Immunostimulatory anti-PD-L1-drug conjugates

Abstract

The present disclosure provides compounds and methods useful for treating various cancers. The compounds include antibody-drug conjugates (ADCs) configured to selectively activate immune responses within the tumor microenvironment and reverse tumor-associated macrophage-mediated immunosuppression. Certain aspects of the disclosure relate to TLR7 / 8 agonists conjugated to tumor- and immune cell-targeting antibodies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 394,912, filed August 3, 2022, which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in Extensible Markup Language (XML) format, which is incorporated herein by reference in its entirety. The XML copy, created on July 24, 2023, is named "438442-704021_SL.XML" and is 944 kilobytes in size.

[0003] Incorporation by Reference 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. [Background technology]

[0004] In addition to utilizing multiple different mechanisms for growth and spread, tumors often affect local and systemic immunosuppression. While the majority of cells expressing immunogenic antigens are rapidly eliminated before neoplasia or tumor formation, tumor-mediated immunosuppression often blocks immune activity against cancer cells, allowing tumors to spread unchecked. Because many cytotoxic cancer therapies rely on immune activity for cancer cell clearance, immunosuppressive tumors can be resistant to conventional cancer therapies, which also do not achieve immune reactivation and therefore do not affect immune clearance. Therefore, cancer therapies often require immune activation functions that can override tumor immunosuppression.

[0005] Despite this need, most immunomodulatory therapies exhibit limited efficacy. While the immunosuppressive tumor environment is often localized, many immunostimulatory therapies generate toxic systemic reactions that can limit dosing below the levels required for localized treatment efficacy. In particular, antibody-based treatments often rely on antibody-dependent cellular cytotoxicity (ADCC), whereas non-targeted immunostimulatory complexes can generate dangerous toxic inflammatory and cytokine responses. Furthermore, many immunostimulatory compounds target intracellular receptors present on both cancer and immune cells, meaning treatments must balance the requirements for tumor cell targeting and immune cell uptake.

[0006] Central among such immunostimulatory compounds are Toll-like receptors (TLRs), which play a key role in activating the immune system against invading pathogens and damaged cells with tumorigenic potential (see Kaczanowska, et al., J. Leukoc. Biol. 2013;93(6):847-863). TLRs are a family of membrane-bound proteins that, when activated, recruit adaptor proteins to amplify antigen-induced signals to modify cell phenotype and activity. As immunostimulatory compounds, TLR agonists have been developed as vaccine adjuvants to boost the generation of immune cells that target desired viral or bacterial antigens in vaccines. TLRs also recognize endogenous markers of tumorigenesis, such as cell death and chronic inflammation, and activate innate immune responses against these cells. (See, e.g., Ellerman, et al., Clin. Cancer Res. 2007;13:2836-2848; Hernandez, et al., Oncogene 2016;35:5931-5941; and Urban-Wojciuk, et al., Front. Immunol., Vol. 10, pp. 2388-2398 (2019)). However, due to their immunostimulatory properties, the systemic use of TLR agonists can be limited by dose-limiting toxicity due to systemic cytokine induction. See Adams, S., Immunotherapy 2009;1(6):949-964. Thus, there remains a need for targeted immunostimulatory compounds to localize the immune response to desired cells while minimizing off-target effects. Summary of the Invention

[0007] The present disclosure provides compounds and biomolecular complexes (e.g., antibody-drug conjugates) that elicit cell- and tissue-specific immune responses. Because cancer immunosuppression is often localized within the microenvironment near cancer cells, targeting payloads to these cancer sites may be essential to affect immune reactivation. To this end, in certain embodiments, the present disclosure provides antibody-drug conjugates (ADCs) configured to selectively activate immune responses within the tumor microenvironment. In addition to delivering payloads to targeted cancer sites, the ADCs of the present disclosure can be configured to release their payloads (e.g., TLR agonists) upon uptake by cancer or cancer-associated cells, thereby targeting immune activation to cancer sites and preventing off-target immune activation.

[0008] The ADCs described herein, and pharmaceutically acceptable salts thereof, can be configured for uptake by target cells or tissues. In some embodiments, the ADCs are configured to endocytose upon binding to membrane-bound and / or surface-presented antigens. In such cases, the ADCs can target intracellular receptors, such as TLR7 or TLR8, which are often primarily localized within endosomes. Endocytosis can be assisted by lipid-soluble groups attached to the ADC, such as PEGylation or neutral and nonpolar peptide linkers.

[0009] In addition to targeting, release of the ADC Drug Unit can be controlled so that release occurs at a designated site (e.g., cells targeted by an antibody). Because the linker (L) cleavable group can be configured for cleavage specifically under physiological conditions or by specific enzymes, release of the Drug Unit can be restricted primarily to the target site. Thus, the biological effect of the Drug Unit (e.g., an immunostimulatory effect) can be localized to the target site. Alternatively, the Drug Unit can be configured to remain attached to the antibody, or portion of the antibody and / or linker, and induce its biological effect while coupled to the antibody.

[0010] An aspect of the present disclosure is a compound having the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D is a structure of formula (A): [ka] or a pharmaceutically acceptable salt thereof and R 1 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C 6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C15 -C 27 Trisaccharide and acylated C 15 -C 27 optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R 2 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L; R 3 is (a) the point of covalent attachment to L; or (b) hydrogen, —NR A R B , -C(=O)NR A R B, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C and (i) 1 to 3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi)-CO2H; (vii) C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D RE ] + ; (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); (xii) Halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with -CO2H; (xiii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl of (-5- to 10-membered heteroaryl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6)alkoxycarbonyl, or 5-10 membered heteroaryl optionally substituted with -CO2H -C1-C6 alkyl optionally substituted with; R 4 is C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is optionally further substituted at the point of covalent attachment to L; Each R X is (a) the point of covalent attachment to L; and (b) hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NR G RH , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and wherein no more than one R X is the point of covalent attachment to L; The subscript n is 0, 1, 2, 3, or 4; R A and R B Each occurrence of represents (a) a point of covalent attachment to L, (b) the group consisting of hydrogen and C-C alkyl, and (c) R A and R B are independently selected from the group consisting of: R, ... A and R B at most one occurrence of is the point of covalent attachment to L; R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 independently selected from the group consisting of alkyl; R D , R E , R G , and R H Each occurrence of is selected from the group consisting of: (a) a point of covalent attachment to L; (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-; and (c) R D and R E , or R G and R Hare independently selected from the group consisting of: R, ... D , R E , R G , and R H is the point of covalent attachment to L; R F is independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R I , R J , and R K each occurrence is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C6 alkyl; R I , R J , and R K at most one of which is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO:19 and the second sequence is SEQ ID NO:20; the first sequence is SEQ ID NO:44 and the second sequence is SEQ ID NO:45; the first sequence is SEQ ID NO:55 and the second sequence is SEQ ID NO:56; the first sequence is SEQ ID NO:69 and the second sequence is SEQ ID NO:70; the first sequence is SEQ ID NO:83 and the second sequence is SEQ ID NO:84; The first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:162; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210; the first the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; the first sequence is SEQ ID NO:297 and the second sequence is SEQ ID NO:298; the first sequence is SEQ ID NO:307 and the second sequence is SEQ ID NO:308;The first sequence is SEQ ID NO:315 and the second sequence is SEQ ID NO:316; the first sequence is SEQ ID NO:323 and the second sequence is SEQ ID NO:324; the first sequence is SEQ ID NO:331 and the second sequence is SEQ ID NO:332; the first sequence is SEQ ID NO:339 and the second sequence is SEQ ID NO:340; the first sequence is SEQ ID NO:347 and the second sequence is SEQ ID NO:348; the first sequence is SEQ ID NO:355 and the second sequence is SEQ ID NO:356; the first sequence is SEQ ID NO:363 and the second sequence is SEQ ID NO:365. the first sequence is SEQ ID NO:371 and the second sequence is SEQ ID NO:372; the first sequence is SEQ ID NO:379 and the second sequence is SEQ ID NO:380; the first sequence is SEQ ID NO:387 and the second sequence is SEQ ID NO:388; the first sequence is SEQ ID NO:395 and the second sequence is SEQ ID NO:396; the first sequence is SEQ ID NO:403 and the second sequence is SEQ ID NO:404; the first sequence is SEQ ID NO:411 and the second sequence is SEQ ID NO:412; the first sequence is SEQ ID NO:419, the first sequence is SEQ ID NO:427 and the second sequence is SEQ ID NO:428; the first sequence is SEQ ID NO:435 and the second sequence is SEQ ID NO:436; the first sequence is SEQ ID NO:443 and the second sequence is SEQ ID NO:444; the first sequence is SEQ ID NO:451 and the second sequence is SEQ ID NO:452; the first sequence is SEQ ID NO:459 and the second sequence is SEQ ID NO:460; the first sequence is SEQ ID NO:467 and the second sequence is SEQ ID NO:468; the first sequence is SEQ ID NO:469 the first sequence is SEQ ID NO:475 and the second sequence is SEQ ID NO:476; the first sequence is SEQ ID NO:483 and the second sequence is SEQ ID NO:484; the first sequence is SEQ ID NO:491 and the second sequence is SEQ ID NO:492; the first sequence is SEQ ID NO:501 and the second sequence is SEQ ID NO:502; the first sequence is SEQ ID NO:509 and the second sequence is SEQ ID NO:510; the first sequence is SEQ ID NO:517 and the second sequence is SEQ ID NO:518; the first sequence is SEQ ID NO:525 and the second sequence is SEQ ID NO:526;The first sequence is SEQ ID NO:533 and the second sequence is SEQ ID NO:534; the first sequence is SEQ ID NO:541 and the second sequence is SEQ ID NO:542; the first sequence is SEQ ID NO:549 and the second sequence is SEQ ID NO:550; the first sequence is SEQ ID NO:557 and the second sequence is SEQ ID NO:558; the first sequence is SEQ ID NO:565 and the second sequence is SEQ ID NO:566; the first sequence is SEQ ID NO:574 and the second sequence is SEQ ID NO:574; the first sequence is SEQ ID NO:581 and the second sequence is SEQ ID NO:582. the first sequence is SEQ ID NO: 589 and the second sequence is SEQ ID NO: 590; the first sequence is SEQ ID NO: 597 and the second sequence is SEQ ID NO: 598; the first sequence is SEQ ID NO: 605 and the second sequence is SEQ ID NO: 606; the first sequence is SEQ ID NO: 613 and the second sequence is SEQ ID NO: 614; the first sequence is SEQ ID NO: 621 and the second sequence is SEQ ID NO: 622; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637, the first sequence is SEQ ID NO:645 and the second sequence is SEQ ID NO:646; the first sequence is SEQ ID NO:653 and the second sequence is SEQ ID NO:654; the first sequence is SEQ ID NO:661 and the second sequence is SEQ ID NO:662; the first sequence is SEQ ID NO:669 and the second sequence is SEQ ID NO:670; the first sequence is SEQ ID NO:677 and the second sequence is SEQ ID NO:678; the first sequence is SEQ ID NO:685 and the second sequence is SEQ ID NO:686; the first sequence is SEQ ID NO:689 the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; the first sequence is SEQ ID NO: 731 and the second sequence is SEQ ID NO: 732;The first sequence is SEQ ID NO:739 and the second sequence is SEQ ID NO:740; the first sequence is SEQ ID NO:747 and the second sequence is SEQ ID NO:748; the first sequence is SEQ ID NO:755 and the second sequence is SEQ ID NO:756; the first sequence is SEQ ID NO:765 and the second sequence is SEQ ID NO:766; the first sequence is SEQ ID NO:773 and the second sequence is SEQ ID NO:774; the first sequence is SEQ ID NO:781 and the second sequence is SEQ ID NO:782; the first sequence is SEQ ID NO:789 and the second sequence is SEQ ID NO: the first sequence is SEQ ID NO:797 and the second sequence is SEQ ID NO:798; the first sequence is SEQ ID NO:805 and the second sequence is SEQ ID NO:806; the first sequence is SEQ ID NO:813 and the second sequence is SEQ ID NO:814; the first sequence is SEQ ID NO:821 and the second sequence is SEQ ID NO:822; the first sequence is SEQ ID NO:829 and the second sequence is SEQ ID NO:830; the first sequence is SEQ ID NO:837 and the second sequence is SEQ ID NO:838; the first sequence is SEQ ID NO:845, the first sequence is SEQ ID NO:853 and the second sequence is SEQ ID NO:854; the first sequence is SEQ ID NO:861 and the second sequence is SEQ ID NO:862; the first sequence is SEQ ID NO:869 and the second sequence is SEQ ID NO:870; the first sequence is SEQ ID NO:877 and the second sequence is SEQ ID NO:878; the first sequence is SEQ ID NO:885 and the second sequence is SEQ ID NO:886; the first sequence is SEQ ID NO:893 and the second sequence is SEQ ID NO:894; the first sequence is SEQ ID NO:895 and the second sequence is SEQ ID NO:896 the first sequence is SEQ ID NO:900 and the second sequence is SEQ ID NO:901; the first sequence is SEQ ID NO:909 and the second sequence is SEQ ID NO:910; the first sequence is SEQ ID NO:917 and the second sequence is SEQ ID NO:918; the first sequence is SEQ ID NO:925 and the second sequence is SEQ ID NO:926; the first sequence is SEQ ID NO:933 and the second sequence is SEQ ID NO:934; the first sequence is SEQ ID NO:941 and the second sequence is SEQ ID NO:942; the first sequence is SEQ ID NO:943 and the second sequence is SEQ ID NO:944;The first sequence is SEQ ID NO:951 and the second sequence is SEQ ID NO:952; the first sequence is SEQ ID NO:959 and the second sequence is SEQ ID NO:960; the first sequence is SEQ ID NO:967 and the second sequence is SEQ ID NO:968; the first sequence is SEQ ID NO:975 and the second sequence is SEQ ID NO:976; the first sequence is SEQ ID NO:983 and the second sequence is SEQ ID NO:984; the first sequence is SEQ ID NO:991 and the second sequence is SEQ ID NO:992; the first sequence is SEQ ID NO:993 and the second sequence is SEQ ID NO:994; one sequence is SEQ ID NO:995 and the second sequence is SEQ ID NO:996; the first sequence is SEQ ID NO:1003 and the second sequence is SEQ ID NO:1004; the first sequence is SEQ ID NO:1011 and the second sequence is SEQ ID NO:1012; the first sequence is SEQ ID NO:1019 and the second sequence is SEQ ID NO:1020; the first sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028; the first sequence is SEQ ID NO:1035 and 1036; or the first sequence is SEQ ID NO:1043 and the second sequence is SEQ ID NO:1044); In some cases, the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is , SEQ ID NO:130; the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; the first sequence is SEQ ID NO:153 and the second sequence is SEQ ID NO:154; the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:162; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; The first sequence is SEQ ID NO: 649 and the second sequence is SEQ ID NO: 650; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637 and the second sequence is SEQ ID NO: 638; the first sequence is SEQ ID NO: 645 and the second sequence is SEQ ID NO: 646; the first sequence is SEQ ID NO: 653 and the second sequence is SEQ ID NO: 654; the first sequence is SEQ ID NO: 661 and the second sequence is SEQ ID NO: 662; the first sequence is SEQ ID NO: 669 and the second sequence is SEQ ID NO: 670;The first sequence is SEQ ID NO:677 and the second sequence is SEQ ID NO:678; the first sequence is SEQ ID NO:685 and the second sequence is SEQ ID NO:686; the first sequence is SEQ ID NO:693 and the second sequence is SEQ ID NO:694; the first sequence is SEQ ID NO:701 and the second sequence is SEQ ID NO:702; the first sequence is SEQ ID NO:703 and the second sequence is SEQ ID NO:704; the first sequence is SEQ ID NO:711 and the second sequence is SEQ ID NO:712; the first sequence is SEQ ID NO:713 and the second sequence is SEQ ID NO:714; the first sequence is SEQ ID NO:715 and the second sequence is SEQ ID NO:716; or the first sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028. In some cases, the first sequence is SEQ ID NO:19 and the second sequence is SEQ ID NO:20. In some cases, the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence;

[0011] Certain aspects of the present disclosure provide a compound having the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D is a structure of formula (A): [ka] or a pharmaceutically acceptable salt thereof and R 1 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C 6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R 2is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L; R 3 is (a) the point of covalent attachment to L; or (b) hydrogen, —NR A R B , -C(=O)NR A R B, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C and (i) 1 to 3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi)-CO2H; (vii) C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D RE ] + ; (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); (xii) Halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with -CO2H; (xiii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl of (-5- to 10-membered heteroaryl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6)alkoxycarbonyl, or 5-10 membered heteroaryl optionally substituted with -CO2H -C1-C6 alkyl optionally substituted with; R 4 is C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is optionally further substituted at the point of covalent attachment to L; Each R X is (a) the point of covalent attachment to L; and (b) hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NR G RH , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and wherein no more than one R X is the point of covalent attachment to L; The subscript n is 0, 1, 2, 3, or 4; R A and R B Each occurrence of represents (a) a point of covalent attachment to L, (b) the group consisting of hydrogen and C-C alkyl, and (c) R A and R B are independently selected from the group consisting of: R, ... A and R B at most one occurrence of is the point of covalent attachment to L; R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 independently selected from the group consisting of alkyl; R D , R E , R G , and R H Each occurrence of is selected from the group consisting of: (a) a point of covalent attachment to L; (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-; and (c) R D and R E , or R G and R Hare independently selected from the group consisting of: R, ... D , R E , R G , and R H is the point of covalent attachment to L; R F is independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R I , R J , and R K each occurrence is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C6 alkyl; R I , R J , and R K at most one of which is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a heavy chain having at least 80% sequence identity with a first sequence and a light chain having at least 80% sequence identity with a second sequence: the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO: is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:46 and the second sequence is SEQ ID NO:48; the first sequence is SEQ ID NO:47 and the second sequence is SEQ ID NO:48; the first sequence is SEQ ID NO:57 and the second sequence is SEQ ID NO:59; the first sequence is SEQ ID NO:58 and the second sequence is SEQ ID NO:59; the first sequence is SEQ ID NO:60 and the second sequence is SEQ ID NO:62. the first sequence is SEQ ID NO:61 and the second sequence is SEQ ID NO:62; the first sequence is SEQ ID NO:71 and the second sequence is SEQ ID NO:73; the first sequence is SEQ ID NO:72 and the second sequence is SEQ ID NO:73; the first sequence is SEQ ID NO:74 and the second sequence is SEQ ID NO:76; the first sequence is SEQ ID NO:75 and the second sequence is SEQ ID NO:76; the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; the first the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:251 and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260;The first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272. the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290; the first sequence is SEQ ID NO:299 and the second sequence is SEQ ID NO:300; the first sequence is SEQ ID NO:493 and the second the sequence is SEQ ID NO:494; the first sequence is SEQ ID NO:717 and the second sequence is SEQ ID NO:718; the first sequence is SEQ ID NO:719 and the second sequence is SEQ ID NO:720; the first sequence is SEQ ID NO:721 and the second sequence is SEQ ID NO:722; the first sequence is SEQ ID NO:723 and the second sequence is SEQ ID NO:724; or the first sequence is SEQ ID NO:757 and the second sequence is SEQ ID NO:758); In some cases, the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; The first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 25 5 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; the first sequence is , SEQ ID NO:269 and the second sequence is SEQ ID NO:270; the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282;The first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; or the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724. In some cases, the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10. In some cases, the heavy chain has at least 90% sequence identity to the first sequence and the light chain has at least 90% sequence identity to the second sequence. In some cases, the heavy chain has at least 98% sequence identity to the first sequence and the light chain has at least 98% sequence identity to the second sequence;

[0012] Various aspects of the present disclosure provide a method for producing a compound having the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D is a structure of formula (A): [ka] or a pharmaceutically acceptable salt thereof and R 1 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C 6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R 2is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L; R 3 is (a) the point of covalent attachment to L; or (b) hydrogen, —NR A R B , -C(=O)NR A R B, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C and (i) 1 to 3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi)-CO2H; (vii) C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D RE ] + ; (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); (xii) Halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with -CO2H; (xiii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl of (-5- to 10-membered heteroaryl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6)alkoxycarbonyl, or 5-10 membered heteroaryl optionally substituted with -CO2H -C1-C6 alkyl optionally substituted with; R 4 is C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is optionally further substituted at the point of covalent attachment to L; Each R X is (a) the point of covalent attachment to L; and (b) hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NR G RH , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and wherein no more than one R X is the point of covalent attachment to L; The subscript n is 0, 1, 2, 3, or 4; R A and R B Each occurrence of represents (a) a point of covalent attachment to L, (b) the group consisting of hydrogen and C-C alkyl, and (c) R A and R B are independently selected from the group consisting of: R, ... A and R B at most one occurrence of is the point of covalent attachment to L; R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 independently selected from the group consisting of alkyl; R D , R E , R G , and R H Each occurrence of is selected from the group consisting of: (a) a point of covalent attachment to L; (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-; and (c) R D and R E , or R G and R Hare independently selected from the group consisting of: R, ... D , R E , R G , and R H is the point of covalent attachment to L; R F is independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R I , R J , and R K each occurrence is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C6 alkyl; R I , R J , and R K at most one of which is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a CDR-H1 comprising at least 80% sequence identity with a first sequence, a CDR-H2 comprising at least 80% sequence identity with a second sequence, a CDR-H3 comprising at least 80% sequence identity with a third sequence, a CDR-L1 comprising at least 80% sequence identity with a fourth sequence, a CDR-L2 comprising at least 80% sequence identity with a fifth sequence, and a CDR-L3 comprising at least 80% sequence identity with a sixth sequence, wherein the first, second, third, fourth, fifth, and sixth sequences are set forth in SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; Sequence numbers 21, 22, 23, 24, 25, and 26; SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOs: 107, 108, 109, 110, 111, and 112, respectively; and SEQ ID NOs: 115, 116, 117, 118, 119, 120, 121, and 122, respectively. 17, 118, 119, and 120; SEQ ID NOs: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NOs: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NOs: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NOs: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NOs: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NOs: 163, 164, 165, 166, 167, and 168, respectively; and SEQ ID NOs: 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, and 188, respectively. 75, and 176; SEQ ID NOs: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NOs: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207, and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NOs: 219, 220, 221, 222, 223, and 224, respectively; and SEQ ID NOs: 227, 228, 229, 230, 231, and 232, respectively.SEQ ID NOs: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NOs: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively; and SEQ ID NOs: 326, 327, 328, 329, and 330, respectively. SEQ ID NOs: 333, 334, 335, 336, 337, and 338; SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NOs: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NOs: 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, and 406, respectively; SEQ ID NOs: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NOs: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NOs: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NOs: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively; and SEQ ID NOs: 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, and 472, respectively. 49, and 450; SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively; and SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NOs: 559, 560, 561, 562, 563, and 564, respectively; and SEQ ID NOs: 561, 562, 563, and 564, respectively. SEQ ID NOs: 567, 568, 569, 570, 571, and 572; SEQ ID NOs: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively; and SEQ ID NOs: 623, 624, 625, 626, 627, 628, 629, 630, and 631, respectively. 25, 626, 627, and 628; SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NOs: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NOs: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NOs: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NOs: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NOs: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NOs: 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, and 696, respectively. SEQ ID NOs: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NOs: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NOs: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively;SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively; and SEQ ID NOs: 810, 811, and 812, respectively. SEQ ID NOs: 815, 816, 817, 818, 819, and 820; SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NOs: 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927 SEQ ID NOs: 873, 874, 875, and 876; SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NOs: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively; and SEQ ID NOs: 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 97 31, and 932; SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively;SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively). In some cases, the first, second, third, fourth, fifth, and sixth sequences are SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOs: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NOs: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NOs: 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, SEQ ID NOs: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NOs: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NOs: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NOs: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NOs: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NOs: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NOs: 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, and 196, respectively. SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NOs: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207, and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NOs: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NOs: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239, and 240, respectively. 240; SEQ ID NOs: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NOs: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NOs: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NOs: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NOs: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NOs: 663, 664, 665, 666, 667, and 668, respectively;SEQ ID NOs: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NOs: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NOs: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NOs: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NOs: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some cases, CDR-H1 comprises at most one mutation compared to the first sequence, CDR-H2 comprises at most one mutation compared to the second sequence, CDR-H3 comprises at most one mutation compared to the third sequence, CDR-L1 comprises at most one mutation compared to the fourth sequence, CDR-L2 comprises at most one mutation compared to the fifth sequence, and CDR-L3 comprises at most one mutation compared to the sixth sequence. In some cases, the first, second, third, fourth, fifth, and sixth sequences are SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively;

[0013] In some cases, the Ab comprises an effector function-attenuating mutation. In some cases, the effector function-attenuating mutation is selected from the group consisting of L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G, and combinations thereof. In some cases, the effector function-attenuating mutation is L234A / L235A.

