Antibody conjugates with high payload to antibody ratios, compositions comprising the same, and methods of their use

Abstract

The present disclosure is related to antibody conjugates, including antibody drug conjugates, comprising multiple payloads at high payload to antibody ratios, pharmaceutical compositions thereof, and the use of the antibody conjugates and compositions thereof for the treatment of diseases and disorders, including proliferative diseases.

Description

ANTIBODY CONJUGATES WITH HIGH PAYLOAD TO ANTIBODY RATIOS, COMPOSITIONS COMPRISING THE SAME, AND METHODS OF THEIR USECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 705,389 filed October 9, 2025, the entirety of which is incorporated herein for all purposes.FIELD

[0002] The present disclosure is related to antibody conjugates, including antibody drug conjugates, comprising multiple payloads at high payload to antibody ratios, pharmaceutical compositions thereof, and the use of the antibody conjugates and compositions thereof for the treatment of diseases and disorders, including proliferative diseases.BACKGROUND

[0003] Antibodies are biological molecules with remarkable affinities for their target antigens. Nature provides antibodies as part of a defense system in certain vertebrates for the elimination or destruction of foreign proteins, cells and organisms. If a certain vertebrate is presented with a foreign protein on, for example, an infected cell or an infectious bacterium, an antibody can bind its target foreign protein to direct the foreign entity to its elimination or destruction.

[0004] The selective affinity of antibodies can be used to target nearly any antigen desired. The antigen can be a protein on an infected cell or infectious microorganism. It can also be, for example, a protein on a cancer cell, a protein on a cell of a target tissue, a protein in the bloodstream, a protein on an inflamed or inflammatory cell or any other protein whose selective binding is useful. Antibodies have thus found use in therapy for conditions such as cancer, inflammatory diseases, autoimmune diseases and transplant rejection. The antibody can signal the immune system to destroy or eliminate a diseased cell, or an engineered antibody can carry a molecular payload to destroy the target. In certain applications therapeutic antibodies are linked to molecular shields to increase their lifetime within an organism. Antibodies have also found use as diagnostics. These antibodies can carry a label to indicate the presence of a target antigen on a cell or in a tissue. These labels are typically linked to the antibodies by covalent bonds.

[0005] To date, techniques for linking antibodies molecular entities such as molecular payloads, molecular shields and labels have been limited by their heterogeneity in degree and location of linking to the antibodies, by their low yields and by losses in activity. Typicalconjugation sites include random locations on antibody chains, e.g. random amines on amino acid side chains, and the N-terminus of certain antibody chains. In such techniques, some antibodies might be linked to the conjugate at one location while some antibodies are linked to the same conjugate at another location, and some antibodies might not be linked at all. The overall number of payloads per antibody has remained low using conventional conjugation techniques.

[0006] There is a need for antibodies modified at site-specific positions optimized for higher ratios of payload to antibody to further the promising use of antibodies in, for example, therapy and diagnostics.SUMMARY

[0007] Described herein are antibody conjugates, including antibody drug conjugates (ADCs), comprising an antibody, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, is covalently linked to a number of payload residues. In particular embodiments, the number of payload residues is provided as the payload to antibody ratio. When the payloads are drug residues, this is the drug to antibody ratio (DAR) known to the person of skill. In certain embodiments, the payload to antibody ratio is greater than 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 22. In certain embodiments, the payload to antibody ratio is at least 24, at least 26, at least 28, or at least 30. In certain embodiments, the payload to antibody ratio is up to 24. In certain embodiments, the payload to antibody ratio is up to 30. In certain embodiments, the high payload to antibody ratios antibody conjugates disclosed herein exhibit improved efficacy and therapeutic index over the administration of similar antibody conjugates with lower payload to antibody ratios.

[0008] The high payload to antibody ratios are achieved by several techniques, or combinations thereof. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise one or more non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise more than one non-natural amino acid residues. The non-natural amino acid residues can provide reactive side chains for conjugating payloads and / or linker-payloads to form antibody conjugates. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise two non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise four non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise eight non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise ten non-natural amino acid residues.In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise twelve non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise fourteen non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise more than ten non-natural amino acid residues. In certain embodiments, the antibodies, or antigen binding fragments thereof, comprise more than fourteen non-natural amino acid residues. Exemplary non-natural amino acid residues and conjugation techniques are described herein.

[0009] The non-natural amino acid residues can be in the antibody, or antigen binding fragment, heavy chain, light chain, or both in the heavy chain and in the light chain. In certain embodiments, the antibody, or antigen binding fragment, heavy chain comprises one non- natural amino acid. In certain embodiments, the antibody, or antigen binding fragment, heavy chain comprises two non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment, heavy chain comprises three non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment, heavy chain comprises four non- natural amino acids. In certain embodiments, the antibody, or antigen binding fragment, heavy chain comprises five non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment, light chain comprises one non-natural amino acid. In certain embodiments, the antibody, or antigen binding fragment, light chain comprises two non-natural amino adds. In certain embodiments, the antibody, or antigen binding fragment, light chain comprises three non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment, comprises combinations of non-natural amino acids on the heavy chains and light chains. Those of skill will recognize that antibodies and antigen binding fragments typically comprise two heavy chains and two light chains. Useful sites for the non-natural amino acid residues and conjugation techniques are described herein.

[0010] The antibody conjugates comprise payloads and linkers. The linkers covalently link the payloads to the antibodies. In certain embodiments, at least one linker is linked to more than one payload. In certain embodiments, at least one linker is linked to two payloads. In certain embodiments, at least one linker is linked to three payloads. In certain embodiments, at least one linker is linked to four payloads. In certain embodiments, at least one linker is linked to more than one payload, and the antibody, or antigen binding fragment, comprises more than one non-natural amino acid residues, as provided herein. Usefill payloads, linkers, linkerpayloads, and conjugation techniques are described herein.

[0011] In some embodiments, the antibody conjugate is represented by the structure of Formula (I):Ab-J-L’-PAY ]nFormula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab is the antibody or antigen-binding fragment thereof; each L* is a linker; each PAY is a payload; and subscript n is an integer selected from 2 to 30; wherein each L* is the same or different, and wherein each PAY is the same or different.

[0012] In another aspect, provided herein are pharmaceutical compositions comprising the antibody conjugates, including the ADCs, described herein. In a further aspect, provided herein are kits comprising the antibody conjugates, including the ADCs, 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 antibody conjugate, including an ADC, described herein or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the disease, disorder, or condition is cancer.BRIEF DESCRIPTION OF FIGURES

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

[0015] FIG. 2 shows payload release in human liver S9 graph for exatecan, MMAE, and hemiasterlin.

[0016] FIG. 3 shows payload release in human liver S9 graph for MMAE and hemiasterlin.

[0017] FIG. 4 shows total antibody concentration in mouse plasma following a single IV administration of select conjugates at 3 mg / kg.

[0018] FIG. 5A-FIG. 5D show the calculated DAR of aHER2 dual conjugates over 21 Days.

[0019] FIG. 6 are time profiles of the high DAR aTF dual payload conjugates in Table 6 compared to its corresponding ADC in mouse plasma following a single IV administration.

[0020] FIG. 7 is the lysosomal release of the DBCO hydrophilic branched β-Glu cleavable Exatecan linker payloads.

[0021] FIG. 8 are graphs of the cell killing activity via anti-HER2 ADCs with DBCO bis- PEG2 spacer branched linker-payloads.

[0022] FIG. 9 are graphs of the cell killing activity via anti-HER2 ADCs with beta-alanine spacer branched linker-payloads.

[0023] FIG. 10 are graphs of the cell killing activity via anti-HER2 ADCs with bis-PEGylated branched linker-payloads.

[0024] FIG. 11 is the LCMS graph of DAR14 and DAR 16 ADCs.

[0025] FIG. 12 provides a graph of TAb Concentration - Time Profiles in Mouse Plasma Following a Single IV Administration of dpADCs (5 mg / kg).

[0026] FIG. 13 provides IGROV-1-ENR1 tumor growth curves in response to treatment with a single z.v. dose of 10 mg / kg of Conjugate 109or Conjugate 111.

[0027] FIG. 14 provides a scatter plot of individual tumor volumes on day 44 or 46 post treatment. Day 44 tumor volumes were used for the vehicle- and Conjugate 111 -treated groups while day 46 tumor volumes were used for the Conjugate 109-treated group. Statistical analysis was performed on tumor volumes using a Welch’s ANOVA with Dunnett’s T3 multiple comparisons test versus the vehicle group. A probability of less than 5% (p<0.05) was considered significant. ** = p<0.01; *** = p<0.001. All graphs are presented as individual values or mean ± SEM.

[0028] FIG. ISA provides HCT-116 tumor growth curves in response to treatment with a single z.v. dose of 5 mg / kg of Conjugate 109, Conjugate 110, Conjugate 111, or Conjugate 112.

[0029] FIG. 15B provides scatter plot of individual tumor volumes on day 22 post treatment. Statistical analysis was performed on tumor volumes on day 22 using a Welch’s ANOVA with Dunnett’s T3 multiple comparisons test versus the vehicle group. A probability of less than 5% (p<0.05) was considered significant. **** = p<0.0001. All graphs are presented as individual values or mean ± SEM.

[0030] FIG.16A shows MC38-hHER2 tumor growth curves in response to treatment with a single z. v. dose of 20 mg / kg a reference anti-HER2 antibody conjugate (Enhertu®) or 3, 10, or 20 mg / kg Conjugate 45.

[0031] FIG. 16B shows a scatter plot of individual tumor volumes on day 21 post treatment. Statistical analysis was performed on tumor volumes on day 21 using a Welch’s ANOVA with Dunnett’s T3 multiple comparisons test versus the vehicle group. A probability of less than 5% (p<0.05) was considered significant. ** = p<0.01; *** = p<0.001. All graphs are presented as individual values or mean ± SEM.DETAILED DESCRIPTION

[0032] Described herein are antibody conjugates, including antibody drug conjugates, with high payload to antibody ratios. In certain embodiments, the antibody conjugates described herein comprise multiple non-natural amino acids at advantageous specific antibody sequence sites and / or linkers that link to more than one payload.

[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 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 “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 CHI (or CHI), CH2 (or CH2), and CH3 (or CH3). Each light chain typically comprises a light chain variable region (VL or VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL or CL.

[0039] The term “antibody” is used herein in its broadest sense. An antibody includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments (e.g., antigen binding fragments of antibodies). 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.

[0040] The VH and VL regions 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 VH and VL generally 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.

[0041] 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.

[0042] 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: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0043] 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 Pliickthun, J. Mol. Biol, 2001, 309:657-70 (“AHo” numbering scheme), each of which is incorporated by reference in its entirety.

[0044] 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.

[0045] Table A. Residues in CDRs according to Kabat and Chothia numbering schemes.CDR Kabat ChothiaLI L24-L34 L24-L34L2 L50-L56 L50-L56L3 L89-L97 L89-L97 H31-H35BHl (Kabat Numbering) H26-H32 or H34*Hl (Chothia Numbering) H31-H35 H26-H32H2 H50-H65 H52-H56H3 H95-H102 H95-H102

[0046] * 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 particularCDR herein is the Kabat / Chothia 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 either Kabat or Chothia. For convenience, CDR-H3 is sometimes referred to herein as either Kabat or Chothia. 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 “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.

[0050] 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 fragments, Fab fragments, F(ab’)a fragments, Fab’ fragments, scFv (sFv) fragments, and scFv- Fc fragments.

[0051] “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.

[0052] “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 (CHI) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0053] “F(ab')a” fragments contain two Fab' fragments joined, near the hinge region, by disulfide bonds. F(ab')2 fragments 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 0 -mercaptoethanol.

[0054] “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Pliickthim A. (1994). In some embodiments, the linker is GGGGSGGGGSGGGGS (SEQ ID NO: 10). In some embodiments, the linker is AAGSDQEPKSS (SEQ ID NO: 15). 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.

[0055] “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-VL or VL-VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgGl Fc domain. In some embodiments, the IgGl Fc domain comprises SEQ ID NO:30, or a portion thereof. SEQ ID NO:30 provides the sequence of CHI, CH2, and CH3 of the human IgGl constant region. SEQ ID NO:30 IgGl Fc from scFv- Fc:AAGSDQEPKSSDKTHTCPPCSAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQKSLSLSPGK

[0056] 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. A monoclonal antibody is typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further altered, for example, to improve affinity for the target (“affinity maturation”), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0057] 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.

[0058] “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 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. Humanized antibodies may also comprise residues that are not found in either the recipient antibody or the donor antibody. Such modifications may be made to further refine antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525; Riechmann et al., Nature, 1988, 332:323- 329; and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0059] 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 sourcethat 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.

[0060] An “isolated antibody” is one that has been separated and / or recovered from a component of its natural environment. Components of the natural environment may include enzymes, hormones, and other proteinaceous or nonproteinaceous materials. In some embodiments, an isolated antibody is purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence, for example by use of a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or nonreducing conditions, with detection by Coomassie blue or silver stain. An isolated antibody includes an antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is not present. In some aspects, an isolated antibody is prepared by at least one purification step.

[0061] In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by weight. In some embodiments, an isolated antibody is purified to at least 80%, 85%, 90%, 95%, or 99% by volume. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by weight. In some embodiments, an isolated antibody is provided as a solution comprising at least 85%, 90%, 95%, 98%, 99% to 100% by volume.

[0062] “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.

[0063] 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 acontrol 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.

[0064] 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 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.

[0065] The term “amino acid” or “amino acid residue” refers to a D- or L- natural, non-natural amino acid, or modified amino acid. In one embodiment, the term “amino acid” refers to a “natural amino acid” or one of the twenty common naturally occurring amino acids. Naturally occurring amino acids or “natural amino acids” include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gin; Q), Glycine (Gly; G); histidine (His; H), isoleucine (He; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Vai; V), and the less common 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.

[0066] The term “non-natural amino acid” (or “unnatural amino acid”) or “synthetic amino acids” are α, β, γ, or δ amino acids, includes but is not limited to, a derivative of an amino acid 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 (Om), norleucine (Nle), 3 -nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, and methionine sulfone.

[0067] In one embodiment, he “non-natural amino acid” or “modified amino acid” is an 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, 0-4- allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-A benzoyl-L-phenylalanine, p-iodo- phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine. The terms “non-natural amino acids” and “modified amino acids” are used herein interchangeably.

