Immunostimulatory Anti-pd-l1-drug conjugates

Abstract

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

Description

IMMUNOSTIMULATORY ANTI-PD-L1 -DRUG CONJUGATESCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. Provisional Application No. 63 / 394,912, filed August 3, 2022, which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in extensible Markup Language (XML) format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 24, 2023, is named “438442- 704021_SL.XML” and is 944 kilobytes in size.INCORPORATION BY REFERENCE

[0003] 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

[0004] In addition to leveraging numerous disparate mechanisms for proliferation and expansion, tumors often affect local and systemic immunosuppression. While the majority of cells which express immunogenic antigens are rapidly cleared before neoplasia or tumorigenicity, tumor-mediated immunosuppression often blocks immune activity against cancer cells, and can allow tumors to spread unchecked. As many cytotoxic cancer therapies rely on immune activity for cancer cell clearance, immunosuppressive tumors can be resilient against conventional cancer therapies which do not also achieve immune reactivation, and therefore do not affect immune clearance. Accordingly, cancer therapies often require immune activating functions which can override tumor immunosuppression.

[0005] In spite of this need, most immunomodulatory therapies exhibit limited efficacies. While immunosuppressive tumor environments are often localized, many immunostimulatory therapies generate toxic systemic responses which can limit dosing below levels required for localized treatment efficacy. In particular, antibody-based treatments often affect antibody dependent cellular cytotoxicities (ADCCs), while untargeted immunostimulatory complexes can generate dangerous toxic inflammatory and cytokine responses. Furthermore, many immunostimulatory compounds target intracellular receptors present in both cancer and immune cells, such that treatments must balance requirements for tumor cell targeting and immune cell uptake.

[0006] Central among such immunostimulatory compouds, toll-like receptors (TLRs) play an important role in activitating the immune system against invading pathogens and against damaged cells with the potential to become tumorigenic (see Kaczanowska, et al., J. Leukoc. Biol. 2013; 93(6): 847-863). TLRs are a family of membrane bound proteins that, when activated, recuit adaptor proteins to propagate antigen-induced signals to modify cellular phenotype and activity. As immunostimulatory compounds, TLR agonists have been developed as vaccine adjuvants, to boost production of immune cells that target the desired viral or bacterial antigen in the vaccine. TLRs also recognize endogenous markers of tumorigenesis such as cell death and chronic inflammation and activate an innate immune response to 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, systemic use of TLR agonists may be restricted by dose-limiting toxicities resulting from 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 the desired cells while minimizing off-target effects.SUMMARY

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

[0008] The ADCs described herein, as well as pharmaceutically acceptable salts thereof, can be configured for uptake by a target cell or tissue. In some embodiments, an ADC is configured to endocytose upon binding to a membrane bound and / or surface displayed antigen. In such cases, the ADC may target intracellular receptors such as TLR7 or TLR8, which are often primarily localized within endosomes. Endocytosis can be aided by lipophilic groups appended to the ADC, such as PEGylated or neutral and nonpolar peptidic linkers.

[0009] In addition to targeting, release of an ADC drug unit can be controlled such that the release occurs at a designated site (e.g., within a cell targeted by the antibody). As a linker (L) cleavable group can be configured for cleavage within particular physiological conditions or by specific enzymes, release of the Drug Unit can be limited primarily to the target site. Accordingly, the biological effects of the Drug Unit (such as immunostimulatory effects) can be localized to a target site. Alternatively, the Drug Unit can be configured to remain attached to the antibody, or a portion of the antibody and / or linker and induce its biological effect while coupled to the antibody.

[0010] Aspects of the present disclosure provide an antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (A):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 memberedheteroaryl is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N( C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L; each Rxis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, -C(=O)ORE, -C(=O)NRGRH, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, 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 -NRARB; wherein no more than one Rxis the point of covalent attachment to L; subscript n is 0, 1, 2, 3, or 4; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl( C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and(c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein 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: 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 isSEQ 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: 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 and the second sequence is SEQ ID NO: 412; 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: 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: 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 secondsequence 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 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; 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: 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 and the second sequence is SEQ ID NO: 838; 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: 893 and the second sequence is SEQ ID NO: 894; the first sequence is SEQ ID NO: 900 and thesecond 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; the first 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 thesecond 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 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 an antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (A):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L; each Rxis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, -C(=O)ORE, -C(=O)NRGRH, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NRARB; wherein no more than one Rxis the point of covalent attachment to L; subscript n is 0, 1, 2, 3, or 4; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C1o alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein 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: 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 SEQID 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 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: 299 and the second sequence is SEQ ID NO: 300; the first sequence is SEQ ID NO: 493 and the second 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 secondsequence 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: 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 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 secondsequence 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 an antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (A):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L; each Rxis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, -C(=O)ORE, -C(=O)NRGRH, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, 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 -NRARB; wherein no more than one Rxis the point of covalent attachment to L; subscript n is 0, 1, 2, 3, or 4; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen;each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein Ab 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: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NO: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively;SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NO: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NO: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NO: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NO: 325, 326, 327, 328, 329, and 330, respectively; SEQ ID NO: 333, 334, 335, 336, 337, and 338, respectively; SEQ ID NO: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NO: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NO: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NO: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NO: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NO: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NO: 389, 390, 391, 392, 393, and 394, respectively; SEQ ID NO: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NO: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NO: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NO: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NO: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NO: 437, 438, 439, 440, 441, and 442, respectively; SEQ ID NO: 445, 446, 447, 448, 449, and 450, respectively; SEQ ID NO: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NO: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NO: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NO: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NO: 495, 496, 497, 498, 499, and 500, respectively; SEQ ID NO: 503, 504, 505, 506, 507, and 508, respectively; SEQ ID NO: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NO: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NO: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NO: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NO: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NO: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NO: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NO: 567, 568, 569, 570, 571, and 572, respectively; SEQ ID NO: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NO: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NO: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NO: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NO: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NO: 615, 616, 617, 618, 619, and 620, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688,689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NO: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NO: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NO: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NO: 749, 750, 751, 752, 753, and 754, respectively; SEQ ID NO: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NO: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NO: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NO: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NO: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NO: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NO: 807, 808, 809, 810, 811, and 812, respectively; SEQ ID NO: 815, 816, 817, 818, 819, and 820, respectively; SEQ ID NO: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NO: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NO: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NO: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NO: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NO: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NO: 871, 872, 873, 874, 875, and 876, respectively; SEQ ID NO: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NO: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NO: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NO: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NO: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NO: 919, 920, 921, 922, 923, and 924, respectively; SEQ ID NO: 927, 928, 929, 930, 931, and 932, respectively; SEQ ID NO: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NO: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NO: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NO: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NO: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NO: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NO: 985, 986, 987, 988, 989, and 990, respectively; SEQ ID NO: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NO: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NO: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NO: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NO: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. In some cases, the first, second, third, fourth, fifth, and sixth sequences are: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156,157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some cases, the CDR-H1 comprises at most one mutation relative to the first sequence, the CDR-H2 comprises at most one mutation relative to the second sequence, the CDR- H3 comprises at most one mutation relative to the third sequence, the CDR-L1 comprises at most one mutation relative to the fourth sequence, the CDR-L2 comprises at most one mutation relative to the fifth sequence, and the CDR-L3 comprises at most one mutation relative to the sixth sequence. In some cases, the first, second, third, fourth, fifth, and sixth sequences are: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively.

[0013] In some cases, Ab comprises an effector function-diminishing mutation. In some cases, the effector function diminishing 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 diminishing mutation is L234A / L235A.

[0014] In some cases, each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of -C(=O)ORF, -NO2, -CN, -CF3-C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 - NRARB; and m is 0, 1, 2, or 3.

[0015] In some cases, each D has the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein is the point of covalent attachment to L; R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of - C(=O)ORF, -NO2, -CN, -CF3-C(=O)NR°RH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NRARB; and m is 0, 1, 2, or 3.

[0016] In some cases, each D has the structure of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 - NRARB, and m is 0, 1, 2, or 3.

[0017] In some cases, each D has the structure of Formula (III):or a pharmaceutically acceptable salt thereof, wherein R4Ais (a) the point of covalent attachment to L or (b) C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) - ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE; (ix) -[N(C1-C6 alkyl)RDRE]+; (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; (xi) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NRDREor -CO2H; (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein its C1- C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or 5 - 10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, or -CO2H; wherein when R4Ais (b) the C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L; R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of - C(=O)ORE, -NO2, -CN, -CF3-C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3.

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

[0019] In some cases, R1or R4is the point of covalent attachment to L. In some cases, R1selected 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; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5- C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide. In some cases, R1selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. In some cases, R1is hydrogen or C1-C3 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2. In some cases, R1is hydrogen or C1-C3 alkyl. In some cases, R1is hydrogen.

[0020] In some cases, R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases, R2is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the of C1-C3 alkyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases, R2is hydrogen or C1-C3 alkyl. In some cases, R2is hydrogen.

[0021] In some cases, R3is selected from the group consisting of -NRARB, -C(=O)NRARB, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases, R3is C1-C5 alkyl optionally substituted with 1 substituent selected from the group consisting of hydroxyl, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio, and -NRARB. In some cases, R3is selected from the group consisting of butyl, -CH2-O-CH2CH3, -CH2-CH2-O-CH3, and -CH2-NH-CH2CH3.

[0022] In some cases, R4is hydrogen; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H. In some cases, R4is hydrogen or C1- C6 alkyl substituted with: (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+. In some cases, R4is selected from the group consisting ofindependently 1, 2, or 3. In some cases, R4is selected from the group consisting of

[0023] In some cases, R5is selected from the group consisting of hydrogen, -C(=O)ORE, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO2RK; and each R6is independentlyselected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases, R5is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases, R5is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and subscript m is zero. In some cases, R5has: (i) a pka of at most about 7.0; (ii) a dipole moment of at least about 2.0 Debye; or (i) and (ii).

[0024] In some cases, each Rxis independently selected from the group consisting of hydrogen, -C(=O)ORF, -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, - S(O3)RK, 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 -NRARB. In some cases, subscript n is 1.

[0025] In some cases, each instance of RAand RBis independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases, each instance of Rcis independently selected from the group consisting of hydrogen and C1-C4 alkyl. In some cases, each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C4-C6 cycloalkyl(C1-C3 alkyl)-, aryl, and aryl(C1-C3 alkyl). In some cases, each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl.wherein represents the point of covalent attachment to L. In some cases, each D isof covalent attachment to L. In some cases, Ab comprises a heavy chain with at least 80% sequence identity to SEQ ID NO: 3 or SEQ ID NO: 4 and a light chain with at least 80% sequence identity to SEQ ID NO: 5.

[0027] In some cases, the linker comprises a length of between 10 and 40 atoms as defined by the pathway between D and Ab through the fewest number of bonds. In some cases, the linker comprises a length of between 15 and 30 atoms as defined by the pathway between D and Ab through the fewest number of bonds. In some cases, the linker comprises a PEG Unit from PEG1 to PEG72, a monosaccharide, a disaccharide, a trisaccharide, an oligopeptide, or a combination thereof.In some cases, L has the formula -M-(A)a-(W)w-(Y)y-(X)x-, wherein: 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 a succinimide, a hydrolyzed succinimide, an amide, a methyl ketone, a disulfide, a dihydropyridazine, or a triazole; A is a C2- 20 alkylene optionally substituted with 1-4 Ral; or a 2 to 40 membered heteroalkylene optionally substituted with 1-4 Rbl; each Ralis independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, -OH, =0, -NRdlRel, -(C1-6 alkylene)- NRdlRel, -C(=O)NRdlRel, -C(=O)(C1-6 alkyl), and -C(=O)O((C1-6 alkyl); each Rblis independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy,halogen, -OH, -NRdlRel, -(C1-6 alkylene)-NRdlRel, -C(=O)NRdlRel, -C(=O)((C1-6 alkyl), and - C(=O)O((C1-6 alkyl); each Rdland Relare independently hydrogen or C1-3 alkyl; W is from 1-12 amino acids or has the structure:wherein Su is a Sugar moiety;_-OA- represents the oxygen atom of a glycosidic bond; each Rgis 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; W1is absent, *-C(=O)-O-, or *-O-C(=O)-; rfvw represents covalent attachment to A or M; * represents covalent attachment to X, Y, or D; Y is self-immolative moiety, a non-self-immolative releasable moiety, or a non-cleavable moiety; X is a C1-C6 alkylene or a 3-6 membered heteroalkylene; and L is optionally substituted with a PEG Unit from PEG1 to PEG72.

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

[0029] In some cases, subscript y is 1. In some cases, Y is a self-immolative moiety. In someH cases, Y is. 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 PEG 12. In some cases, y is 0.In some cases, subscript w is 1. In some cases, W is from 6-12 amino acids. In some cases, W is from 6-9 amino acids. In some cases, each amino acid in W is independently selected from the group consisting of alanine, glycine, lysine, serine, aspartic acid, aspartate methyl ester, N,N- dimethyl-lysine, phenylalanine, citrulline, valine-alanine, valine-citrulline, phenylalanine-lysine, and homoserine methyl ether. In some cases, W has the structure:wherein Su is a Sugar moiety; -OA- represents the oxygen atom of a glycosidic bond; each Rgis 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; W1is absent, *-C(=O)-O-, or *-O-C(=O)-; v'ww’representscovalent attachment to A or M; and * represents covalent attachment to X, Y, or D. In some cases, W1is absent. In some cases, W1is *-C(=O)-O-. In some cases, W1is *- O-C(=O)-. In some cases, one Rgis 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 Rgare hydrogen.In some cases, each Rgis hydrogen. In some cases, w is 0.