[0014] In some cases, each D has the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, 5 is (a) the point of covalent attachment to L; or (b) —C(═O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)RJ , -N(R I )-S(O2)R K , and SO3R K each R 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and m is 0, 1, 2, or 3.

[0015] In some cases, each D has the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein [ka] is the point of covalent attachment to L; R 5 is (a) the point of covalent attachment to L; or (b) —C(═O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K each R 6is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and m is 0, 1, 2, or 3.

[0016] In some cases, each D has the structure of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof, 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and m is 0, 1, 2, or 3.

[0017] In some cases, each D has the structure of formula (III): [ka] or a pharmaceutically acceptable salt thereof, 4A is (a) the point of covalent attachment to L or (b) (i) one to three independently selected halogens; (ii) -OR C ;(iii)-SR C (iv) -NH-S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR DR E ;(ix)-NR D R E (ix) -[N(C1-C6 alkyl)R D R E ] + (x) -(phenyl) C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens; (xi) halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NR D R E or -COH; (xii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E or C1-C6 alkyl optionally substituted with 5-10 membered heteroaryl optionally substituted with -CO2H; R 4A is (b) C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is further substituted at the point of covalent attachment to L; 5 is (a) the point of covalent attachment to L; or (b) —C(═O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R Keach R 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and m is 0, 1, 2, or 3.

[0018] In some cases, each D has the structure of formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0019] In some cases, R 1 or R 4 is the point of covalent attachment to L. In some cases, R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, or 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15-C 27 In some cases, R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides. 1 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, and acylated C5-C9 monosaccharides. 1 is hydrogen or C1-C3 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2. 1 is hydrogen or C1-C3 alkyl. In some cases, R 1 is hydrogen.

[0020] In some cases, R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases, R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein C1-C3 alkyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R BIn some cases, R 2 is hydrogen or C1-C3 alkyl. In some cases, R 2 is hydrogen.

[0021] In some cases, R 3 is -NR A R B , -C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases, R 3 is hydroxyl, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio, and -NR A R B In some cases, R is C1-C5 alkyl optionally substituted with one substituent selected from the group consisting of 3 is selected from the group consisting of butyl, —CH2—O—CH2CH3, —CH2—CH2—O—CH3, and —CH2—NH—CH2CH3.

[0022] In some cases, R 4 is hydrogen; -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R Cor (i) one to three independently selected halogens; (ii) —O(C1-C6 alkyl); (iii) —S(C1-C6 alkyl); (iv) —NH—S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl optionally substituted with phenyl substituted with -CO2H. In some cases, R 4 is hydrogen or (ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + In some cases, R 4 teeth, [ka] wherein each occurrence of the subscript z is independently 1, 2, or 3. In some cases, R 4 teeth, [ka] is selected from the group consisting of:

[0023] In some cases, R 5 is hydrogen, -C(=O)OR F , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases, R 5 is —C(═O)OH or —C(═O)O(C1-C3 alkyl); each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases, R 5 is —C(═O)OH or —C(═O)O(C1-C3 alkyl); the subscript m is zero. In some cases, R 5 has (i) a pkA of at most about 7.0; (ii) a Debye dipole moment of at least about 2.0; or (iii) (i) and (ii).

[0024] In some cases, each R X is hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NRG R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , -S(O3)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B In some cases, the subscript n is 1.

[0025] In some cases, R A and R B Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. C Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl). F is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl.

[0026] In some cases, each D is [ka] [ka] [ka] [ka] and [ka] represents a point of covalent attachment to L. In some cases, each D is [ka] and [ka] represents the point of covalent attachment to L. In some cases, the Ab comprises a heavy chain having at least 80% sequence identity to SEQ ID NO:3 or SEQ ID NO:4 and a light chain having at least 80% sequence identity to SEQ ID NO:5.

[0027] In some cases, the linker, when defined by the path between D and Ab via the fewest number of bonds, comprises a length of 10 to 40 atoms. In some cases, the linker, when defined by the path between D and Ab via the fewest number of bonds, comprises a length of 15 to 30 atoms. In some cases, the linker comprises PEG units from PEG1 to PEG72, monosaccharides, disaccharides, trisaccharides, oligopeptides, or combinations thereof. In some cases, L has the formula -M-(A) a -(W) w -(Y) y -(X) x where subscript a is 0 or 1; subscript y is 0 or 1; subscript w is 0 or 1; subscript x is 0 or 1; M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine, or triazole; A is one to four R a1 C optionally substituted with 2-20 alkylene; or 1 to 4 R b1is a 2- to 40-membered heteroalkylene optionally substituted with a 1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, =O, -NR d1 R e1 , -(C 1-6 (Alkylene)-NR d1 R e1 , -C(=O)NR d1 R e1 , -C(=O)(C 1-6 alkyl), and -C(=O)O(C 1-6 alkyl); each R b1 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NR d1 R e1 , -(C 1-6 (Alkylene)-NR d1 R e1 , -C(=O)NR d1 R e1 , -C(=O)(C 1-6 alkyl), and -C(=O)O(C 1-6 alkyl); each R d1 and R e1 are independently hydrogen or C 1-3 alkyl; W is 1 to 12 amino acids, or the structure: [ka] where Su is a sugar moiety; A - represents the oxygen atom of the glycosidic bond; each R g are independently hydrogen, halogen, C1-C6 alkoxy, —N(C1-C6 alkyl)2, —NHC(═O)(C1-C6 alkyl), —CN, —CF3, acyl, carboxamido, C1-C6 alkyl, or —NO2; W 1is absent, *-C(=O)-O-, or *-OC(=O)-; [ka] represents a covalent bond to A or M; * represents a covalent bond to X, Y, or D; Y is a self-immolative moiety, a self-immolative releasable moiety, or a non-cleavable moiety; X is C1-C6 alkylene or 3- to 6-membered heteroalkylene; and L is optionally substituted with a PEG unit from PEG1 to PEG72.

[0028] In some cases, the subscript x is 1. In some cases, X is C1-C6 alkylene. In some cases, X is C1-C3 alkylene. In some cases, X is 3- to 6-membered heteroalkylene. In some cases, X is 3- to 4-membered heteroalkylene. In some cases, the subscript x is 0.

[0029] In some cases, the subscript y is 1. In some cases, Y is a self-immolative moiety. In some cases, Y is [ka] In some cases, Y is a non-cleavable moiety. In some cases, Y is a cyclohexanecarboxyl, undecanoyl, caproyl, hexanoyl, butanoyl, or propionyl group. In some cases, Y is PEG4 to PEG12. In some cases, y is 0. In some cases, the subscript w is 1. In some cases, W is 6 to 12 amino acids. In some cases, W is 6 to 9 amino acids. In some cases, each amino acid in W is independently selected from the group consisting of alanine, glycine, lysine, serine, aspartic acid, aspartic acid methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine-alanine, valine-citrulline, phenylalanine-lysine, and homoserine methyl ether. In some cases, W is selected from the group consisting of: [ka] (wherein Su is a sugar moiety; -OA- represents the oxygen atom of a glycosidic bond; each R g are independently hydrogen, halogen, C1-C6 alkoxy, —N(C1-C6 alkyl)2, —NHC(═O)(C1-C6 alkyl), —CN, —CF3, acyl, carboxamido, C1-C6 alkyl, or —NO2; W 1 is absent, *-C(=O)-O-, or *-OC(=O)-; [ka] represents a covalent bond to A or M; * represents a covalent bond to X, Y, or D). 1 is non-existent. In some cases, W 1 is *-C(=O)-O-. In some cases, W 1 is *-OC(=O)-. In some cases, one R g is halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, carboxamido, C1-C6 alkyl, or -NO2, and the remaining R g is hydrogen. In some cases, each R g is hydrogen. In some cases, w is 0.

[0030] In some cases, the subscript a is 1. In some cases, A is 1 to 4 R a1 C2- optionally substituted with 20 In some cases, A is an alkylene group. a1 C optionally substituted with 4-10 In some cases, A is an alkylene. a1 C2- substituted with 20 In some cases, A is an alkylene. a1 C replaced with 4-10 In some cases, A is C 2-20 In some cases, A is C 4-10 In some cases, A is an alkylene group. b1 In some cases, A is a 2-40 membered heteroalkylene optionally substituted with 1-4 R b1 In some cases, A is a 4- to 12-membered heteroalkylene optionally substituted with one R b1 In some cases, A is a 2- to 40-membered heteroalkylene optionally substituted with one R b1 In some cases, A is a 4- to 12-membered heteroalkylene optionally substituted with: In some cases, A is a 2- to 40-membered heteroalkylene. In some cases, A is a 4- to 12-membered heteroalkylene. In some cases, A is [ka] (In the formula, [ka] represents a covalent bond to W and * represents a covalent bond to M). In some cases, the subscript a is 0.

[0031] In some cases, L is substituted with a PEG unit from PEG1 to PEG72. In some cases, A is substituted with a PEG unit from PEG1 to PEG72. In some cases, M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine, or triazole.

[0032] Various aspects of the present disclosure provide methods of treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of an ADC of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject. In some cases, the Ab of the ADC targets a cancer-associated antigen. In some cases, the ADC is configured to be internalized into a cell. In some cases, the cell expresses a cancer-associated antigen. In some cases, the cell does not express a cancer-associated antigen. In some cases, the cell is an immune cell. In some cases, the immune cell is a CD8 + T cells, CD4 + The immune cell is a T cell, a T regulatory cell, a macrophage, or a natural killer cell. In some cases, the immune cell is a macrophage. In some cases, the immune cell expresses TLR7, TLR8, or TLR7 and TLR8. In some cases, the cancer cell does not express TLR7 or TLR8. In some cases, the immune cell expresses a surface protein that binds to a cancer-associated antigen. In some cases, the internalization comprises endocytosis or micropinocytosis. In some cases, the ADC is configured to bind to Toll-like receptor 7, Toll-like receptor 8, or Toll-like receptor 7 and Toll-like receptor 8. In some cases, the linker (L) of the ADC is configured to undergo cleavage after internalization within the immune cell.

[0033] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Brief explanation of the drawings]

[0034] [Figure 1] Responses of human PBMC from one donor to selected small molecule TLR7 / 8 agonists are shown. [Figure 2] Shown are the mean responses of human PBMC isolated from three donors to selected small molecule TLR7 / 8 agonists. [Figure 3] Figure 1 shows the response of human PBMC to selected TLR7 / 8 agonists bearing either a carboxylic acid (S5b, S8b, S11b) or a methyl ester functional group (S5a, S8a, S11a). [Figure 4] Figure 1 shows the response of human immune cells to various small molecule TLR7 / 8 agonists. [Figure 5] Figure 1 shows the response of human immune cells to selected TLR7 / 8 agonists bearing either a carboxylic acid (S18b) or a methyl ester functional group (S18a). [Figure 6] Figure 1 shows the response of human immune cells to various TLR7 / 8 agonists conjugated to targeting antibodies. [Figure 7] Figure 1 shows the response of human immune cells to selected TLR7 / 8 agonists bearing either a carboxylic acid (S18b) or a methyl ester functionality (S18a) conjugated to a targeting antibody. [Figure 8] Figure 1 shows the response of human immune cells to selected TLR7 / 8 agonists with either carboxylic acid (S14b, S18b, S76b) or methyl ester functional groups (S14a, S18a, S76a) conjugated to targeting antibodies. [Figure 9] 1 shows a comparison of the levels of aggregation of various conjugated immunostimulatory ADCs. [Figure 10] 1 shows the anti-tumor response of CT26 tumor-bearing mice to treatment with S8a or S8b immune cell-targeting antibody drug conjugates. [Figure 11]1 shows the anti-tumor response of CT26 tumor-bearing mice to treatment with S14a or S14b immune cell-targeting antibody drug conjugates. [Figure 12] 1 shows the anti-tumor response of MC38 tumor-bearing mice to treatment with S8a, S8b, S18a, or S18b antibody drug conjugates. [Figure 13] 1 shows the anti-tumor response of mice bearing CT26 tumors to treatment with S18b antibody drug conjugates with either targeting or non-targeting antibodies. [Figure 14] 1 shows the antitumor response of Renca tumor-bearing mice to treatment with S18a free drug and S18a and S18b antibody drug conjugates. [Figure 15] 1 shows the cytokine response of non-tumor-bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkages. [Figure 16] 1 shows the cytokine response of non-tumor-bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkages. [Figure 17] 1 shows the cytokine response of CT26 tumor-bearing mice to treatment with S18b antibody drug conjugates linked via an N1 or C4 linkage and bearing targeting or non-targeting antibodies. [Figure 18] 1 shows the anti-tumor response of CT26-bearing mice to treatment with S18b antibody-drug conjugates linked via an N1 or C4 linkage and bearing targeting or non-targeting antibodies. [Figure 19] 1 shows the cytokine response of Renca tumor-bearing mice to treatment with S18b drug conjugates linked via N1 or C4 linkages at a dose of 2 mg / kg. [Figure 20] 1 shows the anti-tumor response of Renca-bearing mice to treatment with S18b antibody-drug conjugates linked via N1 or C4 linkages at a dose of 2 mg / kg. [Figure 21]Figure 1 shows the activation of human immune cells in vitro in response to TLR7 / 8 antibody conjugates linked via the N1 or C4 position. [Figure 22] 1 shows the anti-tumor response of Renca-bearing mice to treatment with S18b antibody-drug conjugates linked via N1 or C4 linkages at different dose levels. [Figure 23] 1 shows the cytokine response of Renca tumor-bearing mice to treatment with S18b antibody drug conjugates via N1 or C4 linkage at different dose levels. [Figure 24] 1 shows an in vitro evaluation of TLR7 vs. TLR8 selectivity for various TLR7 / 8 small molecule agonists in HEK Blue hTLR7 and TLR8 cells. [Figure 25] 1 shows an in vivo evaluation of TLR7 versus TLR8 selectivity for various TLR7 / 8 small molecule agonists in C57BL / 6 mice bearing subcutaneous MC38 tumors. [Figure 26] 1 shows the anti-tumor response of Renca-bearing mice to treatment with S18a antibody-drug conjugates with different linkage sites and with or without a PEG group in the linker. [Figure 27] 1 shows the anti-tumor response of Renca-bearing mice to treatment with S18a antibody-drug conjugates linked at the N1 or C4 position, with different linker configurations, linkage sites, and with or without a PEG group in the linker. [Figure 28] 1 provides tumor size in mice treated with targeted antibody-TLR7 / 8 agonist conjugates. [Figure 29] IL6 (top left), IL1b (top right), MIP1b (bottom left), and TNFα (bottom right) responses in human peripheral blood mononuclear cells (PBMCs) induced with several imidazoquinoline conjugates are provided. [Figure 30]Figure 1 summarizes cytokine responses in human immune cells after treatment with imidazoquinolines. The upper left panel summarizes IL6 levels after treatment, the upper right panel summarizes TNFα levels after treatment, the lower left panel summarizes MCP1 levels after treatment, and the lower right panel summarizes IP10 levels after treatment. [Figure 31] Figure 1 summarizes tumor size profiles over time after tumor implantation in TLR7-positive and TLR7-knockout mice. The upper left panel summarizes tumor growth in TLR7-positive mice, the lower left panel summarizes tumor growth in TLR7-knockout mice, and the right panel summarizes tumor volume at day 36 after implantation for all mice. [Figure 32] 1 provides tumor size in Renca tumor-bearing mice after treatment with TLR7 / 8 agonists. [Figure 33] Renca tumor volumes in untreated mice, mice treated with imidazoquinoline TLR agonists coupled to tumor-targeted antibodies or isotype controls are provided. [Figure 34] Renca tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist coupled with C4 to tumor-targeted antibody or isotype control are provided. [Figure 35] CT26 tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist N1 coupled to tumor-targeted antibody or isotype control are provided. [Figure 36] CT26 tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist coupled with C4 to tumor-targeted antibody or isotype control are provided. [Figure 37] 4T1 tumor volumes in untreated mice, mice treated with naked EphA2-targeting antibodies, and mice treated with TLR7 / 8 agonist EphA2-targeting antibody conjugates are summarized. [Figure 38]CT26 tumor volumes are provided for untreated mice, mice treated with tumor and immune-targeting antibody alone, mice treated with a non-targeting isotype antibody conjugated to a TLR7 / 8 agonist, and mice treated with tumor and a TLR7 / 8 agonist conjugated to an immune-targeting antibody. [Figure 39A] 1 provides cell viability for Hodgkin's lymphoma after treatment with ADCs consistent with the present disclosure. [Figure 39B] 1 provides cell viability for breast cancer after treatment with ADCs consistent with the present disclosure. [Figure 39C] 1 provides cell viability for pancreatic cancer following treatment with ADCs consistent with the present disclosure. [Figure 39D] 1 provides cell viability for lung cancer following treatment with ADCs consistent with the present disclosure. [Figure 39E] 1 provides cell viability for anaplastic large cell lymphoma following treatment with ADCs consistent with the present disclosure. [Figure 39F] 1 provides cell viability for CD30-positive anaplastic large T-cell lymphoma following treatment with ADCs consistent with the present disclosure. [Figure 40A] 1 summarizes interleukin-6 (IL-6) induction in pancreatic cancer tumor cells after incubation with ADCs consistent with the present disclosure. [Figure 40B] 1 summarizes interleukin-6 (IL-6) induction in human lung squamous cell carcinoma tumor cells after incubation with ADCs consistent with the present disclosure. [Figure 40C] 1 summarizes interleukin-6 (IL-6) induction in anaplastic large cell lymphoma tumor cells after incubation with ADCs consistent with the present disclosure. [Figure 40D] 1 summarizes interleukin-6 (IL-6) induction in anaplastic large cell lymphoma tumor cells after incubation with ADCs consistent with the present disclosure. [Figure 41A] 1 summarizes IL-6 production by M0 macrophage populations treated with multiple ADCs, antibodies, and compounds consistent with the present disclosure. [Figure 41B] 1 summarizes IL-6 production by M1 macrophage populations treated with multiple ADCs, antibodies, and compounds consistent with the present disclosure. [Figure 41C] 1 summarizes IL-6 production by M2 macrophage populations treated with multiple ADCs, antibodies, and compounds consistent with the present disclosure. [Figure 42A] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. CD69 levels in Karpas299 co-cultures after ADC and antibody treatment are provided. [Figure 42B] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. CD69 levels in EBC-1 co-cultures after ADC and antibody treatment are provided. [Figure 42C] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. IFN-γ levels in Karpas299 co-cultures after ADC and antibody treatment are provided. [Figure 42D] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. IFN-γ levels in EBC-1 co-cultures after ADC and antibody treatment are provided. [Figure 42E] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. CD86 levels in Karpas299 co-cultures after ADC and antibody treatment are provided. [Figure 42F] 1 summarizes the immune activation response in tumor and immune cell co-cultures after treatment with various ADCs and antibodies consistent with the present disclosure. 1 provides CD86 levels in EBC-1 co-cultured cells after ADC and antibody treatment. [Figure 43] 1 summarizes the frequencies of CD45+PDL1+ immune cells and CD45-PDL1+ tumor cells from human non-small cell lung cancer tumors from multiple subjects. [Figure 44]AB summarize IL-6 and TNFα induction in human non-small cell lung cancer tumors following ADC and antibody treatment consistent with the present disclosure. [Figure 45] 1 summarizes the change in tumor volume over 4 weeks of treatment with ADCs and antibodies consistent with this disclosure. [Figure 46A] 1 provides the tumor volume time course following a 2 mg / kg dose of ADC consistent with the present disclosure. [Figure 46B] 1 provides the tumor volume time course following 1 mg / kg dosing of ADC consistent with the present disclosure. [Figure 46C] 1 provides the tumor volume time course following a 0.5 mg / kg dose of ADC consistent with the present disclosure. [Figure 47A] 1 provides tumor growth responses of PDL1-positive tumors in untreated mice. [Figure 47B] 1 provides tumor growth responses of PDL1-positive tumors in antibody-treated mice. [Figure 47C] 1 provides tumor growth responses of PDL1-positive tumors in mice treated with non-targeting ADCs. [Figure 47D] 1 provides tumor growth responses of PDL1-positive tumors in mice treated with targeted ADCs. [Figure 48] Tumor growth inhibition for ADC and antibody treated mice is summarized. [Figure 49A] 1 provides CD4+ T cell populations in MC38 and Renca mouse tumors. [Figure 49B] 1 provides regulatory T cell populations in MC38 and Renca mouse tumors. [Figure 49C] 1 provides CD8+ T cell populations in MC38 and Renca mouse tumors. [Figure 49D] 1 provides macrophage populations in MC38 and Renca mouse tumors. [Figure 50] AB provide tumor growth responses of implanted MC38 (A) and Renca tumors (B) in mouse models treated with ADCs consistent with the present disclosure. [Figure 51]1 is a set of plots of tumor growth response and area under the curve (AUC) values for two different tumor models treated with ADCs consistent with the present disclosure. [Figure 52-1] 1 is a series of plots of cytokine responses in two tumor models following treatment with ADCs consistent with the present disclosure. [Figure 52-2] 1 is a series of plots of cytokine responses in two tumor models following treatment with ADCs consistent with the present disclosure. [Figure 52-3] 1 is a series of plots of cytokine responses in two tumor models following treatment with ADCs consistent with the present disclosure. [Figure 53-1] 1 is a group of plots of PDL1, CD4, CD8, and F4 / 80 expression in two tumor models. [Figure 53-2] 1 is a group of plots of PDL1, CD4, CD8, and F4 / 80 expression in two tumor models. DETAILED DESCRIPTION OF THE INVENTION

[0035] Many cancers are immunosuppressive, actively inhibiting immune cell proliferation, signaling, and activity to avoid detection and clearance. While certain TLR agonists can reactivate immune cells suppressed by cancer, TLR agonist treatment is often limited by dose-limiting toxicity. Sustained TLR activation, even from mild agonist doses, can lead to immune-related adverse events, including rheumatoid and thyroid disorders, nausea, rashes, and general discomfort.

