Immunostimulatory anti-PD-L1-drug conjugates

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 394,912, filed on August 3, 2022, which is hereby incorporated by reference in its entirety.

[0003] Sequence Listing

[0004] This 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. The XML copy was created on July 24, 2023, is named "438442-704021_SL.XML", and is 944 kilobytes in size.

[0005] Incorporated by Reference

[0006] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Background Art

[0007] In addition to utilizing a variety of different proliferation and expansion mechanisms, tumors often induce local and systemic immunosuppression. Although most cells expressing immunogenic antigens are rapidly eliminated before neoplasia or tumorigenicity, tumor-mediated immunosuppression often blocks immune activity against cancer cells and can allow tumors to spread uncontrollably. Because many cytotoxic cancer therapies rely on immune activity to eliminate cancer cells, immunosuppressive tumors can resist conventional cancer therapies, which also fail to achieve immune reactivation and therefore do not affect immune clearance. Therefore, cancer therapies often require immune activation functions that can overcome tumor immunosuppression.

[0008] Despite this need, most immunomodulatory therapies have limited efficacy. While the immunosuppressive tumor environment is often localized, many immunostimulatory therapies produce toxic systemic reactions that may limit doses to levels below those required for local therapeutic efficacy. In particular, antibody-based therapies often affect antibody-dependent cellular cytotoxicity (ADCC), while non-targeted immunostimulatory complexes can produce dangerously toxic inflammatory and cytokine responses. Furthermore, many immunostimulatory compounds target intracellular receptors present on both cancer cells and immune cells, so treatments must balance the requirements of tumor cell targeting with immune cell uptake.

[0009] Among such immunostimulatory compounds, toll-like receptors (TLRs) play an important role in activating the immune system to defend against invading pathogens and damaged cells with potential tumorigenicity (see Kaczanowska et al., J. Leukoc. Biol. 2013; 93(6): 847-863). TLRs are a family of membrane-bound proteins that, when activated, recruit adaptors to propagate antigen-induced signals, thereby changing cell phenotype and activity. As immunostimulatory compounds, TLR agonists have been developed as vaccine adjuvants to enhance the production of immune cells that target viral or bacterial antigens required in vaccines. TLRs also recognize endogenous markers of tumor formation, such as cell death and chronic inflammation, and activate innate immune responses 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, the systemic use of TLR agonists may be limited by dose-limiting toxicities due to systemic cytokine induction. See Adams, S., Immunotherapy 2009; 1(6): 949-964. Therefore, there remains a need for targeted immunostimulatory compounds to localize the immune response to the desired cells while minimizing off-target effects. Summary of the Invention

[0010] The present disclosure provides compounds and biomolecule complexes (e.g., antibody-drug conjugates) that trigger cell and tissue-specific immune responses. Since cancer immunosuppression is typically located in the microenvironment near cancer cells, targeting payloads to these cancer sites may be crucial for affecting immune reactivation. To achieve this, in certain embodiments, the present disclosure provides antibody-drug conjugates (ADCs) that are constructed to selectively activate immune responses within the tumor microenvironment. In addition to delivering payloads to targeted cancer sites, ADCs of the present disclosure can also be constructed to release their payloads (e.g., TLR agonists) after being taken up by cancer or cancer-associated cells, thereby targeting immune activation to cancer sites and preventing off-target immune activation.

[0011] The ADCs described herein and their pharmaceutically acceptable salts can be constructed to be taken up by target cells or tissues. In some embodiments, the ADCs are constructed to be endocytosed after binding to membrane-bound and / or surface-displayed antigens. In such cases, the ADCs can target intracellular receptors, such as TLR7 or TLR8, which are often primarily localized within endosomes. Lipophilic groups attached to the ADCs (e.g., PEGylation or neutral and non-polar peptide linkers) can facilitate endocytosis.

[0012] In addition to targeting, the release of the ADC drug unit can be controlled so that the release occurs at a specified site (e.g., within the cell targeted by the antibody). Since the linker (L) cleavable group can be configured to be cleaved under specific physiological conditions or by a specific enzyme, the release of the drug unit can be primarily limited to the target site. Therefore, the biological effect of the drug unit (e.g., an immunostimulatory effect) can be localized to the target site. Alternatively, the drug unit can be configured to remain attached to the antibody, or a portion of the antibody and / or the linker, and induce its biological effect when coupled to the antibody.

[0013] Aspects of the present disclosure provide an antibody drug conjugate (ADC) having the following structure:

[0014] Ab-(LD) p

[0015] or a pharmaceutically acceptable salt thereof;

[0016] in:

[0017] Ab is antibody;

[0018] Each L is a connector;

[0019] wherein each D is coupled to a linker;

[0020] wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of Ab;

[0021] Subscript p is an integer from 1 to 16;

[0022] Each D has the structure of formula (A):

[0023]

[0024] or a pharmaceutically acceptable salt thereof;

[0025] in:

[0026] R 1is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 trisaccharide;

[0027] R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or

[0028] R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L;

[0029] R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ;

[0030] R 4 Selected from the group consisting of: point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by:

[0031] (i) 1-3 independently selected halogens;

[0032] (ii)-OR C ;

[0033] (iii)-SR C ;

[0034] (iv)-NH-S(O2)R C ;

[0035] (v)-OC(=O)R C ;

[0036] (vi) -CO2H;

[0037] (vii) C1-C6 alkoxycarbonyl;

[0038] (viii) -C(=O)NR D R E ;

[0039] (ix)-NR D R E ;

[0040] (x)-[N(C1-C6 alkyl)R D R E ] + ;

[0041] (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of said -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocycle, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens;

[0042] (xii) phenyl substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H;

[0043] (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of said (-5-10 membered heteroaryl)C1-C6 alkyl is substituted with: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or

[0044] (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H;

[0045] When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point of covalent attachment to L;

[0046] Each R Xare independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ; of which no more than one R X is the point of covalent attachment to L;

[0047] Subscript n is 0, 1, 2, 3, or 4;

[0048] R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B is a point of covalent attachment to L;

[0049] R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl;

[0050] R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or RG and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R D 、R E 、R G and R H Only one of them is the point of covalent attachment to L;

[0051] R F Each instance of is independently selected from the group consisting of: (a) a 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;

[0052] R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl;

[0053] where R I 、R J and R K At most one of them is a point of covalent attachment to L;

[0054] wherein each D has only one point of covalent attachment to L; and

[0055] wherein the Ab comprises a heavy chain variable region having at least 80% sequence identity to the first sequence and a light chain variable region having at least 80% sequence identity to the 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: 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: 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: 381 and the second sequence is SEQ ID NO: 382. 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:470 and the second sequence is SEQ ID NO:471; 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: 591 and the second sequence is SEQ ID NO: 592; 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: 680 and the second sequence is SEQ ID NO: 681; 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: 791 and the second sequence is SEQ ID NO: 792. 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:880 and the second sequence is SEQ ID NO:881; 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; 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 NOs: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: 230 and the second sequence is SEQ ID NO: 231; 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: 690 and the second sequence is SEQ ID NO: 691; the first sequence is SEQ ID NO: 692 and the second sequence is SEQ ID NO: 693; the first sequence is SEQ ID NO: 694 and the second sequence is SEQ ID NO: 695; the first sequence is SEQ ID NO: 696 and the second sequence is SEQ ID NO: 697; the first sequence is SEQ ID NO: 698 and the second sequence is SEQ ID NO: 699; the first sequence is SEQ ID NO: 699 and the second sequence is SEQ ID NO: 691; the first sequence is SEQ ID NO: 699 and the second sequence is SEQ ID NO: 691; the first sequence is SEQ ID NO: 691 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 with the first sequence, and the light chain variable region has at least 90% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity with the first sequence, and the light chain variable region has at least 98% sequence identity with the second sequence.

[0056] Certain aspects of the present disclosure provide an antibody drug conjugate (ADC) having the following structure:

[0057] Ab-(LD) p

[0058] or a pharmaceutically acceptable salt thereof;

[0059] in:

[0060] Ab is antibody;

[0061] Each L is a connector;

[0062] wherein each D is coupled to a linker;

[0063] wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of Ab;

[0064] Subscript p is an integer from 1 to 16;

[0065] Each D has the structure of formula (A):

[0066]

[0067] or a pharmaceutically acceptable salt thereof;

[0068] in:

[0069] R 1is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 trisaccharide;

[0070] R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or

[0071] R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L;

[0072] R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ;

[0073] R 4 Selected from the group consisting of: point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by:

[0074] (i) 1-3 independently selected halogens;

[0075] (ii)-OR C ;

[0076] (iii)-SR C ;

[0077] (iv)-NH-S(O2)R C ;

[0078] (v)-OC(=O)R C ;

[0079] (vi) -CO2H;

[0080] (vii) C1-C6 alkoxycarbonyl;

[0081] (viii) -C(=O)NR D R E ;

[0082] (ix)-NR D R E ;

[0083] (x)-[N(C1-C6 alkyl)R D R E ] + ;

[0084] (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of said -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocycle, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens;

[0085] (xii) phenyl substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H;

[0086] (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of said (-5-10 membered heteroaryl)C1-C6 alkyl is substituted with: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or

[0087] (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H;

[0088] When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point of covalent attachment to L;

[0089] Each R Xare independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ; of which no more than one R X is the point of covalent attachment to L;

[0090] Subscript n is 0, 1, 2, 3, or 4;

[0091] R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B is a point of covalent attachment to L;

[0092] R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl;

[0093] R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or RG and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R D 、R E 、R G and R H Only one of them is the point of covalent attachment to L;

[0094] R F Each instance of is independently selected from the group consisting of: (a) a 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;

[0095] R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl;

[0096] where R I 、R J and R K At most one of them is a point of covalent attachment to L;

[0097] wherein each D has only one point of covalent attachment to L; and

[0098] wherein the Ab comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: 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: 68 and the second sequence is SEQ ID NO: 79; the first sequence is SEQ ID NO: 80 and the second sequence is SEQ ID NO: 81; the first sequence is SEQ ID NO: 82 and the second sequence is SEQ ID NO: 83; the first sequence is SEQ ID NO: 84 and the second sequence is SEQ ID NO: 85; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 86; the first sequence is SEQ ID NO: 87 and the second sequence is SEQ ID NO: 88; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 89; the first sequence is SEQ ID NO: 91 and the second 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: 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; 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. 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. 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. NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280;The first sequence is SEQ ID NO:281 and the second sequence is SEQ ID NO:282; the first sequence is SEQ ID NO:283 and the second sequence is SEQ ID NO:284; the first sequence is SEQ ID NO:285 and the second sequence is SEQ ID NO:286; the first sequence is SEQ ID NO:287 and the second sequence is SEQ ID NO:288; the first sequence is SEQ ID NO:289 and the second sequence is SEQ ID NO:290; the first sequence is SEQ ID NO:717 and the second sequence is SEQ ID NO:718; the first sequence is SEQ ID NO:719 and the second sequence is SEQ ID NO:720; the first sequence is SEQ ID NO:721 and the second sequence is SEQ ID NO:722; or the first sequence is SEQ ID NO:723 and the second sequence is SEQ ID NO:724. In some cases, the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10. In some cases, the heavy chain has at least 90% sequence identity with the first sequence, and the light chain has at least 90% sequence identity with the second sequence. In some cases, the heavy chain has at least 98% sequence identity with the first sequence, and the light chain has at least 98% sequence identity with the second sequence. ;

[0099] Various aspects of the present disclosure provide an antibody drug conjugate (ADC) having the following structure:

[0100] Ab-(LD) p

[0101] or a pharmaceutically acceptable salt thereof;

[0102] in:

[0103] Ab is antibody;

[0104] Each L is a connector;

[0105] wherein each D is coupled to a linker;

[0106] wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of Ab;

[0107] Subscript p is an integer from 1 to 16;

[0108] Each D has the structure of formula (A):

[0109]

[0110] or a pharmaceutically acceptable salt thereof;

[0111] in:

[0112] R 1 is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 trisaccharide;

[0113] R 2is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or

[0114] R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L;

[0115] R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ;

[0116] R 4 Selected from the group consisting of: point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)ORC ;-C(=O)SR C ;-C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by:

[0117] (i) 1-3 independently selected halogens;

[0118] (ii)-OR C ;

[0119] (iii)-SR C ;

[0120] (iv)-NH-S(O2)R C ;

[0121] (v)-OC(=O)R C ;

[0122] (vi) -CO2H;

[0123] (vii) C1-C6 alkoxycarbonyl;

[0124] (viii) -C(=O)NR D R E ;

[0125] (ix)-NR D R E ;

[0126] (x)-[N(C1-C6 alkyl)R D R E ] + ;

[0127] (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of said -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocycle, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens;

[0128] (xii) phenyl substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H;

[0129] (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of said (-5-10 membered heteroaryl)C1-C6 alkyl is substituted with: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or

[0130] (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H;

[0131] When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point of covalent attachment to L;

[0132] Each R X are independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ; of which no more than one R X is the point of covalent attachment to L;

[0133] Subscript n is 0, 1, 2, 3, or 4;

[0134] R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and RB Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B is a point of covalent attachment to L;

[0135] R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl;

[0136] R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R D 、R E 、R G and R H Only one of them is the point of covalent attachment to L;

[0137] R F Each instance of is independently selected from the group consisting of: (a) a 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;

[0138] R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl;

[0139] where R I 、R J and R KAt most one of them is a point of covalent attachment to L;

[0140] wherein each D has only one point of covalent attachment to L; and

[0141] wherein Ab comprises a CDR-H1 having at least 80% sequence identity to a first sequence, a CDR-H2 having at least 80% sequence identity to a second sequence, a CDR-H3 having at least 80% sequence identity to a third sequence, a CDR-L1 having at least 80% sequence identity to a fourth sequence, a CDR-L2 having at least 80% sequence identity to a fifth sequence, and a CDR-L3 having at least 80% sequence identity to a sixth sequence, wherein the first, second, third, fourth, fifth and sixth sequences are SEQ ID NOs: 13, 14, 15, 16, 17 and 18, respectively; SEQ ID NOs: 21, 22, 23, 24, 25 and 26, respectively; SEQ ID NOs: 38, 39, 40, 41, 42 and 43, respectively; SEQ ID NOs: 49, 50, 51, 52, 53 and 54, respectively; SEQ ID NOs: 63, 64, 65, 66, 67 and 68, respectively; SEQ ID NOs: 69, 70, 71, 72 and 73, respectively; 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:145 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; NO: 211, 212, 213, 214, 215 and 216; SEQ ID NO: 219, 220, 221, 222, 223 and 224, respectively;SEQ ID NOs: 227, 228, 229, 230, 231 and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239 and 240, respectively; SEQ ID NOs: 243, 244, 245, 246, 247 and 248, respectively; SEQ ID NOs: 291, 292, 293, 294, 295 and 296, respectively; SEQ ID NOs: 301, 302, 303, 304, 305 and 306, respectively; SEQ ID NOs: 309, 310, 311, 312, 313 and 314, respectively; SEQ ID NOs: 317, 318, 319, 320, 321 and 322, respectively; SEQ ID NOs: 325, 326, 327, 328, 329 and 330, respectively; SEQ ID NOs: 331, 332, 333, 334, 335 and 336, respectively. NO:333, 334, 335, 336, 337 and 338; 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:395 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:459, 460, 461, 462, 463 and 464, respectively NO: 461, 462, 463, 464, 465 and 466; SEQ ID NO: 469, 470, 471, 472, 473 and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481 and 482, respectively;SEQ ID NOs: 485, 486, 487, 488, 489 and 490, respectively; SEQ ID NOs: 495, 496, 497, 498, 499 and 500, respectively; SEQ ID NOs: 503, 504, 505, 506, 507 and 508, respectively; SEQ ID NOs: 511, 512, 513, 514, 515 and 516, respectively; SEQ ID NOs: 519, 520, 521, 522, 523 and 524, respectively; SEQ ID NOs: 527, 528, 529, 530, 531 and 532, respectively; SEQ ID NOs: 535, 536, 537, 538, 539 and 540, respectively; SEQ ID NOs: 543, 544, 545, 546, 547 and 548, respectively; NO:551, 552, 553, 554, 555 and 556; 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:613, 614, 615, 616, 617, 618, 619, 620, 621 and 622, respectively NO: 615, 616, 617, 618, 619 and 620; 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: 677 NO: 679, 680, 681, 682, 683 and 684; SEQ ID NO: 687, 688, 689, 690, 691 and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699 and 700, respectively;SEQ ID NOs: 705, 706, 707, 708, 709 and 710, respectively; SEQ ID NOs: 725, 726, 727, 728, 729 and 730, respectively; SEQ ID NOs: 733, 734, 735, 736, 737 and 738, respectively; SEQ ID NOs: 741, 742, 743, 744, 745 and 746, respectively; SEQ ID NOs: 749, 750, 751, 752, 753 and 754, respectively; SEQ ID NOs: 759, 760, 761, 762, 763 and 764, respectively; SEQ ID NOs: 767, 768, 769, 770, 771 and 772, respectively; SEQ ID NOs: 775, 776, 777, 778, 779 and 780, respectively; SEQ ID NOs: 781, 782, 783, 784, 785, 786, 787, 788, 789 and 790, respectively. NO:783, 784, 785, 786, 787 and 788; 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; 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:909, 910, 911, 912, 913, 914, 915, 916, 917 and 918, respectively; NO:911, 912, 913, 914, 915 and 916; 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: 999, 1001, 1002 and 1003, respectively. NO: 1005, 1006, 1007, 1008, 1009 and 1010; 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 NOs: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NOs: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NOs: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NOs: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NOs: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NOs: 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 17 NO: 139, 140, 141, 142, 143 and 144; 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 NOs: 179, 180, 181, 182, 183 and 184, respectively; SEQ ID NOs: 187, 188, 189, 190, 191 and 192, respectively; SEQ ID NOs: 195, 196, 197, 198, 199 and 200, respectively; SEQ ID NOs: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NOs: 211, 212, 213, 214, 215 and 216, respectively; SEQ ID NOs: 219, 220, 221, 222, 223 and 224, respectively; SEQ ID NOs: 227, 228, 229, 230, 231 and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239 and 240, respectively; SEQ ID NOs: 241, 242, 243, 244, 245, 246, 247, 248, 249 and 250, respectively; NO: 243, 244, 245, 246, 247 and 248; 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; 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some cases, CDR-H1 comprises at most one mutation relative to the first sequence, CDR-H2 comprises at most one mutation relative to the second sequence, CDR-H3 comprises at most one mutation relative to the third sequence, CDR-L1 comprises at most one mutation relative to the fourth sequence, CDR-L2 comprises at most one mutation relative to the fifth sequence, and 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 NOs: 13, 14, 15, 16, 17, and 18, respectively.

