comprises one or more sequences selected from SEQ ID NO: 1-1047.

[0264] E52 A ligand-drug conjugate molecule of any one of embodiments E48 to E51, or a pharmaceutically acceptable salt thereof, wherein the protein targets a cancer cell.

[0265] E53 A pharmaceutical composition comprising the compound of any one of embodiments El to E27, the drug-linker compound of any one of embodiments E28 to E35, or the liganddrug conjugate molecule of any one of embodiments E36 to E52, and a pharmaceutically acceptable excipient.

[0266] E54 A pharmaceutical composition of embodiment E53, further comprising a pharmaceutically acceptable carrier.

[0267] E55 A pharmaceutical composition of any one of embodiments E53 to E54, further comprising a pharmaceutically acceptable stabilizer.

[0268] E56 A method of treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of any one of embodiments of El to E27, the drug-linker compound of any one of embodiments E28 to E35, or the ligand-drug conjugate of any one of embodiments E36 to E52, or the pharmaceutical composition of any one of embodiments E53 to E55 to the subject, thereby treating the cancer.

[0269] E57 The method of embodiment E56, wherein the compound has an LD50of less than about 500 nM for the cancer.

[0270] E58 The method of any one of embodiments E56 to E57, wherein the cancer is nonHodgkin’s lymphoma, adenocarcinoma, or malignant histiocytosis, lymphoma, Hodgkin Lymphoma, leukemia, a solid tumor, a hematopoietic cancer, follicular lymphoma,anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, multiple myeloma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

[0271] E59 The method of any one of embodiments E56 to E58, wherein the cancer is nonHodgkin’s lymphoma, adenocarcinoma, or malignant histiocytosis.

[0272] E60 The method of any one of embodiments E56 to E59, wherein the cancer is nonHodgkin’s lymphoma.

[0273] Each of the embodiments described herein may be combined with any other embodiments described herein not inconsistent with the embodiments with which it is combined. In addition, any of the compounds described in the Examples, or a pharmaceutically acceptable salt thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or a pharmaceutically acceptable salt thereof, for any of the embodiments described herein.

[0274] Definitions

[0275] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art in some aspects of this disclosure are also used. The materials, methods, and examples are illustrative only and not intended to be limiting. Allpublications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control. When trade names are used herein, the trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.

[0276] The terms “a,” “an,” or “the” as used herein not only include aspects with one member but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a linker” includes reference to one or more such linkers, and reference to “the cell” includes reference to a plurality of such cells.

[0277] As used herein, “comprising” is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, “consisting of excludes any element, step, or ingredient not specified in the claim element. As used herein, “consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0278] Number ranges are to be understood as inclusive, i.e., including the indicated lower and upper limits.

[0279] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may include the range 0.9-1.1. In reference to an antibody-drug conjugate (ADC) composition comprising a distribution of ADCs as described herein, the average number of conjugated aminonucleoside compounds to an antibody in the composition can be an integer or a non-integer, particularly when the antibody is to be partially loaded. Thus, the term “about” recited prior to an average drug loading value is intended to capture the expected variations in drug loading within an ADC composition.

[0280] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.

[0281] As used herein, the term “subject” broadly refers to any animal, including but not limited to, human and non-human animals (e.g., dogs, cats, cows, horses, sheep, pigs, poultry, fish, crustaceans, etc.).

[0282] As used herein, the term “effective amount” refers to the amount of a composition sufficient to effect beneficial or desired results. An effective amount can be administered in oneor more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0283] As used herein, the term “therapeutically effective amount” is an amount that is effective to ameliorate a symptom of a disease. A therapeutically effective amount can be a “prophylactically effective amount” as prophylaxis can be considered therapy.

[0284] As used herein, the terms “administration” and “administering” refer to the act of giving a drug, prodrug, or other agent, or therapeutic treatment to a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs. Exemplary routes of administration to the human body can be through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal or lingual), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like.

[0285] As used herein, the term “treatment” means an approach to obtaining a beneficial or intended clinical result. The beneficial or intended clinical result can include alleviation of symptoms, a reduction in the severity of the disease, inhibiting an underlying cause of a disease or condition, steadying diseases in a non-advanced state, delaying the progress of a disease, and / or improvement or alleviation of disease conditions.

[0286] As used herein, the term “pharmaceutical composition” refers to the combination of an active ingredient with a carrier, inert or active, making the composition especially suitable for therapeutic or diagnostic use in vitro, in vivo, or ex vivo.

[0287] The terms “pharmaceutically acceptable” or “pharmacologically acceptable,” as used herein, refer to compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.

[0288] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), glycerol, liquid polyethylene glycols, aprotic solvents such as dimethylsulfoxide, N-methylpyrrolidone and mixtures thereof, and various types of wetting agents, solubilizing agents, anti-oxidants, bulking agents, protein carriers such as albumins, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintegrants (e.g., potato starch or sodium starch glycolate), and the like. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 21st Ed., Mack Publ. Co., Easton, Pa. (2005), incorporated herein by reference in its entirety.An “antibody” refers to an immunoglobulin capable of specific binding to a target through at least one antigen binding domain located in the variable region of the immunoglobulin. As used herein, the term “antibody” encompasses any type of antibody, such as monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific and trispecific antibodies), and antibodies that are covalently linked to another entity (e.g., an antibody that is part of an antibody-drug conjugate or a fusion protein). The term “antibody” also encompasses portions of intact antibodies that retain the ability to bind to a given antigen (e.g. an “antigen binding fragment”), and any other modified configuration of an immunoglobulin that comprises an antigen binding domain. Antigen binding fragments include, for example, Fab, Fab', F(ab')₂, Fd, Fv, domain antibodies (dAbs, e.g., shark and camelid antibodies), fragments including complementarity determining regions (CDRs), single chain variable fragment antibodies (scFv), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv, and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. The variable regions or chains of an antibody may or may not be covalently attached to one another.

[0289] An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains (HC), immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0290] Examples of antibody antigen-binding fragments and modified configurations include (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); and (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody. Furthermore, although the two domains of an Fv fragment, VL and VH, are coded for 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 (scFv); see e.g., BIRD, R. E., et al., “Single-Chain Antigen-Binding Proteins,” Science, 1988, 242(4877):423-442 and HUSTON, J. S., et al., “Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli,” Proceedingsof the National Academy of Science, 1988, 85(16):5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed.

[0291] In addition, further encompassed are antibodies that are missing a C-terminal lysine (K) amino acid residue on a heavy chain polypeptide (e.g. human IgGl heavy chain comprises a terminal lysine). As is known in the art, the C-terminal lysine is sometimes clipped during antibody production, resulting in an antibody with a heavy chain lacking the C-terminal lysine. Alternatively, an antibody heavy chain may be produced using a nucleic acid that does not include a C-terminal lysine.

[0292] Further encompassed are antibodies that have post-translational modifications (e.g., glycosylation, sialyation) at one or more amino acids in one or both of the heavy chain and light chain.

[0293] In some embodiments, the antibodies of the present disclosure include those having one or more engineered cysteine (eCys) residues. In some embodiments, derivatives of cysteine (Cys) include, but are not limited to beta-2-Cys, beta-3 -Cys, homocysteine, and N-methyl cysteine.

[0294] In some embodiments, the antibodies of the present disclosure include those having one or more engineered lysine (eLys) residues. In some embodiments, one or more native lysine and / or eLys residues are activated prior to conjugation with a drug-linker intermediate (to form an ADC, as described herein). In some embodiments, the activation comprises contacting the antibody with a compound comprising a succinimydyl ester and a functional group selected from the group consisting of: maleimido, pyridyldisulfidem, and iodoacetamido.

[0295] As used herein, an “antibody-drug conjugate, "antibody drug conjugate”, or “ADC”, (used interchangeably herein) refers to an antibody conjugated to a therapeutic agent (e.g. a cytotoxic agent, cytostatic agent, immunomodulatory molecule, anti-infective agent, etc.). An antibody-drug conjugate typically binds to the target antigen on a cell surface followed by internalization of the antibody-drug conjugate into the cell where the drug is released.

[0296] As used herein, an “antigen” refers to the molecular entity used for immunization of an immunocompetent vertebrate to produce the antibody that recognizes the antigen or to screen an expression library (e.g., phage, yeast or ribosome display library, among others) for antibody selection. Herein, antigen is termed more broadly and is generally intended to include target molecules that are specifically recognized by the antibody, thus including fragments or mimics of the molecule used in an immunization process for raising the antibody or in library screening for selecting the antibody.

[0297] The terms “specific binding” and “specifically binds” mean that the antibody or antibody fragment thereof will bind, in a selective manner, with its corresponding target antigen and notwith a multitude of other antigens. Typically, the antibody or antibody fragment binds with an affinity of at least about 1x10-7M, for example, 10-8M to 10-9M, 10-10M, 10-11M, or 10-12M. In some embodiments, the antibody binds to its target antigen and optionally to closely related analogues (e.g., single amino acid mutants of a target peptide) with an affinity that is at least two-fold greater than its affinity for binding to a non-specific target (e.g., BSA, casein).

[0298] The term “binding affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art. Low-affinity antibodies generally bind antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind antigen faster and tend to remain bound longer. In particular, the term "binding affinity" is intended to refer to the dissociation rate of a particular antigen-antibody interaction. The KD is the ratio of the rate of dissociation, also called the "off-rate (koff)" or “kd” to the association rate, or "on-rate (kon)" or “ka”. Thus, KD equals koff / kon(or kd / ka) and is expressed as a molar concentration (M). It follows that the smaller the KD, the stronger the affinity of binding. Therefore, a KD of 1 pM indicates weaker binding affinity compared to a KD of 1 nM. KD values for antibodies can be determined using methods well established in the art. One exemplary method for determining the KD of an antibody is by using surface plasmon resonance (SPR), typically using a biosensor system such as BIACORE system. BIACORE kinetic analysis comprises analyzing the binding and dissociation of an antigen from chips with immobilized molecules (e.g., molecules comprising epitope binding domains), on their surface. Another method for determining the KD of an antibody is by using Bio-Layer Interferometry, typically using OCTET® technology (Octet QKesystem, ForteBio).

[0299] Alternatively, or in addition, a KinExA (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, ID) can also be used.

[0300] The term “amino acid” as used herein, can refer to a natural or a non-natural amino acid. In many cases, the term “amino acid” encompasses 2-, 3-, 4-, and 5-amino carboxylic acids, as well as condensates thereof, with variable side chain functionalization, and with D- and L- betacarbon configurations. Amino acids typically include an N-terminal amine, a C-terminal carboxylate, and a carbon backbone connecting the N-terminal amine and the C-terminal carboxylate. The term “amino acid” can denote a proteinogenic amino acid, a natural amino acid, a non-natural amino acid (e.g., perfluoroalanine), an amino acid with an alternate backbone (e.g., a beta-amino acid), or a combination thereof. Exemplary amino acids include, but are notlimited to alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, ornithine, P-alanine, citrulline, serine methyl ether, aspartate methyl ester, glutamate methyl ester, homoserine methyl ether, and A A-di methyl lysine.

[0301] As used herein, the term “amino acid residue” can denote a portion of an amino acid which has a bond to a molecule (e.g., a peptide) in place of a leaving group, such as a carboxylic acid hydroxyl.

[0302] As used herein, the term “peptide bond” can denote a covalent amide linkage between the N-terminal amino acid of a first amino acid and the C-terminal carboxylate of a second amino acid (e.g., through condensation).

[0303] The term “inhibit” or “inhibition of’ means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0304] The term “therapeutically effective amount” refers to an amount of a drug (e.g., a compound of Formula I or an ADC comprising a compound of Formula I) that is effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount can, for example, reduce the number of cancer cells in a subject or cell population, reduce the size of a tumor; inhibit metastasis; inhibit tumor growth and / or cancer cell proliferation; diminish a symptom of the cancer, or a combination thereof.

[0305] Unless otherwise indicated or implied by context, the term “substantial” or “substantially” refers to a majority, i.e., >50% of a population, of a mixture, or a sample, typically more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99%.

[0306] The term “subject,” as used herein, generally refers to an individual to which a compound as described herein, or conjugate comprising such compound, is administered.

[0307] Examples of a “subject” include, but are not limited to, a mammal such as a human, rat, mouse, guinea pig, non-human primate, pig, goat, cow, horse, dog, cat, bird, and fowl. Typically, a subject is a rat, mouse, dog, non-human primate, or human. In some aspects, the subject is a human.

[0308] As used herein, the terms “treat” or “treatment,” unless otherwise indicated or implied by context, can refer to therapeutic treatment and prophylactic measures to prevent relapse, wherein the object is to inhibit an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” in some aspects also means prolonging survival as compared to expected survival if not receiving treatment.

[0309] The term “salt,” as used herein, refers to organic or inorganic salts of a compound, such as an aminonucleoside (e.g., a compound of Formula I), a linker, a drug-linker conjugate, or an ADC, such as those described herein. In some aspects, a compound adopts a positive charge, for example through protonation of an amino group (e.g., to form -NH3+or -NH2+-) or a guanidine group, and forms a salt through complexation with an anion such as sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate, or pamoate (i.e., 1,1’ methylene bis-(2 hydroxy 3 naphthoate)). In some aspects, a compound adopts a negative charge, for example through deprotonation of a carboxylic acid, and forms a salt through complexation with a cation such as Li+, Na+, Mg2+, K+, or Ca2+. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.

[0310] Furthermore, a salt has one or more than one charged atom in its structure. In instances where there are multiple charged atoms as part of the salt, multiple counter ions can be present. Hence, a salt can have one or more charged atoms and / or one or more counterions. A “pharmaceutically acceptable salt” is one that is suitable for administration to a subject as described herein and in some aspects includes salts as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002, the list for which is specifically incorporated by reference in its entirety. In some embodiments, the ADCs described herein are present in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are present in the form of a pharmaceutically acceptable salt.

[0311] As used herein, the term “tautomers” can refer to compounds whose structures differ in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to be understood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer. Examples of tautomers include keto-enol pairs, epsilon- and delta-protonated histidine, and amine-imine pairs. In some embodiments, a compound is taken to encompass all hydrogen-positionaltautomers. For example,

[0312]

[0313] may be taken to cover

[0314]

[0315] unless specified otherwise.

[0316] " Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical that has a specified number of carbon atoms, including straight chain or branched chain groups. Alkyl groups may contain, but are not limited to, 1 to 12 carbon atoms (“C1-C12 alkyl”), 1 to 8 carbon atoms (“Ci-Cs alkyl”), 1 to 6 carbon atoms (“Ci-Ce alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”), 1 to 3 carbon atoms (“C1-C3 alkyl”), or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionally substituted, unsubstituted or substituted, as further defined herein. In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example, “haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number.

[0317] The term “alkylene” refers to a bivalent unsubstituted saturated branched or straight chain hydrocarbon of the stated number of carbon atoms (e.g., a Ci-Ce alkylene has from 1 to 6 carbon atoms) and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Alkylene groups can be substituted. Alkylene groups include but are not limited to: methylene (CEE), ethylene (CH2CH2), n-propylene (CH2CH2CH2), n-propylene (CH2CH2CH2), n-butylene (CH2CH2CH2CH2).

[0318] The term “alkenyl” refers to an unsubstituted straight chain or branched, hydrocarbon having at least one carbon-carbon double bond and the indicated number of carbon atoms (e.g., “C2-C8 alkenyl” or “C2-C10” alkenyl have from 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkenyl group has from 2 to 6 carbon atoms.

[0319] The term “alkenylene” refers to a straight- or branched-chain bivalent alkenyl group. The bivalent positions may be on the same or different atoms within the alkenyl chain. Examples of alkenylene include ethynelene, propenylene, isopropenylene, butenylene, and the like.

[0320] The term “alkynyl” refers to an unsubstituted straight chain or branched, hydrocarbon having at least one carbon-carbon triple bond and the indicated number of carbon atoms (e.g., “C2-C8 alkynyl” or “C2-C10” alkynyl have from 2 to 8 or 2 to 10 carbon atoms, respectively).When the number of carbon atoms is not indicated, the alkynyl group has from 2 to 6 carbon atoms.

[0321] The term “alkynylene” refers to a straight- or branched-chain bivalent alkynyl group. The bivalent positions may be on the same or different atoms within the alkenyl chain. Examples of alkenylene include ethenylene, propenylene, isopropenylene, butenylene, and the like.

[0322] The term “heteroalkyl” refers to a stable straight or branched chain saturated hydrocarbon having the stated number of total atoms and at least one (e.g., 1 to 15) heteroatom selected from the group consisting of O, N, Si and S. The carbon and heteroatoms of the heteroalkyl group can be oxidized (e.g., to form ketones, N-oxides, sulfones, and the like) and the nitrogen atoms can be quaternized. The heteroatom(s) can be placed at any interior position of the heteroalkyl group and / or at any terminus of the heteroalkyl group, including termini of branched heteroalkyl groups), and / or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Examples of heteroalkyl groups include, but are not limited to, CH2CH2OCH3, CH2CH2NHCH3, CH2CH2N(CH3)2, C(O)NHCH2CH2NHCH3, C(O)N(CH3)CH2CH2N(CH3)2, C(O)NHCH2CH2NHC(O)CH2CH3, C(O)N(CH3)CH2CH2N(CH3)C(O)CH2CH3, OCH2CH2CH2NH(CH3), OCH2CH2CH2N(CH3)2, OCH2CH2CH2NHC(O)CH2CH3, OCH2CH2CH2N(CH3)C(O)CH2CH3, CH2CH2CH2NH(CH3), OCH2CH2CH2N(CH3)2, CH2CH2CH2NHC(O)CH2CH3, CH2CH2CH2N(CH3)C(O)CH2CH3, CH2SCH2CH3, CH2CH2S(O)CH3, NHCH2CH2NHC(O)CH2CH3, CH2CH2S(O)2CH3, CH2CH2OCF3, and Si(CH3)3. Up to two heteroatoms may be consecutive, such as, for example, CH2NHOCH3 and CH2OSi(CH3)3. A terminal polyethylene glycol (PEG) moiety is a type of heteroalkyl group.

[0323] The term “acyl” refers to an alkyl, haloalkyl, alkenyl, alkynyl, aryl cycloalkyl, heteroaryl, or heterocyclyl group, as defined herein, connected to the remainder of the compound by a C(O) (carbonyl) group.

[0324] The term “carboxamido” refers to a C(O)NRR’ group, wherein R and R’ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl cycloalkyl, heteroaryl, and heterocyclyl, as defined herein.

[0325] The term “heteroalkylene” refers to a bivalent unsubstituted straight or branched group derived from heteroalkyl (as defined herein). Examples of heteroalkylene groups include, but are not limited to, -CH2CH2OCH2-, -CH2CH2OCF2-, -CH2CH2NHCH2-, -C(O)NHCH2CH2NHCH2--C(O)N(CH3)CH2CH2N(CH3)CH2-, -C(O)NHCH2CH2NHC(O)CH2CH2-, -C(O)N(CH3)CH2CH2N(CH3)C(O)CH2CH2-, -OCH2CH2CH2NHCH2-, -OCH2CH2CH2N(CH3)CH2-, -OCH2CH2CH2NHC(O)CH2CH2-, -OCH2CH2CH2N(CH3)C(O)CH2CH2-, -CH2CH2CH2NHCH2-, -CH2CH2CH2N(CH3)CH2-, -CH2CH2CH2NHC(O)CH2CH2-, -CH2CH2CH2N(CH3)C(O)CH2CH2-, -CH2CH2NHC(O)-, -CH2CH2N(CH3)CH2-, -CH2CH2N+(CH3)2-, -NHCH2CH2(NH2)CH2-, and -NHCH2CH2(NHCH3)CH2-. A bivalent polyethylene glycol (PEG) moiety is a type of heteroalkylene group.