[0068] The term “conjugate” or “antibody conjugate” refers to an antibody linked to one or more payload moieties. The antibody can be any antibody described herein. The payload can be any payload 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” refers to a conjugate wherein at least one payload is a therapeutic moiety such as a drug. A “dual payload antibody conjugate” is an antibody conjugate wherein the antibody is linked to two different payloads. In certain embodiments described herein, the dual payload antibody conjugates comprise two different cytotoxicagents. In certain embodiments, the dual payload antibody conjugate is an “immunomodulatory antibody drug conjugate” or “iADC” wherein the antibody is linked, directly or indirectly via a linker, to at least one immunomodulatory agent, including, but not limited to a STING agonist or a TLR7 agonist, and at least one cytotoxic agent.

[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 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.

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

[0076] “pAcF’ or “pAcPhe” mutation refers to a variant phenylalanine residue, i.e., p-acetyl- 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 topoisomerase inhibitors, tubulin inhibitors and DDR inhibitors described herein.

[0078] A “topoisomerase inhibitor” is any compound that interferes with the topoisomerase I (Topi) or the topoisomerase II (Top2) enzyme to inhibit the religation step during the unwinding of DNA. Topoisomerase inhibitors are divided in two classes: topoisomerase I inhibitors, which include, but are not limited to, camptothecin and its derivatives (for example, topotecan, irinotecan, rubitecan, exatecan, Gly-exatecan, belotecan, and 7-ethyl-10- hydroxycamptothecin (SN-38)) and topoisomerase II inhibitors, which include, but are not limited to, etoposide, teniposide, doxorubicin, idarubicin, epirubicin, and mitoxantrone.

[0079] A “DNA Damage Response (DDR) inhibitor” is any compound that inhibits the repair of single-stranded (SSB) and / or double-stranded (DSB) DNA breaks. In response to DNA damage, cancerous cells will often activate the DDR pathway, or in response to a defective DDR pathway, cancerous cells will become overly reliant on a different DDR pathway. For this reason, DDR inhibitors are widely used as anti-cancer agents. DDR inhibitors include, but are not limited to, PARP1 inhibitors, ATR-inhibitors, ATM-inhibitors, and CHKl / 2-inhibitors.

[0080] The terms “synergy” or “synergism” refers to the interaction of two of more drugs wherein the total effect of the two drugs is greater than the additive effect of each individual drug.

[0081] 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. A “branched linker” includes any suitable linker as would be appreciated by a person of skill in the art that further includes chemical functionality that enables chemical bonding to two or more payloads. Such linkers include, without limitation, trivalent chemical functionality such as carbon (e.g., methine carbon), wherein represents the attachment to the rest of the linker, and thelike.

[0082] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0083] "Triple negative breast cancer” (TNBC) refers to a breast cancer characterized as estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative (HER2-negative). The TNBC can be BRCA1 / 2 wildtype or BRCA1 / 2 mutated. The determination of negative status of the estrogen, progesterone, and Her2 / neu expression is readily determined by one of skill in the art, e.g., in accordance with the current accepted guidelines. For example, guidelines set forth by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) are widely accepted. The ASCO / CAP recommends testing by immunohistochemistry (IHC) or in situ hybridization (ISH) techniques. Further, a cancer is Her2 negative if a single test (or all tests)performed on a tumor specimen show: (a) IHC negative, IHC 1+ or IHC 0, or (b) ISH negative using single-probe ISH or dual-probe ISH. One of skill in the art would recognize that the triple negative cancer described herein does not include any cancer having an apparent histopathologic discordance as observed by the pathologist. Wolff, A C et al. J Clin Oncol. 2013 Nov. l:31(31):3997-4013. Cancer is ER-negative or PR-negative if <1% of tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PR (positive intrinsic controls are seen).

[0084] “PARP inhibitor-resistant” refers to the reduced effectiveness of PARP inhibitors in treating, curing, or improving triple negative breast cancer in a subject. In certain embodiments, the PARP inhibitor-resistance develops with prolonged exposure to one or more PARP inhibitors.

[0085] As used herein, EC50refers 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.

[0086] As used herein, IC50refers 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.

[0087] As used herein, 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 certain embodiments, the subject is refractory or non-responsive to current treatments for hepatitis C infection. 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.

[0088] As used herein, the terms “therapeutic agent,” “therapeutic agents,” “therapeutic moiety” or “therapeutic moieties” 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” or “therapeutic moiety” includes a compound and / or an antibody conjugate provided herein. In certain embodiments, a therapeutic agent or therapeutic moiety 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.

[0089] As used herein, the term “therapeutically effective amount” or “effective amount” refers to an amount of an antibody or composition that when administered to a subject iseffective 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.

[0090] “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.

[0091] As used herein, 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 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 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.

[0092] As used herein, 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 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.

[0093] As used herein, 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 effects) of another therapy (e.g., another prophylactic agent).

[0094] 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., Ci to Cio alkyl. The term includes both substituted and unsubstituted alkyl groups, including halogenated alkyl groups. In some or any embodiments, the alkyl is unsubstituted. In some or any embodiments, the alkyl is substituted. In certain embodiments, the alkyl group is a fluorinated alkyl group. Non-limiting examples of moieties with which the alkyl group can be substituted are selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. In certain embodiments, the alkyl group is selected from the group consisting of methyl, CF3, CCI3, CFCh, CF2CI, ethyl, CH2CF3, CF2CF3, propyl, isopropyl, butyl, isobutyl, secbutyl, / -butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

[0095] The term “lower alkyl,” as used herein, and unless otherwise specified, refers to a saturated straight or branched hydrocarbon having one to six carbon atoms, i.e., Ci to Ce alkyl. In certain embodiments, the lower alkyl group is a primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted moieties.

[0096] 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.

[0097] The term “alkenyl,” as used herein, 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.

[0098] The term “alkenylene,” as used herein, refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C2-C6-alkenylene.

[0099] The term “alkynyl,” as used herein, 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 (-CΞCH), propargyl (-CH2OCH), and the like. “Substituted alkynyl” refers to an alkynyl group substituted as described herein for alkyl.

[0100] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6 alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term “Cx-y alkylene” refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example, “-C1-6 alkylene-” may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted. The terms “C^-alkenyl” and “Cx-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term “-Cx-yalkenylene-” refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, “-C2-6alkenylene-” may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term “-Cx-valkynylene-” refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, “-C2-6alkenylene-” may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0101] 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 selected from the group consisting of halogen (fluoro, chloro, bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphoric acid, phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

[0102] The term “arylene,” as used herein, and unless otherwise specified refers to a divalent aryl group, as defined herein.

[0103] “Alkoxy” and “alkoxyl,” refer to the group -OR' where R' is alkyl or cycloalkyl. Alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0104] “Aryloxy,” refer to the group -OR' where R' is aryl. Aryloxy groups include, by way of example, phenoxy.

[0105] "Arylalkyl” refers to an alkyl group as described herein substituted with one or two aryl groups as described herein.

[0106] “Alkoxycarbonyl” refers to a radical -C(O)-alkoxy where alkoxy is as defined herein.

[0107] “Amino” refers to the radical -NH2.

[0108] The term “alkylamino,” as used herein, and unless otherwise specified, refers to the group -NHR' where R' is Ci-ioalkyl, as defined herein. In some or any embodiments, the alkylamino is Ci-ealkylamino.

[0109] The term “dialkylamino,” as used herein, and unless otherwise specified, refers to the group -NRR' where each R' is independently Ci-ioalkyl, as defined herein. In some or any embodiments, the dialkylamino is di-Ci-ealkylamino.

[0110] 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.[oni] “Carboxyl” or “carboxy” refers to the radical -C(O)OH.

[0112] The term “cycloalkyl,” as used herein, unless otherwise specified, refers to a saturated cyclic hydrocarbon. In certain embodiments, the cycloalkyl group may be a saturated, and / or bridged, and / or non-bridged, and / or a fused bicyclic group. In certain embodiments, the cycloalkyl group includes three to ten carbon atoms, i.e., C3 to C10 cycloalkyl. In some embodiments, the cycloalkyl has from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3- 7) carbon atoms. In certain embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl.

[0113] The term “carbocycle” as used herein, unless otherwise specified, refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is 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 some embodiments, carbocycle includes 3- to 10-membered monocyclic rings, 6-to 12-membered bicyclic rings, and / or 6- to 12- membered bridged rings. In some embodiments, each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, an aromatic ring, for example, phenyl, may be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, or cyclohexene. 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. In certain embodiments, the carbocycle group includes three to ten carbon atoms (i.e., C3 to C10 carbocycle). In certain embodiments, the carbocycle group includes three to twelve carbon atoms (i.e., C3 to C12 carbocycle). In some embodiments, the carbocycle has from three to fifteen carbons (C3-15), from three to twelve carbons (C3-12), from three to ten carbons (C3-10), from three to seven carbons (C3-7), or from three to six carbons (C3-C6). In certain embodiments, the carbocycle group is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, phenyl, indanyl, naphthyl, or adamantyl.

[0114] The term “heterocyclyl,” “heterocyclic,” and “heterocycle” refer to a monovalent monocyclic non-aromatic ring system and / or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms of the non-aromatic ring are carbon atoms, and wherein any aromatic ring atoms are optionally heteroatoms independently selected from O, S, and N and the remaining ring atoms of the non-aromatic ring are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, from 4 to 11, or from 5 to 6 ring atoms. Heterocyclyl groups are bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom of its non-aromatic ring whichresults in the creation of a stable compound. Heterocycloalkyl refers to a heterocycle which is a monovalent, monocyclic or multicyclic, non-aromatic ring system. In some or any embodiments, heterocycloalkyl is a monovalent, monocyclic or multicyclic, fully-saturated ring system. Examples of such heterocyclic and / or heterocycloalkyl radicals include, but are not limited to, 2,5-diazabicyclo[2.2.2]octanyl, 3,9-diazabicyclo[3.3.2]decanyl), azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β- carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted as described herein. In some or any embodiments, heterocyclic and heterocycloalkyl are substituted with 1, 2, or 3 groups independently selected from halogen (fluoro, chloro, bromo or iodo), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a hetercycloalkyl group may comprise 1, 2, 3, or 4 heteroatoms. Those of skill in the art will recognize that a 4-membered heterocycloalkyl may generally comprise 1 or 2 heteroatoms, a 5-6 membered heterocycloalkyl may generally comprise 1 or 2 heteroatoms, and a 7-10 membered heterocycloalkyl may generally comprise 1, 2, 3, or 4 heteroatoms.

[0115] The term “heteroaryl” refers to 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 O, S, and N in the ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N 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 5 to 20, from 5 to 15, or from 5 to 10 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, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. 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, isothiazolyl, 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 certain embodiments, heteroaryl may also be optionally substituted as described herein. “Substituted heteroaryl” is heteroaryl substituted as defined for aryl.

[0116] “Partially saturated heteroaryl” refers to a multicyclic (e.g., bicyclic, tricyclic) fused ring system that contains at least one non-aromatic ring and at least one aromatic ring, wherein one or more of the non-aromatic ring atoms and / or one or more of the aromatic ring atoms are heteroatoms independently selected from O, S, andN; and the remaining ring atoms are carbon atoms. Partially saturated heteroaryl groups are bonded to the rest of the molecule through the aromatic ring. In certain embodiments, the partially saturated heteroaryl group has from 6 to 20, from 6 to 15, from 6 to 10, from 6 to 8, or from 8 to 11 ring atoms. In certain embodiments, the partially saturated heteroaryl group has 8, 9, 10, or 11 ring atoms (in some embodiments 9 or 10). The partially saturated heteroaryl may be attached to the main structure at any heteroatom or carbon atom of its aromatic ring which results in the creation of a stable compound. In some or any embodiments, an oxo group may be present as a substituent on one of the ring atoms. A partially saturated heteroaryl radical consists of one of the following or comprises one or more of the following: benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, chromanyl, chromonyl, cirmolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, tetrahydropyrazinyl, dihydropyrazinonyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, furanonyl, imidazolinyl, indolinyl, tetrahydroindolyl, isoindolinyl, tetrahydroisoindolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, dihydroisoxazolyl, oxazinyl, dihydrooxazinyl, oxo-oxazolyl, dihydrooxazolyl, dihydropiperidonyl, dihydro-4-piperidonyl, dihydropyrazolyl, dihydropyrazolinyl, dihydropyrrolyl, azabicyclo[2.2.2]oct-2-enyl, dihydrofuryl, tetrahydroisoquinolinyl, dihydropyranyl, pyranyl, dihydrothienyl, oxathiazinyl, dihydrothiazolyl, tetrahydroquinolinyl, and 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl. In certain embodiments, the partially saturated heteroaryl radical is benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, chromanyl, chromonyl, coumarinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydroisoindolyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, or 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazinyl. In certain embodiments, partially saturated heteroaryl may also be optionally substituted as described herein.

[0117] Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkoxycarbonyl; alkyl; cycloalkyl, alkenyl; alkynyl, alkoxy; aryloxy such as phenoxy, alkylamino; aryl; arylalkyl; or a heterocyclic group as described herein. In certain embodiments “optionally substituted” includes one or more substituents independently selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. When a group described herein is optionally substituted, the optional substituent bonded to the group is unsubstituted unless specified otherwise.

[0118] The term “protecting group” as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

[0119] “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 counterions 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-l- carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, fert-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, TV-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0120] 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, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4- hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), eetthhaanneessuullffoonnaattee,, 1,2-ethane-disulfonate, 2 -hydroxyethanesulfonate, benzenesulfonate ((bbeessyyllaattee)),, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4- toluenesulfonate, ccaammpphhoorraattee,, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-l- carboxylate, glucoheptonate, 3 -phenylpropionate, trimethylacetate, fert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like.

[0121] 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 thatcompound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers.

[0122] 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.

[0123] “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.

[0124] “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.

[0125] “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 conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0126] “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.

[0127] 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.

[0128] 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.

[0129] In some chemical structures illustrated herein, certain substituents, chemical groups, and atoms are depicted with a curvy / wavy line (e.g., A) 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 fragment as well as the atoms in the backbone of a conjugate or linker-payload structure to which the illustrated chemical entity is bonded.

[0130] 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 RT and RAis described generically, i.e., not directly attached to any vertex ofthe bond line structure, i.e., specific ring carbon atom, includes the following, non-limiting examples of groups in which the substituent RAand RT is bonded to a specific ring carbon atom:

[0131] Conjugates

[0132] Provided herein are antibody conjugates, including antibody drug conjugates, that comprise an antibody, or antigen binding fragment thereof, wherein the antibody, or antigen binding fragment thereof, is covalently linked to greater than eight payload moieties. The conjugates comprise an antibody or antigen-binding fragment thereof recognizing a suitable antigen covalently linked, optionally via linkers, to payloads. In certain embodiments, the increased payload to antibody ratios of the conjugates provide greater payload delivery to targets and / or reduced toxicity to patients. When the payloads are drugs, the payload toantibody ratio is the drug to antibody ratio, or DAR, familiar to those of skill in the art. To achieve the high payload to antibody ratios, the antibody drug conjugates comprise antibodies with one or more non-natural amino acids at specific sites in the antibody chains and / or linkers that link the antibody to more than one payload. In certain embodiments, the antibody conjugate comprises more than one payload and each payload is different. In alternative embodiments, the antibody conjugate comprises more than one payload and each payload is the same. Similarly, in certain embodiments, the antibody conjugate comprises more than one linker and each linker is different, and in alternative embodiments, the antibody conjugate comprises more than one linker and each linker is the same.

