Sting agonist immunostimulatory antibody drug conjugates

Abstract

The present disclosure is related to dual payload immunostimulatory antibody drug conjugates comprising at least STING agonist and at least one cytotoxic agent, pharmaceutical compositions thereof, and the use of the dual payload immunostimulatory antibody drug conjugates and compositions thereof for the treatment of diseases and disorders, including proliferative diseases.

Description

Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 STING AGONIST IMMUNOSTIMULATORY ANTIBODY DRUG CONJUGATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Provisional Patent Application No.63 / 653,575 filed May 30, 2025, the entirety of which is incorporated by reference for all purposes. FIELD

[0002] The present disclosure is related to dual payload immunostimulatory antibody drug conjugates comprising at least one STING agonist and at least one cytotoxic agent, pharmaceutical compositions thereof, and the use of the dual payload immunostimulatory antibody drug conjugates and compositions thereof for the treatment of diseases and disorders, including proliferative diseases. BACKGROUND

[0003] Cancer treatments commonly employ combinations of drugs that may display therapeutic activity by acting through complementary mechanisms of action. For instance, cytotoxic drugs are often employed in combination with adjuvants and / or immune system modulators. However, conventional cytotoxic drugs are not tumor specific and are often associated with side effects.

[0004] One way to circumvent the non-specificity of cytotoxic drugs is to conjugate the cytotoxic drug to an antibody because tumor cells express specific antigens that can be targeted by the antibody. Additionally, if an immune response can be induced at the same time, the immune system can recruit immune cells to target tumors expressing the specific antigens to boost the therapeutic efficacy of the antibody-drug conjugate cancer treatment. Further, the immune response may not be limited to targeting only tumor cells that express those tumor antigens; tumor cells in the periphery may also be targeted via antigen spreading and / or through less specific mechanisms of tumor cell killing (e.g., cytokine release).

[0005] One protein that is important to induce immunity is stimulator of interferon genes (STING). In particular, the cGAS-STING pathway helps to detect and protect against harmful cytosolic DNA, which is an indication of cellular and tissue damage (because the cytosol is normally free of DNA, leaked cytosolic DNA is often indicative of DNA damage events and tumorigenesis). cGAS recognizes cytosolic DNA and catalyzes the synthesis of cyclic dinucleotides (CDNs), including cGAMP, which in turn bind and activate STING. Once STING is bound to a CDN, STING undergoes a conformational change, translocates from the - 1 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 endoplasmic reticulum to the Golgi apparatus, and triggers the transcription factor TBK1 to phosphorylate transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB). This induces type I interferons (IFNs), immune-stimulated genes, and the production of pro-inflammatory cytokines, such as IL-6, TNF-α, and IFN-γ.

[0006] It is well-established that IFNs can inhibit tumor cell proliferation via multiple mechanisms. As described in Jiang, M. et al. Journal of Hematology & Oncology, 2020, 81, 13, STING-deficiency is correlated with cancer incidence in at least melanoma cell lines, colorectal adenocarcinoma human cell lines, and lung cancer.

[0007] A number of STING agonists have been developed and studied for oncological indications (Le Naour et al. Oncoimmunology, 2020; 9(1): 1777624), including DMXAA (or Vadimezan), a tumor-vascular disrupting agent that has been studied in clinical trials for its effect on advanced solid tumors, prostate cancer, urothelial carcinoma, and small cell lung cancer. Despite promising preclinical results, DMXAA has thus far only yielded poor results in human clinical trials. MIW815 (ADU-S100) in combination with pembrolizumab was recently studied in a Phase 2 clinical trial for patients with head and neck cancer, but was terminated due to a lack of substantial anti-tumor activity (NCT03937141). A Phase 1 trial to study the effect of MIW815 as a single agent and in combination with ipilimumab in patients with advanced / metastatic solid tumors or lymphomas (NCT02675439) was also terminated for showing a lack of substantial anti-tumor activity.

[0008] Other STING agonists include diamidobenzimidazole (di-ABZI) STING agonists, for example, those described in U.S. Patent No.11,377,440. U.S. Patent No.11,155,567 describes di-ABZI STING agonists, including XMT-2056, however, a Phase I clinical trial of XMT-2056 for HER2+ recurrent or metastatic solid tumors was on temporary clinical hold in March 2023 following a patient death (NCT05514717). Additional di-ABZI STING agonists are described in PCT Applications WO 2020 / 042995; WO 2020 / 156363; WO 2023 / 025256; WO 2021 / 013250; and WO 2022 / 272039.

[0009] Given the importance of the STING pathway in inducing an immune response in response to damaged DNA associated with cellular proliferative disorders, there is a medical need to develop STING agonists that can be used safely and effectively in combination with cytotoxic and chemotherapeutic agents. - 2 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 SUMMARY

[0010] Described herein are dual payload immunostimulatory antibody drug conjugates (iADCs) comprising an anti-TROP2 antibody or antigen binding fragment thereof wherein the anti-TROP2 antibody or antigen binding fragment thereof is linked to at least one STING agonist via a first linker, and the anti-TROP2 antibody or antigen binding fragment thereof is also linked to at least one cytotoxic agent via a second linker. In certain embodiments, the at least one STING agonist and / or the at least one cytotoxic agent are covalently linked to the anti-TROP2 antibody or antigen-binding fragment thereof. In certain embodiments, the immunostimulatory antibody drug conjugate comprises an antibody that specifically binds to TROP2, and the antibody is linked site-specifically to at least one STING agonist, and the antibody is linked site-specifically to at least one cytotoxic agent.

[0011] In some embodiments, the iADC is represented by the structure of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab is an anti-TROP2 antibody or antigen-binding fragment thereof; Lais a first linker; Lbis a second linker; CY is independently a residue of a cytotoxic agent; STING is independently a residue of a STING agonist; n is an integer selected from 1 to 10; and m is an integer selected from 1 to 10.

[0012] In another aspect, provided herein are pharmaceutical compositions comprising the iADCs described herein. In a further aspect, provided herein are kits comprising the iADCs described herein or pharmaceutical compositions thereof.

[0013] In another aspect, provided herein is a method for treating diseases, disorders, or conditions, including cancer and proliferative diseases, comprising administering an iADC described herein or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the disease, disorder, or condition is cancer. - 3 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 BRIEF DESCRIPTION OF FIGURES

[0014] FIG.1 provides a comparison of the Kabat and Chothia numbering systems for CDR- H1. Adapted from Martin A.C.R. (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In R. Kontermann & S. Dübel (Eds.), Antibody Engineering vol. 2 (pp.33-51). Springer-Verlag, Berlin Heidelberg.

[0015] FIG.2 is a graph of the anti-tumor activity of ADC 1, ADC 2, and ADC 4 in a syngeneic mouse tumor model until day 18 post treatment.

[0016] FIG.3A is a graph of the anti-tumor activity of iADC 1, iADC 2, and iADC 3, administered at a dose of 2 mg / kg, in a syngeneic mouse tumor model compared to ADC 4, also administered at a dose of 2 mg / kg.

[0017] FIG.3B is a graph of the anti-tumor activity of iADC 1, iADC 2, and iADC 3, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model.

[0018] FIG.4A is a graph of the anti-tumor activity of iADC 15 and iADC 18, administered at a dose of 2 mg / kg, in a syngeneic mouse tumor model compared to ADC 4, also administered at a dose of 2 mg / kg.

[0019] FIG.4B is a graph of the anti-tumor activity of iADC 1, iADC 9, iADC 15, and iADC 18, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model.

[0020] FIG.4C is a graph of the anti-tumor activity of iADC 16 and iADC 17, administered at a dose of 2 mg / kg, in a syngeneic mouse tumor model compared to ADC 4, also administered at a dose of 2 mg / kg.

[0021] FIG.4D is a graph of the anti-tumor activity of iADC 1, iADC 7, iADC 16, and iADC 17, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model.

[0022] FIG.5A is a graph of the anti-tumor activity of iADC 1, iADC 9 and iADC 17, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model compared to ADC 4 and ADC 6, also administered at a dose of 1 mg / kg.

[0023] FIG.5B is a graph of the anti-tumor activity of iSAC 1 and iADC 1, administered at a dose of 0.5 mg / kg, in a syngeneic mouse tumor model.

[0024] FIG.5C is a graph of the anti-tumor activity of iSAC 1 and iADC 1, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model compared to ADC 4, also administered at a dose of 1 mg / kg.

[0025] FIG.5D is a graph of the anti-tumor activity of iADC 17 and iSAC 14, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model compared to ADC 4, also administered at a dose of 1 mg / kg. - 4 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0026] FIG.5E is a graph of the anti-tumor activity of iADC 9 and iSAC 2, administered at a dose of 1 mg / kg, in a syngeneic mouse tumor model compared to ADC 6, also administered at a dose of 1 mg / kg.

[0027] FIG.6A is a graph measuring the IFNβ in plasma in a syngeneic mouse tumor model following administration of iADC 1, iADC 9, and iADC 17, administered at a dose of 1 mg / kg.

[0028] FIG.6B is a graph measuring the TNFα in plasma in a syngeneic mouse tumor model following administration of iADC 1, iADC 9, and iADC 17, administered at a dose of 1 mg / kg.

[0029] FIG.6C is a graph measuring the GranzymeB positive NK cells in a syngeneic mouse tumor model following administration of iADC 1, iADC 9, and iADC 17, administered at a dose of 1 mg / kg.

[0030] FIG.6D is a graph measuring the GranzymeB positive CD8-T cells in a syngeneic mouse tumor model following administration of iADC 1, iADC 9, and iADC 17, administered at a dose of 1 mg / kg.

[0031] FIG.6E is a graph measuring the increase of monocytes in a syngeneic mouse tumor model following administration of iADC 1, iADC 9, and iADC 17, administered at a dose of 1 mg / kg. DETAILED DESCRIPTION

[0032] Described herein are dual payload immunostimulatory antibody drug conjugates (iADCs) comprising an anti-TROP2 antibody or antigen binding fragment thereof conjugated to at least one STING agonist and at least one cytotoxic agent.

[0033] Definitions

[0034] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art, such as, for example, the widely utilized molecular cloning methodologies described in Green & Sambrook, Molecular Cloning: A Laboratory Manual - 5 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 4thed. (2012), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; and Ausubel et al., Current Protocols in Molecular Biology, John Wiley & Sons. As appropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0035] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0036] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value. In certain embodiments, for example, logarithmic scales (e.g., pH), the term “about” indicates the designated value ± 0.3, ±0.2, or ± 0.1.

[0037] The term “combinations thereof” includes every possible combination of elements to which the term refers to.

[0038] The term “TROP2” refers to, unless specified otherwise, any variants, isoforms and species homologs of human Trophoblast cell surface antigen 2 (TROP2) that are naturally expressed by cells, or that are expressed by cells transfected with a TROP2 or TROP2 gene. TROP2 proteins include, for example, human TROP2 (SEQ ID NO: 1). In some embodiments, TROP2 proteins include cynomolgus monkey TROP2 (SEQ ID NO: 2). In some embodiments, TROP2 proteins include murine TROP2 (SEQ ID NO: 3).

[0039] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region typically comprises three domains, abbreviated CH1 (or CH1), CH2 (or CH2), and CH3 (or CH3). Each light chain typically comprises a light chain variable region (VLor VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL or CL. - 6 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0040] The term “antibody” describes a type of immunoglobulin molecule and is used herein in its broadest sense. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments. Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer.

[0041] The term “anti-TROP2 antibody” is an antibody, as described herein, which binds specifically to TROP2. In some embodiments, the antibody binds the extracellular domain of TROP2. As used herein, unless otherwise specified, an antibody may also comprise an “antibody fragment” as defined herewithin.

[0042] The VHand VLregions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs)”; also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VHand VLgenerally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, incorporated by reference in its entirety.

[0043] The light chain from any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain.

[0044] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and µ, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0045] The amino acid sequence boundaries of a CDR can be determined by one of skill in the art using any of a number of known numbering schemes, including those described by Kabat et al., supra (“Kabat” numbering scheme); Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (“Chothia” numbering scheme); MacCallum et al., 1996, J. Mol. Biol.262:732- 745 (“Contact” numbering scheme); Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme); and Honegge and Plückthun, J. Mol. Biol., 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety. - 7 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0046] Table A provides the positions of CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 as identified by the Kabat and Chothia schemes. For CDR-H1, residue numbering is provided using both the Kabat and Chothia numbering schemes. Table A. Residues in CDRs according to Kabat and Chothia numbering schemes.* The C-terminus of CDR-H1, when numbered using the Kabat numbering convention, varies between H32 and H34, depending on the length of the CDR, as illustrated in FIG.1.

[0047] Unless otherwise specified, the numbering scheme used for identification of a particular CDR herein is the Kabat numbering scheme. Where the residues encompassed by these two numbering schemes diverge (e.g., CDR-H1 and / or CDR-H2), the numbering scheme is specified as Kabat. For convenience, CDR-H3 is sometimes referred to herein as Kabat. However, this is not intended to imply differences in sequence where they do not exist, and one of skill in the art can readily confirm whether the sequences are the same or different by examining the sequences.

[0048] CDRs may be assigned, for example, using antibody numbering software, such as Abnum, available at www.bioinf.org.uk / abs / abnum / , and described in Abhinandan and Martin, Immunology, 2008, 45:3832-3839, incorporated by reference in its entirety.

[0049] The “framework region” refers to a subdivision of the variable region acting as a scaffold for the CDRs. Unless specified otherwise, there are four framework regions for each heavy chain and light chain, wherein each CDRs is flanked by one framework region. Unless stated otherwise, the numbering of the framework region is based on using the Kabat numbering scheme.

[0050] The “EU numbering scheme” is generally used when referring to a residue in an antibody heavy chain constant region (e.g., as reported in Kabat et al., supra). Unless stated otherwise, the EU numbering scheme is used to refer to residues in antibody heavy chain constant regions described herein.

[0051] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv - 8 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments.

[0052] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0053] “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0054] “F(ab′)2” fragments contain two Fab′ fragments joined, near the hinge region, by disulfide bonds. F(ab′)2fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab′) fragments can be dissociated, for example, by treatment with β-mercaptoethanol.

[0055] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VHdomain and a VLdomain in a single polypeptide chain. The VHand VLare generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp.269-315). Springer-Verlag, New York, incorporated by reference in its entirety.

[0056] “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow the VH or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VLor VL-VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG1 Fc domain.

[0057] The term “monoclonal antibody” refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies comprises antibodies that are substantially similar and that bind the same epitope(s), except for variants that may normally arise during production of the monoclonal antibody. Such variants are generally present in only minor amounts.

[0058] The term “chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0059] “Humanized” forms of non-human antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. A humanized antibody is generally a human immunoglobulin (recipient antibody) in which residues from one or more CDRs are - 9 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 replaced by residues from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody having a desired specificity, affinity, or biological effect. In some instances, selected framework region residues of the recipient antibody are replaced by the corresponding framework region residues from the donor antibody.

[0060] A “human antibody” is one which possesses an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or derived from a non-human source that utilizes a human antibody repertoire or human antibody-encoding sequences (e.g., obtained from human sources or designed de novo). Human antibodies specifically exclude humanized antibodies.

[0061] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology, such as a Biacore®instrument. In some embodiments, the affinity is determined at 25°C.

[0062] With regard to the binding of an antibody to a target molecule, the terms “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule. Specific binding can also be determined by competition with a control molecule that mimics the antibody binding site on the target. In that case, specific binding is indicated if the binding of the antibody to the target is competitively inhibited by the control molecule.

[0063] An “affinity matured” antibody is one with one or more alterations in one or more CDRs or FRs that result in an improvement in the affinity of the antibody for its antigen, compared to a parent antibody which does not possess the alteration(s). In some embodiments, an affinity matured antibody has nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies may be produced using a variety of methods known in - 10 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 the art. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated by reference in its entirety) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of CDR and / or framework residues is described by, for example, Barbas et al. (Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813); Schier et al., Gene, 1995, 169:147-155; Yelton et al., J. Immunol., 1995, 155:1994-2004; Jackson et al., J. Immunol., 1995, 154:3310-33199; and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is incorporated by reference in its entirety.

[0064] The term “amino acid” refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include pyrrolysine and selenocysteine. Natural amino acids also include citrulline. Naturally encoded amino acids include post-translational variants of the 22 naturally occurring amino acids such as prenylated amino acids, isoprenylated amino acids, myrisoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-linked glycosylated amino acids, phosphorylated amino acids, and acylated amino acids. The term “amino acid” also includes “non-natural amino acids” and “modified amino acids.” The terms “non-natural amino acids” and “modified amino acids” are used herein interchangeably.

[0065] The term “non-natural amino acid” (or “unnatural amino acid”) or “synthetic amino acids” are α, β, γ, or δ amino acids, and includes but is not limited to, amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine and histidine. In certain embodiments, the amino acid is in the L- configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl, β-prolinyl, β-phenylalaninyl, β- tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β- asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl or β-histidinyl. Unnatural amino acids are not proteinogenic amino acids, or post translationally modified variants thereof that either occur naturally or are chemically synthesized. In particular, the term unnatural amino acid refers to an amino acid that is not one of the 20 common amino acids or pyrrolysine or selenocysteine, or post translationally modified variants thereof. Non- limiting examples of unnatural amino acids include sulfoalanine, hydroxyproline (Hyp), beta- alanine, citrulline (Cit), ornithine (Orn), norleucine (Nle), 3-nitrotyrosine, nitroarginine, - 11 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, and methionine sulfone.

[0066] The term "post translationally modified" refers to an antibody expressed in a cell that is modified after translation. Examples of the post-translational modification include modification such as pyroglutamylation, glycosylation, oxidation, deamidation or glycation of glutamine or glutamic acid at the heavy chain N-terminal, and lysine deletion by cutting lysine at the heavy chain C-terminal with carboxypeptidase. It is known that such post- translational modification is caused in various antibodies (J. Pharm. Sci., 2008, Vol.97, p. 2426-2447).

[0067] The term “modified amino acid” is an amino acid or non-natural amino acid that comprises a reactive group capable of forming a covalent bond to a linker payload. The reactive group can be an amino, carboxy, acetyl, hydrazino, hydrazido, hydroxylamine, semicarbazido, sulfanyl, azido or alkynyl group. Non-limiting examples of non-natural amino acids include p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4- allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo- phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine.

[0068] The term “conjugate” or “antibody conjugate” refers to an antibody or antigen binding fragment thereof linked to one or more payload moieties. The antibody can be any antibody described herein. The payload can be any payload such as cytotoxic agents and immunostimulants described herein. The antibody can be directly linked to the payload via a covalent bond, or the antibody can be linked to the payload indirectly via a linker. Typically, the linker is covalently bonded to the antibody and also covalently bonded to the payload. The term “antibody drug conjugate” or “ADC” as used herein refers to an antibody or antigen binding fragment thereof directly or indirectly, via a linker, covalently bound to at least one cytotoxic agent. The term “immunostimulatory antibody conjugate” or “iSAC” as used herein refers to an antibody or antigen binding fragment thereof directly or indirectly, via a linker, covalently bound to at least one STING agonist. The term “immunomodulatory antibody drug conjugate” or “iADC” as used herein refers to a dual antibody or antigen binding fragment thereof directly or indirectly, via a linker, covalently bound to at least one STING agonist and at least one cytotoxic agent. - 12 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0069] The term “epitope” means a portion of an antigen capable of specific binding to an antibody. Epitopes frequently consist of surface-accessible amino acid residues and / or sugar side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non-conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents. An epitope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination.

[0070] Percent “identity” between a polypeptide sequence and a reference sequence, is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0071] The term “site-specific” refers to a modification of a polypeptide at a predetermined sequence location in the polypeptide. The modification is at a single, predictable residue of the polypeptide with little or no variation. In particular embodiments, a modified amino acid is introduced at that sequence location, for instance recombinantly or synthetically. Similarly, a moiety can be “site-specifically” linked to a residue at a particular sequence location in the polypeptide. In certain embodiments, a polypeptide can comprise more than one site-specific modification.

[0072] A “conservative substitution” or a “conservative amino acid substitution,” refers to the substitution of an amino acid with a chemically or functionally similar amino acid. Conservative substitution tables providing similar amino acids are well known in the art. Polypeptide sequences having such substitutions are known as “conservatively modified variants.” Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles. By way of example, the groups of - 13 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 amino acids provided in Tables B-D are, in some embodiments, considered conservative substitutions for one another. Table B. Selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.Table C. Additional selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.Table D. Further selected groups of amino acids that are considered conservative substitutions for one another, in certain embodiments.- 14 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0073] Additional conservative substitutions may be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W. H. Freeman & Co., New York, NY. An antibody generated by making one or more conservative substitutions of amino acid residues in a parent antibody is referred to as a “conservatively modified variant.”

[0074] “pAMF” mutation refers to a variant phenylalanine residue, i.e., para-azidomethyl-L- phenylalanine, added or substituted into a polypeptide.

[0075] “pAcF” mutation refers to a variant phenylalanine residue, i.e., para-acetyl-L- phenylalanine, added or substituted into a polypeptide.

[0076] “pAzF” mutation refers to a variant phenylalanine residue, i.e., para-azido-L- phenylalanine, added or substituted into a polypeptide.

[0077] The term “payload” refers to a molecular moiety that can be conjugated to an antibody. In particular embodiments, payloads are selected from the group consisting of therapeutic moieties, for example, the STING agonists and cytotoxic agents described herein.

[0078] The term “linker” refers to a molecular moiety that is capable of forming at least two covalent bonds. Typically, a linker is capable of forming at least one covalent bond to an antibody and at least another covalent bond to a payload. In certain embodiments, a linker can form more than one covalent bond to an antibody. In certain embodiments, a linker can form more than one covalent bond to a payload or can form covalent bonds to more than one payload. After a linker forms a bond to an antibody, or a payload, or both, the remaining structure, i.e., the residue of the linker after one or more covalent bonds are formed, may still be referred to as a “linker” herein. The term “linker precursor” refers to a linker having one or more reactive groups capable of forming a covalent bond with an antibody or payload, or both. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker can be one that is released by a bio-labile function, which may or may not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, a non-cleavable linker can be one that is released upon degradation of the antibody.

[0079] The term “EC50” refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked, or potentiated by the particular test compound.

[0080] The term “IC50” refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. - 15 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0081] The terms “subject” and “patient” are used interchangeably herein. The terms “subject” and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human), and for example, a human. In another embodiment, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain embodiments, the subject is a human.

[0082] The terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound and / or an antibody conjugate provided herein. In certain embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

[0083] The term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject is effective to treat a disease or disorder. In some embodiments, a therapeutically effective amount or effective amount refers to an amount of an antibody or composition that when administered to a subject is effective to prevent or ameliorate a disease or the progression of the disease, or result in amelioration of symptoms. A “therapeutically effective amount” can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0084] The term “treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder, or delaying or preventing recurrence of the disease or disorder. In yet another embodiment, “treating” or “treatment” includes the reduction or elimination of either the disease or disorder, or to retard the progression of the disease or disorder or of one or more symptoms of the disease or disorder, or to reduce the severity of the disease or disorder or of one or more symptoms of the disease or disorder. - 16 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0085] The term “inhibits growth” (e.g., referring to cells, such as tumor cells) is intended to include any measurable decrease in cell growth (e.g., tumor cell growth) when contacted with an antibody or antibody conjugate, as compared to the growth of the same cells not in contact with the antibody or antibody conjugate. In some embodiments, growth may be inhibited by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%. The decrease in cell growth can occur by a variety of mechanisms, including but not limited to antibody internalization, apoptosis, necrosis, and / or effector function-mediated activity.