[0030] In some cases, subscript a is 1. In some cases, A is C2-20 alkylene optionally substituted with 1-4 Ral. In some cases, A is C4-10 alkylene optionally substituted with 1-4 Ral. In some cases, A is C2-20 alkylene substituted with one Ral. In some cases, A is C4-10 alkylene substituted with one Ral. In some cases, A is C2-20 alkylene. In some cases, A is C4-10 alkylene. In some cases, A is a 2 to 40 membered heteroalkylene optionally substituted with 1-4 Rbl. In some cases, A is a 4 to 12 membered heteroalkylene optionally substituted with 1-4 Rbl. In some cases, A is a 2 to 40 membered heteroalkylene optionally substituted with one Rbl. In some cases, A is a 4 to 12 membered heteroalkylene optionally substituted with one Rbl. In some cases, A is a 2 to 40 membered hetero alkylene. In some cases, A is a 4 to 12 membered heteroalkylene. In some cases,represents covalent attachment to W, and * represents covalent linkage to M. In some cases, 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 a succinimide, a hydrolyzed succinimide, an amide, a methyl ketone, a disulfide, a dihydropyridazine, or a triazole.

[0032] Various aspects of the present disclosure provide a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an ADC of the present disclosure, or a pharmaceutically acceptable saltthereof. In some cases, Ab of the ADC targets a cancer-associated antigen. In some cases, the ADC is configured to internalize within a cell. In some cases, the cell expresses the cancer- associated antigen. In some cases, the cell does not express the cancer-associated antigen. In some cases, the cell is an immune cell. In some cases, the immune cell is a CD8+T-cell, a CD4+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 which binds to the cancer-associated antigen. In some cases, the internalizing comprises endocytosis or microp inocytosis. 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 subsequent to internalizing within the immune cell.BRIEF DESCRIPTION OF THE FIGURES

[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:

[0034] FIGURE 1 illustrates the responses of human PBMCs from a single donor to selected small molecule TLR7 / 8 agonists.

[0035] FIGURE 2 illustrates the average response of human PBMCs isolated from 3 donors to selected small molecule TLR7 / 8 agonists.

[0036] FIGURE 3 illustrates the responses of human PBMCs to selected TLR7 / 8 agonists having either a carboxylic acid (S5b, S8b, SI lb) or methyl ester functional group (S5a, S8a, Sila).

[0037] FIGURE 4 illustrates the responses of human immune cells to various small molecule TLR7 / 8 agonists.

[0038] FIGURE 5 illustrates the responses of human immune cells to selected TLR7 / 8 agonists having either a carboxylic acid (S18b) or methyl ester functional group (S18a).

[0039] FIGURE 6 illustrates the responses of human immune cells to various TLR7 / 8 agonists conjugated to a targeting antibody.

[0040] FIGURE 7 illustrates the responses of human immune cells to selected TLR7 / 8 agonists having either a carboxylic acid (S18b) or methyl ester functional group (S18a) conjugated to a targeting antibody.

[0041] FIGURE 8 illustrates the responses of human immune cells to selected TLR7 / 8 agonists having either a carboxylic acid (S14b, S18b, S76b) or methyl ester functional group (S14a, S18a, S76a) conjugated to a targeting antibody.

[0042] FIGURE 9 illustrates the comparison of level of aggregation of various conjugated immunostimulatory ADCs.

[0043] FIGURE 10 illustrates the anti-tumor responses of mice bearing CT26 tumors to treatment with S8a or S8b immune cell targeted antibody drug conjugates.

[0044] FIGURE 11 illustrates the anti-tumor responses of mice bearing CT26 tumors to treatment with S14a or S14b immune cell targeted antibody drug conjugates.

[0045] FIGURE 12 illustrates the anti-tumor responses of mice bearing MC38 tumors to treatment with S8a, S8b, S18a or S18b antibody drug conjugates.

[0046] FIGURE 13 illustrates the anti-tumor responses of mice bearing CT26 tumors to treatment with S18b antibody drug conjugates with either a targeting or a non-targeting antibody.

[0047] FIGURE 14 illustrates the anti-tumor responses of mice bearing Renca tumors to treatment with S18a free drug, and S18a and S18b antibody drug conjugates.

[0048] FIGURE 15 illustrates cytokine responses of non-tumor bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkage.

[0049] FIGURE 16 illustrates the cytokine response of non-tumor bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkage.

[0050] FIGURE 17 illustrates the cytokine response of CT26-tumor bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkage and with targeting or non-targeting antibody.

[0051] FIGURE 18 illustrates the anti-tumor response of CT26-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkage and with targeting or non- targeting antibody.

[0052] FIGURE 19 illustrates the cytokine response of Renca-tumor bearing mice to treatment with S18b drug conjugates linked via N1 or C4 linkage at 2 mg / kg dose.

[0053] FIGURE 20 illustrates the anti-tumor response of Renca-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkage at 2 mg / kg dose.

[0054] FIGURE 21 illustrates the activation of in vitro human immune cells in response to TLR7 / 8 antibody conjugates linked via N1 or C4 positions.

[0055] FIGURE 22 illustrates the anti-tumor response of Renca-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkage at different dose levels.

[0056] FIGURE 23 illustrates the cytokine response of Renca-tumor bearing mice to treatment with S18b antibody drug conjugates via N1 or C4 linkage at different dose levels.

[0057] FIGURE 24 illustrates the in vitro assessment of TLR7 vs. TLR8 selectivity for various TLR7 / 8 small molecule agonists in HEK Blue hTLR7 and TLR8 cells.

[0058] FIGURE 25 illustrate the in vivo assessment of TLR7 vs. TLR8 selectivity for various TLR7 / 8 small molecule agonists in C57BL / 6 mice bearing subcutaneous MC38 tumors.

[0059] FIGURE 26 illustrate 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.

[0060] FIGURE 27 illustrates the anti-tumor response of Renca-bearing mice to treatment with S18a antibody drug conjugates linked at the N1 or C4 positions, with different linker configurations, linkage sites and with or without a PEG group in the linker.

[0061] FIGURE 28 provides tumor sizes in mice treated with targeted antibody-TLR7 / 8 agonist complexes.

[0062] FIGURE 29 provides IL6 (top left), ILlb (top right), MIPlb (bottom left), and TNFa (bottom right) responses in human peripheral blood mononuclear cells (PBMCs) elicited with multiple imidazoquinoline complexes.

[0063] FIGURE 30 summarizes cytokine responses in human immune cells following imidazoquinoline treatment. The top left panel summarizes IL6 levels following treatment, the top right panel summarizes TNFa levels following treatment, the bottom left panel summarizes MCP1 levels following treatment, and the bottom right panel summarizes IP 10 levels following treatment.

[0064] FIGURE 31 summarizes tumor size profiles over time post tumor implantation, in TLR7 positive and TLR7 knockout mice. The top left panel summarizes tumor growth in TLR7 positive mice, the bottom left panel summarizes tumor growth in TLR7 knockout mice, and the right panel summarizes tumor volumes on Day 36 post implantation for all mice.

[0065] FIGURE 32 provides tumor sizes in mice bearing Renca tumors following treatment with TLR7 / 8 agonists.

[0066] FIGURE 33 provides Renca tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist-coupled to a tumor targeted antibody or isotype control.

[0067] FIGURE 34 summarizes Renca tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist C4-coupled to a tumor targeted antibody, or isotype control.

[0068] FIGURE 35 summarizes CT26 tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist N1 -coupled to a tumor targeted antibody, or isotype conrol.

[0069] FIGURE 36 provides CT26 tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist C4-coupled to a tumor targeted antibody, or isotype control.

[0070] FIGURE 37 summarizes 4T1 tumor volumes in untreated mice, mice treated with a bare EphA2-targeted antibody, and mice treated with a TLR7 / 8 agonist EphA2 -targeted antibody conjugate.

[0071] FIGURE 38 provides CT26 tumor volumes for untreated mice, mice treated with a tumor and immune targeting antibody alone, mice treated with a non-targeted isotype antibody conjugated to a TLR7 / 8 agonist, and mice treated with a TLR7 / 8 agonist conjugated to the tumor and immune targeting antibody.

[0072] FIGURES 39A-F provide cell survival rates for Hodgkin’s lymphoma (FIGURE 39A), breast carcinoma (FIGURE 39B), pancreatic carcinoma (FIGURE 39C), lung carcinoma (FIGURE 39D), anaplastic large-cell lymphoma (FIGURE 39E), and CD30-positive anaplastic large T-cell lymphoma (FIGURE 39F) following treatment with an ADC consistent with the present disclosure.

[0073] FIGURES 40A-D summarize interleukin-6 (IL-6) induction in pancreatic carcinoma (FIGURE 40A), human lung squamous cell carcinoma (FIGURE 40B), and anaplastic large-cell lymphoma (FIGURES 40C-D) tumor cells following incubation with an ADC consistent with the present disclosure.

[0074] FIGURES 41A-C summarize IL-6 production by M0 (FIGURE 41 A), Ml (FIGURE 41B), and M2 (FIGURE 41C) macrophage populations treated multiple ADCs, antibodies, and compounds consistent with the present disclosure.

[0075] FIGURES 42A-F summarizes immune activation responses in tumor and immune cell co-cultures following treatment with various ADCs and antibodies consistent with the present disclosure. FIGURE 42A provides CD69 levels in Karpas299 co-cultures following ADC and antibody treatment. FIGURE 42B provides CD69 levels in EBC-1 co-cultures following ADC and antibody treatment. FIGURE 42C provides IFN-y levels in Karpas299 co-cultures following ADC and antibody treatment. FIGURE 42D provides IFN-y levels in EBC-1 co-cultures following ADC and antibody treatment. FIGURE 42C provides CD86 levels in Karpas299 co- cultures following ADC and antibody treatment. FIGURE 42D provides CD86 levels in EBC-1 co-cultures cells following ADC and antibody treatment.

[0076] FIGURE 43 summarizes frequencies of CD45+ PDL1+ immune cells and CD45- PDL1+ tumor cells from human non-small cell lung cancer tumors from multiple subjects.

[0077] FIGURES 44A-B summarize IL-6 and TNFa induction in the human non-small cell lung cancer tumors following ADC and antibody treatments consistent with the present disclosure.

[0078] FIGURE 45 summarizes changes in tumor volume over 4 weeks of treatment with ADCs and antibodies consistent with the present disclosure.

[0079] FIGURES 46A-C provide tumor volume time courses following 2 mg / kg (FIGURE 46A), 1 mg / kg (FIGURE 46B), and 0.5 mg / kg (FIGURE 46C) doses of an ADC consistent with the present disclosure.

[0080] FIGURES 47A-D provide tumor growth responses of PDL1 positive tumors in untreated (FIGURE 47A), antibody-treated (FIGURE 47B), non-targeted ADC treated (FIGURE 47C), and targeted ADC treated (FIGURE 47D) mice.

[0081] FIGURE 48 summarizes tumor growth inhibition for ADC and antibody-treated mice.

[0082] FIGURES 49A-D provide CD4+T-cell (FIGURE 49A), regulatory T-cell (FIGURE 49B), CD8+T-cell (FIGURE 49C), and macrophage (FIGURE 49D) populations in MC38 and Renca mouse tumors.

[0083] FIGURES 50A-B provide tumor growth responses of MC38 (FIGURE 50A) and Renca tumors (FIGURE 50B) implanted in mouse models treated with ADCs consistent with the present disclosure.

[0084] FIGURE 51 is a set of plots of tumor growth responses and area under curve (AUC) values for two different tumor models treated with ADCs consistent with the present disclosure.

[0085] FIGURE 52 is a series plots of cytokine responses in two tumor models following treatment with ADCs consistent with the present disclosure.

[0086] FIGURE 53 is a group of plots of PDL1, CD4, CD8, F4 / 80 expression in two tumor models.DETAILED DESCRIPTION

[0087] Many cancers are immunosuppressive, actively inhibiting immune cell proliferation, signaling, and activity to avoid detection and clearance. While certain TLR agonists can reactivate cancer-suppressed immune cells, TLR agonist treatments are often restricted by dose-limiting toxicities. Sustained TLR activation, even from mild agonist doses, can affect immune-related adverse events, including rheumatic and thyroid disorders, nausea, rashes, and general discomfort.

[0088] Circumventing toxicity-based dosing limitations commonly associated with TLR agonists, certain ADCs of the present disclosure elicit minimal cytokine responses from outside of target tumor sites. A surprising discovery disclosed herein is that broad TLR7 / 8 activation within tumor microenvironments can primarily activate immune cells without generating undesired responses from cancer and bystander cells. Leveraging this discovery, tumor-targetedADCs of the present disclosure can utilize appreciable concentrations of high potency TLR agonists to affect localized immune stimulation while avoiding dose-limiting systemic toxicities.Definitions

[0089] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art in some aspects of this disclosure are also used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control. When trade names are used herein, the trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.