[0326] The term “alkoxy” refers to an alkyl group, as defined herein, which is attached to a molecule via an oxygen atom. For example, alkoxy groups include, but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

[0327] The term “cycloalkyl”, used synonymously herein with “carbocyclo”, refers to a cyclic, saturated or partially unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., “C3-8 cycloalkyl” or “C3-6 cycloalkyl” have from 3 to 8 or 3 to 6 carbon atoms, respectively). When the number of carbon atoms is not indicated, the cycloalkyl group has from 3 to 6 carbon atoms. Cycloalkyl groups include bridged, fused, and spiro ring systems, and bridged bicyclic systems where one ring is aromatic and the other is unsaturated. Representative “C3-6 cycloalkyl” groups include but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0328] The term “cycloalkylene” refers to a bivalent cyclic, saturated or partially unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., “C3-s cycloalkylene” or “C3-6 cycloalkylene” have from 3 to 8 or 3 to 6 carbon atoms, respectively). When the number of carbon atoms is not indicated, the cycloalkylene group has from 3 to 6 carbon atoms.

[0329] Cycloalkylene groups include bridged, fused, and spiro ring systems, and bridged bicyclic systems where one ring is aromatic and the other is unsaturated. Representative “C3-6 cycloalkylene” groups include, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0330] The term “aryl” refers to a carbocyclic aromatic hydrocarbon group of 6-10 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, biphenyl, and the like. In some embodiments, the term aryl can denote an aromatic ring with 6 carbons.

[0331] The term “arylene” refers to a bivalent carbocyclic aromatic hydrocarbon group of 6-10 carbon atoms derived by the removal of two hydrogen atoms from two carbon atoms of a parent aromatic ring system.

[0332] The term “heterocycle”, used synonymously herein with the terms “heterocyclo” and “heterocycloalkyl”, refers to a saturated or partially unsaturated ring or a multiple condensed ring system, including bridged, fused, and spiro ring systems, that includes at least one heteroatom (e.g., N, O, S, P, etc.). Heterocycles can be described by the total number of atoms in the ring system, for example a 3-10 membered heterocycle has 3 to 10 total ring atoms. The termincludes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3, or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more heterocycles (e.g., decahydronapthyridinyl), carbocycles (e.g., decahydroquinolyl) or aryls. The rings of a multiple condensed ring system can be connected to each other via fused, spiro, and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocycle or heterocycle multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, oxiranyl, thiaranyl, oxetanyl, pyrrolidinyl, piperidinyl, 1,4-dioxanyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3 -dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0333] The term “heteroaryl” refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from the group consisting of O, N and S. In some embodiments, heteroaryl groups have 5-10 total ring atoms and 1, 2, or 3 heteroatoms (referred to as a “5-10 membered heteroaryl”). Heteroaryl groups include, but are not limited to, imidazole, triazole, thiophene, furan, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0334] The term “heteroarylene” refers to a bivalent aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from the group consisting of O, N, and S.

[0335] The term “hydroxyl” refers to an OH group.

[0336] The term “cyano” refers to a CN group.

[0337] The term “carboxy” refers to a C(O)OH group.

[0338] The term “oxo” refers to an =0 group.The term “alkanoyl” refers to an alkyl group, as defined herein, connected to the remainder of the molecule by a C(O) group. Exemplary alkanoyl groups include, but are not limited to acetyl, n-propanoyl, and n-butanoyl.

[0339] The term “alkanoyloxy” refers to an alkyl group, as defined herein, connected to the remainder of the molecule by an OC(O) group. Exemplary alkanoyloxy groups include, but are not limited to acetoxy, n-propanoyloxy, and n-butanoyl oxy.

[0340] The term “alkoxycarbonyl” refers to an alkoxy group, as defined herein, connected to a -C(O)- group via the oxygen atom of the alkoxy (i.e., an alkyl ester group).

[0341] The term “alkoxythiocarbonyl” refers to an alkoxy group, as defined herein, connected to a C(=S)- group via the oxygen atom of the alkoxy (i.e., an alkyl thioester group).

[0342] The term “carbamoyl”, as defined herein, refers to C(0)N(R)2, wherein ‘R’ denotes variable substitution.

[0343] The term “amidine”, as defined herein, refers to C(N)N(R)2, wherein ‘R’ denotes variable substitution.

[0344] The term “sulfone”, as defined herein, refers to S(O)2R, wherein ‘R’ denotes variable substitution.

[0345] The term “thione”, as defined herein, refers to C(S)R, wherein ‘R’ denotes variable substitution.

[0346] The terms “arylalkyl” and “cycloalkylalkyl” refer to an aryl group or a cycloalkyl group (as defined herein) connected to the remainder of the molecule by an alkyl group, as defined herein. Exemplary arylalkyl groups include, but are not limited to benzyl and phenethyl.

[0347] Exemplary cycloalkylalkyl groups include, but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, and cyclohexylethyl.

[0348] As used herein, the term “hydrolyzable group” refers to a moiety which undergoes spontaneous hydrolytic cleavage under specific conditions. For example, a hydrolyzable group may be inert in neutral and basic solutions, but may undergo hydrolytic cleavage in days, hours, minutes, or seconds under acidic conditions. In some embodiments, a hydrolyzable group is configured to undergo hydrolytic cleavage in a particular physiological environment, such as blood (e.g., peripheral blood) or oxidative (e.g., lysosomal) or reductive (e.g., cytoplasmic) intracellular compartments. In some embodiments, a hydrolyzable group is configured for catalytic cleavage, for example by enzymes present in a specific organism (e.g., humans) or tissues (e.g., metabolically active tissues such as liver, kidney, or brain). A hydrolyzable group can be configured for cleavage by a range of enzymes, or by a specific enzyme. For example, a hydrolyzable group can comprise an oligopeptide of the sequence arginine-arginine-valine-arginine, for which human furin may have high cleavage activity. A hydrolyzable group can beconfigured for cleavage within a particular environment, such as endosomes or lysozomes of human cells. In such cases, the hydrolyzable group may be stable outside of the environment in which it is configured for cleavage. For example, a hydrolyzable group may be stable in circulation within peripheral blood, but hydrolytically cleave upon uptake into a cell. Examples of hydrolyzable groups include organophosphates such as phosphate esters, thiophosphates, and dithiophosphates, carbamates, carbonates, thioesters, quaternary amines, ureas, disulfides, organosulfates, diorganosulfates, certain amides and esters, and peptides with protease cleavage sites.

[0349] When referring to hydrogen, one or more hydrogen atoms can be replaced by a deuterium. It is well established that deuteration of physiologically active compounds offer the advantage of retaining the pharmacological profile of their hydrogen counterparts while positively impacting their metabolic outcome. Selective replacement of one or more hydrogen with deuterium, in a compound of the present disclosure, could improve the safety, tolerability and efficacy of the compound when compared to its all-hydrogen counterpart.

[0350] Methods for incorporation of deuterium into compounds is well established. Using metabolic studies establish in the art, the compound of the present disclosure can be tested to identify sites for selective placement of a deuterium isotope, wherein the isotope will not be metabolized. Moreover, these studies identify sites of metabolism as the location where a deuterium atom would be placed.

[0351] It will be appreciated by those skilled in the art that compounds described herein having a chiral center may exist in and be isolated in optically active (e.g., of a pure enantiomeric form, of an optically active mixture of enantiomeric forms, etc.) and racemic forms.

[0352] As used herein, the term “free drug” refers to a biologically active species that is not covalently attached to an antibody. Accordingly, free drug refers to a compound as it exists immediately upon cleavage from the ADC. The release mechanism can be via a cleavable linker in the ADC, or via intracellular conversion or metabolism of the ADC. In some aspects, the free drug will be protonated and / or may exist as a charged moiety. The free drug is a pharmacologically active species which is capable of exerting the desired biological effect. In some embodiments, the pharamacologically active species is the parent drug alone. In some embodiments, the pharamacologically active species is the parent drug bonded to a component or vestige of the ADC (e.g., a component of the linker, succinimide, hydrolyzed succinimide, and / or antibody that has not undergone subsequent intracellular metabolism).Compounds

[0353] In some embodiments of the compound of Formula I as defined herein, Y is O and X is N.

[0354] In some embodiments of the compound of Formula I, Y is O and X is C(R7).

[0355] In some embodiments of the compound of Formula I, R1is a Ci-Ce alkyl or C3-C8 cycloalkyl, wherein the Ci-Ce alkyl and C3-C8 cycloalkyl are each independently unsubstituted.

[0356] In some embodiments of the compound of Formula I, R1is a Ci-Ce alkyl or C3-C8 cycloalkyl, wherein the Ci-Ce alkyl and C3-C8 cycloalkyl are each independently substituted with 1 or 2 instances of R8.

[0357] In some embodiments of the compound of Formula I, R2is Ci-Ce alkyl, wherein the Ci-Ce alkyl is unsubstituted. In some embodiments of the compound of Formula I, R2is CH3.

[0358] In some embodiments of the compound of Formula I, R2is Ci-Ce alkyl, wherein the Ci- Ce alkyl is substituted.

[0359] In some embodiments of the compound of Formula I, R4is hydrogen and R3is C(O)R10. In some embodiments of the compound of Formula I, R6Ais hydrogen and R6Bis hydrogen.

[0360] In some embodiments, the compound is a compound of Formula la:

[0361]

[0362] Formula la

[0363] or a pharmaceutically acceptable salt thereof, wherein:

[0364] X is N or C(R7);

[0365] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0366] R3is hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R6Aand R6Bare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0367] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;

[0368] each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0369] R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0370] 3- to 10-membered heterocycloalkyl,

[0371]

[0372] or

[0373]

[0374] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0375] R10A, R10B, R10C

[0376]

[0377] independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0378] R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0379] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0380] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- Cio aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0381] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10aryl is unsubstituted or substituted with 1-3 instances of C1-C3alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8cycloalkyl; and

[0382] n is 0, 1, 2, 3, 4, or 5.

[0383] In some embodiments, R10is selected from:

[0384]

[0385] In some embodiments, the compound is a compound of Formula lb:

[0386]

[0387] Formula lb

[0388] or a pharmaceutically acceptable salt thereof, wherein:

[0389] X is N or C(R7);

[0390] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0391] R8is independently halogen, OR9, or C1-C6 alkyl;

[0392] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0393] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0394] R13is hydrogen or C1-C3 alkyl; and

[0395] m is 0, 1, 2, or 3.

[0396] In some embodiments, the compound is a compound of Formula Ic:

[0397]

[0398] Formula Ic

[0399] or a pharmaceutically acceptable salt thereof, wherein:

[0400] X is N or C(R7);

[0401] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl,wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0402] R8is independently halogen, OR9, or C1-C6 alkyl;

[0403] R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0404] R10Aand R10Bare each independently hydrogen, halogen, or C1-C6alkyl, wherein C1-C6alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0405] R10Lis hydrogen or C1-C12 alkyl, wherein the C1-C12 alkyl is unsubstituted or substituted with 1 to 3 instances ofR12;

[0406] each instance ofR12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

[0407] In some embodiments, the compound is a compound of Formula Id:

[0408]

[0409] Formula Id

[0410] or a pharmaceutically acceptable salt thereof, wherein:

[0411] X is N or C(R7);

[0412] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0413] R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0414] R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- Cio aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, and wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen; and

[0415] n is 0, 1, 2, 3, 4, or 5.

[0416] In some embodiments, the compound of Formula I is selected from Table 1.

[0417]

[0418]

[0419]

[0420]

[0421]

[0422] Table 1

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from Table 2.

[0441]

[0442]

[0443]

[0444] Drug-linker compounds

[0445] In some embodiments, the present disclosure provides a compound of Formula I coupled to a linker to form a drug-linker compound. When preparing Ligand-Drug Conjugate molecules described herein, it can be desirable to synthesize the full Drug-Linker compound prior to conjugation to a targeting agent, which becomes the Ligand Unit of the Ligand-Drug conjugate molecule. In such embodiments, Drug-Linker compounds as described herein, are intermediate compounds. In those embodiments, the Stretcher Unit in a Drug-Linker compound is not yet covalently attached to the Ligand Unit (i.e., is a Stretcher Unit precursor, Z'), and therefore has a functional group for conjugation to a targeting agent. In some embodiments, a Drug-Linker compound comprises a moiety of a compound of the disclosure (shown herein as Formula I, la, lb, Ic, or Id) or, and a Linker Unit (Q) through which the Ligand Unit is connected to the Drug Unit.

[0446] The linker can modulate localization, solubility, and activity of the compound of the disclosure such as a compound of Formula I. Linker hydrophobicity and hydrophilicity of the linker can affect its partitioning following uptake and cleavage, thereby affecting the activity of the compound of the disclosure. The linker can be configured to promote specific tissue, cell, or sub-cellular localization. In some embodiments, linker lipophilicity promotes endocytic uptake by a target cell. For example, the linker can include a partitioning unit S* such as polyethylene glycol, a lipid, a non-charged and non-polar peptide, or a further membrane-permeable group which localizes a compound of the disclosure to or promotes uptake by a target cell. Linker length, rigidity, and hydrophilicity can also alter the hydrodynamic radii of Formula I containing compounds and molecules, affecting its clearance.

[0447] A Drug-Linker compound can include a compound of Formula I, la, lb, Ic, or Id, as a Drug Unit and a Linker Unit (Q) comprising a Releasable Linker (RL) through which the Ligand Unit is connected to the compound of Formula I. The Releasable Linker can be configured for cleavage by particular enzymes or under specific physiological conditions. When coupled to a ligand which directs coupling to or uptake by specific cells or tissues, the linker can promote location-specific drug release. For example, the Releasable Linker can be configured for cleavage at low pH, such as that typically present in a tumor microenvironment; or in an oxidizing environment, such as those of lysosomes and some endosomes, increasing target-site localization of compounds of the disclosure. In some embodiments, the Releasable Linker is configured for acid-mediated cleavage. In some embodiments, the Releasable Linker is configured for base-mediated cleavage. In some embodiments, the Releasable Linker is configured for reductant- (e.g., glutathione) mediated cleavage. In some embodiments, the Releasable Linker is configured for oxidant- (e.g., hydrogen peroxide) Releasable Linkercleavage. In some embodiments, the linker has an acid or base cleavable carbamate or quaternary ammonium. In some embodiments, the linker has a protease recognition sequence.

[0448] In some embodiments, the Releasable Linker is coupled to the drug such that the bond between the drug and linker is cleavable. Cleavage of the bond between the drug and linker can liberate the drug without a residual portion of the linker. In particular embodiments disclosed herein, the linker is coupled to a nitrogen atom of an amino group of Formula I, la, lb, Ic, or Id to form a carbonate, a carbamate, a thiocarbamate, or a positive-charged quaternary amine.

[0449] The linker can include a Stretcher Unit (Z’), a bond or a Connector Unit (A); a Parallel Connector Unit (B); a Partitioning Agent (S*); a Releasable Linker (RL); an Amino Acid Unit (W); a Spacer Unit (T); or a combination thereof.

[0450] i. Stretcher United (Z ’)

[0451] The Stretcher Unit (Z) can connect the Ligand Unit to the remainder of the conjugate. A Stretcher Unit precursor (Z1) is a component of a Drug-Linker compound or intermediate thereof has a functional group that can form a bond with a functional group of a targeting ligand to form a Stretcher Unit (Z).

[0452] In some embodiments, a Stretcher Unit precursor (Z1) has an electrophilic group that is capable of interacting with a reactive nucleophilic group present on a Ligand Unit (e.g., an antibody) to provide a covalent bond between a Ligand Unit and the Stretcher Unit of a Linker Unit. Nucleophilic groups on an antibody having that capability include but are not limited to, sulfhydryl, hydroxyl and amino functional groups. In some embodiments, the heteroatom of the nucleophilic group of an antibody is reactive to an electrophilic group on a Stretcher Unit precursor and can provide a covalent bond between the Ligand Unit and Stretcher Unit of a Linker Unit or Drug-Linker moiety. Useful electrophilic groups for that purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters. The electrophilic group provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate molecule or Ligand Unit-Linker intermediate compound.

[0453] In other embodiments, a Stretcher Unit precursor has a reactive site which has a nucleophilic group that is reactive to an electrophilic group present on a Ligand Unit (e.g., an antibody). Useful electrophilic groups on an antibody for that purpose include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of a nucleophilic group of a Stretcher Unit precursor can react with an electrophilic group on an antibody and form a covalent bond to the antibody. Useful nucleophilic groups on a Stretcher Unit precursor for that purpose include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The electrophilic group on anantibody provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate molecule or Ligand Unit-Linker intermediate compound.

[0454] In some embodiments, a sulfur atom of a Ligand Unit is bound to a succinimide ring system of a Stretcher Unit formed by reaction of a thiol functional group of a targeting ligand with a maleimide moiety of the corresponding Stretcher Unit precursor. In other embodiments, a thiol functional group of a Ligand Unit reacts with an alpha haloacetamide moiety to provide a sulfur-bonded Stretcher Unit by nucleophilic displacement of its halogen substituent.

[0455] Illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprise a maleimide moiety and are represented by structures including that of formula Z'a

[0456]

[0457] wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and / or B, R27is

[0458] -(CH2)1-5- or -CH2CH2(OCH2CH2)1-36-. In some embodiments, R27is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH2CH2OCH2CH2-, -CH2CH2(OCH2CH2)2--CH2CH2(OCH2CH2)3-, -CH2CH2(OCH2CH2)4-, -CH2CH2(OCH2CH2)5- -CH2CH2(OCH2CH2)6-, -CH2CH2(OCH2CH2)7-, -CH2CH2(OCH2CH2)8- -CH2CH2(OCH2CH2)10-, -CH2CH2(OCH2CH2)12- -CH2CH2(OCH2CH2)14--CH2CH2(OCH2CH2)16-, -CH2CH2(OCH2CH2)18- -CH2CH2(OCH2CH2)20--CH2CH2(OCH2CH2)24-, -CH2CH2(OCH2CH2)28-, -CH2CH2(OCH2CH2)32-, or -CH2CH2(OCH2CH2)36-.

[0459] Other illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprises a maleimide moiety and are represented by structures including that of formula Z'a-BU

[0460]

[0461] wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and / or B, R17is R17is-(CH2)1-5- or -CH2CH2(OCH2CH2)1-5-, substituted with a Basic Unit (BU), such as an optionally substituted aminoalkyl, e.g., -(CH2)XNH2, -(CH2)xNHRa, and -(CH2)xN(Ra)2, wherein subscript x is an integer of from 1-4, preferably R17is -CH2- or -CH2CH2- and subscript x is 1 or 2, and each Rais independently selected from the group consisting of Ci-6 alkyl and Ci-6 haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group.

[0462] In some embodiments of formula Z'a, a Stretcher Unit precursor (Z1) is represented by one of the following structures:

[0463]

[0464] wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU.

[0465] In other embodiments the Stretcher unit precursor (Z1) comprises a maleimide moiety and is represented by the structure of:

[0466]

[0467] wherein the wavy line adjacent to the carbonyl is as defined for Z'a and the amino group is optional protonated or protected by an amino protecting group.

[0468] In Stretcher Units having a BU moiety, it will be understood that the amino functional group of that moiety is typically protected by an amino protecting group during synthesis, e.g., an acid labile protecting group (e.g., BOC).

[0469] Illustrative Stretcher Unit precursors covalently attached to a Connector Unit that comprise the structure of Z'a or Z'a-BU in which -R27- or -R27(BU)- is -CH2-, -CH2CH2- or -CH(CH2NH2)- have the following structures:

[0470]

[0471] wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU.