[0086] The terms “prophylactic agent” and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a compound provided herein. In certain other embodiments, the term “prophylactic agent” does not refer to a compound provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression, and / or severity of a disorder.

[0087] The phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence, or onset of one or more symptoms associated with a disorder (, or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

[0088] The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to ten carbon atoms (i.e., C1to C10alkyl). In certain embodiments, the alkyl is a lower alkyl, for example, C1-6alkyl, and the like. In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl. In certain embodiments, “substituted alkyl” refers to an alkyl substituted with, for example, one, two, or three groups independently selected from a halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, -CN, -NO2, amido, -C(O)-, -C(S)-, ester, carbamate, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, dialkylamino, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, alkyl is unsubstituted. In one embodiment, alkyl is methyl or ethyl. - 17 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0089] The term “alkylene,” as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. “Substituted alkylene” refers to an alkylene group substituted as described herein for alkyl. In some embodiments, alkylene is unsubstituted. In one embodiment, alkylene is C6alkylene.

[0090] “Alkenyl” refers to an olefinically unsaturated hydrocarbon group, in certain embodiments, having up to about eleven carbon atoms or from two to six carbon atoms (e.g., “lower alkenyl”), which can be straight-chained or branched, and having at least one or from one to two sites of olefinic unsaturation. “Substituted alkenyl” refers to an alkenyl group substituted as described herein for alkyl.

[0091] “Alkenylene” refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C2-C6-alkenylene. In one embodiment, alkylene is C2alkenylene.

[0092] “Alkynyl” refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about eleven carbon atoms or from two to six carbon atoms (e.g., “lower alkynyl”), which can be straight-chained or branched, and having at least one or from one to two sites of acetylenic unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CH2C≡CH), and the like. “Substituted alkynyl” refers to an alkynyl group substituted as described herein for alkyl.

[0093] “Alkynylene” refers to a divalent alkynyl as defined herein. Lower alkynylene is, for example, C2-C6-alkynylene.

[0094] “Amino” refers to -NH2.

[0095] The term “aminoalkyl,” as used herein, and unless otherwise specified, refers to the an alkyl group, as defined herein, which is substituted with one or more amino groups. In some embodiments, the aminoalkyl is an alkyl group substituted with one -NH2group (e.g., - R′(NH2) wherein R′ is alkyl as defined herein).

[0096] The term “alkylamino,” as used herein, and unless otherwise specified, refers to the group –NHR′′ where R′′ is, for example, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, C1-10haloalkyl, and the like as defined herein. In certain embodiments, alkylamino is C1-6alkylamino.

[0097] The term “dialkylamino,” as used herein, and unless otherwise specified, refers to the group –NR′′R′′ where each R′′ is independently C1-10alkyl, as defined herein. In certain embodiments, dialkylamino is, for example, di-C1-6alkylamino, C2-10alkenyl, C2-10alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, C1-10 haloalkyl, and the like. - 18 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0098] The term “aryl,” as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl. The term includes both substituted and unsubstituted moieties. An aryl group can be substituted with any described moiety including, but not limited to, one or more moieties (e.g., in some embodiments one, two, or three moieties) selected from the group consisting of halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, wherein each moiety is independently either unprotected, or protected as necessary, as would be appreciated by those skilled in the art (see, e.g., Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991); and wherein the aryl in the arylamino and aryloxy substituents are not further substituted.

[0099] The term “arylamino,” as used herein, and unless otherwise specified, refers to an - NR′R′′ group where R′ is hydrogen or C1-C6-alkyl; and R′′ is aryl, as defined herein.

[0100] The term “arylene,” as used herein, and unless otherwise specified, refers to a divalent aryl group, as defined herein.

[0101] The term “aryloxy,” as used herein, and unless otherwise specified, refers to an -OR group where R is aryl, as defined herein.

[0102] “Alkarylene” refers to an arylene group, as defined herein, wherein the aryl ring is substituted with one or two alkyl groups. “Substituted alkarylene” refers to an alkarylene, as defined herein, where the arylene group is further substituted, as defined herein for aryl.

[0103] “Aralkylene” refers to a -CH2-arylene-, -arylene-CH2-, or -CH2-arylene-CH2- group, where arylene is as defined herein. “Substituted aralkylene” refers to an aralkylene, as defined herein, where the aralkylene group is substituted, as defined herein for aryl.

[0104] “Carboxyl” or “carboxy” refers to -C(O)OH or -COOH.”

[0105] “Divalent hydrophilic group;” as used herein, and unless otherwise specified, refers to PEG, for example of the formula, wherein e is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

[0106] “Polyethylene glycoloxy (PEG)” as used herein, and unless otherwise specified, refers to the monovalent or divalent residue of polyethylene glycol (PEG), for example of the formula, respectively, wherein e or f is an - 19 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula. In one embodiment, e is an integer between 1 and 10. In one embodiment, e is an integer between 5 and 10. In one embodiment, f is an integer between 11 and 20.

[0107] “Methoxypolyethylene glycoloxy” as used herein, and unless otherwise specified, refers to the monovalent residue of poly(ethylene glycol) monomethyl ether (mPEG) and is of the formula wherein f is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula. In one embodiment, f is an integer between 1 and 20. In one embodiment, f is an integer between 11 and 20.

[0108] “Methoxypolyethylene glycoloxy-CH2CH2-C(O)-” as used herein, and unless otherwise specified, refers to the monovalent residue of mPEG as described herein further substituted with -CH2CH2-C(O)- (mPEG-CH2CH2-C(O)-) and is of the formulawherein g is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula. In one embodiment, g is an integer between 1 and 20. In one embodiment, g is an integer between 11.

[0109] “Polyethylene glycoloxy-CH2CH2C(O)-” as used herein, and unless otherwise specified, refers to the monovalent residue of PEG as described herein further substituted with -CH2CH2-C(O)- (PEG-CH2CH2-C(O)-) and is of the formulawherein h is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula. In one embodiment, h is an integer between 1 and 20. In one embodiment, h is an integer between 11 and 20.

[0110] The term “carbocycle” as used herein, unless otherwise specified, refer to a saturated, unsaturated, or aromatic ring in which all atoms of the ring are carbon. In certain embodiments, the “carbocycle” group may be saturated, and / or bridged, and / or non-bridged, and / or a fused bicyclic group, and / or a spirocyclic bicyclic group. In certain embodiments, the “carbocycle” group includes three to ten carbon atoms (i.e., C3 to C10 cycloalkyl). In some embodiments, the “carbocycle” has from three to fifteen carbons (C3-15), from three to ten carbons (C3-10), from three to seven carbons (C3-7), or from three to six carbons (C3-C6) (i.e., - 20 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 “lower cycloalkyl”). In certain embodiments, the “carbocycle” group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl Exemplary “carbocycles” include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl phenyl, indanyl, and naphthyl. “Carbocycle” includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems. Non-limiting examples of bridged bicyclic carbocycle groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, and 2-oxabicyclo[2.2.2]octyl. Non-limiting examples of spirocyclic carbocycle groups include, but are not limited to, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, and spiro[5.7]tridecyl.

[0111] “Carbocyclene” refers to a divalent carbocycle as defined herein.

[0112] The term “bicyclic ring system” includes 6-12 (e.g., 8-12 or 9-, 10-, or 11-) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., two atoms in common). Bicyclic rings can be fused, bridged, or spirocyclic. Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.

[0113] The term “bridged bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 6-azabicyclo[3.1.1]heptyl, 6- azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7- azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2- oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including - 21 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0114] The term “spiro bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which 2 or 3 rings are linked together by one common atom. Spiro compounds depicted with overlapping rings indicate that the rings can bond at any vertex. For instance, in the spiro group, the two rings can bond at any of the three available vertex atoms in either ring. In some embodiments, a spiro bicyclic ring is a 3- to 12- membered spirocyclic bicyclic heterocycle comprising two nitrogen atoms and one oxygen atom. Non-limiting examples of a spirocyclic bicyclic heterocycle include a 10- membered spirocyclic bicyclic heterocycle, a 9- membered spirocyclic bicyclic heterocycle, and a 8- membered spirocyclic bicyclic heterocycle. The 3- to 12- membered spirocyclic bicyclic heterocycle include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms, for example two nitrogen atoms and one oxygen atom. For example, a 5-oxa-2,8- diazaspiro[3.5]nonane is a compound in which a 4 membered heterocyclic ring and a 6 membered heterocyclic ring are bonded through a single carbon atom wherein an oxygen atom is in the 6 membered heterocyclic ring.

[0115] The term “cycloalkylene,” as used herein refers to a divalent cycloalkyl group, as defined herein. In certain embodiments, the cycloalkylene group is cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like. Lower cycloalkylene refers to a C3-C6-cycloalkylene. - 22 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0116] The term “cycloalkylalkyl,” as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, substituted with one or two cycloalkyl, as defined herein.

[0117] The term “ester,” as used herein, refers to -C(O)OR or -COOR where R is alkyl, as defined herein.

[0118] The term “fluorene” as used herein refers to, wherein any one or more carbons bearing one or more hydrogens can be substituted with a chemical functional group as described herein.

[0119] The term “haloalkyl” refers to an alkyl group, as defined herein, substituted with one or more halogen atoms (e.g., in some embodiments one, two, three, four, or five) which are independently selected.

[0120] The term “heteroalkyl” refers to an alkyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkenyl” refers to an alkenyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkynyl” refers to an alkynyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl. “Substituted heteroalkyl” refers to heteroalkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a heteroalkyl group may comprise one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered heteroalkyl may generally comprise one or two heteroatoms, a 5- or 6-membered heteroalkyl may generally comprise one, two, or three heteroatoms, and a 7- to 10-membered heteroalkyl may generally comprise one, two, three, or four heteroatoms.

[0121] The term “heteroalkylene,” as used herein, refers to a divalent heteroalkyl, as defined herein. “Substituted heteroalkylene” refers to a divalent heteroalkyl, as defined herein, substituted as described for heteroalkyl.

[0122] The term “heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms where - 23 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 the nitrogen or sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized and the remaining ring atoms of the non-aromatic ring are carbon atoms. A “heterocycle” includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. In certain embodiments, “heterocycle” is a monovalent, monocyclic, or multicyclic fully-saturated ring system. In certain embodiments, the “heterocycle” group may be unsaturated, and / or bridged, and / or non- bridged, and / or a fused bicyclic group, and / or a spirocyclic bicyclic group. A bicyclic “heterocycle” includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6- 7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. In certain embodiments, the “heterocycle” group has from three to twenty, from three to fifteen, from three to twelve from three to ten, from three to eight, from four to seven, from four to eleven, or from five to six ring atoms. The “heterocycle” may be attached to a core structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the “heterocycle” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged or spirocyclic ring system and in which the nitrogen or sulfur atoms may be optionally oxidized, and / or the nitrogen atoms may be optionally quaternized. In some embodiments, “heterocycle” radicals include, but are not limited to, 2,5-diazabicyclo[2.2.2]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, azetidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. Non-limiting examples of bridged heterocycle groups include, but are not limited to, 6- azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2- azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2-oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. Non-limiting examples of spirocyclic heterocycle groups include, but are not limited to, 2,8- diazaspiro[4.5]decyl; 2,7-diazaspiro[3.5]nonyl; 3,9-diazaspiro[5.5]undecyl; 3- azaspiro[5.5]undecyl; 2-oxa-6-azaspiro[3.4]octyl; 2-oxa-9-azaspiro[5.5]undecyl; 3-oxa-9- - 24 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 azaspiro[5.5]undecyl; 7-azaspiro[3.5]nonyl; 2-azaspiro[3.5]nonyl; 7-oxaspiro[3.5]nonyl; and 2-oxaspiro[3.5]nonyl. In certain embodiments, “heterocycle” may also be optionally substituted as described herein. In certain embodiments, “heterocycle” is substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a “heterocycle” group may comprise one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered “heterocycle” may generally comprise one or two heteroatoms, a 5- or 6-membered “heterocycle” may generally comprise one, two, or three heteroatoms, and a 7- to 10-membered “heterocycle” may generally comprise one, two, three, or four heteroatoms.

[0123] The term “heterocycloalkylene” refers to a divalent heterocycloalkyl as defined herein.

[0124] The term “heteroaryl” refers to a monovalent, monocyclic aromatic group and / or multicyclic aromatic group, wherein at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of a heteroaryl group can contain one or two oxygen atoms, one or two sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from five to twenty, from five to fifteen, or from five to ten ring atoms. A heteroaryl may be attached to the rest of the molecule via a nitrogen or a carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In - 25 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 certain embodiments, heteroaryl may also be optionally substituted as described herein. “Substituted heteroaryl” is a heteroaryl substituted as defined for aryl.

[0125] The term “heteroarylene” refers to a divalent heteroaryl group, as defined herein. “Substituted heteroarylene” is a heteroarylene substituted as defined for aryl.

[0126] “Pharmaceutically acceptable salt” refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1- carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0127] Pharmaceutically acceptable salts further include, by way of example only and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, - 26 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2- hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2- naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4- methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like.

[0128] The term “substantially free of” or “substantially in the absence of” with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in certain embodiments 95%, 98 %, 99% or 100% by weight, of the designated enantiomer of that compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers.

[0129] Similarly, the term “isolated” with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, and 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers.

[0130] “Solvate” refers to a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0131] “Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.

[0132] “Isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using - 27 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0133] “Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0134] As used herein, “alkyl,” “alkylene,” “alkylamino,” “dialkylamino,” “cycloalkyl,” “aryl,” “alkoxy,” “alkoxycarbonyl,” “amino,” “carboxyl,” “heterocyclyl,” “heterocycloalkyl,” “heteroaryl,” “partially saturated heteroaryl,” “carboxyl,” and “amino acid” groups optionally comprise deuterium at one or more positions where hydrogen atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.

[0135] Also as used herein, “alkyl,” “alkylamino,” “dialkylamino,” “cycloalkyl,” “aryl,” “alkoxy,” “alkoxycarbonyl,” “amino,” “carboxyl,” “heterocyclyl,” “heteroaryl,” “carboxyl” and “amino acid” groups optionally comprise carbon-13 at an amount other than the natural isotopic composition.

[0136] In some chemical structures illustrated herein, certain substituents, chemical groups, and atoms are depicted with a curvy / wavy line (e.g., ) that intersects a bond or bonds to indicate the atom through which the substituents, chemical groups, and atoms are bonded. For example, in some structures, such as but not limited to,, the curvy / wavy lines indicates the atoms in the backbone of a conjugate structure to which the illustrated chemical entity is bonded. In some structures, such as but not limited to,, the curvy / wavy lines indicate the atoms in the antibody or antibody - 28 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 fragment as well as the atoms in the backbone of a conjugate or linker-payload structure to which the illustrated chemical entity is bonded.

[0137] As used herein, illustrations showing substituents bonded to a cyclic group (e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) through a bond between ring atoms are meant to indicate, unless specified otherwise, that the cyclic group may be substituted with that substituent at any ring position in the cyclic group or on any ring in the fused ring group, according to techniques set forth herein or which are known in the field to which the instant disclosure pertains. For example, the group,, wherein subscripts z and y are integers and in which the positions of substituents -O-Su and RAis described generically, i.e., not directly attached to any vertex of the bond line structure, i.e., specific ring carbon atom, includes the following, non-limiting examples of groups in which the substituent RAand Osu is bonded to a specific ring carbon atom:, , , - 29 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01Conjugates

[0138] Provided herein are dual payload immunostimulatory antibody-drug conjugates (iADCs) that comprise an anti-TROP2 antibody or antigen binding fragment thereof, at least one STING agonist via a first linker, and at least one cytotoxic agent. In certain embodiments, the immunostimulatory antibody drug conjugate comprises an anti-TROP2 antibody or antigen binding fragment thereof, wherein the anti-TROP2 antibody or antigen binding fragment thereof is linked site-specifically to at least one STING agonist via first linker, and also linked site-specifically to at least one cytotoxic agent via a second linker. In certain embodiments, the iADCs comprise means for binding TROP2, at least one STING agonist via a first linker, and at least one cytotoxic agent.

[0139] Some embodiments of the present invention are shown below: Embodiment [1]: The conjugate is of Formula I:Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab is an anti-TROP2 antibody or antigen-binding fragment thereof; Lais a first linker; Lbis a second linker; CY is independently a residue of a cytotoxic agent; STING is independently a residue of a STING agonist; n is an integer selected from 1 to 10; and m is an integer selected from 1 to 10. - 30 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0140] Embodiment [1-1]: The conjugate of embodiment [1], wherein the conjugate of Formula (I) is Formula (Ib) or Formula (Ic):Formula (Ic) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein: Y is –X1-C1-6alkylene-[X1-C1-6alkylene]a-[X1]b–, –X1-C2-6alkenylene-[X1-C2-6alkenylene]a-[X1]b–, or–X1-C2-6alkynylene-[X1-C2-6alkynylene]a-[X1]b–, wherein at least one C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene in Y is substituted with one or more substituents selected from R70; and -[X1]b- is attached to RL1or RL01; and wherein the C1-6alkylene, C2-6alkenylene, or C2-6alkynylene in Y is optionally substituted with one or more substituents selected from R71; R70is –C1-6 alkylene-X2-[C1-6 alkylene]c-HP2, –C2-6 alkenylene-X2-[C2-6 alkenylene]c- HP2, or –C2-6alkynylene-X2-[C2-6alkynylene]c-HP2, wherein each C1-6alkylene, C2-6alkenylene, or C2-6 alkynylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, - C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl; R71is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl; X1and X2are independently selected from –N(R60)–, –C(O)–, and –N(R60)C(O)–; - 31 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 a is an integer selected from 0, 1, 2, and 3; b is an integer selected from 0 and 1; c is an integer selected from o and 1; and Su is a hexose form of a monosaccharide.

[0141] Embodiment [1-2]: The conjugate of embodiment [1-1], wherein the conjugate of Formula (Ib) is Formula (Ib-1):Formula (Ib-1).

[0142] Embodiment [1-3]: The conjugate of embodiment [1-1], wherein the conjugate of Formula (Ib) is Formula (Ib-2):Formula (Ib-2).

[0143] Embodiment [1-4]: The conjugate of embodiment [1-1], wherein the conjugate of Formula (Ic) is Formula (Ic-1):Formula (Ic-1).

[0144] Embodiment [1-5]: The conjugate of embodiment [1-1], wherein the conjugate of Formula (Ic) is Formula (Ic-2): - 32 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01Formula (Ic-2).

[0145] Embodiment [2]: The conjugate of any one of embodiments [1]-[1-5], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein STING is independently a residue of a compound of Formula (S-I) or (S-II):or a tautomer or stereoisomer thereof; wherein: X is selected from N and CR3; R20is selected from hydrogen and -CON(R3a)(R3b); R1a, R1b, R3aand R3bare independently selected from hydrogen and optionally substituted C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R50; R2aand R2bare independently selected from: (a) optionally substituted C1- 6 alkyl, wherein the C1-6alkyl is optionally substituted with one or more R51and (b) optionally substituted C3-12 carbocycle or optionally substituted 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R53; or R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; - 33 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 or R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; R3is hydrogen, -OR30, -SR30, -C(O)N(R30)2, -N(R30)C(O)R30, -N(R30)C(O)N(R30)2, -N(R30)2, -C(O)R30, -C(O)OR30, -OC(O)R30, -NO2, or -CN; L1is selected from a bond, -C1-10alkylene-, -C2-10alkenylene-, -C2-10alkynylene-, -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, C3-6carbocyclene, and -C1-6alkylene-(C3-6carbocyclene)-C1-6alkylene-, wherein -C1- 10 alkylene-, -C2-10 alkenylene-, -C2-10 alkynylene-, C3-6 carbocyclene, and each C1-6 alkylene of -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, and -C1-6alkylene-(C3-6carbocyclene)-C1-6alkylene- are optionally substituted with one or more R50; L2is optionally substituted -C1-6alkylene- or -C1- 6alkylene-O-, wherein the -C1-6alkylene- or the C1-6alkylene of -C1-6alkylene-O- is optionally substituted with one or more R50and wherein the -C1-6 alkylene-O- is attached to the A ring, or Lbif the A ring is absent, via the oxygen atom; Ring A is absent; an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one N atom and at least one O atom, wherein the heterocycle is optionally substituted with one or more R53; or, a 3- to 12- membered heterocycle substituted with R4; Ring B is an optionally substituted C3-12carbocycle or an optionally substituted 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; R4is an optionally substituted 3- to 12-membered heterocycle optionally comprising at least one NR5and, wherein the heterocycle is optionally substituted with one or more R53; R5is independently selected from hydrogen, R6, -C(O)-C1-6alkyl, -C(O)- heteroC1-6alkyl, C1-6 alkyl, and heteroC1-6alkyl wherein the C1-6 alkyl, either alone or part of another group, is optionally substituted with one or more R50; R6is independently an amino acid residue; R30is independently selected from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which, except hydrogen, is optionally substituted with one or more R55; - 34 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R50is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, C3-12carbocycle, and 3- to 12-membered heterocycle; R51is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; R52is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, -NO2, =O, =S, =N(R61), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; R53is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, optionally substituted C1-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3- 12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one or more R54and the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted with one or more R52; R54is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, - NO2, =O, =S, =N(R61), and -CN; R55is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and R60and R61are independently selected from hydrogen, C1-10 alkyl optionally substituted with NH2or NHC1-6alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle; wherein when Ring A is absent, L2is -C1-6 alkylene-O-; wherein the residue of Formula (S-I) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6alkylene-O- of L2, an amino group of R54, or an amino group of R4, and the residue of Formula (S-II) is attached to Lbvia an amino group of Ring B. - 35 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0146] Embodiment [2-1]: The conjugate of any one of embodiments [1] to [2], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein STING is independently a residue of a compound of Formula (S-I):(S-I) or a tautomer or stereoisomer thereof; wherein: X is selected from N and CR3; R20is selected from hydrogen and -CON(R3a)(R3b); R1a, R1b, R3aand R3bare hydrogen; R2aand R2bare independently selected from: optionally substituted 3- to 12- membered heterocycle, each of which is optionally substituted with one or more R53; R3is hydrogen or -OR30; L1is selected from a bond and -C2-10alkenylene-; L2is optionally substituted -C1-6 alkylene-; Ring A is absent; an optionally substituted spirocyclic bicyclic heterocycle comprising at least one N atom and at least one O atom, wherein the heterocycle is optionally substituted with one or more R53; or, a 3- to 12-membered heterocycle substituted with R4; R4is an optionally substituted 3- to 12-membered heterocycle optionally comprising at least one NR5and wherein the heterocycle is optionally substituted with one or more R53; R5is independently selected from hydrogen, R6, -C(O)-C1-6alkyl, -C(O)- heteroC1-6alkyl, C1-6alkyl, and heteroC1-6alkyl wherein the C1-6alkyl, either alone or part of another group, is optionally substituted with one or more R50; R6is independently an amino acid residue; - 36 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R30is independently selected from hydrogen and C1-10 alkyl; R50is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, C3-12carbocycle, and 3- to 12- membered heterocycle; R53is independently selected from optionally substituted 3- to 12-membered heterocycle, wherein the 3- to 12-membered heterocycle is optionally substituted with one or more R52; and wherein when Ring A is absent, L2is -C1-6 alkylene-O-; wherein the residue of Formula (S-I) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6alkylene-O- of L2, an amino group of R54, or an amino group of R4, and the residue of Formula (S-II) is attached to Lbvia an amino group of Ring B.