[0090] The terms “a,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a linker” includes reference to one or more such linkers, and reference to “the cell” includes reference to a plurality of such cells.

[0091] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range. In reference to an ADC composition comprising a distribution of ADCs as described herein, the average number of conjugated TLR agonist compounds to an antibody in the composition can be an integer or a non-integer, particularly when the antibody is to be partially loaded. Thus, the term “about” recited prior to an average drug loading value is intended to capture the expected variations in drug loading within an ADC composition.

[0092] The term “antibody” as used herein covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), including intact antibodies and antigen binding antibody fragments, and reduced forms thereof in which one or more of the interchain disulfide bonds are disrupted, that exhibit the desired biological activity and provided that the antigen binding antibody fragments have the requisite number of attachment sites for the desired number of attached groups, such as a linker (L), as described herein. In some aspects, the linkers are attached via a succinimide or hydrolyzedsuccinimide to the sulfur atoms of cysteine residues of reduced interchain disulfide bonds and / or cysteine residues introduced by genetic engineering. The native form of an antibody is a tetramer and consists 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) are together primarily responsible for binding to an antigen. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs.” The light chain and heavy chains also contain constant regions that may be recognized by and interact with the immune system, (see, e.g., Janeway et al., 2001, Immuno. Biology, 5th Ed., Garland Publishing, New York). An antibody includes any isotype (e.g., IgG, IgE, IgM, IgD, and IgA) or subclass (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) thereof. The antibody is derivable from any suitable species. In some aspects, the antibody is of human or murine origin, and in some aspects the antibody is a human, humanized or chimeric antibody. Antibodies can be fucosylated to varying extents or afucosylated.

[0093] An “intact antibody” is one which comprises an antigen-binding variable region as well as light chain constant domains (CL) and heavy chain constant domains, CHI, CH2, CH3 and CH4, as appropriate for the antibody class. The constant domains are either native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof.

[0094] An “antibody fragment” comprises a portion of an intact antibody, comprising the antigen-binding or variable region thereof. Antibody fragments of the present disclosure include 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, an antibody fragment includes Fab, Fab', or F(ab')2.

[0095] As used herein the term “engineered cysteine residue” or “eCys residue” refers to a cysteine amino acid or a derivative thereof that is incorporated into a protein (e.g., an antibody) and which would otherwise not be present at its position within the protein. In those aspects one or more eCys residues can be incorporated into an antibody, and typically, the eCys residues are incorporated into either the heavy chain or the light chain of an antibody. Generally, incorporation of an eCys residue into an antibody is performed by mutagenizing a nucleic acid sequence of a parent antibody to encode for one or more amino acid residues with a cysteine or a derivative thereof. Suitable mutations include replacement of a desired residue in the light or heavy chain of an antibody with a cysteine or a derivative thereof, incorporation of an additional cysteine or a derivative thereof at a desired location in the light or heavy chain of an antibody, as well as addingan additional cysteine or a derivative thereof to the N- and / or C-terminus of a desired heavy or light chain of an amino acid. Further information can be found in U.S. Pat. No. 9,000,130, the contents of which are incorporated herein in its entirety. Derivatives of cysteine (Cys) include but are not limited to beta-2-Cys, beta-3-Cys, homocysteine, and N-methyl cysteine.

[0096] In some embodiments, the antibodies of the present disclosure include those having one or more engineered cysteine (eCys) residues. In some embodiments, derivatives of cysteine (Cys) include, but are not limited to beta-2-Cys, beta-3-Cys, homocysteine, and N-methyl cysteine.

[0097] In some embodiments, the antibodies of the present disclosure include those having one or more engineered lysine (eLys)residues. In some embodients, one or more native lysine and / or eLys residues are activated prior to conjugation with a drug-linker intermediate (to form an ADC, as described herein). In some embodiments, the activation comprises contacting the antibody with a compound comprising a succinimydyl ester and a functional group selected from the group consisting of: maleimido, pyridyldisulfidem and iodoacetamido.

[0098] As used herein, an “antigen” can be an entity to which an antibody specifically binds.

[0099] The terms “specific binding” and “specifically binds” can refer to selective binding to a specific target. In reference to an antibody, these terms can denote binding to a specific antigen or epitope over a multitude of other antigens or epitopes. Typically, an antibody or antibody fragment binds with an affinity of at least about IxlO'7M, for example, 10'8M to 10'9M, 10'10M, 10'11M, or 10'12M and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen.

[0100] The term “amino acid” as used herein can refer to natural and non-natural, and 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, [l-alaninc, citrulline, serine methyl ether, aspartate methyl ester, glutamate methyl ester, homoserine methyl ether, and N, A-dimethyl lysine.

[0101] “Percent (%) sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various waysthat are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where 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.

[0102] A “sugar moiety” as used herein, refers to a monosaccharide group, for example, a pyranose or a furanose. A sugar moiety can comprise a hemiacetal or a carboxylic acid (from oxidation of the pendant -CH2OH group). In some embodiments, the sugar moiety is in the [J-D conformation. In some embodiments, the sugar moiety is a glucose, glucuronic acid, or mannose group.

[0103] The term “inhibit” or “inhibition of’ means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0104] As used herein, TLR7 / 8 can denote toll-like receptor 7 and toll-like receptor 8, just toll-like receptor, or just 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.

[0105] A “TLR7 / 8 agonist” as defined herein includes any compound exhibiting selective TLR7 / 8 activity. Exemplary TLR7 / 8 agonists can exhibit activity (EC50) against TLR7 / 8 of less than about 10 pM, less than about 5 pM, less than about 2 pM, less than about 1 pM, less than about 500 nM, less than about 250 nM, less than about 100 nM, or less than about 10 nM as measured in an assay as described herein. In some embodiments, a TLR7 / 8 agonist can exhibit selectivity for TLR7 over TLR8 of about 3.5-fold to about 25-fold, for example, 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, a TLR7 / 8 agonist can exhibit selectivity for TLR8 over TLR7 of about 3.5-fold to about 25-fold, for example, 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 about15-fold, about 12-fold to about 18-fold, about 15-fold to about 20-fold, or about 18-fold to about 25-fold.

[0106] The term “therapeutically effective amount” refers to an amount of an ADC, or a pharmaceutically acceptable salt thereof (as described herein) or a compound (as described herein, e.g. a compound of Formula (IX), or a pharmaceutically acceptable salt thereof), that is effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the ADC or the compound provides one or more of the following biological effects: reduction of the number of cancer cells; reduction of tumor size; inhibition of cancer cell infiltration into peripheral organs; inhibition of tumor metastasis; inhibition, to some extent, of tumor growth; and / or relief, to some extent, of one or more of the symptoms associated with the cancer. For cancer therapy, efficacy, in some aspects, is measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0107] Unless otherwise indicated or implied by context, the term “substantial” or “substantially” refers to a majority, i.e., >50% of a population, of a mixture, or a sample, typically more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99%.

[0108] The terms “intracellularly cleaved” and “intracellular cleavage” refer to a metabolic process or reaction occurring inside a cell, in which the cellular machinery acts on the ADC or a fragment thereof, to intracellularly release free drug from the ADC, or other degradant products thereof. The moieties resulting from that metabolic process or reaction are thus intracellular metabolites.

[0109] 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” comprises multiple cancerous cells.

[0110] “Subject” as used herein can refer to an individual to which an ADC or TLR7 / 8 agonist, as described herein, is administered. “Subject” as used herein can also refer to an individual from which a sample (e.g., a tumor resection) is collected. Examples of a “subject” include, but are not limited to, a mammal such as a human, rat, mouse, guinea pig, non-human primate, pig, goat, cow, horse, dog, cat, bird and fowl. Typically, a subject is a rat, mouse, dog, non-human primate, or human. In some aspects, the subject is a human.

[0111] The terms “treat” or “treatment,” unless otherwise indicated or implied by context, refer to therapeutic treatment and prophylactic measures to prevent relapse, wherein the object is to inhibit an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of the present disclosure, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” in some aspects also means prolonging survival as compared to expected survival if not receiving treatment.

[0112] In the context of cancer, the term “treating” includes any or all of: inhibiting growth of cancer cells or of a tumor; inhibiting replication of cancer cells, lessening of overall tumor burden or decreasing the number of cancer cells, and ameliorating one or more symptoms associated with the disease.

[0113] The term “salt,” as used herein, refers to organic or inorganic salts of a compound, such as a TLR7 / 8 agonist (e.g., a compound of Formula (IX)), Drug Unit (D) (e.g., a compound of any of Formulae (A), (I)-(VIII), (Ila), or (Illa)), a linker, a drug-linker intermediate (e.g., a compound of Formula (X)), or an ADC, such as those described herein. In some aspects, the compound contains at least one amino group, and accordingly 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, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-tolucncsul fonatc, and pamoate (i.e., l,l ’-methylene-bis-(2 -hydroxy-3 -naphthoate)) salts. A salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a salt has one or more than one charged atom in its structure. In instances where there are multiple charged atoms as part of the salt, multiple counter ions can be present. Hence, a salt can have one or more charged atoms and / or one or more counterions. A “pharmaceutically acceptable salt” is one that is suitable for administration to a subject as described herein and in some aspects includes salts as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002, the list for which is specifically incorporated by reference in its entirety. In some embodiments, the ADCs described herein are present in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein are present in the form of a pharmaceutically acceptable salt.

[0114] The term “tautomer,” as used herein refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium, and it is to beunderstood that compounds provided herein may be depicted as different tautomers, and when compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the disclosure, and the naming of the compounds does not exclude any tautomer.

[0115] The term “optionally substituted,” refers to an indicated group being either substituted or unsubstituted.

[0116] The term “alkyl” refers to an unsubstituted straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms (e.g., “C1-C4 alkyl,” “C1-C6 alkyl,” “C1-C8 alkyl,” or “C1-C10” alkyl have from 1 to 4, 1 to 6, 1 to 8, or 1 to 10 carbon atoms, respectively) and is derived by the removal of one hydrogen atom from the 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.

[0117] The term “alkylene” refers to a bivalent unsubstituted saturated branched or straight chain hydrocarbon of the stated number of carbon atoms (e.g., a C1- C6 alkylene has from 1 to 6 carbon atoms) and having two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Alkylene groups can be substituted with 1-6 fluoro groups, for example, on the carbon backbone (as -CHF- or -CF2-) or on terminal carbons of straight chain or branched alkylenes (such as -CHF2 or -CF3). Alkylene groups include but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), difluoromethylene (-CF2-), tetrafluoro ethylene (-CF2CF2-), and the like.

[0118] The term “alkenyl” refers to an unsubstituted straight chain or branched, hydrocarbon having at least one carbon-carbon double bond and the indicated number of carbon atoms (e.g., “C2-C8 alkenyl” or “C2-C10” alkenyl have from 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkenyl group has from 2 to 6 carbon atoms.

[0119] The term “alkynyl” refers to an unsubstituted straight chain or branched, hydrocarbon having at least one carbon-carbon triple bond and the indicated number of carbon atoms (e.g., “C2- Cs alkynyl” or “C2-C10” alkynyl have from 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkynyl group has from 2 to 6 carbon atoms.

[0120] The term “heteroalkyl” refers to a stable straight or branched chain saturated hydrocarbon having the stated number of total atoms and at least one (e.g., 1 to 15) heteroatom selected from the group consisting of O, N, Si and S. The carbon and heteroatoms of the heteroalkyl group can be oxidized (e.g., to form ketones, N-oxides, sulfones, and the like) and the nitrogen atoms can be quaternized. The heteroatom(s) can be placed at any interior position of theheteroalkyl group and / or at any terminus of the heteroalkyl group, including termini of branched heteroalkyl groups), and / or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Heteroalkyl groups can be substituted with 1-6 fluoro groups, for example, on the carbon backbone (as -CHF- or -CF2-) or on terminal carbons of straight chain or branched heteroalkyls (such as -CHF2 or -CF3). Examples of heteroalkyl groups include, but are not limited to, -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-NH-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-CH3, -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-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH- CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-S(O)2-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.

[0121] The term “acyl” refers to an alkyl, haloalkyl, alkenyl, alkynyl, aryl cycloalkyl, heteroaryl, or heterocyclyl group, as defined herein, connected to the remainder of the compound by a C=O (carbonyl) group.

[0122] The term “carboxamido” refers to a -C(=O)NRR’ group, wherein R and R’ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl cycloalkyl, heteroaryl, and heterocyclyl, as defined herein.

[0123] The term “heteroalkylene” refers to a bivalent unsubstituted straight or branched group derived from heteroalkyl (as defined herein). Examples of heteroalkylene groups include, but are not limited to, -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+(CH3)2-, -NH-CH2-CH2(NH2)-CH2-, and -NH-CH2- CH2(NHCH3)-CH2-. A bivalent polyethylene glycol (PEG) moiety is a type of heteroalkylene group.

[0124] The term “alkoxy” refers to an alkyl group, as defined herein, which is attached to a molecule via an oxygen atom. For example, alkoxy groups include, but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

[0125] The term “alkylthio” refers to an alkyl group, as defined herein, which is attached to a molecule via a sulfur atom. For example, alkythio groups include, but are not limited to thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, and the like.