[0142] In some cases, the Ab comprises an effector function reducing mutation. In some cases, the effector function reducing 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 reducing mutation is L234A / L235A.

[0143] In some cases, each D has the structure of Formula (I):

[0144]

[0145] or a pharmaceutically acceptable salt thereof, wherein R 5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ; and m is 0, 1, 2 or 3.

[0146] In some cases, each D has the structure of Formula (II):

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein is the point of covalent attachment to L; R 5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(RI )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ; and m is 0, 1, 2 or 3.

[0149] In some cases, each D has the structure of Formula (IIa):

[0150]

[0151] or a pharmaceutically acceptable salt thereof, wherein each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B , and m is 0, 1, 2 or 3.

[0152] In some cases, each D has a structure of Formula (III):

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein R 4A is (a) the point of covalent attachment to L or (b) C1-C6 alkyl optionally substituted with: (i) 1-3 independently selected halogens; (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E; (ix)-[N(C1-C6 alkyl)R D R E ] + (x) - (phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; (xi) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or 5-10 membered heteroaryl, which is optionally substituted with halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; when R 4A When (b) C1-C6 alkyl, the C1-C6 alkyl or its substituent is further substituted by a point covalently attached to L; R 5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B; and m is 0, 1, 2 or 3.

[0155] In some cases, each D has the structure of Formula (IIIa):

[0156]

[0157] or a pharmaceutically acceptable salt thereof.

[0158] In some cases, R 1 or R 4 is the point of covalent attachment to L. In some cases, R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 In some cases, R 1 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl or phenyl is optionally substituted by 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharides and acylated C5-C9 monosaccharides. In some cases, R 1 is hydrogen or C1-C3 alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, and -NH2. In some cases, R 1 is hydrogen or C1-C3 alkyl. In some cases, R 1 For hydrogen.

[0159] In some cases, R2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein 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: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases, R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases, R 2 is hydrogen or C1-C3 alkyl. In some cases, R 2 For hydrogen.

[0160] In some cases, R 3 Selected from the group consisting of: -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl and 5-10 membered heteroaryl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl or 5-10 membered heteroaryl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases, R 3 is a C1-C5 alkyl group optionally substituted by one substituent selected from the group consisting of hydroxy, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio and -NR A R B In some cases, R 3 Selected from the group consisting of butyl, -CH2-O-CH2CH3, -CH2-CH2-O-CH3 and -CH2-NH-CH2CH3.

[0161] In some cases, R 4 is hydrogen; -C(=O)NRD R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H. In some cases, R 4 is hydrogen or C1-C6 alkyl substituted by: (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + In some cases, R 4 Selected from the group consisting of:

[0162] wherein each instance of the subscript z is independently 1, 2, or 3. In some cases, R 4 Selected from the group consisting of:

[0163]

[0164] In some cases, R 5 Selected from the group consisting of: hydrogen, -C(=O)OR F 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; and each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases, R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases, R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and subscript m is 0. In some cases, R 5 Having: (i) a pKa of at most about 7.0; (ii) a dipole moment of at least about 2.0 Debye; or (i) and (ii).

[0165] In some cases, each R X are independently selected from the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K 、-S(O3)R K, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B In some cases, the subscript n is 1.

[0166] In some cases, R A and R B Each instance of is independently selected from the group consisting of hydrogen and C1-C3 alkyl. C Each instance of is independently selected from the group consisting of hydrogen and C1-C4 alkyl. D 、R E 、R G and R H Each instance of is 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). F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl.

[0167] In some cases, each D is

[0168]

[0169]

[0170]

[0171] in represents a point of covalent attachment to L. In some cases, each D is in indicates the point of covalent attachment to L. In some cases, the Ab comprises a heavy chain having at least 80% sequence identity to SEQ ID NO:3 or SEQ ID NO:4 and a light chain having at least 80% sequence identity to SEQ ID NO:5.

[0172] In some cases, the linker comprises a length of between 10 and 40 atoms, as defined by the path between D and Ab via the minimum number of bonds. In some cases, the linker comprises a length of between 15 and 30 atoms, as defined by the path between D and Ab via the minimum 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.

[0173] 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 succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine or triazole; A is C 2-20 Alkylene, which is optionally substituted by 1-4 R a1 or 2 to 40 membered heteroalkylene, which is optionally substituted with 1-4 R b1 Replace; each R a1 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, =O, -NR d1 R e1 、-(C 1-6 Alkylene)-NR d1 R e1 、-C(=O)NR d1 R e1 、-C(=O)(C 1-6 alkyl) and -C(=O)O(C 1-6 alkyl); each R b1 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NR d1 R e1 、-(C 1-6 Alkylene)-NR d1 R e1 、-C(=O)NR d1 R e1 、-C(=O)(C 1-6 alkyl) and -C(=O)O(C 1-6 alkyl); each R d1 and R e1 are independently hydrogen or C 1-3 Alkyl; W is 1-12 amino acids or has the following structure:

[0174]

[0175] Where Su is the sugar part; -O A - represents the oxygen atom of the glycosidic bond; each Rg W is independently hydrogen, halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, formamido, C1-C6 alkyl or -NO2; 1 Absent, *-C(=O)-O- or *-OC(=O)-; represents a covalent linkage to A or M; * represents a covalent linkage to X, Y or D; Y is a 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.

[0176] In some cases, the subscript x is 1. In some cases, X is C1-C6 alkylene. In some cases, X is C1-C3 alkylene. In some cases, X is 3-6 membered heteroalkylene. In some cases, X is 3-4 membered heteroalkylene. In some cases, the subscript x is 0.

[0177] In some cases, subscript y is 1. In some cases, Y is a self-immolative moiety. In some cases, Y is In some cases, Y is a non-cleavable moiety. In some cases, Y is cyclohexanecarboxyl, undecanoyl, caproyl, hexanoyl, butyryl, or propionyl. In some cases, Y is PEG4 to PEG12. In some cases, y is 0.

[0178] In some cases, the subscript w is 1. In some cases, W is 6-12 amino acids. In some cases, W is 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, aspartic acid methyl ester, N,N-dimethyl-lysine, phenylalanine, citrulline, valine-alanine, valine-citrulline, phenylalanine-lysine, and homoserine methyl ether. In some cases, W has the following structure:

[0179]

[0180] Where Su is the sugar moiety; -OA- represents the oxygen atom of the glycosidic bond; each R g W is independently hydrogen, halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, formamido, C1-C6 alkyl or -NO2; 1 Absent, *-C(=O)-O- or *-OC(=O)-; indicates a covalent bond to A or M; and * indicates a covalent bond to X, Y, or D. In some cases, W 1 Does not exist. In some cases, W 1 In some cases, W 1 In some cases, one R g is halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, formamide, C1-C6 alkyl or -NO2, and the remaining R g is hydrogen. In some cases, each R g In some cases, w is 0.

[0181] In some cases, subscript a is 1. In some cases, A is optionally substituted with 1-4 R a1 Substituted C 2-20 In some cases, A is optionally substituted with 1-4 R a1 Substituted C 4-10 In some cases, A is replaced by one R a1 Substituted C 2-20 In some cases, A is replaced by one R a1 Substituted C 4-10 In some cases, A is C 2-20 In some cases, A is C 4-10 In some cases, A is optionally substituted with 1-4 R b1 In some cases, A is optionally substituted with 1-4 R b1 In some cases, A is optionally substituted with one R b1 In some cases, A is optionally substituted with one R b1 In some cases, A is a 2- to 40-membered heteroalkylene. In some cases, A is a 4- to 12-membered heteroalkylene. In some cases, A is in represents a covalent attachment to W, and * represents a covalent linkage to M. In some cases, the subscript a is 0.

[0182] In some cases, L is substituted with a PEG unit from PEG1 to PEG72. In some cases, A is substituted with a PEG unit from PEG1 to PEG72. In some cases, M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine, or triazole.

[0183] Various aspects of the present disclosure provide a method for 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 salt thereof. In some cases, the Ab of the ADC targets a cancer-associated antigen. In some cases, the ADC is constructed to be internalized within a cell. In some cases, the cell expresses a cancer-associated antigen. In some cases, the cell does not express a cancer-associated antigen. In some cases, the cell is an immune cell. In some cases, the immune cell is a CD8 + T cells, CD4 + 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, cancer cells do not express TLR7 or TLR8. In some cases, the immune cell expresses a surface protein that binds to a cancer-associated antigen. In some cases, internalization includes endocytosis or micropinocytosis. In some cases, the ADC is constructed 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 constructed to undergo cleavage after internalization in the immune cell. BRIEF DESCRIPTION OF THE DRAWINGS

[0184] The novel features of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention may be obtained by referring to the following detailed description, which sets forth illustrative embodiments utilizing the principles of the present invention, and the accompanying drawings, in which:

[0185] Figure 1 Shown are the responses of human PBMCs from a single donor to selected small molecule TLR7 / 8 agonists.

[0186] Figure 2 Shown are the average responses of human PBMCs isolated from three donors to selected small molecule TLR7 / 8 agonists.

[0187] Figure 3 Shown are the responses of human PBMCs to selected TLR7 / 8 agonists with carboxylic acid (S5b, S8b, S11b) or methyl ester functional groups (S5a, S8a, S11a).

[0188] Figure 4 Shown are the responses of human immune cells to various small molecule TLR7 / 8 agonists.

[0189] Figure 5 Shown are the responses of human immune cells to selected TLR7 / 8 agonists with either a carboxylic acid (S18b) or a methyl ester functional group (S18a).

[0190] Figure 6 Shown are the responses of human immune cells to various TLR7 / 8 agonists conjugated to targeting antibodies.

[0191] Figure 7 Shown are the responses of human immune cells to selected TLR7 / 8 agonists with carboxylic acid (S18b) or methyl ester functional groups (S18a) conjugated to targeting antibodies.

[0192] Figure 8 Shown are the responses of human immune cells to selected TLR7 / 8 agonists with carboxylic acid (S14b, S18b, S76b) or methyl ester functional groups (S14a, S18a, S76a) conjugated to targeting antibodies.

[0193] Figure 9 Shown is a comparison of the aggregation levels of various conjugated immunostimulatory ADCs.

[0194] Figure 10 Shown are the anti-tumor responses of CT26 tumor-bearing mice to treatment with S8a or S8b immune cell-targeting antibody drug conjugates.

[0195] Figure 11 Shown are the anti-tumor responses of CT26 tumor-bearing mice to treatment with S14a or S14b immune cell-targeting antibody drug conjugates.

[0196] Figure 12 Shown are the anti-tumor responses of MC38 tumor-bearing mice to treatment with S8a, S8b, S18a, or S18b antibody drug conjugates.

[0197] Figure 13 Shown are the anti-tumor responses of CT26 tumor-bearing mice to treatment with S18b antibody drug conjugates with targeting or non-targeting antibodies.

[0198] Figure 14 Shown are the anti-tumor responses of Renca tumor-bearing mice to treatment with S18a free drug and S18a and S18b antibody drug conjugates.

[0199] Figure 15 Shown are the cytokine responses of non-tumor bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkages.

[0200] Figure 16 Shown are the cytokine responses of non-tumor bearing mice to treatment with S18b free drug and S18b antibody drug conjugates linked via N1 or C4 linkages.

[0201] Figure 17 Shown are the cytokine responses of CT26 tumor-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkages and with targeting or non-targeting antibodies.

[0202] Figure 18 Shown are the anti-tumor responses of CT26-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkages and with targeting or non-targeting antibodies.

[0203] Figure 19 Shown are the cytokine responses of Renca tumor-bearing mice to treatment with S18b drug conjugates linked via N1 or C4 linkages at a dose of 2 mg / kg.

[0204] Figure 20 Shown are the anti-tumor responses of Renca-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkages at a dose of 2 mg / kg.

[0205] Figure 21 Shown is the activation of human immune cells in vitro in response to TLR7 / 8 antibody conjugates linked via the N1 or C4 positions.

[0206] Figure 22 Shown are the anti-tumor responses of Renca-bearing mice to treatment with S18b antibody drug conjugate linked via N1 or C4 linkage at different dose levels.

[0207] Figure 23 Shown are the cytokine responses of Renca tumor-bearing mice to treatment with S18b antibody drug conjugates linked via N1 or C4 linkages at different dose levels.

[0208] Figure 24 Shown are in vitro assessments of TLR7 versus TLR8 selectivity for various TLR7 / 8 small molecule agonists in HEK Blue hTLR7 and TLR8 cells.

[0209] Figure 25 Shown is an in vivo evaluation of TLR7 versus TLR8 selectivity for various TLR7 / 8 small molecule agonists in C57BL / 6 mice bearing subcutaneous MC38 tumors.

[0210] Figure 26 Shown are the anti-tumor responses 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.

[0211] Figure 27Shown are the antitumor responses of Renca-bearing mice to treatment with S18a antibody drug conjugates linked at the N1 or C4 position, with different linker configurations, linkage sites, and with or without a PEG group in the linker.

[0212] Figure 28 Tumor sizes in mice treated with targeting antibody-TLR7 / 8 agonist complexes are presented.

[0213] Figure 29 Provided are IL6 (upper left), IL1b (upper right), MIP1b (lower left), and TNFα (lower right) responses in human peripheral blood mononuclear cells (PBMCs) primed with multiple imidazoquinoline complexes.

[0214] Figure 30 The cytokine responses in human immune cells following imidazoquinoline treatment are summarized. The upper left panel summarizes IL6 levels following treatment, the upper right panel summarizes TNFα levels following treatment, the lower left panel summarizes MCP1 levels following treatment, and the lower right panel summarizes IP10 levels following treatment.

[0215] Figure 31 Tumor size profiles over time after tumor implantation in TLR7-positive and TLR7-knockout mice are summarized. The upper left panel summarizes tumor growth in TLR7-positive mice, the lower left panel summarizes tumor growth in TLR7-knockout mice, and the right panel summarizes tumor volume on day 36 post-implantation for all mice.

[0216] Figure 32 Presented are tumor sizes in Renca tumor-bearing mice following treatment with TLR7 / 8 agonists.

[0217] Figure 33 Presented are Renca tumor volumes in untreated mice, mice treated with an imidazoquinoline TLR agonist conjugated to a tumor-targeting antibody or an isotype control.

[0218] Figure 34 Renca tumor volumes are summarized in untreated mice, mice treated with the imidazoquinoline TLR agonist C4 conjugated to a tumor-targeting antibody or an isotype control.

[0219] Figure 35 CT26 tumor volumes are summarized in untreated mice, mice treated with the imidazoquinoline TLR agonist N1 conjugated to a tumor-targeting antibody or an isotype control.

[0220] Figure 36 Presented are CT26 tumor volumes in untreated mice, mice treated with the imidazoquinoline TLR agonist C4 conjugated to a tumor-targeting antibody or an isotype control.

[0221] Figure 37 4T1 tumor volumes in untreated mice, mice treated with naked EphA2-targeting antibody, and mice treated with a TLR7 / 8 agonist EphA2-targeting antibody conjugate are summarized.

[0222] Figure 38 Provided are CT26 tumor volumes for untreated mice, mice treated with tumor and immune-targeting antibodies alone, mice treated with a non-targeting isotype antibody conjugated to a TLR7 / 8 agonist, and mice treated with a TLR7 / 8 agonist conjugated to tumor and immune-targeting antibodies.

[0223] Figure 39A -F provides Hodgkin's lymphoma (Hodgkin's lymphoma) after treatment with ADC according to the present disclosure ( Figure 39A ), breast cancer( Figure 39B ), pancreatic cancer ( Figure 39C ), lung cancer( Figure 39D ), anaplastic large cell lymphoma ( Figure 39E ) and CD30-positive anaplastic large T-cell lymphoma ( Figure 39F ) of cell viability.

[0224] Figure 40A -D summarizes the results of incubation with ADCs according to the present disclosure in pancreatic cancer ( Figure 40A ), human lung squamous cell carcinoma ( Figure 40B ) and anaplastic large cell lymphoma ( Figure 40C -D) Interleukin-6 (IL-6) induction in tumor cells.

[0225] Figure 41A -C summarizes MO( treated with various ADCs, antibodies and compounds according to the present disclosure Figure 41A )、M1( Figure 41B ) and M2( Figure 41C ) IL-6 production by macrophage populations.