[0147] Embodiment [2-2]: The conjugate of embodiment [2-1], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein STING is independently a residue of a compound of Formula (S-I), or a tautomer or stereoisomer thereof;, - 37 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01wherein is the point of attachment to Lband is the point of attachment to L2; andwherein X5, X6, X9, X10are independently selected from N and CR13; X7and X8are independently selected from NH, O, and CHR13; R13is independently hydrogen or C1-6alkyl; wherein if four of any one of X5-X10are present, at least one is CR13or CHR13; andis the point of attachment to Ring A andis the point of attachment to Lb.

[0148] Embodiment [2-3]: The conjugate of embodiment [2-1], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein STING is independently a residue of a compound of Formula (S-I), or a tautomer or stereoisomer thereof; - 38 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 wherein Ringis the point of attachment to Lband is the point of attachment to L2; andthe point of attachment to ring A andthe point of attachment to Lb.

[0149] Embodiment [3]: The conjugate of any one of embodiments [1]-[2-3], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein CY is a residue of a compound selected from the group consisting of an alkylating agent, a DNA- crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone-deacetylase (HDAC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, and a topoisomerase inhibitor.

[0150] Embodiment [4]: The conjugate of embodiment [3], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein CY is a topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan.

[0151] Embodiment [5]: The conjugate of embodiment [4], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein CY is exatecan.

[0152] Embodiment [6]: The conjugate of any one of embodiments [1] to [5], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Laand Lbindependently comprise a protease cleavable linker, an enzyme cleavable linker, a pH- sensitive linker, or a non-cleavable linker.

[0153] Embodiment [7]: The conjugate of any one of embodiments [1] to [6], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Lais -W1-W2-SG1-HP1-RL1-; Lbis -RL01-HP01-SG01-W02-W01-; and the antibody conjugate of Formula (I) is represented by Formula (Ia): - 39 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 [CY-W1-W2-SG1-HP1-RL1-]m-Ab-[-RL01-HP01-SG01-W02-W01-STING]n (Ia) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein: Ab is the anti-TROP2 antibody or antigen-binding fragment thereof; CY is the residue of the cytotoxic agent; STING is the residue of the STING agonist; SG1and SG01are independently, at each occurrence, absent or a divalent spacer group; W1and W01are independently, at each occurrence, absent,wherein the -NH- is bound to W2or W02and eachindicates a point of attachment to the rest of the formula; L3is independently a bond or an optionally substituted C1-6alkylene wherein the C1-6alkylene is optionally substituted with one, two, or three substituents selected from halogen, C1-6alkyl, haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy; R16is independently a residue of an amino acid sidechain; R11is independently hydrogen or C1-6 alkyl; w is an integer selected from 0, 1, and 2; W2and W02are independently, at each occurrence, absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP2group; HP1and HP01are independently, at each occurrence, absent or a divalent hydrophilic group; HP2, when present, is a monovalent hydrophilic group; RAis independently, at each occurrence, optionally substituted C1-6alkyl wherein the C1-6 alkyl is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6 alkyl, hydroxyl, amino, alkylC1-6 amino, and C1-6 alkoxy; - 40 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 O-Su is independently, at each occurrence, a release trigger group; RL1and RL01are independently, at each occurrence, a reactive linker; y is an integer independently selected from 0, 1, and 2; and z is an integer independently selected from 0 and 1.

[0154] Embodiment [8]: The conjugate of any one of embodiments [1] to [7], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein R1aand R1bare both hydrogen.

[0155] Embodiment [9]: The conjugate of any one of embodiments [1] to [8], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein R2aand R2bare independently an optionally substituted 3- to 12-membered heterocycle comprising at least one N atom.

[0156] Embodiment

[0010] : The conjugate of embodiment [8] or [9], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein R2aand R2bare independently selected fromwherein R2cand R2dare independently selected from hydrogen, C1-6alkyl optionally substituted with one or more R54, halo, and 3-12 membered heterocycle; R2eis hydrogen or C1-6 alkyl; andis the point of attachment to the rest of the formula.

[0157] Embodiment

[0011] : The conjugate of any one of embodiments [2] to

[0010] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2)], wherein the STING is a residue of a compound of Formula (S-I) wherein Ring A is an optionally substituted 3- to 12- membered N-linked spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to Lb, and at least one oxygen atom; or a 3- to 12- membered N-linked monocyclic heterocycle substituted with R4.

[0158] Embodiment [11-1]: The conjugate of any one of embodiments [2] -

[0011] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein the STING is a residue of a compound of Formula (S-I) whereinselected from - 41 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01the point of attachment to Lbandis the point of attachment to L2; or b) Ring A is selected from,wherein is the point of attachment to L2.

[0159] Embodiment [11-2]: The conjugate of any one of embodiments [2] -

[0011] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein the STING is a residue of a compound of Formula (S-I) wherein Ring- 42 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01the point of attachment to Lband is the point of attachment to L2.

[0160] Embodiment

[0012] : The conjugate of any one of embodiments [2] -

[0011] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) wherein ,the point of attachment to Lband is the point of attachment to L2.

[0161] Embodiment

[0013] : The conjugate of embodiment

[0012] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) , wherein- 43 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 whereinis the point of attachment to Lbandis the point of attachment to L2.

[0162] Embodiment

[0014] : The conjugate of any one of embodiments [2] to

[0013] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Ring A is an N-linked mono 3- to 12-membered heterocycle substituted with R4.

[0163] Embodiment

[0015] : The conjugate of any one of embodiments [2] to

[0011] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Ring Athe point of attachment to L2.

[0164] Embodiment

[0016] : The conjugate of embodiment

[0014] or

[0015] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Ring A is.

[0165] Embodiment

[0017] : The conjugate of any one of embodiments [2] to

[0011] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) wherein R4is a 5- 5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N bound to Lb.

[0166] Embodiment

[0018] : The conjugate of any one of embodiments [2] to

[0011] or

[0016] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), - 44 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01wherein X5, X6, X9, X10are independently selected from N and CR13; X7and X8are independently selected from NH, O, and CHR13; R13is independently hydrogen or C1-6alkyl; wherein if four of any one of X5-X10are present, at least one is CR13or CHR13; andis the point of attachment to ring A andis the point of attachment to Lb.

[0167] Embodiment

[0019] : The conjugate of embodiment

[0018] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein.

[0168] Embodiment

[0020] : The conjugate of any one of embodiments [1] to

[0019] , wherein the conjugate is of any one of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein Ring B is an optionally substituted 3- to 12-membered heterocycle.

[0169] Embodiment

[0021] : The conjugate of any one of embodiments [1] to

[0020] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein L2is - C1-6 alkylene-. - 45 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0170] Embodiment

[0022] : The conjugate of any one of embodiments [2] to

[0021] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein eachW01is independently absent,L3is bond or -CH2- ; y is 0 or 1; and z is 0 or 1.

[0171] Embodiment [22-1]: The conjugate of any one of embodiments [2]-

[0021] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein eachwherein L3is -CH2-, y is 0, and z is 1; and W01is independently absent;wherein L3is bond, y is 0, and z is 0; or,- 46 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0172] Embodiment

[0023] : The conjugate of embodiment

[0022] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein, whereinrepresents attachment to the remainder of the compound.

[0173] Embodiment

[0024] : The conjugate of embodiment

[0022] to

[0023] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) wherein Su is , wherein represents attachment to the remainder of the compound.

[0174] Embodiment

[0025] : The conjugate of any one of embodiment [2] to

[0024] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each W2and W02are independently absent or a group selected from -(C(O)CHR10NR11)o-, -(C(O)CH2CHR10NR11)p-, -(C(O)CHR10CH2NR11)p-, -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-, and -(C(O)CHR10CH2NR11)p- (C(O)CHR10NR11)o-; wherein R10is independently an amino acid sidechain residue optionally substituted with HP2; R11is independently hydrogen or C1-6alkyl; o and p are independently an integer between 1 and 10, inclusive; and the -C(O)- of W2and W02are bound to W1.

[0175] Embodiment [26-1]: The conjugate of embodiment

[0025] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each W2and W02is independently absent or -(C(O)CH2CHR10NR11)p- (C(O)CHR10NR11)o- wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycoloxy-CH2CH2C(O)- (PEG- CH2CH2C(O)-); methoxypolyethylene glycoloxy-CH2CH2C(O)- (mPEG- - 47 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 CH2CH2C(O)-); poly(propylene glycoloxy-CH2CH2C(O)-) (PPG-CH2CH2C(O)-); poly(oxyethylated polyol)oxy-CH2CH2C(O)-; poly(olefinic alcohol)oxy- CH2CH2C(O)-; poly(saccharides)-CH2CH2C(O)-; poly(vinyl alcohol)oxy- CH2CH2C(O)-; or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0176] Embodiment

[0026] : The conjugate of embodiment

[0025] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each W2and W02is independently absent or -(C(O)CH2CHR10NR11)p- (C(O)CHR10NR11)o- wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycoloxy-CH2CH2C(O)- (PEG- CH2CH2C(O)-); methoxypolyethylene glycoloxy-CH2CH2C(O)- (mPEG- CH2CH2C(O)-); poly(propylene glycoloxy-CH2CH2C(O)-) (PPG-CH2CH2C(O)-); poly(oxyethylated polyol)oxy-CH2CH2C(O)-; poly(olefinic alcohol)oxy- CH2CH2C(O)-; poly(saccharides)-CH2CH2C(O)-; poly(vinyl alcohol)oxy- CH2CH2C(O)-; or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0177] Embodiment

[0027] : The conjugate of embodiment

[0026] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein HP2is a methoxypolyethylene glycoloxy-CH2CH2-C(O)- (mPEG-CH2CH2-C(O)-).

[0178] Embodiment

[0028] : The conjugate of embodiment

[0024] or

[0027] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each W2and W02is independently absent or of the formula:, - 48 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01formula.

[0179] Embodiment [28-1]: The conjugate of embodiment

[0024] or

[0027] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each W2,eachis the point of attachment to the rest of the formula.

[0180] Embodiment [28-2]: The conjugate of embodiment [28-1], wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein W2is of the formula: - 49 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01rest of the formula.

[0181] Embodiment

[0029] : The conjugate of any one of embodiments [2] to

[0028] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein SG1is independently -C(O)-C1-6alkylene-C(O)-, and SG01is independently absent or -C1-6alkylene-C(O)- wherein the -C(O)- is bound to W2and W02.

[0182] Embodiment

[0030] : The conjugate of any one of embodiments [2] to

[0029] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each P1H and HP01is independently absent or wherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

[0183] Embodiment [30-1]: The conjugate of embodiment [2] to

[0029] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each HP1is absentand HP01is independently absent or wherein R2is hydrogen or methyl - 50 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

[0184] Embodiment [30-2]: The conjugate of embodiment [2] to

[0029] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each HP1and HP01is independently absent,,wherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

[0185] Embodiment [30-3]: The conjugate of embodiment [2] to

[0029] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein each HP1is independently absent,, and HP01is independently absentwherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

[0186] Embodiment

[0031] : The conjugate of any one of embodiments [2] to

[0030] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2)], wherein each RL and RL01is independently selected, - 51 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 ,.

[0187] Embodiment

[0032] : The conjugate of embodiment

[0031] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein RL1is independentlyattachment to the rest of the formula.

[0188] Embodiment

[0033] : The conjugate of embodiment

[0032] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), whereineach is a point of attachment to the rest of the formula.

[0189] Embodiment

[0034] : The conjugate of any one of embodiments [2] to

[0033] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein CY is - 52 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01each is a point of attachment to the rest of the formula.

[0190] Embodiment

[0035] : The conjugate of embodiment

[0034] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein CY is independently selected from.

[0191] Embodiment

[0036] : The conjugate of any one of embodiments [1]-

[0035] , wherein the conjugate is of Formula (I) or (Ia), wherein -[Lb-STING]n is independently - 53 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 , ,, - 54 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

[0192] Embodiment

[0037] : The conjugate of any one of embodiments [1]-

[0036] , wherein the conjugate of Formula (I) or (Ia) wherein -[Lb-STING]n is a structure selected from:- 55 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 56 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 57 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 58 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 59 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

[0193] Embodiment

[0038] : The conjugate of any one of embodiments [1] to

[0037] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein, - 60 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 ,, - 61 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

[0194] Embodiment

[0039] : The conjugate of any one of embodiments [1] to

[0038] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein [CY-La-]m- is - 62 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01-[Lb-STING]n is.

[0195] Embodiment

[0040] : The conjugate of any one of embodiments [1] to

[0039] , wherein the conjugate is of Formula (I), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), wherein [CY-La-]m - is-[Lb-STING]n is a structure selected from- 63 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0196] Embodiment

[0041] : The conjugate of any one of embodiments [1] to

[0040] , wherein of m and n is an integer independently between 1 and 8, inclusive.

[0197] Embodiment

[0042] : The conjugate of any one of embodiments [1] to

[0041] , wherein n is between 1 and 6, inclusive.

[0198] Embodiment

[0043] : The conjugate of any one of embodiments [1] to

[0042] , wherein m is between 1 and 6, inclusive.

[0199] Embodiment

[0044] : The conjugate of any one of embodiments [1] to

[0043] , wherein of m is an integer independently between 1 and 6 and n is an integer independently between 1 and 6, inclusive.

[0200] Embodiment

[0045] :The conjugate of any one of embodiments [1] to

[0044] , wherein the molar ratio of CY to STING is about 2:1.

[0201] Embodiment

[0046] :The conjugate of any one of embodiments [1] to

[0044] , wherein the molar ratio of m to n is about 2:1.

[0202] Embodiment

[0047] : The conjugate is of Formula (Ia): [CY-W1-W2-SG1-HP1-RL1-]m-Ab-[-RL01-HP01-SG01-W02-W01-STING]nwherein CY is independently a residue of a cytotoxic agent; W1and W01are independentlySu is , whereinrepresents attachment to the remainder of the compound; W2and W02are independently absent or -(C(O)CH2CHR10NR11)p- (C(O)CHR10NR11)o-; wherein - 64 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG) thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; p is 1; SG1is independently -C(O)-C1-6 alkylene-C(O)-, and SG01is independently absent or -C1-6alkylene-C(O)- wherein the -C(O)- is bound to W2and W02; 1 P01HP and H is independently absent or wherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula; RL1and RL01are independently, at each occurrence, a reactive linker;rest of the formula; STING is independently a residue of a STING agonist; Wherein the STING agonist is a residue of a compound of Formula (S-I) or (S-II):(S-I) (S-II) or a tautomer or stereoisomer thereof; wherein: X is CR3; - 65 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R20is -CON(R3a)(R3b); R1a, R1b, R3aand R3bare independently hydrogen; R2aand R2bare independently selected from:wherein R2c, R2dand R2eare independently C1-6alkyl; R3is hydrogen, -OR30, -SR30, -C(O)N(R30)2, -N(R30)C(O)R30, - N(R30)C(O)N(R30)2, -N(R30)2, -C(O)R30, -C(O)OR30, -OC(O)R30, -NO2, or -CN; L1is -C2-10alkenylene-; L2is -C1-6 alkylene-; Ring A is bwherein is the point of attachment to Land; Ring B is azetidine; R30is independently selected from hydrogen and C1-10alkyl; wherein the residue of Formula (S-I) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6 alkylene-O- of L2, or an amino group of R4, and the residue of Formula (S-II) is attached to Lbvia an amino group of Ring B; subscript n is an integer selected from 1 to 10; and subscript m is an integer selected from 1 to 10.

[0203] Embodiment

[0048] : The antibody conjugate according to Embodiment

[0047] , wherein CY is a topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan.

[0204] Embodiment

[0049] : The antibody conjugate according to Embodiment

[0047] or

[0048] , wherein CY is exatecan.

[0205] Embodiment

[0050] : The antibody conjugate according to any one of Embodiments

[0047] -

[0049] , wherein W2and W02is independently absent or of the formula: - 66 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01, , , , , oris the point of attachment to the rest of the formula. 1. Linkers

[0206] The first linker (La) and the second linker (Lb) can be any linkers capable of forming at least one bond to the anti-TROP2 antibody and at least one bond to a payload wherein the first linker forms at least one bond with the either the STING agonist and the second linker forms a bond with the cytotoxic agent. The first linker and the second linker can have the same structure, but in a preferable embodiment, the first linker and the second linker are different structures. In some embodiments, including any of the foregoing, the first and second linker independently comprise a protease cleavable linker, an enzyme cleavable linker, a pH-sensitive linker, or a non-cleavable linker.

[0207] In certain embodiments of Laand Lb, W1and W01are independently absent,bond or -CH2-; y is 0 or 1; and, z is 0 or 1.

[0208] In certain embodiments,, whereinrepresents attachment to the remainder of the compound. - 67 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0209] In certain embodiments,, whereinrepresents attachment to the remainder of the compound.

[0210] In certain embodiments, each W2and W02is independently absent or a group selected from -(C(O)CHR10NR11)o-, -(C(O)CH2CHR10NR11)p-, -(C(O)CHR10CH2NR11)p-, -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-, and -(C(O)CHR10CH2NR11)p- (C(O)CHR10NR11)o-; wherein R10is independently an amino acid sidechain residue optionally substituted with HP2; R11is independently hydrogen or C1-6alkyl; o and p is independently an integer between 1 and 10, inclusive; and the -C(O)- of W2and W02is bound to W1.

[0211] In certain embodiments, each W2and W02is independently absent or -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o- wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycoloxy-CH2CH2C(O)- (PEG-CH2CH2C(O)-); methoxypolyethylene glycoloxy-CH2CH2C(O)- (mPEG-CH2CH2C(O)-); poly(propylene glycoloxy-CH2CH2C(O)-) (PPG-CH2CH2C(O)-); poly(oxyethylated polyol)oxy- CH2CH2C(O)-; poly(olefinic alcohol)oxy-CH2CH2C(O)-; poly(saccharides)-CH2CH2C(O)-; poly(vinyl alcohol)oxy-CH2CH2C(O)-; or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0212] In certain embodiments, each W2and W02is independently absent or -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o- wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; - 68 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 HP2is independently polyethylene glycoloxy-CH2CH2C(O)- (PEG-CH2CH2C(O)-); methoxypolyethylene glycoloxy-CH2CH2C(O)- (mPEG-CH2CH2C(O)-); poly(propylene glycoloxy-CH2CH2C(O)-) (PPG-CH2CH2C(O)-); poly(oxyethylated polyol)oxy- CH2CH2C(O)-; poly(olefinic alcohol)oxy-CH2CH2C(O)-; poly(saccharides)-CH2CH2C(O)-; poly(vinyl alcohol)oxy-CH2CH2C(O)-; or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0213] In certain embodiments, HP2is a methoxypolyethylene glycol (mPEG).

[0214] In certain embodiments, each W2and W02is independently absent or of the formula:attachment to the rest of the formula.

[0215] In certain embodiments, each W2and W02is independently of the formula:, - 69 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01the point of attachment to the rest of the formula.

[0216] In certain embodiments, SG1is independently -C(O)-C1-6alkylene-C(O)-, and SG01is independently absent or -C1-6 alkylene-C(O)- wherein the -C(O)- is bound to W2and W02. 101

[0217] In certain embodiments, each HP and HP is independently absent or wherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula.

[0218] In certain embodiments, each RL and RL01is independently selected fromattachment to the rest of the formula. - 70 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0219] In certain embodiments, RL1is independently selected froma eac is a point of attachment to the rest of the formula.

[0220] In certain embodiments, RL01isand eachis a point of attachment to the rest of the formula.

[0221] In certain embodiments, SG1and SG01are divalent spacer groups that facilitate incorporation of eliminator groups, release trigger groups, hydrophobic groups, attaching groups, and / or the conjugating group into a compound. Spacer groups that facilitate the spacing of the conjugating group from the other groups of the compounds can lead to more efficient conjugation of the compounds described herein to a second compound as well as more efficient cleavage of the active catabolite. Spacer groups can also stabilize the conjugating group and lead to improved overall antibody-drug conjugate properties. Useful spacer groups are known to, and are apparent to, those of skill in the art. Examples of useful spacer groups are provided herein. In certain embodiments, a spacer group can comprise a divalent ketone, divalent ester, divalent ether, divalent amide, divalent amine, alkylene, arylene, sulfide, disulfide, carbonylene, or a combination thereof. In certain embodiments a spacer group can comprise –C(O)–, –O–, –C(O)NH–, –C(O)NH-alkyl–, –OC(O)NH–, –SC(O)NH–, –NH–, –NH-alkyl–, –C(O)N(CH3)–, –C(O)N(CH3)-alkyl–, –N(CH3)–,–N(CH3)-alkyl–, –N(CH3)CH2CH2N(CH3)–, –C(O)CH2CH2CH2C(O)–, –S–, –S- S–, –OCH2CH2O–, or the reverse (e.g. –NHC(O)–) thereof, or a combination thereof.

[0222] In certain embodiments of Formula (Ia), SG1and SG01are independently absent or selected from -C1-6 alkylene-, -C(O)-, -C1-6 alkylene-C(O)-, -C(O)(C1-6 alkylene)-C(O)- NR1C1-6alkylene- wherein the -C(O)- is bound to W2or W02, respectively, -C(O)-C1-6alkylene-6 alkylene)OC(O)-, and -C(O)(C1-6 alkylene)SC(O)-; wherein R1is hydrogen or optionally substituted C1-6 alkyl; and the C1-6 alkylene of SG1or SG01, alone or part of another group, is optionally substituted with one, - 71 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, C1- 6alkylamino, and C1-6alkoxy.

[0223] In certain embodiments of Formula (Ia), including any of the foregoing, SG1and SG01are independently absent, -C(O)(C1-6alkylene)OC(O)-, -C1-6alkylene-C(O)-, or -C(O)(C1-6alkylene)-C(O)-NR1C1-6alkylene- wherein the -C(O)- is bound to W2or W02, respectively. In certain embodiments of Formula (Ia), including any of the foregoing, SG1is -C(O)(C1-6 alkylene)OC(O)-. In certain embodiments of Formula (Ia), including any of the foregoing, SG1is -C(O)(C2-4 alkylene)OC(O)-. In certain embodiments of Formula (Ia), including any of the foregoing, SG1is -C(O)(C1-6 alkylene)-C(O)-NR1C1-6alkylene- wherein the -C(O)- is bound to W2. In certain embodiments of Formula (Ia), including any of the foregoing, SG1is -C(O)(C3alkylene)-C(O)-N(CH3)C2alkylene- wherein the -C(O)- is bound to W2. In certain embodiments of Formula (Ia), including any of the foregoing, SG01is -C1-6 alkylene-C(O)- wherein the -C(O)- is bound to W02.

[0224] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), SG1and SG01are independently absent or selected from -C1-6 alkylene-, -C(O)-, -C1-6 alkylene-C(O)- , -C(O)(C1-6 alkylene)-C(O)-NR1C1-6alkylene- wherein the -C1-6 alkylene- is bound to Y, -C(O)-C1-6alkylene-C(O)-, -C(O)(C1-6alkylene)NR1C(O)-, -C(O)(C1-6alkylene)OC(O)-, and -C(O)(C1-6 alkylene)SC(O)-; wherein R1is hydrogen or optionally substituted C1-6 alkyl; and the C1-6 alkylene of SG1or SG01, alone or part of another group, is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy.

[0225] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), SG1and SG01are independently -C1-6alkylene-. In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), SG1and SG01are -CH2-.