[0126] The term “haloalkyl” refers to an unsubstituted straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms (e.g., “C1-C4 alkyl,” “C1-C6 alkyl,” “C1-C8 alkyl,” or “C1-C10” alkyl have from 1 to 4, 1 to 6, 1 to 8, or 1 to 10 carbon atoms, respectively) wherein at least one hydrogen atom of the alkyl group is replaced by a halogen (e.g., fluoro, chloro, bromo, or iodo). When the number of carbon atoms is not indicated, the haloalkyl group has from 1 to 6 carbon atoms. Representative C1-6 haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, and 1 -chloroisopropyl.

[0127] The term “haloalkoxy” refers to a haloalkyl group, as defined herein, which is attached to a molecule via an oxygen atom. For example, haloalkoxy groups include, but are not limited to trifluoromethoxy, 2,2,2-trifluoroethoxy, and l,l,l-trifhioro2-methylpropoxy.

[0128] The term “cycloalkyl” refers to a cyclic, saturated or partially unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., “C3-8 cycloalkyl” or “C3-6” cycloalkyl have from 3 to 8 or 3 to 6 carbon atoms, respectively). When the number of carbon atoms is not indicated, the cycloalkyl group has from 3 to 6 carbon atoms. Cycloalkyl groups include bridged, fused, and spiro ring systems, and bridged bicyclic systems where one ring is aromatic and the other is unsaturated. Representative “C3-6 cycloalkyl” groups include, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0129] The term “aryl” refers to an unsubstituted monovalent carbocyclic aromatic hydrocarbon group of 6-10 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, biphenyl, and the like.

[0130] The term “heterocycle” refers to a saturated or partially unsaturated ring or a multiple condensed ring system, including bridged, fused, and spiro ring systems. Heterocycles can be described by the total number of atoms in the ring system, for example a 3-10 membered heterocycle has 3 to 10 total ring atoms. The term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocyclering (as defined above) can be condensed with one or more heterocycles (e.g., decahydronapthyridinyl), carbocycles (e.g., decahydroquinolyl) or aryls. The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system including a heterocycle, aryl and carbocycle portion of the ring. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocycle or heterocycle multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0131] The term “heteroaryl” refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from the group consisting of O, N and S. The ring or ring system has 4n +2 electrons in a conjugated 7i system where all atoms contributing to the conjugated 7i system are in the same plane. In some embodiments, heteroaryl groups have 5-10 total ring atoms and 1, 2, or 3 heteroatoms (referred to as a “5-10 membered heteroaryl”). Heteroaryl groups include, but are not limited to, imidazole, triazole, thiophene, furan, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0132] The term “hydroxyl” refers to an -OH group.

[0133] The term “cyano” refers to a -CN group.

[0134] The term “carboxy” refers to a -C(=O)OH group.

[0135] The term “oxo” refers to a =0 group.

[0136] 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.

[0137] 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.

[0138] The term “alkoxycarbonyl” refers to an alkoxy group, as defined herein, connected to a -C(=O)- group via the oxygen atom of the alkoxy (i.e., an alkyl ester group).

[0139] The term “alkoxythiocarbonyl” refers to an alkoxy group, as defined herein, connected to a C(=S)- group via the oxygen atom of the alkoxy (i.e., an alkyl thioester group).

[0140] The term “carbamoyl”, as defined herein, refers to -C(=O)-N(R)2, wherein ‘R’ denotes variable substitution.

[0141] The term “amidine”, as defined herein, refers to C(=N)-N(R)2, wherein ‘R’ denotes variable substitution.

[0142] The term “sulfone”, as defined herein, refers to -S(=O)2-R, wherein ‘R’ denotes variable substitution.

[0143] The term “thione”, as defined herein, refers to -C(=S)-R, wherein ‘R’ denotes variable substitution.

[0144] 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.

[0145] The term “succinimide” as used as part of an antibody-drug conjugate (ADC) can refer

[0146] The term “hydrolyzed succinimide” can refer to a succinimide in which the imide hydrolyzes to form a carboxylic acid and an amide. Examples of hydrolyzed succinimides include

[0147] As used herein, the term “hydrolysable group” refers to a moiety which undergoes spontaneous hydrolytic cleavage under specific conditions. For example, a hydrolysable group may be inert in neutral and basic solutions, but may undergo hydrolytic cleavage in days, hours, minutes, or seconds under acidic conditions. In some cases, a hydrolysable group is configured to undergo hydrolytic cleavage in a particular physiological environment, such as blood (e.g., peripheral blood) or oxidative (e.g., lysosomal) or reductive (e.g., cytoplasmic) intracellular compartments. In some cases, a hydrolysable group is configured for catalytic cleavage, for example by enzymes present in a specific organism (e.g., humans) or tissues (e.g., metabolically active tissues such as liver, kidney, or brain). A hydrolysable group can be configured for cleavageby a range of enzymes, or by a specific enzyme. For example, a hydrolysable group can comprise an oligopeptide of the sequence arginine-arginine-valine-arginine, for which human furin may have high cleavage activity. A hydrolysable group can be configured for cleavage within a particular environment, such as endosomes or lysozomes of human cells. In such cases, the hydrolysable group may be stable outside of the environment in which it is configured for cleavage. For example, a hydrolysable group may be stable in circulation within peripheral blood, but hydrolytically cleave upon uptake into a cell. Examples of hydrolysable groups include organophosphates such as phosphate esters, thiophosphates, and dithiophosphates, carbamates, carbonates, thioesters, quaternary amines, ureas, disulfides, organosulfates, diorganosulfates, certain amides and esters, and peptides with protease cleavage sites.

[0148] It will be appreciated by those skilled in the art that compounds described herein having a chiral center may exist in and be isolated in optically active and racemic forms.

[0149] As used herein, the term “free drug” refers to a biologically active species that is not covalently attached to an antibody. Accordingly, free drug refers to a compound as it exists immediately upon cleavage from the ADC. The release mechanism can be via a cleavable linker in the ADC, or via intracellular conversion or metabolism of the ADC. In some aspects, the free drug will be protonated and / or may exist as a charged moiety. The free drug is a pharmacologically active species which is capable of exerting the desired biological effect. In some embodiments, the pharamacologically active species is the parent drug alone. In some embodiments, the pharamacologically active species is the parent drug bonded to a component or vestige of the ADC (e.g., a component of the linker, succinimide, hydrolyzed succinimide, and / or antibody that has not undergone subsequent intracellular metabolism). In some embodiments, free drug refers to a compound of any one of Formulae (A), (I)-(VIII), (Ila), or (Illa), or a pharmaceutically acceptable salt thereof, as described herein, for example, wherein 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, or a pharmaceutically acceptable salt thereof, disclosed in U.S. Publ. No. 2017 / 0217960, which is incorporated by reference in its entirety.

[0150] As used herein, the term “Drug Unit” refers to the free drug that is conjugated to an antibody in an ADC, as described herein.Antibody Drug Conjugates (ADCs)

[0151] Aspects of the present disclosure provide an antibody drug conjugate (ADC) with a TLR7 / 8 payload. As many cells express TLR7 and TLR8 (including epithelial and myeloid cells), localizing the effects of TLR7 / 8 agonists to specified disease sites can be important for treatmentefficacy. To this end, many of the ADCs disclosed herein are configured to release their payloads within target disease sites. In many cases, the ADCs affect immune cell activation within tumor suppressive microenvironments, thereby avoiding systemic cytokine and antibody-dependent toxicities often elicited by free antibodies and TLR7 / 8 agonists.

[0152] Some embodiments provide an antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody consistent with the present disclosure; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to Ab via a sulfur atom of a cysteine residue or an e-amino group of a lysine residue; subscript p is an integer from 1 to 16; each D is a TLR7 / 8 agonist.

[0153] Some embodiments provide an antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody consistent with the present disclosure; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (A):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharidedisaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L; each Rxis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, -C(=O)ORE, -C(=O)NRGRH, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, 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 -NRARB; wherein no more than one Rxis the point of covalent attachment to L; subscript n is 0, 1, 2, 3, or 4; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c)RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C1o alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L.

[0154] In some cases, the antibody drug conjugate (ADC) has the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L;R5is selected from the group consisting of -C(=O)ORE, -NO2, -CN, -CF3 -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L.

[0155] In some cases, a structure of Formula (A) is a structure of Formula (I), Formula (II), Formula (Ila), Formula (III), Formula (Illa), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII). Accordingly, in some cases, D has the structure of Formula (I), Formula (II), Formula (Ila), Formula (III), Formula (Illa), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII) wherein R1, R2, R3, R4, R4A, R5, R6, R6A, Rx, RA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, n, m, q, and are as defined herein.

[0156] In some cases, each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, RA, RB, Rc, RD, RE, RF, RG, RH, R1, RJ, and RKare as defined herein, and wherein 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.

[0157] In some cases, each D has the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R4, R5, R6, RA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, and m are as defined herein, and represents the point of covalent attachment to L.

[0158] In some cases, each D has the structure of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein each of R3, R4, R6, RA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, m, and are as defined herein. In some cases, m is 0 or 1. In some cases, m is O.

[0159] In some cases, each D has the structure of Formula (III):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4A, R5, R6, RA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, and m are as defined herein.

[0160] In some cases, each D has the structure of Formula (Illa):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4A, R6, RA, RB, Rc, RD,RE, RF, RG, RH, R1, RJ, RK, and m are as defined herein.

[0161] In some cases, each D has the structure of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R4, R5, R6, RA, RB, Rc, RD,RE, RE, RG, RH, R1, RJ, RK, m, and are as defined herein.

[0162] In some cases, each D has the structure of Formula (V):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R6, RA, RB, Rc, RD,RE, RE, RG, RH, R1, RJ, RK, m, and '~ware as defined herein.

[0163] In some cases, each D has the structure of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, RA, RB, Rc, RD, RE, RF, RG, RH, R1, RJ, RK, and are as defined herein, each instance of R6Ais independently selected from the group consisting of 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 -NRARB; and subscript q is 0, 1, or 2.

[0164] In some cases, each D has the structure of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6ARA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, subscript q, and are as defined herein.

[0165] In some cases, each D has the structure of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6ARA, RB, Rc, RD, RE, RE, RG, RH, R1, RJ, RK, subscript q, and ■~vvare as defined herein.

[0166] In some cases of Formulae (A) and (I), R1, R2, R3, R4, or an instance of RA, RB, Rc, RDRE, RE, RG, RH, R1, RJ, orRKis the point of covalent attachment to L. In some cases of Formulae (A) and (I), R1, R3, R4, or an instance of RAor RBis the point of covalent attachment to L. In some cases of Formulae (A) and (I), R1, R3, or R4is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R1or R4is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R1is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R2is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R1andR2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R3is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R4is the point of covalent attachment to L. In some cases of Formulae (A) and (I), R4is C1-C6 alkyl, and the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L. In some cases of Formulae (A) and (I), R4is C1-C6 alkyl, and the C1-C6 alkyl is further substituted with the point of covalent attachment to L. In some cases of Formulae (A) and (I), R4is C1-C6 alkyl (h), and a substituent of the C1-C6 alkyl is further substituted with the point of covalent attachment to L. In some cases of Formulae (A) and (I), R4comprises an instance of Rc, RD, RE, RG, and / or RHwhich is the point of covalent attachment to L. In some cases of Formula (A), one instance of Rxis the point of covalent attachment to L. In some cases of Formula (A), an instance of Rxcontains an instance of RA, RB, RF, RG, RH, R1, RJ, or RKwhich is the point of covalent attachment to L. In some cases of Formulae (A) and (I), an instance of R1or R2is substituted with -NRARB, of which RAor RBis the point of covalent attachment to L. In some cases of Formula (A), an instance of Rxis -NRARB, of which RAor RBis the point of covalent attachment to L.

[0167] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to Ab via a sulfur atom of a cysteine residue, an e-amino group of a lysine residue, an imidazole of a histidine residue, a guanidinium of an arginine residue, a thiol of a methionine residue, a carboxylate of an aspartate or glutamate residue, a phenol of a tyrosine residue, or an indole of a tryptophan residue. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to Ab via a sulfur atom of a cysteine residue or an e-amino group of a lysine residue. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each L is covalently attached to glycosylation of the Ab.

[0168] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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, - NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10- C1s disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected 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; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5- C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected 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; wherein each C1-C6 alkyl C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, and 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5- C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected from the group consisting of hydrogen and C1-C6 alkyloptionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected from the group consisting of hydrogen and C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected 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 Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is hydrogen.

[0169] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy ,-NRARB, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C3 alkoxy ,-NRARB, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, C1-C3 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is substituted with 1-3 substituents. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is substituted with 1 substituent. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is substituted with at most one substituent. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1is not substituted.

[0170] In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is 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; wherein 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 optionally substituted with 1-3 substituents independently 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-NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is 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; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with a substituent 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the of C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen and C1-C6 alkyl, wherein the of C1-C6 alkyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae(A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the of C1-C3 alkyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the of 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 Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is hydrogen or C1-C3 alkyl. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is hydrogen.

[0171] In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C3 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, C1-C3 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is substituted with 1-3 substituents. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is substituted with 1 substituent. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is substituted with at most one substituent. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R2is not substituted.