[0226] Figure 42A Figure 3 summarizes the immune activation responses in tumor and immune cell co-cultures following treatment with various ADCs and antibodies according to the present disclosure. Figure 42A CD69 levels in Karpas299 co-cultures after ADC and antibody treatment are provided. Figure 42B CD69 levels in EBC-1 co-cultures after ADC and antibody treatment are provided. Figure 42C Provided are IFN-γ levels in Karpas299 co-cultures after ADC and antibody treatment. Figure 42DIFN-γ levels in EBC-1 co-cultures after ADC and antibody treatment are provided. Figure 42C CD86 levels in Karpas299 co-cultures after ADC and antibody treatment are provided. Figure 42D CD86 levels in EBC-1 co-cultures after ADC and antibody treatment are provided.

[0227] Figure 43 The frequencies of CD45+PDL1+ immune cells and CD45-PDL1+ tumor cells in human non-small cell lung cancer tumors from multiple subjects were summarized.

[0228] Figure 44A -B summarizes IL-6 and TNFα induction in human non-small cell lung cancer tumors following treatment with ADCs and antibodies according to the present disclosure.

[0229] Figure 45 Summarized are the changes in tumor volume during 4 weeks of treatment with ADCs and antibodies according to the present disclosure.

[0230] Figure 46A -C provides 2 mg / kg ( Figure 46A )、1mg / kg( Figure 46B ) and 0.5mg / kg( Figure 46C ) Time course of tumor volume after dose.

[0231] Figure 47A -D provides the Figure 47A ), antibody therapy ( Figure 47B ), non-targeted ADC therapy ( Figure 47C ) and targeted ADC therapy ( Figure 47D ) of PDL1-positive tumors in mice.

[0232] Figure 48 Tumor growth inhibition in mice treated with ADC and antibodies is summarized.

[0233] Figure 49A -D provides CD4 in MC38 and Renca mouse tumors + T cells ( Figure 49A ), regulatory T cells ( Figure 49B ), CD8 + T cells ( Figure 49C ) and macrophages ( Figure 49D )group.

[0234] Figure 50A -B provides MC38 ( implanted in a mouse model treated with ADC according to the present disclosure Figure 50A ) and Renca tumors ( Figure 50B ) tumor growth response.

[0235] Figure 51 is a set of graphs of tumor growth responses and area under the curve (AUC) values ​​for two different tumor models treated with ADCs according to the present disclosure.

[0236] Figure 52 is a series of graphs showing cytokine responses in two tumor models following treatment with ADCs according to the present disclosure.

[0237] Figure 53 is a set of graphs showing the expression of PDL1, CD4, CD8, and F4 / 80 in two tumor models. DETAILED DESCRIPTION

[0238] Many cancers are immunosuppressive, actively suppressing immune cell proliferation, signaling, and activity to avoid detection and elimination. While some TLR agonists can reactivate cancer-suppressed immune cells, TLR agonist therapy is often limited by dose-limiting toxicities. Even at mild agonist doses, persistent TLR activation can influence immune-related adverse events, including rheumatologic and thyroid disorders, nausea, rash, and general malaise.

[0239] By circumventing the toxicity-based dose limitations typically associated with TLR agonists, certain ADCs disclosed herein elicit minimal cytokine responses from outside the target tumor site. A surprising discovery disclosed herein is that widespread TLR7 / 8 activation within the tumor microenvironment can primarily activate immune cells without generating undesirable responses from cancer and bystander cells. Leveraging this discovery, the tumor-targeted ADCs disclosed herein can utilize significant concentrations of highly potent TLR agonists to achieve local immune stimulation while avoiding dose-limiting systemic toxicity.

[0240] definition

[0241] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. Methods and materials used in this application are described herein; in some aspects of the present disclosure, other suitable methods and materials known in the art are also used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, this specification (including definitions) shall prevail. Unless the context indicates otherwise, when a trademark name is used herein, the trademark name includes the active pharmaceutical ingredient of the product preparation, generic drug, and trademarked product.

[0242] As used herein, the terms "a," "an," or "the" include not only aspects having one member, but also aspects having more than one member. For example, 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.

[0243] When referring to a number or a numerical range, the term "about" means that the number or numerical range mentioned is an approximation, for example, within experimental variability and / or statistical experimental error, and therefore the number or numerical range may vary up to ±10% of the specified number or numerical range. With respect to ADC compositions comprising an ADC distribution as described herein, the average number of TLR agonist compounds coupled to the antibody in the composition may be an integer or non-integer, particularly when the antibody is partially loaded. Therefore, the term "about" cited before the average drug loading value is intended to capture the expected variation in drug loading within the ADC composition.

[0244] As used herein, the term "antibody" encompasses complete monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), including complete antibodies and antigen-binding antibody fragments and reduced forms thereof, wherein one or more interchain disulfide bonds are destroyed, which exhibit the desired biological activity, and provided that the antigen-binding antibody fragment has the desired number of linking groups (e.g., linkers (L)) and the desired number of attachment sites, as described herein. In some aspects, the linker is connected to the cysteine ​​residues of the reduced interchain disulfide bonds and / or the sulfur atoms of the cysteine ​​residues introduced by genetic engineering via succinimide or hydrolyzed succinimide. The native form of the antibody is a tetramer and consists of two pairs of identical immunoglobulin chains, each pair having a light chain and a heavy chain. In each pair, the light chain and heavy chain variable domains (VL and VH) are primarily responsible for binding to the antigen together. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also referred to as "complementarity determining region" or "CDR." The light and heavy chains also contain constant regions that can be recognized by and interact with the immune system. (See, for example, Janeway et al., 2001, Immuno. Biology, 5th edition, Garland Publishing, New York). Antibodies include any isotype thereof (e.g., IgG, IgE, IgM, IgD, and IgA) or its subclasses (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Antibodies can be derived from any suitable species. In some aspects, the antibodies are of human or murine origin, and in some aspects, the antibodies are human, humanized, or chimeric antibodies. Antibodies can be fucosylated or afucosylated to varying degrees.

[0245] An "intact antibody" is one comprising an antigen-binding variable region and a light chain constant domain (C L ) and heavy chain constant domain C H 1. C H 2. C H 3 and C H 4. The constant domain is a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof.

[0246] "Antibody fragments" comprise a portion of an intact antibody, including its antigen-binding or variable region. Antibody fragments disclosed herein 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, antibody fragments include Fab, Fab', or F(ab')2.

[0247] As used herein, the term "engineered cysteine ​​residues" or "eCys residues" refers to a cysteine ​​amino acid or derivative thereof that is incorporated into a protein (e.g., an antibody) and that would not otherwise be present at its position within the protein. In those aspects, one or more eCys residues can be incorporated into an antibody, and typically, an eCys residue is incorporated into the heavy or light chain of an antibody. Typically, incorporation of an eCys residue into an antibody is performed by mutagenizing the nucleic acid sequence of a parent antibody to encode one or more amino acid residues with cysteine ​​or its derivatives. Suitable mutations include replacing the desired residue in the light or heavy chain of an antibody with cysteine ​​or its derivatives, incorporating additional cysteine ​​or its derivatives at the desired position in the light or heavy chain of an antibody, and adding additional cysteine ​​or its derivatives to the N-terminus and / or C-terminus of the desired amino acid heavy or light chain. Further information can be found in U.S. Patent No. 9,000,130, the contents of which are incorporated herein in their entirety. Derivatives of cysteine ​​(Cys) include, but are not limited to, β-2-Cys, β-3-Cys, homocysteine, and N-methylcysteine.

[0248] In some embodiments, the antibodies of the present disclosure include those with one or more engineered cysteine ​​(eCys) residues. In some embodiments, derivatives of cysteine ​​(Cys) include, but are not limited to, β-2-Cys, β-3-Cys, homocysteine, and N-methylcysteine.

[0249] In some embodiments, the antibodies of the present disclosure include those with one or more engineered lysine (eLys) residues. In some embodiments, one or more native lysine and / or eLys residues are activated prior to conjugation with a drug-linker intermediate (to form an ADC, as described herein). In some embodiments, activation comprises contacting the antibody with a compound comprising a succinimidyl ester and a functional group selected from the group consisting of: maleimide, pyridyl disulfide, and iodoacetamide.

[0250] As used herein, an "antigen" may be an entity to which an antibody specifically binds.

[0251] The terms "specific binding" and "specifically binds" may refer to selective binding to a particular target. In the context of antibodies, these terms may refer to binding to a specific antigen or epitope over many other antigens or epitopes. Typically, an antibody or antibody fragment binds to a specific antigen or epitope at a rate of at least about 1 x 10 -7 M, for example 10 -8 M to 10 -9 M, 10 -10 M, 10 -11 M or 10 -12 The invention relates to a novel method for the present invention that binds to a predetermined antigen with an affinity that is at least two times greater than its binding affinity to a nonspecific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen.

[0252] As used herein, the term "amino acid" may refer to natural and non-natural as well as proteinogenic amino acids. Exemplary amino acids include, but are not limited to, alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, ornithine, β-alanine, citrulline, serine methyl ether, aspartic acid methyl ester, glutamate methyl ester, homoserine methyl ether, and N,N-dimethyllysine.

[0253] "Percentage (%) sequence identity" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a reference polypeptide sequence, after aligning the sequences and (where necessary) introducing gaps to obtain the maximum percentage of sequence identity and not considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining percentage amino acid sequence identity can be achieved in various ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. For example, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can be expressed as a given amino acid sequence A having or comprising a certain % sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 × fraction X / Y, where X is the number of amino acid residues for which the sequences were scored as perfect matches in the program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be understood that when the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity between A and B will not be equal to the % sequence identity between B and A.

[0254] As used herein, "sugar moiety" refers to a monosaccharide group, such as a pyranose or furanose. The sugar moiety may comprise a hemiacetal or a carboxylic acid (from oxidation of a pendant -CH2OH group). In some embodiments, the sugar moiety is in a β-D conformation. In some embodiments, the sugar moiety is a glucose, glucuronic acid, or mannose group.

[0255] The term "inhibit" or "inhibition" means to reduce by a measurable amount, or to completely prevent (eg, 100% inhibition).

[0256] As used herein, TLR7 / 8 can refer to both toll-like receptor 7 and toll-like receptor 8, only toll-like receptor, or only 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.

[0257] As defined herein, a "TLR7 / 8 agonist" includes any compound that exhibits selective TLR7 / 8 activity. Exemplary TLR7 / 8 agonists may exhibit less than about 10 μM, less than about 5 μM, less than about 2 μM, less than about 1 μM, less than about 500 nM, less than about 250 nM, less than about 100 nM, or less than about 10 nM of activity against TLR7 / 8 (EC 50), as measured in an assay as described herein. In some embodiments, a TLR7 / 8 agonist can show a selectivity of TLR7 relative to TLR8 of about 3.5 times to about 25 times, for example, about 3.5 times to about 15 times, about 10 times to about 20 times, about 15 times to about 25 times, about 3.5 times to about 8 times, about 5 times to about 12 times, about 8 times to about 15 times, about 12 times to about 18 times, about 15 times to about 20 times, or about 18 times to about 25 times. In some embodiments, a TLR7 / 8 agonist can show a selectivity of TLR8 relative to TLR7 of about 3.5 times to about 25 times, for example, about 3.5 times to about 15 times, about 10 times to about 20 times, about 15 times to about 25 times, about 3.5 times to about 8 times, about 5 times to about 12 times, about 8 times to about 15 times, about 12 times to about 18 times, about 15 times to about 20 times, or about 18 times to about 25 times.

[0258] 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 in treating a disease or condition in a mammal. In the case of cancer, a therapeutically effective amount of an ADC or compound provides one or more of the following biological effects: reducing the number of cancer cells; reducing tumor size; inhibiting cancer cell infiltration into surrounding organs; inhibiting tumor metastasis; inhibiting tumor growth to a certain extent; and / or alleviating to a certain extent one or more symptoms associated with cancer. For cancer therapy, in some aspects, efficacy is measured by assessing time to disease progression (TTP) and / or determining a response rate (RR).

[0259] Unless the context indicates or implies otherwise, the terms "substantially" or "substantially" refer to a majority of a mixture or sample population, i.e., >50%, typically greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

[0260] The terms "intracellular cleavage" and "intracellular cleavage" refer to metabolic processes or reactions occurring inside cells, wherein cellular machinery acts on an ADC or a fragment thereof to release free drug from the ADC or another degradation product thereof within the cell. Thus, the moiety produced by such metabolic processes or reactions is an intracellular metabolite.

[0261] 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 a variety of cancerous cells.

[0262] As used herein, "subject" may refer to an individual to whom an ADC or TLR7 / 8 agonist as described herein is administered. As used herein, "subject" may also refer to an individual from whom a sample (e.g., a tumor resection) is collected. Examples of "subjects" include, but are not limited to, mammals, such as humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, the subject is a rat, mouse, dog, non-human primate, or human. In some aspects, the subject is human.

[0263] Unless the context indicates otherwise or implies, the term "treat" or "treatment" refers to therapeutic treatment and preventive measures to prevent recurrence, wherein the purpose is to inhibit undesirable physiological changes or symptoms, such as the development or spread of a disease. For the purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, weakening of the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement and alleviation of the disease state, and relief (partial or complete), whether detectable or undetectable. "Treatment" in some aspects also means an extension of survival compared to the expected survival if no treatment is received.

[0264] In the context of cancer, the term "treating" includes any or all of the following: inhibiting the growth of cancer cells or tumors; inhibiting the replication of cancer cells, reducing the overall tumor burden or reducing the number of cancer cells, and ameliorating one or more symptoms associated with the disease.

[0265] As used herein, the term "salt" refers to an organic or inorganic salt of a compound such as a TLR7 / 8 agonist (e.g., a compound of Formula (IX)), a drug unit (D) (e.g., a compound of any one of Formulas (A), (I)-(VIII), (IIa), or (IIIa)), a linker, a drug-linker intermediate (e.g., a compound of Formula (X)), or an ADC (e.g., those described herein). In some aspects, the compound contains at least one amino group and, therefore, can form acid addition salts with amino groups. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Salts may involve the inclusion of another molecule such as acetate ion, succinate ion or other counter ion. Counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, salts have one or more charged atoms in their structure. In the case of the presence of multiple charged atoms as part of the salt, multiple counterions may be present. Thus, a salt may have one or more charged atoms and / or one or more counterions. A "pharmaceutically acceptable salt" is a salt suitable for administration to a subject as described herein, and in some aspects includes salts as described in P.H. Stahl and C.G. Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002, the list of which is specifically incorporated by reference in its entirety. In some embodiments, the ADC described herein exists in the form of a pharmaceutically acceptable salt. In some embodiments, the compounds described herein exist in the form of a pharmaceutically acceptable salt.

[0266] As used herein, the term "tautomer" refers to compounds whose structures differ significantly in the arrangement of their atoms but exist in facile and rapid equilibrium, and it is understood that the compounds provided herein may be described as different tautomers, and when a compound has tautomeric forms, all tautomeric forms are intended to be within the scope of the present disclosure, and the naming of the compound does not exclude any tautomer.

[0267] The term "optionally substituted" means that the indicated group is substituted or unsubstituted.

[0268] The term "alkyl" refers to an unsubstituted straight or branched chain saturated hydrocarbon having a specified number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "C1-C8 alkyl" groups have 1 to 4, 1 to 6, 1 to 8 or 1 to 10 carbon atoms, respectively) and are derived by removing one hydrogen atom from a parent alkane. Representative straight-chain "C1-C8 alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl; while branched-chain C1-C8 alkyl groups include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl and 2-methylbutyl.

[0269] The term "alkylene" refers to a divalent, unsubstituted, saturated, branched or straight-chain hydrocarbon (e.g., C1-C6 alkylene has 1 to 6 carbon atoms) having the number of carbon atoms indicated and having two monovalent centers derived by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Alkylene may be substituted with 1-6 fluoro groups, for example, on the carbon backbone (e.g., -CHF- or -CF2-) or on the terminal carbon (e.g., -CHF2 or -CF3) of a straight or branched alkylene group. Alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), difluoromethylene (-CF2-), tetrafluoroethylene (-CF2CF2-), and the like.

[0270] The term "alkenyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon double bond and the specified number of carbon atoms (e.g., "C2-C8 alkenyl" or "C2-C8 alkenyl"). 10 "Alkenyl" has 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not specified, the alkenyl has 2 to 6 carbon atoms.

[0271] The term "alkynyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon triple bond and the specified number of carbon atoms (e.g., "C2-C8 alkynyl" or "C2-C8 10 "Alkynyl" has 2 to 8 or 2 to 10 carbon atoms, respectively). When the number of carbon atoms is not specified, the alkynyl has 2 to 6 carbon atoms.

[0272] The term "heteroalkyl" refers to a stable straight or branched saturated hydrocarbon having a total number of atoms and at least one (e.g., 1 to 15) heteroatomic group selected from the group consisting of O, N, Si, and S. The carbon and heteroatoms of the heteroalkyl group can be oxidized (e.g., to form ketones, N-oxides, sulfones, etc.) and the nitrogen-atoms can be quaternized. The heteroatoms can be located at any internal position of the heteroalkyl group and / or at any end of the heteroalkyl group, including the end of a branched heteroalkyl group, and / or at the position where the heteroalkyl group is connected to the remainder of the molecule. The heteroalkyl group can be substituted with 1 to 6 fluoro groups, for example, at a carbon backbone (e.g., -CHF- or -CF2-) or at a terminal carbon (e.g., -CHF2 or -CF3) of a straight or branched heteroalkyl group. 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, -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(= -CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-NH(CH3), -O-CH2-CH2-CH2-N(CH3)2, -CH2-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-S(O)2-CH3, -CH2-CH2-O-CF3 and -Si(CH3)3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The terminal polyethylene glycol (PEG) moiety is one type of heteroalkyl group.