[0472] Other Stretcher Unit precursors bonded a Connector Unit (A) have the structures above wherein A in any one of the above Z'-A- and Z'(BU)-A- structures is replaced by a Parallel Connector Unit and Partitioning Agent (-B(S*)-) having the structure of

[0473]

[0474] wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; RPEGis a PEG Capping Unit, preferably H, CH3, or CH2CH2CO2H, the asterisk (*) indicates covalent attachment to the Stretcher Unit precursor corresponding in structure to formula Z'a and the wavy line indicates covalent attachment to RL. In instances such as those shown here, the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit.In some embodiments of the prevent disclosure the Stretcher Unit has a mass of no more than about 1000 Daltons, no more than about 500 Daltons, no more than about 200 Daltons, from about 30, 50 or 100 Daltons to about 1000 Daltons, from about 30, 50 or 100 Daltons to about 500 Daltons, or from about 30, 50 or 100 Daltons to about 200 Daltons.

[0475] ii. Connector Unit (A)

[0476] In some embodiments, a Connector Unit (A), is included in a Drug-Linker Compound in instances where it is desirable to add additional distance between the Stretcher Unit precursor (Z1) and the Releasable Linker. In some embodiments, the extra distance will aid with activation within RL. Accordingly, the Connector Unit (A), when present, extends the framework of the Linker Unit. In that regard, a Connector Unit (A) is covalently bonded with the Stretcher Unit (or its precursor) at one terminus and is covalently bonded to the optional Parallel Connector Unit or the Partitioning Agent (S*) at its other terminus.

[0477] The skilled artisan will appreciate that the Connector Unit is any group that serves to provide for attachment of the Releasable Linker to the remainder of the Linker Unit (Q). The Connector Unit can, for example, comprise one or more (e.g., 1-10, preferably, 1, 2, 3, or 4) proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, diamino residues. In some embodiments, the Connector Unit is a single proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, or diamino residue. An exemplary amino acid capable of acting as Connector units is P-alanine.

[0478] In some of those embodiments, the Connector Unit has the formula denoted below:

[0479]

[0480] wherein the wavy lines indicate attachment of the Connector Unit within the Drug-Linker Compound; and wherein R111is independently selected from the group consisting of hydrogen, -hydroxybenzyl, methyl, isopropyl, isobutyl,.scc-butyl, -CH2OH, -CH(0H)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2 -pyridylmethyl-, 3 -pyridylmethyl-, 4-pyridylmethyl-,

[0481]

[0482] and each R100is independently selected from hydrogen or -Ci-C3alkyl, preferably hydrogen or CH3; and subscript c is an independently selected integer from 1 to 10, preferably 1 to 3.

[0483] A representative Connector Unit having a carbonyl group for attachment to the Partitioning Agent (S*) or to -B(S*)- is as follows:

[0484]

[0485] wherein in each instance R33is independently selected from the group consisting of -CH2CH2(OCH2CH2)k-, -Ci-Ce alkylene-, -C3-Cscarbocyclo-, -arylene-, -Ci-Cioheteroalkylene-, -C3-Csheterocyclo-, -Ci-Cioalkylene-arylene-, -arylene-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Cscarbocyclo)-, -(C3-Cscarbocyclo)-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Cs heterocyclo)-, and -(C3-Cs heterocyclo)-Ci-Cio alkylene-, wherein subscript k is an integer ranging from 1 to 36 and the subscript c is an integer ranging from 1 to 4. In some embodiments R33is -Ci-Ce alkylene and c is 1.

[0486] Another representative Connector Unit having a carbonyl group for attachment to Partitioning Agent (S*) or to -B(S*)- is as follows:

[0487]

[0488] wherein R13is -CH2CH2(OCH2CH2)k-, -Ci-Ce alkylene-, -C3-Cscarbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -C3-Csheterocyclo-, -Ci-Cioalkylene-arylene-, -arylene-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Cscarbocyclo)-, -(C3-Cscarbocyclo)-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Csheterocyclo)-, or -(C3-C8 heterocyclo)-Ci-Cio alkylene-, wherein subscript k is an integer ranging from 1 to 36. In some embodiments R13is -Ci-Ce alkylene.

[0489] A representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S*) or to -B(S*)- is as follows:

[0490]

[0491] wherein in each instance, R33is independently selected from the group consisting of -CH2CH2(OCH2CH2)k-, -Ci-Ce alkylene-, -Cs-Cscarbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -Cs-Csheterocyclo-, -Ci-Cioalkylene-arylene-, -arylene-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Cscarbocyclo)-, -(C3-Cscarbocyclo)-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-Cs heterocyclo)-, and -(C3-C8 heterocyclo)-Ci-Cio alkylene-, wherein subscript k is an integer ranging from 1 to 36 and subscript c is an integer ranging from 1 to 36. In some embodiments R13is -Ci-Ce alkylene and subscript c is 1.

[0492] Another representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S*) or to -B(S*)- is as follows:

[0493]

[0494] 2

[0495] wherein R33is -CH2CH2(OCH2CH2)k-, -Ci-Ce alkylene-, -Cs-Cscarbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -Cs-Csheterocyclo-, -Ci-Cioalkylene-arylene-, -arylene-Ci-Cioalkylene-, -Ci-Cioalkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -Ci-Cioalkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-Ci-Cio alkylene-, -C(O)Ci-Ce alkylene- or -Ci-Ce alkylene-C(O)-Ci-Ce alkylene, wherein subscript k is an integer ranging from 1 to 36.

[0496] Selected embodiments of Connector Units include those having the following structure of:

[0497]

[0498] wherein the wavy line adjacent to the nitrogen indicates covalent attachment a Stretcher Unit (Z) (or its precursor Z'), and the wavy line adjacent to the carbonyl indicates covalent attachment to Partitioning Agent (S*) or to -B(S*)-; and m is an integer ranging from 1 to 6, preferably 2 to 6, more preferably 2 to 4.iii. Releasable Linker (RL)

[0499] The Releasable Linker (RL) is capable of linking to the Spacer Unit (Y) or the Drug Unit (D). RL can comprise a cleavable bond (i.e., a reactive site) that upon action by an enzyme present within or near a target cell or upon non-enzymatic action due to conditions more likely experienced within or near a target cell (e.g., a low pH tumor microenvironment), undergoes cleavage to release the free drug. In some embodiments, RL comprises a cleavable bond that is more likely acted upon intracellularly in a hyper-proliferating cell or hyper-activated immune cell due to preferential entry into such cells in comparison to normal cells.

[0500] In some embodiments, the Releasable Linker is a Peptide Releasable Linker. In some embodiments, the Peptide Releasable Linker (RL) will comprise one or more contiguous or noncontiguous sequences of amino acids (e.g., so that RL has 1 to no more than 12 amino acids). The Peptide Releasable Linker can comprise or consist of, for example, an amino acid, a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit. In some aspects, in the presence of an enzyme (e.g., a tumor-associated protease), an amide linkage between the amino acids is cleaved, which ultimately leads to release of free drug.

[0501] Each amino acid can be proteinogenic or non-proteinogenic and / or a D- or L-isomer provided that RL comprises a cleavable bond that, when cleaved, initiates release of the Drug Unit. In some embodiments, the Peptide Releasable Linker will comprise only proteinogenic amino acids. In some aspects, the Peptide Releasable Linker will have from 1 to no more than 12 amino acids in contiguous sequence.

[0502] In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, P-alanine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino-heterocyclo-alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, and selenocysteine. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine,tyrosine, threonine, isoleucine, proline, tryptophan, and valine. In some embodiments, each amino acid is selected from the proteinogenic or the non-proteinogenic amino acids.

[0503] In another embodiment, each amino acid is independently selected from the group consisting of the following L-(proteinogenic) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.

[0504] In another embodiment, each amino acid is independently selected from the group consisting of the following D-isomers of these proteinogenic amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.

[0505] In certain embodiments, the Peptide Releasable Linker comprises only proteinogenic amino acids. In other embodiments, the Peptide Releasable Linker comprises only non-proteinogenic amino acids. In some embodiments, the Peptide Releasable Linker comprises a proteinogenic amino acid attached to a non-proteinogenic amino acid. In some embodiments, Peptide Releasable Linker comprises a proteinogenic amino acid attached to a D-isomer of a proteinogenic amino acid.

[0506] In another embodiment, each amino acid is independently selected from the group consisting of P-alanine, N-methylglycine, glycine, lysine, valine and phenylalanine.

[0507] Exemplary Peptide Releasable Linkers include dipeptides or tripeptides with-Val-Lys-Gly-, -Val-Cit-, -Phe-Lys- or -Vai-Ala-.

[0508] Useful Peptide Releasable Linkers are designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease. In some embodiments, cleavage of a linkage is catalyzed by cathepsin B, C or D, or a plasmin protease.

[0509] In some embodiments, the Peptide Releasable Linker (RL) will be represented by -(-AA-)1 - 12-, or (-AA-AA-)l-6 wherein AA is at each occurrence independently selected from proteinogenic or non-proteinogenic amino acids. In one aspect, AA is at each occurrence independently selected from proteinogenic amino acids. In another aspect, RL is a tripeptide having the formula: AA1-AA2- AA3, wherein AA1, AA2 and AA3 are each independently an amino acid and wherein AA1 attaches to -NH- and AA3 attaches to S*. In yet another aspect, AA3 is gly or P-ala.

[0510] In some embodiments, the Peptide Releasable Linker has the formula denoted below in the square brackets, the subscript w is an integer ranging from 1 to 12; or w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or w is 2, 3, or 4; or w is 3; or w is 4:

[0511]

[0512] wherein R29is, in each instance, independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, ec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2 -pyridylmethyl-, 3 -pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,

[0513]

[0514] In some embodiments, the subscript w is not 3.

[0515] In some embodiments, each R29is independently hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NH2, or -(CH2)4NH2. In some aspects, each R19is independently hydrogen, isopropyl, or -(CH2)4NH2.

[0516] In some embodiments, RL comprises a peptide selected from the group consisting of gly-gly, gly-gly-gly, gly-gly-gly-gly (SEQ ID NO: 1043), val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly (SEQ ID NO:

[0517] 1046), gly-gly-phe-gly-gly (SEQ ID NO: 1047), val-gly, and val-lys-P-ala. In other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly, gly-gly-gly-gly (SEQ ID NO: 1043), val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly (SEQ ID NO: 1046), and val-lys-P-ala. In still other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-P-ala. In yet other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly-gly (SEQ ID NO: 1043), gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), and gly-gly-phe-gly (SEQ ID NO: 1046). In other embodiments, RL is a peptide selected from the group consisting of val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-P-ala. In still other embodiments, RL is val-lys-gly. In still other embodiments, RL is val-lys-P-ala. In some embodiments, the Releasable Linker RL is

[0518]

[0519] wherein the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z' or the Connector Unit A and the wavy line adjacent to the -C(O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D.

[0520] In some embodiments, the Releasable Linker is a Glycoside (e.g., Glucuronide) Unit. In such embodiments, a self-immolation cascade is activated by operation of a glycosidase on a carbohydrate moiety of the Glycoside (e.g., Glucuronide) Unit. A number of sugars are useful in the embodiments described herein. Particular carbohydrate moieties include those of Galactose, Glucose, Mannose, Xylose, Arabinose, Mannose-6-phosphate, Fucose, Rhamnose, Gulose, Allose, 6-deoxy-glucose, Lactose, Maltose, Cellobiose, Gentiobiose, Maltotriose, GlcNAc, GalNAc and maltohexaose.

[0521] A Glycoside (e.g., Glucuronide) Unit typically comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative spacer. Cleavage of the oxygen glycosidic bond initiates the self-immolation reaction sequence that result in release of free drug. In some embodiments, the self-immolation sequence is activated from cleavage by P -glucuronidase of a Glycoside (e.g., Glucuronide) Unit, which is an exemplary glycoside unit. The Glycoside (e.g., Glucuronide) Unit comprises an activation unit and a self-immolative Spacer Unit. TheGlycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative Spacer Unit.

[0522] In some embodiments, a Glycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycoside bond (-O'-) to a Self-immolative Unit (SP) of the formula:

[0523]

[0524] wherein the wavy lines indicate covalent attachment to the Drug Unit or to a Spacer Unit that is attached to the Drug Unit, and to the Stretcher Unit precursor (Z1), either directly or indirectly through the Connector Unit (A) or Parallel Connector Unit (B), Partitioning Agent (S*) or combinations of the Connector Unit and Parallel Connector Unit, as the case may be.

[0525] The oxygen glycosidic bond (-O'-) is typically a P-glucuronidase-cleavage site (i.e., Su is from glucuronide), such as a glycoside bond cleavable by human, lysosomal P-glucuronidase.

[0526] In some embodiments, the Glycoside (e.g., Glucuronide) Unit is represented by formula Ga, Gb, or Gc:

[0527]

[0528] wherein Su is a Sugar moiety, -O'- represents an oxygen glycosidic bond; R1S, R2S and R3S independently are hydrogen, a halogen, CN, NO2, or other electron withdrawing group, or an electron donating group; RBZis selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, a PEG unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, and a dendrimer; and wherein the wavy line indicates attachment to a Stretcher Unit precursor (Z1), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit); and # indicates attachment to the Drug Unit or to a Spacer (either directly or indirectly via an intervening functional group or other moiety).

[0529] In some embodiments, R1S, R2S, and R3Sare independently selected from hydrogen, halogen, CN, or NO2. In some embodiments, R1S, R2Sand R3Sare each hydrogen. In some embodiments, R2Sis an electron withdrawing group, preferably NO2, and R1Sand R3Sare each hydrogen.

[0530] In some such aspects the activatable self-immolative group capable of glycosidase cleavage to initiate the self-immolative reaction sequence is represented by the formula Gd:

[0531]

[0532] wherein R4Sis CH2OH or –CO2H, the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit, and the hash mark (#) indicates covalent attachment to the methylene carbamate unit.

[0533] In some embodiments wherein the activatable self-immolative moiety comprises a Glycoside (e.g., Glucuronide) Unit, it is represented by the following formula Ge:

[0534]

[0535] wherein the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit and the hash mark (#) indicates covalent attachment of thebenzylic carbon of a Spacer or functional group attached to the Drug Unit. In some embodiments, the structure of formula Ge is attached to the Drug Unit via a quaternized tertiary amine (N+), wherein the nitrogen atom is from a tertiary amine functional group on the unconjugated Drug Unit.

[0536] Another type of Releasable Linker that provides a mechanism for separation of the Drug Unit from the Ligand Unit and other components of the Linker Unit through activation of a self-immolation cascade within the Linker Unit comprises a p-aminobenzyloxy carbonyl (PAB) moiety whose phenylene component is substituted with Jmwherein the subscript m indicating the number of substituents is an integer ranging from 0-4, and each J is independently Ci-Cs alkyl, O(Ci-Cs alkyl), halogen, nitro or cyano.

[0537] In some embodiments, RL is a self-immolative group capable of releasing -D without the need for a separate hydrolysis step or subsequent self-immolative event. In some embodiments, -RL- is a PAB moiety that is linked to the carbonyl of -W- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group. In related embodiments, -RL-comprises a PAB moiety that is linked to the carbonyl of

[0538] -A-, -S*- or -B- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group. Without being bound by any particular theory or mechanism, a possible mechanism of Drug release from RL comprises a PAB moiety in which RL is attached directly to -D via a carbonate group is shown in Toki et al. (2002) J Org. Chem. 67:1866-1872.

[0539] In some embodiments, RL units containing a PAB moiety are represented by the formula:

[0540]

[0541] wherein subscript m is an integer ranging from 0-4, and each J is independently Ci-Cs alkyl, -O-(Ci-Cs alkyl), -halogen, -nitro or -cyano.

[0542] Other examples of self-immolative groups include, but are not limited to, aromatic compounds that are electronically similar to the PAB moiety such as 2-aminoimidazol-5-methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho or paraaminobenzylacetals. Other RLs undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm, et al., J. Amer. Chem. Soc., 1972, 94, 5815) and 2-aminophenylpropionic acid amides (Amsberry, et al., J. Org. Chem., 1990, 55, 5867).In one embodiment, RL is a branched bis(hydroxymethyl)styrene (BHMS) unit.

[0543] In some embodiments, RL has the formula:

[0544]

[0545] wherein the wavy line marked with ** indicates the site of attachment to D; and the wavy line marked with * indicates the point of attachment to additional linker components of Q. In some embodiments, a P AB -containing RL is directly attached to the Drug Unit.

[0546] iv. Partitioning Agent (S*)

[0547] The Ligand-Drug Conjugates described herein can also include a Partitioning Agent (S*). The Partitioning Agent portions are useful, for example, to mask the hydrophobicity of particular Drug Units or Linking Unit components.

[0548] Representative Partitioning Agents include polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides, and dendrimers.

[0549] When the polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides or dendrimers are included in Q, the groups may be present as an ‘in line’ component or as a side chain or branched component. For those embodiments in which a branched version is present, the Linker Units can include a lysine residue (or Parallel Connector Unit, B) that provides simple functional conjugation of, for example, the PEG unit, to the remainder of the Linking Unit

[0550] When present, poly disperse PEGs, monodisperse PEGs, and discrete PEGs are used as part of the Partitioning Agents in Compounds of the present disclosure. Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight. Preferred PEG Units are discrete PEGs, compounds that are synthesized in stepwise fashion and not via a polymerization process. Discrete PEGs provide a single molecule with defined and specified chain length.

[0551] The PEG Unit provided herein can comprise one or multiple polyethylene glycol chains. A polyethylene glycol chain is composed of at least two ethylene oxide (CH2CH2O) subunits. In some embodiments the polyethylene glycol chains are linked together, for example, in a linear, branched or star shaped configuration. Typically, at least one of the PEG chains is derivitized at one end for covalent attachment to an appropriate site on a component of the Linker Unit (e.g. B) or is used as an in-line (e.g., bifunctional) linking group within to covalently join two of theLinker Unit components (e.g., Z-A-S*-RL-, Z-A-S*-RL-T- ). Exemplary attachments within the Linker Unit are by means of non-conditionally cleavable linkages or via conditionally cleavable linkages. Exemplary attachments are via amide linkage, ether linkages, ester linkages, hydrazone linkages, oxime linkages, disulfide linkages, peptide linkages or triazole linkages. In some embodiments, attachment within the Linker Unit is by means of a non-conditionally cleavable linkage. In some embodiments, attachment within the Linker Unit is not via an ester linkage, hydrazone linkage, oxime linkage, or disulfide linkage. In some embodiments, attachment within the Linker Unit is not via a hydrazone linkage.

[0552] A conditionally cleavable linkage refers to a linkage that is not substantially sensitive to cleavage while circulating in the plasma but is sensitive to cleavage in an intracellular or intratumoral environment. A non-conditionally cleavable linkage is one that is not substantially sensitive to cleavage in any biological environment. Chemical hydrolysis of a hydrazone, reduction of a disulfide, and enzymatic cleavage of a peptide bond or glycosidic linkage are examples of conditionally cleavable linkages.

[0553] In some embodiments, the PEG Unit is directly attached to a Parallel Connector Unit B, wherein the other terminus (or termini) of the PEG Unit is free and untethered and may take the form of a methoxy, carboxylic acid, alcohol or other suitable functional group. The methoxy, carboxylic acid, alcohol or other suitable functional group acts as a cap for the terminal PEG subunit of the PEG Unit. By untethered, it is meant that the PEG Unit will not be attached at that untethered site to a Drug Unit, to an antibody, or to another linking component. The skilled artisan will understand that the PEG Unit in addition to comprising repeating ethylene glycol subunits may also contain non-PEG material (e.g., to facilitate coupling of multiple PEG chains to each other). Non-PEG material refers to the atoms in the PEG Unit that are not part of the repeating -CH2CH2O- subunits. In some embodiments provided herein, the PEG Unit comprises two monomeric PEG chains attached to each other via non-PEG elements. In other embodiments provided herein, the PEG Unit comprises two linear PEG chains attached to a central core or Parallel Connector Unit (i.e., the PEG Unit itself is branched).