[0226] In certain embodiments, W1and W01are eliminator groups. Eliminator groups facilitate separation of a biologically active portion of a compound or conjugate described herein from the remainder of the compound or conjugate in vivo and / or in vitro. Eliminator groups can also facilitate separation of a biologically active portion of a compound or conjugate described herein in conjunction with a release trigger group. For example, the eliminator group and the release trigger group can react in a Releasing Reaction to release a biologically active portion of a compound or conjugate described herein from the compound or conjugate in vivo and / or in vitro. Upon initiation of the Releasing Reaction by the release trigger, the eliminator group cleaves the biologically active moiety, or a prodrug form of the - 72 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 biologically active moiety, and forms a stable, non-toxic entity that has no further effect on the activity of the biologically active moiety.

[0227] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1is absent. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W01is absent. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the. certain embodiments of (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are independently. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic- 1), or (Ic-2), including any of the foregoing, W1and W01are independently. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are independently. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are - 73 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 independently. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are independently.

[0228] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are independently absent,,

[0229] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W1and W01are independently absent,bond or -CH2-; y is 0 or 1; and z is 0 or 1.

[0230] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, y is 0. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib- 1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, z is 0. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, z is 1. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, OSu is a β-glucuronidase-cleavable β-glucuronide. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the - 74 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 foregoing,the point of attachment to the rest of the formula. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing,.

[0231] When z is 1, the conjugate comprises a release trigger group, designated as OSu herein, which facilitates the separation of a biologically active portion of a compound or conjugate described herein from the remainder of the compound or conjugate in vivo and / or in vitro. Release trigger groups can also facilitate separation of a biologically active portion of a compound or conjugate described herein in conjunction with an eliminator group. For example, the eliminator group and the release trigger group can react in a Releasing Reaction to release a biologically active portion of a compound or conjugate described herein from the compound or conjugate in vivo and / or in vitro. In certain embodiment, the release trigger can act through a biologically-driven reaction with high tumor:nontumor specificity, such as the proteolytic action of an enzyme overexpressed in a tumor environment.

[0232] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), W1and W01are independently. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), W1and W01are independently.

[0233] Hydrophilic groups, designated HP1, HP01, and HP2herein, facilitate increasing the hydrophilicity of the compounds described herein. It is believed that increased hydrophilicity allows for greater solubility in aqueous solutions, such as aqueous solutions found in - 75 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 biological systems. Hydrophilic groups can also function as spacer groups, which are described in further detail herein. Useful hydrophilic groups include those described herein.

[0234] In certain embodiments, Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP1and HP01are independently a divalent poly(ethylene glycol). In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP1and HP01are independently absent orwherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the formula. In certain embodiments, R2is hydrogen. In certain embodiments, x1 is an integer between 1 and 10, inclusive. In certain embodiments, R2is hydrogen. In certain embodiments, x1 is an integer between 1 and 15, inclusive. In certain embodiments, x1 is 10. In certain embodiments, x1 is an integer between 1 and 5, inclusive. In certain embodiments, x1 is 4. In certain embodiments, x1 is an integer between 1 and 5, inclusive. In certain embodiments, x1 is 13. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP1is absent. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP01is.

[0235] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently absent or an amino acid residue or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP2. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently an amino acid residue or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP2. In certain embodiments, the at least one non-natural amino acid is selected from 3-sulfoalanine, hydroxyproline (Hyp), citrulline (Cit), ornithine (Orn), norleucine (Nle), 3-nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, methionine sulfone, 2,3- diaminopropionate, and beta-alanine. In certain embodiments, the at least one non-natural amino acid is citrulline (Cit). In certain embodiments, the at least one non-natural amino acid is 2,3-diaminopropionate. - 76 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0236] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently an amino acid residue. In certain embodiments, the amino acid residue is a beta-amino acid.

[0237] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently selected from -(C(O)CHR10NR11)o-, -(C(O)CH2CHR10NR11)p-, -(C(O)CHR10CH2NR11)p-, -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-, -(C(O)CHR10CH2NR11)p-(C(O)CHR10NR11)o-, -(C(O)CHR10NR11)o-(C(O)CH2CHR10NR11)p-, and –(C(O)CHR10NR11)o- (C(O)CHR10CH2NR11)o-; wherein R10is independently an amino acid sidechain residue optionally substituted with HP2; R11is independently hydrogen or C1-6 alkyl; o and p is an integer independently an integer between 1 and 10, inclusive; and the - C(O)- of W2or W02is bound to W1or W01, respectively.

[0238] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently selected from -(C(O)CHR10NR11)o-, -(C(O)CH2CHR10NR11)p-, -(C(O)CHR10CH2NR11)p-, -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-, and -(C(O)CHR10CH2NR11)p- (C(O)CHR10NR11)o-.

[0239] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2or W02is -(C(O)CHR10NR11)o-. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2or W02is -(C(O)CH2CHR10NR11)p-. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2or W02is -(C(O)CH2CHR10NR11)o-(C(O)CHR10NR11)o-.

[0240] In certain embodiments, including any of the foregoing, R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate optionally substituted with HP2. In certain embodiments, including any of the foregoing, R11is hydrogen. In certain embodiments, including any of the foregoing, o is independently an integer between 1 and 4, inclusive. In certain embodiments, including any of the foregoing, p is 1.

[0241] In certain embodiments, including any of the foregoing, R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, and 2,3- - 77 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 diaminopropionate optionally substituted with HP2. In certain embodiments, including any of the foregoing, R11is hydrogen. In certain embodiments, including any of the foregoing, o is independently an integer between 1 and 4, inclusive. In certain embodiments, including any of the foregoing, p is 1.

[0242] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently absent or -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-; wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), polysarcosine, or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0243] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently absent or -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-; wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independently polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), polysarcosine, or a combination thereof; - 78 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R11is hydrogen; o is independently an integer between 1 and 4, inclusive; and p is 1.

[0244] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently absent or of the formula:certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently of the formula:,, - 79 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01is the point of attachment to the rest of the formula. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2and W02are independently of the formula:,certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2. certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2or W02is. - 80 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0245] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP2is independentlywherein R2is hydrogen or methyl and x2 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula. In certain embodiments, x2 is independently an integer between 10 and 20, inclusive. In certain embodiments, x2 is 12. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, W2or W02is absent.

[0246] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), -W1-attachment to the rest of the formula. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib- 1), (Ib-2), (Ic-1), or (Ic-2), -W1-W2- or -W01-W02-is independently. In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib- - 81 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 1), (Ib-2), (Ic-1), or (Ic-2), -W1-W2- or -W01-W02-is independently.

[0247] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), -W1-

[0248] In certain embodiments of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), -W1-of Formula (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), -W1-W2- or -W01-W02-is - 82 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

[0249] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, Y is –X1-C1-4 alkylene-X1-C1-4 alkylene-X1-C1-4 alkylene-X1–, wherein at least one C1-4 alkylene in Y is substituted with one or more substituents selected from R70. In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, Y is –X1-C1-4alkylene-X1-C1-4alkylene-X1–, wherein at least one C1-4alkylene in Y is substituted with one or more substituents selected from R70; and -[X1]b- is attached to RL1or RL01.

[0250] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, R70is –C1-6 alkylene-X2-[C1-6 alkylene]c-HP2, wherein each alkylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)N NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0251] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, c is 1.

[0252] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP2is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), polysarcosine, or a combination thereof. In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP2is a - 83 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG). In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, HP2is independentlywherein R2is hydrogen or methyl and x2 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula. In certain embodiments, x2 is independently an integer between 10 and 20, inclusive. In certain embodiments, x2 is 12.

[0253] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including- 84 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 Ring C is an optionally substituted N-linked bridged, fused, or spirocyclic bicyclic heterocycle; and each is a point of attachment to the rest of the formula.

[0254] In certain embodiments, L4is a bond. In certain embodiments, L4is -C(O)C1-6alkylene-NR11C(O)-. In certain embodiments,wherein RingC is a spirocyclic bicyclic heterocycle.

[0255] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), includingFormula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, RL1is.

[0256] In certain embodiments of Formula (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing,.

[0257] In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),. certain embodiments of Formula (- 85 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01SG1is -C(O)C1-6alkylene-C(O)-. In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),

[0258] In certain embodiments of Formula (Ib), (Ib-1), or (Ib-2), -SG1-Y-RL1- is -CH2-Y-C(O)(C1-6alkylene)OC(O)-. In certain embodiments of Formula (Ib), (Ib-1), or (Ib- 2), -SG1-Y-RL1- is -CH2-X1-C1-6alkylene-[X1-C1-6alkylene]a-[X1]b–C(O)(C1-6alkylene)OC(O)-. In certain embodiments of Formula (Ib), (Ib-1), or (Ib-2), -SG1-Y-RL1- is - CH2-NHC(O)-C1-6 alkylene-NHC(O)-C1-6 alkylene-NH–C(O)(C1-6 alkylene)OC(O)-. - 86 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0259] In certain embodiments of Formula (.

[0260] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),

[0261] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),C(O)CH2-O-N=C(CH3)- or -C(O)(CH2)5-O-N=C(CH3)-.

[0262] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),wherein - 87 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

[0263] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),HP01-RL01- is -C(O)CH2CH2-(OCH2CH2)x1-O-N=C(CH3)-.

[0264] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),-C(O)CH2CH2-(OCH2CH2)x1-O-N=C(CH3)-.

[0265] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),

[0266] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2),- 88 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 -C(O)CH2CH2-(OCH2CH2)x1-O-N=C(CH3)-. In certain embodiments of Formula (Ia), (Ib),is -(C(O)CHR10NR11)o-, and SG01-HP01-RL01- is -C(O)CH2CH2-(OCH2CH2)x1-O-N=C(CH3)-. 2. Cytotoxic agent (CY)

[0267] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), CY is a cytotoxic agent. Any cytotoxic agent can be used as far as the agent has cytotoxic activity. For example, CY is selected from the group consisting of irinotecan, SN-38, topotecan, exatecan, etoposide, teniposide, tafluposide, hemiasterlins, 3-aminopheny hemiasterlin, taltobulin (HTI-286) amanitin , deruxtecan (DXd), camptothecins, PNU- 159682, pyrrolobenzodiazepine (PBD), EDA PNU-159682 derivatives, MMAF, MMAE, daunorubicin, anthracycline, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicinm, mitoxantrone, valrubicin, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, vorinostat, romidepsin, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, vemurafenib, azacitidine, azathioprine, capecitabine, cyatarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, and tioguanine (formerly thioguanine), doxifluridine, gemcitabine, methotrexate, carboplatin, cisplatin, and oxaliplatin.

[0268] In certain embodiments, CY is selected from the group consisting of an alkylating agent, a DNA-crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone-deacetylase (HDAC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, and a topoisomerase inhibitor. In certain embodiments, CY is selected from the group consisting of topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan. In certain embodiments, CY is exatecan. - 89 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0269] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2),. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), CY is independently selected from. - 90 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0270] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2),a derivative thereof; and eachis a point of attachment to the rest of the formula. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), CY is independently selected from,, - 91 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01a derivative thereof.

[0271] In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),- 92 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

[0272] In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),- 93 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 94 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

[0273] In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),- 95 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0274] In certain embodiments of Formula (Ia), (Ic), (Ic-1), or (Ic-2),- 96 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0275] Formula 202; or a mixture of Formula 201 and Formula 202; whereinis the point of attachment to the rest of the formula. - 97 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0276] In one embodiment of Formula (I),isFormula 202A; or a mixture of Formula 201A and Formula 202A; whereinis the point of attachment to the rest of the formula. - 98 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0277] In one embodiment of Formula (I),isFormula 204 or a mixture of Formula 203 and Formula 204; whereinis the point of attachment to the rest of the formula.Formula 203A; or - 99 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01Formula 204A or a mixture of Formula 203A and Formula 204A; whereinis the point of attachment to the rest of the formula.

[0279] In one embodiment of Formula (I),isFormula 206; or a mixture of Formula 205 and Formula 206; whereinis the point of attachment to the rest of the formula. - 100 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0280] In one embodiment of Formula (I),isFormula 206A or a mixture of Formula 205A and Formula 206A; whereinis the point of attachment to the rest of the formula.

[0281] In one embodiment of Formula (I),isFormula 208 or a mixture of Formula 207 and Formula 208; - 101 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 whereinis the point of attachment to the rest of the formula.

[0282] In one embodiment of Formula (I),isFormula 208A or a mixture of Formula 207A and Formula 208A; whereinis the point of attachment to the rest of the formula.

[0283] In one embodiment of Formula (I),isFormula 210 - 102 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 or a mixture of Formula 209 and Formula 210; whereinis the point of attachment to the rest of the formula.

[0284] In one embodiment of Formula (I),isFormula 210A or a mixture of Formula 209A and Formula 210A; whereinis the point of attachment to the rest of the formula. STING agonist (STING)

[0285] In some embodiments, the STING agonist is a diamidobenzimidazole (diabzi) STING agonist. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the STING agonist is independently a residue of a compound of Formula (S-I): - 103 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01or a tautomer or stereoisomer thereof; wherein: X is selected from N and CR3; R20is selected from hydrogen and -CON(R3a)(R3b); R1a, R1b, R3aand R3bare independently selected from hydrogen and optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more R50; R2aand R2bare independently selected from: (a) optionally substituted C1- 6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more R51and (b) optionally substituted C3-12carbocycle or optionally substituted 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R53; or R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; or R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; R3is hydrogen, -OR30, -SR30, -C(O)N(R30)2, -N(R30)C(O)R30, -N(R30)C(O)N(R30)2, -N(R30)2, -C(O)R30, -C(O)OR30, -OC(O)R30, -NO2, or -CN; L1is selected from a bond, -C1-10alkylene-, -C2-10alkenylene-, -C2-10alkynylene-, -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, C3-6carbocyclene, and -C1-6alkylene-(C3-6carbocyclene)-C1-6alkylene-, wherein -C1-10alkylene-, -C2-10alkenylene-, -C2-10alkynylene-, C3-6carbocyclene, and each C1-6alkylene of -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, and -C1-- 104 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 6alkylene-(C3-6carbocyclene)-C1-6alkylene- are optionally substituted with one or more R50; L2is optionally substituted -C1-6alkylene- or -C1- 6alkylene-O-, wherein the -C1-6alkylene- or the C1-6alkylene of -C1-6alkylene-O- is optionally substituted with one or more R50and wherein the -C1-6 alkylene-O- is attached to the A ring, or Lbif the A ring is absent, via the oxygen atom; Ring A is absent; an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one N atom and at least one O atom, wherein the heterocycle is optionally substituted with one or more R53; or, a 3- to 12- membered heterocycle substituted with R4; R4is an optionally substituted 3- to 12-membered heterocycle optionally comprising at least one NR5and, wherein the heterocycle is optionally substituted with one or more R53; R5is independently selected from hydrogen, R6, -C(O)-C1-6alkyl, -C(O)- heteroC1-6alkyl, C1-6 alkyl, and heteroC1-6alkyl wherein the C1-6 alkyl, either alone or part of another group, is optionally substituted with one or more R50; R6is independently an amino acid residue; R30is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which, except hydrogen, is optionally substituted with one or more R55; R50is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, C3-12carbocycle, and 3- to 12-membered heterocycle; R51is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, optionally substituted C3-12 carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; R52is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, -NO2, =O, =S, =N(R61), -CN, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; R53is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, - 105 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 -NO2, =O, =S, =N(R60), -CN, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3- 12carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one or more R54and the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted with one or more R52; R54is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, - NO2, =O, =S, =N(R61), and -CN; R55is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and R60and R61are independently selected from hydrogen, C1-10alkyl optionally substituted with NH2or NHC1-6alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle; wherein when Ring A is absent, L2is -C1-6 alkylene-O-; wherein the residue of Formula (S-I) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6 alkylene-O- of L2, an amino group of R4, an amino group of R54, or an amino group of R2bwhen R2bis an optionally substituted C3-12 carbocycle or optionally substituted 3- to 12-membered heterocycle.

[0286] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein R1aand R1bare both hydrogen.

[0287] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein R2aand R2bare independently an optionally substituted 3- to 12- membered heterocycle comprising at least one N atom.

[0288] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein R2aand R2bare independently selected from- 106 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 wherein R2cand R2dare independently selected from hydrogen, C1-6 alkyl optionally substituted with one or more R54, halo, and 3-12 membered heterocycle; R2eis hydrogen or C1-6alkyl; and is the point of attachment to the rest of the formula.

[0289] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) = wherein Ring A is an optionally substituted 3- to 12- membered N-linked spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to Lb, and at least one oxygen atom; or a 3- to 12- membered N-linked monocyclic heterocycle substituted with R4.

[0290] In some embodiments, the STING agonist is independently a residue of a compoundpoint of attachment to Lband is the point of attachment to L2.

[0291] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein. - 107 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0292] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I)wherein Ring A is an N-linked mono 3- to 12-membered heterocycle substituted with R4.

[0293] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein Ring A is selected from, ,wherein is the point of attachment to L2.

[0294] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein Ring.

[0295] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein R4is a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N bound to Lb. - 108 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0296] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein,; wherein X5, X6, X9, X10are independently selected from N and CR13; X7and X8are independently selected from NH, O, and CHR13; R13is independently hydrogen or C1-6 alkyl; wherein if four of any one of X5-X10are present, at least one is CR13or CHR13; andis the point of attachment to ring A andis the point of attachment to .

[0297] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-I) wherein. - 109 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0298] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the STING agonist is independently a residue of a compound of Formula (S-II):or a tautomer or stereoisomer thereof; wherein: Ring B is an optionally substituted C3-12 carbocycle or an optionally substituted 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; R1a, R2a, R1b, R2b, L1, R20, and R52are as defined herein; and wherein the residue of Formula (S-II) is attached to Lbvia an amino group of Ring B.

[0299] In some embodiments, the STING agonist is independently a residue of a compound of Formula (S-II) wherein ring B is an optionally substituted azetidine.

[0300] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the STING agonist is independently a residue of a compound of Formula (S-III):- 110 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 (S-III) or a pharmaceutically acceptable salt thereof or tautomer thereof; wherein: Ring A1is C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R53; X3is selected from N and CR3; R3is selected from hydrogen, –OR30, -SR30, -C(O)N(R30)2, -N(R30)C(O)R30, -N(R30)C(O)N(R30)2, -N(R30)2, -C(O)R30, -C(O)OR30, -OC(O)R30, -NO2, and -CN; each R30is independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R55; R9a, R10a, R9b, R10b, L1, L2, R20, R30, R53, and R55are as defined herein; and wherein the residue of Formula (S-III) is attached to Lbvia an amino group of Ring A1.

[0301] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the STING agonist is independently a residue of a compound of Formula (S-IV):(S-IV) or a pharmaceutically acceptable salt thereof or tautomer thereof; wherein Ring A, L1, L2, X3, R1a, R2a, R2b, and R20are as defined herein; and wherein the residue of Formula (S-IV) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6 alkylene-O- of L2, or an amino group of R4. - 111 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 Embodiments of Formulas (S-I)-(S-IV) when used as STING in Conjugates of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2)

[0302] In one embodiment of Formula (S-I), (S-II), or (S-IV), R1ais hydrogen. In one embodiment of Formula (S-I) or (S-II), R1bis hydrogen. In one embodiment of Formula (S-I) or (S-II), R1ais C1-6 alkyl, for example methyl. In one embodiment of Formula (S-I) or (S-II), R1bis C1-6 alkyl, for example methyl. In one embodiment of Formula (S-I) or (S-II), R1aand R1bare both hydrogen.

[0303] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 3- to 12-membered heterocycle. In one embodiment of Formula (S-I), (S-II), or (S- IV), including any of the foregoing, R2ais a 5- to 6-membered heterocycle. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 3- to 12-membered heterocycle containing at least one N atom. In one embodiment of Formula (S- I), (S-II), or (S-IV), including any of the foregoing, R2ais a 5- to 6-membered heterocycle containing at least one N atom. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1-6alkyl, halogen, and haloC1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1-6alkyl, halogen, and haloC1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis a 3- to 12-membered heterocycle containing at least one N atom. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis a 5- to 6-membered heterocycle containing at least one N atom. In one embodiment of Formula (S- I), (S-II), or (S-IV), including any of the foregoing, R2bis a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I), (S-II), or (S-IV), - 112 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 including any of the foregoing, R2bis a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1- 6 alkyl, halogen, and haloC1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1- 6 alkyl, halogen, and haloC1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand R2bare both a 3- to 12-membered heterocycle containing at least one N atom. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand R2bare both a 5- to 6-membered heterocycle containing at least one N atom. In one embodiment Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand R2bare both a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1-6alkyl, halogen, and haloC1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand R2bare both a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1-6 alkyl, halogen, and haloC1-6 alkyl.

[0304] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1ais hydrogen, R1bis hydrogen, and R2aand R2bare both a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53selected from C1-6alkyl, halogen, and haloC1-6alkyl.

[0305] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand / or R2bare independently selected from an optionally substituted pyrazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrolidine, an optionally substituted phenyl, an optionally substituted pyridine, and an optionally substituted pyridazine. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand / or R2bare independently selected from an optionally substituted pyrazole, an optionally substituted oxazole, an optionally substituted thiazole, an optionally substituted pyrrolidine, and an optionally substituted pyridazine. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand / or R2bare independently selected from an optionally substituted pyrazole, an optionally substituted oxazole, and an optionally substituted thiazole. - 113 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0306] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand / or R2bare independently selected from, , ,wherein R2cand R2dare independently hydrogen, halo, C1-6 alkyl optionally substituted with one or more R54, or 3- to 12-membered heterocycle; R2eis hydrogen or C1-6alkyl; Xa, Xb, Xc, Xd, and Xeare independently selected from -N- and -CR2c- wherein no more than two of Xa-Xeare N; R54is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, -NO2, =O, =S, =N(R61), and -CN; R61is independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle; and is the point of attachment to the rest of the compound.

[0307] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eand R2dare both C1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eis C1-6alkyl and R2dis halo. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eis C1-6alkyl and R2dis C1-6 alkyl optionally substituted with one or more R54. In one embodiment of Formula (S-I), (S- II), or (S-IV), including any of the foregoing, R2eis C1-6alkyl and R2dis haloC1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eis C1-6 alkyl and R2dis aminoC1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eis C1-6 alkyl and R2dis 3- to 12-membered heterocycle. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2eis C1-6 alkyl and R2dis hydrogen.

[0308] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2cand R2dare both C1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2cis hydrogen and R2dis C1-6alkyl. - 114 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0309] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing,

[0310] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing,.

[0311] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand / or R2bare independently selected from, , , ,

[0312] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2a and / or R2b are independently selected- 115 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0313] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2aand R2bare both. one embodiment of Formula (S-I), (S-II), or (S- IV), including any of the foregoing, R2aand R2bare both. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing,and R2bis.. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the

[0314] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2aand R2bare bothare both hydrogen. In one embodiment of Formula (S- I) or (S-II), including any of the foregoing,- 116 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R1bare both hydrogen. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing,are both hydrogen. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing,are both hydrogen.

[0315] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more R51. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais optionally substituted C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one R51and R51is 3- to 12-membered heterocycle optionally substituted with one or more R52. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and R51is 5- to 6-membered heterocycle optionally substituted with one or more R52. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais -CH2- R51wherein R51is 3- to 12-membered heterocycle optionally substituted with one or more R52and R52is C1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais -CH2- R51wherein R51is 5- to 6- membered heterocycle optionally substituted with one or more R52and R52is C1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2ais - CH2- R51wherein R51is an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole.

[0316] In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis optionally substituted C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more R51. In one embodiment of Formula (S-I), (S-II), or (S-IV),including any of the foregoing, R2bis optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and R51is 3- to 12-membered heterocycle optionally substituted with one or more R52. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally - 117 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 substituted with one R51and R51is 5- to 6-membered heterocycle optionally substituted with one or more R52. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis -CH2- R51wherein R51is 3- to 12-membered heterocycle optionally substituted with one or more R52and R52is C1-6alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis -CH2- R51wherein R51is 5- to 6- membered heterocycle optionally substituted with one or more R52and R52is C1-6 alkyl. In one embodiment of Formula (S-I), (S-II), or (S-IV), including any of the foregoing, R2bis - CH2- R51wherein R51is an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole.