[0036] Avoiding toxicity-based dosing limitations commonly associated with TLR agonists, certain ADCs of the present disclosure elicit minimal cytokine responses from outside the target tumor site. A surprising discovery disclosed herein is that widespread TLR7 / 8 activation within the tumor microenvironment can activate primarily immune cells without generating undesirable responses from cancer and bystander cells. Leveraging this discovery, tumor-targeted ADCs of the present disclosure can utilize substantial concentrations of highly potent TLR agonists to affect localized immune stimulation while avoiding dose-limiting systemic toxicity.

[0037] definition 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 this application; other suitable methods and materials known in the art may also be used in some embodiments of this disclosure. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entities, and other references cited herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. When trade names are used herein, they include the product formulation, generic drug, and active pharmaceutical ingredient(s) of the trade name product unless otherwise indicated by context.

[0038] As used herein, the terms "a," "an," or "the" include not only aspects with one member but also aspects with multiple members. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to a "linker" includes a reference to one or more such linkers, and a reference to a "cell" includes a reference to a plurality of such cells.

[0039] The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation, e.g., within experimental variation and / or statistical experimental error, and thus the number or numerical range may vary by up to ±10% of the stated number or numerical range. With respect to ADC compositions comprising a distribution of ADCs described herein, the average number of TLR agonist compounds conjugated to antibodies in the composition may be an integer or a non-integer (particularly when the antibodies are partially loaded). Thus, the term "about" preceding an average drug loading value is intended to capture expected variations in drug loading within an ADC composition.

[0040] The term "antibody," as used herein, encompasses intact monoclonal, polyclonal, monospecific, and multispecific antibodies (e.g., bispecific antibodies), including intact antibodies and antigen-binding antibody fragments, as well as reduced forms thereof in which one or more interchain disulfide bonds have been disrupted, that exhibit the desired biological activity, provided that the antigen-binding antibody fragment has the requisite number of binding sites for the desired number of linking groups, such as linkers (L) described herein. In some embodiments, the linker is attached via succinimide or hydrolyzed succinimide to the sulfur atom of a cysteine residue of a reduced interchain disulfide bond and / or a cysteine residue introduced by genetic engineering. The native form of an antibody is a tetramer, consisting of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable domains (VL and VH) together are primarily responsible for binding to an antigen. Light and heavy chain variable domains consist of a framework region separated by three hypervariable regions, also called "complementarity-determining regions" or "CDRs." Light and heavy chains also contain constant regions that can be recognized by and interact with the immune system. (See, e.g., Janeway et al., 2001, Immuno. Biology, 5th Ed., Garland Publishing, New York.) Antibodies include any isotype (e.g., IgG, IgE, IgM, IgD, and IgA) or subclass thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Antibodies can be derived from any suitable species. In some embodiments, the antibody is of human or murine origin, and in some embodiments, the antibody is human, humanized, or chimeric. Antibodies can be fucosylated to various degrees or defucosylated.

[0041] An "intact antibody" is an antibody that contains an antigen-binding variable region as well as a light chain constant domain (C L ) and heavy chain constant domain, C H 1. C H 2. C H 3 and CH 4. The constant domains are either native sequence constant domains (eg, human native sequence constant domains) or amino acid sequence variants thereof.

[0042] An "antibody fragment" comprises a portion of an intact antibody, including its antigen-binding or variable region. Antibody fragments of the present disclosure contain at least one cysteine residue (natural or engineered) that provides a site for attachment of a linker and / or linker-drug compound. In some embodiments, antibody fragments include Fab, Fab', or F(ab')2.

[0043] As used herein, the term "engineered cysteine residue" or "eCy residue" refers to a cysteine amino acid or derivative thereof that is incorporated into a protein (e.g., an antibody) and would not otherwise be present at that position in the protein. In these embodiments, one or more eCys residues may be incorporated into the antibody, and typically, the eCys residues are incorporated into either the heavy or light chain of the antibody. Incorporation of eCys residues into an antibody is usually carried out by mutagenizing the nucleic acid sequence of the parent antibody to encode one or more amino acid residues bearing a cysteine or derivative thereof. Suitable mutations include replacing a desired residue in the light or heavy chain of the antibody with a cysteine or derivative thereof, incorporating an additional cysteine or derivative thereof at a desired position in the light or heavy chain of the antibody, and adding an additional cysteine or derivative thereof to the N- and / or C-terminus of a desired heavy or light chain amino acid. Further information can be found in U.S. Patent No. 9,000,130, the contents of which are incorporated herein in their entirety. Derivatives of cysteine (Cys) include, but are not limited to, beta-2-Cys, beta-3-Cys, homocysteine, and N-methylcysteine.

[0044] In some embodiments, antibodies of the present disclosure include those with 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-methylcysteine.

[0045] In some embodiments, antibodies of the present disclosure include those with 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 described herein). In some embodiments, activation comprises contacting the antibody with a compound comprising a functional group selected from the group consisting of succinimidyl ester and maleimide, pyridyl disuldem, and iodoacetamide.

[0046] As used herein, an "antigen" may be an entity to which an antibody specifically binds.

[0047] The terms "specific binding" and "specifically bind" can refer to selective binding to a particular target. With respect to antibodies, these terms can refer to binding to a specific antigen or epitope over multiple other antigens or epitopes. Typically, an antibody or antibody fragment binds to at least about 1x10 -7 M, e.g., 10 -8 M~10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M, and binds to a given antigen with an affinity that is at least two-fold higher than its affinity for binding to a nonspecific antigen other than the given antigen or a closely related antigen (e.g., BSA, casein).

[0048] The term "amino acid" as used herein can refer to natural and non-natural amino acids, as well as proteogenic amino acids. Exemplary amino acids include, but are not limited to, alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, ornithine, β-alanine, citrulline, serine methyl ether, aspartic acid methyl ester, glutamic acid methyl ester, homoserine methyl ether, and N,N-dimethyllysine.

[0049] "Percent sequence identity (%)" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and, if necessary, introducing gaps to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms required to achieve maximum alignment across the entire length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (which may alternatively be expressed as a given amino acid sequence A having or comprising a predetermined % sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequences in the program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not equal the % sequence identity of B to A.

[0050] "Sugar moiety," as used herein, refers to a monosaccharide group, e.g., a pyranose or furanose. The sugar moiety may include a hemiacetal or a carboxylic acid (from oxidation of a pendant -CHOH group). In some embodiments, the sugar moiety is in the β-D conformation. In some embodiments, the sugar moiety is a glucose, glucuronic acid, or mannose group.

[0051] The terms "inhibit" or "inhibition of" mean to reduce by a measurable amount or to prevent entirely (eg, 100% inhibition).

[0052] As used herein, TLR7 / 8 can refer to Toll-like receptor 7 and Toll-like receptor 8, simply Toll-like receptor, or simply Toll-like receptor 8. For example, a TLR7 / 8 ligand can be a TLR7 ligand, a TLR8 ligand, or a bifunctional TLR7 and TLR8 ligand.

[0053] As defined herein, a "TLR7 / 8 agonist" includes any compound that inhibits selective TLR7 / 8 activity. Exemplary TLR7 / 8 agonists have an activity (EC ) for TLR7 / 8 of less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 500 nM, less than about 250 nM, less than about 100 nM, or less than about 10 nM, as measured in the assays described herein. 50 In some embodiments, the TLR7 / 8 agonist may exhibit about 3.5-fold to about 25-fold selectivity for TLR7 over TLR8, e.g., about 3.5-fold to about 15-fold, about 10-fold to about 20-fold, about 15-fold to about 25-fold, about 3.5-fold to about 8-fold, about 5-fold to about 12-fold, about 8-fold to about 15-fold, about 12-fold to about 18-fold, about 15-fold to about 20-fold, or about 18-fold to about 25-fold. In some embodiments, the TLR7 / 8 agonist may exhibit selectivity for TLR8 over TLR7 of about 3.5-fold to about 25-fold, e.g., about 3.5-fold to about 15-fold, about 10-fold to about 20-fold, about 15-fold to about 25-fold, about 3.5-fold to about 8-fold, about 5-fold to about 12-fold, about 8-fold to about 15-fold, about 12-fold to about 18-fold, about 15-fold to about 20-fold, or about 18-fold to about 25-fold.

[0054] The term "therapeutically effective amount" refers to an amount of an ADC, or a pharmaceutically acceptable salt thereof (described herein), or a compound (e.g., a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, described herein) effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of an ADC or compound provides one or more of the following biological effects: a reduction in the number of cancer cells; a reduction in tumor size; inhibition of cancer cell invasion into peripheral organs; inhibition of tumor metastasis; inhibition to some extent of tumor growth; and / or relief to some extent of one or more symptoms associated with cancer. In the case of cancer therapy, efficacy is measured in some embodiments by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0055] Unless otherwise indicated or indicated by context, the terms "substantial" or "substantially" refer to the majority of a population, mixture, or sample, i.e., >50%, typically greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0056] The terms "intracellularly cleaved" and "intracellular cleavage" refer to a metabolic process or reaction that occurs within a cell, where the cellular machinery acts on the ADC or a fragment thereof to release free drug from the ADC or other degradation product intracellularly. Thus, the moieties that result from that metabolic process or reaction are intracellular metabolites.

[0057] The terms "cancer" and "cancerous" refer to or describe the physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A "tumor" contains multiple cancerous cells.

[0058] "Subject," as used herein, can refer to an individual to whom an ADC or TLR7 / 8 agonist described herein is administered. "Subject," as used herein, can also refer to an individual from whom a sample (e.g., a tumor resection) is obtained. Examples of "subjects" include, but are not limited to, mammals, such as humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, the subject is a rat, mouse, dog, non-human primate, or human. In some embodiments, the subject is a human.

[0059] The terms "treat" or "treatment," unless otherwise indicated or indicated by context, refer to therapeutic treatment and prophylactic measures to prevent recurrence, the purpose being to inhibit an undesirable physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, attenuation of the extent of disease, stabilized (i.e., not worsening) disease, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment," in some aspects, also means prolonging survival as compared to expected survival if not receiving treatment.

[0060] In the context of cancer, the term "treating" includes any or all of inhibiting the growth of cancer cells or tumors; inhibiting the replication of cancer cells, reducing the overall tumor burden or the number of cancer cells, and ameliorating one or more symptoms associated with the disease.

[0061] The term "salt," as used herein, refers to an organic or inorganic salt of a compound such as a TLR7 / 8 agonist (e.g., a compound of Formula (IX)), a Drug Unit (D) (e.g., a compound of any of Formulas (A), (I)-(VIII), (IIa), or (IIIa)), a Linker, a Drug-Linker Intermediate (e.g., a compound of Formula (X)), or an ADC, such as those described herein. In some embodiments, the compounds contain at least one amino group, and thus, acid addition salts can be formed with the amino group. Exemplary salts include, but are not limited to, 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, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Salts may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. Counterions can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, salts have one or more charged atoms in their structure. When multiple charged atoms are present as part of a salt, multiple counterions can be present. Thus, a salt can have one or more charged atoms and / or one or more counterions. "Pharmaceutically acceptable salts" are those suitable for administration to subjects as described herein, and in some embodiments, include salts 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 of which is specifically incorporated by reference in its entirety).In some embodiments, the ADCs described herein are in the form of pharmaceutically acceptable salts. In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts.

[0062] The term "tautomer," as used herein, refers to compounds whose structures differ significantly in the arrangement of atoms, but which exist in ready and rapid equilibrium; the compounds provided herein may be represented as different tautomers; it is understood that when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of a compound does not exclude any tautomer.

[0063] The term "optionally substituted" refers to the indicated group being substituted or unsubstituted.

[0064] The term "alkyl" refers to any group having the indicated number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "Alkyl" refers to an unsubstituted straight-chain or branched saturated hydrocarbon having 1 to 4, 1 to 6, 1 to 8, or 1 to 10 carbon atoms, respectively, derived by the removal of one hydrogen atom from a parent alkane. Representative straight-chain "C1-C8 alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl, while branched C1-C8 alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl.

[0065] The term "alkylene" refers to a divalent unsubstituted saturated branched or straight-chain hydrocarbon of the stated number of carbon atoms (e.g., C1-C6 alkylene has 1 to 6 carbon atoms) having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. An alkylene group can be substituted with 1 to 6 fluoro groups, for example, at the carbon backbone of the straight-chain or branched alkylene (e.g., -CHF- or -CF2-) or at a terminal carbon (e.g., -CHF2 or -CF3). Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), difluoromethylene (-CF2-), tetrafluoroethylene (-CF2CF2-), and the like.

[0066] The term "alkenyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon double bond and the number of carbon atoms indicated (e.g., "C2-C8 alkenyl" or "C2-C 10 "Alkenyl has 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkenyl group has 2 to 6 carbon atoms.

[0067] The term "alkynyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon triple bond and the number of carbon atoms indicated (e.g., "C2-C8 alkynyl" or "C2-C 10 "Alkynyl has 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkynyl group has 2 to 6 carbon atoms.

[0068] 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, etc.), and the nitrogen atom can be quaternized. The heteroatom(s) can be located at any interior position of the heteroalkyl group and / or at any terminal position of the heteroalkyl group, including the terminal end of a branched heteroalkyl group, and / or at the position at which the heteroalkyl group is attached to the remainder of the molecule. The heteroalkyl group can be substituted with 1 to 6 fluoro groups, for example, on the carbon backbone of the straight- or branched heteroalkyl (e.g., -CHF- or -CF2-) or on a terminal carbon (e.g., -CHF2 or -CF3). Examples of heteroalkyl groups include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)2, -C(=O)-NH-CH2-CH2-NH-CH3, -C(=O)-N(CH3)-CH2-CH2-N(CH3)2, -C(=O)-NH-CH2-CH2-N H-C(=O)-CH2-CH3, -C(=O)-N(CH3)-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -O-CH2-CH2-CH2-NH(CH3), -O-CH2-CH2-CH2-N(CH3)2, -O-CH2-CH2-CH2-NH-C(=O)-CH2-CH 3, -O-CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-NH(CH3), -O-CH2-CH2-CH2-N(CH3)2, -CH2-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-O-CF3, and -Si(CH3)3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.A terminal polyethylene glycol (PEG) moiety is a type of heteroalkyl group.

[0069] The term "acyl" refers to an alkyl, haloalkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl, or heterocyclyl group, as defined herein, attached to the remainder of the compound by a C=O (carbonyl) group.

[0070] The term "carboxamide" refers to the group -C(=O)NRR', where R and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl, and heterocyclyl, as defined herein.

[0071] The term "heteroalkylene" refers to a divalent unsubstituted straight or branched group derived from heteroalkyl (as defined herein). Examples of heteroalkylene groups include -CH2-CH2-O-CH2-, -CH2-CH2-O-CF2-, -CH2-CH2-NH-CH2-, -C(=O)-NH-CH2-CH2-NH-CH2-C(=O)-N(CH3)-CH2-CH2-N(CH3)-CH2-, -C(=O)-NH-CH2-CH2-NH-C(=O)-CH2-CH2-, -C(=O)-N(CH3)-CH2-CH2-N(CH3)-C(=O)-CH2-CH2-, -O-CH2-CH2-CH2-NH-CH2-, -O-CH2-CH2-CH2-N( CH3)-CH2-, -O-CH2-CH2-CH2-NH-C(=O)-CH2-CH2-, -O-CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH2-, -CH2-CH2-CH2-NH-CH2-, -CH2-CH2-CH2-N(CH3)- CH2-, -CH2-CH2-CH2-NH-C(=O)-CH2-CH2-, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH2-, -CH2-CH2-NH-C(=O)-, -CH2-CH2-N(CH3)-CH2-, -CH2-CH2-N +These include, but are not limited to, -(CH3)2-, -NH-CH2-CH2(NH2)-CH2-, and -NH-CH2-CH2(NHCH3)-CH2-. A divalent polyethylene glycol (PEG) moiety is a type of heteroalkylene group.

[0072] The term "alkoxy" refers to an alkyl group, as defined herein, 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.

[0073] The term "alkylthio" refers to an alkyl group, as defined herein, attached to a molecule through a sulfur atom. For example, alkyl groups include, but are not limited to, thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, etc.

[0074] The term "haloalkyl" refers to any group having the indicated number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "Alkyl" refers to an unsubstituted straight or branched saturated hydrocarbon having 1 to 4, 1 to 6, 1 to 8, or 1 to 10 carbon atoms, respectively, in which at least one hydrogen atom of the alkyl group is replaced by a halogen (e.g., fluoro, chloro, bromo, or iodo). If the number of carbon atoms is not indicated, haloalkyl groups have 1 to 6 carbon atoms. Representative C 1-6 Haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, and 1-chloroisopropyl.

[0075] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, attached to a molecule via an oxygen atom. For example, haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and 1,1,1-trifluoro-2-methylpropoxy.

[0076] The term "cycloalkyl" refers to a cyclic saturated or partially unsaturated hydrocarbon having the number of carbon atoms indicated (e.g., "C 3-8 cycloalkyl" or "C 3-6 "Cycloalkyl has 3 to 8 or 3 to 6 carbon atoms, respectively). If the number of carbon atoms is not specified, the cycloalkyl group has 3 to 6 carbon atoms. Cycloalkyl groups include bridged, fused, and spiro ring systems, as well as bridged bicyclic systems in which one ring is aromatic and the other is unsaturated. Representative "C" groups include: 3-6 "Cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] The term "aryl" refers to an unsubstituted monovalent carbocyclic aromatic hydrocarbon group of 6 to 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.

[0078] The term "heterocycle" refers to a saturated or partially unsaturated ring or multiple condensed ring system, including bridged, fused, and spiro ring systems. A heterocycle can be represented by the total number of atoms in the ring system; for example, a 3- to 10-membered heterocycle has 3 to 10 total ring atoms. The term includes single saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) of about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring can be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms can 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 containing 2, 3, or 4 rings) in which a single heterocycle (defined above) can be fused to 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 through fused, spiro, and bridged bonds, where permitted by valence requirements. It is understood that the point of attachment of a multiple condensed ring system (defined above for heterocycle) can be at any position of the multiple condensed ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It is also understood that the point of attachment for a heterocycle or heterocyclic multiple condensed ring system can be at any suitable atom of the heterocycle or heterocyclic multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0079] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from the group consisting of O, N, and S in a single ring or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π-system, and all atoms contributing to the conjugated π-system lie in the same plane. In some embodiments, heteroaryl groups have 5 to 10 total ring atoms and 1, 2, or 3 heteroatoms (referred to as "5-10-membered heteroaryl"). Heteroaryl groups include, but are not limited to, imidazole, triazole, thiophene, furan, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0080] The term "hydroxyl" refers to an --OH group.

[0081] The term "cyano" refers to the group --CN.

[0082] The term "carboxy" refers to the group -C(=O)OH.

[0083] The term "oxo" refers to the group =O.

[0084] 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.

[0085] 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-butanoyloxy.

[0086] The term "alkoxycarbonyl" refers to an alkoxy group, as defined herein (ie, an alkyl ester group), attached to a -C(=O)- group through the oxygen atom of the alkoxy.

[0087] The term "alkoxythiocarbonyl" refers to an alkoxy group, as defined herein, attached to a C(=S)-group through the oxygen atom of the alkoxy (ie, an alkylthioester group).

[0088] The term "carbamoyl," as defined herein, refers to -C(=O)-N(R)2, where "R" indicates variable substitution.

[0089] The term "amidine," as defined herein, refers to C(=N)-N(R)2, where "R" indicates variable substitution.

[0090] The term "sulfone," as defined herein, refers to -S(=O)2-R, where "R" indicates variable substitution.

[0091] The term "thione," as defined herein, refers to --C(.dbd.S)--R, where "R" indicates variable substitution.

[0092] 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. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, and cyclohexylethyl.

[0093] The term "succinimide" when used in the context of antibody-drug conjugates (ADCs) refers to: [ka] It can refer to:

[0094] The term "hydrolyzed succinimide" may refer to a succinimide in which the imide is hydrolyzed to form a carboxylic acid and an amide. Examples of hydrolyzed succinimides include: [ka] Includes:

[0095] As used herein, the term "hydrolyzable group" refers to a moiety that undergoes spontaneous hydrolytic cleavage under certain conditions. For example, a hydrolyzable group may be inert in neutral and basic solutions, but may undergo hydrolytic cleavage in days, hours, minutes, or even seconds under acidic conditions. In some cases, the hydrolyzable group is configured to undergo hydrolytic cleavage in a specific physiological environment, such as blood (e.g., peripheral blood) or an oxidative (e.g., lysosome) or reductive (e.g., cytoplasmic) intracellular compartment. In some cases, the hydrolyzable group is configured for catalytic cleavage by enzymes present in, for example, a particular organism (e.g., human) or tissue (e.g., metabolically active tissue, e.g., liver, kidney, or brain). The hydrolyzable group may be configured for cleavage by various enzymes or by a specific enzyme. For example, the hydrolyzable group may include an oligopeptide of the sequence arginine-arginine-valine-arginine, for which human furin may have high cleavage activity. The hydrolyzable group may be configured for cleavage in a specific environment, such as the endosome or lysosome of a human cell. In such cases, the hydrolyzable group may be stable outside of an environment configured for cleavage. For example, the hydrolyzable group may be stable while circulating in peripheral blood, but may be hydrolytically cleaved upon uptake into cells. Examples of hydrolyzable groups include organophosphates, e.g., phosphate esters, thiophosphates, and dithiophosphates, carbamates, carbonates, thioesters, quaternary amines, ureas, disulfides, organosulfates, diorganosulfates, certain amides and esters, and peptides with protease cleavage sites.