[0554] There are a number of PEG attachment methods available to those skilled in the art, [see, e.g., Goodson, et al. (1990) Bio / Technology 8:343 (PEGylation of interleukin-2 at its glycosylation site after site-directed mutagenesis); EP 0401 384 (coupling PEG to G-CSF); Malik, et al., (1992) Exp. Hematol. 20:1028-1035 (PEGylation of GM-CSF using tresyl chloride); PCT Pub. No. WO 90 / 12874 (PEGylation of erythropoietin containing a recombinantly introduced cysteine residue using a cysteine-specific mPEG derivative); U. S. Pat. No. 5,757,078 (PEGylation of EPO peptides); U. S. Pat. No. 5,672,662 (Polyethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functionalderivatives thereof for biotechnical applications); U. S. Pat. No. 6,077,939 (PEGylation of anN-terminal.alpha.-carbon of a peptide); Veronese et al., (1985) Appl. Biochem. Biotechnol 11:141-142 (PEGylation of an N-terminal a-carbon of a peptide with PEG-nitrophenylcarbonate ("PEG-NPC") or PEG-trichlorophenylcarbonate); and Veronese (2001) Biomaterials 22:405-417 (Review article on peptide and protein PEGylation)].

[0555] For example, PEG may be covalently bound to amino acid residues via a reactive group. Reactive groups are those to which an activated PEG molecule may be bound (e.g., a free amino or carboxyl group). For example, N-terminal amino acid residues and lysine (K) residues have a free amino group; and C-terminal amino acid residues have a free carboxyl group. Thiol groups (e.g., as found on cysteine residues) can also be useful as a reactive group for attaching PEG. In addition, enzyme-assisted methods for introducing activated groups (e.g., hydrazide, aldehyde, and aromatic-amino groups) specifically at the C-terminus of a polypeptide have been described (see Schwarz, et al. (1990) Methods Enzymol. 184:160; Rose, et al. (1991) Bioconjugate Chem.

[0556] 2:154; and Gaertner, et al. (1994) J. Biol. Chem. 269:7224],

[0557] In some embodiments, PEG molecules may be attached to amino groups using methoxylated PEG ("mPEG") having different reactive moieties. Non-limiting examples of such reactive moieties include succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenylcarbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride. Non-limiting examples of such mPEGs include mPEG-succinimidyl succinate (mPEG-SS), mPEG2-succinimidyl succinate (mPEG2-SS); mPEG-succinimidyl carbonate (mPEG-SC), mPEG2-succinimidyl carbonate (mPEG2-SC); mPEG-imidate, mPEG-para-nitrophenylcarbonate (mPEG-NPC), mPEG-imidate; mPEG2-para-nitrophenylcarbonate (mPEG2-NPC); mPEG-succinimidyl propionate (mPEG-SPA); mPEG2-succinimidyl propionate (mPEG2-SPA); mPEG-N-hydroxy-succinimide (mPEG-NHS); mPEG2-N-hydroxy-succinimide (mPEG2-NHS); mPEG-cyanuric chloride; mPEG2-cyanuric chloride; mPEG2-Lysinol-NPC, and mPEG2-Lys-NHS.

[0558] Generally, at least one of the PEG chains that make up the PEG Unit is functionalized so that it is capable of covalent attachment to other Linker Unit components.

[0559] Functionalization includes, for example, via an amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or other functional group. In some embodiments, the PEG Unit further comprises non-PEG material (i.e., material does not comprise -CH2CH2O-) that provides coupling to other Linker Unit components or to facilitate coupling of two or more PEG chains.

[0560] The presence of the PEG Unit (or other Partitioning Agent) in the Linker Unit can have two potential impacts upon the pharmacokinetics of the resulting Ligand-Drug Conjugate. The desired impact is a decrease in clearance (and consequent increase in exposure) that arises fromthe reduction in non-specific interactions induced by the exposed hydrophobic elements of the Ligand-Drug Conjugate or to the Drug Unit itself. The second impact is undesired and is a decrease in volume and rate of distribution that sometimes arises from the increase in the molecular weight of the Ligand-Drug Conjugate.

[0561] Increasing the number of PEG subunits increases the hydrodynamic radius of a conjugate, typically resulting in decreased diffusivity. In turn, decreased diffusivity typically diminishes the ability of the Ligand-Drug Conjugate to penetrate into a tumor (Schmidt and Wittrup, Mol Cancer Ther 2009;8:2861-2871). Because of these two competing pharmacokinetic effects, it is desirable to use a PEG that is sufficiently large to decrease the Ligand-Drug Conjugate clearance thus increasing plasma exposure, but not so large as to greatly diminish its diffusivity, to an extent that it interferes with the ability of the Ligand-Drug Conjugate to reach the intended target cell population. See the examples (e.g., examples 1, 18, and 21) of US2016 / 0310612, which are incorporated by reference herein, for methodology for selecting an optimal PEG size for a particular drug-linker.

[0562] In one group of embodiments, the PEG Unit comprises one or more linear PEG chains each having at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits. In some embodiments, the PEG Unit comprises a combined total of at least 4 subunits, at least 6 subunits, at least 8 subunits, at least 10 subunits, or at least 12 subunits. In some such embodiments, the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits.

[0563] In one group of embodiments, the PEG Unit comprises one or more linear PEG chains each having 2 subunits, 3 subunits, 4 subunits, 5 subunits, 6 subunits, 7 subunits, 8 subunits, 9 subunits, 10 subunits, 11 subunits, 12 subunits, 13 subunits, 14 subunits, 15 subunits, 16 subunits, 17 subunits, 18 subunits, 19 subunits, 20 subunits, 21 subunits, 22 subunits, 23 subunits, or 24 subunits. In some embodiments, the PEG Unit comprises a combined total of 4 subunits, 6 subunits, 8 subunits, 10 subunits, or 12 subunits. In some such embodiments, the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits.

[0564] In another group of embodiments, the PEG Unit comprises a combined total of from 4 to 72, 4 to 60, 4 to 48, 4 to 36 or 4 to 24 subunits, from 5 to 72, 5 to 60, 5 to 48, 5 to 36 or 5 to 24 subunits, from 6 to 72, 6 to 60, 6 to 48, 6 to 36 or from 6 to 24 subunits, from 7 to 72, 7 to 60, 7to 48, 7 to 36 or 7 to 24 subunits, from 8 to 72, 8 to 60, 8 to 48, 8 to 36 or 8 to 24 subunits, from 9 to 72, 9 to 60, 9 to 48, 9 to 36 or 9 to 24 subunits, from 10 to 72, 10 to 60, 10 to 48, 10 to 36 or 10 to 24 subunits, from 11 to 72, 11 to 60, 11 to 48, 11 to 36 or 11 to 24 subunits, from 12 to 72, 12 to 60, 12 to 48, 12 to 36 or 12 to 24 subunits, from 13 to 72, 13 to 60, 13 to 48, 13 to 36 or 13 to 24 subunits, from 14 to 72, 14 to 60, 14 to 48, 14 to 36 or 14 to 24 subunits, from 15 to 72, 15 to 60, 15 to 48, 15 to 36 or 15 to 24 subunits, from 16 to 72, 16 to 60, 16 to 48, 16 to 36 or 16 to 24 subunits, from 17 to 72, 17 to 60, 17 to 48, 17 to 36 or 17 to 24 subunits, from 18 to 72, 18 to 60, 18 to 48, 18 to 36 or 18 to 24 subunits, from 19 to 72, 19 to 60, 19 to 48, 19 to 36 or 19 to 24 subunits, from 20 to 72, 20 to 60, 20 to 48, 20 to 36 or 20 to 24 subunits, from 21 to 72, 21 to 60, 21 to 48, 21 to 36 or 21 to 24 subunits, from 22 to 72, 22 to 60, 22 to 48, 22 to 36 or 22 to 24 subunits, from 23 to 72, 23 to 60, 23 to 48, 23 to 36 or 23 to 24 subunits, or from 24 to 72, 24 to 60, 24 to 48, 24 to 36 or 24 subunits.

[0565] In some embodiments, the Partitioning Agent S* is a linear PEG Unit comprising from 2 to 20, or from 2 to 12, or from 4 to 12, or 4, 8, or 12 -CH2CH2O- subunits. In some embodiments, the linear PEG Unit is connected at one end of the PEG Unit to the RL Unit and at the other end of the PEG Unit to the Stretcher / Connector Units (Z-A-). In some embodiments, the PEG Unit is connected to the RL Unit via a -CH2CH2C(O)- group that forms an amide bond with the RL Unit (e.g., -(CH2CH2O)n-CH2CH2C(O)-RL) and to the Stretcher Unit / Connector Unit (Z-A-) via an -NH- group (e.g., Z-A-NH-(CH2CH2O)n-) that forms an amide bond with the Z-A- portion.

[0566] Illustrative embodiments for PEG Units that are connected to the RL and Stretcher / Connector Units (Z-A-) are shown below:

[0567]

[0568] i H

[0569] ├—N— (CH2CH2O)b-CH2CH2NH— (CH2CH2O)— CH2CH2C(O)—

[0570] and in a particular embodiment, the PEG Unit is:

[0571]

[0572] 2

[0573] wherein the wavy line on the left indicates the site of attachment to Z-A-, the wavy line on the right indicates the site of attachment to RL, and each b is independently selected from 2 to 72, 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 2 to 24, 4 to 24, 6 to 24, or 8 to 24, 2 to 12, 4 to 12, 6 to 12, and 8 to 12. In some embodiments, subscript b is 2, 4, 8, 12, or 24. In some embodiments,subscript b is 2. In some embodiments, subscript b is 4. In some embodiments, subscript b is 8. In some embodiments, subscript b is 12.

[0574] In some embodiments, the linear PEG Unit that is connected to the Parallel Connector Unit at one end and comprises a terminal cap at the other end. In some embodiments, the PEG Unit is connected to the Parallel Connector Unit via a carbonyl group that forms an amide bond with the Parallel Connector Unit lysine residue amino group (e.g., –CH2CH2(OCH2CH2)k–C(O)-B-, wherein k is an integer from 1 to 36) and includes a PEG Unit terminal cap group selected from the group consisting of C1-4alkyl and C1-4alkyl-CO2H. In some embodiments, the Partitioning Agent S* is a linear PEG Unit comprising 4, 8, or 12 -CH2CH2O- subunits and a terminal methyl cap.

[0575] Illustrative linear PEG Units that are used in any of the embodiments provided herein are as follows:

[0576]

[0577] and in a particular embodiment, the PEG Unit is:

[0578]

[0579] wherein the wavy line indicates site of attachment to the Parallel Connector Unit (B), and each n is independently selected from 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 6 to 24, or 8 to 24. In some embodiments, subscript b is about 4, about 8, about 12, or about 24.

[0580] As used to herein, terms “PEG2”, “PEG4”, “PEG8”, and “PEG12” refers to specific embodiments of PEG Unit which comprises the number of PEG subunits (i.e., the number of subscription “b”). For example, “PEG2” refers to embodiments of PEG Unit that comprises 2 PEG subunits, “PEG4” refers to embodiments of PEG Unit that comprises 4 PEG subunits, “PEG8” refers to embodiments of PEG Unit that comprises 8 PEG subunits, and “PEG12” refers to embodiments of PEG Unit that comprises 12 PEG subunits.

[0581] As described herein, the PEG unit is selected such that it improves clearance of the resultant Ligand-Drug Conjugate but does not significantly impact the ability of the Conjugate to penetrate into the tumor. In embodiments, the PEG unit to be selected for use will preferablyhave from 2 subunits to about 24 subunits, from 4 subunits to about 24 subunits, more preferably about 4 subunits to about 12 subunits.

[0582] In some embodiments of the present disclosure the PEG Unit is from about 300 Daltons to about 5 kiloDaltons; from about 300 Daltons, to about 4 kiloDaltons; from about 300 Daltons, to about 3 kiloDaltons; from about 300 Daltons, to about 2 kiloDaltons; or from about 300 Daltons, to about 1 kiloDalton. In some such aspects, the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits. In some such aspects, the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits but no more than 72 subunits, preferably no more than 36 subunits.

[0583] It will be appreciated that when referring to PEG subunits, and depending on context, the number of subunits can represent an average number, e.g., when referring to a population of Ligand-Drug Conjugates or Drug-Linker Compounds, and / or using polydisperse PEGs.

[0584]

[0585] In some embodiments, the Ligand-Drug Conjugates and Drug-Linker Compounds will comprise a Parallel Connector Unit to provide a point of attachment to a Partitioning Agent (shown in the Linker Units as -B(S*)-). In some embodiments, the PEG Unit is attached to a Parallel Connector Unit such as lysine as shown below wherein the wavy line and asterisks indicate covalent linkage within the Linker Unit of a Ligand-Drug Conjugate or Drug-Linker Compound:

[0586]

[0587] In some embodiments, the Parallel Connector Unit (B) and Partitioning Agent (S*) (together, -B(S*)-) have the structure of

[0588]

[0589] wherein m ranges from 0 to 6; n ranges from 2 to 24; RPEG is a PEG Capping Unit, preferably H, -CH3, or -CH2CH2CO2H, the asterisk (*) indicates covalent attachment to a Connector UnitA corresponding in formula Za, Za', Zb' or Zc' and the wavy line indicates covalent attachment to the Releasable Linker (RL). In some embodiments, the structure is attached to a Connector Unit A in formula Za or Za’. In some embodiments, n is 2, 4, 8, or 12. In instances such as those shown here, the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit.

[0590] vi. Spacer Unit (T)

[0591] In some embodiments, the Ligand-Drug Conjugates provided herein will have a Spacer (T) between the Releasable Linker (RL) and the Drug Unit. The Spacer Unit is a functional group to facilitate attachment of RL to the Drug Unit or provides additional structural components to further facilitate release of the Drug Unit from the remainder of the Conjugate (e.g., a methylene carbamate unit or a self-immolative para-aminobenzyl (PAB) component).

[0592] In those embodiments to further facilitate release of the Drug Unit as free drug, the Spacer Unit T is represented by one of the following formulae:

[0593]

[0594] wherein EWG represents an electron-withdrawing group, and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. In some embodiments, EWG is selected from the group consisting of CN, NO2, CX3, -X, C(O)OR', C(0)N(R')2, C(O)R', C(O)X, S(O)2R', S(O)2OR', S(O)2NHR', S(O)2N(R')2, P(O)(OR')2, P(O)(CH3)NHR', NO, N(R')3+, wherein X is -F, -Br, -Cl, or -I, and R' is independently selected from the group consisting of hydrogen and Ci-Ce alkyl.

[0595] In some embodiments, the Spacer Unit is represented by the formula:

[0596]

[0597] wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the benzylic carbon atom connects to a Drug Unit. In some embodiments, the Drug Unit is attached to the benzylic carbon atom via a quatemized tertiary amine (N+) of D.

[0598] In some embodiments, the Spacer Unit is represented by the formula:

[0599]

[0600] wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the -OC(O)- group connects to a Drug Unit. In some embodiments, the Drug Unit is attached via a primary or secondary amine.

[0601] In some embodiments, the present disclosure provides a drug-linker compound of Formula II:

[0602] Q-D

[0603] Formula II

[0604] or a pharmaceutically acceptable salt thereof, wherein:

[0605] Q is a Linker Unit selected from the group consisting of:

[0606] (i) Z'-A-RL-,

[0607] (ii) Z'-A-RL-T-,

[0608] (iii) Z'-A-S*-RL-,

[0609] (iv) Z'-A-S*-RL-T-,

[0610] (v) Z'-A-B(S*)-RL-,

[0611] (vi) Z'-A-B(S*)-RL-T-,

[0612] (vii) Z'-A-,

[0613] (viii) Z'-A-S*-W-,

[0614] (ix) Z'-A-B(S*)-W-,

[0615] (x) Z'-A-S*-W-RL-, and

[0616] (xi) Z'-A-B(S*)-W-RL-;

[0617] Z' is a Stretcher Unit;

[0618] A is a bond or a Connector Unit;

[0619] B is a Parallel Connector Unit;

[0620] S* is a Partitioning Agent;

[0621] RL is a Releasable Linker;

[0622] W is an Amino Acid Unit;

[0623] T is a Spacer unit; and

[0624] D is a compound of Formula I:

[0625]

[0626] Formula I

[0627] or a pharmaceutically acceptable salt thereof, wherein:

[0628] X is N or C(R7);

[0629] Y is O or S

[0630] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0631] R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0632] R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0633] R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0634] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;

[0635] each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0636] R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0637]

[0638] or

[0639]

[0640] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or C1-C6alkyl, wherein C1-C6alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form Cx-Cx cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0641] R10K, R10L, and R10Mare independently hydrogen or C1-C12alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0642] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0643] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0644] R11is hydrogen, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;

[0645] each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0646] and

[0647] n is 0, 1, 2, 3, 4, or 5.

[0648] In some embodiments of the drug-linker compounds, Q is selected from:

[0649]

[0650] wherein R14, R15, R16, and R17are each independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0651] In some embodiments, Q is coupled to N-terminus of the amino acid or oligopeptide of D. Alternatively, Q can be coupled to a non-terminal nitrogen of D. In some embodiments, Q is coupled to a carbon (e.g., a carbonyl carbon) or a non-nitrogen heteroatom (e.g., a tyrosine phenolate) of D.

[0652] In some embodiments, the Stretcher Unit Z’ comprises a succinimidyl ester, anNHS-ester, a mal eimide, a haloacetyl, a fluorenylmethyloxycarbonyl (Fmoc), an isothiocyanate, a vinyl sulfone, a vinyl sulfonamide, an azide, an alkyne, a sulfhydryl, a 4-nitrophenyl ester, a pentafluorophenyl ester, a tetrafluorophenyl ester, an anhydride, an acid chloride, a sulfonyl chloride, an isocyanate, an isothiocyanate, an alpha-haloketone, an alpha-O-sulfonate ketone, an alkyl hydrazine, a hydrazide, a hydroxylamine, an iodoketone, or a disulfide. In some embodiments, the Stretcher Unit Z’ comprises an NHS-ester, an Fmoc, a maleimide, a haloacetyl, an isothiocyanate, or a vinyl sulfone.In some embodiments, the Stretcher Unit

[0653]

[0654] wherein R27is - CH2CH2(OCH2CH2)k-, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(Ci-Cs alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-Ci-Cio alkylene-, -C1-C10 alkylene-(Cs-Cs carbocyclo)-, -(C3-C8 carbocyclo)-Ci-Cio alkylene-, -C3-C8 heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-Ci-Cio alkylene-, -C1-C10 alkylene-C(O)-, C1-C10 heteroalkylene-C(O)-, -C3-C8 carbocyclo-C(O)-, -O-(Ci-C8 alkylene)-C(O)-, -arylene-C(O)-, -C1-C10 alkylene-arylene-C(O)-, -arylene-Ci-Cio alkylene-C(O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(O)-,-(C3-C8 carbocyclo)-Ci-Cio alkylene-C(O)-, -C3-C8 heterocyclo-C(O)-, -Ci-C10 alkylene-(C3-C8 heterocyclo)-C(O)-, -(C3-C8 heterocyclo)-Ci-Cio alkylene-C(O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene-NH-, -C3-C8 carbocyclo-NH-, -O-(Ci-C8 alkylene)-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-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-Ci-C 10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(Ci-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-Ci-Cio alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-Ci-Cio alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-Ci-Cio alkylene-S-; R27is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. (CH2 )XNH2, (CH2 )xNHRa, and (CH2 )xNRa2, wherein x is an integer of from 1-4 and each Rais independently selected from the group consisting of Ci-6 alkyl and Ci-6 haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; subscript k is an integer ranging from 1 to 36; R27Aand R27Bare each independently hydrogen, Br, SH, or S(Ci-Ce alkyl); and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound. In some embodiments, R27Aand R27Bare hydrogen.