[0317] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais optionally substituted C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one R51and R51is 3- to 12-membered heterocycle optionally substituted with one or more R52and R2bis a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and R51is 5- to 6-membered heterocycle optionally substituted with one or more R52and R2bis a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais optionally substituted C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one R51and R51is an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole and R2bis an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole.

[0318] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2bis optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and R51is 3- to 12-membered heterocycle optionally substituted with one or more R52and R2ais a 3- to 12-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2bis optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and R51is 5- to 6-membered heterocycle optionally substituted with one or more R52and R2ais a 5- to 6-membered heterocycle containing at least one N atom and the heterocycle is further substituted with at least one R53. In one embodiment of Formula (S-I) or (S-II),including any of the foregoing, R2bis optionally - 118 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one R51and an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole and R2ais an optionally substituted pyrazole, an optionally substituted oxazole, or an optionally substituted thiazole.

[0319] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2aR2c, R2d, R2eand Xa-Xeare as defined herein.

[0320] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2bis

[0321] In one embodiment of Formula (S-I) or (S-II),including any of the foregoing, R2bis

[0322] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais- 119 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0323] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais selected from

[0324] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais

[0325] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2aisare both hydrogen.

[0326] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 8- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted N-C(O)-linked 3- to 12-membered fused - 120 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 heterocycle. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted N-C(O)-linked 8- to 12-membered fused heterocycle.

[0327] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 8- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted N-C(O)-linked 3- to 12-membered fused heterocycle. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted N-C(O)-linked 8- to 12-membered fused heterocycle.

[0328] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53, R1ais hydrogen or C1-6 alkyl, and R2ais a 3- to 12-membered heterocycle, which is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53, R1bis hydrogen or C1-6alkyl, and R2bis a 3- to 12-membered heterocycle, which is optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53and R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12- membered heterocycle wherein the heterocycle is optionally substituted with one or more R53.

[0329] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, the optionally substituted 3- to 12-membered heterocycle is an optionally substituted N-C(O)- - 121 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 linked 3- to 12-membered fused heterocycle. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, the optionally substituted 3- to 12-membered heterocycle is an optionally substituted N-C(O)-linked 8- to 12-membered fused heterocycle.

[0330] In one embodiment of Formula (S-III), including any of the foregoing, R9aand R10aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53, R9bis hydrogen or C1-6alkyl, and R10bis a 3- to 12-membered heterocycle, which is optionally substituted with one or more R53. In one embodiment of Formula (S-III), including any of the foregoing, R9band R10bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53, R9ais hydrogen or C1-6 alkyl, and R10ais a 3- to 12-membered heterocycle, which is optionally substituted with one or more R53. In one embodiment of Formula (S-III), including any of the foregoing, R9aand R10aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53and R9band R10bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle wherein the heterocycle is optionally substituted with one or more R53.

[0331] In one embodiment of Formula (S-III), including any of the foregoing, the optionally substituted 3- to 12-membered heterocycle is an optionally substituted N-C(O)-linked 3- to 12-membered fused heterocycle.

[0332] In one embodiment of Formula (S-I)-(S-V), including any of the foregoing, the optionally substituted N-C(O)-linked 3- to 12-membered fused heterocycle is an optionally substituted 5-5 fused ring system, an optionally substituted 5-6 fused ring system, an optionally substituted 6-6 fused ring system, or an optionally substituted 5-7 fused ring system.

[0333] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R1ais hydrogen;, - 122 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01R1band R2bare joined together with the atoms to which they are attached to form.

[0334] In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais a C3-12 carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2ais a C8-12carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2bis a C3-12 carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2bis a C8-12carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, the C3-12 carbocycle is an optionally substituted bicyclic C3-12carbocycle, and can be bridged, fused, or spirocyclic. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, the C8-12 carbocycle is an optionally substituted bicyclic C3-12 carbocycle, and can be bridged, fused, or spirocyclic. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2aand / or R2bis an optionally substituted bridged C3-12carbocycle substituted with one R53and R53is C1-6alkyl. In one embodiment of Formula (S-I) or (S-II), including any of the foregoing, R2aand / or R2bis an optionally substituted bridged C8-12 carbocycle substituted with one R53and R53is C1- 6 alkyl.

[0335] In one embodiment of Formula (S-I)-(S-IV), including any of the foregoing, L1is -C2- 10alkenyl- optionally substituted with one or more R50. In one embodiment of Formula (S-I)- (S-IV), including any of the foregoing, L1is -CH=CH- optionally substituted with one R50. In one embodiment of Formula (S-I)-(S-IV), including any of the foregoing, L1is -CH=CH-.

[0336] In one embodiment of Formula (S-I)-(S-IV), including any of the foregoing, L1is -C1- 10alkyl- optionally substituted with one or more R50. In one embodiment of Formula (S-I)-(S- IV), including any of the foregoing, L1is -CH2-CH2- optionally substituted with one R50. In one embodiment of Formula (SI)-(SIV), including any of the foregoing, L1is -CH2-CH2-. - 123 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0337] In one embodiment of Formula (S-I)-(S-IV), including any of the foregoing, L1is.

[0338] In one embodiment of Formula (S-I), (S-III), (S-IV), including any of the foregoing, L2is C1-6 alkyl. In one embodiment of Formula (S-I), (S-III), (S-IV), including any of the foregoing, L2is C3-6 alkylene. In one embodiment of Formula (S-I), (S-III), (S-IV), including any of the foregoing, L2is -(CH2)3-. In one embodiment of Formula (S-I), (S-III), (S-IV), including any of the foregoing, L2is C1-6alkylene optionally substituted with one R50.

[0339] In one embodiment, Formula (S-I) is of Formula (S-IA):wherein is the point of attachment to the rest of the formula; or a pharmaceutically acceptable salt or tautomer thereof.

[0340] In one embodiment of Formula (S-IA), L2is –(CH2)3-; R1bis hydrogen; and R2bis one embodiment of Formula (S-IA), L2is –(CH2)3-; R1bis hydrogen; and R2bis. In one embodiment of Formula (S-IA), L2is –(CH2)3-; R1bis hydrogen;. - 124 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0341] In one embodiment, Formula (S-II) is of Formula (S-IIA) or (S-IIB):wherein is the point of attachment to the rest of the formula; or a pharmaceutically acceptable salt or tautomer thereof.

[0342] In one embodiment of Formula (S-IIA), R1bis hydrogen;. one embodiment of Formula (S-IIB), R1bis hydrogen;. one embodiment - 125 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

[0343] In one embodiment, Formula (S-IV) is of Formula (S-IVA):wherein is the point of attachment to the rest of the formula; or a pharmaceutically acceptable salt or tautomer thereof.

[0344] In one embodiment of Formula

[0345] In one embodiment, Formula (S-I) is of Formula (S-IC-1):- 126 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 (S-IC-1) wherein B1optionally substituted C3-12 carbocycle or optionally substituted 3- to 12- membered heterocycle, each of which is optionally substituted with one or more R52; and is the point of attachment to the rest of the formula; or a pharmaceutically acceptable salt or tautomer thereof.

[0346] In one embodiment, Formula (S-I) is of Formula (S-IC-2):(S-IC-2) wherein B1optionally substituted C3-12 carbocycle or optionally substituted 3- to 12- membered heterocycle, each of which is optionally substituted with one or more R52; and is the point of attachment to the rest of the formula; or a pharmaceutically acceptable salt or tautomer thereof.

[0347] In one embodiment of Formula (S-IC-1) or (S-IC-2),is.

[0348] In one embodiment of Formula (S-I), L1is -CH2CH2-; R1aand R1bare both hydrogen;- 127 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0349] In one embodiment of Formula (S-I), L1is -CH=CH-; R20is hydrogen; R1aand R1bare both hydrogen; and R2aand R2bare both.

[0350] In one embodiment of Formula (S-II), L1is -CH=CH-; R1aand R1bare both hydrogen and R2aand R2bare both.

[0351] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one N atom and at least one O atom wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 3- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to L2, and at least one oxygen atom. In one embodiment of Formula (S-I), (S-IA) (S- IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 8- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to L2, and at least one oxygen atom. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 3- to 12- membered N-linked bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to L2, and at least one oxygen atom. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 8- to 12- membered N- linked bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to L2, and at least one oxygen atom. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 3- to 12- membered N-linked spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to L2, and at least one oxygen atom. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC- 1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is an optionally substituted 3- to 12- membered N-linked spirocyclic bicyclic heterocycle comprising two - 128 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 nitrogen atoms, including the nitrogen bound to L2and a nitrogen bound to Lb, and one oxygen atom.

[0352] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-point of attachment to Lband is the point of attachment to L2.

[0353] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-. - 129 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0354] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is selected from,

[0355] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is selected from. one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring.

[0356] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is a 3- to 12-membered heterocycle substituted with R4. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is a 8- to 12-membered heterocycle substituted with R4.

[0357] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is a N-linked monocyclic 3- to 12-membered heterocycle comprising the N to which the ring is attached wherein the heterocycle is substituted with R4. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is a N-linked monocyclic 8- to 12-membered heterocycle comprising the N to which the ring is attached and a second NH and wherein the heterocycle is substituted with R4. - 130 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0358] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is selected from, ,, , , , , , and; wherein is the point of attachment to the rest of the compound.

[0359] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-

[0360] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, Ring A is selected fromand. In one embodiment Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, Ring A is.

[0361] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S- IVA), including any of the foregoing, R4is a 3- to 12- membered bridged or fused bicyclic heterocycle comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O. In one - 131 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, R4is a 8- to 12- membered bridged or fused bicyclic heterocycle comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S-IV), or (S-IVA), including any of the foregoing, R4is a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IC-1), (S-IC-2), (S- IV), or (S-IVA), including any of the foregoing, R4is 5-6 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O.

[0362] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any of the foregoing, R4is a 3- to 12- membered bridged or fused bicyclic heterocycle comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is a N bound to -Lb. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any of the foregoing, R4is a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is a N bound to -Lb. In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any of the foregoing, R4is a 5-6 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is a N bound to -Lb.

[0363] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including anywherein X5, X6, X9, X10are independently N or CR13; X7and X8are independently NH, O, or CHR13; R13is independently hydrogen or C1-6alkyl; - 132 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R5is as defined herein; andis the point of attachment to ring A and is a bond to Lb; wherein if four of any one of X5-X10are present, at least one is CR13or CHR13.

[0364] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any

[0365] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any of the foregoing,.

[0366] In one embodiment of Formula (S-I), (S-IA) (S-IB), (S-IV), or (S-IVA), including any of the foregoing, Ring.

[0367] In one embodiment of Formula (S-III) or (S-IIIA), including any of the foregoing, Ring A1is an optionally substituted 3- to 12-membered heterocycle optionally substituted - 133 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 with one or more R53. In one embodiment of Formula (S-III) or (S-IIIA), including any of the foregoing, Ring A1is an optionally substituted 8- to 12-membered heterocycle optionally substituted with one or more R53.

[0368] In one embodiment of Formula (S-III) or (S-IIIA), including any of the foregoing, Ring A1is a N-linked monocyclic 3- to 12-membered heterocycle comprising a N bound to L2and a N bound to Lband wherein the heterocycle is optionally substituted with one or more R53. In one embodiment of Formula (S-III) or (S-IIIA), including any of the foregoing, Ring A1is a N-linked monocyclic 8- to 12-membered heterocycle comprising a N bound to L2and a N bound to Lband wherein the heterocycle is optionally substituted with one or more R53.

[0369] In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted C3-12 carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted C6-12carbocycle optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted 3- to 12-membered heterocycle optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted 5- to 6-membered heterocycle optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted 3- to 12-membered heterocycle comprising at least a N bound to -Lband optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is an optionally substituted 4- to 6-membered heterocycle comprising at least a N bound to -Lband optionally substituted with one or more R53. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is a 3- to 12-membered heterocycle comprising at least a N bound to -Lb. In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is a 4- to 6-membered heterocycle comprising at least a N bound to -Lb.

[0370] In one embodiment of Formula (S-IC-1) or (S-IC-2), including any of the foregoing, Ring B1is selected from the group consisting- 134 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01wherein is the point of attachment to the rest of the compound and is a bond to Lb.

[0371] Non-limiting examples of Formula (S-IA) include:or a stereoisomer thereof. - 135 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0372] Non-limiting examples of Formula (S-IIA), (S-IIB), or (S-IIC) include:or a stereoisomer thereof.

[0373] Non-limiting examples of Formula (S-IVA) include:- 136 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01or a stereoisomer thereof.

[0374] Non-limiting examples of Formula (S-IC-1) include:or a stereoisomer thereof. - 137 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0375] Non-limiting examples of Formula (S-IC-2) include:or a stereoisomer thereof.

[0376] In one embodiment of Formula (S-IA), L1is -CH=CH-; R1aand R1bare both, , , , , , , - 138 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0377] In one embodiment of Formula (S-IA), L1is -CH=CH-; R1ais hydrogen; R1band R2b. - 139 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0378] In one embodiment of Formula (S-IVA), L1is -CH=CH-; R1ais hydrogen; Ring A is

[0379] In one embodiment of Formula (S-IA), L1is -CH=CH-; R1aand R1bare both.

[0380] In one embodiment of Formula (S-IA), L1is -CH2CH2-; R1aand R1bare both. - 140 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0381] In one embodiment of Formula (I),is ,, - 141 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01, - 142 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

[0382] In one embodiment of Formula (I), the STING agonist is a residue of a compound selected from:- 143 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 144 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 145 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 146 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 147 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0383] In one embodiment of Formula (I), the STING agonist is a residue of a compound selected from:- 148 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 149 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 150 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 151 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 152 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 153 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 154 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 155 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0384] Also described herein is a STING agonist residue of the formula:.

[0385] In certain embodiments of Formula (Ia), (Ib), (Ib-1), or (Ib-2), is:- 156 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01. - 157 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0386] In one embodiment of Formula (I), is a structure selected from- 158 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 159 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 160 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 161 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 162 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 163 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula. - 164 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0387] In one embodiment of Formula (I),is a structure selected from- 165 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 166 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 167 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 168 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01-[Lb-STING]nis - 169 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 .-[Lb-STING]n is a structure selected from. - 170 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0390] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, or a mixture of Formula 201 and Formula 202. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, or a mixture of Formula 201A and Formula 202A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib- 1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203, Formula 204, or a mixture of Formula 203 and Formula 204. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203A, Formula 204A, or a mixture of Formula 203A and Formula 204A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 205, Formula 206, or a mixture of Formula 205 and Formula 206. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 205A, Formula 206A, or a mixture of Formula 205A and Formula 206A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 207, Formula 208, or a mixture of Formula 207 and Formula 208. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 207A, Formula 208A, or a mixture of Formula 207A and Formula 208A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 209, Formula 210, or a mixture of Formula 209 and Formula 210. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 209A, Formula 210A, or a mixture of Formula 209A and Formula 210A.

[0391] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 100. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 101 or Formula 101A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 102 or Formula 102A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 103. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib- 1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 104 or Formula 104A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 105 or Formula 105A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises - 171 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 Formula 106 or Formula 106A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 107 or Formula 107A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 108. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib- 1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 109. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 110 or Formula 110A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 111. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 112. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 113. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 114 or Formula 114A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 115 or Formula 115A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 116. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 117 or Formula 117A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 118 or Formula 118A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 119 or Formula 119A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 120 or Formula 120A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 121. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 122 or Formula 122A. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 123. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 124.

[0392] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, Formula 203, Formula 204, Formula 205, Formula 206, Formula 207, Formula 208, Formula 209, or Formula 210, - 172 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at one or more sites.

[0393] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, Formula 203A, Formula 204A, Formula 205A, Formula 206A, Formula 207A, Formula 208A, Formula 209A, or Formula 210A, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at one or more sites.

[0394] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, Formula 203, Formula 204, Formula 205, Formula 206, Formula 207, Formula 208, Formula 209, or Formula 210, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, Formula 203, Formula 204, Formula 205, Formula 206, Formula 207, Formula 208, Formula 209, or Formula 210, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404.

[0395] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, Formula 203A, Formula 204A, Formula 205A, Formula 206A, Formula 207A, Formula 208A, Formula 209A, or Formula 210A, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, Formula 203A, Formula 204A, Formula 205A, Formula 206A, Formula 207A, Formula 208A, Formula 209A, or Formula 210A, wherein the structure binds to para-azidomethyl-L- phenylalanine (pAMF) at HC-Y180 and HC-404.

[0396] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201, Formula 202, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404.

[0397] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, or a mixture thereof, wherein - 173 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 201A, Formula 202A, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404.

[0398] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203, Formula 204, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203, Formula 204, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404.

[0399] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203A, Formula 204A, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises Formula 203A, Formula 204A, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404.

[0400] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at one or more sites. In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at LC-K42.

[0401] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises (a) Formula 201, Formula 202, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404 and (b) a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at LC-K42.

[0402] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises (a) Formula 201, Formula 202, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404 and (b) a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at LC-K42. - 174 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0403] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises (a) Formula 203, Formula 204, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-F241 and HC-404 and (b) a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at LC-K42.

[0404] In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) the antibody conjugate comprises (a) Formula 203, Formula 204, or a mixture thereof, wherein the structure binds to para-azidomethyl-L-phenylalanine (pAMF) at HC-Y180 and HC-404 and (b) a formula selected from Formula 100-Formula 124 wherein the structure binds to para-acetyl-L-phenylalanine (pAcF) at LC-K42. 3. Anti-TROP2 antibody or antigen binding fragment thereof (TROP2)

[0405] The conjugates described herein comprise an anti-TROP2 antibody or antigen binding fragment thereof. The anti-TROP2 antibody or antigen binding fragment thereof selectively binds TROP2, has a property capable of recognizing a TROP2 expressing cell (for example, a tumor cell), has a property of internalizing in a TROP2 expressing cell. In some embodiments, the conjugates described herein comprise means for binding TROP2.

[0406] In some embodiments, the antibody or antigen binding fragment thereof selectively binds to human TROP2. In some embodiments, the antibody or antigen binding fragment thereof selectively binds to the extracellular domain of human TROP2.

[0407] In some embodiments, the antibody or antigen binding fragment thereof binds to a homolog of human TROP2 from a species selected from a group consisting of monkeys, mice, dogs, cats, rats, cows, horses, goats and sheep. In some embodiments, the homolog is a cynomolgus monkey TROP2, a mouse TROP2 or a murine TROP2.

[0408] In some embodiments, the antibody comprises a heavy chain. In some embodiments, the heavy chain is selected from the group consisting of IgA, IgD, IgE, IgG or IgM. In some embodiments, the heavy chain is an IgG. In some embodiments, the heavy chain is an IgG1. In some embodiments, the heavy chain is an IgG2. In some embodiments, the heavy chain is an IgG3. In some embodiments, the heavy chain is an IgG4.

[0409] In some embodiments, the antibody or antigen binding fragment thereof comprises a light chain. In some embodiments, the light chain is a kappa light chain. In some embodiments, the light chain is a lambda light chain.

[0410] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a polyclonal antibody. - 175 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0411] In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0412] In some embodiments, the antibody is an affinity matured antibody. In some embodiments, the antibody is an affinity matured antibody derived from an illustrative sequence provided in this disclosure.

[0413] In some embodiments, the antibody is an antibody fragment. In some embodiments, the antibody fragment is an Fv fragment. In some embodiments, the antibody fragment is a Fab fragment. In some embodiments, the antibody fragment is a F(ab’)2 fragment. In some embodiments, the antibody fragment is a Fab’ fragment. In some embodiments, the antibody fragment is an scFv (sFv) fragment. In some embodiments, the antibody fragment is an scFv- Fc fragment.

[0414] The anti TROP2 antibody can be any anti-TROP2 antibody, or an antigen binding fragment thereof.

[0415] In certain embodiments, the anti-TROP2 antibodies that can be used for this invention are not limited but selected from one of the antibodies that are incorporated in the following ADCs; GS-0132, IMMU-132, Dato-DXd, DS-1062a, MK-2870, SKB264, SHR-A1921, 9MW2921, BAT8008, BIO-106, BL-M02D1, DB-1305, ESG-401, HS-20105, IBI130, LCB84, MHB036C, BAT8003, DXC1002, FDA018, FZ-AD004, JS108, PF-06664178 or STI-3258.

[0416] In certain embodiments, the anti-TROP2 antibody is selected from Sacituzumab (hRS7) and Datopotamab.

[0417] In some embodiments, the antibody comprises three CDRs of a heavy chain selected from the group consisting of SEQ ID NOS:12, 13, 15, and 16, and three CDRs of a light chain selected from the group consisting of SEQ ID NOS:14, and 17. In some embodiments, the antibody comprises three CDRs of a heavy chain and light chain pair selected from the group consisting of SEQ ID NOS:12 / 14, 13 / 14, 15 / 17, and 16 / 17. In some embodiments, the antibody comprises six CDRs of a heavy chain and light chain pair according to SEQ ID NOS:12 / 14. In some embodiments, the antibody comprises six CDRs of a heavy chain and light chain pair according to SEQ ID NOS:13 / 14. In some embodiments, the antibody comprises six CDRs of a heavy chain and light chain pair according to SEQ ID NOS:15 / 17. In some embodiments, the antibody comprises six CDRs of a heavy chain and light chain pair according to SEQ ID NOS:16 / 17. - 176 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0418] In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 comprising the amino acid sequence of SEQ ID NO: 4; a CDR2 comprising the amino acid sequence of SEQ ID NO: 5; and a CDR3 comprises the amino acid sequence of SEQ ID NO: 6; and the light chain variable region comprising a CDR1 comprising the amino acid sequence of SEQ ID NO: 7; a CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 9.

[0419] In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of the amino acid sequence of SEQ ID NO: 4; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 6; and the light chain variable region comprises a CDR1 consisting of the amino acid sequence of SEQ ID NO: 7; a CDR2 consisting of the amino acid sequence of SEQ ID NO: 8; and a CDR3 consisting of the amino acid sequence of SEQ ID NO: 9.

[0420] In some embodiments, the antibody comprises a heavy chain variable region of a heavy chain selected from the group consisting SEQ ID NOS:12, 13, 15, and 16, and a light chain variable region of a light chain selected from the group consisting of SEQ ID NOS:14, and 17.

[0421] In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 10 and the light chain variable region comprises an amino acid sequence of SEQ ID NO: 11.

[0422] In some embodiments, the antibody comprises either one of the following heavy chain and light chain sequences: (a) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 12 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14; (b) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 13 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14; (c) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 15 and a light chain consisting of an amino acid sequence of SEQ ID NO: 17; or - 177 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 (d) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 16 and a light chain consisting of an amino acid sequence of SEQ ID NO: 17.

[0423] In some embodiments, the antibody comprises following heavy chain and light chain sequences: (a) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 12 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14.