[0133] In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 8. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 10. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 12. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 14. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 16. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 18. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 20. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 22. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 26. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 28. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of about 30.

[0134] In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of more than 8. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 10. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 12. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 14. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 16. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 18. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 20. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 22. In certain embodiments, the antibody drug conjugates comprise a payload toantibody ratio of at least 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of up to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 26. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 28. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 30. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of up to 30.

[0135] In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 10 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 12 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 14 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 16 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 18 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 20 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 22 to 24. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 24 to 30. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of greater than 24.

[0136] In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of more than 8:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 10: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 12: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 14:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 16:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 18:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 20: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 22:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 24: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 26:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 28:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of at least 30:1.

[0137] In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 10: 1 to 24: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 12:1 to 24:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 14: 1 to 24: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 16:1 to 24:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 18:1 to 24:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 20:1 to 24:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 22: 1 to 24: 1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of 24:1 to 30:1. In certain embodiments, the antibody drug conjugates comprise a payload to antibody ratio of greater than 24: 1.

[0138] In certain embodiments, the antibody, or antigen binding fragment thereof, comprises one or more non-natural amino acid residues. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 1 to 8 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 1 to 7 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 4 to 6 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 6 to 8 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 8 to 10 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 10 to 12 non- natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 12 to 14 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 1 non-natural amino acid. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 2 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 3 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 4 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 5 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 6 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 7 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 8 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 10 non-natural amino acids. In certain embodiments, the antibody,or antigen binding fragment thereof, comprises 12 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises 14 non-natural amino acids. In certain embodiments, the antibody, or antigen binding fragment thereof, comprises these non-natural amino acids and no further non-natural amino acids. Useful non- natural amino acids are described herein. In certain embodiments, at least one of the non- natural amino acids is selected from p-azidomethyl-L-phenylalanine (pAMF), p-azido-L- phenylalanine (pAzF), and p-acetyl-L-phenylalanine (pAcF).

[0139] In particular embodiments, the non-natural amino acids are linked to payloads or linker payloads. In certain embodiments, one or more natural amino acids of the antibody, or antigen binding fragment, are also linked to a payload or linker payload. Exemplary natural amino acids for linking include cysteine residues, glutamine residues, lysine residues, and aminoterminal residues. Useful payloads, linkers, and linker payloads are described herein. In certain embodiments, the payloads are selected from immunomodulatory agents, alkylating agents, DNA-crosslinking agents, anti-tumor antibiotics, anti-metabolites, anti-mitotic agents, DNA damage response (DDR) inhibitors, histone-deacetylase (HDAC) inhibitors, telomerase inhibitors, immunogenic cell death agents, tubulin inhibitors, and topoisomerase inhibitors.

[0140] In some embodiments, the antibody conjugate 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 the antibody or antigen-binding fragment thereof; each L* is a linker; each PAY is a payload; subscript n is an integer selected from 2 to 30, and in certain embodiments n is an integer selected from 2 to 24; and wherein each L* is the same or different, and wherein each PAY is the same or different. In the formula, each L* can be the same or different. Useful linkers are described herein, each PAY can be the same or different. Useful payloads are described herein. The integer n is selected so that the antibody conjugate has a payload to antibody ratio greater than 8, as described herein.

[0141] Linkers

[0142] The linkers can be any linkers capable of forming at least one bond to the antibody and at least one bond to a payload. The linkers can have the same structure, or the linkers can have different structures. In some embodiments, including any of the foregoing, linkers are selected from cleavable linkers, an enzyme cleavable linkers, pH-sensitive linkers, and non-cleavablelinkers. In some embodiments, the linkers comprise a β-glucuronidase-cleavable β- glucuronide. In some embodiments, the linkers comprise a cathepsin cleavable linker.

[0143] The linkers can be straight or branched. In some embodiments, including any of the foregoing, at least one of the linkers of the antibody conjugate is straight. In some embodiments, including any of the foregoing, at least one of the linkers of the antibody conjugate is branched. In some embodiments, the antibody conjugate comprises at least one straight linker and at least one branched linker.

[0144] Usefill linkers include those described herein. In certain embodiments, each linker is independently any divalent or multivalent linker known to those of skill in the art. Usefill divalent linkers include alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarlyene, and substituted heteroarylene. In certain embodiments, the first and / or second linker is Ci-io alkylene or Ci-io heteroalkylene. In some embodiments, the Ci-ioheteoalkylene is PEG.

[0145] In certain embodiments, at least one of the linkers is hydrolytically stable. Hydrolytically stable linkages means that the linkages are substantially stable in water and do not react with water at useful pH values, including but not limited to, under physiological conditions for an extended period of time, perhaps even indefinitely. In certain embodiments, the first and / or second linker is hydrolytically unstable. Hydrolytically unstable or degradable linkages mean that the linkages are degradable in water or in aqueous solutions, including for example, blood. Enzymatically unstable or degradable linkages mean that the linkage can be degraded by one or more enzymes.

[0146] As understood in the art, PEG and related polymers may include degradable linkages in the polymer backbone or in the linker group between the polymer backbone and one or more of the terminal functional groups of the polymer molecule. For example, ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a biologically active agent generally hydrolyze under physiological conditions to release the agent.

[0147] Other hydrolytically degradable linkages include, but are not limited to, carbonate linkages; imine linkages resulted from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; hydrazone linkages which are reaction product of a hydrazide and an aldehyde; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; peptide linkages formed by an amine group, including but not limited to, at anend of a polymer such as PEG, and a carboxyl group of a peptide; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.

[0148] A number of different cleavable linkers are known to those of skill in the art. See U.S.Pat. Nos. 4,618,492; 4,542,225, and 4,625,014. The mechanisms for release of an agent from these linker groups include, for example, irradiation of a photolabile bond and acid-catalyzed hydrolysis. U.S. Pat. No. 4,671,958, for example, includes a description of immunoconjugates comprising linkers which are cleaved at the target site in vivo by the proteolytic enzymes of the patient's complement system. The length of the linker may be predetermined or selected depending upon a desired spatial relationship between the polypeptide and the molecule linked to it. In view of the large number of methods that have been reported for attaching a variety of radiodiagnostic compounds, radiotherapeutic compounds, drugs, toxins, and other agents to polypeptides one skilled in the art will be able to determine a suitable method for attaching a given agent to a polypeptide.

[0149] The linkers described herein may have a wide range of molecular weight or molecular length. Larger or smaller molecular weight linkers may be used to provide a desired spatial relationship or conformation between the polypeptide and the linked entity. Linkers having longer or shorter molecular length may also be used to provide a desired space or flexibility between the polypeptide and the linked entity. Similarly, a linker having a particular shape or conformation may be utilized to impart a particular shape or conformation to the polypeptide or the linked entity, either before or after the polypeptide reaches its target. The functional groups present on each end of the linker may be selected to modulate the release of a polypeptide or a payload under desired conditions. This optimization of the spatial relationship between the polypeptide and the linked entity may provide new, modulated, or desired properties to the molecule.

[0150] In some embodiments, provided herein are water-soluble bifunctional linkers that have a dumbbell structure that includes: a) an azide, an alkyne, a hydrazine, a hydrazide, a hydroxylamine, or a carbonyl-containing moiety on at least a first end of a polymer backbone; and b) at least a second functional group on a second end of the polymer backbone. The second functional group can be the same or different as the first functional group. The second functional group, in some embodiments, is not reactive with the first functional group. In some embodiments, water-soluble compounds that comprise at least one arm of a branched molecularstructure are provided. For example, the branched molecular structure can be a dendritic structure.

[0151] In some embodiments, the first and / or second linker is independently derived from a linker precursor selected from the group consisting of: N-succinimidyl-3-(2- pyridyldithio)propionate (SPDP), N-succinimidyl 4-(2-pyridyldithio)pentanoate (SPP), N- succinimidyl 4-(2-pyridyldithio)butanoate (SPDB), N-succinimidyl-4-(2-pyridyldithio)-2- sulfo-butanoate (sulfo-SPDB), N-succinimidyl iodoacetate (SIA), N-succinimidyl(4- iodoacetyl)aminobenzoate (STAB), maleimide PEG NHS, N-succinimidyl 4- (maleimidomethyl)cyclohexanecarboxylate (SMCC), N-sulfosuccinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (sulfo-SMCC) or 2,5-dioxopyrrolidin-l-yl 17- (2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)-5,8,ll,14-tetraoxo-4,7,10,13-tetraazaheptadecan-l- oate (CX1-1). In a specific embodiment, the linker is derived from the linker precursor N- succinimidyl 4-(maleimidomethyl)cyclohexanecarboxylate (SMCC).

[0152] In some embodiments, at least one of the linkers is derived from a linker precursor selected from the group consisting of dipeptides, tripeptides, tetrapeptides, and pentapeptides. In such embodiments, the linker can be cleaved by a protease. Exemplary dipeptides include, but are not limited to, valine-citrulline (vc or val-cit), alanine-phenylalanine (af or ala-phe); phenylalanine-lysine (fk or phe-lys); phenylalanine-homolysine (phe-homolys); andN-methyl- valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are not limited to, glycine- valine-citrulline (gly-val-cit), glycine-glycine-glycine (gly-gly-gly), and glycine- methoxyethoxyethyl)serine-valine (gly-val-citalanine OMESerValAla).

[0153] In some embodiments, at least one of the linkers comprises a self-immolative spacer. In certain embodiments, the self-immolative spacer comprises p -ami nobenzyl. In some embodiments, a p-aminobenzyl alcohol is attached to an amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the benzyl alcohol and the payload (Hamann et al. (2005) Expert Opin. Then Patents (2005) 15:1087-1103). In some embodiments, the linker comprises p-aminobenzyloxycarbonyl (PAB). Other examples of self- immolative spacers include, but are not limited to, aromatic compounds that are electronically similar to the PAB group, such as 2-aminoimidazol-5-methanol derivatives (U.S. Pat. No. 7,375,078; Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho- or paraaminobenzylacetals. In some embodiments, spacers can be used that undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al. (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1]and bicyclo[2.2.2] ring systems (Storm et al. (1972) J. Amer. Chem. Soo. 94:5815) and 2-aminophenylpropionic acid amides (Amsberry, et al. (1990) J. Org. Chem. 55:5867). Linkage of a drug to the a-carbon of a glycine residue is another example of a self-immolative spacer that may be useful in conjugates (Kingsbury et al. (1984) J. Med. Chem. 27: 1447).

[0154] In certain embodiments, linker precursors can be combined to form larger linkers. For instance, in certain embodiments, linkers comprise the dipeptide valine-citrulline and p-aminobenzyloxycarbonyl. These are also referenced as citValCit-PAB linkers.

[0155] Conjugates

[0156] In some embodiments, the antibody conjugate is of Formula I:Formula (I)or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab is the antibody, or antigen-binding fragment thereof; each L* is a linker; each PAY is a payload; and subscript n is an integer selected from 2 to 30, and in certain embodiments, n is an integer selected from 20 to 24; wherein each L* is the same or different, and wherein each PAY is the same or different.

[0157] In some embodiments of Formula (I), including any of the foregoing, linkers L* independently comprise a protease cleavable linker, an enzyme cleavable linker, a pH-sensitive linker, or a non-cleavable linker. In some embodiments, linkers L* independently comprise a β-glucuronidase-cleavable β-glucuronide. In some embodiments, linkers L* independently comprise a cathepsin cleavable linker. In some embodiments, Formula I comprises two Ll-PAY moieties and the two linkers (Ll) are different.

[0158] In certain embodiments, the antibody conjugate of Formula (I) is represented by Formula (la-1), (la-2), or (la-3), or a combination thereof:Formula (la-1)Formula (la-2)Formula (la-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is the same or different; each n is an integer selected from 2 to 30; each m is an integer selected from 2 to 30; each SP1, SP2, and SP3is independently, at each occurrence, absent or a divalent spacer group; each W1is independently, at each occurrence, absent, wherein the -NH- is boundto W2and each indicates a point of attachment to the rest of the formula; each W2is independently, at each occurrence, absent, CH2, CH, NH, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP2group; each HP1, is independently, at each occurrence, absent or a divalent hydrophilic group; each HP2, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, optionally substituted Ci-ealkyl wherein the Ci-ealkyl is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy; each RT is independently, at each occurrence, absent or a release trigger group; each RL is a reactive linker residue;y is an integer independently selected from 0, 1, and 2; and z is an integer independently selected from 0 and 1.

[0159] In certain embodiments, each n is an integer selected from 2 to 24 and each m is an integer selected from 2 to 24.