[0096] It will be appreciated by those skilled in the art that compounds described herein containing chiral centers may exist in and be isolated in optically active and racemic forms.

[0097] As used herein, the term "free drug" refers to a biologically active species that is not covalently bound to an antibody. Thus, free drug refers to the compound as it exists immediately upon cleavage from the ADC. The release mechanism can be via a cleavable linker on the ADC or via intracellular transformation or metabolism of the ADC. In some aspects, the free drug can exist as a protonated and / or charged moiety. The free drug is a pharmacologically active species capable of exerting a desired biological effect. In some embodiments, the pharmacologically active species is the parent drug alone. In some embodiments, the pharmacologically active species is the parent drug bound to a component or trace of the ADC (e.g., a linker, a succinimide, a hydrolyzed succinimide, and / or a component of an antibody that has not undergone subsequent intracellular metabolism). In some embodiments, free drug refers to a compound of any one of Formulas (A), (I)-(VIII), (IIa), or (IIIa) described herein, or a pharmaceutically acceptable salt thereof (e.g., one or more of X, Y, W, A, and M are absent). In some embodiments, free drug refers to a compound of Formula (IX). In some embodiments, free drug refers to a compound of Formula (X). In some embodiments, free drug refers to a compound disclosed in U.S. Publication No. 2017 / 0217960 (incorporated by reference in its entirety), or a pharmaceutically acceptable salt thereof.

[0098] As used herein, the term "drug unit" refers to the free drug conjugated to an antibody in the ADCs described herein.

[0099] Antibody Drug Conjugates (ADCs) Embodiments of the present disclosure provide antibody-drug conjugates (ADCs) bearing a TLR7 / 8 payload. Because many cells express TLR7 and TLR8 (including epithelial and myeloid cells), localizing the effects of TLR7 / 8 agonists to specific disease sites can be important for treatment efficacy. To this end, many of the ADCs disclosed herein are configured to release their payload within the target disease site. In many cases, ADCs affect immune cell activation within the tumor-suppressive microenvironment, thereby avoiding the systemic cytokine and antibody-dependent toxicity often induced by free antibodies and TLR7 / 8 agonists.

[0100] Some embodiments have the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is an antibody consistent with the present disclosure; each L is a linker; each D is conjugated to a linker; each L is covalently attached to Ab via the sulfur atom of a cysteine residue or the ε-amino group of a lysine residue; The subscript p is an integer from 1 to 16; Each D is a TLR7 / 8 agonist) to provide.

[0101] Some embodiments have the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is an antibody consistent with the present disclosure; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D is a structure of formula (A): [ka] or a pharmaceutically acceptable salt thereof and R 1 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C 6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides (e.g., [ka] ), C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R 2is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L; R 3 is (a) the point of covalent attachment to L; or (b) hydrogen, —NR A R B , -C(=O)NR A R B, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C and (i) 1 to 3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi)-CO2H; (vii) C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D RE ] + ; (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); (xii) Halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with -CO2H; (xiii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl of (-5- to 10-membered heteroaryl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6)alkoxycarbonyl, or 5-10 membered heteroaryl optionally substituted with -CO2H -C1-C6 alkyl optionally substituted with; R 4 is C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is optionally further substituted at the point of covalent attachment to L; Each R X is (a) the point of covalent attachment to L; and (b) hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NR G RH , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and wherein no more than one R X is the point of covalent attachment to L; The subscript n is 0, 1, 2, 3, or 4; R A and R B Each occurrence of represents (a) a point of covalent attachment to L, (b) the group consisting of hydrogen and C-C alkyl; and (c) R A and R B are independently selected from the group consisting of: R, ... A and R B at most one occurrence of is the point of covalent attachment to L; R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 independently selected from the group consisting of alkyl; R D , R E , R G , and R H Each occurrence of is selected from the group consisting of: (a) a point of covalent attachment to L; (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-; and R D and R E , or R G and R Hare independently selected from the group consisting of: R, ... D , R E , R G , and R H is the point of covalent attachment to L; R F is independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R I , R J , and R K each occurrence of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C-C alkyl; R I , R J , and R K at most one of which is a point of covalent attachment to L; Each D has only one point of covalent attachment to L. to provide.

[0102] In some cases, the antibody drug conjugate (ADC) has the structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof. (In the formula, Ab is antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D is a structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof and R 1 is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C 6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R 2is (a) the point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B or R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L; R 3 is (a) the point of covalent attachment to L; or (b) hydrogen, —NR A R B , -C(=O)NR A R B, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R 4 is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C and (i) 1 to 3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi)-CO2H; (vii) C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D RE ] + ; (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); (xii) Halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with -CO2H; (xiii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl of (-5- to 10-membered heteroaryl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6)alkoxycarbonyl, or 5-10 membered heteroaryl optionally substituted with -CO2H -C1-C6 alkyl optionally substituted with; R 4 is C1-C6 alkyl, then the C1-C6 alkyl or substituent thereof is optionally further substituted at the point of covalent attachment to L; R 5 is -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G RH , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K selected from the group consisting of: Each R 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B independently selected from the group consisting of: m is 0, 1, 2, or 3; R A and R B Each occurrence of represents (a) a point of covalent attachment to L, (b) the group consisting of hydrogen and C-C alkyl, and (c) R A and R B are independently selected from the group consisting of: R, ... A and R B at most one occurrence of is the point of covalent attachment to L; R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 independently selected from the group consisting of alkyl; R D , R E , R G , and R H Each occurrence of is selected from the group consisting of: (a) a point of covalent attachment to L; (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-; and (c) R D and RE , or R G and R H are independently selected from the group consisting of: R, ... D , R E , R G , and R H is the point of covalent attachment to L; R F is independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R I , R J , and R K each occurrence is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C6 alkyl; R I , R J , and R K at most one of which is a point of covalent attachment to L; Each D has only one point of covalent attachment to L. It has.

[0103] In some cases, the structure of Formula (A) is a structure of Formula (I), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII). Thus, in some cases, D is a structure of Formula (I), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), where R 1 , R 2 , R 3 , R 4 , R4A , R 5 , R 6 , R 6A , R X , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K , n, m, q, and [ka] is as defined herein).

[0104] In some cases, each D has the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , and R K are as defined herein and m is an integer equal to n-1 (e.g., if n is 3, then m is 2). In some cases, m is 0, 1, or 2. In some cases, m is 1 or 2. In some cases, m is 0 or 1. In some cases, m is 1. In some cases, m is 0.

[0105] In some cases, each D has the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 3 , R 4 , R 5 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K and m are as defined herein; [ka] represents the point of covalent attachment to L).

[0106] In some cases, each D has the structure of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof, 3 , R 4 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K Each of m and [ka] is as defined herein. In some cases, m is 0 or 1. In some cases, m is 0.

[0107] In some cases, each D has the structure of formula (III): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R4 A , R 5 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K and m are as defined herein.

[0108] In some cases, each D has the structure of formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4A , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K and m are as defined herein.

[0109] In some cases, each D has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 4 , R 5 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K Each of m and [ka] is as defined herein).

[0110] In some cases, each D has a structure of formula (V): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K Each of m and [ka] is as defined herein).

[0111] In some cases, each D has the structure of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 5 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K Each of the following, and [ka] is as defined herein, and R 6A and each occurrence of is selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and the subscript q is 0, 1, or 2.

[0112] In some cases, each D has the structure of formula (VII): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 5 , R 6A , R A , R B , RC , R D , R E , R F , R G , R H , R I , R J , R K Each of the subscripts q and [ka] is as defined herein).

[0113] In some cases, each D has the structure of formula (VIII): [ka] or a pharmaceutically acceptable salt thereof, 1 , R 2 , R 3 , R 4 , R 5 , R 6A , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , R K Each of the subscripts q and [ka] is as defined herein).

[0114] In some cases of formulas (A) and (I), R 1 , R 2 , R 3 , R 4 , or R A , R B , R C , R D , R E , R F , RG , R H , R I , R J , or R K The presence of is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 1 , R 3 , R 4 , or R A Or R B The presence of is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 1 , R 3 , or R 4 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 1 or R 4 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 1 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 2 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 3 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is C1-C6 alkyl, and the C1-C6 alkyl or substituent thereof is further substituted at the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is a C1-C6 alkyl, which is further substituted at the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is C1-C6 alkyl (h), and the C1-C6 alkyl substituent is further substituted at the point of covalent attachment to L. In some cases of formulas (A) and (I), R4 is the point of covalent attachment to L, R C , R D , R E , R G , and / or R H In some cases of formula (A), R x One occurrence of is the point of covalent attachment to L. In some cases of formula (A), R X The presence of R is the point of covalent attachment to L. A , R B , R F , R G , R H , R I , R J , or R K In some cases of formula (A) and (I), R 1 or R 2 The presence of -NR A R B is substituted with R A or R B is the point of covalent attachment to L. In some cases of formula (A), R X The presence of -NR A R B and the R A or R B is the point of covalent attachment to L.

[0115] In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to the Ab via the sulfur atom of a cysteine residue, the epsilon-amino group of a lysine residue, the histidine residue of an imidazole, the guanidinium of an arginine residue, the thiol of a methionine residue, the carboxylate of an aspartic acid or glutamic acid residue, the phenol of a tyrosine residue, or the indole of a tryptophan residue. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to the Ab via the sulfur atom of a cysteine residue or the epsilon-amino group of a lysine residue. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to a glycosylation of the Ab.

[0116] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 Alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A RB , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides. 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, or 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides. 1is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkylC1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfuryl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides, C 10 -C 18 Disaccharide, acylated C 10 -C 18 disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides. 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. 1is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. 1 is hydrogen, as well as hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 represents hydrogen, as well as hydroxyl, halogen, sulfhydryl, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is selected from the group consisting of hydrogen and C1-C3 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1is selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is hydrogen.

[0117] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is hydroxyl, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy, -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C5-C9 monosaccharides, C5-C9 monosaccharides, and acylated C5-C9 monosaccharides. 1 is hydroxyl, halogen, sulfhydryl, cyano, C1-C3 alkoxy, -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C5-C9 monosaccharides, C5-C9 monosaccharides, and acylated C5-C9 monosaccharides. 1 is hydroxyl, C1-C3 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is substituted with 1 to 3 substituents. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is not substituted.

[0118] In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl are selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R BIn some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein C1-C6 alkyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R BIn some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein C1-C3 alkyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with a substituent independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, and -NH2. In some cases of Formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydrogen or C1-C3 alkyl. In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydrogen.

[0119] In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydroxyl, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy, and -NR A R BIn some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydroxyl, halogen, sulfhydryl, cyano, C1-C3 alkoxy, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydroxyl, C1-C3 alkoxy, and -NR A R B In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is substituted with 1 to 3 substituents. In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is substituted with at most one substituent. In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is not substituted.

[0120] In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 and R 2 In some cases of formulas (A) and (I), at least one of R 1 is the point of covalent attachment to L, and R 2is hydrogen. In some cases of formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 and R 2 is hydrogen.

[0121] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is -NR A R B , -C(=O)NR A R B , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, 5-10-membered heteroaryl, and 3-12-membered heterocycle; each C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, 5-10-membered heteroaryl, and 3-12-membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is C1-C6 alkyl substituted with 1 to 3 substituents independently selected from the group consisting of: 3is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is a C1-C6 alkyl substituted with a substituent selected from the group consisting of: 3 is a C1-C6 alkyl substituted with a substituent selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, and -NH2.

[0122] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is -NR A R B , -C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle; each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydrogen, -NR A RB , -C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is -NR A R B , -C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydrogen, -NR A R B, C1-C6 alkyl, C1-C6 alkanoyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is -NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, and phenyl; C1-C6 alkyl, C1-C6 alkanoyl, or phenyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is -NR A R B , C1-C6 alkyl, and C1-C6 alkanoyl; C1-C6 alkyl or C1-C6 alkanoyl is selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is C-C alkyl optionally substituted with a substituent selected from the group consisting of: 3 is C1-C4 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, and -NH2. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is C1-C4 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2.

[0123] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R BIn some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is hydroxyl, halogen, sulfhydryl, cyano, oxo, phenyl, C1-C6 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydroxyl, halogen, sulfhydryl, cyano, oxo, phenyl, C1-C6 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is hydroxyl, cyano, oxo, C1-C6 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: 3 is hydroxyl, cyano, oxo, C1-C6 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is oxo, C1-C3 alkoxy, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3is C1-C3 alkoxy, and -NHR B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is substituted with at most one substituent. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is non-substituted.

[0124] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is hydroxyl, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is C-C alkyl optionally substituted with one substituent selected from the group consisting of: 3 is C1-C3 alkoxy and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R is C-C alkyl optionally substituted with one substituent selected from the group consisting of: 3 is selected from the group consisting of butyl, —CH—O—CH—CH, —CH—CH—O—CH, and —CH—NH—CH—CH. 3 is hydrogen.

[0125] In some cases of formula (A), (I), R 4is the covalent attachment point to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C or (i) one to three independently selected halogens; (ii) —O(C1-C6 alkyl); (iii) —S(C1-C6 alkyl); (iv) —NH—S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with —COH and optionally substituted C1-C6 alkyl; R 4 When R is C1-C6 alkyl, the C1-C6 alkyl or substituent thereof may be further substituted at the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is hydrogen; -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SRC ;-C(=S)R C or (i) one to three independently selected halogens; (ii) —O(C1-C6 alkyl); (iii) —S(C1-C6 alkyl); (iv) —NH—S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with —COH and optionally substituted C1-C6 alkyl; R 4 When is C1-C6 alkyl, the C1-C6 alkyl or substituent thereof can be substituted at the point of covalent attachment to L.

[0126] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen; -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R Cor (i) one to three independently selected halogens; (ii) —O(C1-C6 alkyl); (iii) —S(C1-C6 alkyl); (iv) —NH—S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl optionally substituted with phenyl substituted with -CO2H. In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen or (i) one to three independently selected halogens; (ii) —O(C1-C6 alkyl); (iii) —S(C1-C6 alkyl); (iv) —NH—S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (In the formula, -NR D R E R Dis C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl optionally substituted with phenyl substituted with -CO2H. In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen or (i) 1 to 3 independently selected halogens; (ii) —O(C1-C6 alkyl); (ix) —NR D R E (In the formula, NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) substituted with halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl optionally substituted with phenyl substituted with -CO2H. In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4(ii) —O(C1-C6 alkyl); (ix) —NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + is C1-C6 alkyl optionally substituted with

[0127] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is (i) 1 to 3 independently selected halogens; (ii) —O(C1-C6 alkyl); (ix) —NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) substituted with halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl optionally substituted with phenyl substituted with -CO2H. In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 (ii) —O(C1-C6 alkyl); (ix) —NR D R E(In the formula, -NR D R E R D is C1-C6 alkyl); (x) -[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) substituted with halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or C1-C6 alkyl substituted with phenyl substituted with -CO2H. In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is (ix)-NR D R E (In the formula, -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl of -(phenyl)C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + is a C1-C6 alkyl substituted with

[0128] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C or (i) 1 to 3 independently selected halogens; (ii) -OR C;(iii)-SR C (iv) -NH-S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens; (xii) halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or -COH; (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl (wherein C1-C6 alkyl is 5-10 membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xiv) halogen, —NR D R E , C1-C6 alkoxy, -C(=O)NR D R E , -SR C , (C1-C6) alkoxycarbonyl, or C1-C6 alkyl optionally substituted with 5-10 membered heteroaryl optionally substituted with —CO2H; R 4 is C1-C6 alkyl;

[0129] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 (ii)-OR C ;(iii)-SR C (iv) -NH-S(O2)R C ;(ix)-NR D R E (xi) -(phenyl)C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR D R E , or -[N(C1-C6 alkyl)R D R E ] + or (xii) substituted with halogen, hydroxyl, C1-C6 alkoxy, -NR D R E , -C(=O)NR D R E or phenyl substituted with —CO2H and optionally substituted C1-C6 alkyl.

[0130] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 teeth, [ka] wherein each occurrence of subscript z is independently 1, 2, or 3.

[0131] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 teeth, [ka] In some cases of formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 teeth, [ka] is selected from the group consisting of:

[0132] In some cases of formula (III) and (IIIa), R 4A is (a) the point of covalent attachment to L or (b) (i) one to three independently selected halogens; (ii) -OR C ;(iii)-SR C (iv) -NH-S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (ix) -[N(C1-C6 alkyl)R D R E ] + (x) -(phenyl) C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens; (xi) halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NR D R E or -COH; or (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is a 5-10 membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R Eor C1-C6 alkyl optionally substituted with 5-10 membered heteroaryl optionally substituted with -CO2H; R 4A is (b) C1-C6 alkyl, the C1-C6 alkyl or substituent thereof is further substituted at the point of covalent attachment to L. In some cases of formulas (III) and (IIIa), R 4A is (i) one to three independently selected halogens; (ii) -OR C ;(iii)-SR C (iv) -NH-S(O2)R C ;(v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ;(ix)-NR D R E (ix) -[N(C1-C6 alkyl)R D R E ] + (x) -(phenyl) C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or (xi) halogen, hydroxyl, C1-C6 alkoxy, —C(═O)NR D R E or -COH; (xii) -(5- to 10-membered heteroaryl)C1-C6 alkyl (wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or substituted with 1 to 3 independently selected halogens); or halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R Eor a C1-C6 alkyl optionally substituted with a 5-10 membered heteroaryl optionally substituted with —CO2H; the C1-C6 alkyl or substituent is further substituted at the point of covalent attachment to L. In some cases of formulas (III) and (IIIa), R 4A (ii)-OR C ;(iii)-SR C (iv) -NH-S(O2)R C ;(ix)-NR D R E (ix) -[N(C1-C6 alkyl)R D R E ] + or (x) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or 1 to 3 independently selected halogens); the C1-C6 alkyl or substituent is further substituted at the point of covalent attachment to L. In some cases of formulas (III) and (IIIa), R 4A is (ix)-NR D R E (ix) -[N(C1-C6 alkyl)R D R E ] + or (x) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl is a 5- to 10-membered heteroaryl, -NR D R E , -[N(C1-C6 alkyl)R D R E ] + or 1 to 3 independently selected halogens); the C1-C6 alkyl or substituent is further substituted at the point of covalent attachment to L.

[0133] In some cases of Formula (A), the subscript n is 0, 1, or 2. In some cases of Formula (A), the subscript n is 1. In some cases of Formula (A), the subscript n is 0. In some cases of Formula (A), R X One of the existence of R 5 and R X The remaining existence of R 6 As used herein, the "remaining" R X The group may be 0 or n-1 subscripts R X groups, e.g., 0, 1, 2, or 3 R X Thus, if the subscript n is 0, then there are zero remaining R X If subscript n is 1, then there are zero remaining R X group is present; if the subscript n is 2, then one remaining R X group is present; if the subscript n is 3, then the two remaining R X group is present; if the subscript n is 4, then the three remaining R X There is a group.

[0134] In some cases of formulas (A) and (I), R 5 is (a) the point of covalent attachment to L; or (b) —C(═O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K In some cases of formula (A) and (I), R 5 is (a) the point of covalent attachment to L; or (b) hydrogen, —C(═O)OR F , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3RK In some cases of formula (A) and (I), R 5 is hydrogen, -C(=O)OR F , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K In some cases of formula (A) and (I), R 5 is -C(=O)OR F In some cases of formula (A) and (I), R 5 is —C(═O)OH or —C(═O)O(C1-C3 alkyl); each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases of formulas (A) and (I), R 5 is -C(=O)OH or -C(=O)OCH3.

[0135] In some cases of formulas (A) and (I), each R 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B and wherein no more than one R 6 is the point of covalent attachment to L. In some cases of formulas (A) and (I), each R 6 is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B and wherein no more than one R 6is the point of covalent attachment to L. In some cases of formulas (A) and (I), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B and wherein no more than one R 6 is the point of covalent attachment to L. In some cases of formulas (A) and (I), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B are independently selected from the group consisting of:

[0136] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is hydrogen, -C(=O)OR F , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , and SO3R K In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OR F In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5is —C(═O)OH or —C(═O)O(C1-C3 alkyl), and each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B are independently selected from the group consisting of:

[0137] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B are independently selected from the group consisting of:

[0138] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is —C(═O)OH or —C(═O)O(C1-C3 alkyl); each R6 is halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NR A R B In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is —C(═O)OH or —C(═O)O(C-C alkyl); the subscript m is zero. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is —C(═O)OH; and the subscript m is zero. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OCH3; and the subscript m is zero. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), the subscript m is 0, 1, or 2. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), the subscript m is 1 or 2. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), the subscript m is 0 or 1. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), the subscript m is 1. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), the subscript m is zero.

[0139] In some cases of formulas (A) and (I), R 6 One occurrence of is the point of covalent attachment to L and the other R 6 is, when present, halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R Bare independently selected from the group consisting of:

[0140] In some embodiments disclosed herein, R 5 is acidic, negatively charged, and / or highly polar (e.g., containing a dipole moment of at least about 2.0 Debye). The surprising observations disclosed herein (e.g., as demonstrated in Example 37) suggest that C7 imidazoquinoline functionalization (R 5 ) can enhance Toll-like receptor activation. It is contemplated that the importance of this functionalization on a given imidazoquinoline may have been previously overlooked due to its tendency to reduce cellular uptake, potentially masking its efficacy when applied as a free drug. However, when used in tandem with an effective targeting and uptake system, such as an antibody disclosed herein, imidazoquinolines with negative or highly polar C7 functionalization may affect enhanced TLR7 / 8 responses. Without being limited by theory, it is hypothesized that TLR7 / 8 binding may position the imidazoquinoline C7 near charged or polar protic residues, allowing for strong hydrogen-bonding interactions that improve binding strength and agonist behavior.

[0141] Thus, in certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 is negatively charged and / or highly polar (e.g., containing a dipole moment of at least about 2.0 Debye) under physiological conditions. In certain cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprises a dipole moment of at least about 2.0 Debye (e.g., calculated by density functional theory). In certain cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 In certain cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 contains a dipole moment of at most about 7.0 pkA or at least 2.0 Debye.

[0142] In some cases of formula (A), each R X is hydrogen, -C(=O)OR F , -C(=O)NR G RH , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , -S(O3)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B In some cases of formula (A), R X One occurrence of is the point of covalent attachment to L and R X All other occurrences of, if present, hydrogen, -C(=O)OR F , -C(=O)NR G R H , -S(O2)NR G R H , -N(R I )-C(=O)R J , -N(R I )-S(O2)R K , halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B are independently selected from the group consisting of:

[0143] In some cases of Formula (A), n is 0, 1, or 2. In some cases of Formula (A), n is 1 or 2. In some cases of Formula (A), n is 0 or 1. In some cases of Formula (A), n is 0. In many cases, n is 1.