[0172] In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), at least one of R1and R2is hydrogen. In some cases of Formulae (A) and (I), R1is the point of covalent attachment to L and R2is hydrogen. In some cases of Formulae (A), (I), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), R1and R2are hydrogen.

[0173] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of -NRARB, -C(=O)NRARB, 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; wherein each C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, 5-10membered heteroaryl, and 3-12 membered heterocycle is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C6 alkyl substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C6 alkyl substituted with a substituent selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C6 alkyl substituted with a substituent selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, and -NH2.

[0174] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of-NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of -NRARB, -C(=O)NRARB, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6alkylthio, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of hydrogen, -NRARB, C1-C6 alkyl, C1-C6 alkanoyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl or phenyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of-NRARB, C1-C6 alkyl, C1- C6 alkanoyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl or phenyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of -NRARB, C1-C6 alkyl, and C1-C6 alkanoyl; wherein the C1-C6 alkyl or C1-C6 alkanoyl is optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C4 alkyl optionally substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C4 alkyl optionally substituted with a substituent 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is 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 Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C4 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2.

[0175] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is substituted with 1-3 substituents independently 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 -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo,phenyl, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, oxo, phenyl, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, cyano, oxo, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with a substituent selected from the group consisting of hydroxyl, cyano, oxo, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with a substituent selected from the group consisting of oxo, C1-C3 alkoxy, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is optionally substituted with a substituent selected from the group consisting of C1-C3 alkoxy, and -NHRB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is substituted one substituent. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is substituted with at most one substituent. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is unsubstituted.

[0176] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C5 alkyl optionally substituted with 1 substituent selected from the group consisting of hydroxyl, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is C1-C5 alkyl optionally substituted with 1 substituent selected from the group consisting of C1-C3 alkoxy and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (V), (VI), (VII), and (VIII), R3is selected from the group consisting of butyl, -CH2-O-CH2CH3, -CH2-CH2-O-CH3, and -CH2-NH-CH2CH3. In some cases, R3is hydrogen.

[0177] In some cases of Formulae (A), (I), R4is the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof may be further substituted with the point of covalentattachment to L. In some cases of Formulae (A) and (I), R4is hydrogen; -C(=O)NRDRE; - C(=O)ORc; -C(=O)SRc; -C(=S)Rc; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(02)Rc; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof may be further substituted with the point of covalent attachment to L.

[0178] In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is hydrogen; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)RC; (V) -OC(=O)RC; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) - C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H. In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is hydrogen or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H. In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is hydrogen or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) - (phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H. In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is C1-C6 alkyl optionally substituted with: (ii) -O(C1-C6 alkyl); (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; or(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+.

[0179] In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) - (phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H. In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is C1-C6 alkyl substituted with: (ii) -O(C1-C6 alkyl); (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor - CO2H. In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is C1- C6 alkyl substituted with: (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; or (xi) - (phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+.

[0180] In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is - C(=O)NRDRE; -C(=O)ORC; -C(=O)SRC; -C(=S)RC; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE; (x) -[N(C1-C6alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, - NRDRE, -C(=O)NRDREor -CO2H; (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1- C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl.

[0181] In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is C1-C6 alkyl optionally substituted with: (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (ix) -NRDRE; (xi) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, or -[N(C1-C6 alkyl)RDRE]+; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H.

[0182] In some cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4isindependently 1, 2, or 3.

[0183] In some cases of Formulae (A selected from the group consistingsome cases of Formulae (A), (I), (II), (Ila), (IV), (V), (VI), (VII), and (VIII), R4is selected from

[0184] In some cases of Formulas (III) and (Illa), and R4Ais (a) the point of covalent attachment to L or (b) C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE; (ix) -[N(C1-C6 alkyl)RDRE]+; (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1- C6 alkyl)RDRE]+, or 1-3 independently selected halogen; (xi) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NRDREor -CO2H; or (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, or -CO2H; wherein when R4Ais (b) the C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L. In some cases of Formulas (III) and (Illa), R4Ais C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE; (ix) -[N(C1-C6 alkyl)RDRE]+; (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5- 10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xi) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NRDREor - CO2H; (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, or -CO2H; wherein the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L. In some cases of Formulas (III) and (Illa), R4Ais C1-C6 alkyl substituted with: (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (ix) -NRDRE; (ix) - [N(C1-C6 alkyl)RDRE]+; or (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5- 10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; wherein the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L. In some cases of Formulas (III) and (Illa), R4Ais C1-C6 alkyl substituted with (ix) -NRDRE; (ix) -[N(C1-C6 alkyl)RDRE]+; or (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; wherein the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L.

[0185] In some cases of Formula (A), subscript n is 0, 1, or 2. In some cases of Formula (A), subscript n is 1. In some cases of Formula (A), subscript n is 0. In some cases of Formula (A), one instance of Rxis R5and the remaining instances of Rxare R6. As used herein, the “remaining” Rxgroups refers to 0 or subscript n-1 Rxgroups, e.g., 0, 1, 2, or 3 Rxgroups. Thus, when subscript n is 0, there are zero remaining Rxgroups; when subscript n is 1, there are also zero remaining Rxgroups; when subscript n is 2, there is 1 remaining Rxgroup; when subscript n is 3, there are 2 remaining Rxgroups; when subscript n is 4, there are 3 remaining Rxgroups.

[0186] In some cases of Formulae (A) and (I), R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of -C(=O)ORF, -NO2, -CN, -CF3 -C(=O)NRGRH, - S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK. In some cases of Formulae (A) and (I), R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, somecases of Formulae (A) and (I), R5is selected from the group consisting of hydrogen, -C(=O)ORF, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK. In some cases of Formulae (A) and (I), R5is -C(=O)ORF. In some cases of Formulae (A) and (I), R5is -C(=O)OH or -C(=O)O(C1-C3alkyl); and each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases of Formulae (A) and (I), R5is -C(=O)OH or -C(=O)OCH3.

[0187] In some cases of Formulae (A) and (I), each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 - NRARB; wherein no more than one R6is the point of covalent attachment to L. In some cases of Formulae (A) and (I), each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB; wherein no more than one R6is the point of covalent attachment to L. In some cases of Formulae (A) and (I), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB; wherein no more than one R6is the point of covalent attachment to L. In some cases of Formulae (A) and (I), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB.

[0188] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is selected from the group consisting of -C(=O)ORF, -NO2, -CN, -CF3-C(=O)NRGRH, -S(O2)NRGRH, -NfR1)- C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is selected from the group consisting of hydrogen, -C(=O)ORF, -S(O2)NRGRH, - N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is -C(=O)ORF. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is -C(=O)OH or -C(=O)O(C1-C3alkyl), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB.

[0189] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and-NRARB. In some cases of Formulae (A),(I), (II), (Ila), (III), (Illa), and (IV), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases of Formulae (A), (I),(II), (Ila), (III), (Illa), and (IV), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB.

[0190] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and subscript m is zero. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is -C(=O)OH; and subscript m is zero. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), R5is - C(=O)OCH3; and subscript m is zero. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), subscript m is 0, 1, or 2. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), subscript m is 1 or 2. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), subscript m is 0 or 1. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), subscript m is 1. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), and (IV), subscript m is zero.

[0191] In some cases of Formulae (A) and (I), one instance of R6is the point of covalent attachment to L and the other R6, if any, are independently selected from the group consisting of 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 - NRARB.

[0192] In some embodiments disclosed herein, R5is acidic, negatively charged, and / or highly polar (e.g., comprises a dipole moment of at least about 2.0 Debye). A surprising observation disclosed herein (e.g., as demonstrated in Example 37) is that C7 imidazoquinoline functionalization (R5) can enhance toll-like receptor activation. It is contemplated that the importance of this functionalization in certain imidazoquinolines may have been previously missed due to its tendency to decrease cellular uptake, potentially masking its potency when applied as a free drug. However, when used in tandem with an effective targeting and uptake system, such as an antibody as disclosed herein, imidazoquinolines with negative or highly polar C7 functionalizations can affect enhanced TLR7 / 8 responses. Without being limited by theory, it is posited that TLR7 / 8 binding may position the imidazoquinoline C7 proximal to charged or polarprotic residues, enabling strong hydrogen bonding interactions which enhance binding strength and agonist behavior.

[0193] Accordingly, in certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5is negatively charged under physiological conditions and / or highly polar (e.g., comprises a dipole moment of at least about 2.0 Debye), in certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 7.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 6.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 5.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 4.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 3.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pKa of at most about 2.0. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a dipole moment of at least about 2.0 Debye (e.g., as calculated with density functional theory). In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a dipole moment of at least about 2.5 Debye, in certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a dipole moment of at least about 3.0 Debye. In certain cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (VI), (VII), and (VIII), R5comprises a pka of at most about 7.0 or a dipole moment of at least 2.0 Debye.

[0194] In some cases of Formula (A), each Rxis independently selected from the group consisting of hydrogen, -C(=O)ORF, -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N / R1)- S(O2)RK, -S(O2)RK, 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 -NRARB. In some cases of Formula (A), one instance of Rxis the point of covalent attachment to L and all other instances of Rx, if any, are independently selected from the group consisting of hydrogen, -C(=O)ORF, -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, - N(RI)-S(O2)RK, 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 -NRARB.

[0195] 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.

[0196] In some cases of Formulae (A) and (I), each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formulae (A) and (I), each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A) and (I), each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and methyl. In some cases of Formulae (A) and (I), at most one instance of RAand RBis (a) the point of covalent attachment to L, and the remaining instances of RAand RBare hydrogen.

[0197] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RAand RBis independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RAand RBis independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RAand RBis independently selected from the group consisting of hydrogen and methyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), all instances of RAand RBare hydrogen.

[0198] In some cases of Formulae (A) and (I), each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen. In some cases of Formulae (A) and (I), each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C4 alkyl optionally substituted with phenyl. In some cases of Formulae (A) and (I), each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C4 alkyl. In some cases of Formulae (A) and (I), each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl.

[0199] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of Rcis independently selected from the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of Rcis independently selected from the group consisting of hydrogen, phenyl, and C1-C4 alkyl optionally substituted with phenyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of Rcis independently selected from the group consisting of hydrogen and C1-C4 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III),(Illa), (IV), (V), (VI), (VII), and (VIII), each instance of Rcis independently selected from the group consisting of hydrogen and methyl.

[0200] In some cases of Formulae (A) and (I), each instance of RD, RE, RG, and RHis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-. In some cases of Formulae (A) and (I), each instance of RD, RE, RG, and RHis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C4-C6 cycloalkyl(C1-C3 alkyl)-, aryl, and aryl(C1-C3 alkyl)-. In some cases of Formulae (A) and (I), each instance of RD, RE, RG, and RHis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formulae (A) and (I), each instance of RD, RE, RG, and RHis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl.

[0201] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C4-C6 cycloalkyl(C1-C3 alkyl)-, aryl, and aryl(C1-C3 alkyl)-. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen and methyl.

[0202] In some cases of Formulae (A) and (I), each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulae (A) and (I), each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and(b) the group consisting of hydrogen, trifluoromethyl, C3-C6 cycloalkyl, aryl, aryl(C1-C3 alkyl)-, and C1-C6 alkyl optionally substituted with 1 substituent selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulae (A) and (I), each instance of RFis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of Formulae (A) and (I), each instance of RFis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, and C1-C3 alkyl. In some cases of Formulae (A) and (I), each instance of RFis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, and methyl.

[0203] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, C3-C6 cycloalkyl, aryl, aryl(C1-C3 alkyl)-, and C1-C6 alkyl optionally substituted with 1 substituent selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C3 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and methyl.

[0204] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), when RFis trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1- C6 alkyl)-, or C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; R4is - [N(C1-C6alkyl)RDRE]+; -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with -[N(C1-C6 alkyl)RDRE]+; or -(5-10 membered heteroaryl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with -[N(C1-C6 alkyl)RDRE]+.

[0205] In some cases of Formulae (A) and (I), each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A) and (I), each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl. In some cases of Formulae (A) and (I), each instance of R1, RJ, and RKis independently selected from the group consisting of(a) the point of covalent attachment to L; and (b) hydrogen.

[0206] In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of R1, RJ, and RKis independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of R1, RJ, and RKis independently selected from the group consisting of hydrogen and methyl. In some cases of Formulae (A), (I), (II), (Ila), (III), (Illa), (IV), (V), (VI), (VII), and (VIII), each instance of R1, RJ, and RKis hydrogen.

[0207] In some cases of Formulae (VI), (VII), and (VIII), each instance of R6Ais independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, and -NRARB. In some cases of Formulae (VI), (VII), and (VIII), each instance of R6Ais independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and -NRARB. In some cases of Formulae (VI), (VII), and (VIII), each instance of R6Ais independently selected from the group consisting of C1-C6 alkyl and -NRARB. In some cases of Formulae (VI), (VII), and (VIII), subscript q is 0 or 1. In some cases of Formulae (VI), (VII), and (VIII), subscript q is 0., wherein •^n' represents the point of covalent attachment to L. In some cases, eachwherein represents the point of covalent attachment to L. In some cases, each D is, wherein represents the point of covalent attachment to L.