[0160] In certain embodiments, the antibody conjugate of Formula (I) is represented by Formula (Ib-1), (Ib-2), or (Ib-3), or a combination thereof:Formula (Ib-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is independently, at each occurrence, a payload residue and is the same or different;L2is -Ci-6 alkylene- optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(0)-, -C(S)-, -C(OX)CH2C6H5, -NHC(OX)CH2C6H5, CI-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; each Y* is, independently, at each occurrence, -X^i-e alkylene-P^-Ci-e alkylene]a-[X1]b-, -X^M alkenylene-[X1-C2-6 alkenylene]a-[X1]b-, or-X1-C2-6 alkynylene-fX1^^ alkynyleneJa-P^Jb-, wherein at least one alkylene, alkenylene, or alkynylene in Y* is substituted with one or more substituents independently selected from R50, and wherein the alkylene, alkenylene, or alkynylene in Yais optionally substituted with one or more substituents independently selected from R51;R50is -C1-6 alkylene-X^Ci-e alkylene]c-HP2, -C2-6 alkenylene-X2-[C2-6 alkenylene]c- HP2, or -C2-6 alkynylene-X2-[C2-6 alkynylene]c- HP2, wherein each alkylene, alkenylene, or alkynylene of R50is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -NjR10)^ - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6HS, CI-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;R51is independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2- 10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; a is an integer selected from zero, one, two, and three; b is an integer selected from zero and one; c is an integer selected from zero and one;Su is a hexose form of a monosaccharide;X is -C1-C10 alkylene-X1-, -X^Ci-Cio alkylene-X1-, -C1-C10 alkylene-X1-R2-, -X^i.Cio alkylene-X1-R2-, -X^Ci-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene- X1-, -[POLY]-Ci-Cio alkylene-X1-, -C2-C10 alkenylene-X1-, -X1-C2-Cio alkenylene-X1- , -C2-C10 alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1- R2-X1-[POLY]-C2-CIO alkenylene-X1-, -[POLY]-C2-CIO alkenylene-X1-, -C2-C10 alkynylene-X1-, -X1-C2-Cio alkynylene-X1-, -C2-C10 alkynylene-X1-R2-, -X1-C2-Cio alkynylene-X^R2-, or -X1-C2-Cio alkynylene-X1-R2-X1-[POLY]-C2-CIO alkynylene- X1-, or -[POLY]-C2-CIO alkynylene-X1-, wherein the alkylene, alkenylene, or alkynylene of X is optionally substituted with one or more substituents independentlyselected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6Hs, - NHC(O)OCH2C6HS, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and Ci-iohaloalkyl; each X1is independently selected from -NQt1)-, -C(O)-, and -C^NfR1)-; each Y** is independently -[POLY]-CI-C6 alkylene- Y1-,-[POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-,-[POLY]-CI-C6alkylene-Y1-R2-Y1-Ci-C6alkylene-Y1--[POLY]-C2-C6 alkenylene- Y1-, -[POLYJ-C2-C6 alkenylene- Y1-C2-Ce alkenylene- Y1-, -[POLY]-C2-C6 alkenylene-Y1-R2-Y1-C2-C6 alkenylene- Y1-, -[POLY]-C2-C6 alkynylene-Y1-, -[POLYJ-C2-C6 alkynylene-Y1-C2-C6 alkynylene-Y1-, -[POLY]-C2-C6 alkynylene-Y1-R2-Y1-C2-C6 alkynylene-Y1-, wherein the alkylene, alkenylene, or alkynylene of Ybis optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, - C(O)OCH2C6HS, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-iohaloalkyl; each Y1is independently selected from -N(R10)-, -C(O)-, and -C(O)N(R10)-; each Z is independently -C1-C10 alkylene-; each R10is independently hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, or Ci-2ohaloalkyl;R2iswherein each R3is independently an amino acid side chain or a non-amino acid side chain; each POLY is a divalent water-soluble polymer; aa is an integer from one to five;RL is a reactive linker residue; andL2is -C1-6 alkylene- optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0161] In certain embodiments, Formula (Ib-1), (Ib-2), or (Ib-3) are represented by:Formula (Ib-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is independently, at each occurrence, a payload residue; each Y* is, independently, at each occurrence, -X^i-e alkylene-P^-Ci-e alkylene]a-[X1]b-, -X1-C2-6 alkenylene-[X1-C2-6 alkenylene]a-[X1]b-, or-X1-C2-6 alkynylene-[X1-C2-6 alkynyleneja-pc^b-, wherein at least one alkylene, alkenylene, or alkynylene in Y is substituted with one or more substituents selected from R50, and wherein the alkylene, alkenylene, or alkynylene in Y is optionally substituted with one or more substituents selected from R51;R50is -Ci-6 alkylene-X^Ci-e alkylene]c-HP2, -C2-6 alkenylene-X2-[C2-6 alkenylene]c- HP2, or -C2-6 alkynylene-X2-[C2-6 alkynylene]c- HP2, wherein each alkylene, alkenylene, or alkynylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-,-C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;R51is independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2. 10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; a is an integer selected from zero, one, two, and three; b is an integer selected from zero and one; c is an integer selected from zero and one; Su is a hexose form of a monosaccharide;X is -C1-C10 alkylene-X1-, -X^i-Cio alkylene-X1-, -C1-C10 alkylene-X1-R2-, -X^i.Cio alkylene-X^R2-, -X^i-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene- X1-, -C2-C10 alkenylene-X1-, -X1-C2-Cio alkenylene-X1-, -C2-C10 alkenylene-X1^2-, -X1-C2-Cio alkenylene-X^R2-, -XMkCio alkenylene-X1-R2-X1-[POLY]-C2-Cio alkenylene-X1-, -C2-C10 alkynylene-X1-, -X1-C2-Cio alkynylene-X1-, -C2-C10 alkynylene-X1^2-, -X1-C2-Cio alkynylene-X1-R2-, or -X1-C2-Cio alkynylene-X1-R2- X1-[POLY]-C2-CIO alkynylene-X1-, wherein the alkylene, alkenylene, or alkynylene of X is optionally substituted with one or more substituents selected from halogen, - CN, -NO2, -OH, -NCR10^, -C(O)N(R10)2, -C(O)OCH2C6HS, -NHC(OK>CH2C6H5, CI. 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-10 haloalkyl; each X1is independently selected from -NQt1)-, -C(O)-, and -C^NfR1)-; each Ybis independently -[POLY]-CI-C6 alkylene- Y1-, -[POLY]-CI-C6 alkylene- Y1-CI-C6 alkylene- Y1-,[POLYJ-Ci-Ce alkylene- Y1-R2-Y1-Ci-C6alkylene-Y1-, -[POLY]-C2-C6 alkenylene- Y1-, -[POLY]-C2-C6 alkenylene- Y1-C2-Ce alkenylene-Y1-, -[POLY]-C2-Ce alkenylene- Y1-R2-Y1-C2-C6 alkenylene- Y1-,-[POLY]-C2-C6 alkynylene- Y1-, -[POLY]-C2-C6 alkynylene- Y1-C2-Ce alkynylene-Y1-, -[POLY]-C2-Ce alkynylene- Y1-R2-Y1-C2-C6 alkynylene-Y1-, wherein the alkylene, alkenylene, or alkynylene of Y is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NfR10^, -C(O)N(R10)2, -C(O)OCH2C6Hs, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle,3- to 12-membered heterocycle, and C1-10 haloalkyl;each Y1is independently selected from -N(R10)-, -C(O)-, and -C(O)N(R10)-; each Z is independently -C1-C10 alkylene-; each R10is independently hydrogen, Ci-2o alkyl, C2.2o alkenyl, C2.2o alkynyl,€3-12 caibocycle, 3- to 12-membered heterocycle, or Ci-2o haloalkyl;R2is whereineach R3is independently an amino acid side chain or a non-amino acid side chain; each POLY is a divalent water-soluble polymer; aa is an integer from one to five;RL is a reactive linker residue; andL2is -Ci-6 alkylene- optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, - C(S)-, -C(OX)CH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-io alkenyl, CMO alkynyl, €3-12 caibocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0162] Also disclosed herein are dual payload antibody conjugates of Formula (Ic-1) and (Ic-2)Formula (Ic-1)Formula (Ic-2) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein Ab, RL, X, Ya, Y**, Z, L2, SP1, SP2, SP3, HP1, W1, W2, Su, PAY, m and n are independently as defined herein.

[0163] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), Formula (Ib- 1), Formula (Ib-2), or Formula (Ib-3), each PAY is the same. In one embodiment, each PAY is different.

[0164] In certain embodiments, SP2and SP3are divalent attaching groups that facilitate incorporation of eliminator groups, release trigger groups, hydrophobic groups, spacer 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 group can also stabilize the conjugating group and lead to improved overall antibody-drug conjugate properties. Usefill attaching groups are known to, and are apparent to, those of skill in the art. Examples of useful attaching groups are provided herein. In certain embodiments, an attaching 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 an attaching 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.

[0165] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), SP1and SP3are independently absent or selected from Ci-ealkylene-; -C(O)-, Ci- 6alkylene-C(O)- wherein the -C(O)- is bound to W2or HP1, respectively; -C(O)-Ci-6alkylene- C(O)-; -CCOXCi-galkylenejNR^CO)-; -C(O)(Ci-6alkylene)OC(O)-; and -C(OXCi- 6alkylene)SC(O)-; wherein R1is hydrogen or optionally substituted Ci-ealkyl and the Ci-ealkylene, alone or part of another group, is optionally substituted with one, two, or three substituents selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy.

[0166] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)- wherein the -C(O)- is bound to W2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently Ci- 6alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently Ci-2alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently C3-4alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently Cs-6alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently -CH2-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently -CH2CH2-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently - (CH2)S-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is absent.

[0167] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP3is independently absent or -C(O)-Ci-6alkylene-C(O)- . In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic- 2), including any of the foregoing, SP3is absent. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP3is independently -C(O)-Ci-6alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP3is independently -C(O)-Ci-4alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP3is independently -C(O)-C4alkylene-C(O)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP3is independently -C(O)(Ci-6alkylene)NR1C(O)- wherein R1is hydrogen.

[0168] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), and including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)-and SP3is independently absent or -C(O)-Ci-6alkylene-C(O)- wherein the -C(O)- of SP2is bound to W2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently absent or Ci-ealkylene- C(O)- and SP3is absent wherein the -C(O)- of SP2is bound to W2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)- wherein the -C(O)- of SP2is bound to W2; SP3is independently absent or -C(O)-Ci-6alkylene-C(O)-; and SP1is absent.

[0169] In certain embodiments, SP1is a divalent attaching group that facilitates incorporation and the release of the payload. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is independently absent or selected from -NR5CH2- and -NR4-arylene-CH2- wherein R5is Ci-ealkyl-OClfc and R4is hydrogen or Ci-6 alkyl.

[0170] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is absent. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is independently -NR5CH2- In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is -N(CH2CH2OCH3)CH2- In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is independently -NR4-arylene-CH2- In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is independently -NH-arylene-CH2- In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP1is ; and each is the point of attachment to the rest of thecompound.

[0171] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)- wherein the -C(O)- of SP2is bound to W2and SP1is absent. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)- wherein the -C(O)- of SP2is bound to W2and SP1is independently selected from -NR5CH2- and -NR4-arylene-CH2-

[0172] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is C2alkylene-C(O)- and SP1is - N(CH2CH2OCH3)CH2- wherein the -C(O)- of SP2is bound to W2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, SP2is C2alkylene-C(O)- and SP1is wherein the -C(O)- of SP2is bound to W2.

[0173] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, SP2is independently absent or Ci-6alkylene-C(O)- wherein the -C(O)- of SP2is bound to W2; SP3is independently absent or -C(O)-Ci-6alkylene- C(O)-; and SP1is independently absent or is selected from -NR5CH2- and -NR4-arylene-CH2-

[0174] In certain embodiments, W1is an eliminator group. 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 biologically active moiety, and forms a stable, non-toxic entity that has no further effect on the activity of the biologically active moiety.

[0175] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W1is independently

[0176] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, z is 0. In certain embodiments of Formula (la-1),Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, z is 1. When z is 1, the conjugate comprises a release trigger group, designated as RT 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 tumornontumor specificity, such as the proteolytic action of an enzyme overexpressed in a tumor environment.

[0177] Hydrophilic groups, designated HP1and 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 biological systems. Hydrophilic groups can also function as spacer groups, which are described in further detail herein. Useful hydrophilic groups include those described herein. In certain embodiments, HP1is independently a divalent poly(ethylene glycol). In certain embodiments of Formula (la-1), Formula (la-2), and Formula (la-3), including any of the foregoing, HP1is independentlywherein R2is hydrogen or methyl and xl is an integer between1 and 50, inclusive; and each is the point of attachment to the rest of the compound. Incertain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, R2is hydrogen. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, R2is methyl.

[0178] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, xl is independently an integer between 1 and 10, inclusive. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, xl is independently an integer between 1 and 5, inclusive. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, xl is 4.

[0179] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, xl is independently an integer between 1 and 10, inclusive, and R2is hydrogen. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, xl is independently an integer between 1 and 5, inclusive, and R2is hydrogen. In certain embodiments of Formula (la- 1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, xl is 4 and R2is hydrogen.

[0180] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, HP1is absent.

[0181] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, RT is a β-glucuronidase-cleavable β-glucuronide. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, RT iswherein is the point ofattachment to the rest of the compound. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, RT is

[0182] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W1is independently. certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is independently. in certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, y is 0. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, y is 1. In certain embodiments ofFormula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, y is 2.

[0183] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, L1is independently a bond. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, L1is independently unsubstituted Ci-ealkylene. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, L1is independently an optionally substituted Ci-ealkylene wherein the Ci-ealkylene is optionally substituted with one, two, or three substituents selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy.

[0184] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, RAis independently, at each occurrence, unsubstituted Ci-ealkyl. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, RAis independently, at each occurrence, methyl. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, RAis independently, at each occurrence, methyl and y is 1. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, RAis independently, at each occurrence, Ci- ealkyl optionally substituted with one, two, or three substituents selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy.

[0185] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W1is independently absent, , or. In certain embodiments of Formula (la-1), Formula (la-2), Formula(la-3), and Formula (Ic-2), including any of the foregoing, W1is independently absent, in certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is independently absent, certain embodiments of Formula (la-1),Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is absent. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W1is . In certain embodimentsof Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is. In certain embodiments of Formula (la-1), Formula(la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is In certain embodiments of Formula (la-1), Formula (la-2), Formula(la-3), and Formula (Ic-2), including any of the foregoing, W1isIn certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1isIn certain embodiments ofFormula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of theforegoing, W1is. In certain embodiments of Formula (la-1),Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is independently absent,, In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing,certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is certain embodiments of Formula (la-1), Formula (la-2),Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is Incertain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, certain embodiments ofFormula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is independently absent,, In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W1is independently absent,

[0186] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is absent. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is 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 of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently an unsubstituted amino acid residue. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently an amino acid residue wherein the amino acid residue is substituted with HP2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently an unsubstituted peptide residue. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently a peptide residue wherein the peptide residue is substituted with HP2.

[0187] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently a peptide residue, and the peptide residue comprises at least one non-natural amino acid. In certain embodiments of Formula (la- 1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2isindependently a peptide residue, and the peptide residue comprises one non-natural amino acid. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently a peptide residue, and the peptide residue comprises two non-natural amino acid. In certain embodiments of Formula (la-1), Formula (la- 2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently a peptide residue, and the peptide residue comprises at least one non-natural amino acid and the peptide residue is optionally substituted with HP2.

[0188] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the at least one non-natural amino acid is selected from 3 -sulfoalanine, hydroxyproline (Hyp), citrulline (Cit), ornithine (Om), norleucine (Nle), 3- nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, methionine sulfone, and 2,3-diaminopropionate. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the at least one non-natural amino acid is selected from 3 -sulfoalanine, citrulline (Cit), 2,3-diaminopropionate, and beta-alanine.

[0189] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently a peptide residue wherein the peptide residue is optionally substituted with HP2and the peptide residue comprises valine, citrulline (Cit), 3 -sulfoalanine, alanine, 2,3-diaminopropionate, or beta-alanine.

[0190] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises citrulline (Cit). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises beta-alanine. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises 2,3-diaminopropionate.