[0655] In some embodiments, subscript k is an integer ranging from 1 to 30. In some embodiments, subscript k is an integer ranging from 1 to 24. In some embodiments, subscript k is an integer ranging from 1 to 18. In some embodiments, subscript k is an integer ranging from 1 to 12. In some embodiments, subscript k is an integer ranging from 1 to 8. In some embodiments, subscript k is an integer ranging from 1 to 6. In some v, subscript k is an integer ranging from 1 to 4. In some embodiments, subscript k is an integer ranging from 2 to 36. In some embodiments, subscript k is an integer ranging from 2 to 30. In some embodiments, subscript k is an integer ranging from 2 to 24. In some embodiments, subscript k is an integerranging from 2 to 18. In some embodiments, subscript k is an integer ranging from 2 to 12. In some embodiments, subscript k is an integer ranging from 2 to 8. In some embodiments, subscript k is an integer ranging from 2 to 6. In some embodiments, subscript k is an integer ranging from 2 to 4. In some embodiments, subscript k is an integer ranging from 4 to 36. In some embodiments, subscript k is an integer ranging from 4 to 30. In some embodiments, subscript k is an integer ranging from 4 to 24. In some embodiments, subscript k is an integer ranging from 4 to 18. In some embodiments, subscript k is an integer ranging from 4 to 12. In some embodiments, subscript k is an integer ranging from 4 to 8. In some embodiments, subscript k is an integer ranging from 8 to 36. In some embodiments, subscript k is an integer ranging from 4 to 30. In some embodiments, subscript k is an integer ranging from 8 to 24. In some embodiments, subscript k is an integer ranging from 8 to 18. In some embodiments, subscript k is an integer ranging from 12 to 36. In some embodiments, subscript k is an integer ranging from 12 to 30. In some embodiments, subscript k is an integer ranging from 12 to 24. In some embodiments, subscript k is an integer ranging from 12 to 18. In some embodiments, subscript k is an integer ranging from 18 to 36. In some embodiments, subscript k is an integer ranging from 18 to 30. In some embodiments, subscript k is an integer ranging from 24 to 36. In some embodiments, subscript k is an integer ranging from 24 to 30.

[0656] In some embodiments, the Stretcher Unit Z’ is

[0657]

[0658] wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug-Linker compound.In some embodiments, the Stretcher Unit

[0659]

[0660]

[0661] , wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug-Linker compound.

[0662] In some embodiments, the Connector Unit A is

[0663]

[0664] wherein each R100is independently selected from hydrogen or -C1-C3 alkyl; R111is independently selected from the group consisting of hydrogen, / ?-hydroxybenzyl, methyl, isopropyl, isobutyl, ec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-

[0665] pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,

[0666]

[0667]

[0668] each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Drug-Linker compound.

[0669] In some embodiments, the Connector Unit A is

[0670]

[0671] c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound.

[0672] In some embodiments, A is a bond.

[0673] In some embodiments,

[0674]

[0675] each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Drug-Linker compound or salt thereof. In some embodiments, B is an amino

[0676]

[0677] wherein the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Drug-Linker structure.

[0678] In some embodiments, the Partitioning Agent S* is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 72 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 48 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 36 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 24 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 16 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 8 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 8 to 72 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 8 to 48 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 8 to 36 (CH2CH2O) subunits. In some embodiments, thePartitioning Agent S* is a PEG Unit comprising from 8 to 24 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 16 to 72 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 16 to 48 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 16 to 36 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S is a PEG Unit comprising from 24 to 72 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 24 to 48 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 24 to 36 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 36 to 72 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 36 to 48 (CH2CH2O) subunits. In some embodiments, the Partitioning Agent S* terminates in a (CH2CH2OH) subunit. In some embodiments, the Partitioning Agent S* terminates in a (CH2CH2OCH3) subunit. In some embodiments, the PEG Unit is

[0679]

[0680] b is an integer between 4 and 36 (e.g., 4, 5, 6, etc.); and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. In some embodiments, b is is an integer between 4 to 30. In some embodiments, b is is an integer between 4 to 24. In some embodiments, b is an integer between 4 to 18. In some embodiments, b is an integer between 4 to 12. In some embodiments, b is an integer between 4 and 8. In some embodiments, b is an integer between 8 and 36. In some embodiments, b is an integer between 8 and 30. In some embodiments, b is an integer between 8 and 24. In some embodiments, b is an integer between 8 and 18. In some embodiments, b is an integer between 8 and 12. In some embodiments, b is an integer between 12 and 36. In some embodiments, b is an integer between 12 and 30. In some embodiments, b is an integer between 12 and 24. In some embodiments, b is an integer between 12 and 18. In some embodiments, b is an integer between 18 and 36. In some embodiments, b is an integer between 18 and 30. In some embodiments, b is an integer between 18 and 24. In some embodiments, b is an integer between 24 and 36.

[0681] In some embodiments, the Releasable Linker RL is –(AA)1-12–; and each AA is independently a proteinogenic or non-proteinogenic amino acid. In some embodiments, theReleasable Linker RL is -AA1-AA2- or -AA1-AA2-AA3-, wherein AAi is attached to the Stretcher Unit Z’ or the Connector Unit A.

[0682] In some embodiments, the Releasable Linker RL is a peptide comprising 2 to 12 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 2 to 8 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 2 to 6 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 2 to 4 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 4 to 12 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 4 to 8 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 6 to 12 amino acid residues. In some embodiments, the Releasable Linker RL is a peptide comprising 8 to 12 amino acid residues. In some embodiments, the peptide comprises a protease recognition sequence. In some embodiments, the protease recognition sequence is a carboxypeptidase A recognition sequence, a carboxypeptidase B recognition sequence, a carboxypeptidase P recognition sequence, a carboxypeptidase Y recognition sequence, a cathepsin C recognition sequence, a chymotrypsin recognition sequence, a clostripain recognition sequence, an elastase recognition sequence, an endoproteinase Arg-C recognition sequence, an endoproteinase Glu-C recognition sequence, an endoproteinase Lys-C recognition sequence, a glutamyl endopeptidase recognition sequence, a kallikrein recognition sequence, a papain recognition sequence, a pepsin recognition sequence, a proteinase K recognition sequence, a subtilisin recognition sequence, a TEV protease recognition sequence, a thermolysin recognition sequence, a trypsin recognition sequence, or a combination thereof.

[0683] In some embodiments, the Releasable Linker RL is

[0684]

[0685] wherein the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z’ or the Connector Unit A and the wavy line adjacent to the -C(O)- group indicates attachment to the Spacer unit T or the Drug Unit D.

[0686] In some embodiments, the Releasable Linker

[0687]

[0688] wherein the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z’ or theConnector Unit A and the wavy line adjacent to the -C(O)- group indicates attachment to the Spacer unit T or the Drug Unit D.

[0689] In some embodiments, the Releasable Linker RL is a glycoside. In some embodiments, the Releasable Linker RL is

[0690]

[0691] wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

[0692] In some embodiments, the Releasable Linker RL is

[0693]

[0694] wherein the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

[0695] In some embodiments, the Spacer unit T is

[0696]

[0697] wherein W4Ais O, N(W4E), S, or is absent, W4Bis arylene or heteroarylene substituted with 0 to 3 instances of W4F, W4Cis C1-C6alkylene substituted with 0 to 3 instances of W4For is absent, W4Dis -C(O)-, -OC(O)-, -N(W4E)C(O)-, -SC(O)-, or is absent, W4Eis hydrogen or C1-C3alkyl, and each instance of W4Fis independently C1-C6alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, heteroaryl, monosaccharide, or disaccharide. In some embodiments, the

[0698] Spacer Unit

[0699]

[0700] some embodiments, the Spacer unit T is

[0701]

[0702] some embodiments, the spacer unit

[0703]

[0704]

[0705] embodiments, W4Ais -N(W4E)-. In some embodiments, W4Eis hydrogen or methyl. In some embodiments, each instance of W4Fis independently a monosaccharide. In some embodiments, each instance of W4Fis independently a Cs or Ce monosaccharide.

[0706] In some embodiments, the Spacer unit T is

[0707]

[0708] wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. In some embodiments, the Spacer unit T is

[0709]

[0710] wherein the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.

[0711] In some embodiments, the drug-linker compound is selected from Table 3.

[0712]

[0713]

[0714]

[0715]

[0716]

[0717] Table 3

[0718]

[0719] Table 3

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743] In some embodiments, the present disclosure provides a drug-linker compound, or a pharmaceutically acceptable salt thereof, selected from:

[0744]

[0745] Coupling a ligand to a compound of the present disclosure can increase the activity and in vivo half-life of the compound and can further target the compound to a particular biological location, such as a tumor. In some cases, the ligand diminishes in vivo clearance, for example by having sufficient size to prevent or limit phagocytosis or biliary clearance. The ligand can also promote or inhibit cellular uptake, for example by having a cell receptor binding domain (such as an antibody Fc receptor binding domain) to promote endocytosis, or by having a size which is prohibitive towards cellular uptake.

[0746] Disclosed herein are complexes of drug-linker compounds and ligands. In context of Ligand-Drug Conjugate molecules, the assembly can be described by the component groups as described for Drug-Linker molecules, with the exception of the Stretcher Unit Z and the Ligand Unit L, wherein the Stretcher Unit Z is coordinated to the Ligand Unit L in Ligand-Drug Conjugate molecules, as described below. While some procedures for the preparation of Ligand-Drug Conjugate molecules are described herein, the order of assembly and the general conditions to prepare the molecules will be well understood by one of skill in the art.

[0747] In some embodiments, a Ligand-Drug Conjugate molecules comprises a compound of Formula (I), or any subformula thereof, a Linker Unit (Q) comprising a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit through which the Ligand Unit isconnected to the conjugated compound of Formula (I) and the Ligand Unit (L). The Linker Unit can comprise, in addition to RL, a Stretcher Unit (Z) connected to the Ligand Unit and is capable of (directly or indirectly) connecting the RL to the Ligand Unit. In some embodiments, a Parallel Connector Unit (B) is present when it is desired to add a Partitioning Agent (S*) as a side chain appendage. In any one of those embodiments, a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and RL.

[0748] In some embodiments, a Ligand-Drug Conjugate molecules comprises a compound of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is a Glycoside (e.g., Glucuronide) Unit, directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate molecules Linker Unit (i.e., A, S* and / or B(S*)), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit).

[0749] In some embodiments, a Ligand-Drug Conjugate molecules comprises a compound of Formula (I), or any subformula thereof, a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate molecule’s Linker Unit (i.e., A, S* and / or B(S*)), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit).

[0750] In some embodiments, a Ligand-Drug Conjugate molecule is a molecule of Formula III:

[0751] L-(Q-D)P

[0752] Formula III

[0753] or a pharmaceutically acceptable salt thereof, wherein

[0754] L is a Ligand Unit;

[0755] p is an integer selected from 1 to 36;

[0756] Q is a Linker Unit selected from the group consisting of:

[0757] (i) Z'-A-RL-,

[0758] (ii) Z'-A-RL-T-,

[0759] (iii) Z'-A-S*-RL-,

[0760] (iv) Z'-A-S*-RL-T-,

[0761] (v) Z'-A-B(S*)-RL-,

[0762] (vi) Z'-A-B(S*)-RL-T-,

[0763] (vii) Z'-A-,

[0764] (viii) Z'-A-S*-W-,

[0765] (ix) Z'-A-B(S*)-W-,

[0766] (x) Z'-A-S*-W-RL-, and(xi) Z'-A-B(S*)-W-RL-;

[0767] Z' is a Stretcher Unit;

[0768] A is a bond or a Connector Unit;

[0769] B is a Parallel Connector Unit;

[0770] S* is a Partitioning Agent;

[0771] RL is a Releasable Linker;

[0772] W is an Amino Acid Unit;

[0773] T is a Spacer unit; and

[0774] D is a compound of Formula I:

[0775]

[0776] Formula I

[0777] or a pharmaceutically acceptable salt thereof, wherein:

[0778] X is N or C(R7);

[0779] Y is O or S

[0780] R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0781] R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0782] R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;

[0783] R6A, R6B, R6Cand R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;

[0784] each instance of R8is independently halogen, OR9, or C1-C6 alkyl;

[0785] each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,

[0786] 3- to 10-membered heterocycloalkyl,

[0787]

[0788] or

[0789]

[0790] , wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0791] R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0792] R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;

[0793] or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0794] or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;

[0795] R11is hydrogen, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;

[0796] and

[0797] n is 0, 1, 2, 3, 4, or 5.

[0798] In some embodiments of the Ligand-Drug Conjugate molecule, Q is selected from:

[0799]

[0800] wherein:

[0801] * denotes the point of attachment to L; and

[0802] R14, R15, R16, and R17are each independently hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, p is an integer representing the number of instances of Q-D are attached to the Ligand Unit.

[0803]

[0804] Subscript p represents the number of Drug-Linker moi eties on a Ligand Unit of an individual Ligand-Drug Conjugate molecule and can be an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, or 16 Drug Linker moieties conjugated to a Ligand Unit of an individual Ligand-Drug Conjugate molecule.

[0805] In some embodiments, any of the structures and descriptions as described herein represent a population of individual Ligand-Drug Conjugate molecules substantially identical except for the number of Drug-Linker moieties bound to each Ligand Unit (i.e., a Ligand-Drug Conjugate composition) so that subscript p represents the average number of Drug-Linker moieties bound to the Ligand Units of the Ligand-Drug Conjugate composition. In that group of embodiments, subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, from 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8. In some aspects, p is about 2. In some aspects, p is about 4. In some aspects, p is about 8. In some aspects, p is about 16. In some aspects, p is 2. In some aspects, p is 4. In some aspects, p is 8. In some aspects, p is 16. In some embodiments, the value of subscript p refers to the average drug loading as well as the drug loading of the predominate Ligand-Drug Conjugate molecule in the composition.

[0806] In some embodiments, conjugation will be via the reduced interchain disulfides and there will from 1 to about 8 Drug-Linker Compound molecules conjugated to a targeting agent that becomes a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue as well as reduced interchain disulfides and there will be from 1 to 10 or 1 to 12 or 1 to 14 or 1 to 16 Drug-Linker Compound moieties conjugated to a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue and there will be 2 or 4 Drug-Linker Compound molecules conjugated to a Ligand Unit.

[0807] ii. Ligand Unit

[0808] In some embodiments of the invention, one or more instances of Q-D is coupled to a Ligand Unit. The Ligand Unit (L-) can be a targeting agent that specifically binds to a target moiety, such as a cell component (a Cell Binding Agent) or to another target molecule of interest. The Ligand Unit acts to target and present the Drug Unit (such as one of Formula (I) or any subformula thereof) to the particular target cell population with which the Ligand Unit interacts due to the presence of its targeted component or molecule and allows for subsequent release of free drug within (i.e., intracellularly) or within the vicinity of the target cells (i.e., extracellularly). Ligand Units, L, include, but are not limited to, proteins, polypeptides and peptides. Suitable Ligand Units include, for example, antibodies, e.g., full-length antibodies and antigen binding fragments thereof, interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient-transport molecules (such as, but not limited to,transferrin), or any other cell binding molecule or substance. In some embodiments, the Ligand Unit (L) is from an antibody or a non-antibody protein targeting agent.

[0809] In one group of embodiments a Ligand Unit is bonded to Q (a Linker Unit) which comprises a Glucuronide Releasable Linker. As noted above, in some aspects other linking components are present in the conjugates described herein to serve the purpose of providing additional space between the Drug Unit compound and the Ligand Unit (e.g., a Stretcher Unit and optionally a Connector Unit, A), or providing attributes to the composition to increases solubility (e.g., a Partitioning Agent, S*). In some of those embodiments, the Ligand Unit is bonded to Z of the Linker Unit via a heteroatom of the Ligand Unit. Heteroatoms that may be present on a Ligand Unit for that bonding include sulfur (in one embodiment, from a sulfhydryl group of a targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of a targeting ligand) and nitrogen, optionally substituted (in one embodiment, from a primary or secondary amine functional group of a targeting ligand or in another embodiment from an optionally substituted amide nitrogen). Those heteroatoms are present on the targeting ligand in the ligand’s natural state, for example in a naturally occurring antibody, or are introduced into the targeting ligand via chemical modification or biological engineering.

[0810] In some embodiments, the Ligand Unit is an antibody. In some embodiments, the liganddrug conjugate is an antibody-drug conjugate. In some embodiments, the antibody is a polyclonal antibody. Useful polyclonal can be heterogeneous populations of antibody molecules derived from the sera of immunized animals. In some embodiments, the antibody is a monoclonal antibody. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer or immune cell antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. The antibodies include full-length antibodies and antigen binding fragments thereof. Human monoclonal antibodies may be made by any of numerous techniques known in the art e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor etal., 1983, Immunology Today 4:72-79; and Olsson etal., 1982, Meth. Enzymol. 92:3-16).

[0811] In some embodiments, an antibody includes a functionally active fragment, derivative or analog of an antibody that binds specifically to target cells (e.g., cancer cell antigens) or other antibodies bound to cancer cells or matrix. In this regard, “functionally active” means that the fragment, derivative or analog is able to bind specifically to target cells. To determine whichCDR sequences bind the antigen, synthetic peptides containing the CDR sequences are typically used in binding assays with the antigen by any binding assay method known in the art (e.g., the Biacore assay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0812] In some cases, the antibody is a recombinant antibody, such as chimeric and humanized monoclonal antibody comprising both human and non-human portions. In some cases, the antibody is a chimeric antibody, which can be a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and a constant region derived from a human immunoglobulin. See, e.g., U. S. Patent No. 4,816,567; and U. S. Patent No. 4,816,397, which are incorporated herein by reference in their entireties. Humanized antibodies are antibody molecules from non-human species having one or more CDRs from the non-human species and a framework region from a human immunoglobulin molecule. See, e.g., U. S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87 / 02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86 / 01533; U. S. Patent No. 4,816,567; European Patent Publication No. 012023; Berter et al., 1988, Science 240:1041-1043; Liu etal., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu etal., 1987, J. Immunol. 139:3521-3526; Sun etal., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Cancer. Res. 47:999- 1005; Wood et al., 1985, Nature 314:446-449; and Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; U. S. Patent No. 5,225,539; Jones et al., 1986, Nature 321: 522-525; Verhoeyan et al, 1988, Science 239:1534; and Beidler etal., 1988, J. Immunol. 141:4053-4060; each of which is incorporated herein by reference in its entirety.

[0813] In some embodiments, an antibody is a completely human antibody. In some embodiments, an antibody is produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes, but which are capable of expressing human heavy and light chain genes.

[0814] In some embodiments, an antibody is an intact or fully-reduced antibody. The term ‘fully-reduced’ is meant to refer to an antibody in which all four inter-chain disulfide linkages have been reduced to provide eight thiols that can be attached to a linker (L).Attachment to an antibody can be via thioether linkages from native and / or engineered cysteine residues, or from an amino acid residue engineered to participate in a cycloaddition reaction (such as a click reaction) with the corresponding linker intermediate. See, e.g., Maerle, et al., PLOS One 2019: 14(1); e0209860. In some embodiments, an antibody is an intact or fully-reduced antibody, or is an antibody bearing engineered an cysteine group that is modified with a functional group that can participate in, for example, click chemistry or other cycloaddition reactions for attachment of other components of the ADC as described herein (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions). See, e.g., Agard, et al., J. Am. Chem. Soc. Vol.

[0815] 126, pp. 15046-15047 (2004); Laughlin, et al., Science, Vol. 320, pp. 664-667 (2008); Beatty, et al., ChemBioChem, Vol. 11, pp. 2092-2095 (2010); and Van Geel, et al., Bioconjug. Chem. Vol.

[0816] 26, pp.2233-2242 (2015).

[0817] Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.

[0818] In some embodiments, the antibody can be used for the treatment of a cancer (e.g., an antibody approved by the FDA and / or EMA). Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.