[0209] In some embodiments, the ADC is capable of releasing (i) a component of the linker bound to D; (ii) a component of antibody bound to L-D; and / or (iii) the parent compound D as the free drug (as defined herein). 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 theintended 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, the binding of the free drug to a TLR exhibits an agonist effect on the TLR. In some embodiments, the binding of the free drug to a TLR exerts an immunostimulatory effect.Antibodies

[0210] For many of the ADCs disclosed herein, the antibody targets an antigen associated with a clinically relevant disease state. Such antibodies can localize the ADCs to disease sites, thereby enabling targeted TLR7 / 8 agonist payload delivery and site-specific treatment. As untargeted TLR7 / 8 agonists can affect systemic immune-related toxicities, TLR7 / 8-mediated immune reactivation is often only feasible when the agonist payloads are delivered in a site- specific manner. Accordingly, targeted ADC antibodies disclosed herein can enable use of highly potent TLR7 / 8 agonists which would otherwise exhibit prohibitively high toxicities through systemic delivery. In some cases, the antibody further mediates cellular uptake to affect intracellular or subcellular TLR7 / 8 agonist delivery.

[0211] 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 comprise identical sequences except for possible minor amounts of 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.

[0212] Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer or immune cell antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture.

[0213] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. The antibodies include full-length antibodies and antigen binding fragments thereof. Human monoclonal antibodies may be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et a / ., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).

[0214] In some embodiments, an antibody includes a functionally active fragment, derivative or analog of an antibody that binds specifically to target cells (e.g., cancer cell antigens) or other antibodies bound to cancer cells or matrix. In this regard, “functionally active” means that the fragment, derivative or analog is able to bind specifically to target cells. To determine which CDR sequences bind the antigen, synthetic peptides containing the CDR sequences are typically used in binding assays with the antigen by any binding assay method known in the art (e.g., the Biacore assay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0215] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which are typically obtained using standard recombinant DNA techniques, are useful antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and a constant region derived from a human immunoglobulin. See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entireties. Humanized antibodies are antibody molecules from non-human species having one or more CDRs from the non-human species and a framework region from a human immunoglobulin molecule. See, e.g., U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87 / 02671 ; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86 / 01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012 023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987 , Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu etal., 1987 , J. Immunol. 139:3521- 3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Cancer. Res. 47:999-1005; Wood et al., 1985, Nature 314:446-449; and Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; U.S. Patent No. 5,225,539; Jones etal., 1986, Nature 321: 522-525; Verhoeyan etal., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060; each of which is incorporated herein by reference in its entirety.

[0216] In some embodiments, an antibody is a completely human antibody. In some embodiments, an antibody is produced using transgenic mice that are incapable of expressingendogenous immunoglobulin heavy and light chain genes, but which are capable of expressing human heavy and light chain genes.

[0217] In some embodiments, an antibody is an intact or fully-reduced antibody. The term ‘fully-reduced’ is meant to refer to an antibody in which all four inter-chain disulfide linkages have been reduced to provide eight thiols that can be attached to a linker (L).

[0218] Attachment to an antibody can be via thioether linkages from native and / or engineered cysteine residues, or from an amino acid residue engineered to participate in a cycloaddition reaction (such as a click reaction) with the corresponding linker intermediate. See, e.g., Maerle, et al., PLOS One 2019: 14(1); e0209860. In some embodiments, an antibody is an intact or fully- reduced antibody, or is an antibody bearing engineered an cysteine group that is modified with a functional group that can participate in, for example, click chemistry or other cycloaddition reactions for attachment of other components of the ADC as described herein (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions). See, e.g., Agard, et al., J. Am. Chem. Soc. Vol. 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).

[0219] Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.

[0220] In some embodiments, the antibody can be used for the treatment of a cancer (e.g., an antibody approved by the FDA and / or EMA). Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.

[0221] In some cases, the antibody has a mutation or post-translational modification which affects non-Fab mediated uptake. Peripheral immune cells, which are highly responsive to TLR7 / 8 agonists can facilitate strong, systemic responses when activated through non-antigen specific, Fc-mediated uptake of the TLR7 / 8 antibody drug conjugate which may be harmful or otherwise undesirable. In such cases, the antibody can have an effector function-diminishingmutation, such as L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G or a combination thereof, which diminishes non-immune uptake (e.g., FcyR-mediated uptake).

[0222] In some embodiments, an antibody can be configured to bind to a surface antigen of a cell. The antibody, or a complex comprising the antibody, can be configured to internalize within a cell upon binding to the surface antigen. For example, the antibody or an ADC comprising the antibody can be configured to endocytose upon binding to a surface antigen of a cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to internalize within a cancer cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to internalize within an immune cell. In some embodiments, the immune cell is a tumor associated macrophage. In some embodiments, the surface antigen is a receptor or a receptor complex (e.g., expressed on lymphocytes). In some embodiments, the receptor or receptor complex comprises an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein or other immune cell expressed surface receptor.

[0223] In some embodiments, an antibody is configured to bind specifically to a cancer cell antigen. In some embodiments, an antibody is configured to bind specifically to an immune cell antigen. In some embodiments, the immune cell antigen is a tumor associated macrophage antigen. In some embodiments, an antibody is configured to bind specifically to EphA2. It will be understood that the antibody component in an ADC is an antibody in residue form such that “Ab” in the ADC structures described herein incorporates the structure of the antibody.

[0224] Non-limiting examples of antibodies that can be used for treatment of cancer and antibodies that bind specifically to tumor associated antigens are disclosed in Franke, A. E., Sievers, E. L., and Scheinberg, D. A., “Cell surface receptor-targeted therapy of acute myeloid leukemia: a review” Cancer Biother Radiopharm. 2000,15, 459-76; Murray, J. L., “Monoclonal antibody treatment of solid tumors: a coming of age” Semin Oncol. 2000, 27, 64-70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998, each of which is hereby incorporated by reference in its entirety.

[0225] Non-limiting examples of antigens which antibodies of the present disclosure may 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., idactamab); Axl (e.g., BA3011; tilvestamab); 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; 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 (see, e.g., International Publication No. WO 2015077826); CAMPATH-1 (e.g., alemtuzumab; ALLO-647; ANT 1034); carcinoembryonic antigen (e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab); CCNB1; CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabiralizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD138; CD142; CD166; CD147 (e.g., gavilimomab; metuzumab); CD155 (e.g., U.S. Publication No. 2018 / 0251548); CD19 (e.g., ALLO-501); CD20 (e.g., divozilimab; 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., adebrelimab; atezolizumab; garivulimab); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD288; CD352 (e.g., SGN-CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN- CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD56; CD59; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD79b; CD96; CD97; CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (see, e.g., International Publication No. WO 2018115231); CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-Claudin-1); CLDN16; CLDN18.1 (e.g., zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO 2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No. 10,822,427); CXCR4 (e.g., ulocuplumab); CYP1B1; c-Met; DCLK1 (see, e.g., International Publication No. WO 2018222675); DDR1; de2-7 EGFR (e.g., MAb 806); 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 receptors; EPHA2; ERBB2 (e.g., trastuzumab); ERBB3; ERVMER34 1; ETV6-AML (e.g., Catalog #PA5-81865); FAS; FasL; Fas-related antigen 1; FBP; FGFR1 (e.g., RG7992); FGFR2 (e.g., aprutumab); FGFR3 (e.g., vofatamab); FGFR4 (e.g., MM-161); FLT3 (e.g., 4G8SDIEM); FN; FN1; FOLR1 (e.g., farletuzumab); FRa; FSHR; FucGMl (e.g., BMS- 986012); FZD5; FZD8; G250; GAGE; GCC; GD2 (e.g., dinutuximab); GD3 (e.g., mitumomab); GITR (e.g., ragifdimab); GloboH; GM2 (e.g., BIW-8962); GM3 (e.g., racotumomab); gplOO;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; IL 1 RAP (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., encelimab); 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-l-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); a metalloproteinase; MFSD13A; MICA (e.g., 1E2C8, Catalog #66384-l-IG); MICB (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 #MA1-17O); NAU; NCAM1 (e.g., ThermoFisher Catalog #MA5-11563); Nectin-4 (e.g., enfortumab); NOXI (e.g., Catalog #PA5-103220); NT5E (e.g., 7G2, ThermoFisher Catalog #41-0200); NY-BR-1 (e.g., NY-BR-1 No. 2, Catalog #MA5-12645); NY-ESO-1 (e.g., E978m, Catalog #35-6200); 0X40 (e.g., ABM193); OY-TES1; p53; p53mutant; PAP; PAX3 (e.g., GT1210, ThermoFisher Catalog #MA5-31583); PAX5; PDGFR-B (e.g., rinucumab); PDPN (e.g., ThermoFisher Catalog #14-5381-82); PLAV1; PMSA; polysialic acid (see, e.g., Watzlawik et al. J Nat Sci. 2015; l(8):el41); PR1; PROMI (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., BAY 2315497); PTK7 (e.g., cofetuzumab); PVRIG; Ras mutant (e.g., Shin et al. Sci Adv. 2020; 6(3):eaay2174); RET (e.g., W02020210551); RGS5 (e.g., TF-TA503075); RhoC (e.g., ThermoFisher Catalog PA5-77866); ROR1 (e.g., cirmtuzumab); ROR2 (e.g., BA3021); ROS1 (e.g., WO 2019107671); Sarcoma translocation breakpoints; SART3 (e.g., TF 18025-1-AP); Sialyl-Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One. 2018; 13(7): e0201314); Siglecs 1-16 (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 #12039-l-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., sirtratumab); Sperm protein 17 (e.g., BS-5754R); SSX2 (e.g., ThermoFisher Catalog #MA5- 24971); survivin (e.g., PAI-16836); TACSTD2 (e.g., PA5-47074); TAG-72 (e.g., MAI-25956); tenascin; TF (e.g., tisotumab); Tie3; TLR2 / 4 / 1 (e.g., tomaralimab); TM4SF5 (e.g., 18239-1-AP); TMEM132A (e.g., Catalog #PA5-62524); TMEM40 (e.g., PA5-60636); TMPRSS1 ID (e.g., PAS- 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., 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 XAGEl (e.g., ThermoFisher Catalog #PA5-46413).

[0226] Non-limiting examples of target antigens include Axl (e.g., BA3011; tilvestamab); 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; cabiralizumab; 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., TBI 304H); CD19 (e.g., ALLO-501); CD2 (e.g., BTI-322; siplizumab); CD20 (e.g., divozilimab; 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., adebrelimab; atezolizumab; garivulimab); CD278 (e.g., feladilimab; 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; AMG 673); CD352 (e.g., SGN-CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD40 (e.g., dacetuzumab; lucatumumab); CD44 (e.g., RG7356); CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD51; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD83 (e.g., CBT004); CD97; CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepoditamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., ulocuplumab); DCIR; DCSIGN (see, e.g., International Publication No. WO 2018134389); Dectinl (see, e.g., U.S. Patent No. 9,045,542); Dectin2 (e.g.,ThermoFisher Catalog #MA5-16250); DR4 (e.g., mapatumumab); endosialin (e.g., ontuxizumab); FasL; FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HER2; 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 av[36; LAG-3 (e.g., encelimab); LAMP1; LAYN; LCK; LILRB2; LILRB4; MerTk (e.g., DS5MMER, Catalog #12-5751-82); Mesothelin; MICA (e.g., 1E2C8, Catalog #66384-l-IG); MICB (e.g., Catalog #MA5-29422); MICA; Mincle (e.g., OTI2A8, Catalog #TA505101); MRC1 (e.g., ThermoFisher Catalog #12-2061-82); MUC1; Mucl6; NcaPi2B; Nectin-4; 0X40 (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); Siglecs 1-16 (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); SLTRK6; STEAP1; TIGIT (e.g., etigilimab); TLR2 / 4 / 1 (e.g., tomaralimab); 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 av[36).

[0227] In some cases, an antibody target is selected from the group consisting of ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, 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, DLL-3, DPEP-3, EGFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, Integrin avp6 , h2A2, H2G12 / STn, HER2, HER3, ZIP6, IGF-1R, ILlRap, ITGav / CD51, Mesothelin, MICA, MUC-1, Mucl6, NaPi2B, Nectin-4, PD-L1, Prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, and TROP2.

[0228] In some cases, an antibody of the present disclosure targets an immune checkpoint. Among the diverse mechanisms which can contribute to unchecked cell growth, certain cancers utilize immune checkpoint proteins to generate immunosuppressive environments which limit immune activity proximal to cancer sites. As these cancers often generate high abundances of immune checkpoints, immune checkpoint targeting can be an effective means for localizing ADCs, and thereby TLR7 / 8 agonist payloads, to cancer sites. In some cases, an antibody of the present disclosure targets 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 combinationsthereof. In some cases, an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, TIGIT, or a combination thereof.

[0229] TABLE 1 provides exemplary antibody sequences consistent with the present disclosure. In this table, all targets correspond to human orthologs unless otherwise specified.TABLE 1Ill(i) Heavy Chain and Light Chain Variable Regions

[0230] In some cases, an antibody of the present 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, and 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 IDNO: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: 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: 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 and the second sequence is SEQ ID NO: 412; 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: 467 and the second sequence is SEQ ID NO: 468; the first sequence isSEQ 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 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; 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 firstsequence 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: 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 and the second sequence is SEQ ID NO: 838; 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: 893 and the second sequence is SEQ ID NO: 894; 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; the first 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.