[0144] In some cases of formulas (A) and (I), R A and RB Each occurrence of R is independently selected from the group consisting of (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C6 alkyl. A and R B Each occurrence of R is independently selected from the group consisting of (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C3 alkyl. A and R B Each occurrence of R is independently selected from the group consisting of (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and methyl. A and R B At most one occurrence of is (a) a point of covalent attachment to L and R A and R B The remaining occurrences are hydrogen.

[0145] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B Each occurrence of R is independently selected from the group consisting of hydrogen and methyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R BAll that exists is hydrogen.

[0146] In some cases of formulas (A) and (I), R C Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 In some cases of formulas (A) and (I), R C Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C-C alkyl optionally substituted with phenyl. In some cases of Formulas (A) and (I), R C Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C-C alkyl. In some cases of Formulas (A) and (I), R C Each occurrence of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl.

[0147] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C each occurrence is selected from hydrogen, phenyl, and C-C optionally substituted with phenyl or 1 to 3 independently selected halogens. 10 In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C Each occurrence of R is independently selected from the group consisting of hydrogen, phenyl, and C-C alkyl optionally substituted with phenyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R CEach occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C Each occurrence of is independently selected from the group consisting of hydrogen and methyl.

[0148] In some cases of formulas (A) and (I), R D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-. In some cases of Formulas (A) and (I), R D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, C-C alkyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-. In some cases of Formulas (A) and (I), R D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C6 alkyl. In some cases of Formulas (A) and (I), R D , R E , R G , and R H Each occurrence of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl.

[0149] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D , RE , R G , and R H Each occurrence of R is independently selected from the group consisting of hydrogen, C-C alkyl, C-C alkenyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of hydrogen, C-C alkyl, C-C cycloalkyl, C-C cycloalkyl(C-C alkyl)-, aryl, and aryl(C-C alkyl)-. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D , R E , R G , and R H Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D , R E , R G , and R H Each occurrence of is independently selected from the group consisting of hydrogen and methyl.

[0150] In some cases of formulas (A) and (I), R F is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulas (A) and (I), R Fis independently selected from the group consisting of (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, C3-C6 cycloalkyl, aryl, aryl(C1-C3 alkyl)-, and C1-C6 alkyl optionally substituted with one substituent selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulas (A) and (I), R F Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, and C-C alkyl. In some cases of Formulas (A) and (I), R F Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, and C1-C3 alkyl. In some cases of Formulas (A) and (I), R F Each occurrence of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, and methyl.

[0151] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F is independently selected from the group consisting of hydrogen, trifluoromethyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R Fis independently selected from the group consisting of hydrogen, trifluoromethyl, C-C cycloalkyl, aryl, aryl(C-C alkyl)-, and C-C alkyl optionally substituted with one substituent selected from the group consisting of halogen, C-C alkanoyloxy, and C-C alkoxy. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each occurrence of R is independently selected from the group consisting of hydrogen, trifluoromethyl, and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each occurrence of R is independently selected from the group consisting of hydrogen, trifluoromethyl, and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each occurrence of R is independently selected from the group consisting of hydrogen, trifluoromethyl, and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each occurrence of is independently selected from the group consisting of hydrogen, trifluoromethyl, and methyl.

[0152] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F is trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, or C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R 4 is -[N(C1-C6 alkyl)R DR E ] + -(phenyl)C1-C6 alkyl, where C1-C6 alkyl is -[N(C1-C6 alkyl)R D R E ] + or -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with -[N(C1-C6 alkyl)R D R E ] + (which is replaced by ).

[0153] In some cases of formulas (A) and (I), R I , R J , and R K Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and C1-C3 alkyl. In some cases of Formulas (A) and (I), R I , R J , and R K Each occurrence of R is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen and methyl. In some cases of Formulas (A) and (I), R I , R J , and R K Each occurrence of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen.

[0154] In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I , R J , and R K Each occurrence of R is independently selected from the group consisting of hydrogen and C-C alkyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I , R J , and R KEach occurrence of R is independently selected from the group consisting of hydrogen and methyl. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I , R J , and R K Each occurrence of is hydrogen.

[0155] In some cases of formulas (VI), (VII), and (VIII), R 6A Each occurrence of is selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, and -NR A R B In some cases of formulas (VI), (VII), and (VIII), R 6A Each occurrence of is selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NR A R B In some cases of formulas (VI), (VII), and (VIII), R 6A Each occurrence of is C1-C6 alkyl and -NR A R B In some cases of formulas (VI), (VII), and (VIII), the subscript q is 0 or 1. In some cases of formulas (VI), (VII), and (VIII), the subscript q is 0.

[0156] In some cases, each D is [ka] [ka] [ka] [ka] and [ka] represents a point of covalent attachment to L. In some cases, each D is [ka] and [ka] represents a point of covalent attachment to L. In some cases, each D is [ka] and [ka] represents the point of covalent attachment to L.

[0157] In some embodiments, the ADC is capable of releasing (i) a component of the linker attached to D; (ii) a component of the antibody attached to LD; and / or (iii) the parent compound D (as defined herein) as free drug. In some embodiments, the free drug is released at the intended site of action targeted by the antibody. In some embodiments, the free drug is released within the intended site of action targeted by the antibody. In some embodiments, the free drug is capable of binding to a Toll-like receptor (TLR). In some embodiments, binding of the free drug to the TLR exerts an agonistic effect on the TLR. In some embodiments, binding of the free drug to the TLR exerts an immunostimulatory effect.

[0158] antibody For many of the ADCs disclosed herein, the antibodies target antigens associated with clinically relevant disease states. Such antibodies can localize the ADC to disease sites, thereby enabling targeted TLR7 / 8 agonist payload delivery and site-specific treatment. Because non-targeted TLR7 / 8 agonists can affect systemic immune-related toxicity, TLR7 / 8-mediated immune reactivation is often only feasible if the agonist payload is delivered in a site-specific manner. Thus, the targeted ADC antibodies disclosed herein may enable the use of highly potent TLR7 / 8 agonists that would otherwise exhibit prohibitive toxicity via systemic delivery. In some cases, the antibodies further mediate cellular uptake to affect intracellular or subcellular TLR7 / 8 agonist delivery.

[0159] The term "monoclonal antibody," as used herein, can refer to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population contain identical sequences, except for possible minor naturally occurring mutations. Often, monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0160] Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the serum of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies against a particular antigenic determinant (e.g., cancer or immune cell antigen, protein, peptide, carbohydrate, chemical, nucleic acid, or fragment thereof). Monoclonal antibodies (mAbs) against an antigen of interest can be prepared by using any technique known in the art that provides for the production of antibody molecules by continuous cell lines in culture.

[0161] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. Antibodies include full-length antibodies and antigen-binding fragments thereof. Human monoclonal antibodies can be produced by any of a number of 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 et al., 1982, Meth. Enzymol. 92:3-16).

[0162] In some embodiments, the antibody includes a functionally active fragment, derivative, or analog of an antibody that specifically binds to a target cell (e.g., a cancer cell antigen) or other antibody that binds to a cancer cell or matrix. In this regard, "functional activity" means that the fragment, derivative, or analog can specifically bind to a target cell. To determine which CDR sequence binds an antigen, synthetic peptides containing the CDR sequence are typically used in binding assays with the antigen by any binding assay method known in the art (e.g., 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).

[0163] Recombinant antibodies, such as chimeric and humanized monoclonal antibodies, containing both human and non-human portions, typically obtained using standard recombinant DNA techniques, are also useful antibodies. Chimeric antibodies are molecules in which different portions are derived from different animal species, such as 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 (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 (incorporated herein by reference in their entirety).Such chimeric and humanized monoclonal antibodies are described, for example, in International Publication No. WO 87 / 02671; European Patent Publication No. 0184187; European Patent Publication No. 0171496; European Patent Publication No. 0173494; International Publication No. WO 86 / 01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012 023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. 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 et al. al., 1988, J. Immunol. 141:4053-4060, each of which is incorporated herein by reference in its entirety, and may be produced by recombinant DNA techniques known in the art.

[0164] In some embodiments, the antibody is fully human. In some embodiments, the antibody is produced using transgenic mice capable of expressing endogenous immunoglobulin heavy and light chain genes, but capable of expressing human heavy and light chain genes.

[0165] In some embodiments, the antibody is an intact or fully reduced antibody. The term "fully reduced" refers to an antibody in which all four interchain disulfides have been reduced to provide eight thiols that can be attached to a linker (L).

[0166] Conjugation to the antibody can be via a thioether bond from native and / or engineered cysteine residues, or from amino acid residues engineered to participate in cycloaddition reactions (e.g., click reactions) using corresponding linker intermediates. See Maerle, et al., PLOS One 2019:14(1); e0209860. In some embodiments, the antibody is an intact or fully reduced antibody, or an antibody bearing an engineered cysteine group modified with a functional group capable of participating in click chemistry or other cycloaddition reactions (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions), e.g., for conjugation to other components of the ADCs described herein. See, for example, Agard, et al., J. Am. Chem. Soc. Vol. 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. 26, pp. 2233-2242 (2015).

[0167] Antibodies that specifically bind to cancer or immune cell antigens are commercially available or produced by any method known to those skilled in the art, such as chemical synthesis or recombinant expression techniques. Nucleotide sequences encoding antibodies that specifically bind to cancer or immune cell antigens can be obtained, for example, from the GenBank database or similar databases, literature publications, or by routine cloning and sequencing.

[0168] In some embodiments, the antibody can be used for the treatment of cancer (e.g., an antibody approved by the FDA and / or EMA). Antibodies that specifically bind to cancer or immune cell antigens are commercially available or produced by any method known to those skilled in the art, such as recombinant expression techniques. Nucleotide sequences encoding antibodies that specifically bind to cancer or immune cell antigens can be obtained, for example, from the GenBank database or similar databases, literature publications, or by routine cloning and sequencing.

[0169] In some cases, the antibody has a mutation or post-translational modification that affects non-Fab-mediated uptake. Peripheral immune cells that are highly reactive to TLR7 / 8 agonists can promote a strong systemic response when activated through non-antigen-specific Fc-mediated uptake of TLR7 / 8 antibody-drug conjugates, which may be harmful or otherwise undesirable. In such cases, the antibody may have an effector function-attenuating mutation that attenuates non-immune uptake (e.g., FcgR-mediated uptake), such as L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G, or a combination thereof.

[0170] In some embodiments, the antibody can be configured to bind to a surface antigen on a cell. The antibody, or a complex comprising the antibody, can be configured to be internalized into the 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 on a cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to be internalized into a cancer cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to be internalized into a cancer cell. In some embodiments, the immune cell is a tumor-associated macrophage. In some embodiments, the surface antigen is a receptor or 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.

[0171] In some embodiments, the antibody is configured to specifically bind to a cancer cell antigen. In some embodiments, the antibody is configured to specifically bind to an immune cell antigen. In some embodiments, the immune cell antigen is a tumor-associated macrophage antigen. In some embodiments, the antibody is configured to specifically bind to EphA2. It will be understood that the antibody component in an ADC is an antibody in the residual form such that "Ab" in the ADC structures described herein incorporates the structure of an antibody.

[0172] Non-limiting examples of antibodies that can be used to treat cancer and antibodies that specifically bind to tumor-associated antigens are disclosed in Franke, AE, Sievers, EL, and Scheinberg, DA, "Cell surface receptor-targeted therapy of acute myeloid leukemia: a review" Cancer Biother Radiopharm. 2000, 15, 459-76; Murray, JL, "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 incorporated herein by reference in its entirety).

[0173] Non-limiting examples of antigens that the antibodies of the present disclosure can target include ADAM12 (e.g., catalog #14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher catalog #PA5-25959); AGR2 (e.g., ThermoFisher catalog #PA5-34517); AKAP-4 (e.g., catalog #PA5-52230); ALK (e.g., DLX521); ALPP (e.g., catalog #MA5-15652); ALPPL2 (e.g., catalog #PA5-22336); AMHR2 (e.g., , ThermoFisher catalog #PA5-13902); androgen receptor (e.g., ThermoFisher catalog #MA5-13426); ANTXR1 (e.g., catalog #MA1-91702); ANXA1 (e.g., catalog #71-3400); ARTN (e.g., ThermoFisher catalog #PA5-47063); ASCT2 (e.g., inductamab); Axl (e.g., BA3011; tilvestamab); B7-DC (e.g., catalog #PA5-20344); B7-H3 (e.g., enoblituzumab, ombin rutamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., catalog #14-5949-82); B7-H6 (e.g., catalog #12-6526-42); B7-H7; BAFF-R (e.g., catalog #14-9117-82); BCMA; BCR-ABL; BMPR2; BORIS; C4.4a; CanAg; C5 complement (e.g., BCD-148; CAN106); CA-125; CA19-9 (e.g., AbGn-7; MVT-5873); CA9 (e.g., girentuximab); CALCR (e.g., International Publication No. WO 2015077826); CAMPATH-1 (e.g., alemtuzumab; ALLO-647; ANT1034); carcinoembryonic antigen (e.g., arcitumomab; sergituzumab; amnaleukin; labetuzumab); CCNB1; CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabilalizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD138; CD142; CD166;CD147 (e.g., gabirimomab; metuzumab); CD155 (e.g., U.S. Publication No. 2018 / 0251548); CD19 (e.g., ALLO-501); CD20 (e.g., divodilimab; ibritumomab tiuxetan); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD27 (e.g., varlilumab); CD274 (e.g., adebremumab; atezolizumab; galibrimab); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD33 (e.g., lintuzumab; BI836858; AMG673); CD288; CD352 (e.g., SGN-CD352A); CD37 (e.g., rilotomab; GEN3009); CD38 (e.g., Felzalutamab; AMG424; CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD45 (e.g., apamistamab); CD47 (e.g., retaprimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT304; zolimomab alitox); CD56; CD59; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (e.g., International Publication No. WO202025211 0); CD79b; CD96; CD97; CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (e.g., see International Publication No. WO2018115231); CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-claudeferzalutamab-1); CLDN16; CLDN18.1 (e.g., , zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No. 10,822,427); CXCR4 (e.g., urocuplumab); CYP1B1; c-Met; DCLK1 (see, e.g., International Publication No. WO2018222675); DDR1;de2-7EGFR (e.g., MAb806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (see, e.g., U.S. Patent No. 10,836,823); EGF; EGFR; endosialin (e.g., ontuxizumab); ENPP1; EPCAM (e.g., adecatumumab); EPHA receptor; EPHA2; ERBB2 (e.g., trastuzumab); ERBB3; ERVMER34_1; ETV6-AML (e.g., catalog #PA5-81865); FAS; FasL; Fas-associated antigen 1; FBP; FGFR1 (e.g., RG7992); FGFR2 (e.g., apruzumab); FGFR3 (e.g., vofatamab); FGFR4 (e.g., MM-161); FL T3 (e.g., 4G8SDIEM); FN; FN1; FOLR1 (e.g., farletuzumab); FRa; FSHR; FucGM1 (e.g., BMS-986012); FZD5; FZD8; G250; GAGE; GCC; GD2 (e.g., dinutuximab); GD3 (e.g., mitumomab); GITR (e.g., ragifilimab); GloboH; GM2 (e.g., BIW-8962); GM3 (e.g., racotumomab); gp100; GPA33 (e.g., KRN330); GPC3 (e.g., codrituzumab); gpNMB (e.g., glembatumumab); GPR87; GUCY2C (e.g., indusatumab); HAS3; HAVCR2; HLA-E; HLA-F; HLA-G (e.g., TTX-080); HPV E6 E7; hTERT; ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IL13Ra2; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); ITGAV (e.g., abituzumab); ITGB6; ITGB8; KISS1R; L1CAM (e.g., JCAR023); LAG-3 (e.g., enselimab); LAMP1; LCK; legumain; LMP2; LY6G6D (e.g., PA5-23303); LY9 (e.g., PA5-95601); LYPD1 (e.g., ThermoFisher catalog #PA5-26749); MAD-CT-1; MAD-CT-2; MAGEA1 (e.g., catalog #MA5-11338);MAGEA3 (e.g., ThermoFisher catalog #60054-1-IG); MAGEA4 (e.g., catalog #MA5-26117); MAGEC2 (e.g., ThermoFisher catalog #PA5-64010); MELTF (e.g., ThermoFisher catalog #H00004241-M04A); MerTk (e.g., DS5MMER, catalog #12-5751-82); metalloproteinases; MFSD13A; MICA (e.g., 1E2C8, catalog #66384-1-IG); MICB (e.g., e.g., catalog #MA5-29422); Mincle (e.g., OTI2A8, catalog #TA505101); MLANA (e.g., catalog #MA5-15237); ML-IAP (e.g., 88C570, ThermoFisher catalog #40958); MSLN (e.g., 5B2, catalog #MA5-11918); MUC1 (e.g., MH1(CT2), ThermoFisher catalog #MA5-11202); MUC5AC (e.g., 45M1, catalog #MA5-12178); MYCN (e.g., NCM-II 100, ThermoFisher catalog #MA1-170); NA17; NCAM1 (e.g., ThermoFisher catalog #MA5-11563); Nectin-4 (e.g., enfortumab); NOX1 (e.g., catalog #PA5-103220); NT5E (e.g., 7G2, ThermoFisher catalog #41-0200); NY-BR-1 (e.g., NY-BR-1 number 2, catalog #MA5-12645); NY-ESO -1 (e.g., E978m, catalog #35-6200); OX40 (e.g., ABM193); OY-TES1; p53; p53 mutants; PAP; PAX3 (e.g., GT1210, ThermoFisher catalog #MA5-31583); PAX5; PDGFR-B (e.g., linucumab); PDPN (e.g., ThermoFisher catalog #14-5381-82); PLAVl; PMSA; polysialic acid (see, e.g., Watzlawik et al. J Nat Sci. 2015;1(8):e141); PR1; PROM1 (e.g., catalog #14-1331-82); PSA (e.g., ThermoFisher catalog #PA1-38514;Daniels-Wells et al. BMC Cancer 2013;13:195); PSCA (e.g., AGS-1C4D4); PSMA (e.g., BAY2315497); PTK7 (e.g., cofetuzumab); PVRIG; Ras mutants (e.g., Shin et al. Sci Adv. 2020;6(3):eaay2174); RET (e.g., WO2020210551); RGS5 (e.g., TF-TA503075); RhoC (e.g., ThermoFisher catalog PA5-77866); ROR1 (e.g., cirumutuzumab); ROR2 (e.g., BA3021); ROS1 (e.g., WO2019107671); sarcoma translocation breakpoints; SART3 (e.g., TF 18025-1-AP); sialyl Thomsen nouveau antigen (e.g., Eavarone et al. al. PLoS One. 2018;13(7):e0201314); Siglecs1-16 (see, e.g., Angata et al. Trends Pharmacol Sci. 2015;36(10):645-660); SIRPa (e.g., catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLC10A2 (e.g., ThermoFisher catalog #PA5-18990); SLC12A2 (e.g., ThermoFisher catalog #13884-1-AP); SLC17A2 (e.g., ThermoFisher catalog #PA5-106752); SLC38A1 (e.g., ThermoFisher catalog #PA5-106752) #12039-1-AP); SLC39A5 (e.g., ThermoFisher catalog #MA5-27260); SLC39A6 (e.g., ladiratuzumab); SLC44A4 (e.g., ASG-5ME); SLC6A15 (e.g., ThermoFisher catalog #PA5-52586); SLC6A6 (e.g., ThermoFisher catalog #PA5-53431); SLC7A11 (e.g., ThermoFisher catalog #PA1-16893); SLC7A5; sLe; SLITRK6 (e.g., siltratumab); sperm protein 17 (e.g., BS-5754R);SSX2 (e.g., ThermoFisher catalog #MA5-24971); survivin (e.g., PA1-16836); TACSTD2 (e.g., PA5-47074); TAG-72 (e.g., MA1-25956); tenascin; TF (e.g., tisotumab); Tie3; TLR2 / 4 / 1 (e.g., tomala; limab); TM4SF5 (e.g., 18239-1-AP); TMEM132A (e.g., catalog #PA5-62524); TMEM40 (e.g., PA5-60636); TMPRSS11D (e.g., PA5-30927); Tn; TNFRSF12 (e.g., BAY-356); TRAIL (e.g., catalog #12-9927-42); TRAIL1; TRP-2 (e.g., PA5-52736); ULBP1 / 2 / 3 / 4 / 5 / 6 (e.g., PA5-82302); uPAR (e.g., ATN-658); UPK1B (e.g., ThermoFi ThermoFisher catalog #PA5-56863); UPK2 (e.g., ThermoFisher catalog #PA5-60318); UPK3B (e.g., ThermoFisher catalog #PA5-52696); VEGF (e.g., GNR-011); VEGFR2 (e.g., gentuximab); VSIR (e.g., ThermoFisher catalog #PA5-52493); WT1 (e.g., ThermoFisher catalog #MA5-32215); and XAGE1 (e.g., ThermoFisher catalog #PA5-46413).