[0819] In some cases, the antibody has a mutation or post-translational modification which affects non-Fab mediated uptake. Peripheral immune cells, which are highly responsive to TLR7 / 8 agonists can facilitate strong, systemic responses when activated through non-antigen specific, Fc-mediated uptake of the TLR7 / 8 antibody drug conjugate which may be harmful or otherwise undesirable. In such cases, the antibody can have an effector function-diminishing mutation, such as L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G or a combination thereof, which diminishes non-immune uptake (e.g., FcgR-mediated uptake).

[0820] In some embodiments, an antibody can be configured to bind to a surface antigen of a cell. The antibody, or a complex comprising the antibody, can be configured to internalize within a cell upon binding to the surface antigen. For example, the antibody or an ADC comprising the antibody can be configured to endocytose upon binding to a surface antigen of a cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured tointernalize within a cancer cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to internalize within an immune cell. In some embodiments, the immune cell is a tumor associated macrophage. In some embodiments, the surface antigen is a receptor or a receptor complex (e.g., expressed on lymphocytes). In some embodiments, the receptor or receptor complex comprises an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein or other immune cell expressed surface receptor.

[0821] In some embodiments, an antibody is configured to bind specifically to a cancer cell antigen. In some embodiments, an antibody is configured to bind specifically to an immune cell antigen. In some embodiments, the immune cell antigen is a tumor associated macrophage antigen. In some embodiments, an antibody is configured to bind specifically to EphA2. It will be understood that the antibody component in an ADC is an antibody in residue form such that “Ab” in the ADC structures described herein incorporates the structure of the antibody.

[0822] Non-limiting examples of antibodies that can be used for treatment of cancer and antibodies that bind specifically to tumor associated antigens are disclosed in Franke, A. E., Sievers, E. L., and Scheinberg, D. A., “Cell surface receptor-targeted therapy of acute myeloid leukemia: a review” Cancer Biother Radiopharm. 2000,15, 459-76; Murray, J. L., “Monoclonal antibody treatment of solid tumors: a coming of age” Semin Oncol. 2000, 27, 64-70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998, each of which is hereby incorporated by reference in its entirety.

[0823] In yet another embodiment, the Ligand Unit is from an antibody and the sulfhydryl functional group is chemically introduced into the antibody, for example, by introduction of a cysteine residue or reduction of a disulfide bond. Accordingly, in some embodiments, the Linker Unit (with or without an attached compound as defined herein) is conjugated to a Ligand Unit through an introduced cysteine residue of a Ligand Unit.

[0824] It has been observed for bioconjugates that the site of drug conjugation can affect a number of parameters including ease of conjugation, drug-linker stability, effects on biophysical properties of the resulting bioconjugates, and in vitro cytotoxicity. With respect to drug-linker stability, the site of conjugation of a drug-linker moiety to a Ligand Unit can affect the ability of the conjugated drug-linker moiety to undergo an elimination reaction, in some instances, to cause premature release of free drug. Sites for conjugation on a targeting agent include, for example, a reduced interchain disulfide as well as selected cysteine residues at engineered sites. In some embodiments conjugation methods to form ligand-drug conjugates as described herein use thiol residues at genetically engineered sites that are less susceptible to the eliminationreaction (e.g., positions 239 according to the EU index as set forth in Kabat) in comparison to conjugation methods that use thiol residues from a reduced disulfide bond. In other embodiments conjugation methods to form Conjugates as described herein use thiol residues resulting from interchain disulfide bond reduction.

[0825] In some embodiments, a ligand-drug conjugate comprises a non-immunoreactive protein, polypeptide, or peptide as its Ligand Unit. Accordingly, in some embodiments, the Ligand Unit is from a non-immunoreactive protein, polypeptide, or peptide. Examples include, but are not limited to, transferrin, epidermal growth factors (“EGF”), bombesin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factors (“TGF”), such as TGF-α and TGF-β, vaccinia growth factor (“VGF”), insulin and insulin-like growth factors I and II, somatostatin, lectins and apoprotein from low density lipoprotein.

[0826] Particularly preferred Ligand Units are from antibodies. Accordingly, in any one of the embodiments described herein, the Ligand Unit is from an antibody. Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest in some embodiments is prepared by using any technique known in the art, which provides for production of antibody molecules by continuous cell lines in culture.

[0827] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. The antibodies include full-length antibodies and antigen binding fragments thereof. Human monoclonal antibodies can be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson etal., 1982, Meth. Enzymol. 92:3-16).

[0828] An antibody useful for inclusion into the Ligand-Drug conjugates of the disclosure is an intact antibody or a functionally active fragment, derivative, or analog of an antibody, wherein the antibody or fragment thereof is capable of immunospecific binding to target cells (e.g., cancer cell antigens, viral antigens, or microbial antigens) or other antibodies that are bound to tumor cells or matrix. In this regard, “functionally active” means that the fragment, derivative, or analog is able to immunospecifically bind to target cells. To determine which CDR sequences bind the antigen, synthetic peptides containing the CDR sequences in some embodiments are used in binding assays with the antigen by a binding assay method known in the art (e.g., the Biacore™ assay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest,Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0829] Other useful Ligands include fragments of antibodies such as, but not limited to, F(ab’)2 fragments, Fab fragments, Fvs, single chain antibodies, diabodies, triabodies, tetrabodies, scFv, scFv-FV, or any other molecule with the same specificity as the antibody.

[0830] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which in some embodiments are made using standard recombinant DNA techniques, are useful antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and human immunoglobulin constant regions. (See, e.g., U. S. Patent No. 4,816,567; and U. S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g., U. S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety.) Such chimeric and humanized monoclonal antibodies in some embodiments are produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87 / 02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86 / 01533; U. S. Patent No. 4,816,567; Berter et al., Science (1988) 240: 1041-1043; Liu et al., Proc. Nat'l. Acad. Sci. USA (1987) 84: 3439-3443; Liu et al., J. Immunol. (1987) 139: 3521-3526; Sun et al., Proc. Natl. Acad. Sci. USA (1987) 84: 214-218; Nishimura et al., Cancer. Res. (1987) 47: 999-1005; Wood et al., Nature (1985) 314: 446-449; Shaw et al., J. Natl. Cancer Inst. (1988) 80: 1553-1559; Morrison, Science (1985) 229: 1202-1207; Oi et al., BioTechniques (1986) 4: 214-221; U. S. Patent No. 5,225,539; Jones et al., Nature (1986) 321: 552-525; Verhoeyan et al., Science (1988) 239: 1534-1536; and Beidler et al., J. Immunol. (1988) 141: 4053-4060; each of which is incorporated herein by reference in its entirety.

[0831] Completely human antibodies in some instances (e.g., when immunogenicity to a non-human or chimeric antibody may occur) are more desirable and in some embodiments are produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which are capable of expressing human heavy and light chain genes.

[0832] Antibodies include analogs and derivatives that are either modified, i.e., by the covalent attachment of any type of molecule as long as such covalent attachment permits the antibody toretain its antigen binding immunospecificity. For example, but not by way of limitation, derivatives and analogs of the antibodies include those that have been further modified, e.g, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivitization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular antibody unit or other protein, etc. In some embodiments one or more of those numerous chemical modifications are carried out by known techniques including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc. In other embodiments, an analog or derivative of an antibody contains one or more unnatural amino acids, which is sometimes in combination with one or more of the above-described chemical modifications.

[0833] In some embodiments the antibody has one or more modifications (e.g, substitutions, deletions or additions) in amino acid residues that interact with Fc receptors. Those include modifications in amino acid residues identified as involved in the interaction between the anti-Fc domain and the FcRn receptor (see, e.g., International Publication No. WO 97 / 34631, which is incorporated herein by reference in its entirety).

[0834] In some embodiments, antibodies immunospecific for a cancer cell antigen are obtained commercially or produced by a method known to one of skill in the art such as, recombinant expression techniques. The nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen is sometimes obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.

[0835] In a specific embodiment, a known antibody for the treatment of cancer is used.

[0836] In another specific embodiment, an antibody for the treatment of an autoimmune disease is used in accordance with the compositions and methods of the invention.

[0837] In certain embodiments, useful antibodies bind to a receptor or a receptor complex expressed on an activated lymphocyte. That receptor or receptor complex, in some embodiments, is an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.

[0838] In some enbodiments, the antibody that is incorporated into a ligand-drug conjugate will specifically bind B7-H4, CD19, CD30, CD33, CD70, CD228, ITGB6 (integrin beta 6), Nectin-4, TF (tissue factor), Her2, STn, ALPP, or LIV-1.

[0839] Exemplary antigens are provided below. Exemplary antibodies that bind the indicated antigen are shown in parentheses.

[0840] In some embodiments, the antigen is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a transmembrane protein. For example, the following antigensare transmembrane proteins: ANTXR1, BAFF-R, CA9 (exemplary antibodies include girentuximab), CD 147 (exemplary antibodies include gavilimomab and metuzumab), CD 19, CD20 (exemplary antibodies include rituximab, divozilimab and ibritumomab), CD274 also known as PD-L1 (exemplary antibodies include adebrelimab, atezolizumab, garivulimab, durvalumab, and avelumab), CD30 (exemplary antibodies include iratumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include apamistamab), CD47 (exemplary antibodies include letaplimab and magrolimab), CLPTM1L, DLL3, DPP4, EGFR, ERVMER34-1, FASL, FSHR, FZD5, FZD8, GUCY2C (exemplary antibodies include indusatumab), IFNAR1 (exemplary antibodies include anifrolumab), IFNAR2, LMP2, MLANA, SIT1, TLR2 / 4 / 1 (exemplary antibodies include tomaralimab), TM4SF5, TMEM132A, TMEM40, UPK1B, VEGF, and VEFGR2 (exemplary antibodies include gentuximab).

[0841] In some embodiments, the tumor-associated antigen is a transmembrane transport protein. For example, the following antigens are transmembrane transport proteins: ASCT2 (exemplary antibodies include idactamab), MFSD13A, Mincle, NaPi2b, NOX1, SLC10A2, SLC12A2, SLC17A2, SLC38A1, SLC39A5, SLC39A6 also known as LIV1 (exemplary antibodies include ladiratuzumab), SLC44A4, SLC6A15, SLC6A6, SLC7A11, and SLC7A5.

[0842] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CA-125, CA19-9, CAMPATH- 1 / CD 52 (exemplary antibodies include alemtuzumab), carcinoembryonic antigen / CEA (exemplary antibodies include arcitumomab), CEACAM5 (exemplary antibodies include cergutuzumab and labetuzumab), CD112, CD155, CD24, CD247, CD37 (exemplary antibodies include lilotomab), CD38 (exemplary antibodies include felzartamab), CD3D, CD3E (exemplary antibodies include foralumab and teplizumab), CD3G, CD96, CDCP1, CDH17, CDH3, CDH6, CEACAM1, CEACAM6, CLDN1, CLDN16, CLDN18.1, CLDN18.2 (exemplary antibodies include zolbetuximab), CLDN19, CLDN2, CLEC12A (exemplary antibodies include tepoditamab), DPEP1, DPEP3, DSG2, endosialin (exemplary antibodies include ontuxizumab), ENPP1, EPC AM (exemplary antibodies include adecatumumab), FN, FN1, Gp100, GPA33, gpNMB (exemplary antibodies include glembatumumab), ICAM1, L1CAM, LAMP1, MELTF also known as CD228, NCAM1, Nectin-4 (exemplary antibodies include enfortumab), PDPN, PMSA, PR0M1, PSCA, PSMA, Siglecs 1-16, SIRPa, SIRPg, TACSTD2, TAG-72, Tenascin, Tissue Factor also known as TF (exemplary antibodies include tisotumab), and ULBP1 / 2 / 3 / 4 / 5 / 6.

[0843] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane ormembrane-associated receptor kinases: ALK, Axl (exemplary antibodies include tilvestamab), BMPR2, DCLK1, DDR1, EPHA receptors, EPHA2, ERBB2 also known as HER2 (exemplary antibodies include disitamab, trastuzumab, pertuzumab, and margetuximab), ERBB3, FLT3, PDGFR-B (exemplary antibodies include rinucumab), PTK7 (exemplary antibodies include cofetuzumab), RET, ROR1 (exemplary antibodies include cirmtuzumab), ROR2, ROS1, and Tie3.

[0844] In some embodiments, the tumor-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: ALPP, ALPPL2, ANXA1, FOLR1 (exemplary antibodies include farletuzumab), IL13Ra2, IL1RAP (exemplary antibodies include nidanilimab), NT5E, 0X40, Ras mutant, RGS5, RhoC, SLAMF7 (exemplary antibodies include elotuzumab), and VSIR.

[0845] In some embodiments, the tumor-associated antigen is a transmembrane G-protein coupled receptor (GPCR). For example, the following antigens are GPCRs: CALCR, CD97, GPR87, and KISS1R.

[0846] In some embodiments, the tumor-associated antigen is cell-surface-associated or a cellsurface receptor. For example, the following antigens are cell-surface-associated and / or cellsurface receptors: B7-DC, BCMA, CD137, CD244, CD3 (exemplary antibodies include otelixizumab and visilizumab), CD48, CD5 (exemplary antibodies include zolimomab), CD70 (exemplary antibodies include cusatuzumab and vorsetuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD262 / DR5 (exemplary antibodies include tigatuzumab), DR4 (exemplary antibodies include mapatumumab), FAS, FGFR1, FGFR2 (exemplary antibodies include aprutumab), FGFR3 (exemplary antibodies include vofatamab), FGFR4, GITR (exemplary antibodies include ragifilimab), HAVCR2, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include encelimab), LY6G6D, LY9, MICA, MICB, MSLN, MUC1, MUC5AC, NY-ESO-1, OY-TES1, PVRIG, Sialyl-Thomsen-Nouveau Antigen, Sperm protein 17, TNFRSF12, and uPAR.

[0847] In some embodiments, the tumor-associated antigen is a chemokine receptor or cytokine receptor. For example, the following antigens are chemokine receptors or cytokine receptors: CD115 (exemplary antibodies include axatilimab, cabiralizumab, and emactuzumab), CD123, CXCR4 (exemplary antibodies include ulocuplumab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

[0848] In some embodiments, the tumor-associated antigen is a co-stimulatory or co-inhibitory, surface-expressed protein. For example, the following antigens are co-stimulatory or co-inhibitory, surface-expressed proteins: B7-H3 (exemplary antibodies include enoblituzumab and omburtamab), B7-H4, B7-H6, and B7-H7.In some embodiments, the tumor-associated antigen is a transcription factor or a DNA-binding protein. For example, the following antigens are transcription factors: ETV6-AML, MYCN, PAX3, PAX5, and WT1. The following protein is a DNA-binding protein: BORIS.

[0849] In some embodiments, the tumor-associated antigen is an integral membrane protein. For example, the following antigens are integral membrane proteins: SLITRK6 (exemplary antibodies include sirtratumab), UPK2, and UPK3B.

[0850] In some embodiments, the tumor-associated antigen is an integrin. For example, the following antigens are integrin antigens: integrin alpha v beta 6, ITGAV (exemplary antibodies include abituzumab), ITGB6, and ITGB8.

[0851] In some embodiments, the tumor-associated antigen is a glycolipid. For example, the following are glycolipid antigens: FucGMl, GD2 (exemplary antibodies include dinutuximab), GD3 (exemplary antibodies include mitumomab), GloboH, GM2, and GM3 (exemplary antibodies include racotumomab).

[0852] In some embodiments, the tumor-associated antigen is a cell-surface hormone receptor. For example, the following antigens are cell-surface hormone receptors: AMHR2 and androgen receptor.

[0853] In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated protease. For example, the following antigens are transmembrane or membrane-associated proteases: ADAM12, ADAM9, TMPRSS11D, and metalloproteinase.

[0854] In some embodiments, the tumor-associated antigen is aberrantly expressed in individuals with cancer. For example, the following antigens may be aberrantly expressed in individuals with cancer: AFP, AGR2, AKAP-4, ARTN, BCR-ABL, C5 complement, CCNB1, CSPG4, CYP1B1, De2-7 EGFR, EGF, Fas-related antigen 1, FBP, G250, GAGE, HAS3, HPV E6, HPV E7, hTERT, IDO1, LCK, Legumain, LYPD1, MAD-CT-1, MAD-CT-2, MAGEA3, MAGEA4, MAGEC2, MerTk, ML-IAP, NA17, NY-BR-1, p53, p53 mutant, PAP, PLAVI, polysialic acid, PR1, PSA, Sarcoma translocation breakpoints, SART3, sLe, SSX2, Survivin, Tn, TRAIL, TRAIL 1, TRP-2, and XAGE1.

[0855] In some embodiments, the antigen is an immune-cell-associated antigen. In some embodiments, the immune-cell-associated antigen is a transmembrane protein. For example, the following antigens are transmembrane proteins: BAFF-R, CD163, CD19, CD20 (exemplary antibodies include rituximab, ocrelizumab, divozilimab; ibritumomab), CD25 (exemplary antibodies include basiliximab), CD274 also known as PD-L1 (exemplary antibodies include adebrelimab, atezolizumab, garivulimab, durvalumab, and avelumab), CD30 (exemplary antibodies include iratumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include apamistamab), CD47 (exemplaryantibodies include letaplimab and magrolimab), CTLA4 (exemplary antibodies include ipilimumab), FASL, IFNAR1, IFNAR2, LAYN, LILRB2, LILRB4, PD-1 (exemplary antibodies include nivolumab, pembrolizumab, balstilimab, budigalimab, geptanolimab, toripalimab, and pidilizumab), SIT1, and TLR2 / 4 / 1 (exemplary antibodies include tomaralimab).

[0856] In some embodiments, the immune-cell-associated antigen is a transmembrane transport protein. For example, Mincle is a transmembrane transport protein.

[0857] In some embodiments, the immune-cell-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CD112, CD155, CD24, CD247, CD28, CD30L, CD37 (exemplary antibodies include lilotomab), CD38 (exemplary antibodies include felzartamab), CD3D, CD3E (exemplary antibodies include foralumab and teplizumab), CD3G, CD44, CLEC12A (exemplary antibodies include tepoditamab), DCIR, DC SIGN, Dectin 1, Dectin 2, ICAM1, LAMP1, Siglecs 1-16, SIRPa, SIRPg, and ULBP1 / 2 / 3 / 4 / 5 / 6.

[0858] In some embodiments, the immune-cell-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane or membrane-associated receptor kinases: Axl (exemplary antibodies include tilvestamab) and FLT3.

[0859] In some embodiments, the immune-cell-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: CD83, IL1RAP (exemplary antibodies include nidanilimab), 0X40, SLAMF7 (exemplary antibodies include elotuzumab), and VSIR.

[0860] In some embodiments, the immune-cell-associated antigen is a transmembrane G-protein coupled receptor (GPCR). For example, the following antigens are GPCRs: CCR4 (exemplary antibodies include mogamulizumab-kpkc), CCR8, and CD97.

[0861] In some embodiments, the immune-cell-associated antigen is cell-surface-associated or a cell-surface receptor. For example, the following antigens are cell-surface-associated and / or cellsurface receptors: B7-DC, BCMA, CD137, CD2 (exemplary antibodies include siplizumab), CD244, CD27 (exemplary antibodies include varlilumab), CD278 (exemplary antibodies include feladilimab and vopratelimab), CD3 (exemplary antibodies include otelixizumab and visilizumab), CD40 (exemplary antibodies include dacetuzumab and lucatumumab), CD48, CD5 (exemplary antibodies include zolimomab), CD70 (exemplary antibodies include cusatuzumab and vorsetuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD262 / CD5 (exemplary antibodies include tigatuzumab), DR4 (exemplary antibodies include mapatumumab), GITR (exemplary antibodies include ragifilimab), HAVCR2, HLA-DR, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include encelimab), MICA, MICB, MRC1,PVRIG, Sialyl-Thomsen-Nouveau Antigen, TIGIT (exemplary antibodies include etigilimab), Trem2, and uPAR.