[0424] In some embodiments, the antibody comprises a heavy chain and light chain pair selected from the group consisting of SEQ ID NOS:12 / 14, 13 / 14, 15 / 17, and 16 / 17. In some embodiments, the antibody comprises a heavy chain and light chain pair according to SEQ ID NOS:12 / 14. In some embodiments, the antibody comprises a heavy chain and light chain pair according to SEQ ID NOS:13 / 14. In some embodiments, the antibody comprises a heavy chain and light chain pair according to SEQ ID NOS:15 / 17. In some embodiments, the antibody comprises a heavy chain and light chain pair according to SEQ ID NOS:16 / 17. 4. Non-natural or Modified Amino Acids

[0425] When the antibody conjugate comprises a modified amino acid, the modified amino acid can be any modified amino acid deemed suitable by the practitioner. In particular embodiments, the modified amino acid comprises a reactive group useful for forming a covalent bond to a linker precursor or to a payload precursor. In certain embodiments, the modified amino acid is a non-natural amino acid. In certain embodiments, the reactive group is selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido and alkynyl. Modified amino acids are also described in, for example, WO2013 / 185115 and WO 2015 / 006555, each of which is incorporated herein by reference in its entirety.

[0426] In certain embodiments, the non-natural or modified amino acid for use in the present conjugates are those described in WO 2013 / 185115 and WO 2015 / 006555, each of which is incorporated herein by reference in its entirety. In particular embodiments, the anti-TROP2 antibody or the antigen-binding fragment thereof in the antibody conjugate comprises at modified amino acid residues are at positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70, according to the Kabat or Chothia or EU numbering scheme, or a post translationally modified variant thereof. - 178 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0427] In particular embodiments, the anti-TROP2 antibody or the antigen-binding fragment thereof in the antibody conjugate comprises at least two modified amino acid residues suitable for conjugation that are covalently linked to Laand / or Lb. In particular embodiments, the anti-TROP2 antibody or the antigen-binding fragment thereof in the antibody conjugate comprises at least three modified amino acid residues suitable for conjugation that are covalently linked to Laand / or Lb. In particular embodiments, the anti-TROP2 antibody or the antigen-binding fragment thereof in the antibody conjugate comprises (a) a modified amino acid residue suitable for conjugation that is covalently linked to Laand (b) a modified amino acid residue suitable for conjugation that is covalently linked to Lband different than the modified amino acid in (a). the antibody conjugate of the anti-TROP2 antibody or antigen- binding fragment thereof is covalently linked to Lavia a modified amino acid and (b) the anti-TROP2 antibody or antigen binding fragment thereof is covalently linked to Lbvia a modified amino acid that is different than the modified amino acid in (a). In particular embodiments, the modified amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine. In particular embodiments, the modified amino acid residue is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4- allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo- phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine. In particular embodiments, the modified amino acid residue is selected from the group consisting of p- azidomethyl-L-phenyl alanine and p-acetyl-L-phenylalanine.

[0428] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided - 179 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at light chain position 42 according to the Kabat or Chothia numbering system.

[0429] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, - 180 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at light chain position 42 according to the Kabat or Chothia numbering system.

[0430] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue of para- azido-L-phenylalanine. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises the modified amino acid residue para-azido-phenylalanine at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue of para- azido-L-phenylalanine at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue para-azido-L- phenylalanine at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue para-acetyl- phenylalanine at light chain position 42 according to the Kabat or Chothia numbering system. In particular embodiments, the anti-TROP2 antibody of the antibody conjugate comprises modified amino acid residues at least two positions selected from the group consisting of heavy chain position 180 according to the EU numbering system (HC-Y180), heavy chain position 241 according to the EU numbering system (HC-F241), heavy chain position 404 according to the EU numbering system (HC-F404), and light chain position 52 according to the Kabat or Chothia numbering system (LC-K52). In particular embodiments, the anti- TROP2 antibody of the antibody conjugate comprises modified amino acid residues at HC- Y180, HC-F404 and LC-K52. In particular embodiments, the anti-TROP2 antibody of the antibody conjugate comprises modified amino acid residues at HC-F241, HC-F404 and LC- - 181 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 K52. In one embodiment, the anti-TROP2 antibody of the antibody conjugate comprises p- acetyl-L-phenylalanine at LC-K42. In one embodiment, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine at HC-F404 and HC-F241 and p-acetyl-L-phenylalanine at LC-K42. In one embodiment, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine at HC-F404 and HC- Y180 and p-acetyl-L-phenylalanine at LC-K42. In particular embodiments, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine at HC-F404, HC-F241, and / or HC-Y180, and p-acetyl-L-phenylalanine at LC-K42. In particular embodiments, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl- L-phenyl alanine residues at HC-Y180 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K52. In particular embodiments, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine residues at HC-Y241 and HC-F404 and p-acetyl- L-phenylalanine residue at LC-K52. In one embodiment, the anti-TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC- F404. In particular embodiments, the anti-TROP2 antibody is post translationally modified.

[0431] In any of the foregoing embodiments, for instance wherein the antibody conjugate has a structure according to a formula described herein, for example, according to any one of Formulas 100-124 and / or Formula 201-210B, the bracketed structure can be covalently bonded to one or more non-natural or modified amino acids of the antibody, wherein the one or more non-natural or modified amino acids are located at sites independently selected from the group consisting of: HC-F241, HC-F404, HC-Y180, and LC-K42, and combinations thereof, according to the Kabat or EU numbering scheme of Kabat. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site HC-F404 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site HC-Y180 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site HC-F241 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-Y180 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-Y180 of the antibody, and the other bracketed structure is bonded to a non-natural or - 182 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 modified amino acids at site LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-F241 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-F241 of the antibody, and the other bracketed structure is bonded to a non-natural or modified amino acids at site LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F241, HC-F404, and HC-Y180 of the antibody.

[0432] In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-Y180 and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404, HC-Y180, and LC-K42 of the antibody. In some embodiments, one bracketed structure binds to L-para-acetyl-phenylalanine (pAcF) at one or more sites and the other bracketed structure binds to a residue according to L-para-azido-phenylalanine (pAMF) at one or more sites. In one embodiment of Formula (I), Ab is the anti-TROP2 antibody of the antibody conjugate and Ab comprises p-azidomethyl-L-phenyl alanine residues at HC- Y180 and HC-F404 and [CY-La-]m - is bonded to the p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404. In one embodiment of Formula (I), including any of the foregoing, Ab is the anti-TROP2 antibody of the antibody conjugate and Ab comprises p- acetyl-L-phenylalanine at LC-K42 and -[Lb-STING]n is bonded to the p-acetyl-L- phenylalanine at LC-K42.

[0433] In particular embodiments of Formula (I), Ab is the anti-TROP2 antibody of the antibody conjugate and Ab comprises p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K42, [CY-La-]m - is bonded to the p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404, and -[Lb-STING]nis bonded to the p-acetyl-L-phenylalanine at LC-K42.

[0434] In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F241 and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino - 183 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 acids at sites HC-F404, HC-F241, and LC-K42 of the antibody. In some embodiments, one bracketed structure binds to L-para-acetyl-phenylalanine (pAcF) at one or more sites and the other bracketed structure binds to a residue according to L-para-azido-phenylalanine (pAMF) at one or more sites. In particular embodiments of Formula (I), Ab is the anti-TROP2 antibody of the antibody conjugate and Ab comprises p-azidomethyl-L-phenyl alanine residues at HC-F241 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K42, [CY-La- ]m- is bonded to the p-azidomethyl-L-phenyl alanine residues at HC-F241 and HC-F404, and -[Lb-STING]n is bonded to the p-acetyl-L-phenylalanine at LC-K42.

[0435] In some embodiments, the antibody conjugate binding to the anti-TROP2 antibody is a conjugate wherein [CY-La-]m- is-[Lb-STING]n iswherein the anti-TROP2 antibody comprises a heavy chain consisting of an amino acid sequence of SEQ ID NO: 12 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14 wherein the antibody comprises p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K42, [CY-La-]m- is bonded to the p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404, and -[Lb- STING]nis bonded to the p-acetyl-L-phenylalanine at LC-K42. - 184 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0436] In some embodiments, the antibody conjugate binding to the anti-TROP2 antibody is a conjugate wherein [CY-La-]m- is-[Lb-STING]nis a structure selected from.

[0437] Optically Active Compounds

[0438] In certain embodiments, compounds, linker-payloads, and conjugates provided herein may have several chiral centers and may exist in and be isolated in optically active and racemic forms. In certain embodiments, some compounds, linker-payloads, or conjugates may exhibit polymorphism. A person of skill in the art will appreciate that compounds, linker-payloads, and conjugates provided herein can exist in any racemic, optically-active, diastereomeric, polymorphic, regioisomeric and / or stereoisomeric form, and / or mixtures thereof. - 185 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0439] A person of skill in the art will also appreciate that such compounds, linker-payloads, and conjugates described herein that possess the useful properties also described herein are within the scope of this disclosure. A person of skill in the art will further appreciate how to prepare optically active forms of the compounds, linker-payloads, and conjugates described herein, for example, by resolution of racemic forms via recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In addition, most amino acids are chiral (i.e., designated as L- or D-, wherein the L- enantiomer is the naturally occurring configuration) and can exist as separate enantiomers.

[0440] Examples of methods to obtain optically active materials are known in the art, and include at least the following: physical separation of crystals – a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate, and the crystals are visually distinct); ii) simultaneous crystallization – a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions – a technique wherein partial or complete separation of a racemate is accomplished by virtue of different rates of reaction of the enantiomers in the presence of an enzyme; iv) enzymatic asymmetric synthesis – a synthetic technique wherein at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis – a synthetic technique wherein the desired enantiomer is synthesized from an achiral precursor using chiral catalysts or chiral auxiliaries to produce asymmetry (i.e., chirality) in the product; vi) diastereomer separations – a technique wherein a racemic compound is treated with an enantiomerically pure reagent (a chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct diastereomeric differences, and then the chiral auxiliary is removed to obtain each enantiomer; - 186 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 vii) first- and second-order asymmetric transformations – a technique wherein diastereomers of the racemate equilibrate in solution to yield a preponderance of a diastereomer of the desired enantiomer, or where kinetic or thermodynamic crystallization of the diastereomer of the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then derived from the diastereomer; viii) kinetic resolutions – this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral or non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors – a synthetic technique wherein the desired enantiomer is obtained from chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography – a technique wherein the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the different interactions; xi) chiral gas chromatography – a technique wherein the racemate is volatilized and enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic adsorbent phase; xii) extraction with chiral solvents – a technique wherein the enantiomers are separated by virtue of kinetic or thermodynamic dissolution of one enantiomer into a particular chiral solvent; a) transport across chiral membranes – a technique wherein a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic nature of the membrane which allows only one enantiomer of the racemate to pass through.

[0441] In some embodiments, provided herein are compositions of the compounds, linker- payloads, or conjugates of the present disclosure that are substantially free of a designated - 187 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 stereoisomer of that compound, linker-payload, or conjugate, respectively. In certain embodiments, in the methods, compounds, linker-payloads, and conjugates of this disclosure, the compounds, linker-payloads, or conjugates are substantially free of other stereoisomers. In some embodiments, the composition includes a compound, linker-payload, or conjugate that is at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, linker- payload or conjugate, respectively, the remainder comprising other chemical species or enantiomers. In some embodiments, provided herein are compositions of conjugates, linker- payloads, or compounds described herein that are substantially free of a designated enantiomer of that conjugate, linker-payload, or compound, respectively. In certain embodiments, in the methods, compounds, linker-payloads, and conjugates of this disclosure, the compounds, linker-payloads, or conjugates are substantially free of other enantiomers. In some embodiments, the composition includes a compound, linker-payload, or conjugate that is at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, linker- payload, or conjugate, respectively, the remainder comprising other chemical species or enantiomers.

[0442] Isotopically Enriched Compounds

[0443] Also provided herein are isotopically enriched compounds, linker-payloads, and conjugates of the compounds, linker-payloads, and conjugates described herein.

[0444] Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and / or toxicity profiles, has been previously demonstrated within some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res.308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact.117: 191 (1999).

[0445] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites; (2) increase the half-life of the parent drug; (3) decrease the number of doses needed to achieve a desired effect; (4) decrease the amount of a dose necessary to achieve a desired effect; (5) increase the formation of active metabolites, if any are formed; and / or (6) decrease the production of deleterious metabolites in specific tissues. Isotopic enrichment of a drug can also be used to create a more effective and / or safer drug for combination therapy, whether the combination therapy is intentional or not. - 188 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0446] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C–H bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), substitution of a (heavier) isotope for that reactive hydrogen will cause a decrease in the reaction rate. The Deuterium Kinetic Isotope Effect (“DKIE”) is the most common form of KIE. (See, e.g., Foster et al., Adv. Drug Res., vol.14, pp.1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol.77, pp.79-88 (1999)).

[0447] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C–H bond is broken, and the same reaction where deuterium is substituted for hydrogen and the C–D bond is broken. The DKIE can range from about one (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium has been substituted for hydrogen.

[0448] Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements including, but not limited to,13C or14C for carbon;33S,34S, or36S for sulfur; 15N for nitrogen; and17O or18O for oxygen may lead to a similar kinetic isotope effect.

[0449] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon- hydrogen (C–H) bond to either a carbon-oxygen (C–O) or carbon-carbon (C=C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different PK / PD, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. Therefore, these drugs often require the administration of multiple or high daily doses.

[0450] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacologic, PK, PD, and / or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. - 189 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0451] Preparation of Antibodies and Antibody Conjugates

[0452] Antigen Preparation

[0453] The protein to be used for isolation of the antibodies may be intact antigen or a fragment of antigen. The intact protein, or fragment of the antigen, may be in the form of an isolated protein or protein expressed by a cell. Other forms of antigens useful for generating antibodies will be apparent to those skilled in the art.

[0454] Monoclonal Antibodies

[0455] Monoclonal antibodies may be obtained, for example, using the hybridoma method first described by Kohler et al., Nature, 1975, 256:495-497 (incorporated by reference in its entirety), and / or by recombinant DNA methods (see e.g., U.S. Patent No.4,816,567, incorporated by reference in its entirety). Monoclonal antibodies may also be obtained, for example, using phage or yeast-based libraries. See e.g., U.S. Patent Nos.8,258,082 and 8,691,730, each of which is incorporated by reference in its entirety.

[0456] In the hybridoma method, a mouse or other appropriate host animal is immunized to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes are then fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. See Goding J.W., Monoclonal Antibodies: Principles and Practice 3rded. (1986) Academic Press, San Diego, CA, incorporated by reference in its entirety.

[0457] The hybridoma cells are seeded and grown in a suitable culture medium that contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0458] Useful myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive media conditions, such as the presence or absence of HAT medium. Among these, preferred myeloma cell lines are murine myeloma lines, such as those derived from MOP-21 and MC-11 mouse tumors (available from the Salk Institute Cell Distribution Center, San Diego, CA), and SP-2 or X63-Ag8-653 cells (available from the American Type Culture Collection, Rockville, MD). Human myeloma and mouse-human heteromyeloma cell lines also have - 190 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 been described for the production of human monoclonal antibodies. See e.g., Kozbor, J. Immunol., 1984, 133:3001, incorporated by reference in its entirety.

[0459] After the identification of hybridoma cells that produce antibodies of the desired specificity, affinity, and / or biological activity, selected clones may be subcloned by limiting dilution procedures and grown by standard methods. See Goding, supra. Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal.

[0460] DNA encoding the monoclonal antibodies may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the monoclonal antibodies). Thus, the hybridoma cells can serve as a useful source of DNA encoding antibodies with the desired properties. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as bacteria (e.g., E. coli), yeast (e.g., Saccharomyces or Pichia sp.), COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody, to produce the monoclonal antibodies.

[0461] Humanized Antibodies

[0462] Humanized antibodies may be generated by replacing most, or all, of the structural portions of a non-human monoclonal antibody with corresponding human antibody sequences. Consequently, a hybrid molecule is generated in which only the antigen-specific variable, or CDR, is composed of non-human sequence. Methods to obtain humanized antibodies include those described in, for example, Winter and Milstein, Nature, 1991, 349:293-299; Rader et al., Proc. Nat. Acad. Sci. U.S.A., 1998, 95:8910-8915; Steinberger et al., J. Biol. Chem., 2000, 275:36073-36078; Queen et al., Proc. Natl. Acad. Sci. U.S.A., 1989, 86:10029-10033; and U.S. Patent Nos.5,585,089, 5,693,761, 5,693,762, and 6,180,370; each of which is incorporated by reference in its entirety.

[0463] Human Antibodies

[0464] Human antibodies can be generated by a variety of techniques known in the art, for example by using transgenic animals (e.g., humanized mice). See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. U.S.A., 1993, 90:2551; Jakobovits et al., Nature, 1993, 362:255-258; Bruggermann et al., Year in Immuno., 1993, 7:33; and U.S. Patent Nos.5,591,669, 5,589,369 and 5,545,807; each of which is incorporated by reference in its entirety. Human antibodies can also be derived from phage-display libraries (see e.g., Hoogenboom et al., J. Mol. Biol., 1991, 227:381-388; Marks et al., J. Mol. Biol., 1991, 222:581-597; and U.S. Pat. - 191 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 Nos.5,565,332 and 5,573,905; each of which is incorporated by reference in its entirety). Human antibodies may also be generated by in vitro activated B cells (see e.g., U.S. Patent. Nos.5,567,610 and 5,229,275, each of which is incorporated by reference in its entirety). Human antibodies may also be derived from yeast-based libraries (see e.g., U.S. Patent No.8,691,730, incorporated by reference in its entirety).

[0465] Conjugation

[0466] The antibody conjugates can be prepared by standard techniques. In certain embodiments, an antibody is contacted with a payload precursor under conditions suitable for forming a bond from the antibody to the payload to form an antibody-payload conjugate. In certain embodiments, an antibody is contacted with a linker precursor under conditions suitable for forming a bond from the antibody to the linker. The resulting antibody-linker is contacted with a payload precursor under conditions suitable for forming a bond from the antibody-linker to the payload to form an antibody-linker-payload conjugate. In certain embodiments, a payload precursor is contacted with a linker precursor under conditions suitable for forming a bond from the payload to the linker. The resulting payload-linker is contacted with an antibody under conditions suitable for forming a bond from the payload- linker to the antibody to form an antibody-linker-payload conjugate. Suitable linkers for preparing the antibody conjugates are disclosed herein, and exemplary conditions for conjugation are described in the Examples below.

[0467] In some embodiments, the conjugate is prepared by contacting an antibody disclosed herein with 1) a linker precursor having a structure of any of the following STING linker payloads:- 192 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 193 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 194 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 195 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 196 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 LP-S3-3;- 197 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 198 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 199 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; and 2) a linker precursor having a structure of any of the following cytotoxin linker payloads: - 200 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01LP-C3; - 201 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01LP-C5 or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof.

[0468] Reactive Groups

[0469] Reactive groups facilitate conjugation of the compounds of linker-payloads as described herein to the antibody or antigen binding fragment described herein to form a conjugate of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) as described herein. Reactive groups can react via any suitable reaction mechanism known to those of skill in the art. In certain embodiments, a reactive group reacts through a [3+2] alkyne-azide cycloaddition reaction, inverse-electron demand Diels-Alder ligation reaction, thiol- electrophile reaction, or carbonyl-oxyamine reaction, as described in detail herein. In certain embodiments, the reactive group comprises an alkyne, strained alkyne, tetrazine, thiol, para- acetyl-phenylalanine residue, oxyamine, maleimide, or azide. In certain embodiments, the- 202 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01, –N3, or –SH; wherein RBis lower alkyl. In certain embodiments, RBis methyl, ethyl, or propyl. In some embodiments, RBis methyl. In some embodiments, RTis ethyl. In some embodiments, RBis propyl. Additional reactive groups are described in, for example, U.S. Patent Application Publication No.2014 / 0356385, U.S. Patent Application Publication No.2013 / 0189287, U.S. Patent Application Publication No.2013 / 0251783, U.S. Patent No. 8,703,936, U.S. Patent No.9,145,361, U.S. Patent No.9,222,940, and U.S. Patent No. 8,431,558.

[0470] In certain embodiments, the reactive group. - 203 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0471] After conjugation, a divalent residue of the reactive group (referred to as RL herein) is formed and is bonded to antibody or antigen binding fragment thereof. The structure of the divalent residue is determined by the type of conjugation reaction employed to form the conjugate.

[0472] [3+2] Alkyne-Azide Cycloaddition Reaction

[0473] Advantageously, the compounds described herein comprising a conjugating alkyne group or an azide group facilitate selective and efficient reactions with a second compound comprising a complementary azide group or alkyne group. It is believed the azide and alkyne groups react in a 1,3-dipolar cycloaddition reaction to form a 1,2,3-triazolylene moiety which links the compounds described herein comprising an alkyne group or an azide group to the second compound. This reaction between an azide and alkyne to form a triazole is generally known to those in the art as a Huisgen cycloaddition reaction or a [3+2] alkyne-azide cycloaddition reaction.

[0474] The unique reactivity of azide and alkyne functional groups makes them useful for the selective modification of polypeptides and other biological molecules. Organic azides, particularly aliphatic azides, and alkynes are generally stable toward common reactive chemical conditions. In particular, both the azide and the alkyne functional groups are inert toward the side chains of the twenty common amino acids found in naturally-occurring polypeptides. It is believed that, when brought into close proximity, the "spring-loaded" nature of the azide and alkyne groups is revealed and azide and alkyne groups react selectively and efficiently via a [3+2] alkyne-azide cycloaddition reaction to generate the corresponding triazole. See, e.g., Chin J., et al., Science 301:964-7 (2003); Wang, Q., et al., J. Am. Chem. Soc.125, 3192-3193 (2003); Chin, J. W., et al., J. Am. Chem. Soc.124:9026-9027 (2002).

[0475] Because the [3+2] alkyne-azide cycloaddition reaction involves a selective cycloaddition reaction [see, e.g., Padwa, A., in COMPREHENSIVE ORGANIC SYNTHESIS, Vol.4, (ed. Trost, B. M., 1991), pp.1069-1109; Huisgen, R. in 1,3-DIPOLAR CYCLOADDITION CHEMISTRY, (ed. Padwa, A., 1984), pp.1-176] rather than a nucleophilic substitution, the incorporation of non-natural or modified amino acids bearing - 204 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 azide and alkyne-containing side chains permits the resultant polypeptides to be modified selectively at the position of the non-natural or modified amino acid. Cycloaddition reactions involving azide or alkyne-containing compounds can be carried out at room temperature under aqueous conditions by the addition of Cu(II) (including, but not limited to, catalytic amounts of CuSO4) in the presence of a reducing agent for reducing Cu(II) to Cu(I), in situ, in catalytic amounts. See, e.g., Wang, Q., et al., J. Am. Chem. Soc.125, 3192-3193 (2003); Tornoe, C. W., et al., J. Org. Chem.67:3057-3064 (2002); Rostovtsev, et al., Angew. Chem. Int. Ed.41:2596-2599 (2002). Exemplary reducing agents include, but are not limited to, ascorbate, metallic copper, quinine, hydroquinone, vitamin K, glutathione, cysteine, Fe2+, Co2+, and an applied electric potential.

[0476] In certain embodiments when a conjugate is formed through a [3+2] alkyne-azide cycloaddition reaction, the divalent residue of the reactive group (e.g., RL) comprises a triazole ring or fused cyclic group comprising a triazole ring. In certain embodiments, when a conjugate is formed through a strain-promoted [3+2] alkyne-azide cycloaddition (SPAAC) reaction, the divalent residue of the reactive group.

[0477] If a conjugate of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) is formed by a [3+2] alkyne-azide cycloaddition, the conjugate encompasses both regioisomers. In certain embodiments, a conjugate of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) is a mixture of regioisomers formed from a [3+2] alkyne-azide cycloaddition.