[0191] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises citrulline (Cit) and 3- sulfoalanine. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises beta-alanine and 2,3-diaminopropionate.

[0192] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises valine and citrulline (Cit). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2),including any of the foregoing, the peptide residue comprises valine, citrulline (Cit), and 3- sulfoalanine. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises valine and alanine. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises valine, citrulline (Cit), and 2,3 -diaminopropionate. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, the peptide residue comprises beta-alanine and 2,3 -diaminopropionate.

[0193] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently an amino acid residue wherein the amino acid residue is optionally substituted with HP2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently an amino acid residue and the amino acid residue is a betaamino acid. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently beta-alanine.

[0194] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W2is independently selected from

[0195] -(C(O)CHR3NR4),-, <C(O)CH2CHR3NR4)b-, -(C(O)CHR3CH2NR4)b-,-(C(O)CH2CHR3NR4)b-(C(O)CHR3NR4)a-, -(C(O)CHR3CH2NR4)b-(C(O)CHR3NR4)a-,-(C(O)CHR3NR4)a-(C(O)CH2CHR3NR4)b-, and-(C(O)CHR3NR4),-(C(O)CHR3CH2NR4)b-; wherein R3is independently an amino acid sidechain residue optionally substituted withHP2;R4is independently hydrogen or Ci-6 alkyl; each of a and b is an integer independently between 1 and 10, inclusive; and the -C(O)- of W2is bound to W1.

[0196] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CHR3NR4),-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CHR3NH),- wherein a is 1. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CHR3NH),- wherein a is 2. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), includingany of the foregoing, W2is independently -(C(O)CHR3NH),- wherein a is 3. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CHR3NR4),- and R3is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, 3 -sulfoalanine and 2,3- diaminopropionate.

[0197] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CHR3NR4)b-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CHR3NH)-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CH2NH)-.

[0198] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CHR3NR4)b- (C(O)CHR3NR4)a-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently - (C(O)CH2CHR3NH)b-(C(O)CHR3NH)a-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CH2NH)-(C(O)CHR3NH)a-. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently -(C(O)CH2CH2NH)-(C(O)CHR3NH)- wherein R3is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, 3 -sulfoalanine and 2,3- diaminopropionate.

[0199] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W2is independently of the formula:; and each is the point ofattachment to the rest of the compound.

[0200] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently of the formula:

[0201] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, W2is independently of the formula:

[0202] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, -W^-W2- is independently of the formula:

[0203] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, -W^-W2- is independently of the formula:

[0204] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, HP2is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), polypropylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, polypxyethylated polyol), polyplefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(Ar- acryloylmorpholine), polysarcosine, or a combination thereof. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polyethylene glycol (PEG). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is methoxypolyethylene glycol (mPEG). In certain embodiments of Formula (la-1), Formula (la- 2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polypropylene glycol) (PPG). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is copolymers of ethylene glycol and propylene glycol. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polypxyethylated polyol). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polyplefinic alcohol). In some embodiments, HP2is poly(vinylpyrrolidone). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is poly(hydroxyalkylmethacrylamide). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is poly(hydroxyalkylmethacrylate). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is poly(saccharides). In some embodiments, HP2is poly(a-hydroxy acid). In certain embodiments of Formula (la- 1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is poly(vinyl alcohol). In some embodiments, HP2is polyphosphazene. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polyoxazolines (POZ). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, POLY is poly(Y- acryloylmorpholine). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is polysarcosine. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, HP2is a nonpeptidic, water-soluble polymer.

[0205] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, HP2is independently a monovalent poly(ethylene glycol). In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), andFormula (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 compound. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, R2is hydrogen. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, R2is methyl.

[0206] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, x2 is independently an integer between 1 and 20, inclusive. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, x2 is independently an integer between 10 and 20, inclusive. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, x2 is 12.

[0207] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, x2 is independently an integer between 1 and 20, inclusive, and R2is hydrogen. In certain embodiments of Formula (la-1), Formula (la-2),Formula (la-3), and Formula (Ic-2), including any of the foregoing, x is independently an integer between 10 and 20, inclusive, and R2is hydrogen. In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula (Ic-2), including any of the foregoing, x is 12 and R2is hydrogen.

[0208] In certain embodiments of Formula (la-1), Formula (la-2), Formula (la-3), and Formula(Ic-2), including any of the foregoing, W2is independently of the formula:

[0209] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, L2is -C1-3 alkylene-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic- 2), including any of the foregoing, L2is -CH2-. In some embodiments, L2is -CH2CH2-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, L2is -CH2CH2CH2-.

[0210] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, b is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X^Ci-e alkylene-fX^Ci-e alkylenej.-X1-, wherein at least one alkylene in Yais substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X1-C2-6 alkenylene-[X1-C2-6 alkenyleneja-X1- wherein at least one alkenylene in Y* is substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X1-C2-6 alkynylene-fX1- C2-6 alkynyleneja-X1- wherein at least one alkynylene in Yais substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic- 2), including any of the foregoing, a is zero. In some embodiments, a is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is two. In certain embodiments Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is three.

[0211] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, b is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X*-Ci-4 alkylene-P^-Cw alkyleneja-X1-, wherein at leastone alkylene in Yais substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is two. In some embodiments, a is three.

[0212] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, b is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Yais -X*-Ci4 alkylene-X1-CM alkylene-X1-CM alkylene-X1- C1-4 alkylene-X1-, wherein at least one alkylene in Y* is substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic- 2), including any of the foregoing, Y* is -X^M alkylene-X1-CM alkylene-X1-CM alkylene- X1-, wherein at least one alkylene in Yais substituted with one or more substituents selected from R50. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X*-Ci4 alkylene-X1-CM alkylene-X1-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R50

[0213] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, b is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Yais -X*-CM alkylene-P^-Ci-e alkylene],-, wherein at least one alkylene in Yais substituted with one or more substituents selected from R50, and wherein the alkylene in Yais optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1) or (Ib-3), including any of the foregoing, Y* is -X1-C2- 6 alkenylene-[X1-C2-6 alkenylene],-, wherein at least one alkenylene in Y* is substituted with one or more substituents selected from R50, and wherein the alkenylene in Y* is optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X1-C2-6 alkynylene-fX1- C2-6 alkynylene],-, wherein at least one or alkynylene in Y* is substituted with one or more substituents selected from R50, and wherein the alkynylene in Y* is optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is two. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is three.

[0214] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, b is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y is -X^i-e alkylene-P^-Ci-e alkylene],-, wherein at least one alkylene in Yais substituted with one or more substituents selected from R50, and wherein the alkylene in Yais optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is *-X1-Ci-4 alkylene-tX^Cw alkylene],-, wherein at least one alkylene in Y* is substituted with one or more substituents selected from R50, and wherein the alkylene in Y* is optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Y* is -X*-Ci4 alkylene-X^Cw alkylene-X^M alkylene-, wherein at least one alkylene in Y* is substituted with one or more substituents selected from R50, and wherein the alkylene in Y* is optionally substituted with one or more substituents selected from R51. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is one. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is two. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a is three. In certain embodiments of Formula (Ib-1) or (Ib-3), including any of the foregoing, R51is independently selected from halogen, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R51is halogen. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R51is -CN. In some embodiments, R51is -NO2. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R51is -OH. In some embodiments, R51is -NH2. In some embodiments, R51is -C(O)NH2. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R51is -C(O)-.

[0215] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, X1and X2are independently selected from -N(R10)-, -C(O)-, and -N(R10)C(O)-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, X1and X2are independently selected from -NH-, -C(O)-, and -N(R10)C(O)-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, X1and X2are independently selected from -C(O)-, and -N(R10)C(O)-. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, X1and X2are independently selected from -C(O)-, and -NHC(O)-.

[0216] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R50is -Ci-6 alkylene-X^Ci-e alkylene]c-HP2, wherein each alkylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, - N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5,-NHC(OX)CH2C6H5, Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12- membered heterocycle, and CMO haloalkyl. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R50is -CMalkylene-X^tCwalkylenejc- HP2, wherein each alkylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N^10^, -C^N^10^, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CMO alkyl, CMO alkenyl, CMO alkynyl, C3-i2carbocycle, 3- to 12-membered heterocycle, and CMO haloalkyl. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, each alkylene of R50is optionally substituted with one or more substituents selected from halogen, -OH, -N^10^, - C^N^10^, -C(O)-, Ci-10 alkyl, CMO alkenyl, CMO alkynyl, C3-i2carbocycle, 3- to 12- membered heterocycle, and CMO haloalkyl. In some embodiments, c is zero. In some embodiments, c is one.

[0217] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R50is -CM alkenylene-X2-[C2-6 alkenylene]c- HP2, wherein each alkenylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N^10^, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CMO alkyl, CMO alkenyl, CMO alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and CMO haloalkyl. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, c is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, c is one.

[0218] In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, R50is -CM alkynylene-X2-[C2-6 alkynylene]c- HP2, wherein each alkynylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N^10^, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CMO alkyl, CMO alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and CMO haloalkyl. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, c is zero. In certain embodiments of Formula (Ib-1), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, c is one.

[0219] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -C1-C10 alkylene-X1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^i-Cio alkylene-X1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^Ci-Ce alkylene-X1-, wherein the alkylene of X is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6H5,-NHC(O)OCH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -C1-C10 alkylene-X1-R2-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^i-Cio alkylene-X1-R2-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^i-Cio alkylene-X1-R2- and X is -X^Ci-Ce alkylene-X1-R2-, wherein the alkylene of X is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(OX)CH2C6H5, -NHC(O)OCH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^i-Cio alkylene- X1-R2-X1-[POLY]-CI-CIO alkylene-X1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^Ci-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene-X1- and X is -X^i-Ce alkylene-X1-R2-X1-[POLY]-Ci-C6 alkylene-X1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -[POLY]-Ci-Cio alkylene-X1-. In certain embodiments of Formula (Ib- 2), (Ic-1), or (Ic-2), X is -[POLY]-CI-C6alkylene-X1-.

[0220] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, X1is -C(O)-.

[0221] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, each Y** is independently -[POLY]-CI-C6 alkylene- Y1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, each Y1* is independently - [POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-. In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, each Ybis independently -[POLY]-CI-C6 alkylene- Y1-R2-Y1-CI-C6 alkylene- Y1-.

[0222] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -C1-C10 alkylene-X1- and each Y1* is independently-[POLY]-Ci-C6 alkylene- Y1-R2-Y1-Ci-Ce alkylene- Y1-.

[0223] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -C1-C10 alkylene-X1- and each Y1* is independently -[POLY]-CI-C6 alkylene- Y1-R2-Y1-Ci-Ce alkylene- Y1-; each R3is independently a non-amino acid side chain; and aa is one.

[0224] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -Ci-Cio alkyleno-X1- and each Y6is independently -[POLYj-Ci-Ce alkylene- Y^R^Y^i-Cs alkylene- Y1-; each R3is independently a non-amino add side chain; aa is one; and the non-amino add side chain is independently -C1-C20 alkylene-X^i-Cao alkyleno-[POLY]-OCH3.

[0225] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -C1.C10 alkyleno-X1- and each Y6is independently -fPOLYj-Ci-Ce alkylene- Y^i-Q alkylene- Y1-.

[0226] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkylene- X1- and each Y6is independently -[POLY]-CI-C6 alkylene- Y1-.

[0227] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkylene- X1- and each Y6is independently -fPOLYj-Ci-Ce alkylene- Y^i-Q alkylene- Y1-. In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkyleno-X1- and each Y6is independently -[POLY]-CI-C6 alkylene- Y^R^Y^i-Cs alkylene- Y1-.

[0228] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkylene- X1- and each Y6is independently -fPOLYj-Ci-Ce alkylene-Y^RM^-Ci-Cs alkylene- Y1-; each R3is independently a non-amino add side chain; and aa is one.

[0229] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkyleno- X1- and each Y6is independently -fPOLYj-Ci-Ce alkylene-Y^RM^-Ci-Cs alkylene- Y1-; each R3is independently a non-amino add side chain; aa is one; and the non-amino add side chain is independently -C1-C20 alkylene-X^i-Cao alkylene-[POLY]-OCH3.

[0230] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -C1.C20 alkylene-X1- R2-. In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -C1.C20 alkyleno-X1-R2-; each R3is independently a non-amino add side chain; and aa is one. In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -C1.C20 alkyleno-X1-R2-; each R3is independently a non-anrino add side chain; aa is one; and the non-amino add side chain is independently -Ci- C» alkylene-X^i-Cao alkylene-[POLY]-OCH3.

[0231] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -C1.C20 alkyleno-X1- R2-; each R3is independently a non-amino add side chain; aa is one; and each Y6is independently--[POLY]-Ci-C« alkylene- Y^i-Q alkylene- Y1-.

[0232] In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^I-CM alkyleno- X^R2-. In certain embodiments of Formula Qb-2), Qc-l), or Qc-2), X is -X^i-Cao alkyleno- X^R2-; each R3is indqtendentiy a non-amino add side chain; and aa is one.

[0233] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is one; the non-amino acid side chain is independently -C1-C20 alkylene-X1-CI-CH alkylene-[POLY]-OCH3.

[0234] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is one; and each Y** is independently -[POLY]-CI-C6 alkylene- Y1-.

[0235] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is one; and each Y1* is independently -[POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-.

[0236] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; and aa is two.

[0237] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is two; and the non-amino acid side chain is independently selected from -C1-C20 alkylene-X1-CI-CH alkylene-[POLY]- OCH3 and -C1-C6 alkylene-SOaH.

[0238] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is two; and each Ybis independently -[POLY]-CI-C6 alkylene- Y1-.

[0239] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X^R2-; each R3is independently a non-amino acid side chain; aa is two; and each Ybis independently -[POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-.

[0240] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X1-R2-X1-[POLY]-CI-C6alkylene-X1-.

[0241] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X1-Ci-C2o alkylene- X1-R2-X1-[POLY]-CI-C6 alkylene-X1-; each R3is independently a non-amino acid side chain; and aa is one.

[0242] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the non-amino acid side chain is independently -C1-C6 alkylene-SOaH, optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(OX)CH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-io alkenyl, C2-io alkynyl, €3-12 caibocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0243] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^CI-CM alkylene- X1-R2-X1-[POLY]-CI-C6 alkylene-X1-; each R3is independently a non-amino acid side chain; aa is one; and each Y** is independently -[POLY]-CI-C6 alkylene- Y1-.

[0244] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), X is -X^CI-CM alkylene- X1-R2-X1-[POLY]-CI-C6 alkylene-X1-; each R3is independently a non-amino acid side chain; aa is one; and each Y1* is independently -[POLY]-CI-C6 alkylene- Y^Ci-Ce alkylene- Y1-.