[0862] In some embodiments, the immune-cell-associated antigen is a chemokine receptor or cytokine receptor. For example, the following antigens are chemokine receptors or cytokine receptors: CD115 (exemplary antibodies include axatilimab, cabiralizumab, and emactuzumab), CD123, CXCR4 (exemplary antibodies include ulocuplumab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

[0863] In some embodiments, the immune-cell-associated antigen is a co-stimulatory or co-inhibitory, surface-expressed protein. For example, the following antigens are co-stimulatory or co-inhibitory, surface-expressed proteins: B7-H3 (exemplary antibodies include enoblituzumab and omburtamab), B7-H4, B7-H6, and B7-H7.

[0864] In some embodiments, the immune-cell-associated antigen is a peripheral membrane protein. For example, the following antigens are peripheral membrane proteins: B7-1 (exemplary antibodies include galiximab) and B7-2.

[0865] In some embodiments, the immune-cell-associated antigen is aberrantly expressed in individuals with cancer. For example, the following antigens may be aberrantly expressed in individuals with cancer: C5 complement, IDO1, LCK, MerTk, and Tyrol.

[0866] In some embodiments, the antigen is a stromal-cell-associated antigen. In some embodiments, the stromal-cell-associated antigen is a transmembrane or membrane-associated protein. For example, the following antigens are transmembrane or membrane-associated proteins: FAP (exemplary antibodies include sibrotuzumab), IFNAR1, and IFNAR2.

[0867] In some embodiments, the antigen is CD30. In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD30, such as described in International Patent Publication No. WO 02 / 43661. In some embodiments, the anti-CD30 antibody is cAClO, which is described in International Patent Publication No. WO 02 / 43661. cAClO is also known as brentuximab. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAClO. In some embodiments, the CDRs are as defined by the Kabat numbering scheme. In some embodiments, the CDRs are as defined by the Chothia numbering scheme. In some embodiments, the CDRs are as defined by the IMGT numbering scheme. In some embodiments, the CDRs are as defined by the AbM numbering scheme. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ IDNO: 7 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11.

[0868] In some embodiments, the antigen is CD70. In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD70, such as described in International Patent Publication No. WO 2006 / 113909. In some embodiments, the antibody is a hlF6 anti-CD70 antibody, which is described in International Patent Publication No. WO 2006 / 113909. hlF6 is also known as vorsetuzumab. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising the three CDRs of SEQ ID NOs: 279, 280, and 281 and a light chain variable region comprising the three CDRs of SEQ ID NOs: 282, 283, and 284. In some embodiments, the CDRs are as defined by the Kabat numbering scheme. In some embodiments, the CDRs are as defined by the Chothia numbering scheme. In some embodiments, the CDRs are as defined by the IMGT numbering scheme. In some embodiments, the CDRs are as defined by the AbM numbering scheme. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 285 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 286. In some embodiments, the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 287 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 288.

[0869] In some embodiments, the antigen is interleukin-1 receptor accessory protein (IL1RAP). IL1RAP is a co-receptor of the IL1 receptor (IL1R1) and is required for interleukin-1 (IL1) signaling. IL1 has been implicated in the resistance to certain chemotherapy regimens. IL1RAP is overexpressed in various solid tumors, both on cancer cells and in the tumormicroenvironment, but has low expression on normal cells. IL1RAP is also overexpressed in hematopoietic stem and progenitor cells, making it a candidate to target for chronic myeloid leukemia (CML). IL1RAP has also been shown to be overexpressed in acute myeloid leukemia (AML). Antibody binding to IL1RAP could block signal transduction from IL-1 and IL-33 into cells and allow NK-cells to recognize tumor cells and subsequent killing by antibody-dependent cellular cytotoxicity (ADCC).

[0870] In some embodiments, the antigen is ASCT2. ASCT2 is also known as SLC1A5. ASCT2 is a ubiquitously expressed, broad-specificity, sodium-dependent neutral amino acid exchanger. ASCT2 is involved in glutamine transport. ASCT2 is overexpressed in different cancers and is closely related to poor prognosis. Downregulating ASCT2 has been shown to suppress intracellular glutamine levels and downstream glutamine metabolism, including glutathione production. Due to its high expression in many cancers, ASCT2 is a potential therapeutic target. These effects attenuated growth and proliferation, increased apoptosis and autophagy, and increased oxidative stress and mTORCl pathway suppression in head and neck squamous cell carcinoma (HNSCC). Additionally, silencing ASCT2 improved the response to cetuximab in HNSCC.

[0871] In some embodiments, an antibody-drug conjugate (ADC) provided herein binds to TROP2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 289, 290, 291, 292, 293, and 294, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 295 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 296. In some embodiments, the antibody of the antibody drug conjugate is sacituzumab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequences of SEQ ID NOs: 297, 298, 299, 300, 301, and 302, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 303 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 304. In some embodiments, the antibody of the antibody drug conjugate is datopotamab.

[0872] In some embodiments, an antibody-drug conjugate provided herein binds to MICA. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 305, 306, 307, 308, 309, and 310, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 311 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 312. In some embodiments, the antibody of the antibody drug conjugate is h1D5v11 hIgG1K. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 313, 314, 315, 316, 317, and 318, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 319 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 320. In some embodiments, the antibody of the antibody drug conjugate is MICA.36 hIgG1K G236A. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 321, 322, 323, 324, 325, and 326, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 327 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 328. In some embodiments, the antibody of the antibody drug conjugate is h3F9 H1L3 hIgG1K. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ IDNOs: 329, 330, 331, 332, 333, and 334, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 335 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 336. In some embodiments, the antibody of the antibody drug conjugate is CM33322 Ab28 hIgG1K.

[0873] In some embodiments, an antibody-drug conjugate provided herein binds to CD24. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 1035, 1036, 1037, 1038, 1039, and 1040, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1041 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1042. In some embodiments, the antibody of the antibody drug conjugate is SWA11.

[0874] In some embodiments, an antibody-drug conjugate provided herein binds to ITGav (also known as CD51). In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 337, 338, 339, 340, 341, and 342, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 343 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 344. In some embodiments, the antibody of the antibody drug conjugate is intetumumab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 345, 346, 347, 348, 349, and 350, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%,at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 351 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 352. In some embodiments, the antibody of the antibody drug conjugate is abituzumab.

[0875] In some embodiments, an antibody-drug conjugate provided herein binds to gpA33. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 353, 354, 355, 356, 357, and 358, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 359 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 360.

[0876] In some embodiments, an antibody-drug conjugate provided herein binds to ILlRap. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 361, 362, 363, 364, 365, and 366, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 367 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 368. In some embodiments, the antibody of the antibody drug conjugate is nidanilimab.

[0877] In some embodiments, an antibody-drug conjugate provided herein binds to EpCAM. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 369, 370, 371, 372, 373, and 374, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 375 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to the amino acid sequence of SEQ ID NO: 376. In some embodiments, the antibody of the antibody drug conjugate is adecatumumab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 377, 378, 379, 380, 381, and 382, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 383 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 384. In some embodiments, the antibody of the antibody drug conjugate is Epl57305. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 385, 386, 387, 388, 389, and 390, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 391 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 392. In some embodiments, the antibody of the antibody drug conjugate is Ep3-171. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 393, 394, 395, 396, 397, and 398, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 399 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 400. In some embodiments, the antibody of the antibody drug conjugate is Ep3622w94. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 401, 402, 403, 404, 405, and 406, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 407 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 408. In some embodiments, the antibody of the antibody drug conjugate is EpING1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 409, 410, 411, 412, 413, and 414, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 415 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 416. In some embodiments, the antibody of the antibody drug conjugate is EpAb2-6.

[0878] In some embodiments, an antibody-drug conjugate provided herein binds to CS1 (also known as SLAMF7). In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 425, 426, 427, 428, 429, and 430, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 431 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 432. In some embodiments, the antibody of the antibody drug conjugate is elotuzumab.

[0879] In some embodiments, an antibody-drug conjugate provided herein binds to CD38. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 433, 434, 435, 436, 437, and 438, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 439 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to the amino acid sequence of SEQ ID NO: 440. In some embodiments, the antibody of the antibody drug conjugate is daratumumab.

[0880] In some embodiments, an antibody-drug conjugate provided herein binds to CD25. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 441, 442, 443, 444, 445, and 446, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 447 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 448. In some embodiments, the antibody of the antibody drug conjugate is daclizumab.

[0881] In some embodiments, an antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 449, 450, 451, 452, 453, and 454, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 455 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 456. In some embodiments, the antibody of the antibody drug conjugate is chMAbA9-A. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 457, 458, 459, 460, 461, and 462, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 463 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 464. In some embodiments, the antibody of the antibody drug conjugate is hMAbA9-A.In some embodiments, an antibody-drug conjugate provided herein binds to CD59. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 465, 466, 467, 468, 469, and 470, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 471 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 472.

[0882] In some embodiments, an antibody-drug conjugate provided herein binds to CD25. In some embodiments, the antibody of the antibody drug conjugate is Clone123.

[0883] In some embodiments, an antibody-drug conjugate provided herein binds to CD229. In some embodiments, the antibody of the antibody drug conjugate is h8A10.

[0884] In some embodiments, an antibody-drug conjugate provided herein binds to CD 19. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 473, 474, 475, 476, 477, and 478, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 479 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 480. In some embodiments, the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 481 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 482. In some embodiments, the antibody of the antibody drug conjugate is denintuzumab, which is also known as hBU12. See W02009052431.

[0885] In some embodiments, an antibody-drug conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 675, 676, 677, 678, 679, and 680, respectively. In some embodiments, the antibody of theantibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 681 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 682. In some embodiments, the antibody of the antibody drug conjugate is mirzotamab.

[0886] In some cases, an antibody provided herein binds to B7-H4. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID Nos: 57-62, SEQ ID Nos: 71-76, SEQ ID Nos: 79-84, SEQ ID Nos: 87-92, SEQ ID Nos: 95-100, SEQ ID Nos: 103-108, SEQ ID Nos: 111-116, SEQ ID Nos: 119-124, SEQ ID Nos: 127-132, SEQ ID Nos: 135-140, SEQ ID Nos: 143-148, SEQ ID Nos: 151-156, SEQ ID Nos: 159-164, SEQ ID Nos: 167-172, SEQ ID Nos: 175-180, SEQ ID Nos: 183-188, SEQ ID Nos: 191-196, SEQ ID Nos: 199-204, SEQ ID Nos: 207-212, SEQ ID Nos: 215-220, and SEQ ID Nos: 223-228. In some cases, the anti-B7-H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequences of SEQ ID NO: 65 and 67, SEQ ID NO: 66 and 67, SEQ ID NO: 68 and 67, SEQ ID NO: 69 and 67, SEQ ID NO: 68 and 70, SEQ ID NO: 69 and 70, SEQ ID NO: 231 and 232, SEQ ID NO: 233 and 234, SEQ ID NO: 235 and 236, SEQ ID NO: 237 and 238, SEQ ID NO: 239 and 240, SEQ ID NO: 241 and 242, SEQ ID NO: 243 and 244, SEQ ID NO: 245 and 246, SEQ ID NO: 247 and 248, SEQ ID NO: 249 and 250, SEQ ID NO: 251 and 252, SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, or SEQ ID NO: 269 and 270, respectively. In some embodiments, the anti-B7-H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequences of SEQ ID NO: 63 and 64, SEQ ID NO: 77 and 78, SEQ ID NO: 85 and 86, SEQ ID NO: 93 and 94, SEQ ID NO: 101 and 102, SEQ ID NO: 109 and 110, SEQ ID NO: 117 and 118, SEQ ID NO: 125 and 126, SEQ ID NO: 133 and 134, SEQ ID NO: 141 and 142, SEQ ID NO: 149 and 150, SEQ ID NO: 157 and 158, SEQ ID NO: 165 and 166, SEQ ID NO: 173 and 174, SEQ ID NO:181 and 182, SEQ ID NO: 189 and 190, SEQ ID NO: 197 and 198, SEQ ID NO: 205 and 206, SEQ ID NO: 213 and 214, SEQ ID NO: 221 and 222, or SEQ ID NO: 229 and 230, respectively.

[0887] In some embodiments, an antibody-drug conjugate provided herein binds to CD138. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 483, 484, 485, 486, 487, and 488, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 489 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 490. In some embodiments, the antibody of the antibody drug conjugate is indatuxumab.

[0888] In some embodiments, an antibody-drug conjugate provided herein binds to CD 166. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 491, 492, 493, 494, 495, and 496, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 497 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 498. In some embodiments, the antibody of the antibody drug conjugate is praluzatamab.

[0889] In some embodiments, an antibody-drug conjugate provided herein binds to CD56. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 499, 500, 501, 502, 503, and 504, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 505 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 506. In some embodiments, the antibody of the antibody drug conjugate is lorvotuzumab.In some embodiments, an antibody-drug conjugate provided herein binds to CD74. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 507, 508, 509, 510, 511, and 512, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 513 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 514. In some embodiments, the antibody of the antibody drug conjugate is milatuzumab.

[0890] In some embodiments, an antibody-drug conjugate provided herein binds to CEACAM5. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 515, 516, 517, 518, 519, and 520, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 521 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 522. In some embodiments, the antibody of the antibody drug conjugate is labetuzumab.

[0891] In some embodiments, an antibody-drug conjugate provided herein binds to CanAg. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 523, 524, 525, 526, 527, and 528, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 529 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 530. In some embodiments, the antibody of the antibody drug conjugate is cantuzumab.

[0892] In some embodiments, an antibody-drug conjugate provided herein binds to DLL-3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2,CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 531, 532, 533, 534, 535, and 536, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 537 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 538. In some embodiments, the antibody of the antibody drug conjugate is rovalpituzumab.

[0893] In some embodiments, an antibody-drug conjugate provided herein binds to DPEP-3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 539, 540, 541, 542, 543, and 544, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 545 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 546. In some embodiments, the antibody of the antibody drug conjugate is tamrintamab.

[0894] In some embodiments, an antibody-drug conjugate provided herein binds to EGFR. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 547, 548, 549, 550, 551, and 552, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 553 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 554. In some embodiments, the antibody of the antibody drug conjugate is laprituximab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 555, 556, 557, 558, 559, and 560, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 561 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 562. In some embodiments, the antibody of the antibody drug conjugate is losatuxizumab. In some embodiments, the antibody of the antibody drug conjugate is serclutamab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 563, 564, 565, 566, 567, and 568, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 569 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 570. In some embodiments, the antibody of the antibody drug conjugate is cetuximab.

[0895] In some embodiments, an antibody-drug conjugate provided herein binds to FRa. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 571, 572, 573, 574, 575, and 576, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 577 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 578. In some embodiments, the antibody of the antibody drug conjugate is mirvetuximab. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 579, 580, 581, 582, 583, and 584, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 585 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acidsequence of SEQ ID NO: 586. In some embodiments, the antibody of the antibody drug conjugate is farletuzumab.

[0896] In some embodiments, an antibody-drug conjugate provided herein binds to MUC-1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 587, 588, 589, 590, 591, and 592, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 593 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 594. In some embodiments, the antibody of the antibody drug conjugate is gatipotuzumab.

[0897] In some embodiments, an antibody-drug conjugate provided herein binds to mesothelin. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 595, 596, 597, 598, 599, and 600, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 601 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 602. In some embodiments, the antibody of the antibody drug conjugate is anetumab.

[0898] In some embodiments, an antibody-drug conjugate provided herein binds to ROR-1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 603, 604, 605, 606, 607, and 608, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 609 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 610. In some embodiments, the antibody of the antibody drug conjugate is zilovertamab.In some embodiments, an antibody-drug conjugate provided herein binds to B7-H3. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 611, 612, 613, 614, 615, and 616, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 617 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 618. In some embodiments, the antibody of the antibody drug conjugate is chAb-A (BRCA84D). In some embodiments, the antibody of the antibody drug conjugate is hAb-B. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 619, 620, 621, 622, 623, and 624, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 625 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 626. In some embodiments, the antibody of the antibody drug conjugate is hAb-C. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 627, 628, 629, 630, 631, and 632, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 633 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 634. In some embodiments, the antibody of the antibody drug conjugate is hAb-D. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 635, 636, 637, 638, 639, and 640, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 641 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 642. In some embodiments, the antibody of the antibody drug conjugate is chM30. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 643, 644, 645, 646, 647, and 648, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 649 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 650. In some embodiments, the antibody of the antibody drug conjugate is hM30-Hl-L4. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 651, 652, 653, 654, 655, and 656, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 657 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 658. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAbl8-v4. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 659, 660, 661, 662, 663, and 664, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 665 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 666. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb3-v6. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2,CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 667, 668, 669, 670, 671, and 672, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 673 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 674. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAb3-v2.6.. In some embodiments, the antibody of the antibody drug conjugate is AbV_huAbl3-vl-CR. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 683, 684, 685, 686, 687, and 688, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 689 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 690. In some embodiments, the antibody of the antibody drug conjugate is 8H9-6m. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 691 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 692. In some embodiments, the antibody of the antibody drug conjugate is m8517. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 693, 694, 695, 696, 697, and 698, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 699 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 700. Insome embodiments, the antibody of the antibody drug conjugate is TPP-5706. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 701 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 702. In some embodiments, the antibody of the antibody drug conjugate is TPP-6642. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 703 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 704. In some embodiments, the antibody of the antibody drug conjugate is TPP-6850.

[0899] In some embodiments, an antibody-drug conjugate provided herein binds to HER3. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 705 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 706. In some embodiments, the antibody of the antibody drug conjugate is patritumab. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 707 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 708. In some embodiments, the antibody of the antibody drug conjugate is seribantumab. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 709 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ IDNO: 710. In some embodiments, the antibody of the antibody drug conjugate is elgemtumab. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 711 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 712. In some embodiments, the antibody of the antibody drug conjugate is lumretuzumab.

[0900] In some embodiments, an antibody-drug conjugate provided herein binds to RON. In some embodiments, the antibody of the antibody drug conjugate is Zt / g4.

[0901] In some embodiments, an antibody-drug conjugate provided herein binds to claudin-2. In some embodiments, an antibody-drug conjugate provided herein binds to HLA-G. In some embodiments, an antibody-drug conjugate provided herein binds to PTK7. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 713, 714, 715, 716, 717, and 718, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 719 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 720. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab 1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 721, 722, 723, 724, 725, and 726, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 727 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 728. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab 2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 729, 730, 731, 732, 733, and 734, respectively. In someembodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 735 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 736. In some embodiments, the antibody of the antibody drug conjugate is PTK7 mab 3.

[0902] In some embodiments, an antibody-drug conjugate provided herein binds to LIV1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 737, 738, 739, 740, 741, and 742, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 743 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 744. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 745 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 746. In some embodiments, the antibody of the antibody drug conjugate is ladiratuzumab, which is also known as hLIV22 and hglg. See WO2012078668.

[0903] In some embodiments, an antibody-drug conjugate provided herein binds to integrin avb6 (or integrin beta 6 / ITGB6). In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 43, 44, 45, 46, 47, and 48, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chaincomprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51 or SEQ ID NO: 52 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 55 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody of the antibody drug conjugate is h2A2. See PCT / US20 / 63390. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 747, 748, 749, 750, 751, and 752, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 753 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 754. In some embodiments, the antibody of the antibody drug conjugate is hl5H3. See WO 2013 / 123152.

[0904] In some embodiments, an antibody-drug conjugate provided herein binds to CD48. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 755, 756, 757, 758, 759, and 760, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 761 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 762. In some embodiments, the antibody of the antibody drug conjugate is hMEM102. See WO2016149535.

[0905] In some embodiments, an antibody-drug conjugate provided herein binds to PD-L1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2,CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 271, 272, 273, 274, 275, and 276, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 277 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 278. In some embodiments, the antibody of the antibody drug conjugate is SG-559-01 mAb or SG-559-01 LALA mAb. See PCT / US2020 / 054037.