[0174] Non-limiting examples of target antigens include Axl (e.g., BA3011; tilvesta- mab); B7-1 (e.g., galiximab); B7-2 (e.g., catalog #12-0862-82); B7-DC (e.g., catalog #PA5-20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., catalog #14-5949-82); B7-H6 (e.g., catalog #12-6526-42); B7-H7; BAFF-R (e.g., catalog #14-9117-82); BCMA; C5 complement (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamulizumab-kpkc); CCR8 (e.g., JTX-1811); CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabilalizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD155 (e.g., U.S. Publication No. 2018 / 0251548); CD163 (e.g., TBI304H); CD19 (e.g., ALLO-501); CD2 (e.g., BTI-322; siplizumab); CD20 (e.g., divodilimab; ibritumomab); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD25 (e.g., basiliximab); CD27 (e.g., varlilumab); CD274 (e.g., adeburelimab; atezolizumab; galibrimab); CD278 (e.g., ferazilimab; vopratelimab); CD28 (e.g., REGN5668); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD30L (see, e.g., U.S. Patent No. 9,926,373); CD32 (e.g., mAb 2B6); CD33 (e.g., lintuzumab; BI 836858; AMG673); CD352 (e.g., SGN-CD352A); CD37 (e.g., rilotomab; GEN3009); CD38 (e.g., felzalutamab; AMG424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD40 (e.g., dacetuzumab;lucatumumab); CD44 (e.g., RG7356); CD45 (e.g., apamistamab); CD47 (e.g., retaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT304; zolimomab alitox); CD51; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO2020252110); CD83 (e.g., CBT004); CD97; CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepozi tamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., urocupulumab); DCIR; DCSIGN (see, e.g., International Publication No. WO2018134389); Dectin-1 (see, e.g., U.S. Patent No. 9,045,542); Dectin-2 (e.g., ThermoFisher Catalog #MA5-16250); DR4 (e.g., mapatumumab); endosialin (e.g., ontuxizumab); FasL; FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HE R2; HER3; HLA-DR; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IGF-1R; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); integrin αvβ6; LAG-3 (e.g., enselimab); LAMP1; LAYN; LCK; LILRB2; LILRB4; MerTk (e.g., DS5MMER, catalog #12-5751-82); Mesothelin; MICA (e.g., 1E2C8, catalog #66384-1-IG); MICB (e.g., catalog #MA5-29422); MICA; Mincle (e.g., OTI2A8, catalog #TA505101); MRC1 (e.g., ThermoFisher catalog #12-2061-82); MUC1; Muc16; NcaPi2B; Nectin-4; OX40 (e.g., ABM193); PD-1 (e.g., balstilimab; budigalimab; geptanolimab); PD-L1; prolactin receptor; PTK7; PVRIG; ROR-1;Sialyl Thomsen Nouveau antigen (e.g., Eavarone et al. PLoS One, 2018;13(7):e0201314); Siglec1-16 (e.g., Angata et al. Trends Pharmacol Sci. 2015;36(10):645-660);); SIRPa (e.g., catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLTRK6; STEAP1; TIGIT (e.g., etigilimab); TLR2 / 4 / 1 (e.g., tomalalimab); Trem2 (e.g., PY314); TROP2; Tyrol; ULBP1 / 2 / 3 / 4 / 5 / 6 (e.g., PA5-82302); uPAR (e.g., ATN-658); VSIR (e.g., ThermoFisher catalog #PA5-52493); ZIP6 (anti-integrin αvβ6);

[0175] In some cases, the antibody target is selected from the group consisting of ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, claudin-18.2, c-Met, gpNMB, CS1, DLL3, DPEP-3, E The tumor marker is selected from the group consisting of GFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, integrin αvβ6, h2A2, H2G12 / STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav / CD51, mesothelin, MICA, MUC-1, Muc16, NaPi2B, nectin-4, PD-L1, prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, and TROP2.

[0176] In some cases, the antibodies of the present disclosure target immune checkpoints. Among the various mechanisms that can contribute to unchecked cell growth, certain cancers utilize immune checkpoint proteins to create an immunosuppressive environment that limits immune activity near the cancer site. Because these cancers often produce abundant immune checkpoints, immune checkpoint targeting can be an effective means to localize ADCs, and thereby TLR7 / 8 agonist payloads, to cancer sites. In some cases, the antibodies of the present disclosure target an immune checkpoint selected from the group consisting of PDL1, PD1, CTLA-4, B7H4, B7H3, TIGIT, TIM-3, VISTA, GITR / GITRL, CD80 / CD86, CD155, PDL1, PDL2, galectin-9, CD40, OX40L, 4-1BB / 4-1BBL, ICOS / ICOSL, CD70, and combinations thereof. In some cases, the antibody of the disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, TIGIT, or a combination thereof.

[0177] Table 1 provides exemplary antibody sequences consistent with the present disclosure. In this table, all targets correspond to the human ortholog unless otherwise specified. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

[0178] (i) Heavy and light chain variable regions In some cases, an antibody of the disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; the first sequence is SEQ ID NO: 83 and the second sequence is , SEQ ID NO:84; the first sequence is SEQ ID NO:97 and the second sequence is SEQ ID NO:98; the first sequence is SEQ ID NO:105 and the second sequence is SEQ ID NO:106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO:114; the first sequence is SEQ ID NO:121 and the second sequence is SEQ ID NO:122; the first sequence is SEQ ID NO:129 and the second sequence is SEQ ID NO:130; the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; the first sequence is SEQ ID NO:153, the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:162; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:203 and the second sequence is SEQ ID NO:204. the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210; the first sequence is SEQ ID NO:217 and the second sequence is SEQ ID NO:218; the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; the first sequence is SEQ ID NO:297 and the second sequence is SEQ ID NO:298;The first sequence is SEQ ID NO:307 and the second sequence is SEQ ID NO:308; the first sequence is SEQ ID NO:315 and the second sequence is SEQ ID NO:316; the first sequence is SEQ ID NO:323 and the second sequence is SEQ ID NO:324; the first sequence is SEQ ID NO:331 and the second sequence is SEQ ID NO:332; the first sequence is SEQ ID NO:339 and the second sequence is SEQ ID NO:340; the first sequence is SEQ ID NO:347 and the second sequence is SEQ ID NO:348; the first sequence is SEQ ID NO:355 and the second sequence is SEQ ID NO:359. the first sequence is SEQ ID NO:363 and the second sequence is SEQ ID NO:364; the first sequence is SEQ ID NO:371 and the second sequence is SEQ ID NO:372; the first sequence is SEQ ID NO:379 and the second sequence is SEQ ID NO:380; the first sequence is SEQ ID NO:387 and the second sequence is SEQ ID NO:388; the first sequence is SEQ ID NO:395 and the second sequence is SEQ ID NO:396; the first sequence is SEQ ID NO:403 and the second sequence is SEQ ID NO:404; the first sequence is SEQ ID NO:411, the first sequence is SEQ ID NO:419 and the second sequence is SEQ ID NO:420; the first sequence is SEQ ID NO:427 and the second sequence is SEQ ID NO:428; the first sequence is SEQ ID NO:435 and the second sequence is SEQ ID NO:436; the first sequence is SEQ ID NO:443 and the second sequence is SEQ ID NO:444; the first sequence is SEQ ID NO:451 and the second sequence is SEQ ID NO:452; the first sequence is SEQ ID NO:459 and the second sequence is SEQ ID NO:460; the first sequence is SEQ ID NO:461 the first sequence is SEQ ID NO:467 and the second sequence is SEQ ID NO:468; the first sequence is SEQ ID NO:475 and the second sequence is SEQ ID NO:476; the first sequence is SEQ ID NO:483 and the second sequence is SEQ ID NO:484; the first sequence is SEQ ID NO:491 and the second sequence is SEQ ID NO:492; the first sequence is SEQ ID NO:501 and the second sequence is SEQ ID NO:502; the first sequence is SEQ ID NO:509 and the second sequence is SEQ ID NO:510; the first sequence is SEQ ID NO:517 and the second sequence is SEQ ID NO:518;The first sequence is SEQ ID NO:525 and the second sequence is SEQ ID NO:526; the first sequence is SEQ ID NO:533 and the second sequence is SEQ ID NO:534; the first sequence is SEQ ID NO:541 and the second sequence is SEQ ID NO:542; the first sequence is SEQ ID NO:549 and the second sequence is SEQ ID NO:550; the first sequence is SEQ ID NO:557 and the second sequence is SEQ ID NO:558; the first sequence is SEQ ID NO:565 and the second sequence is SEQ ID NO:566; the first sequence is SEQ ID NO:574 and the second sequence is SEQ ID NO:575. the first sequence is SEQ ID NO:581 and the second sequence is SEQ ID NO:582; the first sequence is SEQ ID NO:589 and the second sequence is SEQ ID NO:590; the first sequence is SEQ ID NO:597 and the second sequence is SEQ ID NO:598; the first sequence is SEQ ID NO:605 and the second sequence is SEQ ID NO:606; the first sequence is SEQ ID NO:613 and the second sequence is SEQ ID NO:614; the first sequence is SEQ ID NO:621 and the second sequence is SEQ ID NO:622; the first sequence is SEQ ID NO:629, the first sequence is SEQ ID NO:637 and the second sequence is SEQ ID NO:638; the first sequence is SEQ ID NO:645 and the second sequence is SEQ ID NO:646; the first sequence is SEQ ID NO:653 and the second sequence is SEQ ID NO:654; the first sequence is SEQ ID NO:661 and the second sequence is SEQ ID NO:662; the first sequence is SEQ ID NO:669 and the second sequence is SEQ ID NO:670; the first sequence is SEQ ID NO:677 and the second sequence is SEQ ID NO:678; the first sequence is SEQ ID NO:699 and the second sequence is SEQ ID NO:670; the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716;The first sequence is SEQ ID NO:731 and the second sequence is SEQ ID NO:732; the first sequence is SEQ ID NO:739 and the second sequence is SEQ ID NO:740; the first sequence is SEQ ID NO:747 and the second sequence is SEQ ID NO:748; the first sequence is SEQ ID NO:755 and the second sequence is SEQ ID NO:756; the first sequence is SEQ ID NO:765 and the second sequence is SEQ ID NO:766; the first sequence is SEQ ID NO:773 and the second sequence is SEQ ID NO:774; the first sequence is SEQ ID NO:781 and the second sequence is SEQ ID NO: the first sequence is SEQ ID NO:789 and the second sequence is SEQ ID NO:790; the first sequence is SEQ ID NO:797 and the second sequence is SEQ ID NO:798; the first sequence is SEQ ID NO:805 and the second sequence is SEQ ID NO:806; the first sequence is SEQ ID NO:813 and the second sequence is SEQ ID NO:814; the first sequence is SEQ ID NO:821 and the second sequence is SEQ ID NO:822; the first sequence is SEQ ID NO:829 and the second sequence is SEQ ID NO:830; the first sequence is SEQ ID NO:837, the first sequence is SEQ ID NO:845 and the second sequence is SEQ ID NO:846; the first sequence is SEQ ID NO:853 and the second sequence is SEQ ID NO:854; the first sequence is SEQ ID NO:861 and the second sequence is SEQ ID NO:862; the first sequence is SEQ ID NO:869 and the second sequence is SEQ ID NO:870; the first sequence is SEQ ID NO:877 and the second sequence is SEQ ID NO:878; the first sequence is SEQ ID NO:885 and the second sequence is SEQ ID NO:886; the first sequence is SEQ ID NO:889 the first sequence is SEQ ID NO: 900 and the second sequence is SEQ ID NO: 901; the first sequence is SEQ ID NO: 909 and the second sequence is SEQ ID NO: 910; the first sequence is SEQ ID NO: 917 and the second sequence is SEQ ID NO: 918; the first sequence is SEQ ID NO: 925 and the second sequence is SEQ ID NO: 926; the first sequence is SEQ ID NO: 933 and the second sequence is SEQ ID NO: 934; the first sequence is SEQ ID NO: 941 and the second sequence is SEQ ID NO: 942;The first sequence is SEQ ID NO:943 and the second sequence is SEQ ID NO:944; the first sequence is SEQ ID NO:951 and the second sequence is SEQ ID NO:952; the first sequence is SEQ ID NO:959 and the second sequence is SEQ ID NO:960; the first sequence is SEQ ID NO:967 and the second sequence is SEQ ID NO:968; the first sequence is SEQ ID NO:975 and the second sequence is SEQ ID NO:976; the first sequence is SEQ ID NO:983 and the second sequence is SEQ ID NO:984; the first sequence is SEQ ID NO:991 and the second sequence is SEQ ID NO:992; the first sequence is SEQ ID NO:993 and the second sequence is SEQ ID NO:984. two sequences are SEQ ID NO:994; one sequence is SEQ ID NO:995 and the second sequence is SEQ ID NO:996; one sequence is SEQ ID NO:1003 and the second sequence is SEQ ID NO:1004; one sequence is SEQ ID NO:1011 and the second sequence is SEQ ID NO:1012; one sequence is SEQ ID NO:1019 and the second sequence is SEQ ID NO:1020; one sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028; one sequence is SEQ ID NO:1035 and 1036; or one sequence is SEQ ID NO:1043 and the second sequence is SEQ ID NO:1044.

[0179] In some cases, the antibodies of the present disclosure target an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; The sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO:114; the first sequence is SEQ ID NO:121 and the second sequence is SEQ ID NO:122; the first sequence is SEQ ID NO:129 and the second sequence is SEQ ID NO:130; the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; the first sequence is SEQ ID NO:153 and the second sequence is SEQ ID NO:154; the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:162; the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210; the first sequence is SEQ ID NO:217 and the second sequence is the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; the first sequence is SEQ ID NO:629 and the second sequence is SEQ ID NO:630; the first sequence is SEQ ID NO:637 and the second sequence is SEQ ID NO:638;The first sequence is SEQ ID NO:645 and the second sequence is SEQ ID NO:646; the first sequence is SEQ ID NO:653 and the second sequence is SEQ ID NO:654; the first sequence is SEQ ID NO:661 and the second sequence is SEQ ID NO:662; the first sequence is SEQ ID NO:669 and the second sequence is SEQ ID NO:670; the first sequence is SEQ ID NO:677 and the second sequence is SEQ ID NO:678; the first sequence is SEQ ID NO:685 and the second sequence is SEQ ID NO:686; the first sequence is SEQ ID NO:693 and the second the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028.

[0180] In some cases, an antibody of the disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106. the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO:114; the first sequence is SEQ ID NO:121 and the second sequence is SEQ ID NO:122; the first sequence is SEQ ID NO:129 and the second sequence is SEQ ID NO:130; the first sequence is SEQ ID NO:137 and the second sequence is SEQ ID NO:138; the first sequence is SEQ ID NO:153 and the second sequence is SEQ ID NO:154; the first sequence is SEQ ID NO:161 and the second sequence is SEQ ID NO:162 the first sequence is SEQ ID NO:169 and the second sequence is SEQ ID NO:170; the first sequence is SEQ ID NO:177 and the second sequence is SEQ ID NO:178; the first sequence is SEQ ID NO:185 and the second sequence is SEQ ID NO:186; the first sequence is SEQ ID NO:193 and the second sequence is SEQ ID NO:194; the first sequence is SEQ ID NO:201 and the second sequence is SEQ ID NO:202; the first sequence is SEQ ID NO:209 and the second sequence is SEQ ID NO:210; the first the first sequence is SEQ ID NO:217 and the second sequence is SEQ ID NO:218; the first sequence is SEQ ID NO:225 and the second sequence is SEQ ID NO:226; the first sequence is SEQ ID NO:233 and the second sequence is SEQ ID NO:234; the first sequence is SEQ ID NO:241 and the second sequence is SEQ ID NO:242; the first sequence is SEQ ID NO:249 and the second sequence is SEQ ID NO:250; or the first sequence is SEQ ID NO:1027 and the second sequence is SEQ ID NO:1028. In some cases, the first sequence is SEQ ID NO:19 and the second sequence is SEQ ID NO:20.

[0181] In some cases, the heavy chain variable region has at least 85% sequence identity with the first sequence, and the light chain variable region has at least 85% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 90% sequence identity with the first sequence, and the light chain variable region has at least 90% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 95% sequence identity with the first sequence, and the light chain variable region has at least 95% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity with the first sequence, and the light chain variable region has at least 98% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 99% sequence identity with the first sequence, and the light chain variable region has at least 99% sequence identity with the second sequence. In some cases, the heavy chain variable region comprises a first sequence and the light chain variable region comprises a second sequence.

[0182] (ii) Heavy and Light Chains In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence: the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 46 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 47 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 57 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 58 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 60 and the second sequence is SEQ ID NO:62; the first sequence is SEQ ID NO:61 and the second sequence is SEQ ID NO:62; the first sequence is SEQ ID NO:71 and the second sequence is SEQ ID NO:73; the first sequence is SEQ ID NO:72 and the second sequence is SEQ ID NO:73; the first sequence is SEQ ID NO:74 and the second sequence is SEQ ID NO:76; the first sequence is SEQ ID NO:75 and the second sequence is SEQ ID NO:76; the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:251 and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260;the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; the first sequence is SEQ ID NO:265 and the second sequence is SEQ ID NO:266; the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; the first sequence is SEQ ID NO:271, the second sequence is SEQ ID NO:272; the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278; the first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; One sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290; the first sequence is SEQ ID NO:299 and the second sequence is SEQ ID NO:300; the first sequence is SEQ ID NO:493 and the second the first sequence is SEQ ID NO:717 and the second sequence is SEQ ID NO:718; the first sequence is SEQ ID NO:719 and the second sequence is SEQ ID NO:720; the first sequence is SEQ ID NO:721 and the second sequence is SEQ ID NO:722; the first sequence is SEQ ID NO:723 and the second sequence is SEQ ID NO:724; or the first sequence is SEQ ID NO:757 and the second sequence is SEQ ID NO:758.

[0183] In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence: the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; The first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:251. and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; The sequence number is 265 and the second sequence is SEQ ID NO:266; the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278;The first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290; the first sequence is SEQ ID NO:717 and the second sequence is SEQ ID NO:718; the first sequence is SEQ ID NO:719 and the second sequence is SEQ ID NO:720; the first sequence is SEQ ID NO:721 and the second sequence is SEQ ID NO:722; or the first sequence is SEQ ID NO:723 and the second sequence is SEQ ID NO:724.

[0184] In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence: the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; The first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:85 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:86 and the second sequence is SEQ ID NO:87; the first sequence is SEQ ID NO:88 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:89 and the second sequence is SEQ ID NO:90; the first sequence is SEQ ID NO:251. and the second sequence is SEQ ID NO:252; the first sequence is SEQ ID NO:253 and the second sequence is SEQ ID NO:254; the first sequence is SEQ ID NO:255 and the second sequence is SEQ ID NO:256; the first sequence is SEQ ID NO:257 and the second sequence is SEQ ID NO:258; the first sequence is SEQ ID NO:259 and the second sequence is SEQ ID NO:260; the first sequence is SEQ ID NO:261 and the second sequence is SEQ ID NO:262; the first sequence is SEQ ID NO:263 and the second sequence is SEQ ID NO:264; The sequence number is 265 and the second sequence is SEQ ID NO:266; the first sequence is SEQ ID NO:267 and the second sequence is SEQ ID NO:268; the first sequence is SEQ ID NO:269 and the second sequence is SEQ ID NO:270; the first sequence is SEQ ID NO:271 and the second sequence is SEQ ID NO:272; the first sequence is SEQ ID NO:273 and the second sequence is SEQ ID NO:274; the first sequence is SEQ ID NO:275 and the second sequence is SEQ ID NO:276; the first sequence is SEQ ID NO:277 and the second sequence is SEQ ID NO:278;The first sequence is SEQ ID NO:279 and the second sequence is SEQ ID NO:280; the first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; or the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290.

[0185] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence: the first sequence is SEQ ID NO:1 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:2 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:3 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:4 and the second sequence is SEQ ID NO:5; the first sequence is SEQ ID NO:6 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:7 and the second sequence is SEQ ID NO:10; the first sequence is SEQ ID NO:8 and the second sequence is SEQ ID NO:10; or the first sequence is SEQ ID NO:9 and the second sequence is SEQ ID NO:10.

[0186] In some cases, an antibody of the disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO:3 or SEQ ID NO:4, and the second sequence is SEQ ID NO:5.

[0187] In some cases, the heavy chain has at least 85% sequence identity with the first sequence, and the light chain has at least 85% sequence identity with the second sequence. In some cases, the heavy chain has at least 90% sequence identity with the first sequence, and the light chain has at least 90% sequence identity with the second sequence. In some cases, the heavy chain has at least 95% sequence identity with the first sequence, and the light chain has at least 95% sequence identity with the second sequence. In some cases, the heavy chain has at least 98% sequence identity with the first sequence, and the light chain has at least 98% sequence identity with the second sequence. In some cases, the heavy chain has at least 99% sequence identity with the first sequence, and the light chain has at least 99% sequence identity with the second sequence. In some cases, the heavy chain comprises the first sequence, and the light chain comprises the second sequence.

[0188] (iii) Complementarity-determining region In some cases, the antibody comprises a CDR-H1 comprising at least 80% sequence identity to a first sequence, a CDR-H2 comprising at least 80% sequence identity to a second sequence, a CDR-H3 comprising at least 80% sequence identity to a third sequence, a CDR-L1 comprising at least 80% sequence identity to a fourth sequence, a CDR-L2 comprising at least 80% sequence identity to a fifth sequence, and a CDR-L3 comprising at least 80% sequence identity to a sixth sequence, wherein the first, second, third, fourth, fifth, and sixth sequences are set forth in SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively. SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOs: 107, 108, 109, 110, 111, and 112, respectively; and SEQ ID NO: 115, respectively. 116, 117, 118, 119, and 120; SEQ ID NOs: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NOs: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NOs: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NOs: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NOs: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NOs: 163, 164, 165, 166, 167, and 168, respectively; and SEQ ID NOs: 171, 172, 173, and 174, respectively. , 175, and 176; SEQ ID NOs: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NOs: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NOs: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207, and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NOs: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NOs: 227, 228, 229, 230, 231, and 232, respectively;SEQ ID NOs: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NOs: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively; and SEQ ID NOs: 326, 327, 328, 329, and 330, respectively. SEQ ID NOs: 333, 334, 335, 336, 337, and 338; SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NOs: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NOs: 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, and 406, respectively; SEQ ID NOs: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NOs: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NOs: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NOs: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively; and SEQ ID NOs: 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, and 472, respectively. 49, and 450; SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively; and SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NOs: 559, 560, 561, 562, 563, and 564, respectively; and SEQ ID NOs: 561, 562, 563, and 564, respectively. SEQ ID NOs: 567, 568, 569, 570, 571, and 572; SEQ ID NOs: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively; and SEQ ID NOs: 623, 624, 625, 626, 627, 628, 629, 630, and 631, respectively. 25, 626, 627, and 628; SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NOs: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NOs: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NOs: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NOs: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NOs: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NOs: 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, and 696, respectively. SEQ ID NOs: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NOs: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NOs: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively;SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively; and SEQ ID NOs: 810, 811, and 812, respectively. SEQ ID NOs: 815, 816, 817, 818, 819, and 820; SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NOs: 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927 SEQ ID NOs: 873, 874, 875, and 876; SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NOs: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively; and SEQ ID NOs: 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 97 31, and 932; SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively;SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.

[0189] In some cases, the antibody of the disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a CDR-H1 comprising at least 80% sequence identity to a first sequence, a CDR-H2 comprising at least 80% sequence identity to a second sequence, a CDR-H3 comprising at least 80% sequence identity to a third sequence, a CDR-L1 comprising at least 80% sequence identity to a fourth sequence, a CDR-L2 comprising at least 80% sequence identity to a fifth sequence, and a CDR-L3 comprising at least 80% sequence identity to a sixth sequence, wherein the first, second, third, fourth, fifth, and sixth sequences are, respectively. SEQ ID NOS: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOS: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOS: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOS: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOS: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NOS: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NOS: 123, 124, 125, 126, 127, and 128, respectively; and SEQ ID NOS: 131 and 132, respectively. , 133, 134, 135, and 136; SEQ ID NOs: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NOs: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NOs: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NOs: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NOs: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NOs: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NOs: SEQ ID NOs: 187, 188, 189, 190, 191, and 192; SEQ ID NOs: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207, and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NOs: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NOs: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239, and 240, respectively;SEQ ID NOs: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NOs: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NOs: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NOs: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NOs: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NOs: 655, 656, 657, 658, 659, and 660, respectively; and SEQ ID NOs: 663, 664, 665, and 666, respectively. , 667, and 668; SEQ ID NOs: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NOs: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NOs: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NOs: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NOs: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.