[0245] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), each Z is independently-Ci- C20 alkylene-.In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, each Z is independently-Ci-Cio alkylene-. In certain embodiments of Formula (Ib- 2), (Ic-1), or (Ic-2), including any of the foregoing, each Z is independently-Ci-Cs alkylene-.

[0246] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, each R10is independently hydrogen or CI-M alkyl.

[0247] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, R3of R2is a non-amino acid side chain.

[0248] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, the non-amino acid side chain is independently -Ci-Ce alkylene-SChH, optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(OX)CH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-io alkenyl, C2-io alkynyl, €3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0249] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing the non-amino acid side chain is independently -Ci-Ce alkylene-X1-Ci-Ce alkylene- POLY, wherein each alkylene is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -NQt10}?, -C(O)N(R10)2, - C(O)OCH2C6HS, -NHC(O)OCH2C6H5, Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, Ca-i2carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; or wherein the non-amino acid side chain is independently -C1-C6 alkylene-SOsH, optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NQt10}?, -C(O)N(R10)2, - C(O)OCH2C6HS, -NHC(O)OCH2C6H5, Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, Ca-i2carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl or -Ci-Ce alkylene-X1-Ci-Ce alkylene-POLY, wherein each alkylene is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N^10^, -C(O)N(R10)2, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, CMO alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl.

[0250] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing POLY comprises a polyethylene glycol (PEG), polysarcosine (PSAR), methoxypolyethylene glycol (mPEG), polypropylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(7V-acryloylmorpholine), polysarcosine, or a combination thereof.

[0251] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY comprises a polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), or a combination thereof.

[0252] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is -[CH2CH2O]n-

[0253] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3.

[0254] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3 and n is an integer from zero to fifty.

[0255] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3 and each n of X is independently an integer from zero to thirty.

[0256] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3 and each n of X is an integer from one to five.

[0257] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3 and each n of Y is independently an integer from zero to thirty.

[0258] In certain embodiments of Formula (Ib-2), (Ic-1), or (Ic-2), including any of the foregoing, POLY is independently -[CH2CH2O]n- or -[OCH2CH2]nOCH3 and each n of Y is an integer from one to five.

[0259] In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or(Ic-2), including any of the foregoing, Su is a sugar moiety. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Su is a hexose form of a monosaccharide. Su may be a glucuronic acid or mannose residue. Incertain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Su is, wherein represents attachment to the remainder of the compound. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1),(Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, Su is , whereinrepresents attachment to the remainder of the compound.

[0260] In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or(Ic-2), including any of the foregoing, RL is independently selected from the group consisting ; wherein each is a pointof attachment to the rest of the compound.

[0261] In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or(Ic-2), including any of the foregoing, RL is In certainembodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2) .includingH any of the foregoing, RL is. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, RL is. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3),including any of the foregoing, RL isIn certain embodiments of Formula (la), Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-,1), or (Ic-2), including any of the foregoing, RL is K . In certain embodiments ofFormula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, RL is

[0262] In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is greater than 8. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 10. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 12. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 14. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 16. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 18. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 20. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 22. In certain embodiments of Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, m is 24.

[0263] In certain embodiments of Formula (Ic-1) or (Ic-2), including any of the foregoing, m is an integer between 8 and 12, inclusive and n is an integer between 2 and 8, inclusive. In certain embodiments of Formula (Ic-1) or (Ic-2), including any of the foregoing, m is 8 and n is 2. In certain embodiments of Formula (Ic-1) or (Ic-2), including any of the foregoing, m is 8 and n is 4. In certain embodiments of Formula (Ic-1) or (Ic-2), including any of the foregoing, m is 8 and n is 6. In certain embodiments of Formula (Ic-1) or (Ic-2), including any of the foregoing, m is 8 and n is 8.

[0264] Payloads

[0265] The payload can be any molecular entity that one of skill in the art might desire to conjugate to the antibody. In certain embodiments, the payload is a therapeutic moiety. In such embodiment, the antibody conjugate can be used to target the therapeutic moiety to its molecular target. In certain embodiments, the payload comprises a labeling moiety. In such embodiments, the antibody conjugate can be used to detect binding of the antibody to its target. In certain embodiments, the payload is a cytotoxic moiety. In such embodiments, the conjugate can be used target the cytotoxic moiety to a diseased cell, for example a cancer cell, to initiate destruction or elimination of the cell. Conjugates comprising other molecular payloads apparent to those of skill in the art are within the scope of the conjugates described herein.

[0266] In certain embodiments, a conjugate can have a payload or a labelling moiety selected from the group consisting of a label, a dye, a polymer, a water-soluble polymer, polyethylene glycol, a derivative of polyethylene glycol, a photocrosslinker, a cytotoxic compound, a radionuclide, a drug, an affinity label, a photoaffinity label, a reactive compound, a resin, a second protein or polypeptide or polypeptide analog, an antibody or antibody fragment, a metal chelator, a cofactor, a fatty acid, a carbohydrate, a polynucleotide, a DNA, a RNA, an antisensepolynucleotide, a peptide, a water-soluble dendrimer, a cyclodextrin, an inhibitory ribonucleic acid, a biomaterial, a nanoparticle, a spin label, a fluorophore, a metal-containing moiety, a radioactive moiety, a novel functional group, a group that covalently or noncovalently interacts with other molecules, a photocaged moiety, a photoisomerizable moiety, biotin, a derivative of biotin, a biotin analogue, a moiety incorporating a heavy atom, a chemically cleavable group, a photocleavable group, an elongated side chain, a carbon-linked sugar, a redox-active agent, an amino thioacid, a toxic moiety, an isotopically labeled moiety, a biophysical probe, a phosphorescent group, a chemiluminescent group, an electron dense group, a magnetic group, an intercalating group, a chromophore, an energy transfer agent, a biologically active agent, a detectable label, a small molecule, or any combination thereof.

[0267] In some embodiments, the payload is an alkylating agent, a DNA-crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone-deacetylase (HD AC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, or a topoisomerase inhibitor. In some embodiments, the payload is a topoisomerase I inhibitor, e.g., camptothecin, irinotecan, SN-38, topotecan, or exatecan. In one example, the payload is exatecan. In some embodiments, the payload is a tubulin inhibitor. In some embodiments, the payload is MMAE. In some embodiments, the payload is a hemiasterlin. The hemiasterlin may be 3-aminophenyl hemiasterlin. In one example, the hemiasterlin linker-payload is or comprises the linker-payload of the following structureor a salt thereof. In one example, the hemiasterlin linker-payload is or comprises the linker-payload of the following structureor a salt thereof. In one example, the hemiasterlin linker-payload is or comprises the linker-payload of the following structureor a salt thereof. In one example, the hemiasterlin linker-payload is or comprises the linker-payload of the following structureor a salt thereof. Additional examples of hemiasterlin linker-payloads include those described in WO2016123582, which is incorporated by reference herein in its entirety.

[0268] In some embodiments, the linker payload comprises a β-glucuronide linker-payload, e.g., a β-glucuronide exatecan linker-payload. In one example, the β-glucuronide exatecan linker-payload is or comprises the linker-payload of the following structureor a salt thereof. Additional examples of β- glucuronide linker-payloads include those described in W02024006272, which is incorporated by reference herein in its entirety.

[0269] In some embodiments, the antibody conjugate comprises a topoisomerase I inhibitors and a tubulin inhibitor. In some embodiments, the antibody conjugate comprises exatecan and a hemiasterlin. In some embodiments, the antibody conjugate comprises (a) the β-glucuronide exatecan linker-payload that is or comprises the linker-payload of the following structuresalt thereof and (b) a hemiasterlin linkerpayload that is or comprises a linker-payload selected from the following structures:andor a salt thereof. In some embodiments, the antibody conjugate comprises (a) the ^-glucuronide exatecan linker-payload that is or comprises the linker-payload of the following structuresalt thereof and (b) a hemiasterlin linkerpayload that is or comprises a linker-payload of the following structures:or a salt thereof.

[0270] Usefill drug payloads include any cytotoxic, cytostatic or immunomodulatory drug. Usefid classes of cytotoxic or immunomodulatory agents include, for example, STING agonists, TLR agonists, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cis-platin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, calmodulin inhibitors, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, maytansinoids, nitrosoureas, platinols, pore-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, rapamycins, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or the like.

[0271] Individual cytotoxic or immunomodulatory agents include, for example, an androgen, anthramycin (AMC), asparaginase, 5-azacytidine, azathioprine, bleomycin, busulfan, buthionine sulfoximine, calicheamicin, calicheamicin derivatives, camptothecin, carboplatin, carmustine (BSNU), CC-1065, chlorambucil, cisplatin, colchicine, cyclophosphamide, cytarabine, cytidine arabinoside, cytochalasin B, dacarbazine, dactinomycin (formerly actinomycin), daunorubicin, decarbazine, DM1, DM4, docetaxel, doxorubicin, etoposide, an estrogen, 5-fluordeoxyuridine, 5-fluorouracil, gemcitabine, gramicidin D, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine (CCNU), maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mithramycin, mitomycin C, mitoxantrone, nitroimidazole, paclitaxel, palytoxin, plicamycin, procarbizine, rhizoxin, streptozotocin,tenoposide, 6-thioguanine, thioTEPA, topotecan, vinblastine, vincristine, vinorelbine, VP-16 and VM-26.

[0272] In some embodiments, suitable cytotoxic agents include, for example, DNA minor groove binders (e.g., enediynes and lexitropsins, a CBI compound; see also U.S. Pat. No. 6,130,237), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycins, vinca alkaloids, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholinodoxorubicin, echinomycin, combretastatin, netropsin, epothilone A and B, estramustine, cryptophycins, cemadotin, maytansinoids, discodermolide, eleutherobin, and mitoxantrone.

[0273] In some embodiments, the payload is an anti-tubulin agent. Examples of anti-tubulin agents include, but are not limited to, taxanes (e.g., Taxol® (paclitaxel), Taxotere® (docetaxel)), T67 (Tularik) and vinca alkyloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Other antitubulin agents include, for example, baccatin derivatives, taxane analogs, epothilones (e.g., epothilone A and B), nocodazole, colchicine and colcimid, estramustine, cryptophycins, cemadotin, maytansinoids, combretastatins, discodermolide, and eleutherobin.

[0274] In certain embodiments, the cytotoxic agent is a maytansinoid, another group of antitubulin agents. For example, in specific embodiments, the maytansinoid can be maytansine or DM-1 (ImmunoGen, Inc.; see also Chari et al., 1992, Cancer Res. 52:127-131).

[0275] In some embodiments, the payload is an auristatin, such as auristatin E or a derivative thereof. For example, the auristatin E derivative can be an ester formed between auristatin E and a keto acid. For example, auristatin E can be reacted with paraacetyl benzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other typical auristatin derivatives include AFP, MMAF, and MMAE. The synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005- 0238649 and 2005-0009751; International Patent Publication No. WO 04 / 010957, International Patent Publication No. WO 02 / 088172, and U.S. Pat. Nos. 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414.In one example, the auristatin linker-payload is or comprises the linker-payload selected from the following structureandn or a salt thereof.

[0276] In some embodiments, the antibody conjugate comprises (a) the ^-glucuronide exatecan linker-payload that is or comprises the linker-payload of the following structuresalt thereof and (b) an auristatin linkerpayload that is or comprises a linker-payload of the following structures:H or a salt thereof.

[0277] In some embodiments, the payload is not a radioisotope. In some embodiments, the payload is not radioactive.

[0278] In some embodiments, the payload is an antimetabolite. The antimetabolite can be, for example, a purine antagonist (e.g., azothioprine or mycophenolate mofetil), a dihydrofolate reductase inhibitor (e.g., methotrexate), acyclovir, ganciclovir, zidovudine, vidarabine, ribavarin, azidothymidine, cytidine arabinoside, amantadine, dideoxyuridine, iododeoxyuridine, poscamet, or trifluridine.

[0279] In other embodiments, the payload is tacrolimus, cyclosporine, FU506 or rapamycin. In further embodiments, the Drug is aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, bexarotene, bexarotene, calusterone, capecitabine, celecoxib, cladribine, Darbepoetin alfa, Denileukin diftitox, dexrazoxane, dromostanolone propionate, epirubicin, Epoetin alfa, estramustine, exemestane, Filgrastim, floxuridine, fludarabine, fulvestrant, gemcitabine, gemtuzumab ozogamicin (MYLOTARG),goserelin, idarubicin, ifosfamide, imatinib mesylate, Interferon alfa-2a, irinotecan, letrozole, leucovorin, levamisole, meclorethamine or nitrogen mustard, megestrol, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, nandrolone phenpropionate, oprelvekin, oxaliplatin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, Rituximab, Sargramostim, streptozocin, tamoxifen, temozolomide, teniposide, testolactone, thioguanine, toremifene, Tositumomab, Trastuzumab (HERCEPTIN), tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine or zoledronate.

[0280] In some embodiments, the payload is an immunomodulatory agent. The immunomodulatory agent can be, for example, ganciclovir, etanercept, tacrolimus, cyclosporine, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil or methotrexate. Alternatively, the immunomodulatory agent can be, for example, a glucocorticoid (e.g., cortisol or aldosterone) or a glucocorticoid analogue (e.g., prednisone or dexamethasone).

[0281] In some embodiments, the immunomodulatory agent is an anti-inflammatory agent, such as arylcarboxylic derivatives, pyrazole-containing derivatives, oxicam derivatives and nicotinic acid derivatives. Classes of anti-inflammatory agents include, for example, cyclooxygenase inhibitors, 5-lipoxygenase inhibitors, and leukotriene receptor antagonists.

[0282] Suitable cyclooxygenase inhibitors include meclofenamic acid, mefenamic acid, carprofen, diclofenac, diflunisal, fenbufen, fenoprofen, indomethacin, ketoprofen, nabumetone, sulindac, tenoxicam and tolmetin.

[0283] Suitable lipoxygenase inhibitors include redox inhibitors (e.g., catechol butane derivatives, nordihydroguaiaretic acid (NDGA), masoprocol, phenidone, lanopalen, indazolinones, naphazatrom, benzofuranol, alkylhydroxylamine), and non-redox inhibitors (e.g., hydroxythiazoles, methoxyalkylthiazoles, benzopyrans and derivatives thereof, methoxytetrahydropyran, boswellic acids and acetylated derivatives of boswellic acids, and quinolinemethoxyphenylacetic acids substituted with cycloalkyl radicals), and precursors of redox inhibitors.