[0906] In some embodiments, an antibody provided herein binds to EphA2. In some embodiments, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 12, 13, 14, 15, 16, and 17, respectively.

[0907] In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20 or SEQ ID NO: 21 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 23 or SEQ ID NO: 24 and a light chain comprising the amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:26 or SEQ ID NO: 27 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibody is h1C1 or 1C1.

[0908] In some embodiments, an antibody-drug conjugate provided herein binds to IGF-1R. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 763, 764, 765, 766, 767, and 768, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 769 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 770. In some embodiments, the antibody of the antibody drug conjugate is cixutumumab.

[0909] In some embodiments, an antibody-drug conjugate provided herein binds to claudin-18.2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 771, 772, 773, 774, 775, and 776, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 777 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 778. In some embodiments, the antibody of the antibody drug conjugate is zolbetuximab (175D10). In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 779, 780, 781, 782, 783, and 784, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 785 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acidsequence of SEQ ID NO: 786. In some embodiments, the antibody of the antibody drug conjugate is 163E12.

[0910] In some embodiments, an antibody-drug conjugate provided herein binds to Nectin-4. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 787, 788, 789, 790, 791, and 792, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 793 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 794. In some embodiments, the antibody of the antibody drug conjugate is enfortumab. See WO 2012047724.

[0911] In some embodiments, an antibody-drug conjugate provided herein binds to SLTRK6. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 795, 796, 797, 798, 799, and 800, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 801 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 802. In some embodiments, the antibody of the antibody drug conjugate is sirtratumab.

[0912] In some embodiments, an antibody-drug conjugate provided herein binds to CD228. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 29, 30, 31, 32, 33, and 34, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the antibody of the antibody drug conjugate is hL49. See WO 2020 / 163225.In some embodiments, an antibody-drug conjugate provided herein binds to STn. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 811, 812, 813, 814, 815, and 816, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 817 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 818. In some embodiments, the antibody of the antibody drug conjugate is h2G12. See WO 2017083582.

[0913] In some embodiments, an antibody-drug conjugate provided herein binds to CD20. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 819, 820, 821, 822, 823, and 824, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 825 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 826. In some embodiments, the antibody of the antibody drug conjugate is rituximab.

[0914] In some embodiments, an antibody-drug conjugate provided herein binds to HER2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 827, 828, 829, 830, 831, and 832, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 833 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 834. In some embodiments, the antibody of the antibody drug conjugate is trastuzumab.

[0915] In some embodiments, an antibody-drug conjugate provided herein binds to FLT3. In some embodiments, an antibody-drug conjugate provided herein binds to CD46. In someembodiments, an antibody-drug conjugate provided herein binds to GloboH. In some embodiments, an antibody-drug conjugate provided herein binds to AG7. In some embodiments, an antibody-drug conjugate provided herein binds to mesothelin. In some embodiments, an antibody-drug conjugate provided herein binds to FCRH5. In some embodiments, an antibodydrug conjugate provided herein binds to ETBR. In some embodiments, an antibody-drug conjugate provided herein binds to Tim-1. In some embodiments, an antibody-drug conjugate provided herein binds to SLC44A4. In some embodiments, an antibody-drug conjugate provided herein binds to ENPP3. In some embodiments, an antibody-drug conjugate provided herein binds to CD37. In some embodiments, an antibody-drug conjugate provided herein binds to CA9. In some embodiments, an antibody-drug conjugate provided herein binds to Notch3. In some embodiments, an antibody-drug conjugate provided herein binds to EphA2. In some embodiments, an antibody-drug conjugate provided herein binds to TRFC. In some embodiments, an antibody-drug conjugate provided herein binds to PSMA. In some embodiments, an antibody-drug conjugate provided herein binds to LRRC15. In some embodiments, an antibody-drug conjugate provided herein binds to 5T4.

[0916] In some embodiments, an antibody-drug conjugate provided herein binds to CD79b. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 835, 836, 837, 838, 839, and 840, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 841 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 842. In some embodiments, the antibody of the antibody drug conjugate is polatuzumab.

[0917] In some embodiments, an antibody-drug conjugate provided herein binds to NaPi2B. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 843, 844, 845, 846, 847, and 848, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 849 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to the amino acid sequence of SEQ ID NO: 850. In some embodiments, the antibody of the antibody drug conjugate is lifastuzumab.

[0918] In some embodiments, an antibody-drug conjugate provided herein binds to Mucl6. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 851, 852, 853, 854, 855, and 856, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 857 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 858. In some embodiments, the antibody of the antibody drug conjugate is sofituzumab.

[0919] In some embodiments, an antibody-drug conjugate provided herein binds to STEAP1. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 859, 860, 861, 862, 863, and 864, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 865 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 866. In some embodiments, the antibody of the antibody drug conjugate is vandortuzumab.

[0920] In some embodiments, an antibody-drug conjugate provided herein binds to BCMA. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 867, 868, 869, 870, 871, and 872, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 873 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 874. In some embodiments, the antibody of the antibody drug conjugate is belantamab.In some embodiments, an antibody-drug conjugate provided herein binds to c-Met. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 875, 876, 877, 878, 879, and 880, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 881 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 882. In some embodiments, the antibody of the antibody drug conjugate is telisotuzumab.

[0921] In some embodiments, an antibody-drug conjugate provided herein binds to EGFR. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 883, 884, 885, 886, 887, and 888, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 889 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 890. In some embodiments, the antibody of the antibody drug conjugate is depatuxizumab.

[0922] In some embodiments, an antibody-drug conjugate provided herein binds to SLAMF7. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 891, 892, 893, 894, 895, and 896, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 897 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 898. In some embodiments, the antibody of the antibody drug conjugate is azintuxizumab.

[0923] In some embodiments, an antibody-drug conjugate provided herein binds to C4.4a (also known as LYPD3). In some embodiments, the antibody of the antibody drug conjugatecomprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 899, 900, 901, 902, 903, and 904, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 905 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 906. In some embodiments, the antibody of the antibody drug conjugate is lupartumab.

[0924] In some embodiments, an antibody-drug conjugate provided herein binds to GCC. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 907, 908, 909, 910, 911, and 912, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 913 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 914. In some embodiments, the antibody of the antibody drug conjugate is indusatumab.

[0925] In some embodiments, an antibody-drug conjugate provided herein binds to Axl. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 915, 916, 917, 918, 919, and 920, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 921 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 922. In some embodiments, the antibody of the antibody drug conjugate is enapotamab.

[0926] In some embodiments, an antibody-drug conjugate provided herein binds to gpNMB. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 923, 924, 925, 926, 927, and 928, respectively. In some embodiments, the antibody of theantibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 929 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 930. In some embodiments, the anti-gpNMB antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 931 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 932. In some embodiments, the antibody of the antibody drug conjugate is glembatumumab.

[0927] In some embodiments, an antibody-drug conjugate provided herein binds to Prolactin receptor (PRLR). In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 933, 934, 935, 936, 937, and 938, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 939 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 940. In some embodiments, the antibody of the antibody drug conjugate is rolinsatamab.

[0928] In some embodiments, an antibody-drug conjugate provided herein binds to FGFR2. In some embodiments, the antibody of the antibody drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 941, 942, 943, 944, 945, and 946, respectively. In some embodiments, the antibody of the antibody drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 947 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 948. In some embodiments, the antibody of the antibody drug conjugate is aprutumab.In some embodiments, an antibody-drug conj...

Claims

CLAIMSWe claim:

1. A compound of Formula I:Formula Ior a pharmaceutically acceptable salt thereof, wherein:X is N or C(R7);Y is O or SR1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;each instance of R8is independently halogen, OR9, or C1-C6 alkyl;each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,3- to 10-membered heterocycloalkyl,znxNHor2, wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R11is hydrogen, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalky;l andn is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R2is CH35. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula la:Formula la6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R3is C(O)R10.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R6Ais OH and R6Bis hydrogen.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R10is C3-C8cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 10- membered heteroaryl.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I of la is a compound of Formula lb:Formula lbwherein:R13is hydrogen or C1-C3 alkyl; andm is 0, 1, 2, or 3.

11. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof,, wherein12. The compound of any one of claims 1-7 or 11, or a pharmaceutically acceptable salt thereof, wherein R10is selected from:

13. The compound of any one of claims 1-7 or 11, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or la is a compound of Formula Ic:Formula Ic14. The compound of any one of claims 1-7 or 11, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or la is a compound of Formula Id:Formula Id15. The compound of claim 14, wherein n is 1, 2, or 3.

16. The compound of claim 14 or 15, wherein R11is selected from CF3,17. The compound of any one of claims 1-16, wherein X is C(R7).

18. The compound of any one of claims 1-17, wherein R7is Ce-Cio aryl, Ci-Ce alkyl, or C3- Cs cycloalkyl.

19. The compound of claim 18, wherein R7is unsubstituted.

20. The compound of claim 18, wherein R7is substituted with 1 to 3 instances of R8.

21. The compound of claim 18, wherein R7is selected from phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, CF3, and CHF2.

22. The compound of any one of claims 1-16, wherein X is N.

23. The compound of any one of claims 1-22, wherein R1is Ce-Cio aryl, Ci-Ce alkyl, or C3- Cs cycloalkyl.

24. The compound of claim 23, wherein R1is unsubstituted.

25. The compound of claim 23, wherein R1is substituted with 1 to 3 instances of R8.

26. The compound of claim 23, wherein R1is selected from phenyl, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, CF3, and CHF2.

27. The compound of any one of claims 1-26, wherein the compound is selected from Table 1.

28. A drug-linker compound of Formula II:Q-DFormula IIor a pharmaceutically acceptable salt thereof, wherein:Q is a linker unit selected from:wherein:R14, R15, R16, and R17are each independently hydrogen, Ci-Ce alkyl, or C3-C8 cycloalkyl;andD is a compound of Formula I:Formula Ior a pharmaceutically acceptable salt thereof,wherein:X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R6A, R6B, R6C, and R6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;each instance of R8is independently halogen, OR9, or C1-C6 alkyl;each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,3- to 10-membered heterocycloalkyl,or, wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- Cio aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3alkyl, C3-C8cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10aryl is unsubstituted or substituted with 1-3 instances of C1-C3alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8cycloalkyl; andn is 0, 1, 2, 3, 4, or 5.

29. The drug-linker compound of claim 28, the compound of Formula I is a compound of Formula la, lb, Ic, or Id:Formula Ic Formula Id, oror a pharmaceutically acceptable salt thereof, wherein R13is hydrogen or C1-C3 alkyl and m is 0, 1, 2, or 3.

30. The drug-linker compound of claim 28 or 29, or a pharmaceutically acceptable saltthereof, wherein the linker unit i31. The drug-linker compound of any one of claims 28-30, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula Ila or a compound of Formula lib:wherein each instance of D is independently a compound of Formula I.

32. The drug-linker compound of any one of claims 28-31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula lie or a compound of Formula lid:wherein:X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl;or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;R13is hydrogen or C1-C3 alkyl; andm is 0, 1, 2, or 3.

33. The drug-linker of any one of claims 28-31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula lie:wherein:X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10Aand R10Bare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-memberedheterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances ofR12;R10Lis hydrogen or C1-C12 alkyl, wherein the C1-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;each instance of R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

34. The drug-linker of any one of claims 28-31, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II is a compound of Formula Ilf:wherein:X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, and wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen; andn is 0, 1, 2, 3, 4, or 5.The drug-linker compound of any one of claims 28-34, wherein the compound is selected from Table 3.A ligand-drug conjugate molecule of Formula III:L-(Q-D)Por a pharmaceutically acceptable salt thereof, wherein:L is a Ligand Unit;p is an integer selected from 1 to 36;Q is a linker unit selected from:wherein:* denotes the point of attachment to L;R14, R15, R16, and R17are each independently hydrogen, Ci-Ce alkyl, or C3-C8 cycloalkyl;andD is a compound of Formula I:Formula Ior a pharmaceutically acceptable salt thereof,wherein:X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R2is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein the C1-C6 alkyl and C3-C8 cycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R3, R4, and R5are each independently hydrogen, C1-C6 alkyl, 5- to 10-membered heteroaryl, or C(O)R10, wherein the C1-C6 alkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R6A, R6B5R6CR6Dare each independently hydrogen, halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of R8;or R6Aand R6Btaken together with the carbon atom to which they are attached form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the C3-C8 cycloalkyl and the 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;each instance of R8is independently halogen, OR9, or C1-C6 alkyl;each instance of R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10is C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl,3- to 10-membered heterocycloalkyl,or, wherein the C1-C6 alkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C8 cycloalkyl and 3- to 10-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10A, R10B, R10C, R10D, R10E, and R10Fare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, R10B, R10C, R10D, R10E, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein substituted the C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10K, R10L, and R10Mare independently hydrogen or C1-C12 alkyl, wherein the Ci-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;or R10Kand R10L, taken together with the nitrogen atom to which they are attached, form 3- to 8-membered heterocycloalkyl or 5- to 10-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10- membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;or R10Kor R10Land any one of R10A, R10B, R10C, R10D, R10E, and R10F, taken together with the nitrogen atom to which R10Kor R10Lis attached, the carbon atom to which R10A, R10B, R10C, R10D, R10E, and R10Fis attached, and any intermediate carbon atoms, form 3- to 8-membered heterocycloalkyl or 5- to 10- membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R11is hydrogen, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted or substituted with 1 to 3 instances of halogen, OR9, or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;each instance of R12is independently halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1-3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;andn is 0, 1, 2, 3, 4, or 5.

37. The ligand-drug conjugate molecule of claim 36, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula la, lb, Ic, or Id:Formula Ic Formula Idor a pharmaceutically acceptable salt thereof.

38. The ligand-drug conjugate molecule of claim 36 or 37, or a pharmaceutically acceptablesalt thereof, wherein the linker unit39. The ligand-drug conjugate molecule of any one of claims 36-38, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug conjugate molecule of Formula Illa:wherein:L is a Ligand Unit;p is an integer selected from 1 to 36; andD is a compound of Formula I.

40. The ligand-drug conjugate molecule of any one of claims 36-38, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug conjugate molecule of Formula Illb:Formula Illbwherein:L is a Ligand Unitp is an integer selected from 1 to 36; andD is a compound of Formula I.

41. The ligand-drug conjugate molecule of any one of claims 36-39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula IIIc:wherein:L is a Ligand Unit;p is an integer selected from 1 to 36;X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

42. The ligand-drug conjugate molecule of any one of claims 36-38, or 40, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula Hid:wherein:L is a Ligand Unit;p is an integer selected from 1 to 36;X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10- membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl;R13is hydrogen or C1-C3 alkyl; andm is 0, 1, 2, or 3.

43. The ligand-drug conjugate molecule of any one of claims 36-39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula Ille:wherein:L is a Ligand Unit;p is an integer selected from 1 to 36;X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R10Aand R10Bare each independently hydrogen, halogen, or Ci-Ce alkyl, wherein Ci-Ce alkyl is unsubstituted or substituted 1 to 3 instances of R12; or any two of R10A, RIOB, R10CR1OD, R1OE, and R10Ftaken together with the carbon atoms to which they are attached and any intermediate carbon atoms, form C3-C8 cycloalkyl or 3- to 8-memberedheterocycloalkyl, wherein substituted the C3-C8cycloalkyl and 3- to 8-membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R12;R10Lis hydrogen or C1-C12 alkyl, wherein the C1-C12 alkyl is unsubstituted or substituted with 1 to 3 instances of R12;each instance of R12is halogen, amino, hydroxyl, CF3, CHF2, CN, C(O)OH, C(O)NH2, C1-C3 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce-Cio aryl is unsubstituted or substituted with 1 to 3 instances of C1-C3 alkyl; or two R12groups, taken together with the atom to which they are attached, form C3-C8 cycloalkyl.

44. The ligand-drug conjugate molecule of any one of claims 36-39, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule of Formula III is a ligand-drug molecule of Formula IIIf:wherein:L is a Ligand Unit;p is an integer selected from 1 to 36;X is N or C(R7);R1and R7are each independently hydrogen, halogen, Ce-Cio aryl, Ci-Ce alkyl, C3-C8 cycloalkyl, 3- to 10- membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl, C1-C6 alkyl, C3-C8 cycloalkyl, and 3- to 10- membered heterocycloalkyl are each independently unsubstituted or substituted with 1 to 3 instances of R8;R8is independently halogen, OR9, or C1-C6 alkyl;R9is independently hydrogen or C1-C6 alkyl, wherein the C1-C6 alkyl is unsubstituted or substituted with 1 to 3 instances of halogen;R11is hydrogen, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein the Ce- C10 aryl and 5- to 10-membered heteroaryl are each independently unsubstituted orsubstituted with 1 to 3 instances of halogen, OR9, or Ci-Ce alkyl, and wherein the Ci-Ce alkyl is unsubstituted or substituted with 1 to 3 instances of halogen; andn is 0, 1, 2, 3, 4, or 5.

45. The ligand-drug conjugate molecule of any one of claims 36-44, or a pharmaceutically acceptable salt thereof, wherein the ligand-drug conjugate molecule is selected from Table 5.

46. The ligand-drug conjugate molecule of any one of claims 36 to 45, or a pharmaceutically acceptable salt thereof, wherein p is an integer selected 2 to 4, 2 to 8, 2 to 16, 1 to 32, 4 to 8, 4 to 16, 4 to 32, 8 to 32, or 16 to 32.

47. The ligand-drug conjugate molecule of any one of claims 36 to 46, or a pharmaceutically acceptable salt thereof, wherein L comprises a protein, a nucleic acid, a saccharide, a polyketide, a nanoparticle, a microparticle, a polymer, a hydrogel, or a combination thereof.

48. The ligand-drug conjugate molecule of any one of claims 36 to 47, or a pharmaceutically acceptable salt thereof, wherein L comprises a protein or is a protein.

49. The ligand-drug conjugate molecule of claim 48, or a pharmaceutically acceptable salt thereof, wherein the protein is an antibody, a fragment antigen binding (Fab), a heavy chain variable domain, a nanobody, a diabody, a triabody, or a minibody, a F(ab')₂ fragment, a Fab fragment, a single chain variable fragment (scFv), or a single domain antibody (sdAb).

50. The ligand-drug conjugate molecule of claim 48 or 49, or a pharmaceutically acceptable salt thereof, wherein the protein is an antibody.

51. The ligand-drug conjugate molecule of any one of claims 48-50, or a pharmaceutically acceptable salt thereof, wherein the protein comprises one or more sequences selected from SEQ ID NO: 1-1047.

52. The ligand-drug conjugate of any one of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein the protein targets a cancer cell.

53. A pharmaceutical composition comprising the compound of any one of claims 1-27, the drug-linker compound of any one of claims 28-35, or the ligand-drug conjugate of any one of claims 36-52, and a pharmaceutically acceptable excipient.

54. The pharmaceutical composition of claim 53, further comprising a pharmaceutically acceptable carrier.

55. The pharmaceutical composition of claim 53 or 54, further comprising a pharmaceutically acceptable stabilizer.

56. A method of treating a cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1-27, the drug-linker compound of any one of claims 28-35, or the ligand-drug conjugate of any one of claims 36-52, or the pharmaceutical composition of any one of claims 53- 55 to the subject, thereby treating the cancer.

57. The method of claim 56, wherein the compound has an LD50of less than about 500 nM for the cancer.

58. The method of claim 56 or 57, wherein the cancer is non-Hodgkin’s lymphoma, adenocarcinoma, or malignant histiocytosis, lymphoma, Hodgkin Lymphoma, leukemia, a solid tumor, a hematopoietic cancer, follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, multiple myeloma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, or retinoblastoma.

59. The method of any one of claims 56-58, wherein the cancer is non-Hodgkin’s lymphoma, adenocarcinoma, or malignant histiocytosis.

60. The method of any one of claims 59, wherein the cancer is non-Hodgkin’s lymphoma.

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