[0231] In some cases, an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in somecases, 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 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: 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 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.

[0232] In some cases, an antibody of the present 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 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.

[0233] In some cases, the heavy chain variable region has at least 85% sequence identity to the first sequence and the light chain variable region has at least 85% sequence identity to the second sequence. 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 95% sequence identity to the first sequence and the light chain variable region has at least 95% 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. In some cases, the heavy chain variable region has at least 99% sequence identity to the first sequence and the light chain variable region has at least 99% sequence identity to thesecond sequence. In some cases, the heavy chain variable region comprises the first sequence and the light chain variable region comprises the second sequence.(ii) Heavy and Light Chains

[0234] 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, wherein: 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 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and thesecond 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: 299 and the second sequence is SEQ ID NO: 300; the first sequence is SEQ ID NO: 493 and the second 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.

[0235] 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, wherein: 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 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 secondsequence 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.

[0236] 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, wherein: 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 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 secondsequence 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.

[0237] 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, wherein: 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.

[0238] 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, wherein: the first sequence is SEQ ID NO: 3 or SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5.

[0239] In some cases, the heavy chain has at least 85% sequence identity to the first sequence and the light chain has at least 85% sequence identity to the second sequence. 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 95% sequence identity to the first sequence and the light chain has at least 95% 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. In some cases, the heavy chain has at least 99% sequence identity to the first sequence and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence and the light chain comprises the second sequence.(Hi) Complementarity-Determining Regions

[0240] 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: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NO: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NO: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NO: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NO: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NO: 325, 326, 327, 328, 329, and 330, respectively; SEQ ID NO: 333, 334, 335, 336, 337, and 338, respectively; SEQ ID NO: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NO: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NO: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NO: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NO: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NO: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NO: 389, 390, 391, 392, 393, and 394, respectively; SEQ ID NO: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NO: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NO: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NO: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NO: 429,430, 431, 432, 433, and 434, respectively; SEQ ID NO: 437, 438, 439, 440, 441, and 442, respectively; SEQ ID NO: 445, 446, 447, 448, 449, and 450, respectively; SEQ ID NO: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NO: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NO: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NO: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NO: 495, 496, 497, 498, 499, and 500, respectively; SEQ ID NO: 503, 504, 505, 506, 507, and 508, respectively; SEQ ID NO: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NO: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NO: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NO: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NO: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NO: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NO: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NO: 567, 568, 569, 570, 571, and 572, respectively; SEQ ID NO: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NO: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NO: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NO: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NO: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NO: 615, 616, 617, 618, 619, and 620, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NO: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NO: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NO: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NO: 749, 750, 751, 752, 753, and 754, respectively; SEQ ID NO: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NO: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NO: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NO: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NO: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NO: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NO: 807, 808, 809, 810, 811, and 812, respectively; SEQ ID NO: 815, 816, 817, 818, 819, and 820, respectively; SEQ ID NO: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NO: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NO: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NO: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NO: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NO: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NO: 871, 872, 873, 874, 875, and876, respectively; SEQ ID NO: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NO: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NO: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NO: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NO: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NO: 919, 920, 921, 922, 923, and 924, respectively; SEQ ID NO: 927, 928, 929, 930, 931, and 932, respectively; SEQ ID NO: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NO: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NO: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NO: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NO: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NO: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NO: 985, 986, 987, 988, 989, and 990, respectively; SEQ ID NO: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NO: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NO: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NO: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NO: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.

[0241] In some cases, an antibody of the present 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: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232,respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.

[0242] In some cases, the antibody comprises a CDR-H1 comprising at least 85% sequence identity to the first sequence, a CDR-H2 comprising at least 85% sequence identity to the second sequence, a CDR-H3 comprising at least 85% sequence identity to the third sequence, a CDR-L1 comprising at least 85% sequence identity to the fourth sequence, a CDR-L2 comprising at least 85% sequence identity to the fifth sequence, and a CDR-L3 comprising at least 85% sequence identity to the sixth sequence. In some cases, the antibody comprises a CDR-H1 comprising at least 90% sequence identity to the first sequence, a CDR-H2 comprising at least 90% sequence identity to the second sequence, a CDR-H3 comprising at least 90% sequence identity to the third sequence, a CDR-L1 comprising at least 90% sequence identity to the fourth sequence, a CDR- L2 comprising at least 90% sequence identity to the fifth sequence, and a CDR-L3 comprising at least 90% sequence identity to the sixth sequence. In some cases, the CDR-H1 comprises at most one mutation relative to the first sequence, the CDR-H2 comprises at most one mutation relative to the second sequence, the CDR-H3 comprises at most one mutation relative to the third sequence, the CDR-L1 comprises at most one mutation relative to the fourth sequence, the CDR- L2 comprises at most one mutation relative to the fifth sequence, and the CDR-L3 comprises at most one mutation relative to the sixth sequence.(iv) Exemplary Antibodies

[0243] In some cases, an antibody provided herein binds to PDL1. PDL1 is expressed in a broad range of cancers, as well as certain immune cells, and often serves as a primary mechanism for immune suppression in tumor microenvironments. The PDL1 agonism of PD-1 can act as an immune checkpoint, diminishing lymphocyte tumor infiltration, and T-cell receptor mediated proliferation and signaling. While PDL1 antagonism can reverse immune suppression, PDL1 targeting can also localize treatments to the sites of cancers, allowing drugs to selectively target cancer cells or stimulate immune responses in the presence of tumors.

[0244] In some cases, an anti-PDLl antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- Ll, CDR-L2, and CDR-L3 comprising 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 to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.

[0245] 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 NO: 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.

[0246] 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: 6-9 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. 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: 6 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: 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.

[0247] 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.

[0248] In some embodiments, an antibody provided herein binds to EphA2. In some embodiments, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively.

[0249] 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 at least 99% identical to the amino acid sequence of SEQ ID NO: 27 and alight 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 at least 99% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 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 that is 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 the amino acid sequence of SEQ ID NO: 31. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising the amino acid sequence that is 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 that is 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 hlCl or 1C1.

[0250] 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.

[0251] In some cases, an antibody provided herein binds to CD30. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative 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 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: 46 or 47 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: 48. In some embodiments, the anti- CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the aminoacid sequence of SEQ ID NO: 44 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: 45.

[0252] In some cases, an antibody provided herein binds to CD228. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some embodiments, the anti-CD228 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: 55 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: 56. 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 of SEQ ID NO: 57 or 58 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: 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 of 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.

[0253] In some cases, an antibody provided herein binds to avB6. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some embodiments, the anti-H2A2 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%, or99% identical to the amino acid sequence of SEQ ID NO: 69 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: 70. 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: 71 or 72 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: 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.

[0254] In some cases, an antibody provided herein binds to B7H4. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ IDNOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ IDNOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203-208, SEQ IDNOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ ID NOs: 235-240, and SEQID NOs: 243-248. 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 comprising at most one mutation relative to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ IDNOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ IDNOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ IDNOs: 203-208, SEQ ID NOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ IDNOs: 235-240, and SEQ ID NOs: 243-248. In some cases, the anti-B7H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acidsequences of SEQ ID NO: 85 and 87, SEQ ID NO: 86 and 87, SEQ ID NO: 88 and 90, SEQ ID NO: 89 and 90, SEQ ID NO: 251 and 252, , SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, SEQ ID NO: 269 and 270, SEQ ID NO: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NO: 275 and 276, SEQ ID NO: 277 and 278, SEQ ID NO: 279 and 280, SEQ ID NO: 281 and 282, SEQ ID NO: 283 and 284, SEQ ID NO: 285 and 286, SEQ ID NO: 287 and 288, or SEQ ID NO: 289 and 290, respectively. In some embodiments, the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 83 and 84, SEQ ID NO: 97 and 98, SEQ ID NO: 105 and 106, SEQ ID NO: 113 and 114, SEQ ID NO: 121 and 122, SEQ ID NO: 129 and 130, SEQ ID NO: 137 and138, SEQ ID NO: 153 and 154, SEQ ID NO: 161 and 162, SEQ ID NO: 169 and 170, SEQ IDNO: 177 and 178, SEQ ID NO: 185 and 186, SEQ ID NO: 193 and 194, SEQ ID NO: 201 and202, SEQ ID NO: 209 and 210, SEQ ID NO: 217 and 218, SEQ ID NO: 225 and 226, SEQ IDNO: 233 and 234, SEQ ID NO: 241 and 242, or SEQ ID NO: 249 and 250, respectively.

[0255] In some cases, an antibody provided herein binds to CD70. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative 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 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: 297 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: 298. In some embodiments, the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299 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: 300.

[0256] In some cases, an antibody provided herein binds to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, an antibody provided herein binds to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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: 309, 310, 311, 312, 313, and 314 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively. 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.

[0257] In some cases, an antibody provided herein binds to MICA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative 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 comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the aminoacid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 each comprising 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 comprising 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 each comprising 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, 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: 323 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: 324. 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: 331 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: 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 regioncomprising 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.

[0258] In some cases, an antibody provided herein binds to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, an antibody provided herein binds to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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: 357, 358, 359, 360, 361, and 362, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively. 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.

[0259] In some cases, an antibody provided herein binds to gpA33. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising 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 variableregion 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.

[0260] In some cases, an antibody provided herein binds to IL 1 Rap. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some embodiments, the anti-ILlRap 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.

[0261] In some cases, an antibody provided herein binds to EpCAM. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, SEQ ID NOs: 389-394, SEQ ID NOs: 397-402, SEQ ID NOs: 405-410, SEQ ID NOs: 413-418, or SEQ ID NOs: 421-426. In some embodiments, the anti- EpCAM antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 387 and 388, SEQ ID NO: 395 and 396, SEQ ID NO: 403 and 404, SEQ ID NO: 411 and 412, SEQ ID NO: 419 and 420, or SEQ ID NO: 427 and 428, respectively.

[0262] In some cases, an antibody provided herein binds to CD352. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutationrelative 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.

[0263] In some cases, an antibody provided herein binds to CS1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some embodiments, the anti-CSl 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.

[0264] In some cases, an antibody provided herein binds to CD38. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative 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.

[0265] In some cases, an antibody provided herein binds to CD25. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative 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.

[0266] In some cases, an antibody provided herein binds to ADAM9. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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: 469, 470, 471, 472, 473, and 474, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively. In some embodiments, the anti-ADAM9 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: 467 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: 468. In some embodiments, the anti-ADAM9 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: 475 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: 476.

[0267] In some cases, an antibody provided herein binds to CD59. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequencescomprising 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: 477, 478, 479, 480, 481, and 482, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively. In some embodiments, the anti-CD59 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: 483 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: 484.

[0268] In some cases, an antibody provided herein binds to CD 19. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising 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: 485, 486, 487, 488, 489, and 490, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively. In some embodiments, the anti-CD19 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: 491 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: 492. In some embodiments, the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 493 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: 494.

[0269] In some cases, an antibody provided herein binds to CD 138. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. An antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L;R5is selected from the group consisting of -C(=O)ORE, -NO2, -CN, -CF3 -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L;each instance of RFis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein 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. 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. 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. An antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 3-12 membered heterocycle is optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L;R5is selected from the group consisting of -C(=O)ORE, -NO2, -CN, -CF3 -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 -NRARB; and subscript m is 0, 1, 2, 3, or 4; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl; each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein 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: the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5.

5. The ADC of claim 4, wherein 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.

6. The ADC of claim 4 or claim 5, wherein 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.

7. An antibody drug conjugate (ADC) having the structure:Ab-(L-D)Por a pharmaceutically acceptable salt thereof; wherein:Ab is an antibody; each L is a linker; wherein each D is conjugated to a linker; wherein each L is covalently attached to an amino acid, N-terminal tag, C-terminal tag, or post-translational modification of Ab; subscript p is an integer from 1 to 16; each D has the structure of Formula (I):or a pharmaceutically acceptable salt thereof; wherein:R1is (a) the point of covalent attachment to L; or (b) 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; wherein each 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 is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide;R2is (a) the point of covalent attachment to L; or (b) 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; wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl, and 5-10membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB; orR1and R2, 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 the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl is optionally the point of covalent attachment to L;R3is (a) the point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -NRARB, -C(=O)NRARB, 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; wherein 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 optionally substituted with 1-3 substituents independently 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 -NRARB;R4is selected from the group consisting of: the point of covalent attachment to L; hydrogen; -ORC; -S(=O)2RC; -C(=O)NRDRE; -C(=O)ORc; -C(=O)SRc; -C(=S)Rc; -PO3RC; and - C1-C6 alkyl optionally substituted with:(i) 1-3 independently selected halogen;(ii) -ORC;(iii) -SRC;(iv) -NH-S(O2)RC;(v) -OC(=O)Rc;(vi) -CO2H;(vii) C1-C6 alkoxycarbonyl;(viii) -C(=O)NRDRE;(ix) -NRDRE;(x) -[N(C1-C6 alkyl)RDRE]+;(xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, - C(=O)NRDREor -CO2H;(xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of the (- 5-10 membered heteroaryl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, - [N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or(xiv) 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, -SRC, (C1-C6)alkoxycarbonyl, or -CO2H; wherein when R4is C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is optionally further substituted with the point of covalent attachment to L;R5is selected from the group consisting of -C(=O)ORE, -NO2, -CN, -CF3 -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of (a) the point of covalent attachment to L; or (b) the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3; each instance of RAand RBis independently selected from the group consisting of: (a) the point of covalent attachment to L, (b) the group consisting of hydrogen and C1-C6 alkyl; and (c) RAand RBtaken 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 only at most one instance of RAand RBis the point of covalent attachment to L; each instance of Rcis independently selected from the group consisting of: (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, phenyl, and C1-C10 alkyl optionally substituted with phenyl or 1-3 independently selected halogen; each instance of RD, RE, RG, and RHis independently selected from the group consisting of: (a) the point of covalent attachment to L; (b) the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl(C1-C6 alkyl)-, aryl, and aryl(C1-C6 alkyl)-; and (c) RDand RE, or RGand RH, 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 only one of RD, RE, RG, and RHis the point of covalent attachment to L; each instance of REis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1- C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl;each instance of R1, RJ, and RKis independently selected from the group consisting of (a) the point of covalent attachment to L; and (b) the group consisting of hydrogen and C1-C6 alkyl; wherein at most one of R1, RJ, and RKis the point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and wherein Ab 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: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively.