[0190] In some cases, the antibody comprises a CDR-H1 that comprises at least 85% sequence identity with a first sequence, a CDR-H2 that comprises at least 85% sequence identity with a second sequence, a CDR-H3 that comprises at least 85% sequence identity with a third sequence, a CDR-L1 that comprises at least 85% sequence identity with a fourth sequence, a CDR-L2 that comprises at least 85% sequence identity with a fifth sequence, and a CDR-L3 that comprises at least 85% sequence identity with a sixth sequence. In some cases, the antibody comprises a CDR-H1 that comprises at least 90% sequence identity with a first sequence, a CDR-H2 that comprises at least 90% sequence identity with a second sequence, a CDR-H3 that comprises at least 90% sequence identity with a third sequence, a CDR-L1 that comprises at least 90% sequence identity with a fourth sequence, a CDR-L2 that comprises at least 90% sequence identity with a fifth sequence, and a CDR-L3 that comprises at least 90% sequence identity with a sixth sequence. In some cases, CDR-H1 comprises at most one mutation compared to the first sequence, CDR-H2 comprises at most one mutation compared to the second sequence, CDR-H3 comprises at most one mutation compared to the third sequence, CDR-L1 comprises at most one mutation compared to the fourth sequence, CDR-L2 comprises at most one mutation compared to the fifth sequence, and CDR-L3 comprises at most one mutation compared to the sixth sequence.

[0191] (iv) Exemplary Antibodies In some cases, the antibodies provided herein bind to PDL1. PDL1 is expressed in a wide range of cancers and in certain immune cells and often functions as a major mechanism for immunosuppression in the tumor microenvironment. PDL1 agonism of PD-1 can act as an immune checkpoint, attenuating lymphocyte tumor infiltration and T cell receptor-mediated proliferation and signaling. PDL1 antagonism can reverse immunosuppression, but PDL1 targeting can also localize treatment to the site of cancer, allowing drugs to be selectively targeted to cancer cells or to stimulate an immune response in the presence of tumors.

[0192] In some cases, the anti-PDL1 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity, respectively, to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18.

[0193] In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4, and a light chain comprising an amino acid sequence that is 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: 5. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1, and a light chain comprising an amino acid sequence that is 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: 5. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2, and a light chain comprising an amino acid sequence that is 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: 5. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3, and a light chain comprising an amino acid sequence that is 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: 5. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, and a light chain comprising an amino acid sequence that is 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:5.

[0194] In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 6-9, and a light chain variable region comprising an amino acid sequence 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: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 6, and a light chain variable region comprising an amino acid sequence 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: 10. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO:7, and a light chain variable region comprising an amino acid sequence that is 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:10. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO:8, and a light chain variable region comprising an amino acid sequence that is 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:10. In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO:9, and a light chain variable region comprising an amino acid sequence that is 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:10.

[0195] In some embodiments, the 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain variable region comprising an amino acid sequence that is 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.

[0196] In some embodiments, the antibodies provided herein bind to EphA2. In some embodiments, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that comprise amino acid sequences 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: 21, 22, 23, 24, 25, and 26, respectively.

[0197] In some embodiments, an anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, an anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33, and a light chain comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the anti-EphA2 antibody comprises a heavy chain at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36, and a light chain comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibody is h1C1 or 1C1.

[0198] 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 27, 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28.

[0199] In some cases, the antibodies provided herein bind to CD30. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 46 or 47, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45.

[0200] In some cases, the antibodies provided herein bind to CD228. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some embodiments, an anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, an anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 57 or 58, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-CD228 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 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 60 or 61, 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 62.

[0201] In some cases, the antibodies provided herein bind to avB6. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some embodiments, an anti-H2A2 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, an anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-H2A2 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 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75, 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76.

[0202] In some cases, the antibodies provided herein bind to B7H4. In some cases, the antibodies comprise a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively), each of which is set forth in SEQ ID NOs: 77-82, 91-96, 99-104, 107-112, 115-120, 123-128, 131-136, 139-144, 147-152, 155-160, 163-168, 171, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 200, 202, 203, 204, 205, 206, 207, 208, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 239, 242, 239, 243, 239, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, to 176, SEQ ID NOs: 179 to 184, SEQ ID NOs: 187 to 192, SEQ ID NOs: 195 to 200, SEQ ID NOs: 203 to 208, SEQ ID NOs: 211 to 216, SEQ ID NOs: 219 to 224, SEQ ID NOs: 227 to 232, SEQ ID NOs: 235 to 240, and SEQ ID NOs: 243 to 248. 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), each of which is set forth in SEQ ID NOs: 77-82, 91-96, 99-104, 107-112, 115-120, 123-128, 131-136, 139-144, 147-152, and SEQ ID NOs: 147-153, respectively. and SEQ ID NOs: 155 to 160, 163 to 168, 171 to 176, 179 to 184, 187 to 192, 195 to 200, 203 to 208, 211 to 216, 219 to 224, 227 to 232, 235 to 240, and 243 to 248.In some cases, the anti-B7H4 antibody is selected from the group consisting of SEQ ID NOs: 85 and 87, SEQ ID NOs: 86 and 87, SEQ ID NOs: 88 and 90, SEQ ID NOs: 89 and 90, SEQ ID NOs: 251 and 252, SEQ ID NOs: 253 and 254, SEQ ID NOs: 255 and 256, SEQ ID NOs: 257 and 258, SEQ ID NOs: 259 and 260, SEQ ID NOs: 261 and 262, SEQ ID NOs: 263 and 264, SEQ ID NOs: 265 and 266, SEQ ID NOs: 267 and 268, SEQ ID NOs: 269 and 270, SEQ ID NOs: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NOs:275 and 276, SEQ ID NOs:277 and 278, SEQ ID NOs:279 and 280, SEQ ID NOs:281 and 282, SEQ ID NOs:283 and 284, SEQ ID NOs:285 and 286, SEQ ID NOs:287 and 288, or SEQ ID NOs:289 and 290. In some embodiments, an anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region, respectively, comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequence of SEQ ID NOs: 83 and 84, SEQ ID NOs: 97 and 98, SEQ ID NOs: 105 and 106, SEQ ID NOs: 113 and 114, SEQ ID NOs: 121 and 122, SEQ ID NOs: 129 and 130, SEQ ID NOs: 137 and 138, SEQ ID NOs: 153 and 154, SEQ ID NOs: 161 and 162, SEQ ID NOs: 169 and 170, SEQ ID NOs: 177 and 178, SEQ ID NOs: 185 and 186, SEQ ID NOs: 193 and 194, SEQ ID NOs: 201 and 202, SEQ ID NOs: 209 and 210, SEQ ID NOs: 217 and 218, SEQ ID NOs: 225 and 226, SEQ ID NOs: 233 and 234, SEQ ID NOs: 241 and 242, or SEQ ID NOs: 249 and 250.

[0203] In some cases, the antibodies provided herein bind to CD70. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 297, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 298. In some embodiments, the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299, and a light chain comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 300.

[0204] In some cases, the antibodies provided herein bind to TROP2. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibodies provided herein bind to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity, respectively, to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314. In some embodiments, the anti-TROP2 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 307 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 308.In some embodiments, the anti-TROP2 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 315 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 316.

[0205] In some cases, the antibodies provided herein bind to MICA. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity, respectively, to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively.In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some embodiments, an anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 323, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 324. In some embodiments, an anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 331, and a light chain variable region comprising an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 332. In some embodiments, the anti-MICA 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:340, 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:340.In some embodiments, the anti-MICA 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 347 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348.

[0206] In some cases, the antibodies provided herein bind to CD51. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibodies provided herein bind to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity, respectively, to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362. In some embodiments, the anti-CD51 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 355 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 356.In some embodiments, the anti-CD51 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 363 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 364.

[0207] In some cases, the antibodies provided herein bind to gpA33. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some embodiments, the anti-gpA33 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 371 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 372.

[0208] In some cases, the antibodies provided herein bind to IL1Rap. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some embodiments, the anti-IL1Rap 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 379 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 380.

[0209] In some cases, the antibodies provided herein bind to EpCAM. In some cases, the antibodies comprise a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively), each of which has at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, 389-394, 397-402, 405-410, 413-418, or 421-426. In some embodiments, the anti-EpCAM antibody comprises a heavy chain variable region and a light chain variable region, respectively, comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequence of SEQ ID NOs: 387 and 388, SEQ ID NOs: 395 and 396, SEQ ID NOs: 403 and 404, SEQ ID NOs: 411 and 412, SEQ ID NOs: 419 and 420, or SEQ ID NOs: 427 and 428.

[0210] In some cases, the antibodies provided herein bind to CD352. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some embodiments, the anti-CD352 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:435 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:436.

[0211] In some cases, the antibodies provided herein bind to CS1. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some embodiments, the anti-CS1 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:443 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:444.

[0212] In some cases, the antibodies provided herein bind to CD38. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some embodiments, the anti-CD38 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:451 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:452.

[0213] In some cases, the antibodies provided herein bind to CD25. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some embodiments, the anti-CD25 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:459 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 98%, or 99% identical to the amino acid sequence of SEQ ID NO:460.

[0214] In some cases, the antibodies provided herein bind to ADAM9. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation compared to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and...

Claims

1. structure: A-(L-D) ｐ or a pharmaceutically acceptable salt thereof. (In the formula, Ab is an antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D has the structure of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof and R １ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, -NR Ａ R Ｂ , phosphoryl, sulfuryl, nitro, C ５ -C ９ Monosaccharide, acylated C ５ -C ９ monosaccharide, C １０ -C １８ Disaccharide, acylated C １０ -C １８ Disaccharide, C １５ -C ２７ Trisaccharide and acylated C １５ -C ２７ optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R ２ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ or R １ and R ２ together with the nitrogen atom to which they are attached, represent 1 to 3 independently selected C １ -C ６ and forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl, wherein said heterocyclyl or said 1 to 3 independently selected C １ -C ６ One of the alkyls is optionally the point of covalent attachment to L; R ３ is (a) the point of covalent attachment to L; or (b) hydrogen, —NR Ａ R Ｂ , —C(═O)NR Ａ R Ｂ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle; each C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ Cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle are hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ４ is the point of covalent attachment to L; hydrogen; -OR Ｃ -S(=O) ２ R Ｃ -C(=O)NR Ｄ R Ｅ -C(=O)OR Ｃ -C(=O)SR Ｃ -C(=S)R Ｃ ;-PO ３ R Ｃ and (i) 1 to 3 independently selected halogens; (ii)-OR Ｃ ; (iii)-SR Ｃ ; (iv)-NH-S(O ２ )R Ｃ ; (v)-OC(=O)R Ｃ ; (vi)-CO ２ H; (vii) C １ -C ６ Alkoxycarbonyl; ( ) ( ) ) ( ) ( ) ) Ｄ ( Ｅ 4 (ix)-NR Ｄ R Ｅ ; (x)-[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ ; (xi)-(phenyl)C １ -C ６ alkyl (wherein the -(phenyl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; (xii) halogen, hydroxyl, C １ -C ６ Alkoxy, —NR Ｄ R Ｅ , —C(═O)NR Ｄ R Ｅ or -CO ２ Phenyl substituted with H; (xiii)-(5- to 10-membered heteroaryl)C １ -C ６ alkyl (wherein the (-5 to 10-membered heteroaryl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, —NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; or (xiv) halogen, —NR Ｄ R Ｅ , C １ -C ６ Alkoxy, —C(═O)NR Ｄ R Ｅ , -SR Ｃ , (C １ -C ６ ) alkoxycarbonyl, or —CO ２ 5-10 membered heteroaryl optionally substituted with H -C optionally substituted with １ -C ６ selected from the group consisting of alkyl; R ４ is C １ -C ６ When it is alkyl, １ -C ６ alkyl or a substituent thereof is optionally further substituted at the point of covalent attachment to L; R ５ is -C(=O)OR Ｆ , -NO ２ , -CN, -CF ３ -C(=O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , and SO ３ R Ｋ selected from the group consisting of: Each R ６ is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ independently selected from the group consisting of: m is 0, 1, 2, or 3; R Ａ and R Ｂ Each occurrence of represents (a) a point of covalent attachment to L, (b) a hydrogen and C １ -C ６ (c) R Ａ and R Ｂ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ａ and R Ｂ at most one occurrence of is the point of covalent attachment to L; R Ｃ Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C optionally substituted with phenyl or 1 to 3 independently selected halogens. １ -C １０ independently selected from the group consisting of alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ Each occurrence of is (a) a point of covalent attachment to L; (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Cycloalkyl (C １ -C ６ alkyl), aryl, and aryl(C １ -C ６ (c) the group consisting of R Ｄ and R Ｅ , or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ is the point of covalent attachment to L; R Ｆ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ Cycloalkyl, aryl, aryl (C １ -C ６ alkyl)-, and halogen, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxy, and C ３ -C ８ C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen and C １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ at most one of is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20).

2. 2. The ADC of claim 1, wherein the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence.

3. 3. The ADC of claim 1 or claim 2, wherein the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence.

4. structure: A-(L-D) ｐ or a pharmaceutically acceptable salt thereof. (In the formula, Ab is an antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D has the structure of formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof and R １ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, -NR Ａ R Ｂ , phosphoryl, sulfuryl, nitro, C ５ -C ９ Monosaccharide, acylated C ５ -C ９ monosaccharide, C １０ -C １８ Disaccharide, acylated C １０ -C １８ Disaccharide, C １５ -C ２７ Trisaccharide and acylated C １５ -C ２７ optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R ２ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ or R １ and R ２ together with the nitrogen atom to which they are attached, represent 1 to 3 independently selected C １ -C ６ and forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl, wherein said heterocyclyl or said 1 to 3 independently selected C １ -C ６ One of the alkyls is optionally the point of covalent attachment to L; R ３ is (a) the point of covalent attachment to L; or (b) hydrogen, —NR Ａ R Ｂ , —C(═O)NR Ａ R Ｂ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle; each C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ Cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle are hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ４ is the point of covalent attachment to L; hydrogen; -OR Ｃ -S(=O) ２ R Ｃ -C(=O)NR Ｄ R Ｅ -C(=O)OR Ｃ -C(=O)SR Ｃ -C(=S)R Ｃ ;-PO ３ R Ｃ and (i) 1 to 3 independently selected halogens; (ii)-OR Ｃ ; (iii)-SR Ｃ ; (iv)-NH-S(O ２ )R Ｃ ; (v)-OC(=O)R Ｃ ; (vi)-CO ２ H; (vii) C １ -C ６ Alkoxycarbonyl; ( ) ( ) ) ( ) ( ) ) Ｄ ( Ｅ 4 (ix)-NR Ｄ R Ｅ ; (x)-[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ ; (xi)-(phenyl)C １ -C ６ alkyl (wherein the -(phenyl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; (xii) halogen, hydroxyl, C １ -C ６ Alkoxy, —NR Ｄ R Ｅ , —C(═O)NR Ｄ R Ｅ or -CO ２ Phenyl substituted with H; (xiii)-(5- to 10-membered heteroaryl)C １ -C ６ alkyl (wherein the (-5 to 10-membered heteroaryl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, —NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; or (xiv) halogen, —NR Ｄ R Ｅ , C １ -C ６ Alkoxy, —C(═O)NR Ｄ R Ｅ , -SR Ｃ , (C １ -C ６ ) alkoxycarbonyl, or —CO ２ 5-10 membered heteroaryl optionally substituted with H -C optionally substituted with １ -C ６ selected from the group consisting of alkyl; R ４ is C １ -C ６ When it is alkyl, １ -C ６ alkyl or a substituent thereof is optionally further substituted at the point of covalent attachment to L; R ５ is -C(=O)OR Ｆ , -NO ２ , -CN, -CF ３ -C(=O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , and SO ３ R Ｋ selected from the group consisting of: Each R ６ is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ independently selected from the group consisting of: The subscript m is 0, 1, 2, 3, or 4; R Ａ and R Ｂ Each occurrence of represents (a) a point of covalent attachment to L, (b) a hydrogen and C １ -C ６ (c) R Ａ and R Ｂ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ａ and R Ｂ at most one occurrence of is the point of covalent attachment to L; R Ｃ Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C optionally substituted with phenyl or 1 to 3 independently selected halogens. １ -C １０ independently selected from the group consisting of alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ Each occurrence of is (a) a point of covalent attachment to L; (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Cycloalkyl (C １ -C ６ alkyl), aryl, and aryl(C １ -C ６ (c) the group consisting of R Ｄ and R Ｅ , or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ is the point of covalent attachment to L; R Ｆ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ Cycloalkyl, aryl, aryl (C １ -C ６ alkyl)-, and halogen, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxy, and C ３ -C ８ C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen and C １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ at most one of is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein said first sequence is SEQ ID NO:3 and said second sequence is SEQ ID NO:5).

5. 5. The ADC of claim 4, wherein the heavy chain has at least 90% sequence identity with the first sequence and the light chain has at least 90% sequence identity with the second sequence.

6. 6. The ADC of claim 4 or claim 5, wherein the heavy chain has at least 98% sequence identity with the first sequence and the light chain has at least 98% sequence identity with the second sequence.

7. structure: A-(L-D) ｐ or a pharmaceutically acceptable salt thereof. (In the formula, Ab is an antibody; each L is a linker; each D is conjugated to a linker; each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of the Ab; The subscript p is an integer from 1 to 16; Each D has the structure of formula (I): 【Chemistry 3】 or a pharmaceutically acceptable salt thereof and R １ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, C １ -C ６ Amidine, C １ -C ６ Sulfone, C １ -C ６ Chion, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, -NR Ａ R Ｂ , phosphoryl, sulfuryl, nitro, C ５ -C ９ Monosaccharide, acylated C ５ -C ９ monosaccharide, C １０ -C １８ Disaccharide, acylated C １０ -C １８ Disaccharide, C １５ -C ２７ Trisaccharide and acylated C １５ -C ２７ optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides; R ２ is (a) the point of covalent attachment to L; or (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C ３ -C ６ Cycloalkyl, phenyl, and 5- to 10-membered heteroaryl are hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ or R １ and R ２ together with the nitrogen atom to which they are attached, represent 1 to 3 independently selected C １ -C ６ and forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl, wherein said heterocyclyl or said 1 to 3 independently selected C １ -C ６ One of the alkyls is optionally the point of covalent attachment to L; R ３ is (a) the point of covalent attachment to L; or (b) hydrogen, —NR Ａ R Ｂ , —C(═O)NR Ａ R Ｂ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ selected from the group consisting of cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle; each C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkanoyloxy, C ３ -C ６ Cycloalkyl, phenyl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocycle are hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ optionally substituted with 1 to 3 substituents independently selected from the group consisting of: R ４ is the point of covalent attachment to L; hydrogen; -OR Ｃ -S(=O) ２ R Ｃ -C(=O)NR Ｄ R Ｅ -C(=O)OR Ｃ -C(=O)SR Ｃ -C(=S)R Ｃ ;-PO ３ R Ｃ and (i) 1 to 3 independently selected halogens; (ii)-OR Ｃ ; (iii)-SR Ｃ ; (iv)-NH-S(O ２ )R Ｃ ; (v)-OC(=O)R Ｃ ; (vi)-CO ２ H; (vii) C １ -C ６ Alkoxycarbonyl; ( ) ( ) ) ( ) ( ) ) Ｄ ( Ｅ 4 (ix)-NR Ｄ R Ｅ ; (x)-[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ ; (xi)-(phenyl)C １ -C ６ alkyl (wherein the -(phenyl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, -NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; (xii) halogen, hydroxyl, C １ -C ６ Alkoxy, —NR Ｄ R Ｅ , —C(═O)NR Ｄ R Ｅ or -CO ２ Phenyl substituted with H; (xiii)-(5- to 10-membered heteroaryl)C １ -C ６ alkyl (wherein the (-5 to 10-membered heteroaryl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, —NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens; or (xiv) halogen, —NR Ｄ R Ｅ , C １ -C ６ Alkoxy, —C(═O)NR Ｄ R Ｅ , -SR Ｃ , (C １ -C ６ ) alkoxycarbonyl, or —CO ２ 5-10 membered heteroaryl optionally substituted with H -C optionally substituted with １ -C ６ selected from the group consisting of alkyl; R ４ is C １ -C ６ When it is alkyl, １ -C ６ alkyl or a substituent thereof is optionally further substituted at the point of covalent attachment to L; R ５ is -C(=O)OR Ｆ , -NO ２ , -CN, -CF ３ -C(=O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , and SO ３ R Ｋ selected from the group consisting of: Each R ６ is (a) the point of covalent attachment to L; or (b) halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ independently selected from the group consisting of: m is 0, 1, 2, or 3; R Ａ and R Ｂ Each occurrence of represents (a) a point of covalent attachment to L, (b) a hydrogen and C １ -C ６ (c) R Ａ and R Ｂ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ａ and R Ｂ at most one occurrence of is the point of covalent attachment to L; R Ｃ Each occurrence of is selected from (a) a point of covalent attachment to L; and (b) hydrogen, phenyl, and C optionally substituted with phenyl or 1 to 3 independently selected halogens. １ -C １０ independently selected from the group consisting of alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ Each occurrence of is (a) a point of covalent attachment to L; (b) hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ３ -C ８ Cycloalkyl, C ３ -C ８ Cycloalkyl (C １ -C ６ alkyl), aryl, and aryl(C １ -C ６ (c) the group consisting of R Ｄ and R Ｅ , or R Ｇ and R Ｈ together with the nitrogen atom to which they are attached, 1 to 3 independently selected C １ -C ６ forming a 3- to 6-membered heterocyclyl optionally substituted with alkyl; R Ｄ , R Ｅ , R Ｇ , and R Ｈ is the point of covalent attachment to L; R Ｆ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen, trifluoromethyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ Cycloalkyl, aryl, aryl (C １ -C ６ alkyl)-, and halogen, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxy, and C ３ -C ８ C optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ Each occurrence of is (a) a point of covalent attachment to L; and (b) hydrogen and C １ -C ６ independently selected from the group consisting of alkyl; R Ｉ , R Ｊ , and R Ｋ at most one of is a point of covalent attachment to L; each D has only one point of covalent attachment to L; The Ab comprises a CDR-H1 comprising at least 80% sequence identity with a first sequence, a CDR-H2 comprising at least 80% sequence identity with a second sequence, a CDR-H3 comprising at least 80% sequence identity with a third sequence, a CDR-L1 comprising at least 80% sequence identity with a fourth sequence, a CDR-L2 comprising at least 80% sequence identity with a fifth sequence, and a CDR-L3 comprising at least 80% sequence identity with a sixth sequence, wherein said first, second, third, fourth, fifth, and sixth sequences comprise SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.