[0478] Inverse Electron Demand Ligation Reaction- 205 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0479] Advantageously, compounds comprising a terminal tetrazine or strained alkene group facilitate selective and efficient reactions with a second compound comprising a strained alkene or tetrazine group. It is believed that the tetrazine and strained alkene react in an inverse-demand Diels-Alder reaction followed by a retro-Diels-Alder reaction which links compounds comprising a terminal tetrazine or strained alkene group to the second compound. The reaction is believed to be specific, with little to no cross-reactivity with functional groups within biomolecules. The reaction may be carried out under mild conditions, for example, at room temperature and without a catalyst. This reaction between a tetrazine and a strained alkene is generally known to those in the art as a tetrazine ligation reaction.

[0480] In certain embodiments, when a conjugate is formed through a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the reactive group (e.g., RL) comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In certain embodiments, when a conjugate is formed through a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the reactive group (e.g., RL) is.

[0481] If a conjugate of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib-2), (Ic-1), or (Ic-2) is formed by an inverse electron demand ligation reaction, the conjugate encompasses both regioisomers. In certain embodiments, a conjugate of Formula (I), (Ia), (Ib), (Ic), (Ib-1), (Ib- 2), (Ic-1), or (Ic-2) is a mixture of regioisomers formed from an inverse electron demand ligation reaction.

[0482] Thiol Reactions- 206 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0483] Advantageously, compounds comprising a terminal thiol group or suitable electrophilic or disulfide-forming group facilitate selective and efficient reactions with a second compound comprising a complementary electrophilic or disulfide-forming group or thiol group. These reactions are believed to be selective with little to no cross-reactivity with functional groups within biomolecules. In some embodiments, the thiol reaction does not include reaction of a maleimide group.

[0484] In certain embodiments, when a conjugate is formed through a thiol-maleimide reaction, the divalent residue of the reactive group comprisessulfur linkage. In certain embodiments, when a conjugate is formed through a thiol-maleimidereaction, , the divalent residue of the reactive group (e.g., RL) is . In certain embodiments, when a conjugate is formed through a thiol-maleimide reaction,, the divalent residue of the reactive group (e.g., RL) is .

[0485] In certain embodiments, a conjugate is formed through a thiol-N-hydroxysuccinimide reaction using the following group:. The reaction involved for formation of the conjugate comprises the following step:, and the resulting divalent residue of the reactive group- 207 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0486] Carbonyl-Oxyamine Reaction

[0487] Advantageously, compounds comprising a terminal carbonyl or oxyamine group facilitate selective and efficient reactions with a second compound comprising an oxyamine or carbonyl group. It is believed that the carbonyl and oxyamine react to form an oxime linkage. The reaction is believed to be specific, with little to no cross-reactivity with functional groups within biomolecules.

[0488] In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group comprises a divalent residue of a non- natural or modified amino acid. In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group (e.g., RL) is. certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group comprises an oxime linkage. In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group

[0489] Other Reactions

[0490] Other suitable conjugation reactions are described in the literature. See, for example, Lang, K. and Chin, J.2014, Bioorthogonal Reactions for Labeling Proteins, ACS Chem Biol 9, 16-20; Paterson, D. M. et al.2014, Finding the Right (Bioorthogonal) Chemistry, ACS Chem Biol 9, 592-605; King, M. and Wagner, A.2014, Developments in the Field of Bioorthogonal Bond Forming Reactions – Past and Present Trends, Bioconjugate Chem., 2014, 25 (5), pp 825-839; and Ramil, C.P. and Lin, Q., 2013, Bioorthogonal chemistry: strategies and recent developments, Chem Commun 49, 11007-11022. - 208 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0491] Vectors, Host Cells, and Recombinant Methods

[0492] The invention also provides isolated nucleic acids encoding antibodies, vectors and host cells comprising the nucleic acids, and recombinant techniques for the production of the antibodies.

[0493] The antibodies can be prepared according to techniques apparent to the person of skill. In certain embodiments, the antibodies are prepared from isolated nucleic acids encoding antibodies, vectors, and host cells comprising the nucleic acids, and recombinant techniques for the production of the antibodies.

[0494] For recombinant production of the antibody, the nucleic acid(s) encoding it may be isolated and inserted into a replicable vector for further cloning (i.e., amplification of the DNA) or expression. In some aspects, the nucleic acid may be produced by homologous recombination, for example as described in U.S. Patent No.5,204,244, incorporated by reference in its entirety.

[0495] Many different vectors are known in the art. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence, for example as described in U.S. Patent No.5,534,615, incorporated by reference in its entirety.

[0496] Illustrative examples of suitable host cells are provided below. These host cells are not meant to be limiting.

[0497] Suitable host cells include any prokaryotic (e.g., bacterial), lower eukaryotic (e.g., yeast), or higher eukaryotic (e.g., mammalian) cells. Suitable prokaryotes include eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as Escherichia (E. coli), Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella (S. typhimurium), Serratia (S. marcescans), Shigella, Bacilli (B. subtilis and B. licheniformis), Pseudomonas (P. aeruginosa), and Streptomyces. One useful E. coli cloning host is E. coli 294, although other strains such as E. coli B, E. coli X1776, and E. coli W3110 are suitable.

[0498] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are also suitable cloning or expression hosts for antibody-encoding vectors. Saccharomyces cerevisiae, or common baker’s yeast, is a commonly used lower eukaryotic host microorganism. However, a number of other genera, species, and strains are available and useful, such as Spodoptera frugiperda (e.g., SF9), Schizosaccharomyces pombe, Kluyveromyces (K. lactis, K. fragilis, K. bulgaricus K. wickeramii, K. waltii, K. - 209 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 drosophilarum, K. thermotolerans, and K. marxianus), Yarrowia, Pichia pastoris, Candida (C. albicans), Trichoderma reesia, Neurospora crassa, Schwanniomyces (S. occidentalis), and filamentous fungi such as, for example Penicillium, Tolypocladium, and Aspergillus (A. nidulans and A. niger).

[0499] Useful mammalian host cells include COS-7 cells, HEK293 cells; baby hamster kidney (BHK) cells; Chinese hamster ovary (CHO); mouse sertoli cells; African green monkey kidney cells (VERO-76), and the like.

[0500] The host cells used to produce the antibody of this invention may be cultured in a variety of media. Commercially available media such as, for example, Ham’s F10, Minimal Essential Medium (MEM), RPMI-1640, and Dulbecco’s Modified Eagle’s Medium (DMEM) are suitable for culturing the host cells. In addition, any of the media described in Ham et al., Meth. Enz., 1979, 58:44; Barnes et al., Anal. Biochem., 1980, 102:255; and U.S. Patent Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655, and 5,122,469, or WO 90 / 03430 and WO 87 / 00195 may be used. Each of the foregoing references is incorporated by reference in its entirety.

[0501] Any of these media may be supplemented as necessary with hormones and / or other growth factors (such as insulin, transferrin, or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium, and phosphate), buffers (such as HEPES), nucleotides (such as adenosine and thymidine), antibiotics, trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose or an equivalent energy source. Any other necessary supplements may also be included at appropriate concentrations that would be known to those skilled in the art.

[0502] The culture conditions, such as temperature, pH, and the like, are those previously used with the host cell selected for expression and will be apparent to the ordinarily skilled artisan.

[0503] When using recombinant techniques, the antibody can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If the antibody is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, is removed, for example, by centrifugation or ultrafiltration. For example, Carter et al. (Bio / Technology, 1992, 10:163-167) describes a procedure for isolating antibodies which are secreted to the periplasmic space of E. coli. Briefly, cell paste is thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris can be removed by centrifugation. - 210 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0504] In some embodiments, the antibody is produced in a cell-free system. In some aspects, the cell-free system is an in vitro transcription and translation system as described in Yin et al., mAbs, 2012, 4:217-225, incorporated by reference in its entirety. In some aspects, the cell-free system utilizes a cell-free extract from a eukaryotic cell or from a prokaryotic cell. In some aspects, the prokaryotic cell is E. coli. Cell-free expression of the antibody may be useful, for example, where the antibody accumulates in a cell as an insoluble aggregate, or where yields from periplasmic expression are low. The antibodies produced in a cell-free system may be aglycosylated depending on the source of the cells.

[0505] Where the antibody is secreted into the medium, supernatants from such expression systems are generally first concentrated using a commercially available protein concentration filter, for example, an Amicon®or Millipore®Pellcon®ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants.

[0506] The antibody composition prepared from the cells can be purified using, for example, hydroxyapatite chromatography, gel electrophoresis, dialysis, and affinity chromatography, with affinity chromatography being a particularly useful purification technique. The suitability of protein A as an affinity ligand depends on the species and isotype of any immunoglobulin Fc domain that is present in the antibody. Protein A can be used to purify antibodies that are based on human γ1, γ2, or γ4 heavy chains (Lindmark et al., J. Immunol. Meth., 1983, 62:1-13, incorporated by reference in its entirety). Protein G is useful for all mouse isotypes and for human γ3 (Guss et al., EMBO J., 1986, 5:1567-1575, incorporated by reference in its entirety).

[0507] The matrix to which the affinity ligand is attached is most often agarose, but other matrices are available. Mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene allow for faster flow rates and shorter processing times than can be achieved with agarose. Where the antibody comprises a CH3 domain, the BakerBond ABX®resin is useful for purification.

[0508] Other techniques for protein purification, such as fractionation on an ion-exchange column, ethanol precipitation, Reverse Phase HPLC, chromatography on silica, chromatography on heparin Sepharose®, chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are also available, and can be applied by one of skill in the art.

[0509] Following any preliminary purification step(s), the mixture comprising the antibody of interest and contaminants may be subjected to low pH hydrophobic interaction - 211 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 chromatography using an elution buffer at a pH between about 2.5 to about 4.5, generally performed at low salt concentrations (e.g., from about 0 to about 0.25 M salt).

[0510] Pharmaceutical Compositions and Methods of Administration

[0511] (A) In one embodiment, a pharmaceutical composition comprising an antibody conjugate of any one of the embodiments described herein and a pharmaceutically acceptable carrier, excipient, or diluent is provided.

[0512] (B) In one embodiment, the pharmaceutical composition is according to embodiement (A) and is a pharmaceutical composition for treating abnormal cellular proliferation, wherein the abnormal cellular proliferation is cancer.

[0513] (C) In one embodiment, a method of treating abnormal cellular proliferation in a subject in need thereof is provided comprising administering an antibody conjugate of any one of the embodiments described herein or a pharmaceutical composition of embodiement (B), wherein the abnormal cellular proliferation is cancer.

[0514] (D) In one embodiment, the method is of embodiment (C) wherein the cancer is selected from lymphoma, head and neck squamous cell carcinoma, urothelial cancer, lung cancer, breast cancer, prostate cancer, SCLC, bladder cancer, and melanoma.

[0515] (E) In one embodiment, the use of an antibody conjugate of any one of the embodiments described herein or a pharmaceutical composition of embodiement (A) or (B) is provided for the treatment of abnormal cellular proliferation in a subject in need thereof, wherein the abnormal cellular proliferation is cancer.

[0516] (F) In one embodiment, the use of an antibody conjugate of any one of the embodiements described herein or a pharmaceutical composition of embodiment (A) or (B) is provided for the manufacture of a medicament for the treatment of abnormal cellular proliferation in a subject in need thereof, wherein the abnormal cellular proliferation is cancer.

[0517] The antibody conjugates provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the antibody conjugates provided herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration.

[0518] The methods provided herein encompass administering pharmaceutical compositions comprising at least one antibody conjugate provided herein and one or more compatible and pharmaceutically acceptable carriers. In this context, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the - 212 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” includes a diluent, adjuvant (e.g., Freund’s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Martin, E.W., Remington’s Pharmaceutical Sciences.

[0519] In clinical practice the pharmaceutical compositions or antibody conjugates provided herein may be administered by any route known in the art. Exemplary routes of administration include, but are not limited to, the inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. In some embodiments, a pharmaceutical composition, antibody, or antibody conjugate provided herein is administered parenterally.

[0520] The compositions for parenteral administration can be emulsions or sterile solutions. Parenteral compositions may include, for example, propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters (e.g., ethyl oleate). These compositions can also contain wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example using a bacteriological filter, by radiation or by heating. Parenteral compositions can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[0521] In some embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibody conjugates.

[0522] The pharmaceutical composition may comprise one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of ordinary skill in the art is capable of selecting suitable pharmaceutical excipients. Non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, - 213 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a subject and the specific antibody in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Accordingly, the pharmaceutical excipients provided below are intended to be illustrative, and not limiting. Additional pharmaceutical excipients include, for example, those described in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6thEd. (2009), incorporated by reference in its entirety.

[0523] In some embodiments, the pharmaceutical composition comprises an anti-foaming agent. Any suitable anti-foaming agent may be used. In some aspects, the anti-foaming agent is selected from an alcohol, an ether, an oil, a wax, a silicone, a surfactant, and combinations thereof. In some aspects, the anti-foaming agent is selected from a mineral oil, a vegetable oil, ethylene bis stearamide, a paraffin wax, an ester wax, a fatty alcohol wax, a long chain fatty alcohol, a fatty acid soap, a fatty acid ester, a silicon glycol, a fluorosilicone, a polyethylene glycol-polypropylene glycol copolymer, polydimethylsiloxane-silicon dioxide, ether, octyl alcohol, capryl alcohol, sorbitan trioleate, ethyl alcohol, 2-ethyl-hexanol, dimethicone, oleyl alcohol, simethicone, and combinations thereof.

[0524] In some embodiments, the pharmaceutical composition comprises a co-solvent. Illustrative examples of co-solvents include ethanol, poly(ethylene) glycol, butylene glycol, dimethylacetamide, glycerin, and propylene glycol.

[0525] In some embodiments, the pharmaceutical composition comprises a buffer. Illustrative examples of buffers include acetate, borate, carbonate, lactate, malate, phosphate, citrate, hydroxide, diethanolamine, monoethanolamine, glycine, methionine, guar gum, and monosodium glutamate.

[0526] In some embodiments, the pharmaceutical composition comprises a carrier or filler. Illustrative examples of carriers or fillers include lactose, maltodextrin, mannitol, sorbitol, chitosan, stearic acid, xanthan gum, and guar gum.

[0527] In some embodiments, the pharmaceutical composition comprises a surfactant. Illustrative examples of surfactants include d-alpha tocopherol, benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, docusate sodium, glyceryl behenate, glyceryl monooleate, lauric acid, macrogol 15 hydroxystearate, myristyl alcohol, - 214 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sodium lauryl sulfate, sorbitan esters, and vitamin E polyethylene(glycol) succinate.

[0528] In some embodiments, the pharmaceutical composition comprises an anti-caking agent. Illustrative examples of anti-caking agents include calcium phosphate (tribasic), hydroxymethyl cellulose, hydroxypropyl cellulose, and magnesium oxide.

[0529] Other excipients that may be used with the pharmaceutical compositions include, for example, albumin, antioxidants, antibacterial agents, antifungal agents, bioabsorbable polymers, chelating agents, controlled release agents, diluents, dispersing agents, dissolution enhancers, emulsifying agents, gelling agents, ointment bases, penetration enhancers, preservatives, solubilizing agents, solvents, stabilizing agents, and sugars. Specific examples of each of these agents are described, for example, in the Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6thEd. (2009), The Pharmaceutical Press, incorporated by reference in its entirety.

[0530] In some embodiments, the pharmaceutical composition comprises a solvent. In some aspects, the solvent is saline solution, such as a sterile isotonic saline solution or dextrose solution. In some aspects, the solvent is water for injection.

[0531] In some embodiments, the pharmaceutical compositions are in a particulate form, such as a microparticle or a nanoparticle. Microparticles and nanoparticles may be formed from any suitable material, such as a polymer or a lipid. In some aspects, the microparticles or nanoparticles are micelles, liposomes, or polymersomes.

[0532] Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising an antibody conjugate, since, in some embodiments, water can facilitate the degradation of some antibodies.

[0533] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0534] An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable - 215 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0535] Lactose-free compositions provided herein can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions comprise an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.

[0536] Also provided are pharmaceutical compositions and dosage forms that comprise one or more excipients that reduce the rate by which an antibody or antibody-conjugate will decompose. Such excipients, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0537] Parenteral Dosage Forms

[0538] In certain embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to subjects by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses subjects’ natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a subject. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[0539] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0540] Excipients that increase the solubility of one or more of the antibodies disclosed herein can also be incorporated into the parenteral dosage forms. - 216 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0541] Dosage and Unit Dosage Forms

[0542] In human therapeutics, the doctor will determine the posology which he considers most appropriate according to a preventive or curative treatment and according to the age, weight, condition and other factors specific to the subject to be treated.

[0543] In certain embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic antibodies.

[0544] The amount of the antibody conjugate or composition which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the antibody is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the subject. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0545] In certain embodiments, exemplary doses of a composition include milligram or microgram amounts of the antibody conjugate per kilogram of subject or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram).

[0546] In certain embodiment, the dosage of the antibody conjugate provided herein, based on weight of the antibody conjugate, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a subject is between 0.1 mg / kg and 15 mg / kg of the subject’s body weight. In some embodiments, the dosage of the composition administered to a subject is between 0.1 mg and 200 mg.

[0547] The dose can be administered according to a suitable schedule. It may be necessary to use dosages of the antibody or antibody conjugate outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. - 217 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0548] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the antibodies provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same.

[0549] In certain embodiments, treatment or prevention can be initiated with one or more loading doses of an antibody or antibody conjugate or composition provided herein followed by one or more maintenance doses.

[0550] In certain embodiments, a dose of an antibody conjugate or composition provided herein can be administered to achieve a steady-state concentration of the antibody in blood or serum of the subject. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the subject such as height, weight and age.

[0551] Therapeutic Applications

[0552] For therapeutic applications, the antibody conjugates provided herein can be administered to a mammal, generally a human, in a pharmaceutically acceptable dosage form such as those known in the art and those discussed above. For example, the antibody conjugates may be administered to a human intravenously as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intra-cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, or intratumoral routes. The antibody conjugates also are suitably administered by peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects. The intraperitoneal route may be particularly useful, for example, in the treatment of ovarian tumors. In a certain embodiment, the antibody conjugates may be administered to a human intravenously.

[0553] The antibodies provided herein may be useful for the treatment of any disease or condition involving TROP2. In some embodiments, the disease or condition is a disease or condition that can be diagnosed by overexpression of TROP2. In some embodiments, the disease or condition is a disease or condition that can benefit from treatment with an anti- TROP2 antibody. In some embodiments, the disease or condition is abnormal cellular proliferation, for example cancer. - 218 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0554] In certain embodiments, the cancer is a solid tumor. A solid tumor, as used herein, refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas. Additional examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma. In one embodiment, the solid tumor is an advanced solid tumor.

[0555] In some embodiments, the term "cancer" includes, but is not limited to, the following cancers: Cancer to be treated by the present invention is not especially limited, and examples thereof include various peritoneal metastatic cancers, gastric cancer, lung cancer, blood cancers such as acute lymphoblastic leukemia, acute myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B cell lymphoma, multiple myeloma and T cell lymphoma, solid cancers such as myelodysplastic syndromes, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, large cell carcinoma, non-small cell lung cancer, small cell lung cancer, mesothelioma, skin cancer, skin T cell lymphoma, breast cancer, prostate cancer, bladder cancer, vaginal cancer, cervix cancer, head and neck cancer, uterine cancer, cervical cancer, liver cancer, gallbladder cancer, bile duct cancer, kidney cancer, pancreatic cancer, colon cancer, colorectal cancer, rectal cancer, small intestine cancer, gastric cancer, esophageal cancer, testicular cancer, ovarian cancer and brain tumor, cancers of bone tissues, cartilage tissues, adipose tissues, muscle tissues, vascular tissues and blood-forming tissues, sarcomas such as chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma and soft tissue sarcoma, and blastomas such as glioblastoma, glioblastoma multiforme, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma and retinoblastoma. In one embodiment, cancer to be treated by the present invention is colorectal cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, breast cancer or prostate cancer. In one embodiment, cancer to be treated by the present invention is cancer in which TROP2 is highly expressed as compared to a normal tissue. Cancer to be treated by the present invention is preferably cancer in which TROP2 is highly expressed as compared to a normal tissue, or cancer selected from the group consisting of colorectal cancer, rectal cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, breast cancer and prostate cancer. In certain embodiments, the cancer is selected from acute myeloid leukemia, breast cancer, colorectal - 219 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 cancer, glioma, head and neck squamous cell carcinoma, lung cancer, including non-small cell lung cancer, head and neck cancer, lymphoma, including a malignant lymphoma, melanoma, nasopharyngeal carcinoma, ovary cancer, pancreatic cancer, prostate cancer, urothelial cancer, and tongue squamous cell carcinoma. In certain embodiments, the cancer is selected from lymphoma, head and neck squamous cell carcinoma, urothelial cancer, lung cancer, breast cancer, prostate cancer, SCLC, bladder cancer, and melanoma.

[0556] Also provided herein is a method of inducing an immune response in a subject in need thereof comprising administering an antibody conjugate or pharmaceutical composition described herein.

[0557] In certain embodiments, the antibody conjugates provided herein treat the disease, for example cancer, by activating anti-tumor immunity or protective immunity. In certain embodiments, tumor cells pre-treated with an antibody or antibody conjugate provided herein undergo immunogenic cell damage, which can, in turn mount protective immunity in vivo.

[0558] Diagnostic Applications

[0559] In some embodiments, the antibody conjugates provided herein are used in diagnostic applications. These assays may be useful, for example, in making a diagnosis and / or prognosis for a disease, such as cancer.

[0560] In some diagnostic and prognostic applications, the antibody conjugate may be labeled with a detectable moiety. Suitable detectable moieties include, but are not limited to radioisotopes, fluorescent labels, and enzyme-substrate labels. In another embodiment, the antibody conjugate need not be labeled, and the presence of the antibody conjugate can be detected using a labeled antibody which specifically binds to the antibody conjugate.

[0561] Affinity Purification Reagents

[0562] The antibody conjugates provided herein may be used as affinity purification agents. In this process, the antibody conjugates may be immobilized on a solid phase such a resin or filter paper, using methods well known in the art. The immobilized antibodies or antibody conjugate is contacted with a sample containing the antigen (or fragment thereof) to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the protein of interest, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent, such as glycine buffer, pH 5.0 that will release the protein from the antibody. - 220 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0563] Kits

[0564] In some embodiments, an antibody conjugate provided herein is provided in the form of a kit, i.e., a packaged combination of reagents in predetermined amounts with instructions for performing a procedure. In some embodiments, the procedure is a diagnostic assay. In other embodiments, the procedure is a therapeutic procedure.

[0565] In some embodiments, the kit further comprises a solvent for the reconstitution of the antibody conjugate. In some embodiments, the antibody conjugate is provided in the form of a pharmaceutical composition. EXAMPLES

[0566] Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker AscendTM500 MHz spectrometer. NMR spectra are reported as follows: chemical shift δ (ppm), multiplicity, coupling constant J (Hz), and integration. The abbreviations s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and br = broad are used throughout. Mass spectral data were measured using the following systems: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Data was acquired using agilent software and purity characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ion (ESI) (column: Agilent Poroshell 120 EC- C18, 2.7 μm, 4.6×50 mm). Solvents used: acetonitrile / water, containing 0.1% formic acid; flow rate 1 mL / min.

[0567] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Centigrade). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

[0568] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of Biological Chemistry and / or the Journal of the American Chemical Society.

[0569] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner - 221 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0570] Example 1. Synthesis of STING and Toxin Linker Payloads

[0571] Example 1A. Synthesis of Select Intermediates for synthesizing select STING agonists described herein

[0572] Common intermediates of the STING amidobenzimidazole class of agonists examples were prepared according to the following schemes and used to make the select STING agonists compounds described herein.