[0273] The term "acyl" refers to an alkyl, haloalkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl or heterocyclyl group as defined herein attached to the rest of the compound through a C=O (carbonyl) group.

[0274] The term "carboxamido" refers to a -C(=0)NRR' group, where R and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl, and heterocyclyl, as defined herein.

[0275] The term "heteroalkylene" refers to a divalent unsubstituted straight or branched chain group derived from heteroalkyl (as defined herein). Examples of heteroalkylene 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)-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-. The divalent polyethylene glycol (PEG) moiety is a type of heteroalkylene.

[0276] The term "alkoxy" refers to an alkyl group as defined herein attached to a molecule via an oxygen atom. For example, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0277] The term "alkylthio" refers to an alkyl group as defined herein attached to the molecule via a sulfur atom. For example, alkylthio includes, but is not limited to, thiomethyl, thioethyl, thio-n-propyl, thio-isopropyl, and the like.

[0278] The term "haloalkyl" refers to an unsubstituted straight or branched chain saturated hydrocarbon having the specified number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "alkyl" has 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 is replaced by a halogen (e.g., fluorine, chlorine, bromine or iodine). When the number of carbon atoms is not specified, the haloalkyl has 1 to 6 carbon atoms. Representative C 1-6 Haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, and 1-chloroisopropyl.

[0279] The term "haloalkoxy" refers to a haloalkyl group, as defined herein, attached to the molecule via an oxygen atom. For example, haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and 1,1,1-trifluoro2-methylpropoxy.

[0280] The term "cycloalkyl" refers to a cyclic, saturated or partially unsaturated hydrocarbon having the specified number of carbon atoms (e.g., "C 3-8 Cycloalkyl" or "C 3-6 "Cycloalkyl groups have 3 to 8 or 3 to 6 carbon atoms, respectively). When the number of carbon atoms is not specified, the cycloalkyl group has 3 to 6 carbon atoms. Cycloalkyl groups include bridged, fused, and spiro ring systems, as well as bridged bicyclic ring systems in which one ring is aromatic and the other ring is unsaturated. Representative "C 3-6 "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0281] The term "aryl" refers to an unsubstituted monovalent carbocyclic aromatic hydrocarbon radical having 6 to 10 carbon atoms derived by removing a hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl includes, but is not limited to, phenyl, naphthyl, anthracenyl, biphenyl, and the like.

[0282] The term "heterocycle" refers to a saturated or partially unsaturated ring or a polycondensed ring system, including bridged rings, condensed rings and spirocyclic systems. Heterocycle can be described by the total number of atoms in the ring system, for example, a 3-10 membered heterocycle has 3 to 10 ring atoms in total. The term includes a monosaturated or partially unsaturated ring (for example, a 3, 4, 5, 6 or 7 membered ring) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The ring can be substituted by one or more (for example, 1, 2 or 3) oxo groups, and sulfur and nitrogen atoms can also exist in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term "heterocycle" also includes polycondensed ring systems (for example, a ring system comprising 2, 3 or 4 rings), wherein a single heterocycle (as defined above) can be fused with one or more heterocycles (for example, decahydronaphthyridinyl), carbocycle (for example, decahydroquinolinyl) or aryl. When valence requirements permit, the rings of a polycondensed ring system may be connected to each other via fused bonds, spiro bonds, and bridging bonds. It will be understood that the point of attachment of a polycondensed ring system (as defined above for heterocycle) may be located at any position of the polycondensed ring system, including the heterocycle, aryl, and carbocyclic portions of the ring. It will also be understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system may be located at any suitable atom of the heterocycle or heterocyclic polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0283] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom in a monocyclic ring or in a fused ring system, the heteroatom being selected from the group consisting of O, N, and S. The ring or ring system has 4n+2 electrons in a conjugated π system, wherein all atoms contributing to the conjugated π system are in the same plane. In some embodiments, the heteroaryl group has a total of 5-10 ring atoms and 1, 2, or 3 heteroatoms (referred to as "5-10 membered heteroaryl"). Heteroaryl includes, but is not limited to, imidazole, triazole, thiophene, furan, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0284] The term "hydroxy" refers to an -OH group.

[0285] The term "cyano" refers to a -CN group.

[0286] The term "carboxy" refers to a -C(=O)OH group.

[0287] The term "oxo" refers to a =0 group.

[0288] The term "alkanoyl" refers to an alkyl group, as defined herein, attached to the rest of the molecule through a -C(=O) group. Exemplary alkanoyl groups include, but are not limited to, acetyl, n-propionyl, and n-butyryl.

[0289] The term "alkanoyloxy" refers to an alkyl group, as defined herein, attached to the rest of the molecule through a -OC(=O) group. Exemplary alkanoyloxy groups include, but are not limited to, acetoxy, n-propionyloxy, and n-butyryloxy.

[0290] The term "alkoxycarbonyl" refers to an alkoxy group, as defined herein, attached via the oxygen atom of the alkoxy group (ie, an alkyl ester group) to a -C(=O)- group.

[0291] The term "alkoxythiocarbonyl" refers to an alkoxy group, as defined herein, attached via the oxygen atom of the alkoxy group (ie, an alkylthioester group) to a C(=S)- group.

[0292] The term "carbamyl" as defined herein refers to -C(=O)-N(R)2, wherein 'R' represents a variable substitution.

[0293] The term "amidine" as defined herein refers to C(=N)-N(R)2, wherein 'R' represents variable substitution.

[0294] The term "sulfone" as defined herein refers to -S(=O)2-R, wherein 'R' represents variable substitution.

[0295] The term "thione" as defined herein refers to -C(=S)-R, wherein 'R' represents a variable substitution.

[0296] The terms "aralkyl" and "cycloalkylalkyl" refer to an aryl or cycloalkyl group (as defined herein) attached to the remainder of the molecule through an alkyl group (as defined herein). Exemplary aralkyl groups include, but are not limited to, benzyl and phenethyl. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, and cyclohexylethyl.

[0297] The term "succinimide" used as part of an antibody-drug conjugate (ADC) may refer to

[0298] The term "hydrolyzed succinimide" may refer to a succinimide in which the imide is hydrolyzed to form a carboxylic acid and an amide. Examples of hydrolyzed succinimide include

[0299] As used herein, the term "hydrolyzable group" refers to a portion that undergoes spontaneous hydrolytic cleavage under specific conditions. For example, a hydrolyzable group may be inert in neutral and alkaline solutions, but may undergo hydrolytic cleavage under acidic conditions within days, hours, minutes, or seconds. In some cases, a hydrolyzable group is constructed to undergo hydrolytic cleavage in a specific physiological environment, such as blood (e.g., peripheral blood) or oxidation (e.g., lysosomes) or reduction (e.g., cytoplasm) intracellular compartments. In some cases, a hydrolyzable group is constructed for, for example, cleavage by enzymes present in a specific organism (e.g., humans) or tissue (e.g., metabolically active tissues such as liver, kidney, or brain). A hydrolyzable group may be constructed for cleavage by a series of enzymes or specific enzymes. For example, a hydrolyzable group may comprise an oligopeptide of the sequence arginine-arginine-valine-arginine, to which human furin may have high cleavage activity. A hydrolyzable group may be constructed for cleavage within a specific environment, such as the endosomes or lysosomes of human cells. In such cases, the hydrolyzable group may be stable outside of the environment in which it is constructed for cleavage. For example, the hydrolyzable group may be stable in peripheral blood circulation, but hydrolyzes and cleaves when taken into cells. Examples of hydrolyzable groups include organophosphates such as phosphates, phosphorothioates and phosphorodithioates, carbamates, carbonates, thioesters, quaternary amines, ureas, disulfides, organic sulfates, diorganosulfates, certain amides and esters, and peptides with protease cleavage sites.

[0300] It will be appreciated by those skilled in the art that the compounds described herein having chiral centers can exist in and be isolated in optically active and racemic forms.

[0301] As used herein, the term "free drug" refers to a biologically active substance that is not covalently attached to an antibody. Therefore, a free drug refers to a compound that exists immediately after cleavage of the ADC. The release mechanism may 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. A free drug is a pharmacologically active substance that can exert a desired biological effect. In some embodiments, the pharmacologically active substance is a separate parent drug. In some embodiments, the pharmacologically active substance is a parent drug that is bonded to a component or residue of the ADC (e.g., a linker, succinimide, hydrolyzed succinimide, and / or a component of an antibody that has not undergone subsequent intracellular metabolism). In some embodiments, a free drug refers to a compound of any one of formula (A), (I)-(VIII), (IIa), or (IIIa) as described herein, or a pharmaceutically acceptable salt thereof, for example, wherein one or more of X, Y, W, A, and M are absent. In some embodiments, a free drug refers to a compound of formula (IX). In some embodiments, the free drug refers to a compound of formula (X). In some embodiments, the free drug refers to a compound disclosed in U.S. Publication No. 2017 / 0217960, or a pharmaceutically acceptable salt thereof, which is incorporated by reference in its entirety.

[0302] As used herein, the term "drug unit" refers to the free drug conjugated to the antibody in the ADC, as described herein.

[0303] Antibody-drug conjugates (ADCs)

[0304] Aspects of the present disclosure provide an antibody drug conjugate (ADC) with a TLR7 / 8 payload. Since many cells express TLR7 and TLR8 (including epithelial cells and myeloid cells), it is important to localize the effects of TLR7 / 8 agonists to specific disease sites for therapeutic efficacy. To this end, many ADCs disclosed herein are constructed to release their payloads within the target disease site. In many cases, ADCs can affect immune cell activation in the tumor suppressor microenvironment, thereby avoiding systemic cytokine and antibody-dependent toxicity typically induced by free antibodies and TLR7 / 8 agonists.

[0305] Some embodiments provide an antibody drug conjugate (ADC) having the following structure:

[0306] Ab-(LD) p

[0307] or a pharmaceutically acceptable salt thereof;

[0308] in:

[0309] Ab is an antibody according to the present disclosure;

[0310] Each L is a connector;

[0311] wherein each D is coupled to a linker;

[0312] wherein each L is covalently linked to Ab via the sulfur atom of a cysteine ​​residue or the ε-amino group of a lysine residue;

[0313] Subscript p is an integer from 1 to 16;

[0314] Each D is a TLR7 / 8 agonist.

[0315] Some embodiments provide an antibody drug conjugate (ADC) having the following structure:

[0316] Ab-(LD) p

[0317] or a pharmaceutically acceptable salt thereof;

[0318] in:

[0319] Ab is an antibody according to the present disclosure;

[0320] Each L is a connector;

[0321] wherein each D is coupled to a linker;

[0322] wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of Ab;

[0323] Subscript p is an integer from 1 to 16;

[0324] Each D has the structure of formula (A):

[0325]

[0326] or a pharmaceutically acceptable salt thereof;

[0327] in:

[0328] R 1is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharides, acylated C5-C9 monosaccharides (e.g. ),C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 trisaccharide;

[0329] R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or

[0330] R 1 and R 2Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L;

[0331] R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ;

[0332] R 4 Selected from the group consisting of: point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by:

[0333] (i) 1-3 independently selected halogens;

[0334] (ii)-OR C ;

[0335] (iii)-SR C ;

[0336] (iv)-NH-S(O2)R C ;

[0337] (v)-OC(=O)R C ;

[0338] (vi) -CO2H;

[0339] (vii) C1-C6 alkoxycarbonyl;

[0340] (viii) -C(=O)NR D R E ;

[0341] (ix)-NR D R E ;

[0342] (x)-[N(C1-C6 alkyl)R D R E ] + ;

[0343] (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of said -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocycle, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens;

[0344] (xii) phenyl substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H;

[0345] (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of said (-5-10 membered heteroaryl)C1-C6 alkyl is substituted with: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or

[0346] (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H;

[0347] When R4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point of covalent attachment to L;

[0348] Each R X are independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ; of which no more than one R X is the point of covalent attachment to L;

[0349] Subscript n is 0, 1, 2, 3, or 4;

[0350] R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B is a point of covalent attachment to L;

[0351] R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl;

[0352] R D 、R E 、R G and R HEach instance of is independently selected from the group consisting of: (a) a 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 R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R D 、R E 、R G and R H Only one of them is the point of covalent attachment to L;

[0353] R F Each instance of is independently selected from the group consisting of: (a) a 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;

[0354] R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl; wherein R I 、R J and R K At most one of them is a point of covalent attachment to L;

[0355] Each D has only one point of covalent attachment to L.

[0356] In some cases, the antibody drug conjugate (ADC) has the following structure:

[0357] Ab-(LD) p

[0358] or a pharmaceutically acceptable salt thereof;

[0359] in:

[0360] Ab is antibody;

[0361] Each L is a connector;

[0362] wherein each D is coupled to a linker;

[0363] wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a post-translational modification of Ab;

[0364] Subscript p is an integer from 1 to 16;

[0365] Each D has the structure of formula (I):

[0366]

[0367] or a pharmaceutically acceptable salt thereof;

[0368] in:

[0369] R 1 is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 trisaccharide;

[0370] R 2is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or

[0371] R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein the heterocyclyl or one of the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L;

[0372] R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ;

[0373] R 4 Selected from the group consisting of: point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)ORC ;-C(=O)SR C ;-C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by:

[0374] (i) 1-3 independently selected halogens;

[0375] (ii)-OR C ;

[0376] (iii)-SR C ;

[0377] (iv)-NH-S(O2)R C ;

[0378] (v)-OC(=O)R C ;

[0379] (vi) -CO2H;

[0380] (vii) C1-C6 alkoxycarbonyl;

[0381] (viii) -C(=O)NR D R E ;

[0382] (ix)-NR D R E ;

[0383] (x)-[N(C1-C6 alkyl)R D R E ] + ;

[0384] (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of said -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocycle, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens;

[0385] (xii) phenyl substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H;

[0386] (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl of said (-5-10 membered heteroaryl)C1-C6 alkyl is substituted with: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or

[0387] (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H;

[0388] When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point of covalent attachment to L;

[0389] R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ;

[0390] Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ;and

[0391] m is 0, 1, 2, or 3;

[0392] R A and R BEach instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B At most one instance is the point of covalent attachment to L;

[0393] R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl;

[0394] R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted with 1-3 independently selected C1-C6 alkyl groups; wherein R D 、R E 、R G and R H Only one of them is the point of covalent attachment to L;

[0395] R F Each instance of is independently selected from the group consisting of: (a) a 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;

[0396] R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl;

[0397] where R I 、R J and R K At most one of them is a point of covalent attachment to L;

[0398] Each D has only one point of covalent attachment to L.

[0399] In some cases, the structure of Formula (A) is that of Formula (I)-(II), (IIa)-(III), (IIIa)-(IIId), (IV)-(V), (VI)-(VII), or (VIIIl). Thus, in some cases, D has the structure of Formula (I), (II), (IIa)-(III), (IIIa)-(IIId), (IV), (V), (VI), (VII), or (VIIIl), wherein R 1 、R 2 、R 3 、R 4 、R 4A 、R 5 、R 6 、R 6A 、R X 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K , n, m, q and As defined herein.

[0400] In some cases, each D has the structure of Formula (I):

[0401]

[0402] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、RJ and R K Each of is 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.

[0403] In some cases, each D has the structure of Formula (II):

[0404]

[0405] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 、R 4 、R 5 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K Each of and m is as defined herein, and represents the point of covalent attachment to L.

[0406] In some cases, each D has the structure of Formula (IIa):

[0407]

[0408] or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J、 R K , m and Each of m is as defined herein. In some cases, m is 0 or 1. In some cases, m is 0.

[0409] In some cases, each D has a structure of Formula (III):

[0410]

[0411] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R4 A 、R 5 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K Each of and m is as defined herein.

[0412] In some cases, each D has the structure of Formula (IIIa):

[0413]

[0414] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4A 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K Each of and m is as defined herein.

[0415] In some cases, each D has the structure of Formula (IV):

[0416]

[0417] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 4 、R 5 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G、R H 、R I 、R J 、R K , m and Each of which is as defined herein.

[0418] In some cases, each D has a structure of Formula (V):

[0419]

[0420] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 6 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K , m and Each of which is as defined herein.

[0421] In some cases, each D has the structure of Formula (VI):

[0422]

[0423] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K and Each of R 6A Each instance of is independently selected from the group consisting of halogen, hydroxy, 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 -NRA R B ; and the subscript q is 0, 1, or 2.

[0424] In some cases, each D has the structure of Formula (VII):

[0425]

[0426] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6A R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K , subscript q and Each of which is as defined herein.

[0427] In some cases, each D has the structure of Formula (VIII):

[0428]

[0429] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6A R A 、R B 、R C 、R D 、R E 、R F 、R G 、R H 、R I 、R J 、R K , subscript q and Each of which is as defined herein.