[0284] Other suitable lipoxygenase inhibitors include antioxidants (e.g., phenols, propyl gallate, flavonoids and / or naturally occurring substrates containing flavonoids, hydroxylated derivatives of the flavones, flavonol, dihydroquercetin, luteolin, galangin, orobol, derivatives of chaicone, 4,2',4'-trihydroxychalcone, ortho-aminophenols, N-hydroxyureas, benzofuranols, ebselen and species that increase the activity of the reducing selenoenzymes), iron chelatingagents (e.g., hydroxamic acids and derivatives thereof, N-hydroxyureas, 2-benzyl-l -naphthol, catechols, hydroxylamines, camosol trolox C, catechol, naphthol, sulfasalazine, zyleuton, 5- hydroxyanthranilic acid and 4-(omega-arylalkyl)phenylalkanoic acids), imidazole-containing compounds (e.g., ketoconazole and itraconazole), phenothiazines, and benzopyran derivatives.

[0285] Yet other suitable lipoxygenase inhibitors include inhibitors of eicosanoids (e.g., octadecatetraenoic, eicosatetraenoic, docosapentaenoic, eicosahexaenoic and docosahexaenoic acids and esters thereof, PGE1 (prostaglandin El), PGA2 (prostaglandin A2), viprostol, 15- monohydroxyeicosatetraenoic, 15 -monohydroxy-eicosatrienoic and 15- monohydroxyeicosapentaenoic acids, and leukotrienes B5, C5 and D5), compounds interfering with calcium flows, phenothiazines, diphenylbutylamines, verapamil, fiiscoside, curcumin, chlorogenic acid, caffeic acid, 5,8,11,14-eicosatetrayenoic acid (ETYA), hydroxyphenylretinamide, lonapalen, esculin, diethylcarbamazine, phenantroline, baicalein, proxicromil, thioethers, diallyl sulfide and di-(l -propenyl) sulfide.

[0286] Leukotriene receptor antagonists include calcitriol, ontazolast, Bayer Bay-x-1005, Ciba-Geigy CGS-25019C, ebselen, Leo Denmark ETH-615, Lilly LY-293111, Ono ONO- 4057, Terumo TMK-688, Boehringer Ingleheim BI-RM-270, Lilly LY 213024, Lilly LY 264086, Lilly LY 292728, Ono ONO LB457, Pfizer 105696, Perdue Frederick PF 10042, Rhone-Poulenc Rorer RP 66153, SmithKline Beecham SB-201146, SmithKline Beecham SB- 201993, SmithKline Beecham SB-209247, Searle SC-53228, Sumitamo SM 15178, American Home Products WAY 121006, Bayer Bay-o-8276, Warner-Lambert CI-987, Warner-Lambert CI-987BPC-15LY 223982, Lilly LY 233569, Lilly LY-255283, MacroNex MNX-160, Merck and Co. MK-591, Merck and Co. MK-886, Ono ONO-LB-448, Purdue Frederick PF-5901, Rhone-Poulenc Rorer RG14893, Rhone-Poulenc Rorer RP 66364, Rhone-Poulenc Rorer RP 69698, Shionoogi S-2474, Searle SC-41930, Searle SC-50505, Searle SC-51146, Searle SC- 52798, SmithKline Beecham SK&F-104493, Leo Denmark SR-2566, Tanabe T-757 and Teijin TEI-1338.

[0287] Other usefill drug payloads include chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5- FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin yll and calicheamicin omegall (Angew Chem. Inti. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine;elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofiiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"-tri chlorotri ethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, DI.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0288] Other useful payloads include: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3- dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-a, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example,ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti -angiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above. Other anti-angiogenic agents include MMP-2 (matrixmetalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, COX-II (cyclooxygenase n) inhibitors, and VEGF receptor tyrosine kinase inhibitors. Examples of such usefill matrix metalloproteinase inhibitors that can be used in combination with the present compounds / compositions are described in WO 96 / 33172, WO 96 / 27583, EP 818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 606,046, EP 931,788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 99 / 07675, EP 945864, U.S. Pat. No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 780,386, all of which are incorporated herein in their entireties by reference. Examples of VEGF receptor tyrosine kinase inhibitors include 4-(4-bromo-2-fluoroanilino)-6-methoxy-7- (l-methylpiperidin-4-ylmethoxy)qu- -inazoline (ZD6474; Example 2 within WO 01 / 32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)- -quinazoline (AZD2171; Example 240 within WO 00 / 47212), vatalanib (PTK787; WO 98 / 35985) and SU11248 (sunitinib; WO 01 / 60814), and compounds such as those disclosed in PCT Publication Nos. WO 97 / 22596, WO 97 / 30035, WO 97 / 32856, and WO 98 / 13354).

[0289] In certain embodiments, the payload is an antibody or an antibody fragment. In certain embodiments, the pay load antibody or fragment can be encoded by any of the immunoglobulin genes recognized by those of skill in the art. The immunoglobulin genes include, but are not limited to, the K, X, a, y (IgGl, IgG2, IgG3, and IgG4), 5, e and p constant region genes, as well as the immunoglobulin variable region genes. The term includes full-length antibodies and antibody fragments recognized by those of skill in the art, and variants thereof. Exemplary fragments include but are not limited to Fv, Fc, Fab, and (Fab')2, single chain Fv (scFv), diabodies, triabodies, tetrabodies, bifunctional hybrid antibodies, CDR1, CDR2, CDR3, combinations of CDR's, variable regions, framework regions, constant regions, and the like.

[0290] In certain embodiments, the payload is one or more water-soluble polymers. A wide variety of macromolecular polymers and other molecules can be linked to antigen-binding polypeptides to modulate biological properties of the antibody, and / or provide new biological properties to the antibody. These macromolecular polymers can be linked to the antibody via a naturally encoded amino acid, via a non-natural amino acid, or any functional substituent of a natural or non-natural amino acid, or any substituent or functional group added to a natural ornon-natural amino acid. The molecular weight of the polymer may be of a wide range, including but not limited to, between about 100 Da and about 100,000 Da or more.

[0291] The polymer selected may be water soluble so that the protein to which it is attached does not precipitate in an aqueous environment, such as a physiological environment. The polymer may be branched or unbranched. Preferably, for therapeutic use of the end-product preparation, the polymer will be pharmaceutically acceptable.

[0292] The proportion of polyethylene glycol molecules to antibody molecules will vary, as will their concentrations in the reaction mixture. In general, the optimum ratio (in terms of efficiency of reaction in that there is minimal excess unreacted protein or polymer) may be determined by the molecular weight of the polyethylene glycol selected and on the number of available reactive groups available. As relates to molecular weight, typically the higher the molecular weight of the polymer, the fewer number of polymer molecules which may be attached to the protein. Similarly, branching of the polymer should be taken into account when optimizing these parameters. Generally, the higher the molecular weight (or the more branches) the higher the polymerprotein ratio.

[0293] Exemplary water soluble polymers are described below.

[0294] In certain embodiments, the at least one payload is selected from the group consisting of maytansines, hemiasterlins, amanitins, and auristatins. In certain embodiments, the at least one payload is selected from the group consisting of DM1, hemiasterlin, amanitin, MMAF, and MMAE. In certain embodiments, the at least one payload comprises a hemiasterlin derivative. In certain embodiments, the at least one payload comprises a hemiasterlin derivative described in WO2016123582A1, which is incorporated for all purposes by reference. In certain embodiments, the at least one payload comprises:wherein Ar is aryl or heteroaryl, L is a linker, and the wiggly line indicates a bond to the antibody. In certain embodiments, the at least one payload comprises: wherein L is a linker, and the wiggly lineindicates a bond to the antibody.

[0295] The payloads can be any topoisomerase inhibitors or derivatives thereof, such as Topi inhibitors, and DDR inhibitors or derivatives thereof deemed usefill by the practitioner of skill. Usefid payloads are described in the sections and examples below. In some embodiments, the topoisomerase inhibitor is a topoisomerase I (Topi) inhibitor or derivative thereof. In some embodiments, the topoisomerase I inhibitor or derivative thereof is a camptothecin derivative. In some embodiments, the topoisomerase I inhibitor or derivative thereof is selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, rubitecan, MLN576, Belotecan, exatecan, and derivatives thereof. In some embodiments, the topoisomerase I inhibitor or derivative thereof is selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, exatecan, and derivatives thereof. In some embodiments, the topoisomeraseI inhibitor or derivative thereof is exatecan. In some embodiments, the topoisomerase inhibitor is a topoisomerase n inhibitor or derivative thereof. In some embodiments, the topoisomeraseII inhibitor or derivative thereof is selected from etoposide, teniposide, and tafluposide.

[0296] In some embodiments, including any of the foregoing, the DDR inhibitor is a poly (ADP-ribose) polymerase (PARP) inhibitor, a checkpoint kinase 1 (CHK1) inhibitor, an ataxia telangiectasia and Rad3 -related (ATR) inhibitor, a nicotinamide phosphoribosyltransferase 1 (NAMPT1) inhibitor, or a RAD51 inhibitor, or derivative thereof. In some embodiments, including any of the foregoing, the DDR inhibitor or derivative thereof is a PARP inhibitor. In some embodiments, including any of the foregoing, the PARP inhibitor is selected from olaparib, veliparib, talazoparib, rucaparib, niraparib, AZD5305, talzenna, and derivatives thereof. In some embodiments, including any of the foregoing, the PARP inhibitor is talazoparib or derivative thereof.

[0297] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase inhibitor is a topoisomerase I inhibitor or derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase I inhibitor or derivative thereof is a camptothecin derivative. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase I inhibitor or derivative thereof is independently selected from camptothecin, irinotecan, SN-38, topotecan, and exatecan. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase I inhibitor or derivative thereof is exatecan.

[0298] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase inhibitor is independently selected from the group consisting of: thereof; and each is a point of attachment to the rest of the compound.

[0299] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase inhibitor is independently selected from the group consisting of:thereof.

[0300] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase inhibitor is independently selected from the group consisting of:derivative thereof.

[0301] In an alternative embodiment of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of theforegoing, the topoisomerase inhibitor is a topoisomerase II inhibitor or derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the topoisomerase n inhibitor or derivative thereof is independently selected from etoposide, teniposide, and tafluposide.

[0302] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a poly (ADP-ribose) polymerase (PARP) inhibitor, a checkpoint kinase 1 (CHK1) inhibitor, a checkpoint kinase 2 (CHK2) inhibitor, an ataxia telangiectasia and Rad3 -related (ATR) inhibitor, an ataxia telangiectasia mutated (ATM) inhibitor, a nicotinamide phosphoribosyltransferase 1 (NAMPT1) inhibitor, or a RAD51 inhibitor.

[0303] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a poly (ADP-ribose) polymerase (PARP) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a checkpoint kinase 1 (CHK1) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a checkpoint kinase 2 (CHK2) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a checkpoint kinase 1 / 2 (CHK1 / 2) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is an ataxia telangiectasia and Rad3 -related (ATR) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is an ataxia telangiectasia mutated (ATM) inhibitor. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a nicotinamide phosphoribosyltransferase 1 (NAMPT1) inhibitor. In certain embodiments of the antibodyconjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a RAD51 inhibitor.

[0304] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a poly (ADP-ribose) polymerase (PARP) inhibitor and the PARP inhibitor is independently selected from olaparib, veliparib, talazoparib, rucaparib, niraparib, AZD5305, talzenna, and derivatives thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib- 2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is olaparib or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is veliparib or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is talazoparib or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic- 2), including any of the foregoing, the PARP inhibitor is rucaparib or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is niraparib or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is AZD5305 or a derivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is talzenna or a derivative thereof.

[0305] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is independently selected fromderivative thereof; and each is a point ofattachment to the rest of the compound.

[0306] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor i derivative thereof; and each is a pointof attachment to the rest of the compound.

[0307] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is independently selected fromderivative thereof; and each is a point of attachment to the rest of the compound.

[0308] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor IS independently selected fromderivative thereof; and each is a point ofattachment to the rest of the compound.

[0309] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor is independently selected fromderivative thereof.

[0310] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor iderivative thereof. In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1),(Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the PARP inhibitor isderivative thereof.

[0311] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a CHK1 inhibitor independently selected from 7- hydroxystaurosporine, AZD7762, rabusertib, MK-8776, prexasertib. GDC-575, and CCT245737.

[0312] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a CHK1 inhibitor independently selected from thereof; and each is a point of attachment to the rest of the compound.

[0313] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing,the DDR inhibitor or derivative thereof is a CHK1 inhibitor independently selected fromthereof.

[0314] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is a CHK1 inhibitor independently selected froma derivative thereof.

[0315] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof iderivative thereof.

[0316] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the DDR inhibitor or derivative thereof is an ataxia telangiectasia and Rad3 -related (ATR) inhibitor independently selected from Berzosertib, Ceralasertib, Elimusertib, M4344 (VX- 803), BAY1895344, schisandrin B, NU6027, dactolisib, EP-46464, Torin-2, VE-821, AZ20, IMP9064, ATG-018, ATRN-119, and ART0380.

[0317] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the ATR inhibitor is independently selected from; or a derivative thereof; and each is a point of attachment to the rest of the compound.

[0318] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the ATR inhibitor is independently selected from; or a derivative thereof; and each is a point of attachment to the rest of the compound.

[0319] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the ATR inhibito derivative thereof.

[0320] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, a nicotinamide phosphoribosyltransferase 1 (NAMPT1) inhibitor independently selected from GMX1777, FK866, CHS828, OT-82, APO866, KPT-9274, and ATG-019.

[0321] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the NAMPT1 inhibitor is independently selected fromand; or a derivative thereof; and each isa point of attachment to the rest of the compound.

[0322] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the NAMPT1 inhibitor is independently selected fromandor a derivative thereof.

[0323] In certain embodiments of the antibody conjugates described herein, including Formula (la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the NAMPT1 inhibitor is independently selected from and, or a derivative thereof.

[0324] In certain embodiments of the antibody conjugates described herein, including Formula(la-1), (la-2), (la-3), (Ib-1), (Ib-2), or (Ib-3), (Ic-1), or (Ic-2), including any of the foregoing, the NAMPT1 inhibitor is independently selected fromandor a derivative thereof.

[0325] In one example, the PARP inhibitor linker-payload is or comprises the following structureor a salt thereof.

[0326] In some embodiments, the antibody conjugate comprises (a) the ^-glucuronide exatecan linker-payload that is or comprises the linker-payload of the following structure

[0327] or a salt thereof and (b) a PARP inhibitor linker-payload that is or comprises a linker-payload of the following structure:or a salt thereof.

[0328] In some embodiments, the at least one payload comprises an immunomodulatory agent.An immunomodulatory agent is an agent capable of regulating (e.g., stimulating or suppressing) the immune system of a subject.