8. 8. The ADC of claim 7, wherein the CDR-H1 comprises at most one mutation compared to the first sequence, the CDR-H2 comprises at most one mutation compared to the second sequence, the CDR-H3 comprises at most one mutation compared to the third sequence, the CDR-L1 comprises at most one mutation compared to the fourth sequence, the CDR-L2 comprises at most one mutation compared to the fifth sequence, and the CDR-L3 comprises at most one mutation compared to the sixth sequence.

9. 9. The ADC of claim 7 or claim 8, wherein the first, second, third, fourth, fifth, and sixth sequences are SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.

10. The ADC of any one of claims 1 to 9, wherein the Ab comprises an effector function-attenuating mutation.

11. 11. The ADC of claim 10, wherein the effector function-attenuating mutation is selected from the group consisting of L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G, and combinations thereof.

12. The ADC of claim 10 or 11, wherein the effector function-attenuating mutation is L234A / L235A.

13. Each D has the structure of formula (II): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, wherein 【Chemistry 5】 is the point of covalent attachment to L; R ５ is (a) the point of covalent attachment to L; or (b) —C(═O)OR Ｆ , -NO ２ , -CN, -CF ３ -C(=O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , and SO ３ R Ｋ selected from the group consisting of: Each R ６ is halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ are independently selected from the group consisting of: m is 0, 1, 2, or 3. The ADC of any one of claims 1 to 12, having the following structure:

14. Each D has the structure of formula (IIa): 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, ６ is halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ are independently selected from the group consisting of: m is 0, 1, 2, or 3.

14. The ADC of claim 13, having the formula:

15. Each D has the structure of formula (III): 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, wherein R ４Ａ is (a) the point of covalent attachment to L or (b) (i) 1 to 3 independently selected halogens; (ii) -OR Ｃ (iii)-SR Ｃ ;(iv)-NH-S(O ２ ) R Ｃ ;(v)-OC(=O)R Ｃ (vi) -CO ２ H; (vii)-C １ -C ６ (viii) —C(═O)NR Ｄ R Ｅ (ix) -NR Ｄ R Ｅ ; (ix) -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ ; (x)-(phenyl)C １ -C ６ Alkyl (wherein １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, —NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or 1 to 3 independently selected halogens); (xi) halogen, hydroxyl, C １ -C ６ Alkoxy, —C(═O)NR Ｄ R Ｅ or -CO ２ (xii) -(5- to 10-membered heteroaryl)C １ -C ６ Alkyl (wherein １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, —NR Ｄ R Ｅ , -[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or substituted with 1 to 3 independently selected halogens); or halogen, —NR Ｄ R Ｅ , C １ -C ６ Alkoxy, —C(═O)NR Ｄ R Ｅ , or -CO ２ C optionally substituted with 5-10 membered heteroaryl optionally substituted with H １ -C ６ alkyl; R ４Ａ (b) the C １ -C ６ When it is alkyl, １ -C ６ the alkyl or substituent thereof is further substituted at the point of covalent attachment to L; R ５ is -C(=O)OR Ｆ , -NO ２ , -CN, -CF ３ -C(=O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , and SO ３ R Ｋ selected from the group consisting of: Each R ６ is halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ are independently selected from the group consisting of: m is 0, 1, 2, or 3. The ADC of any one of claims 1 to 12, having the formula:

16. Each D has the structure of formula (IIIa): 【Chemistry 8】 or a pharmaceutically acceptable salt thereof.

17. R １ or R ４ is the point of covalent attachment to L.

18. R １ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ carbamoyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Alkoxythiocarbonyl, C １ -C ６ Carbamoyl, phenyl, or 5- to 10-membered heteroaryl is hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, -NR Ａ R Ｂ , phosphoryl, sulfuryl, nitro, C ５ -C ９ Monosaccharide, acylated C ５ -C ９ monosaccharide, C １０ -C １８ Disaccharide, acylated C １０ -C １８ Disaccharide, C １５ -C ２７ Trisaccharide and acylated C １５ -C ２７ 18. The ADC of any one of claims 1 to 17, optionally substituted with 1 to 3 substituents independently selected from the group consisting of trisaccharides.

19. R １ is C １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ alkoxycarbonyl, and phenyl; １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, or phenyl, is hydroxyl, halogen, sulfhydryl, cyano, C １ -C ６ Alkoxy, —NR Ａ R Ｂ , phosphoryl, sulfuryl, nitro, C ５ -C ９ Monosaccharides and acylated C ５ -C ９ 19. The ADC of any one of claims 1 to 18, optionally substituted with 1 to 3 substituents independently selected from the group consisting of monosaccharides.

20. R １ is hydrogen, or hydroxyl, halogen, and -NH ２ C optionally substituted with a substituent selected from the group consisting of １ -C ３ The ADC of any one of claims 1 to 19, which is alkyl.

21. R １ is hydrogen or C １ -C ３ The ADC of any one of claims 1 to 20, which is alkyl.

22. R １ The ADC of any one of claims 1 to 21, wherein is hydrogen.

23. R ２ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ alkoxycarbonyl, and phenyl; １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, or phenyl, is hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ 23. The ADC of any one of claims 1-12 or 15-22, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

24. R ２ is hydrogen and C １ -C ３ alkyl, wherein C １ -C ３ Alkyl is hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ 24. The ADC of any one of claims 1-12 or 15-23, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

25. R ２ is hydrogen or C １ -C ３ The ADC of any one of claims 1 to 12 or 15 to 24, which is alkyl.

26. R ２ The ADC of any one of claims 1 to 12 or 15 to 25, wherein is hydrogen.

27. R ３ is -NR Ａ R Ｂ , —C(═O)NR Ａ R Ｂ , C １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ is selected from the group consisting of alkoxycarbonyl, phenyl, and 5- to 10-membered heteroaryl; １ -C ６ Alkyl, C １ -C ６ Alkanoyl, C １ -C ６ Alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C ３ -C ８ cycloalkyl, phenyl, 5- to 10-membered heteroaryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, and —NR Ａ R Ｂ 27. The ADC of any one of claims 1 to 26, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

28. R ３ is hydroxyl, halogen, cyano, oxo, C １ -C ３ Alkoxy, C １ -C ３ Alkylthio, and —NR Ａ R Ｂ C optionally substituted with one substituent selected from the group consisting of １ -C ５ The ADC of any one of claims 1 to 27, which is alkyl.

29. R ３ is butyl, -CH ２ -O-CH ２ CH ３ , -CH ２ -CH ２ -O-CH ３ , and -CH ２ -NH-CH ２ CH ３ The ADC of any one of claims 1 to 28, selected from the group consisting of:

30. R ４ is hydrogen; —C(═O)NR Ｄ R Ｅ -C(=O)OR Ｃ -C(=O)SR Ｃ -C(=S)R Ｃ or (i) 1 to 3 independently selected halogens; (ii) —O(C １ -C ６ (iii) -S(C alkyl); １ -C ６ (iv) -NH-S(O ２ ) R Ｃ ;(v)-OC(=O)R Ｃ (vi) -CO ２ H; (vii)-C １ -C ６ (viii) —C(═O)NR Ｄ R Ｅ (ix) -NR Ｄ R Ｅ (In the formula, -NR Ｄ R Ｅ The R Ｄ is C １ -C ６ (x)-[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ (xi)-(phenyl)C １ -C ６ alkyl (wherein the -(phenyl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, —[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ or 1 to 3 independently selected halogens); or (xii) halogen, hydroxyl, C １ -C ６ Alkoxy, —NR Ｄ R Ｅ , —C(═O)NR Ｄ R Ｅ or -CO ２ C optionally substituted with phenyl substituted with H １ -C ６ 30. The ADC of any one of claims 1 to 14 or 17 to 29, which is alkyl.

31. R ４ is hydrogen, or (ix) -NR Ｄ R Ｅ (In the formula, -NR Ｄ R Ｅ The R Ｄ is C １ -C ６ (xi) -(phenyl)C １ -C ６ alkyl (wherein the -(phenyl)C １ -C ６ The C of alkyl １ -C ６ Alkyl is a 5- to 10-membered heteroaryl, a 5- to 10-membered heterocycle, —[N(C １ -C ６ alkyl)R Ｄ R Ｅ ] ＋ C substituted with １ -C ６ The ADC of any one of claims 1 to 14 or 17 to 30, which is alkyl.

32. R ４ teeth, 【Chemistry 9】 and each occurrence of subscript z is independently 1, 2, or 3.

33. R ４ teeth, 【Chemistry 10】 The ADC of claims 1 to 14 or 17 to 32, selected from the group consisting of:

34. R ５ is -C(=O)OH or -C(=O)O(C １ -C ３ alkyl); each R ６ is halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, and —NR Ａ R Ｂ 34. The ADC of any one of claims 1 to 13, 15, or 17 to 33, independently selected from the group consisting of:

35. R ５ is -C(=O)OH or -C(=O)O(C １ -C ３ 35. The ADC of any one of claims 1-13, 15, or 17-34, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26

36. R ５ teeth, (i) a pKa of at most about 7.0; (i) a dipole moment of at least about 2.0 Debye; or (ii) (i) and (ii) 36. The ADC of any one of claims 1 to 13, 15, or 17 to 35, having the following structure:

37. Each R Ｘ is hydrogen, -C(=O)OR Ｆ , —C(═O)NR Ｇ R Ｈ , -S(O ２ ) NR Ｇ R Ｈ , -N(R Ｉ )-C(=O)R Ｊ , -N(R Ｉ )-S(O ２ ) R Ｋ , -S(O ３ ) R Ｋ , halogen, hydroxyl, nitro, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, C １ -C ６ Alkanoyl, C １ -C ６ Alkanoyloxy, C １ -C ６ Alkoxycarbonyl, C １ -C ６ Haloalkyl, C １ -C ６ Haloalkoxy, and —NR Ａ R Ｂ The ADC of any one of claims 1 to 12 or 17 to 33, independently selected from the group consisting of:

38. 38. The ADC of any one of claims 1-12, 17-33, or 37, wherein the subscript n is 1.

39. R Ａ and R Ｂ Each occurrence of is hydrogen and C １ -C ３ 39. The ADC of any one of claims 1 to 38, wherein the aryl group is independently selected from the group consisting of alkyl.

40. R Ｃ Each occurrence of is hydrogen and C １ -C ４ 40. The ADC of any one of claims 1 to 39, wherein the aryl, aryl, aryls ...

41. R Ｄ , R Ｅ , R Ｇ , and R Ｈ Each occurrence of is hydrogen, C １ -C ６ Alkyl, C ４ -C ６ Cycloalkyl, C ４ -C ６ Cycloalkyl (C １ -C ３ alkyl), aryl, and aryl(C １ -C ３ 41. The ADC of any one of claims 1 to 40, wherein the aryl group is independently selected from the group consisting of: alkyl.

42. R Ｆ Each occurrence of is selected from hydrogen, trifluoromethyl, and C １ -C ６ 42. The ADC of any one of claims 1 to 41, wherein the aryl group is independently selected from the group consisting of alkyl.

43. Each D is 【Chemistry 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 and 【Chemistry 12】 represents the point of covalent attachment to L.

44. Each D is 【Chemistry 13】 and 【Chemistry 14】 represents the point of covalent attachment to L.

45. 45. The ADC of claim 43 or 44, wherein the Ab comprises a heavy chain having at least 80% sequence identity to SEQ ID NO:3 and a light chain having at least 80% sequence identity to SEQ ID NO:

5.

46. 46. The ADC of any one of claims 1-45, wherein the linker comprises a length of 10 to 40 atoms when defined by the path between D and Ab through the fewest number of bonds.

47. 47. The ADC of any one of claims 1 to 46, wherein the linker comprises a length of 15 to 30 atoms when defined by the path between D and Ab through the fewest number of bonds.

48. 48. The ADC of any one of claims 1 to 47, wherein the linker comprises a PEG unit from PEG1 to PEG72, a monosaccharide, a disaccharide, a trisaccharide, an oligopeptide, or a combination thereof.

49. L is a group represented by the formula -M-(A) ａ - (W) ｗ -(Y) ｙ -(X) ｘ (In the formula, The subscript a is 0 or 1; The subscript y is 0 or 1; The subscript w is 0 or 1; The subscript x is 0 or 1; M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine, or triazole; A is 1 to 4 R ａ１ C optionally substituted with ２－２０ alkylene; or 1 to 4 R ｂ１ is a 2-40 membered heteroalkylene optionally substituted with Each R ａ１ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, halogen, —OH, ═O, —NR ｄ１ R ｅ１ , -(C １－６ alkylene)-NR ｄ１ R ｅ１ , —C(═O)NR ｄ１ R ｅ１ , -C(=O)(C １－６ alkyl), and —C(═O)O(C １－６ alkyl); Each R ｂ１ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, halogen, —OH, —NR ｄ１ R ｅ１ , -(C １－６ alkylene)-NR ｄ１ R ｅ１ , —C(═O)NR ｄ１ R ｅ１ , -C(=O)(C １－６ alkyl), and —C(═O)O(C １－６ alkyl); Each R ｄ１ and R ｅ１ are independently hydrogen or C １－３ is alkyl; W is 1 to 12 amino acids, or has the structure: 【Chemistry 15】 and Su is a sugar moiety; -O Ａ - represents the oxygen atom of the glycosidic bond; Each R ｇ are independently hydrogen, halogen, C １ -C ６ Alkoxy, —N(C １ -C ６ alkyl) ２ , -NHC(=O)(C １ -C ６ alkyl), -CN, -CF ３ , acyl, carboxamide, C １ -C ６ Alkyl, or -NO ２ and W １ is absent, *-C(=O)-O-, or *-O-C(=O)-; 【Chemistry 16】 represents a covalent bond to A or M; * represents a covalent bond to X, Y, or D; Y is a self-immolative moiety, a self-immolative releasable moiety, or a non-cleavable moiety; X is C １ -C ６ alkylene or 3- to 6-membered heteroalkylene; L is optionally substituted with a PEG unit from PEG1 to PEG72. The ADC of any one of claims 1 to 48, having the following structure:

50. 50. The ADC of claim 49, wherein the subscript x is 1.

51. X is C １ -C ６ 51. The ADC of claim 49 or 50, which is alkylene.

52. X is C １ -C ３ 52. The ADC of any one of claims 49 to 51, which is alkylene.

53. 51. The ADC of claim 49 or 50, wherein X is a 3- to 6-membered heteroalkylene.

54. 54. The ADC of any one of claims 49, 50, or 53, wherein X is a 3- to 4-membered heteroalkylene.

55. 50. The ADC of claim 49, wherein the subscript x is 0.

56. 56. The ADC of any one of claims 49 to 55, wherein the subscript y is 1.

57. 57. The ADC of any one of claims 49 to 56, wherein Y is a self-immolative moiety.

58. Y is, 【Chemistry 17】 The ADC of any one of claims 49 to 57,

59. 56. The ADC of any one of claims 49 to 55, wherein Y is a non-cleavable site.

60. 60. The ADC of any one of claims 49-55, or 59, wherein Y is a cyclohexanecarboxyl, undecanoyl, caproyl, hexanoyl, butanoyl, or propionyl group.

61. The ADC of any one of claims 49 to 56, wherein Y is PEG4 to PEG12.

62. 56. The ADC of any one of claims 49 to 55, wherein the subscript y is 0.

63. 63. The ADC of any one of claims 49 to 62, wherein the subscript w is 1.

64. 64. The ADC of any one of claims 49 to 63, wherein W is 6 to 12 amino acids.

65. 65. The ADC of any one of claims 49 to 64, wherein W is 6 to 9 amino acids.

66. 66. The ADC of any one of claims 49-65, wherein each amino acid in W is independently selected from the group consisting of alanine, glycine, lysine, serine, aspartic acid, aspartic acid methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine-alanine, valine-citrulline, phenylalanine-lysine, and homoserine methyl ether.

67. W has the structure: 【Chemistry 18】 where Su is a sugar moiety; -OA- represents the oxygen atom of the glycosidic bond; Each R ｇ are independently hydrogen, halogen, C １ -C ６ Alkoxy, —N(C １ -C ６ alkyl) ２ , -NHC(=O)(C １ -C ６ alkyl), -CN, -CF ３ , acyl, carboxamide, C １ -C ６ Alkyl, or -NO ２ and W １ is absent, *-C(=O)-O-, or *-O-C(=O)-; 【Chemistry 19】 represents a covalent bond to A or M; * represents a covalent bond to X, Y, or D) The ADC of any one of claims 49 to 63, having the following structure:

68. W １ is absent.

69. W １ The ADC of claim 67, wherein is *-C(=O)-O-.

70. W １ The ADC of claim 67, wherein is *-O-C(=O)-.

71. One R ｇ is a halogen, C １ -C ６ Alkoxy, —N(C １ -C ６ alkyl) ２ , -NHC(=O)(C １ -C ６ alkyl), -CN, -CF ３ , acyl, carboxamide, C １ -C ６ Alkyl, or -NO ２ and the remaining R ｇ The ADC of any one of claims 67 to 70, wherein is hydrogen.

72. Each R ｇ The ADC of any one of claims 67 to 71, wherein is hydrogen.

73. 63. The ADC of any one of claims 49 to 62, wherein the subscript w is 0.

74. 74. The ADC of any one of claims 49 to 73, wherein the subscript a is 1.

75. A is 1 to 4 R ａ１ C optionally substituted with ２ - ２０ 75. The ADC of any one of claims 49 to 74, which is alkylene.

76. A is 1 to 4 R ａ１ C optionally substituted with ４－１０ 76. The ADC of any one of claims 49 to 75, which is alkylene.

77. A is one R ａ１ C substituted with ２ - ２０ 76. The ADC of any one of claims 49 to 75, which is alkylene.

78. A is one R ａ１ C substituted with ４ The ADC of any one of claims 49 to 77, wherein the ADC is -10 alkylene.

79. A is C ２－２０ 75. The ADC of any one of claims 49 to 74, which is alkylene.

80. A is C ４－１０ 80. The ADC of any one of claims 49 to 74 or 79, which is alkylene.

81. A is 1 to 4 R ｂ１ 75. The ADC of any one of claims 49 to 74, wherein the heteroalkylene is 2-40 membered, optionally substituted with

82. A is 1 to 4 R ｂ１ 82. The ADC of any one of claims 49-74 or 81, wherein R is 4-12 membered heteroalkylene optionally substituted with

83. A is one R ｂ１ 82. The ADC of any one of claims 49-74 or 81, wherein R is 2-40 membered heteroalkylene optionally substituted with

84. A is one R ｂ１ 84. The ADC of any one of claims 49-74 or 81-83, wherein R is 4-12 membered heteroalkylene optionally substituted with

85. 75. The ADC of any one of claims 49-74, wherein A is 2-40 membered heteroalkylene.

86. 86. The ADC of any one of claims 49-74 or 85, wherein A is a 4- to 12-membered heteroalkylene.

87. A is, 【Chemistry 20】 (In the formula, 【Chemical 21】 represents a covalent bond to W, and * represents a covalent bond to M.

88. 74. The ADC of any one of claims 49 to 73, wherein the subscript a is 0.

89. 89. The ADC of any one of claims 49 to 88, wherein L is substituted with a PEG unit from PEG1 to PEG72.

90. 88. The ADC of any one of claims 49 to 87, wherein A is substituted with a PEG unit from PEG1 to PEG72.

91. 91. The ADC of any one of items 49-90, wherein M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine, or triazole.

92. 92. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the ADC of any one of claims 1 to 91, or a pharmaceutically acceptable salt thereof.

93. 93. The method of claim 92, wherein the ADC is configured to be internalized into a cell.

94. 94. The method of claim 92 or 93, wherein the ADC targets a cancer-associated antigen.

95. 95. The method of any one of claims 92 to 94, wherein the cells express the cancer-associated antigen.

96. 96. The method of any one of claims 92 to 95, wherein the cells do not express the cancer-associated antigen.

97. 97. The method of any one of claims 92 to 96, wherein the cell is an immune cell.

98. The immune cells are CD8 ＋ T cells, CD4 ＋ 98. The method of claim 97, wherein the cell is a T cell, a T regulatory cell, a macrophage, or a natural killer cell.

99. 99. The method of claim 97 or 98, wherein the immune cell is a macrophage.

100. 100. The method of any one of claims 97 to 99, wherein the immune cells express TLR7, TLR8, or TLR7 and TLR8.

101. The method of claims 97-100, wherein the cancer does not express TLR7 or TLR8.

102. 102. The method of any one of claims 97 to 101, wherein the immune cells express a surface protein that binds to the cancer-associated antigen.

103. The method of any one of claims 93 to 102, wherein the internalization comprises endocytosis or micropinocytosis.

104. The method of any one of claims 92 to 103, wherein the D of the ADC is configured to bind to Toll-like receptor 7, Toll-like receptor 8, or Toll-like receptor 7 and Toll-like receptor 8.

105. The method of any one of claims 92 to 104, wherein the linker (L) of the ADC is configured to undergo cleavage after internalization within the immune cell.

106. 106. The method of any one of claims 92-105, wherein the cancer does not express CD4, CD8, an immune checkpoint, or a combination thereof.

107. 107. The method of claim 106, wherein less than about 10%, less than about 7.5%, 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1%, or less than about 0.5% of cancer cells of the cancer express the CD4, the CD8, the immune checkpoint, or the combination thereof.

108. 108. The method of claim 106 or 107, wherein the CD4 expression, the CD8 expression, the immune checkpoint expression, or the combination thereof is membrane expression.

109. The method of any one of claims 106 to 108, wherein the immune checkpoint is PDL1, PD1, CTLA-4, B7H4, B7H3, TIGIT, TIM-3, VISTA, GITR / GITRL, CD80 / CD86, CD155, PDL1, PDL2, galectin-9, CD40, OX40L, 4-1BB / 4-1BBL, ICOS / ICOSL, CD70, or a combination thereof.

110. The method of any one of claims 106 to 109, wherein the immune checkpoint is PDL1.

111. The method of any one of claims 106 to 110, wherein the expression is in cancer cells derived from a tumor.

112. 112. The method of claim 111, wherein the cancer cells derived from the tumor do not include tumor-associated immune cells.

113. 113. The method of claim 111 or claim 112, wherein the cancer cells derived from the tumor include stromal cells from the tumor.

114. 114. The method of any one of claims 106 to 113, wherein determining comprises flow cytometry, immunohistochemistry, immunocytochemistry, immunofluorescence, immunoprecipitation, Western blotting, ELISA, or mRNA analysis.

115. 115. The method of claim 114, wherein said mRNA analysis comprises quantitative polymerase chain reaction (qPCR), reverse transcription qPCR (RT-qPCR), RNA sequencing, microarray analysis, in situ hybridization, or sequential gene expression analysis.

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