[0430] In some cases of Formulas (A) and (I), R 1 、R 2 、R 3 、R 4 , or R A 、R B 、RC 、R D 、R E 、R F 、R G 、R H 、R I 、R J or R K An example of is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 、R 3 、R 4 , or R A or R B An example of is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 、R 3 or R 4 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 or R 4 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 2 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein one of the heterocyclyl or 1-3 independently selected C1-C6 alkyl groups is the point of covalent attachment to L. In some cases of formulas (A) and (I), R 3 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 4 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), R 4 is a C1-C6 alkyl group, and the C1-C6 alkyl group or its substituent is further substituted by a point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is a C1-C6 alkyl group, and the C1-C6 alkyl group is further substituted with a point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 is a C1-C6 alkyl group (h), and the substituents of the C1-C6 alkyl group are further substituted by the point of covalent attachment to L. In some cases of formulas (A) and (I), R 4 Contains R C 、R D 、R E 、R G and / or R H, which is a point of covalent attachment to L. In some instances of Formula (A), R x An example of is the point of covalent attachment to L. In some instances of Formula (A), R X Instances containing R A 、R B 、R F 、R G 、R H 、R I 、R J or R K , which is a point of covalent attachment to L. In some instances of Formulas (A) and (I), R 1 or R 2 Instances of -NR A R B Substituted, where R A or R B is the point of covalent attachment to L. In some instances of Formula (A), R X An example of -NR A R B , where R A or R B is the point of covalent attachment to L.

[0431] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently linked to Ab via a sulfur atom of a cysteine ​​residue, an ε-amino group of a lysine residue, an imidazole group of a histidine residue, a guanidine group of an arginine residue, a thiol group of a methionine residue, a carboxylic acid group of an aspartic acid or glutamic acid residue, a phenol group of a tyrosine residue, or an indole group of a tryptophan residue. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently linked to Ab via a sulfur atom of a cysteine ​​residue or an ε-amino group of a lysine residue. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), each L is covalently linked to a glycosylation of Ab.

[0432] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1is 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 thioketone, 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 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl; C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl; 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: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 trisaccharide and acylated C 15 -C 27 In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl or phenyl is optionally substituted by 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharides and acylated C5-C9 monosaccharides. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R 1 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl or phenyl is optionally substituted by 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B, phosphoryl, sulfyl, nitro, C5-C9 monosaccharides and acylated C5-C9 monosaccharides. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl, the latter optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Selected from the group consisting of hydrogen and C1-C3 alkyl, the latter optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is selected from the group consisting of hydrogen and C1-C3 alkyl, the latter optionally substituted with a substituent selected from the group consisting of hydroxy, halogen and -NH2. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R 1 is selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 For hydrogen.

[0433] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy, -NR A R B , C5-C9 monosaccharides and acylated C5-C9 monosaccharides. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R1 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, C1-C3 alkoxy, -NR A R B , C5-C9 monosaccharides and acylated C5-C9 monosaccharides. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R 1 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 is substituted with 1-3 substituents. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 Not replaced.

[0434] In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 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: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R BIn some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 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 C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 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 C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein 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: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2Selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl or phenyl is optionally substituted by a substituent selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Selected from the group consisting of: C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl and phenyl; wherein 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: hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Selected from the group consisting of hydrogen and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2is selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, and -NH2. In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is hydrogen or C1-C3 alkyl. In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII) and (VIII), R 2 is selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 For hydrogen.

[0435] In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, phenyl, C1-C3 alkoxy and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, C1-C3 alkoxy and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, C1-C3 alkoxy and -NR A R B In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 is substituted with 1-3 substituents. In some cases of Formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 In some cases of Formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2In some cases of Formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 2 Not replaced.

[0436] In some cases of Formula (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 and R 2 At least one of is hydrogen. In some cases of formulas (A) and (I), R 1 is the point of covalent attachment to L and R 2 In some cases of Formulas (A), (I), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R 1 and R 2 For hydrogen.

[0437] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: -NR A R B 、-C(=O)NR A R B , C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; wherein each C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C6 alkyl group substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio and -NR A R BIn some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C6 alkyl group substituted by a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C6 alkyl group substituted by a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo and -NH2.

[0438] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl and 5-10 membered heteroaryl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl or 5-10 membered heteroaryl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl and 5-10 membered heteroaryl; wherein C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl or 5-10 membered heteroaryl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: hydrogen, -NR A R B , C1-C6 alkyl, C1-C6 alkanoyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl or phenyl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: -NR A R B, C1-C6 alkyl, C1-C6 alkanoyl and phenyl; wherein C1-C6 alkyl, C1-C6 alkanoyl or phenyl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Selected from the group consisting of: -NR A R B , C1-C6 alkyl and C1-C6 alkanoyl; wherein C1-C6 alkyl or C1-C6 alkanoyl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is C1-C4 alkyl, which is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C4 alkyl group, which is optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3is C1-C4 alkyl, which is optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo and -NH2. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII) and (VIII), R 3 is a C1-C4 alkyl group, which is optionally substituted with a substituent selected from the group consisting of hydroxy, halogen and -NH2.

[0439] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, phenyl, C1-C6 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, phenyl, C1-C6 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, cyano, oxo, C1-C6 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with a substituent selected from the group consisting of hydroxy, cyano, oxo, C1-C6 alkoxy and -NR A RB In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with a substituent selected from the group consisting of oxo, C1-C3 alkoxy and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Optionally substituted with a substituent selected from the group consisting of C1-C3 alkoxy and -NHR B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 Not replaced.

[0440] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C5 alkyl group, which is optionally substituted by 1 substituent selected from the group consisting of hydroxy, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3 is a C1-C5 alkyl group, which is optionally substituted by 1 substituent selected from the group consisting of a C1-C3 alkoxy group and -NR A R B In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (V), (VI), (VII), and (VIII), R 3is selected from the group consisting of butyl, -CH2-O-CH2CH3, -CH2-CH2-O-CH3, and -CH2-NH-CH2CH3. In some cases, R 3 For hydrogen.

[0441] In some cases of Formula (A) and (I), R 4 is the point of covalent attachment to L; hydrogen; -OR C ;-S(=O)2R C ;-C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C ;-PO3R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H; when R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituents may be further substituted by a point of covalent attachment to L. In some cases of formula (A) and (I), R 4 is hydrogen; -C(=O)NR D R E;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H; when R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent may be further substituted at a point where L is covalently bonded.

[0442] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen; -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)RC (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen, or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] +or 1-3 independently selected halogen substituted; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is hydrogen, or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (ix) -NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is C1-C6 alkyl, which is optionally substituted by: (ii) -O(C1-C6 alkyl); (ix) -NR D R E , where -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + replace.

[0443] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R4 is C1-C6 alkyl, which is optionally substituted with: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (ix) -NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is C1-C6 alkyl, which is substituted by: (ii) -O(C1-C6 alkyl); (ix) -NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is a C1-C6 alkyl group substituted by: (ix)-NR D RE , where -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl of -(phenyl) C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + replace.

[0444] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 -C(=O)NR D R E ;-C(=O)OR C ;-C(=O)SR C ;-C(=S)R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocyclic ring, a -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -CO2H; (xiii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xiv) 5-10 membered heteroaryl, which is optionally substituted with halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6) alkoxycarbonyl or -CO2H; wherein when R 4 When it is a C1-C6 alkyl group, it is a C1-C6 alkyl group.

[0445] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 is C1-C6 alkyl, which is optionally substituted by: (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (ix)-NR D R E (xi) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocyclic ring, a -NR D R E or -[N(C1-C6 alkyl)R D R E ] + or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E Or -CO2H substitution.

[0446] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 Selected from the group consisting of:

[0447] wherein each instance of the subscript z is independently 1, 2, or 3.

[0448] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 Selected from the group consisting of:

[0449] In some cases of Formulas (A), (I), (II), (IIa), (IV), (V), (VI), (VII), and (VIII), R 4 Selected from the group consisting of:

[0450] In some cases of Formulas (III) and (IIIa), and R 4A is (a) the point of covalent attachment to L, or (b) C1-C6 alkyl, optionally substituted with: (i) 1-3 independently selected halogens; (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (ix)-[N(C1-C6 alkyl)R D R E ] + (x) - (phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; (xi) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; or (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or 5-10 membered heteroaryl, which is optionally substituted with halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; when R 4AWhen (b) C1-C6 alkyl, the C1-C6 alkyl or its substituent is further substituted by a point of covalent attachment to L. In some cases of formula (III) and (IIIa), R 4A is C1-C6 alkyl, which is optionally substituted with: (i) 1-3 independently selected halogens; (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (ix)-[N(C1-C6 alkyl)R D R E ] + (x) - (phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or (xi) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or 5-10 membered heteroaryl, which is optionally substituted with halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; wherein the C1-C6 alkyl group or its substituent is further substituted by a point of covalent attachment to L. In some cases of formula (III) and (IIIa), R 4A is a C1-C6 alkyl group substituted by: (ii) -OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (ix)-NR D RE ; (ix)-[N(C1-C6 alkyl)R D R E ] + or (x) - (phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; wherein the C1-C6 alkyl or its substituent is further substituted by the point of covalent attachment to L. In some cases of formula (III) and (IIIa), R 4A is a C1-C6 alkyl group substituted by: (ix)-NR D R E ; (ix)-[N(C1-C6 alkyl)R D R E ] + or (x) - (phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substitutions; wherein the C1-C6 alkyl group or its substituent is further substituted by the point of covalent attachment to L.

[0451] In some instances of Formula (A), subscript n is 0, 1, or 2. In some instances of Formula (A), subscript n is 1. In some instances of Formula (A), subscript n is 0. In some instances of Formula (A), R X An example of R 5 And R X The remaining instances of R 6 As used herein, the “rest” R X A group is 0 or n-1 R X groups, such as 0, 1, 2 or 3 R X Therefore, when the subscript n is 0, the remaining R X There are zero groups; when the subscript n is 1, the remaining R X The group is also zero; when the subscript n is 2, the remaining R X There is 1 group; when the subscript n is 3, the remaining R X There are 2 groups; when the subscript n is 4, the remaining R X There are 3 groups.

[0452] In some cases of Formulas (A) and (I), R5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K In some cases of Formulas (A) and (I), R 5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of hydrogen, -C(=O)OR F 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K In some cases of Formulas (A) and (I), R 5 Selected from the group consisting of: hydrogen, -C(=O)OR F 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K In some cases of Formulas (A) and (I), R 5 -C(=O)OR F In some cases of Formulas (A) and (I), R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases of Formulas (A) and (I), R 5 It is -C(=O)OH or -C(=O)OCH3.

[0453] In some cases of Formulas (A) and (I), each R 6independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ; of which no more than one R 6 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, and -NR A R B ; of which no more than one R 6 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B ; of which no more than one R 6 is the point of covalent attachment to L. In some instances of Formulas (A) and (I), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B .

[0454] In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 Selected from the group consisting of: hydrogen, -C(=O)OR F 、-S(O2)NR G R H 、-N(RI )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 -C(=O)OR F In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B .

[0455] In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B .

[0456] In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and subscript m is 0. In some cases of formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 is -C(=O)OH; and subscript m is 0. In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), and (IV), R 5 and subscript m is 0. In some instances of formula (A), (I), (II), (IIa), (III), (IIIa), and (IV), subscript m is 0, 1, or 2. In some instances of formula (A), (I), (II), (IIa), (III), (IIIa), and (IV), subscript m is 1 or 2. In some instances of formula (A), (I), (II), (IIa), (III), (IIIa), and (IV), subscript m is 0 or 1. In some instances of formula (A), (I), (II), (IIa), (III), (IIIa), and (IV), subscript m is 1. In some instances of formula (A), (I), (II), (IIa), (III), (IIIa), and (IV), subscript m is 0.

[0457] In some cases of Formulas (A) and (I), R 6 An example of a point of covalent attachment to L and another R 6 (if present) are independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B .

[0458] In some embodiments disclosed herein, R 5is acidic, negatively charged, and / or highly polar (e.g., comprises a dipole moment of at least about 2.0 Debye). The surprising observation disclosed herein (e.g., as demonstrated in Example 37) is that C7 imidazoquinoline functionalization (R 5 ) can enhance toll-like receptor activation. It is expected that the importance of this functionalization in certain imidazoquinolines may have been previously overlooked because it tends to reduce cellular uptake, which may mask its effectiveness when applied as a free drug. However, when used in tandem with effective targeting and uptake systems (such as the antibodies disclosed herein), imidazoquinolines with negative or highly polar C7 functionalization can achieve enhanced TLR7 / 8 responses. Without being limited by theory, it is hypothesized that TLR7 / 8 binding can position the imidazoquinoline C7 near charged or polar proton residues, allowing strong hydrogen bonding interactions to be achieved, thereby enhancing binding strength and agonist performance.

[0459] Thus, in certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 Negatively charged and / or highly polar (e.g., comprising a dipole moment of at least about 2.0 Debye) under physiological conditions. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a pKa of up to about 7.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a pKa of up to about 6.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a pKa of up to about 5.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a pKa of up to about 4.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a pKa of up to about 3.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5comprising a pKa of up to about 2.0. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a dipole moment of at least about 2.0 Debye (e.g., as calculated using density functional theory). In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a dipole moment of at least about 2.5 debyes. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 comprising a dipole moment of at least about 3.0 Debye. In certain instances of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (VI), (VII), and (VIII), R 5 Comprising a pKa of at most about 7.0 or a dipole moment of at least about 2.0 Debye.

[0460] In some cases of Formula (A), each R X are independently selected from the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K 、-S(O3)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B In some cases of Formula (A), R X An example of a point of covalent attachment to L and R X All other instances of (if present) are independently selected from the group consisting of hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)RJ 、-N(R I )-S(O2)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B .

[0461] In some instances of Formula (A), n is 0, 1, or 2. In some instances of Formula (A), n is 1 or 2. In some instances of Formula (A), n is 0 or 1. In some instances of Formula (A), n is 0. In many instances, n is 1.

[0462] In some cases of Formulas (A) and (I), R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of formulas (A) and (I), R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of formulas (A) and (I), R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) independently selected from the group consisting of hydrogen and methyl. In some instances of Formulas (A) and (I), R A and R B At most one example of is (a) a point of covalent attachment to L, and R A and R B The remaining example of is hydrogen.

[0463] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B Each instance of is independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R BEach instance of is independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B Each instance of is independently selected from the group consisting of hydrogen and methyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R A and R B All instances of are hydrogen.

[0464] In some cases of Formulas (A) and (I), R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) the group consisting of: hydrogen, phenyl, and C1-C 10 alkyl, which is optionally substituted with phenyl or 1-3 independently selected halogens. In some cases of formula (A) and (I), R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) a group consisting of: hydrogen, phenyl, and C1-C4 alkyl, optionally substituted with phenyl. In some cases of formulas (A) and (I), R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) a group consisting of hydrogen and C1-C4 alkyl. In some instances of Formulas (A) and (I), R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, and (b) the group consisting of hydrogen and methyl.

[0465] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C Each instance of is independently selected from the group consisting of hydrogen, phenyl, and C1-C 10 alkyl, which is optionally substituted with phenyl or 1-3 independently selected halogens. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R CEach instance of is independently selected from the group consisting of hydrogen, phenyl, and C1-C4 alkyl, which is optionally substituted with phenyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C Each instance of is independently selected from the group consisting of hydrogen and C1-C4 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R C Each instance of is independently selected from the group consisting of hydrogen and methyl.

[0466] In some cases of Formulas (A) and (I), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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 formulas (A) and (I), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a 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 formulas (A) and (I), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl. In some cases of formulas (A) and (I), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of hydrogen and methyl.

[0467] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D 、R E 、RG and R H Each instance of is 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 Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D 、R E 、R G and R H Each instance of is 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 Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of hydrogen and C1-C6 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R D 、R E 、R G and R H Each instance of is independently selected from the group consisting of hydrogen and methyl.

[0468] In some cases of Formulas (A) and (I), R F Each instance of is independently selected from the group consisting of: (a) a 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 formulas (A) and (I), R F Each instance of is independently selected from the group consisting of: (a) a 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 formulas (A) and (I), R FEach instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of formulas (A) and (I), R F Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, trifluoromethyl, and C1-C3 alkyl. In some cases of formulas (A) and (I), R F Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) the group consisting of hydrogen, trifluoromethyl, and methyl.

[0469] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, and C1-C6 alkyl, optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, and C1-C6 alkoxy. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each instance of is 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 Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R FEach instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C3 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and methyl.

[0470] In some cases of Formulas (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), when R F is trifluoromethyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, or C1-C6 alkyl (optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C6 alkanoyloxy, C1-C6 alkoxy, and C3-C8 cycloalkyl); R 4 -[N(C1-C6 alkyl)R D R E ] + -(phenyl)C1-C6 alkyl, wherein its C1-C6 alkyl is -[N(C1-C6 alkyl)R D R E ] + or -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by -[N(C1-C6 alkyl)R D R E ] + replace.

[0471] In some cases of Formulas (A) and (I), R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C3 alkyl. In some instances of formulas (A) and (I), R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and methyl. In some instances of Formulas (A) and (I), R I 、R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) hydrogen.

[0472] In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I 、R J and R K Each instance of is independently selected from the group consisting of hydrogen and C1-C3 alkyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I 、R J and R K Each instance of is independently selected from the group consisting of hydrogen and methyl. In some cases of Formula (A), (I), (II), (IIa), (III), (IIIa), (IV), (V), (VI), (VII), and (VIII), R I 、R J and R K Each instance of is hydrogen.