[0573] Synthesis 1A-1. Intermediate I-1-5 and I-1-10:

[0574] Scheme 1. Synthesis of compound I-1-5

[0575] 4-Chloro-3-methoxy-5-nitrobenzamide (I-1-2): Methyl 4-chloro-3-methoxy-5- nitrobenzoate (1) (40g, 163 mmol) was stirred in NH4OH (600 mL) at room temperature for 24 h. The reaction temperature was then increased to 50 °C for 2 h. An additional 120 mL of NH4OH was added to the vessel. After an additional 2h of stirring at 50 °C, the reaction was cooled to room temperature. The solid was filtered and rinsed with cold water. The solid was dried under vacuum to give compound I-1-2 (29 g) as a tan solid. LC-MS [ESI]: Calculated for C8H7ClN2O4[M+H+]: 231.01, Found: 231.1.

[0576] tert-Butyl (E)-(4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1- yl)carbamate (I-1-4): To a suspension of compound I-1-2 (30 g, 130 mmol) in EtOH (400 mL) was added (E)-tert-butyl (4-aminobut-2-en-1-yl) carbamate (I-1-3) (28 g, 150 mmol) and - 222 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 N,N-diisopropylethylamine (hereinafter called DIPEA, 65 mL, 374 mmol). The reaction was stirred at 80 °C for 4 days and allowed to cool to room temperature. The resulting orange color solid was collected by filtration and washed with EtOH (100 mL), dried in vacuum to afford compound I-1-4 as an orange solid (27 g); LC-MS [ESI]: Calculated for C17H24N4O6 [M+H+]: 381.17, Found: 381.2

[0577] tert-Butyl (E)-(4-((2-amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1- yl)carbamate (I-1-5): To compound 4 (27 g, 71 mmol) was added methanol (480 mL). This mixture was cooled down to 0 °C. After 20 minutes of stirring at 0 °C, ammonium hydroxide solution (29 % wt, 100 mL) was added followed by sodium hydrosulfite (75 g, 431 mmol) as a solution in water (194 mL). The flask was removed from the ice bath and stirred at room temperature. After 3 h of stirring at room temperature, water (800 mL) was added until a clear solution was obtained. The methanol was evaporated using reduced pressure. The white solid that formed during evaporation was filtered off, washed with water twice (300 mL each), and dried under vacuum to give compound I-1-5 as a white solid (17 g). LC-MS [ESI]: Calculated for C17H26N4O4 [M+H+]: 351.2, Found: 351.2

[0578] Scheme 2. Synthesis of compound I-1-10

[0579] tert-Butyl 2-(3-bromopropyl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (I- 1-1b):To a stirred solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate 1a (5g, 21.9 mmol) in DCM (45 mL) at room temperature was added 1,3-dibromopropane (2.4 mL, 24.1 mmol). The reaction mixture was stirred at rt for 1h. To this was added triethylamine (3 mL, 21.9 mmol) and the resulting suspension was stirred at rt for 3h. To this another 0.5 eq of 1,3 dibromo propane was added and the reaction was continued for another 2h. After which, the reaction mixture was concentrated under reduced pressure and residue was suspended in EtOAc (25 mL). Solids were filtered and washed with EtOAc (2x10 mL). The combined filtrate was concentrated under reduced pressure and the crude - 223 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 material was purified by column chromatography over silica gel (dry load, 40 g column, 0- 20% MeOH / DCM as eluent) to afford tert-butyl 2-(3-bromopropyl)-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylateI-1-1b(3.5g) as colorless oil.1H NMR (400 MHz, CDCl3) δ 3.61 – 3.56 (m, 2H), 3.55 (s, 2H), 3.45 (t, J = 6.7 Hz, 2H), 3.41 – 3.32 (m, 4H), 2.89 (d, J = 7.7 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 1.92 (p, J = 6.7 Hz, 2H), 1.49 (s, 9H).

[0580] tert-Butyl 2-[3-(5-carbamoyl-2-chloro-3-nitro-phenoxy)propyl]-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate (I-1-10): To a stirred suspension of 4-chloro-3- hydroxy-5-nitro-benzamide I-1-1c (3.2 g, 15.03 mmol), and K2CO3 (3.46 g, 25.05mmol) in DMF (10 mL) at room temperature was added tert-butyl 2-(3-bromopropyl)-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate (I-1-1b, 3.5g, 10 mmol) and the reaction mixture was stirred at 70 °C for 16h. The reaction mixture was cooled to room temperature, quenched with ice cold water, and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with water (3 x 50 mL) followed by brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was triturated with 50% EtOAc in heptane to afford tert-butyl 2-[3-(5-carbamoyl-2-chloro-3-nitro-phenoxy)propyl]-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate (I-1-10, 2.6g,5.3 mmol) as an off white solid.1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 4.25 (t, J = 6.2 Hz, 2H), 3.52 – 3.38 (m, 4H), 3.30 – 3.22 (m, 4H), 2.80 – 2.71 (m, 2H), 2.62 (t, J = 6.8 Hz, 2H), 1.82 (p, J = 6.6 Hz, 2H), 1.39 (s, 9H).13C NMR (101 MHz, DMSO) δ 165.3, 155.5, 154.5, 149.2, 135.0, 116.9, 115.8, 115.7, 79.6, 70.9, 68.6, 62.3, 61.9, 55.8, 28.4, 27.3. LC-MS [ESI]: Calculated for C21H29ClN4O7[M+H+]: 485.18, Found: 485.20; - 224 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0581] Synthesis 1A-2. Intermediate I-1-13

[0582] Scheme 3. Synthesis of Intermediate I-1-13:- 225 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01

[0583] 1-Ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (I-1-7): To a 1L round bottom flask was added 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (I-1-6, 10 g, 65 mmol) and DCM (200 mL). To this heterogeneous solution was added DMF (0.1 mL) followed by the slow addition of oxalyl chloride (7 mL, 82 mmol). After stirring for 1h at room temperature, the volatiles were removed under vacuum and the crude was co- evaporated twice with dichloromethane (100 mL each). Then the crude residue was dissolved in anhydrous acetone (25 mL) and added to a solution of KSCN (8.6 g, 89 mmol) in anhydrous acetone (150 mL) at 0 °C. The mixture was stirred for 20 min. At this time, hexane (100 mL) was added to the reaction mixture and the crude heterogeneous solution was concentrated under reduced pressure to one third of the volume. The process of hexane addition and concentration was repeated twice (200 mL of hexane each). After the last concentration, hexane (200 mL) was added and the solid wa...

Claims

Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 CLAIMS What is claimed is:

1. An antibody conjugate represented by the structure of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab is an anti-TROP2 antibody or antigen-binding fragment thereof; Lais a first linker; Lbis a second linker; CY is independently a residue of a cytotoxic agent; STING is independently a residue of a STING agonist; subscript n is an integer selected from 1 to 10; and subscript m is an integer selected from 1 to 10.

2. The antibody conjugate of claim 1, wherein STING is independently a residue of a compound of Formula (S-I) or (S-II):or a tautomer or stereoisomer thereof; wherein: X is selected from N and CR3; R20is selected from hydrogen and -CON(R3a)(R3b); R1a, R1b, R3aand R3bare independently selected from hydrogen and optionally substituted C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more - 315 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R2aand R2bare independently selected from: (a) optionally substituted C1- 6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more R51and (b) optionally substituted C3-12carbocycle or optionally substituted 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R53; or R1aand R2aare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; or R1band R2bare joined together with the atoms to which they are attached to form an optionally substituted 3- to 12-membered heterocycle, wherein the heterocycle is optionally substituted with one or more R53; R3is hydrogen, -OR30, -SR30, -C(O)N(R30)2, -N(R30)C(O)R30, -N(R30)C(O)N(R30)2, -N(R30)2, -C(O)R30, -C(O)OR30, -OC(O)R30, -NO2, or -CN; L1is selected from a bond, -C1-10alkylene-, -C2-10alkenylene-, -C2-10alkynylene-, -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, C3-6carbocyclene, and -C1-6alkylene-(C3-6carbocyclene)-C1-6alkylene-, wherein -C1- 10 alkylene-, -C2-10 alkenylene-, -C2-10 alkynylene-, C3-6 carbocyclene, and each C1-6 alkylene of -C1-6alkylene-O-C1-6alkylene-, -C1-6alkylene-NH-C1-6alkylene-, and -C1-6alkylene-(C3-6carbocyclene)-C1-6alkylene- are optionally substituted with one or more R50; L2is optionally substituted -C1-6alkylene- or -C1- 6alkylene-O-, wherein the -C1-6alkylene- or the C1-6alkylene of -C1-6alkylene-O- is optionally substituted with one or more R50and wherein the -C1-6 alkylene-O- is attached to the A ring, or Lbif the A ring is absent, via the oxygen atom; Ring B is an optionally substituted C3-12carbocycle or an optionally substituted 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; Ring A is absent; an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one N atom and at least one O atom, wherein the heterocycle is optionally substituted with one or more R53; or, a 3- to 12- membered heterocycle substituted with R4; R4is an optionally substituted 3- to 12-membered heterocycle optionally comprising at least one NR5and, wherein the heterocycle is optionally substituted with one or more R53; - 316 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R5is independently selected from hydrogen, R6, -C(O)-C1-6alkyl, -C(O)- heteroC1-6alkyl, C1-6 alkyl, and heteroC1-6alkyl wherein the C1-6 alkyl, either alone or part of another group, is optionally substituted with one or more R50; R6is independently an amino acid residue; R30is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which, except hydrogen, is optionally substituted with one or more R55; R50is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, C3-12carbocycle, and 3- to 12-membered heterocycle; R51is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, optionally substituted C3-12carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C3-12carbocycle and 3- to 12- membered heterocycle are optionally substituted with one or more R52; R52is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, -NO2, =O, =S, =N(R61), -CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; R53is independently selected from halogen, -OR60, -SR60, -C(O)NR60R61, -N(R60)C(O)R60, -N(R60)C(O)NR60R61, -NR60R61, -C(O)R60, -C(O)OR60, -OC(O)R60, -NO2, =O, =S, =N(R60), -CN, optionally substituted C1-6alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-12carbocycle, and optionally substituted 3- to 12-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one or more R54and the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted with one or more R52; R54is independently selected from halogen, -OR61, -SR61, -C(O)N(R61)2, -N(R61)C(O)R61, -N(R61)C(O)N(R61)2, -N(R61)2, -C(O)R61, -C(O)OR61, -OC(O)R61, - NO2, =O, =S, =N(R61), and -CN; R55is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and - 317 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 R60and R61are independently selected from hydrogen, C1-10 alkyl optionally substituted with NH2 or NHC1-6 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle; wherein when Ring A is absent, L2is -C1-6alkylene-O-; wherein the residue of Formula (S-I) is attached to Lbvia an amino group of Ring A, the oxygen of -C1-6 alkylene-O- of L2, an amino group of R54, or an amino group of R4, and the residue of Formula (S-II) is attached to Lbvia an amino group of Ring B.

3. The antibody conjugate of claim 1 or 2, wherein CY is a residue of a compound selected from the group consisting of an alkylating agent, a DNA-crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone- deacetylase (HDAC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, and a topoisomerase inhibitor.

4. The antibody conjugate of claim 3, wherein CY is a topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan.

5. The antibody conjugate of claim 4, wherein CY is exatecan.

6. The antibody conjugate of any one of claims 1-5, wherein Laand Lbindependently comprise a protease cleavable linker, an enzyme cleavable linker, a pH-sensitive linker, or a non-cleavable linker.

7. The antibody conjugate of any one of claims 1-6, wherein Lais -W1-W2-SG1-HP1-RL1-; Lbis -RL01-HP01-SG01-W02-W01-; and the antibody conjugate of Formula (I) is represented by Formula (Ia): [CY-W1-W2-SG1-HP1-RL1-]m-Ab-[-RL01-HP01-SG01-W02-W01-STING]n (Ia) or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein: Ab is the anti-TROP2 antibody or antigen-binding fragment thereof; CY is the residue of the cytotoxic agent; STING is the residue of the STING agonist; SG1and SG01are independently, at each occurrence, absent or a divalent spacer group; - 318 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 W1and W01are independently, at each occurrence, absent,wherein the -NH- is bound to W2or W02and eachindicates a point of attachment to the rest of the formula; L3is independently a bond or an optionally substituted C1-6alkylene wherein the C1-6alkylene is optionally substituted with one, two, or three substituents selected from halogen, C1-6 alkyl, haloC1-6 alkyl, hydroxyl, amino, C1-6 alkylamino, and C1-6 alkoxy; R16is independently a residue of an amino acid sidechain; R11is independently hydrogen or C1-6 alkyl; w is an integer selected from 0, 1, and 2; W2and W02are independently, at each occurrence, absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP2group; HP1and HP01are independently, at each occurrence, absent or a divalent hydrophilic group; HP2, when present, is a monovalent hydrophilic group; RAis independently, at each occurrence, optionally substituted C1-6alkyl wherein the C1-6alkyl is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6 alkyl, hydroxyl, amino, alkylC1-6 amino, and C1-6 alkoxy; O-Su is independently, at each occurrence, a release trigger group; RL1and RL01are independently, at each occurrence, a reactive linker; y is an integer independently selected from 0, 1, and 2; and z is an integer independently selected from 0 and 1.

8. The antibody conjugate of any one of claims 2-7, wherein R1aand R1bare both hydrogen. - 319 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 9. The antibody conjugate of any one of claims 2-8, wherein R2aand R2bare independently an optionally substituted 3- to 12-membered heterocycle comprising at least one N atom.

10. The antibody conjugate of claim 9, wherein R2aand R2bare independently selected fromwherein R2cand R2dare independently selected from hydrogen, C1-6 alkyl optionally substituted with one or more R54, halo, and 3-12 membered heterocycle; R2eis hydrogen or C1-6 alkyl; andis the point of attachment to the rest of the formula.

11. The antibody conjugate of any one of claims 2-10, wherein the STING is a residue of a compound of Formula (S-I) wherein Ring A is an optionally substituted 3- to 12- membered N-linked spirocyclic bicyclic heterocycle comprising at least one nitrogen atom, including the nitrogen bound to Lb, and at least one oxygen atom; or a 3- to 12- membered N-linked monocyclic heterocycle substituted with R4.

12. The antibody conjugate of any one of claims 2-11, whereinis selected from, - 320 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01the point of attachment to Lbandis the point of attachment to L2.

13. The antibody conjugate of claim 12, whereinwherein is the point of attachment to Lband is the point of attachment to L2.

14. The antibody conjugate of any one of claims 2-11, wherein Ring A is an N-linked mono 3- to 12-membered heterocycle substituted with R4.

15. The antibody conjugate of claim 14, wherein Ring A is selected from,attachment to L2.

16. The antibody conjugate of claim 15, wherein Ring.

17. The antibody conjugate of any one of claims 2-16, wherein R4is a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N bound to Lb. - 321 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 18. The antibody conjugate of claim 17, wherein, ,, or ; wherein X5, X6, X9, X10are independently selected from N and CR13; X7and X8are independently selected from NH, O, and CHR13; R13is independently hydrogen or C1-6alkyl; wherein if four of any one of X5-X10are present, at least one is CR13or CHR13; andis the point of attachment to Ring A andis the point of attachment to Lb.

19. The antibody conjugate of claim18, wherein.

20. The antibody conjugate of any one of claims 2-10, wherein Ring B is an optionally substituted 3- to 12-membered heterocycle.

21. The antibody conjugate of any one of claims 2-19, wherein L2is -C1-6 alkylene-. - 322 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 22. The antibody conjugate of any one of claims 7-21, whereinW01is independently absent,L3is bond or -CH2- y is 0 or 1; and z is 0 or 1.

23. The antibody conjugate of claim 22, wherein, whereinrepresents attachment to the remainder of the compound.

24. The antibody conjugate of any one of claim 23, wherein, whereinrepresents attachment to the remainder of the compound.

25. The antibody conjugate of any one of claims 7-24, wherein W2and W02is independently absent or a group selected from -(C(O)CHR10NR11)o-, -(C(O)CH2CHR10NR11)p-, -(C(O)CHR10CH2NR11)p-, -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o-, and -(C(O)CHR10CH2NR11)p- (C(O)CHR10NR11)o-; wherein R10is independently an amino acid sidechain residue optionally substituted with HP2; R11is independently hydrogen or C1-6 alkyl; - 323 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 o and p is independently an integer between 1 and 10, inclusive; and the - C(O)- of W2and W02is bound to W1.

26. The antibody conjugate of claim 25, wherein each W2and W02is independently absent or -(C(O)CH2CHR10NR11)p-(C(O)CHR10NR11)o- wherein R10is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, leucine, asparagine, lysine and 2,3-diaminopropionate and wherein the amino acid sidechain is optionally substituted with HP2; HP2is independentlywherein h is an integer between 1 and 50, inclusivewherein g is an integer between 1 and 50; poly(propylene glycoloxy-CH2CH2C(O)-); poly(oxyethylated polyol)oxy-CH2CH2C(O)-; poly(olefinic alcohol)oxy-CH2CH2C(O)-; poly(saccharides)-CH2CH2C(O)-; poly(vinyl alcohol)oxy-CH2CH2C(O)-; or a combination thereof; R11is hydrogen; o is independently an integer between 1 and 4, inclusive; p is 1; and and eachis the point of attachment to the rest of the formula.

27. The antibody conjugate claim 25 or 26, wherein HP2iswherein g is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula .

28. The antibody conjugate of claim 25, wherein W2and W02is absent or independently, - 324 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01each is the point of attachment to the rest of the formula.

29. The antibody conjugate of any one of claims 7-28, wherein SG1is independently -C(O)-C1-6 alkylene-C(O)-, and SG01is independently absent or -C1-6 alkylene-C(O)- wherein the -C(O)- is bound to W2and W02.

30. The antibody conjugate of any one of any one of claims 7-29, wherein each HP1and 0HP1is independently absent or wherein R2is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula.

31. The antibody conjugate of any one of claims 7-30, wherein RL1and RL01is; an eac is a point of attachment to the rest of the formula. - 325 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 32. The antibody conjugate of claim 31, wherein RL1is independently selected from33. The antibody conjugate of claim 31 or 32, wherein RL01is and eachis a point of attachment to the rest of the formula.

34. The antibody conjugate of any one of claims 1-3 and 6-33, wherein CY isis a point of attachment to the rest of the formula.

35. The antibody conjugate of claim 1-33, wherein CY is independently selected from. - 326 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 36. The antibody conjugate of any one of claims 1-7, 11 and 21-35, wherein -[Lb- STING]n is independently- 327 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

37. The antibody conjugate of any one of claims 1-6 and 34-35, wherein -[Lb-STING]n- is a structure selected from:- 328 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 329 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 330 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 331 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01- 332 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

38. The antibody conjugate of any one of claims 1-2 and 36-37, wherein [CY-La-]m- is:, - 333 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01, - 334 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01whereinis the point of attachment to the rest of the formula.

39. The antibody conjugate of claim 1, wherein [CY-La-]m- is - 335 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01-[Lb-STING]n is.

40. The antibody conjugate of claim 1, wherein [CY-La-]m - is-[Lb-STING]n is a structure selected from- 336 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01.

41. The antibody conjugate of any one of claims 1-40, wherein m and n is an integer independently between 1 and 8, inclusive.

42. The antibody conjugate of any one of claims 1-41, wherein the molar ratio of CY to STING is about 2:

1.

43. The antibody conjugate of claim 1-42, wherein the anti-TROP2 antibody or the antigen-binding fragment thereof comprises at least two modified amino acid residues suitable for conjugation that are covalently linked to Laand / or Lb.

44. The antibody conjugate of any one of claims 1-42, wherein (a) the anti-TROP2 antibody or antigen-binding fragment thereof is covalently linked to Lavia a modified amino acid and (b) the anti-TROP2 antibody or antigen binding fragment thereof is covalently linked to Lbvia a modified amino acid that is different than the modified amino acid in (a).

45. The antibody conjugate of claim 43 and 44, wherein the modified amino acid residue is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L- tyrosine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p- acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo-phenylalanine, p- bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p- propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine.

46. The antibody conjugate of claim 45, wherein the modified amino acid residue is independently selected from p-azidomethyl-L-phenyl alanine and p-acetyl-L- phenylalanine.

47. The antibody conjugate of any one of claims 43-46, wherein the modified amino acid residues are at positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, - 337 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 HC-S190, HC-K222, HC-R19, HC-Y52, or HC-S70, according to the Kabat or Chothia or EU numbering scheme, or a post translationally modified variant thereof.

48. The antibody conjugate of claim 47, wherein the modified amino acid residues are at positions selected from the group consisting of heavy chain or light chain residues HC-F241, HC-F404, HC-Y180, and LC-K42.

49. The antibody conjugate of claim 48, wherein the modified amino acid residues are p- azidomethyl-L-phenyl alanine at HC-F404, HC-F241, and / or HC-Y180, and p-acetyl- L-phenylalanine at LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post translationally modified variant thereof.

50. The antibody conjugate of claim 49, wherein [CY-La-]m- is bonded to the p- azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404, and -[Lb-STING]nis bonded to the p-acetyl-L-phenylalanine at LC-K42.

51. The antibody conjugate of claim 50, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1 consisting of an amino acid sequence of SEQ ID NO: 4, a CDR2 consisting of an amino acid sequence of SEQ ID NO: 5, and a CDR3 consisting of an amino acid sequence of SEQ ID NO: 6, and the light chain variable region comprises a CDR1 consisting of an amino acid sequence of SEQ ID NO: 7, a CDR2 consisting of an amino acid sequence of SEQ ID NO: 8, and a CDR3 consisting of an amino acid sequence of SEQ ID NO:

9.

52. The antibody conjugate of claim 51, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 10 and the light chain variable region comprises an amino acid sequence of SEQ ID NO:

11.

53. The antibody conjugate of claim 52, wherein the antibody comprises either one of the following heavy chain and light chain sequences: (a) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 12 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14, (b) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 13 and a light chain consisting of an amino acid sequence of SEQ ID NO: 14, (c) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 15 and a light chain consisting of an amino acid sequence of SEQ ID NO: 17, or - 338 -Attorney Docket No.128696.00004 SU 0449WO1; 121108WO01 (d) a heavy chain consisting of an amino acid sequence of SEQ ID NO: 16 and a light chain consisting of an amino acid sequence of SEQ ID NO:

17.

54. A pharmaceutical composition comprising an antibody conjugate of any one of claims 1-53 and a pharmaceutically acceptable carrier, excipient, or diluent.

55. The pharmaceutical composition according to claim 54, which is a pharmaceutical composition for treating abnormal cellular proliferation, wherein the abnormal cellular proliferation is cancer.

56. A method of treating abnormal cellular proliferation in a subject in need thereof comprising administering an antibody conjugate of any one of claims 1-53 or a pharmaceutical composition of claim 54, wherein the abnormal cellular proliferation is cancer.

57. The method of claim 56, wherein the cancer is selected from lymphoma, head and neck squamous cell carcinoma, urothelial cancer, lung cancer, breast cancer, prostate cancer, SCLC, bladder cancer, and melanoma.

58. Use of an antibody conjugate of any one of claims 1-53 or a pharmaceutical composition of claim 54 for the treatment of abnormal cellular proliferation in a subject in need thereof, wherein the abnormal cellular proliferation is cancer.

59. Use of an antibody conjugate of any one of claims 1-53 or a pharmaceutical composition of claim 54 for the manufacture of a medicament for the treatment of abnormal cellular proliferation in a subject in need thereof, wherein the abnormal cellular proliferation is cancer. - 339 -

Images