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

9. The ADC of claim 7 or claim 8, wherein the first, second, third, fourth, fifth, and sixth sequences are: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively.

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

11. The ADC of claim 10, wherein the effector function diminishing 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 diminishing mutation is L234A / L235A.

13. The ADC of any one of claims 1-12, wherein each D has the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein is the point of covalent attachment to L;R5is (a) the point of covalent attachment to L; or (b) selected from the group consisting of -C(=O)ORF, -NO2, -CN, -CF3-C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3.

14. The ADC of claim 13, wherein each D has the structure of Formula (Ila):or a pharmaceutically acceptable salt thereof, wherein each R6is independently selected from the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3.

15. The ADC of any one of claims 1-12, wherein each D has the structure of Formula (III):or a pharmaceutically acceptable salt thereof, whereinR4Ais (a) the point of covalent attachment to L or (b) C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -ORC; (iii) -SRC; (iv) -NH-S(O2)RC; (v) - OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE; (ix) - [N(C1-C6 alkyl)RDRE]+; (x) -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen;(xi) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -C(=O)NRDREor -CO2H; (xii) -(5- 10 membered heteroaryl)C1-C6 alkyl, wherein its C1-C6 alkyl is substituted with 5-10 membered heteroaryl, -NRDRE, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or 5-10 membered heteroaryl optionally substituted with halogen, -NRDRE, C1-C6 alkoxy, -C(=O)NRDRE, or -CO2H; wherein when R4Ais (b) the C1-C6 alkyl, the C1-C6 alkyl or a substituent thereof is further substituted with the point of covalent attachment to L;R5is selected from the group consisting of -C(=O)ORE, -NO2, -CN, -CF3 -C(=O)NRGRH, -S(O2)NRGRH, -N(RI)-C(=O)RJ, -N(RI)-S(O2)RK, and SO3RK; each R6is independently selected from the group consisting of 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 -NRARB; and m is 0, 1, 2, or 3.

16. The ADC of claim 15, wherein each D has the structure of Formula (Illa):or a pharmaceutically acceptable salt thereof.

17. The ADC of any one of claims 1-12, wherein R1or R4is the point of covalent attachment to L.

18. The ADC of any one of claims 1-17, wherein R1selected 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; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1- C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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,-NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C10-C18 disaccharide, acylated C10-C18 disaccharide, C15-C27 trisaccharide, and acylated C15-C27 trisaccharide.

19. The ADC of any one of claims 1-18, wherein R1selected from the group consisting of C1- C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NRARB, phosphoryl, sulfuryl, nitro, C5-C9 monosaccharide, and acylated C5-C9 monosaccharide.

20. The ADC of any one of claims 1-19, wherein R1is hydrogen or C1-C3 alkyl optionally substituted with a substituent selected from the group consisting of hydroxyl, halogen, and -NH2.

21. The ADC of any one of claims 1-20, wherein R1is hydrogen or C1-C3 alkyl.

22. The ADC of any one of claims 1-21, wherein R1is hydrogen.

23. The ADC of any one of claims 1-12 or 15-22, wherein R2is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, and phenyl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, or phenyl is optionally substituted with 1- 3 substituents independently 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 -NRARB.

24. The ADC of any one of claims 1-12 or 15-23, wherein R2is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the of C1-C3 alkyl is optionally substituted with 1-3 substituents independently 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 -NRARB.

25. The ADC of any one of claims 1-12 or 15-24, wherein R2is hydrogen or C1-C3 alkyl.

26. The ADC of any one of claims 1-12 or 15-25, wherein R2is hydrogen.

27. The ADC of any one of claims 1-26, wherein R3is selected from the group consisting of-NRARB, -C(=O)NRARB, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl, or 5-10 membered heteroaryl is optionally substituted with 1-3 substituents independently 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 -NRARB.

28. The ADC of any one of claims 1-27, wherein R3is C1-C5 alkyl optionally substituted with 1 substituent selected from the group consisting of hydroxyl, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio, and -NRARB.

29. The ADC of any one of claims 1-28, wherein R3is selected from the group consisting of butyl, -CH2-O-CH2CH3, -CH2-CH2-O-CH3, and -CH2-NH-CH2CH3.

30. The ADC of any one of claims 1-14 or 17-29, wherein R4is hydrogen; -C(=O)NRDRE; - C(=O)ORc; -C(=O)SRc; -C(=S)Rc; or C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogen; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)RC; (v) -OC(=O)Rc; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NRDRE; (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; (x) -[N(C1-C6 alkyl)RDRE]+; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+, or 1-3 independently selected halogen; or (xii) phenyl substituted with halogen, hydroxyl, C1-C6 alkoxy, -NRDRE, -C(=O)NRDREor -CO2H.

31. The ADC of any one of claims 1-14 or 17-30, wherein R4is hydrogen or C1-C6 alkyl substituted with: (ix) -NRDRE, wherein the RDof -NRDREis C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted with 5-10 membered heteroaryl, 5-10 membered heterocycle, -[N(C1-C6 alkyl)RDRE]+.

32. The ADC of any one of claims 1-14 or 17-31, wherein R4is selected from the group1, 2, or 3.

33. The ADC of claim 1-14 or 17-32, wherein R4is selected from the group consisting of34. The ADC of any one of claims 1-13, 15, or 17-33, wherein R5is -C(=O)OH or - C(=O)O(C1-C3 alkyl); and each R6is independently selected from the group consisting of halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, and -NRARB.

35. The ADC of any one of claims 1-13, 15, or 17-34, wherein R5is -C(=O)OH or - C(=O)O(C1-C3 alkyl); and subscript m is zero.

36. The ADC of any one of claims 1-13, 15, or 17-35, wherein R5has:(i) a pka of at most about 7.0,(ii) a dipole moment of at least about 2.0 Debye, or(iii) (i) and (ii).

37. The ADC of any one of claims 1-12 or 17-33, wherein each Rxis independently selected from the group consisting of hydrogen, -C(=O)ORF, -C(=O)NRGRH, -S(O2)NRGRH, -NfR1)- C(=O)RJ, -N(RI)-S(O2)RK, -S(O3)RK, 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 -NRARB.

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

39. The ADC of any one of claims 1-38, wherein each instance of RAand RBis independently selected from the group consisting of hydrogen and C1-C3 alkyl.

40. The ADC of any one of claims 1-39, wherein each instance of Rcis independently selected from the group consisting of hydrogen and C1-C4 alkyl.

41. The ADC of any one of claims 1-40, wherein each instance of RD, RE, RG, and RHis independently selected from the group consisting of hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C4- C6 cycloalkyl(C1-C3 alkyl)-, aryl, and aryl(C1-C3 alkyl).

42. The ADC of any one of claims 1-41, wherein each instance of RFis independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl.

44. The ADC of any one of claims 1-43, wherein each, wherein represents the point of covalent attachment to L.

45. The ADC of claim 43 or 44, wherein Ab comprises a heavy chain with at least 80% sequence identity to SEQ ID NO: 3 and a light chain with at least 80% sequence identity to SEQ ID NO: 5.

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

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

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

49. The ADC of any one of claims 1-48, wherein L has the formula -M-(A)a-(W)w-(Y)y-(X)x- , wherein: 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 a succinimide, a hydrolyzed succinimide, an amide, a methyl ketone, a disulfide, a dihydropyridazine, or a triazole;A is a C2-20 alkylene optionally substituted with 1-4 Ral; or a 2 to 40 membered heteroalkylene optionally substituted with 1-4 Rbl; each Ralis independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, -OH, =0, -NRdlRel, -(C1-6 alkylene)-NRdlRel, - C(=O)NRdlRel, -C(=O)((C1-6 alkyl), and -C(=O)O((C1-6 alkyl);each Rblis independently selected from the group consisting of: (C1-6 alkyl, (C1-6 haloalkyl, (C1-6 alkoxy, (C1-6 haloalkoxy, halogen, -OH, -NRdlRel, -((C1-6 alkylene)-NRdlRel, -C(=O)NRdlRel, -C(=O)((C1-6 alkyl), and -C(=O)O((C1-6 alkyl); each Rdland Relare independently hydrogen or C1-3 alkyl;W is from 1-12 amino acids or has the structure:wherein Su is a Sugar moiety;-OA- represents the oxygen atom of a glycosidic bond; each Rgis 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;W1is absent, *-C(=O)-O- or *-O-C(=O)-;, / uwrepresentscovalent attachment to A or M;* represents covalent attachment to X, Y, or D;Y is self-immolative moiety, a non-self-immolative releasable moiety, or a non-cleavable moiety;X is a C1-C6 alkylene or a 3-6 membered heteroalkylene;L is optionally substituted with a PEG Unit from PEG1 to PEG72.

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

51. The ADC of claim 49 or 50 wherein X is a C1-C6 alkylene.

52. The ADC of any one of claims 49-51, wherein X is a C1-C3 alkylene.

53. The ADC of claim 49 or 50, wherein X is a 3-6 membered hetero alkylene.

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

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

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

57. The ADC of any one of claims 49-56, wherein Y is a self-immolative moiety.H58. The ADC of any one of claims 49-57, wherein Y is59. The ADC of any one of claims 49-55, wherein Y is a non-cleavable moiety.

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 49-56, wherein Y is PEG4 to PEG12.

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

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

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

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

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, aspartate methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine-alanine, valine-citrulline, phenylalanine-lysine, and homoserine methyl ether.

67. The ADC of any one of claims 49-63, wherein W has the structure:wherein Su is a Sugar moiety;-OA- represents the oxygen atom of a glycosidic bond; each Rgis 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;W1is absent, *-C(=O)-O- or *-O-C(=O)-; vfvw* represents covalent attachment to A or M; and* represents covalent attachment to X, Y, or D.

68. The ADC of claim 67, wherein W1is absent.

69. The ADC of claim 67, wherein W1is *-C(=O)-O-.

70. The ADC of claim 67, wherein W1is *-O-C(=O)-.

71. The ADC of any one of claims 67-70, wherein one Rgis halogen, C1-C6 alkoxy, -N(C1- C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, carboxamido, C1-C6 alkyl, or -NCh, and the remaining Rgare hydrogen.

72. The ADC of any one of claims 67-71, wherein each Rgis hydrogen.

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

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

75. The ADC of any one of claims 49-74, wherein A is C2-20 alkylene optionally substituted with 1-4 Ral.

76. The ADC of any one of claims 49-75, wherein A is C4-10 alkylene optionally substituted with 1-4 Ral.

77. The ADC of any one of claims 49-75, wherein A is C2-20 alkylene substituted with one Ral.

78. The ADC of any one of claims 49-77, wherein A is C4-10 alkylene substituted with one Ral.

79. The ADC of any one of claims 49-74, wherein A is C2-20 alkylene.

80. The ADC of any one of claims 49-74 or 79, wherein A is C4-10 alkylene.

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

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

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

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

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

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

87. The ADC of any one of claims 49-74, wherein A is, represents covalent attachment to W, and * represents covalent linkage to M.

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

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

90. The ADC of any one of claims 49-87, wherein A is substituted with a PEG Unit fromPEG1 to PEG72.

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

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 1-91, or a pharmaceutically acceptable salt thereof.

93. The method of claim 92, wherein the ADC is configured to internalize within a cell.

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

95. The method of any one of claims 92-94, wherein the cell expresses the cancer-associated antigen.

96. The method of any one of claims 92-95, wherein the cell does not express the cancer- associated antigen.

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

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

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

100. The method of any one of claims 97-99, wherein the immune cell expresses TLR7, TLR8, or TLR7 and TLR8.

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

102. The method of any one of claims 97-101, wherein the immune cell expresses a surface protein which binds to the cancer-associated antigen.

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

104. The method of claim 92-103, 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 92-104, wherein the linker (L) of the ADC is configured to undergo cleavage subsequent to internalizing within the immune cell.

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. 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. 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 106-108, 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 106-109, wherein the immune checkpoint is PDL1.

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

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

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

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

115. The method of claim 114, wherein the 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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