[0473] In some cases of Formulas (VI), (VII), and (VIII), R 6A Each instance of is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl and -NR A R B In some cases of Formulas (VI), (VII), and (VIII), R 6A Each instance of is independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy and -NR A R B In some cases of Formulas (VI), (VII), and (VIII), R 6A Each instance of is independently selected from the group consisting of: C1-C6 alkyl and -NR A R B In some instances of Formulas (VI), (VII), and (VIII), subscript q is 0 or 1. In some instances of Formulas (VI), (VII), and (VIII), subscript q is 0.

[0474] In some cases, each D is

[0475]

[0476]

[0477]

[0478] in represents a point of covalent attachment to L. In some cases, each D is in represents a point of covalent attachment to L. In some cases, each D is in represents the point of covalent attachment to L.

[0479] In some embodiments, ADC is capable of releasing (i) a component of a linker bound to D; (ii) a component of an antibody bound to LD; and / or (iii) a parent compound D (as defined herein) as a free drug. In some embodiments, the free drug is released at the intended site of action of the antibody targeting. In some embodiments, the free drug is released within the intended site of action of the antibody targeting. In some embodiments, the free drug is capable of binding to toll-like receptors (TLRs). In some embodiments, the binding of the free drug to TLRs exhibits an agonist effect on the TLRs. In some embodiments, the binding of the free drug to the TLRs exerts an immunostimulatory effect.

[0480] Antibody

[0481] For many ADCs disclosed herein, antibodies target antigens associated with clinically relevant disease states. Such antibodies can localize ADCs to the site of disease, thereby achieving targeted TLR7 / 8 agonist payload delivery and site-specific treatment. Since untargeted TLR7 / 8 agonists can affect systemic immune-related toxicity, TLR7 / 8-mediated immune reactivation is generally only feasible when the agonist payload is delivered in a site-specific manner. Therefore, the targeted ADC antibodies disclosed herein can enable the use of efficient TLR7 / 8 agonists, which would otherwise exhibit extremely high toxicity via systemic delivery. In some cases, antibodies further mediate cellular uptake to achieve intracellular or subcellular TLR7 / 8 agonist delivery.

[0482] As used herein, the term "monoclonal antibody" may refer to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population contain identical sequences except for possible naturally occurring mutations. Typically, 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 population of substantially homogeneous antibodies and should not be construed as requiring production of the antibody by any particular method.

[0483] Useful polyclonal antibodies are heterogeneous antibody molecule populations derived from the serum of immune animals. Useful monoclonal antibodies are homogeneous antibody populations directed against specific antigenic determinants (e.g., cancer or immune cell antigens, proteins, peptides, carbohydrates, chemicals, nucleic acids, or fragments thereof). Monoclonal antibodies (mAbs) directed against an antigen of interest can be prepared using any technology known in the art that provides for the production of antibody molecules by continuous cell lines in culture.

[0484] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. Antibodies include full-length antibodies and antigen-binding fragments thereof. Human monoclonal antibodies can be made by any of a variety of techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).

[0485] In some embodiments, antibodies include functionally active fragments, derivatives or analogs of antibodies that specifically bind to target cells (e.g., cancer cell antigens) or other antibodies that bind to cancer cells or matrix. In this regard, "functional activity" means that fragments, derivatives or analogs are able to specifically bind to target cells. In order to determine which CDR sequences bind to antigens, synthetic peptides containing CDR sequences are typically used in binding assays with antigens by any binding assay method known in the art (e.g., Biacore assays) (e.g., see 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).

[0486] In addition, recombinant antibodies, such as chimeric and humanized monoclonal antibodies comprising human and non-human parts, are useful antibodies, typically obtained using standard recombinant DNA techniques. Chimeric antibodies are molecules in which different parts are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a constant region derived from a human immunoglobulin. See, for example, U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules from non-human species having one or more CDRs from a non-human species and a framework region from a human immunoglobulin molecule. See, for example, 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 the methods described in International Publication No. WO 87 / 02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171496; 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 et al., 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 et al., 1986, Nature 321:522-525; Verhoeyan et al., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060; each of which is herein incorporated by reference in its entirety.

[0487] In some embodiments, the antibodies are fully human antibodies.In some embodiments, antibodies are produced using transgenic mice that are unable to express endogenous immunoglobulin heavy and light chain genes but are able to express human heavy and light chain genes.

[0488] In some embodiments, the antibody is an intact or fully reduced antibody.The term "fully reduced" is intended to refer to an antibody in which all four interchain disulfide linkages have been reduced to provide eight thiols that can be attached to the linker (L).

[0489] The connection to the antibody can be via a thioether linkage from a natural and / or engineered cysteine ​​residue, or from an amino acid residue engineered to participate in a cycloaddition reaction (e.g., a click reaction) with a corresponding linker intermediate. See, for example, Maerle et al., PLOS One 2019: 14(1); e0209860. In some embodiments, the antibody is an intact or fully reduced antibody, or an antibody with an engineered cysteine ​​group modified with a functional group that can participate in, for example, click chemistry or other cycloaddition reactions (e.g., Diels-Alder reaction or other [3+2] or [4+2] cycloaddition) for connecting other components of an ADC as described herein. 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).

[0490] Antibodies that specifically bind to cancer or immune cell antigens can be purchased or produced by any method known to those skilled in the art, such as chemical synthesis or recombinant expression technology. Nucleotide sequences encoding antibodies that specifically bind to cancer or immune cell antigens can be obtained, for example, from the GenBank database or similar databases, literature publications, or by conventional cloning and sequencing.

[0491] In some embodiments, antibodies can be used to treat cancer (e.g., antibodies approved by the FDA and / or EMA). Antibodies that specifically bind to cancer or immune cell antigens can be purchased or produced by any method known to those skilled in the art, such as recombinant expression technology. Nucleotide sequences encoding antibodies that specifically bind to cancer or immune cell antigens can be obtained, for example, from the GenBank database or similar databases, literature publications, or by conventional cloning and sequencing.

[0492] In some cases, the antibody has a mutation or post-translational modification that affects non-Fab-mediated uptake. Peripheral immune cells that are highly responsive to TLR7 / 8 agonists, when activated via non-antigen-specific, Fc-mediated uptake of TLR7 / 8 antibody-drug conjugates, can promote a strong systemic response that may be harmful or otherwise undesirable. In such cases, the antibody may have an effector function-reducing mutation, such as L234A / L235A, D265A / N297A, D270A, K322A, P329A, P329G, or a combination thereof, that reduces non-immune uptake (e.g., FcγR-mediated uptake).

[0493] In some embodiments, the antibody can be constructed to bind to the surface antigen of the cell. The antibody or the complex comprising the antibody can be constructed to internalize in the cell after binding to the surface antigen. For example, the antibody or the ADC comprising the antibody can be constructed to carry out endocytosis after binding to the surface antigen of the cell. In some embodiments, the antibody (or the ADC comprising the antibody) is constructed to internalize in the cancer cell. In some embodiments, the antibody (or the ADC comprising the antibody) is constructed to internalize in the 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 (for example, expressed on lymphocytes). In some embodiments, the receptor or receptor complex comprises a member of the immunoglobulin gene superfamily, a member of the TNF receptor superfamily, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a surface receptor expressed by a complement control protein or other immune cells.

[0494] In some embodiments, the antibodies are constructed to specifically bind to cancer cell antigens. In some embodiments, the antibodies are constructed to specifically bind to immune cell antigens. In some embodiments, the immune cell antigen is a tumor-associated macrophage antigen. In some embodiments, the antibodies are constructed to specifically bind to EphA2. It should be understood that the antibody component of the ADC is the residue form of the antibody, such that the "Ab" in the ADC structures described herein is incorporated into the structure of the antibody.

[0495] Non-limiting examples of antibodies that can be used to treat cancer and antibodies that specifically bind to tumor-associated antigens are disclosed in the following: Franke, AE, Sievers, EL and Scheinberg, DA, "Cell surface receptor-targeted therapy of acute myeloid leukemia: a review" Cancer Biother Radiopharm. 2000, 15, 459-76; Murray, JL, "Monoclonal antibody treatment of solid tumors: a coming of age" Semin Oncol. 2000, 27, 64-70; Breitling, F. and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998, each of which is hereby incorporated by reference in its entirety.

[0496] Non-limiting examples of antigens that can be targeted by the antibodies of the present disclosure include ADAM12 (e.g., catalog number 14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher catalog number PA5-25959); AGR2 (e.g., ThermoFisher catalog number PA5-34517); AKAP-4 (e.g., catalog number PA5-52230); ALK (e.g., DLX521); ALPP (e.g., catalog number MA5- 15652); ALPPL2 (e.g., Catalog No. PA5-22336); AMHR2 (e.g., ThermoFisher Catalog No. PA5-13902); Androgen Receptor (e.g., ThermoFisher Catalog No. MA5-13426); ANTXR1 (e.g., Catalog No. MA1-91702); ANXA1 (e.g., Catalog No. 71-3400); ARTN (e.g., ThermoFisher Catalog No. PA5-47063); ASCT2 (e.g., idactamab); Axl (e.g., BA3011; tilvestamab); B7-DC (e.g., catalog number PA5-20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., catalog number 14-5949-82); B7-H6 (e.g., catalog number No. 12-6526-42); B7-H7; BAFF-R (e.g., Catalog No. 14-9117-82); BCMA; BCR-ABL; BMPR2; BORIS; C4.4a; CanAg; C5 complement (e.g., BCD-148; CAN106); CA-125; CA19-9 (e.g., AbGn-7; MVT-5873); CA9 (e.g., girentuximab); CALCR (e.g., see International Publication No. WO 2015077826); CAMPATH-1 (e.g., alemtuzumab; ALLO-647; ANT1034); carcinoembryonic antigen (e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab); CCNB1; CD112 (e.g., see 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 (e.g., see 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 (e.g., see International Publication No. WO 2020252110); CD79b; CD96; CD97; CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (e.g., see 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 (e.g., see 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 (e.g., see International Publication No. WO 2018222675); DDR1; de2-7 EGFR (e.g., MAb 806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (e.g., see U.S. Patent No. 10,836,823); EGF; EGFR; endosialin (e.g., ontuxizumab); ENPP1; EPCAM (e.g., adecatumumab); EPHA receptor; EPHA2; E RBB2 (e.g., trastuzumab); ERBB3; ERVMER34_1; ETV6-AML (e.g., catalog number PA5-81865); FAS; FasL; Fas-related antigen 1; FBP; FGFR1 (e.g., RG7992); FGFR2 (e.g., aprutumab); FGFR3 (e.g., vofatamab); FGFR4 (e.g., e.g., MM-161); FLT3 (e.g., 4G8SDIEM); FN; FN1; FOLR1 (e.g., farletuzumab); FRa; FSHR; FucGM1 (e.g., BMS-986012); FZD5; FZD8; G250; GAGE; GCC; GD2 (e.g., dinutuximab); GD3 (e.g., mitumomab) ; GITR (e.g., ragifilimab); GloboH; GM2 (e.g., BIW-8962); GM3 (e.g., racotumomab); gp100; GPA33 (e.g., KRN330); GPC3 (e.g., codrituzumab); gpNMB (e.g., glembatumumab); GPR87;GUCY2C (e.g., indusatumab); HAS3; HAVCR2; HLA-E; HLA-F; HLA-G (e.g., TTX-080); HPV E6 E7; hTERT; ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IL13Ra2; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); ITGAV (e.g., abituzumab); ITGB6; ITGB8; KISS1R; L1CAM (e.g., (e.g., JCAR023); LAG-3 (e.g., encelimab); LAMP1; LCK; legumin; LMP2; LY6G6D (e.g., PA5-23303); LY9 (e.g., PA5-95601); LYPD1 (e.g., ThermoFisher catalog number PA5-26749); MAD-CT-1; MAD-CT-2; MAGEA1 (e.g., catalog number MA5-11338); MAGEA3 (e.g., ThermoFisher catalog number 60054 -1-IG); MAGEA4 (e.g., catalog number MA5-26117); MAGEC2 (e.g., ThermoFisher catalog number PA5-64010); MELTF (e.g., ThermoFisher catalog number H00004241-M04A); MerTk (e.g., DS5MMER, catalog number 12-5751-82); metalloproteinases; MFSD13A; MICA (e.g., 1E2C8, catalog number 66384-1-IG); MICB (e.g., catalog number MA5-29422); Mincle (e.g., OTI2A8, catalog number TA505101); MLANA (e.g., catalog number MA5-15237); ML-IAP (e.g., 88C570, ThermoFisher catalog number 40958); MSLN (e.g., 5B2, catalog number MA5-11918); MUC1 (e.g., MH1(CT2), ThermoFisher catalog number MA5-11202); MUC5AC (e.g., 45M1, catalog number MA5-12178); MYCN (e.g., NCM-II 100, ThermoFisher catalog number MA1-170); NA17; NCAM1 (e.g., ThermoFisher catalog number MA5-11563); and adhesion protein-4 (e.g., enfortumab).NOX1 (e.g., catalog number PA5-103220); NT5E (e.g., 7G2, ThermoFisher catalog number 41-0200); NY-BR-1 (e.g., NY-BR-1 No. 2, catalog number MA5-12645); NY-ESO-1 (e.g., E978m, catalog number 35-6200); OX40 (e.g., ABM193); OY-TES1; p53; p53 mutants; PAP; PAX3 (e.g., GT1210, ThermoFisher catalog number MA5-31583); PAX5; PDGFR-B (e.g., rinucumab); PDPN (e.g., ThermoFisher catalog number 14-5381-82); PLAV1; PMSA; polysialic acid (e.g., see Watzlawik et al., J Nat Sci. 2015; 1(8):e141); PR1; PROM1 (e.g., catalog number 14-1331-82); PSA (e.g., ThermoFisher catalog number 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 mutants (e.g., Shin et al. Sci. Adv. 2020; 6(3): eaay2174); RET (e.g., WO2020210551); RGS5 (e.g., TF-TA503075); RhoC (e.g., ThermoFisher catalog PA5-77866); ROR1 (e.g., cirmtuzumab); ROR2 (e.g., BA3021); ROS1 (e.g., WO2019107671); sarcoma translocation breakpoints; SART3 (e.g., TF 18025-1-AP); Sialyl-Thomsen-nouveau antigen (e.g., Eavarone et al. PLoS One. 2018; 13(7): e0201314); Siglecs 1-16 (e.g., see Angata et al., Trends Pharmacol. Sci. 2015; 36(10): 645-660); SIRPa (e.g., catalog number 17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLC10A2 (e.g., ThermoFisher catalog number PA5-18990);SLC12A2 (e.g., ThermoFisher Catalog No. 13884-1-AP); SLC17A2 (e.g., ThermoFisher Catalog No. PA5-106752); SLC38A1 (e.g., ThermoFisher Catalog No. 12039-1-AP); SLC39A5 (e.g., ThermoFisher Catalog No. MA5-27260); SLC39A6 (e.g., ladiratuzumab); SLC44A4 (e.g., ASG-5ME); SLC6A15 (e.g., ThermoFisher Catalog No. PA5-52586); SLC6A6 (e.g., ThermoFisher Catalog No. PA5-53431); SLC7A11 (e.g., ThermoFisher Catalog No. PA1-16893); SLC7A5; sLe; SLITRK6 (e.g., sirtratumab); sperm protein 17 (e.g., BS-5754R); SSX2 (e.g., ThermoFisher Catalog No. MA5-24971); survivin (e.g., PA1-16836); TACSTD2 (e.g., PA5-47074); TAG-72 (e.g., MA1-25956); tenascin; TF (e.g., tisomycin). (e.g., tisotumab); Tie3; TLR2 / 4 / 1 (e.g., tomaralimab); TM4SF5 (e.g., 18239-1-AP); TMEM132A (e.g., catalog number PA5-62524); TMEM40 (e.g., PA5-60636); TMPRSS11D (e.g., PA5-30927); Tn; TNFRSF12 (e.g., BAY-356); TRAIL (e.g., catalog number 12-9927-42); TRAIL1; TRP-2 (e.g., PA5-52736); ULBP1 / 2 / 3 / 4 / 5 / 6 (e.g., PA5- 5-82302); uPAR (e.g., ATN-658); UPK1B (e.g., ThermoFisher Catalog No. PA5-56863); UPK2 (e.g., ThermoFisher Catalog No. PA5-60318); UPK3B (e.g., ThermoFisher Catalog No. PA5-52696); VEGF (e.g., GNR-011); VEGFR2 (e.g., gentuximab); VSIR (e.g., ThermoFisher Catalog No. PA5-52493); WT1 (e.g., ThermoFisher Catalog No. MA5-32215);and XAGE1 (e.g., ThermoFisher Cat. No. PA5-46413). ;

[0497] Non-limiting examples of target antigens include Axl (e.g., BA3011; tevezumab); B7-1 (e.g., galiximab); B7-2 (e.g., catalog number 12-0862-82); B7-DC (e.g., catalog number PA5-20344); B7-H3 (e.g., enoxaparin, obinutuzumab, MGD009, MGC018, DS-7300); B7-H4 (e.g., catalog number 14-5949-82); B7-H6 (e.g., catalog number 12-6526-42); B7-H7; BAFF-R (e.g., catalog number 14-9117-82); BCMA; C5 components (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamulizumab-kpkc); CCR8 (e.g., JTX-1811); CD112 (e.g., see U.S. Publication No. 20100008928); CD115 (e.g., iklimab; cabilizumab; imituzumab); 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., divizumab; ibritumomab); CD24 (e.g., see U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD25 (e.g., basiliximab); CD27 (e.g., varituzumab); CD274 (e.g., adebelimumab; atezolizumab; galivucam); CD278 (e.g., feladilimab; vopelimab); CD28 (e.g., REGN5668); CD3 (e.g., ortelizumab; visilizumab); CD30 (e.g., ituzumab); CD30L (e.g., see U.S. Patent No. 9,926,373); CD32 (e.g., mAb2B6); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD352 (e.g., SGN-CD352A); CD37 (e.g., rilotuzumab; GEN3009); CD38 (e.g., furezetuzumab; AMG 424); CD3D; CD3E (e.g., foraminib; teplizumab); CD3G; CD40 (e.g., dacetuzumab; ruxolitinib); CD44 (e.g., RG7356);CD45 (e.g., etuzumab); CD47 (e.g., leterlimumab; morolimumab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; azotumomab); CD51; CD70 (e.g., gutuzumab); CD74 (e.g., miratumumab); CD79A (e.g., see International Publication No. WO 2020252110); CD83 (e.g., CBT004); CD97; CD262 (e.g., tegtuzumab); CLEC12A (e.g., tepotizumab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., urolulumab); DCIR; DCSIGN (e.g., see International Publication No. WO 2020252110); 2018134389); Dectin 1 (e.g., see U.S. Patent No. 9,045,542); Dectin 2 (e.g., ThermoFisher Catalog No. MA5-16250); DR4 (e.g., mapatumumab); endosialin (e.g., ontuximab); FasL; FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragavulimab); HAVCR2; HER2; HER3; HLA-DR ; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faramoxizumab); IFNAR2; IGF-1R; IL1RAP (e.g., nidalizumab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); integrin αvβ6; LAG-3 (e.g., ansarizumab); LAMP1; LAYN; LCK; LILR B2; LILRB4; MerTk (e.g., DS5MMER, catalog number 12-5751-82); Mesothelin; MICA (e.g., 1E2C8, catalog number 66384-1-IG); MICB (e.g., catalog number MA5-29422); MICA; Mincle (e.g., OTI2A8, catalog number TA505101); MRC1 (e.g., ThermoFisher catalog number 12-2061-82); MUC1; M uc16; NcaPi2B; fibronectin-4; OX40 (e.g., ABM193); PD-1 (e.g., balstilimab; budigalimab; geptanolimab); PD-L1; prolactin receptor; PTK7; PVRIG; ROR-1; Sialyl-Thomsen-nouveau antigen (e.g., Eavarone et al. PLoS One, 2018; 13(7):e0201314);Siglecs 1-16 (see, e.g., Angata et al., Trends Pharmacol Sci. 2015; 36(10): 645-660); ); SIRPα (e.g., catalog number 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., tolarimab); 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 number PA5-52493); ZIP6 (anti-integrin αvβ6). ;

[0498] In some cases, the 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 αvβ6, h2A2, H2G12 / STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav / CD51, mesothelin, MICA, MUC-1, Muc16, NaPi2B, adhesion molecule-4, PD-L1, prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, and TROP2.

[0499] In some cases, the antibodies of the present disclosure target immune checkpoints. Among the various mechanisms that can lead to unstoppable cell growth, certain cancers use immune checkpoint proteins to create an immunosuppressive environment, thereby limiting immune activity near the cancer site. Since these cancers typically produce a large number of immune checkpoints, immune checkpoint targeting can be an effective means of locating ADC and TLR7 / 8 agonist payloads to cancer sites. In some cases, the antibodies of the present disclosure target immune checkpoints selected from the group consisting of: PDL1, PD1, CTLA-4, B7H4, B7H3, TIGIT, TIM-3, VISTA, GITR / GITRL, CD80 / CD86, CD155, PDL1, PDL2, galectin 9, CD40, OX40L, 4-1BB / 4-1BBL, ICOS / ICOSL, CD70, and combinations thereof. In some cases, the antibodies of the present disclosure target immune checkpoints selected from the group consisting of: PDL1, B7H4, B7H3, TIGIT, or combinations thereof.

[0500] Table 1 provides exemplary antibody sequences according to the present disclosure. In this table, all targets correspond to human orthologs unless otherwise indicated.

[0501] Table 1

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567] (i) Heavy and light chain variable regions

[0568] In some cases, the antibodies of the present disclosure comprise a heavy chain variable region that has at least 80% sequence identity to a first sequence and a light chain variable region that has 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 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: 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: 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: 381 and the second sequence is SEQ ID NO: 382. 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:470 and the second sequence is SEQ ID NO:471; 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: 583 and the second sequence is SEQ ID NO: 584. 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:680 and the second sequence is SEQ ID NO:681; 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: 775 and the second sequence is SEQ ID NO: 776. 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:863 and the second sequence is SEQ ID NO:864. 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: 970 and the second sequence is SEQ ID NO: 971; 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. ;

[0569] In some instances, the antibodies of the present disclosure target an immune checkpoint selected from the group consisting of: PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a heavy chain variable region that has at least 80% sequence identity to a first sequence and a light chain variable region that has 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: 155 and the second sequence is SEQ ID NO: 156. 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:254 and the second sequence is SEQ ID NO:255. 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. 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.;

[0570] In some cases, the antibodies of the present disclosure comprise a heavy chain variable region that has at least 80% sequence identity to a first sequence and a light chain variable region that has 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: 155 and the second sequence is SEQ ID NO: 156. 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:243 and the second sequence is SEQ ID NO:244. 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.

[0571] In some cases, the heavy chain variable region has at least 85% sequence identity with the first sequence, and the light chain variable region has at least 85% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 90% sequence identity with the first sequence, and the light chain variable region has at least 90% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 95% sequence identity with the first sequence, and the light chain variable region has at least 95% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity with the first sequence, and the light chain variable region has at least 98% sequence identity with the second sequence. In some cases, the heavy chain variable region has at least 99% sequence identity with the first sequence, and the light chain variable region has at least 99% sequence identity with the second sequence. In some cases, the heavy chain variable region comprises the first sequence and the light chain variable region comprises the second sequence.

[0572] (ii) Heavy and light chains

[0573] 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: 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. 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; 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. 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.;

[0574] 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: 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: 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.

[0575] 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: 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: 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.

[0576] 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.

[0577] 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.

[0578] 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.

[0579] (iii) Complementarity determining regions

[0580] In some cases, the antibody comprises a CDR-H1 having at least 80% sequence identity to a first sequence, a CDR-H2 having at least 80% sequence identity to a second sequence, a CDR-H3 having at least 80% sequence identity to a third sequence, a CDR-L1 having at least 80% sequence identity to a fourth sequence, a CDR-L2 having at least 80% sequence identity to a fifth sequence, and a CDR-L3 having at least 80% sequence identity to a sixth sequence, wherein the first, second, third, fourth, fifth, and sixth sequences are: SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively; 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:145 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:209, 210, 211, 212, 213 and 214, respectively NO: 211, 212, 213, 214, 215 and 216; SEQ ID NO: 219, 220, 221, 222, 223 and 224, respectively;SEQ ID NOs: 227, 228, 229, 230, 231 and 232, respectively; SEQ ID NOs: 235, 236, 237, 238, 239 and 240, respectively; SEQ ID NOs: 243, 244, 245, 246, 247 and 248, respectively; SEQ ID NOs: 291, 292, 293, 294, 295 and 296, respectively; SEQ ID NOs: 301, 302, 303, 304, 305 and 306, respectively; SEQ ID NOs: 309, 310, 311, 312, 313 and 314, respectively; SEQ ID NOs: 317, 318, 319, 320, 321 and 322, respectively; SEQ ID NOs: 325, 326, 327, 328, 329 and 330, respectively; SEQ ID NOs: 331, 332, 333, 334, 335 and 336, respectively. NO:333, 334, 335, 336, 337 and 338; 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; 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:459, 460, 461, 462, 463 and 464, respectively NO: 461, 462, 463, 464, 465 and 466; SEQ ID NO: 469, 470, 471, 472, 473 and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481 and 482, respectively;SEQ ID NOs: 485, 486, 487, 488, 489 and 490, respectively; SEQ ID NOs: 495, 496, 497, 498, 499 and 500, respectively; SEQ ID NOs: 503, 504, 505, 506, 507 and 508, respectively; SEQ ID NOs: 511, 512, 513, 514, 515 and 516, respectively; SEQ ID NOs: 519, 520, 521, 522, 523 and 524, respectively; SEQ ID NOs: 527, 528, 529, 530, 531 and 532, respectively; SEQ ID NOs: 535, 536, 537, 538, 539 and 540, respectively; SEQ ID NOs: 543, 544, 545, 546, 547 and 548, respectively; NO:551, 552, 553, 554, 555 and 556; 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:613, 614, 615, 616, 617, 618, 619, 620, 621 and 622, respectively NO: 615, 616, 617, 618, 619 and 620; 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: 677 NO: 679, 680, 681, 682, 683 and 684; SEQ ID NO: 687, 688, 689, 690, 691 and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699 and 700, respectively;SEQ ID NOs: 705, 706, 707, 708, 709 and 710, respectively; SEQ ID NOs: 725, 726, 727, 728, 729 and 730, respectively; SEQ ID NOs: 733, 734, 735, 736, 737 and 738, respectively; SEQ ID NOs: 741, 742, 743, 744, 745 and 746, respectively; SEQ ID NOs: 749, 750, 751, 752, 753 and 754, respectively; SEQ ID NOs: 759, 760, 761, 762, 763 and 764, respectively; SEQ ID NOs: 767, 768, 769, 770, 771 and 772, respectively; SEQ ID NOs: 775, 776, 777, 778, 779 and 780, respectively; SEQ ID NOs: 781, 782, 783, 784, 785, 786, 787, 788, 789 and 790, respectively; NO:783, 784, 785, 786, 787 and 788; 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; 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:909, 910, 911, 912, 913, 914, 915, 916, 917 and 918, respectively; NO:911, 912, 913, 914, 915 and 916; 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: 998, 999, 1000, 1001 and 1002, respectively. NO: 1005, 1006, 1007, 1008, 1009 and 1010; 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.

[0581] In some instances, the antibodies of the present disclosure target an immune checkpoint selected from the group consisting of: PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a CDR-H1 having at least 80% sequence identity to a first sequence, a CDR-H2 having at least 80% sequence identity to a second sequence, a CDR-H3 having at least 80% sequence identity to a third sequence, a CDR-L1 having at least 80% sequence identity to a fourth sequence, a CDR-L2 having at least 80% sequence identity to a fifth sequence, and a CDR-L3 having at least 80% sequence identity to a sixth sequence, wherein the first, second, third, fourth, fifth, and sixth sequences are: SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NOs: 77, 78, 79, 80, 81, and 82, respectively; SEQ ID NOs: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NOs: 99, 100, 101, 102, 103, and 104, respectively; 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; NO:171, 172, 173, 174, 175 and 176; 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:233, 234, 235 NO: 235, 236, 237, 238, 239 and 240;SEQ ID NOs: 243, 244, 245, 246, 247 and 248, respectively; SEQ ID NOs: 623, 624, 625, 626, 627 and 628, respectively; SEQ ID NOs: 631, 632, 633, 634, 635 and 636, respectively; SEQ ID NOs: 639, 640, 641, 642, 643 and 644, respectively; SEQ ID NOs: 647, 648, 649, 650, 651 and 652, respectively; SEQ ID NOs: 655, 656, 657, 658, 659 and 660, respectively; SEQ ID NOs: 663, 664, 665, 666, 667 and 668, respectively; SEQ ID NOs: 671, 672, 673, 674, 675 and 676, respectively; SEQ ID NOs: 677, 678, 679, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715 and 716, respectively; NO: 679, 680, 681, 682, 683 and 684; 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.

[0582] In some cases, the antibody comprises a CDR-H1 having at least 85% sequence identity to a first sequence, a CDR-H2 having at least 85% sequence identity to a second sequence, a CDR-H3 having at least 85% sequence identity to a third sequence, a CDR-L1 having at least 85% sequence identity to a fourth sequence, a CDR-L2 having at least 85% sequence identity to a fifth sequence, and a CDR-L3 having at least 85% sequence identity to a sixth sequence. In some cases, the antibody comprises a CDR-H1 having at least 90% sequence identity to a first sequence, a CDR-H2 having at least 90% sequence identity to a second sequence, a CDR-H3 having at least 90% sequence identity to a third sequence, a CDR-L1 having at least 90% sequence identity to a fourth sequence, a CDR-L2 having at least 90% sequence identity to a fifth sequence, and a CDR-L3 having at least 90% sequence identity to a sixth sequence. In some cases, CDR-H1 comprises at most one mutation relative to a first sequence, CDR-H2 comprises at most one mutation relative to a second sequence, CDR-H3 comprises at most one mutation relative to a third sequence, CDR-L1 comprises at most one mutation relative to a fourth sequence, CDR-L2 comprises at most one mutation relative to a fifth sequence, and CDR-L3 comprises at most one mutation relative to a sixth sequence.

[0583] (iv) Exemplary Antibodies

[0584] In some cases, the antibodies provided herein bind to PDL1. PDL1 is expressed in a variety of cancers and certain immune cells and often serves as a primary mechanism of immunosuppression in the tumor microenvironment. PDL1 agonism of PD-1 can act as an immune checkpoint, reducing lymphocyte tumor infiltration and T cell receptor-mediated proliferation and signaling. While PDL1 antagonism can reverse immunosuppression, PDL1 targeting can also localize treatment to the cancer site, enabling drugs to selectively target cancer cells or stimulate immune responses in the presence of tumors.

[0585] In some instances, the anti-PDL1 antibody comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 that have 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 instances, the antibody comprises a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 that each comprise no more than one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.

[0586] In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-4, and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1, and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2, and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3, and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4 and a light chain comprising an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:5.

[0587] 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 NOs: 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 NOs: 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.

[0588] 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.

[0589] In some embodiments, the antibodies provided herein bind to EphA2. In some embodiments, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 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 NOs: 21, 22, 23, 24, 25, and 26, respectively.

[0590] 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 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 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 SEQ ID NO: 31. 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: 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 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: 35 or SEQ ID NO: 36, and a light chain comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibody is h1C1 or 1C1.

[0591] 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.

[0592] In some cases, the antibodies provided herein bind to CD30. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation 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 any one of SEQ ID NOs: 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 amino acid 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.

[0593] In some cases, the antibodies provided herein bind to CD228. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation 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 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 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.

[0594] In some cases, the antibodies provided herein bind to avB6. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation 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%, or 99% 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 any one of 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.

[0595] In some cases, the antibodies provided herein bind 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), wherein each sequence has at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% or 100% sequence identity to an amino acid sequence from 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 ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: NO:179-184, SEQ ID NO:187-192, SEQ ID NO:195-200, SEQ ID NO:203-208, SEQ ID NO:211-216, SEQ ID NO:219-224, SEQ ID NO:227-232, SEQ ID NO:235-240, and SEQ ID NO: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) that each comprises at most one mutation relative to an amino acid sequence from an amino acid sequence set 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 ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: NO:203-208, SEQ ID NO:211-216, SEQ ID NO:219-224, SEQ ID NO:227-232, SEQ ID NO:235-240, and SEQ ID NO:243-248. In some instances, the anti-B7H4 antibody comprises a heavy chain 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%, at least 99%, or at least 100% identical to the amino acid sequence of SEQ ID NOs: 85 and 87, SEQ ID NOs: 86 and 87, SEQ ID NOs: 88 and 90, SEQ ID NOs: 89 and 90, SEQ ID NOs: 251 and 252, SEQ ID NOs: 253 and 254, SEQ ID NOs: 255 and 256, SEQ ID NOs: 257 and 258, SEQ ID NOs: 259 and 260, SEQ ID NOs: 261 and 262, SEQ ID NOs: 263 and 264, SEQ ID NOs: 265 and 266, SEQ ID NOs: 267 and 268, SEQ ID NOs: 269 and 270, SEQ ID NOs: 271 and 272, SEQ ID NOs: 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.In some embodiments, the anti-B7H4 antibody comprises a heavy chain variable region 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%, at least 99%, or at least 100% identical to the amino acid sequence of SEQ ID NOs: 83 and 84, SEQ ID NOs: 97 and 98, SEQ ID NOs: 105 and 106, SEQ ID NOs: 113 and 114, SEQ ID NOs: 121 and 122, SEQ ID NOs: 129 and 130, SEQ ID NOs: 137 and 138, SEQ ID NOs: 153 and 154, SEQ ID NOs: 161 and 162, SEQ ID NOs: 169 and 170, SEQ ID NOs: 177 and 178, SEQ ID NOs: 185 and 186, SEQ ID NOs: 193 and 194, SEQ ID NOs: 201 and 202, SEQ ID NOs: 203 and 204, NOs: 209 and 210, SEQ ID NOs: 217 and 218, SEQ ID NOs: 225 and 226, SEQ ID NOs: 233 and 234, SEQ ID NOs: 241 and 242, or SEQ ID NOs: 249 and 250.

[0596] In some instances, the antibodies provided herein bind to CD70. In some such instances, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have 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 instances, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise no more than 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.

[0597] In some cases, the antibodies provided herein bind to TROP2. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibodies provided herein bind to TROP2. In some such cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that has 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 a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that each comprises no more than 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.

[0598] In some cases, the antibodies provided herein bind to MICA. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that has 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: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that each comprises no more than 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 a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that has 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 sequence of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that each comprises no more than one mutation relative to the amino acid sequence of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that has 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 sequence of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively.In some instances, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that each comprises no more than one mutation relative to the amino acid sequence 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 region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348.

[0599] In some cases, the antibodies provided herein bind to CD51. In some such cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that have at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibodies provided herein bind to CD51. In some such cases, the antibody comprises a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that has 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 a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequence that each comprises no more than 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...

Claims

1. An antibody-drug conjugate (ADC) having the following structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof; in: Ab is antibody; Each L is a connector; wherein each D is coupled to a linker; wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a 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; in: R 1 is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; 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; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 trisaccharide; R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L; R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ; R 4 Selected from the group consisting of: a point of covalent attachment to L; hydrogen; -OR C ; -S(=O)2R C ; -C(=O)NR D R E ; -C(=O)OR C ;-C(=O)SR C ; -C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C ; (vi) -CO2H; (vii) C1-C6 alkoxycarbonyl; (viii)-C(=O)NR D R E 4 (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D R E ] + ; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocyclic, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -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 by: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H; When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point covalently attached to L; R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ;and m is 0, 1, 2 or 3; R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B At most one instance is a point of covalent attachment to L; R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl; R D , R E , R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R D , R E , R G and R H Only one of them is the point of covalent attachment to L; R F Each instance of is independently selected from the group consisting of: (a) a 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; R I , R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl; Where R I , R J and R K At most one of them is a 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 with the first sequence, and the light chain variable region has at least 90% sequence identity with the second sequence.

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

4. An antibody-drug conjugate (ADC) having the following structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof; in: Ab is antibody; Each L is a connector; wherein each D is coupled to a linker; wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a 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; in: R 1 is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; 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; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 trisaccharide; R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L; R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ; R 4 Selected from the group consisting of: a point of covalent attachment to L; hydrogen; -OR C ; -S(=O)2R C ; -C(=O)NR D R E ; -C(=O)OR C ;-C(=O)SR C ; -C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C ; (vi) -CO2H; (vii) C1-C6 alkoxycarbonyl; (viii)-C(=O)NR D R E 4 (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D R E ] + ; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocyclic, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -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 by: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H; When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point covalently attached to L; R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ;and Subscript m is 0, 1, 2, 3, or 4; R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B At most one instance is a point of covalent attachment to L; R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl; R D , R E , R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R D , R E , R G and R H Only one of them is the point of covalent attachment to L; R F Each instance of is independently selected from the group consisting of: (a) a 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; R I , R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl; Where R I , R J and R K At most one of them is a point of covalent attachment to L; wherein each D has only one point of covalent attachment to L; and Wherein the Ab comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: 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 with the first sequence, and the light chain has at least 90% sequence identity with 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 following structure: Ab-(LD) p or a pharmaceutically acceptable salt thereof; in: Ab is antibody; Each L is a connector; wherein each D is coupled to a linker; wherein each L is covalently linked to an amino acid, an N-terminal tag, a C-terminal tag, or a 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; in: R 1 is (a) a point of covalent attachment to L; or (b) is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thione, C3-C6 cycloalkyl, phenyl, and 5-10 membered heteroaryl; 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; C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, C1-C6 amidine, C1-C6 sulfone, C1-C6 thioketone, C3-C6 cycloalkyl, phenyl and 5-10 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 trisaccharide; R 2 is (a) a 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 hydroxy, halogen, sulfhydryl, cyano, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, and -NR A R B ;or R 1 and R 2 Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclyl optionally substituted with 1-3 independently selected C1-C6 alkyl groups, wherein one of the heterocyclyl or the 1-3 independently selected C1-C6 alkyl groups is optionally the point of covalent attachment to L; R 3 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: hydrogen, -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkanoyloxy, C3-C6 cycloalkyl, phenyl, 5-10 membered heteroaryl and 3-12 membered heterocyclic ring; 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 heterocyclic ring is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxiranyl, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B ; R 4 Selected from the group consisting of: a point of covalent attachment to L; hydrogen; -OR C ; -S(=O)2R C ; -C(=O)NR D R E ; -C(=O)OR C ;-C(=O)SR C ; -C(=S)R C ;-PO3R C ; and -C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii)-OR C ; (iii)-SR C ; (iv)-NH-S(O2)R C ; (v)-OC(=O)R C ; (vi) -CO2H; (vii) C1-C6 alkoxycarbonyl; (viii)-C(=O)NR D R E 4 (ix)-NR D R E ; (x)-[N(C1-C6 alkyl)R D R E ] + ; (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is substituted by: 5-10 membered heteroaryl, 5-10 membered heterocyclic, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E or -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 by: 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or (xiv) 5-10 membered heteroaryl, optionally substituted by halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E 、-SR C , (C1-C6)alkoxycarbonyl or -CO2H; When R 4 When it is a C1-C6 alkyl group, the C1-C6 alkyl group or its substituent is optionally further substituted by a point covalently attached to L; R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of: (a) a point of covalent attachment to L; or (b) a group consisting of: halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, and -NR A R B ;and m is 0, 1, 2 or 3; R A and R B Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L, (b) a group consisting of hydrogen and C1-C6 alkyl; and (c) R A and R B Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R A and R B At most one instance is a point of covalent attachment to L; R C Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of: hydrogen, phenyl, and C1-C2 optionally substituted with phenyl or 1-3 independently selected halogens. 10 alkyl; R D , R E , R G and R H Each instance of is independently selected from the group consisting of: (a) a 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) R D and R E or R G and R H Together with the nitrogen atom to which they are attached, they form a 3-6 membered heterocyclic group optionally substituted by 1-3 independently selected C1-C6 alkyl groups; wherein R D , R E , R G and R H Only one of them is the point of covalent attachment to L; R F Each instance of is independently selected from the group consisting of: (a) a 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; R I , R J and R K Each instance of is independently selected from the group consisting of: (a) a point of covalent attachment to L; and (b) a group consisting of hydrogen and C1-C6 alkyl; Where R I , R J and R K At most one of them is a 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 having at least 80% sequence identity with a first sequence, a CDR-H2 having at least 80% sequence identity with a second sequence, a CDR-H3 having at least 80% sequence identity with a third sequence, a CDR-L1 having at least 80% sequence identity with a fourth sequence, a CDR-L2 having at least 80% sequence identity with a fifth sequence, and a CDR-L3 having at least 80% sequence identity with a sixth sequence, wherein the first, second, third, fourth, fifth and sixth sequences are: SEQ ID NOs: 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 NOs: 13, 14, 15, 16, 17 and 18, respectively.

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

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

13. The ADC of any one of claims 1-12, wherein each D has a structure of formula (II): or a pharmaceutically acceptable salt thereof, wherein is the point of covalent attachment to L; R 5 is (a) a point of covalent attachment to L; or (b) selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ;and m is 0, 1, 2 or 3.

14. The ADC of claim 13, wherein each D has a structure of formula (IIa): or a pharmaceutically acceptable salt thereof, wherein each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ;and m is 0, 1, 2 or 3.

15. The ADC of any one of claims 1-12, wherein each D has a structure of formula (III): or a pharmaceutically acceptable salt thereof, wherein R 4A is (a) a point of covalent attachment to L, or (b) a C1-C6 alkyl group, which is optionally substituted with: (i) 1-3 independently selected halogens; (ii) -OR C ; (iii)-SR C ; (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E ; (ix)-[N(C1-C6 alkyl)R D R E ] + ; (x) -(phenyl) C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; (xi) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; (xii) -(5-10 membered heteroaryl)C1-C6 alkyl, wherein the C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, -NR D R E 、-[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogen substituted; or 5-10 membered heteroaryl, which is optionally substituted with halogen, -NR D R E , C1-C6 alkoxy, -C(=O)NR D R E or -CO2H; when R 4A When (b) C1-C6 alkyl, the C1-C6 alkyl or its substituent is further substituted by a point covalently attached to L; R 5 Selected from the group consisting of: -C(=O)OR F , -NO2, -CN, -CF3-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K and SO3R K ; Each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B ;and m is 0, 1, 2 or 3.

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

17. The ADC of any one of claims 1 to 12, wherein R 1 or R 4 is the point of covalent attachment to L.

18. The ADC of any one of claims 1 to 17, wherein R 1 The invention is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C1-C6 alkoxythiocarbonyl, C1-C6 carbamoyl, phenyl and 5-10 membered heteroaryl; 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 by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxirane, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio, -NR A R B , phosphoryl, sulfyl, nitro, C5-C9 monosaccharide, acylated C5-C9 monosaccharide, C 10 -C 18 Disaccharide, acylated C 10 -C 18 Disaccharide, C 15 -C 27 Trisaccharide and acylated C 15 -C 27 Trisaccharide.

19. The ADC of any one of claims 1 to 18, wherein R 1 Selected 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 by 1-3 substituents independently selected from the group consisting of: hydroxyl, halogen, sulfhydryl, cyano, C1-C6 alkoxy, -NR A R B , phosphoryl, sulfonyl, nitro, C5-C9 monosaccharides and acylated C5-C9 monosaccharides.

20. The ADC of any one of claims 1 to 19, wherein R 1 is hydrogen, or C1-C3 alkyl, which is optionally substituted by a substituent selected from the group consisting of hydroxy, halogen and -NH2.

21. The ADC of any one of claims 1 to 20, wherein R 1 It is hydrogen or C1-C3 alkyl.

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

23. The ADC of any one of claims 1-12 or 15-22, wherein R 2 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 by 1-3 substituents independently selected from the group consisting of: hydroxy, halogen, sulfhydryl, cyano, oxirane, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B .

24. The ADC of any one of claims 1-12 or 15-23, wherein R 2 Selected from the group consisting of hydrogen and C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxirane, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B .

25. The ADC of any one of claims 1-12 or 15-24, wherein R 2 It is hydrogen or C1-C3 alkyl.

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

27. The ADC of any one of claims 1-26, wherein R 3 Selected from the group consisting of: -NR A R B 、-C(=O)NR A R B , C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl and 5-10 membered heteroaryl; wherein the C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, phenyl or 5-10 membered heteroaryl is optionally substituted by 1-3 substituents independently selected from the group consisting of hydroxy, halogen, sulfhydryl, cyano, oxo, oxirane, C3-C8 cycloalkyl, phenyl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkylthio and -NR A R B .

28. The ADC of any one of claims 1-27, wherein R 3 is a C1-C5 alkyl group, which is optionally substituted by 1 substituent selected from the group consisting of hydroxy, halogen, cyano, oxo, C1-C3 alkoxy, C1-C3 alkylthio and -NR A R B .

29. The ADC of any one of claims 1-28, wherein R 3 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 R 4 is hydrogen; -C(=O)NR D R E ; -C(=O)OR C ;-C(=O)SR C ; -C(=S)R C or C1-C6 alkyl, which is optionally substituted by: (i) 1-3 independently selected halogens; (ii) -O(C1-C6 alkyl); (iii) -S(C1-C6 alkyl); (iv) -NH-S(O2)R C ; (v)-OC(=O)R C ; (vi) -CO2H; (vii) -C1-C6 alkoxycarbonyl; (viii) -C(=O)NR D R E ; (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; (x)-[N(C1-C6 alkyl)R D R E ] + (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + or 1-3 independently selected halogens; or (xii) phenyl, which is substituted by halogen, hydroxy, C1-C6 alkoxy, -NR D R E 、-C(=O)NR D R E Or -CO2H substitution.

31. The ADC of any one of claims 1-14 or 17-30, wherein R 4 is hydrogen or C1-C6 alkyl, said alkyl being substituted by: (ix)-NR D R E , where -NR D R E R D is C1-C6 alkyl; or (xi) -(phenyl)C1-C6 alkyl, wherein the C1-C6 alkyl of the -(phenyl)C1-C6 alkyl is replaced by a 5-10 membered heteroaryl, a 5-10 membered heterocycle, -[N(C1-C6 alkyl)R D R E ] + replace.

32. The ADC of any one of claims 1-14 or 17-31, wherein R 4 Selected from the group consisting of: wherein each instance of the subscript z is independently 1, 2 or 3.

33. The ADC of claims 1-14 or 17-32, wherein R 4 Selected from the group consisting of:

34. The ADC of any one of claims 1-13, 15 or 17-33, wherein R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and each R 6 independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C1-C6 alkyl and -NR A R B .

35. The ADC of any one of claims 1-13, 15 or 17-34, wherein R 5 is -C(=O)OH or -C(=O)O(C1-C3 alkyl); and the subscript m is 0.

36. The ADC of any one of claims 1-13, 15 or 17-35, wherein R 5 have: (i) a pKa of up to 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 R X are independently selected from the group consisting of: hydrogen, -C(=O)OR F 、-C(=O)NR G R H 、-S(O2)NR G R H 、-N(R I )-C(=O)R J 、-N(R I )-S(O2)R K 、-S(O3)R K , halogen, hydroxy, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkanoyl, C1-C6 alkanoyloxy, C1-C6 alkoxycarbonyl, C1-C6 haloalkyl, C1-C6 haloalkoxy and -NR A R B .

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 R A and R B Each instance of is independently selected from the group consisting of hydrogen and C1-C3 alkyl.

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

41. The ADC of any one of claims 1-40, wherein R D , R E , R G and R H Each instance of is 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 R F Each instance of is independently selected from the group consisting of hydrogen, trifluoromethyl, and C1-C6 alkyl.

43. The ADC of any one of claims 1-42, wherein each D is in represents the point of covalent attachment to L.

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

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

5.

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

47. The ADC of any one of claims 1-46, wherein the linker comprises a length between 15 and 30 atoms as defined by the path between D and Ab via the least 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 -,in: Subscript a is 0 or 1; Subscript y is 0 or 1; Subscript w is 0 or 1; Subscript x is 0 or 1; M is succinimide, hydrolyzed succinimide, amide, methyl ketone, disulfide, dihydropyridazine or triazole; A is optionally replaced by 1 to 4 R a1 Substituted C 2-20 or optionally 1-4 R b1 substituted 2- to 40-membered heteroalkylene; Each R a1 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, =O, -NR d1 R e1 、-(C 1-6 Alkylene)-NR d1 R e1 、-C(=O)NR d1 R e1 , -C(=O)(C 1-6 alkyl) and -C(=O)O(C 1-6 alkyl); Each R b1 Independently selected from the group consisting of: C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, -OH, -NR d1 R e1 、-(C 1-6 Alkylene)-NR d1 R e1 、-C(=O)NR d1 R e1 , -C(=O)(C 1-6 alkyl) and -C(=O)O(C 1-6 alkyl); Each R d1 and R e1 are independently hydrogen or C 1-3 alkyl; W is 1-12 amino acids or has the following structure: Where Su is the sugar part; -O A - represents the oxygen atom of the glycosidic bond; Each R g are independently hydrogen, halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, carboxamide, C1-C6 alkyl or -NO2; W 1 does not exist, is *-C(=O)-O- or *-OC(=O)-; Indicates covalent attachment to A or M; * indicates covalent linkage to X, Y or D; Y is a self-immolative moiety, a non-self-immolative releasable moiety, or a non-cleavable moiety; X is C1-C6 alkylene or 3-6 membered heteroalkylene; L is optionally substituted with PEG units 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 C1-C6 alkylene.

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

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

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.

58. The ADC of any one of claims 49-57, wherein Y is 59. 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 cyclohexanecarboxyl, undecanoyl, caproyl, hexanoyl, butyryl or propionyl.

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 6-12 amino acids.

65. The ADC of any one of claims 49-64, wherein W is 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, aspartic acid 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: Where Su is the sugar part; -OA- represents the oxygen atom of the glycosidic bond; Each R g are independently hydrogen, halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, carboxamide, C1-C6 alkyl or -NO2; W 1 does not exist, is *-C(=O)-O- or *-OC(=O)-; represents a covalent link to A or M; and * indicates covalent linkage to X, Y or D.

68. The ADC of claim 67, wherein W 1 Does not exist.

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

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

71. The ADC of any one of claims 67-70, wherein one R g is halogen, C1-C6 alkoxy, -N(C1-C6 alkyl)2, -NHC(=O)(C1-C6 alkyl), -CN, -CF3, acyl, carboxamide, C1-C6 alkyl or -NO2, and the remaining R g For hydrogen.

72. The ADC of any one of claims 67-71, wherein each R g For 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 optionally substituted by 1-4 R a1 Substituted C 2-20 Alkylene.

76. The ADC of any one of claims 49-75, wherein A is optionally substituted with 1-4 R a1 Substituted C 4-10 Alkylene.

77. The ADC of any one of claims 49-75, wherein A is a a1 Substituted C 2-20 Alkylene.

78. The ADC of any one of claims 49-77, wherein A is a a1 Substituted C 4-10 Alkylene.

79. The ADC of any one of claims 49-74, wherein A is C 2-20 Alkylene.

80. The ADC of any one of claims 49-74 or 79, wherein A is C 4-10 Alkylene.

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

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

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

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

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 in indicates a covalent link to W, and * indicates a covalent link 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 PEG units from PEG1 to PEG72.

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

92. A method of treating cancer in a subject in need thereof, the method 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 be internalized 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 cells, CD4 + T cells, T regulatory cells, macrophages or natural killer cells.

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 claims 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 that binds to the cancer associated antigen.

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

104. The method of claims 92-103, wherein D of the ADC is constructed 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 constructed to undergo cleavage upon internalization 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 the cancer cells of the cancer express the CD4, the CD8, the immune checkpoint, or a combination thereof.

108. The method of claim 106 or 107, wherein the CD4 expression, the CD8 expression, the immune checkpoint expression, or a 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 tumor-derived cancer cells do not comprise tumor-associated immune cells.

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

114. The method of any one of claims 106-113, wherein the assay comprises flow cytometry, immunohistochemistry, immunocytochemistry, immunofluorescence, immunoprecipitation, Western blot, 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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