[0329] In some embodiments, the immunomodulatory agent is an agonist of stimulator of interferon gene (STING), Toll-like receptor 7 (TLR7), Toll-like receptor 7 / 8 (TLR7 / 8), or Tolllike receptor 8 (TLR8). In some embodiments, the immunomodulatory agent is an agonist of STING. In some embodiments, the immunomodulatory agent is an agonist of Toll -like receptor 7 (TLR7). In some embodiments, the immunomodulatory agent is an agonist of Toll-like receptor 7 / 8 (TLR7 / 8). In some embodiments, the immunomodulatory agent is an agonist of Toll-like receptor 8 (TLR8). In some embodiments, the agonist of STING is selected from the group consisting of a small molecule agonist of the STING pathway, an antibody that activates STING activity, a recombinant protein that activates the STING pathway, TTI- 10001, DMXAA (ASA404), CDNs, c-di-GMP, 2'3'-cGAMP, MK-1454, ADU-S100 (MIW815), SB 11285, ADU-V19, IACS-8779, IACS-8803, IMSA101, non-CDNs, E7766, MK-2118, diABZI, MSA-2, JNJ-‘6196, bacterial vectors, SYNB1891, and STACT (see, e.g., Luo et al. Molecules 2022, 27, 4638, the contents of which are incorporated herein by reference in their entirety). In some embodiments, the agonist of STING is a small molecule agonist of the STING pathway. In some embodiments, the agonist of STING is an antibody that activates STING activity. In some embodiments, the agonist of STING is a recombinant protein that activates the STING pathway. In some embodiments, the agonist of STING is TTI-10001. In some embodiments, the agonist of STING is DMXAA (ASA404). In some embodiments, the agonist of STING is a CDN(s). In some embodiments, the agonist of STING is c-di-GMP. In some embodiments, the agonist of STING is 2'3'-cGAMP. In some embodiments, the agonist of STINGis MK-1454. In some embodiments, the agonist of STINGis ADU-S100 (MIW815). In some embodiments, the agonist of STING is SB 11285. In some embodiments, the agonist of STING is ADU-V19. In some embodiments, the agonist of STING is IACS-8779. In some embodiments, the agonist of STING is IACS-8803. In some embodiments, the agonist of STING is IMSA101. In some embodiments, the agonist of STING is a non-CDN(s). In some embodiments, the agonist of STING is E7766. In some embodiments, the agonist of STING is MK-21 18. In some embodiments, the agonist of STING is diABZI. In some embodiments, the agonist of STING is MSA-2. In some embodiments, the agonist of STING is JNJ-‘6196. In some embodiments, the agonist of STING is a bacterial vectors). In some embodiments, the agonist of STING is SYNB1891. In some embodiments, the agonist of STING is STACT.

[0330] In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is selected from the group consisting of GS-986, PRTX-007, PRX-034, S-34240, MBS-8, and APR-002 (see, e.g., Bhagchandani et al. Advanced Drug Delivery Reviews 2021, 175, 113803, the contents of which are incorporated by reference in their entirety). In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is GS-986. In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is PRTX-007. In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is PRX-034. In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is S-34240. In some embodiments, the agonist of Toll-like receptor 7 (TLR7) is MBS-8. In some embodiments, the agonist of Toll -like receptor 7 (TLR7) is APR-002.

[0331] In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is selected from the group consisting of imiquimod (R837), resiquimod (R848), 852-A (PF-4878691), vesatolimod (GS-9620), AZD8848, motolimod (VTX-2337), selgantolimod (GS-9688), NKTR-262, RG-7854 (RO 7020531), DSP-0509, BDB-001, BDC-1001, LHC-165, SHR- 2150, JNJ-4964 (TQ-73334), RO-7119929, DN-1508052, VTX-1463, BNT-411 (SCI), APR- 003, ALT-702, TRANSCON, VX-001, SNAPvax, R848-HA, SM360320, and GSK2245035 (see, e.g., Bhagchandani et al. Advanced Drug Delivery Reviews 2021, 175, 113803; and Evans etal. ACS Omega 2019, 4, 13, 15665, the contents of each are incorporated by reference in their entirety). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is imiquimod (R837). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is resiquimod (R848). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is 852-A (PF-4878691). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is vesatolimod (GS-9620). In some embodiments, the agonist of Toll -like receptor 7 / 8 (TLR7 / 8) is AZD8848. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is motolimod (VTX-2337). In some embodiments, the agonist of Toll -like receptor 7 / 8 (TLR7 / 8) is selgantolimod (GS-9688). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is NKTR-262. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is RG-7854 (RO 7020531). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is DSP-0509. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is BDB-001. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is BDC- 1001. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is LHC-165. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is SHR-2150. In some embodiments, the agonist of Toll -like receptor 7 / 8 (TLR7 / 8) is JNJ-4964 (TQ-73334). In some embodiments, the agonist of Toll -like receptor 7 / 8 (TLR7 / 8) is RO-7119929. In someembodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is DN-1508052. In some embodiments, the agonist of Toll -like receptor 7 / 8 (TLR7 / 8) is VTX-1463. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is BNT-411 (SCI). In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is APR-003. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is ALT-702. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is TRANSCON. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is VX-001. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is SNAPvax. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is R848-HA. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is SM360320. In some embodiments, the agonist of Toll-like receptor 7 / 8 (TLR7 / 8) is GSK2245035.

[0332] In some embodiments, the agonist of Toll-like receptor 8 (TLR8) is selected from the group consisting of SBT-6050, SBT-6290, and ZM-TLR8 agonist. In some embodiments, the agonist of Toll-like receptor 8 (TLR8) is SBT-6050. In some embodiments, the agonist of Tolllike receptor 8 (TLR8) is SBT-6290. In some embodiments, the agonist of Toll-like receptor 8 (TLR8) is ZM-TLR8 agonist.

[0333] Additional examples of STING agonists and TLR agonists also include those described in W02020252015, which is incorporated by reference herein in its entirety.

[0334] In one example, the STING agonist linker-payload is or comprises the following structure salt thereof.

[0335] In some embodiments, the antibody conjugate comprises (a) the β-glucuronide exatecan linker-payload that is or comprises the linker-payload of the following structure salt thereof and (b) a STING agonistlinker-payload that is or comprises a linker-payload of the following structure: salt thereof.

[0336] Additional examples of the immunomodulatory agents in the antibody conjugate include toll-like receptor agonists, kinase inhibitors, growth factor inhibitors (e.g, EGFR, PDGF, VEGF inhibitors), Calcineurin inhibitors, CRAC inhibitors, PARP1 antagonists, PPARy agonists, Kvl.3 antagonists, PP2A agonists, MYD88 inhibitors, BCL-2 inhibitors, Adenosine A2A receptor (A2ar) agonists, Toll-like receptor 4 (TLR4) agonists, Toll-like receptor 9 (TLR9) agonists, calcium-activated potassium channel (Kca3.1) agonists, TGFβ-R1 inhibitors, TGFβ-R2 inhibitors, GLi 1 inhibitors, tankyrase (TNKS) antagonists, Traf2 and Nck- interacting kinase (TNIK) antagonists, imides, and vitamin D receptor (VDR) agonists. Further examples of the immunomodulatory agents include kinase inhibitors (e.g., Phosphoinositide 3- kinase (PI3K) inhibitors (e.g, duvelisib, idelalisib), Bruton’s tyrosine kinase (BTK) inhibitors (e.g, ibrutinib, acalabrutinib), Janus kinase (JAK) inhibitors (e.g, ruxolitinib, tofacitinib),mitogen-activated protein kinases (MAPK, MEK), originally called extracellular signal- regulated kinases (ERK) inhibitors, c-jun N-terminal kinase (INK) inhibitors, Anaplastic lymphoma kinase (ALK) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, SRC proto-oncogene, non-receptor tyrosine kinase (Src) inhibitors (e.g., dasatinib, saracatinib, bosutinib, and KX01), Interleukin- 1 Receptor-Associated Kinase 4 (IRAK4) inhibitors (e.g., CA-4948), Receptor tyrosine kinase (cKIT) kinase inhibitors, Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) inhibitors, p38 mitogen-activated protein kinases (p38) inhibitors, Bcr-Abl tyrosine-kinase (TK1) inhibitors (e.g., imitanib), Aurora kinase inhibitors (e.g., barasertib (AZDI 152), alisertib (MLN8237), danusertib (PHA-739358)), tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR) (c-Met) inhibitors (e.g., sunitinib), cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitors (e.g., palbociclib (Ibrance®), ribociclib) or other suitable kinase inhibitors), Calcineurin inhibitors, CRAC inhibitors, PARP1 antagonists, PPARy agonists, Kvl.3 antagonists, PP2A agonists, MYD88 inhibitors, BCL-2 inhibitors (e.g., ABT- 199 (venetoclax, RG7601, GDC-0199), Adenosine A2A receptor (A2ar) agonists, (Tolllike receptor 7 / 8 (TLR7 / 8) agonists, calcium-activated potassium channel (Kca3.1) agonists, TGF-Rl inhibitors, TGF-R2 inhibitors, Epidermal growth factor receptor (EGFR) antagonists (e.g., gefitinib, erlotinib, afatinib, brigatinib, icotinib), Platelet derived growth factor (PDGF) inhibitors, Vascular endothelial growth factor (VEGF) inhibitors, GLi 1 inhibitors, tankyrase (TNKS) antagonists, Traf2 and Nck-interacting kinase (TNIK) antagonists, imides (e.g., lenalidomide, thalidomide, and pomalidomide), and vitamin D receptor (VDR) agonists.

[0337] In some embodiments, inhibitors of TGFpRl kinase include those disclosed in US Published Application 2018 / 0127426, US Patent No. 8,080,568, WO 2012 / 002680, WO 2009 / 009059, WO 2007 / 076127, WO 2007076086, WO 2006026306, Bioorg. Med. Chem., 2014, 22, 2724-2732 and J. Med. Chem. 2014, 57, 4213-4238, the disclosures of which are incorporated by reference herein.

[0338] In some embodiments, inhibitors of the TGFPR2 kinase include those disclosed in WO 2015 / 136073, Bioorg. Med. Chem. Lett., 2013, 23, 3248-3252, Acta Cryst, 2016, D72, 658- 674, WO 2016 / 020864, US Published Application 2014 / 0249135, US Published Application 20120225061 and compounds such as 3-amino-6-(4-(aminomethyl)phenyl)-N- (4- morpholinopyridin-3-yl)pyrazine-2-carboxamide, the disclosures of which are incorporated by reference herein.

[0339] In some embodiments, inhibitors of INKS include those disclosed CN 107226808, EP3313177, US Patent No. 9,505,749, US Published Application No. 2015 / 0045368, WO2014 / 036022, WO 2017 / 076484, WO 2018 / 046933, WO 2018 / 003962, Bur. J. Med. Chem., 2017, 142, 506-522, the disclosures of which are incorporated by reference herein.

[0340] In some embodiments, inhibitors of TNIK include those disclosed US Published Application 2016 / 0264555, WO 2015 / 083833, US Published Application 2010 / 0216795, US Published Application 20100137386, Med. Chem. Commun., 2015, 6, 1564-1572, andBioorg. Med. Chem. Lett., 2013, 23, 569-573, the disclosures of which are incorporated by reference herein.

[0341] In some embodiments, binding of an immunomodulatory agent to its target or protein target can inhibit the function of the protein target expressed in a myofibroblast, an immune cell, or both. In some embodiments, binding of an immunomodulatory agent to its target or target protein can increase the activity of a protein expressed in a myofibroblast, an immune cell, or both.

[0342] Further examples of immunomodulatory agents include agonists of the adenine- receptor A2Ra such as CGS-21680 or sphingosine- 1 analogues that increase activity of the phosphatase PP2A such as FTY720 and derived analogues. Some non-limiting examples of immune-modulatory compounds can include: protein kinase inhibitors for mTOR kinases such as rapamycin, in immune cells; inhibitors of the TGFPR2 kinase such as 3-amino-6-(4- (aminomethyl)phenyl)-N-(4-morpholinopyridin-3-yl)pyrazine-2-carboxamide, in myofibroblasts, immune cells or both; inhibitors of one or both of PI3Ky and PI3K5 such as Duvelisib, TG 100713, and PF 04691502 in immune cells; and inhibitors of TNIK such as KY- 05009 andNCB-0846 [4-((2-((4-(aminomethyl)-lH- benzo[d]imidazol-6-yl)amino)quinazolin- 8-yl)oxy)cyclohexan-l-ol] in myofibroblasts, immune cells or both.

[0343] In some additional embodiments, the immunomodulatory agent is an agent that modulates components of the immune system such that it would enhance the anti-tumor activity of the conjugate. Such agents would include but are not limited to agonists of Toll-Like receptors (e.g., poly-ICLC (Hiltonol), GLA, MEDI9197, VTX-2337 (Motolimid), CpG (SD- 101), and IMO-2125); agonists of the STING (stimulator of interferon genes) pathway (e.g., MK-1454, ADU-S100, and SB11285); activators of RIG-I-Like Receptor (RLR) signaling (e.g., RGT100); inhibitors of adenosinergic signaling (e.g., inhibitors of CD73, CD39 and A2R such as AB680, AB928, A000830, CPI-444), inhibitors of IDO-1 (indoleamine 2,3- dioxygenase 1) (e.g., GDC-0919 (navoximod), BMS-986205, and epacadostat); and small molecule blockers of the PD-1 pathway (e.g., CA-170, BMS-8, BMS-202, and AUNP12).

[0344] In some embodiments, the immunomodulatory agent is an anti-multiple myeloma agent. Examples of such immunomodulatory agents include, for example, lenalidomide, pomalidomide, and proteasome inhibitors. Examples of such proteasome inhibitors include, for example, bortezomib, carfilzomib, and ixazomib.

[0345] Additional examples of immunomodulatory agents include those described in W02020252015, which is incorporated by reference herein in its entirety.

[0346] Antibodies and Antigen Binding Fragments

[0347] The antibody is typically a protein comprising multiple polypeptide chains. In certain embodiments, the antibody is a heterotetramer comprising two identical light (L) chains and two identical heavy (H) chains. Each light chain can be linked to a heavy chain by one covalent disulfide bond. Each heavy chain can be linked to the other heavy chain by one or more covalent disulfide bonds. Each heavy chain and each light chain can also have one or more intrachain disulfide bonds. As is known to those of skill in the art, each heavy chain typically comprises a variable domain (VH) followed by a number of constant domains. Each light chain typically comprises a variable domain at one end (VL) and a constant domain. As is known to those of skill in the art, antibodies typically have selective affinity for their target molecules, i.e., antigens.

[0348] The antibodies provided herein can have any antibody form known to those of skill in the art. They can be full-length, or fragments. Exemplary full-length antibodies include IgA, IgAl, IgA2, IgD, IgE, IgG, IgGl, IgG2, IgG3, IgG4, IgM, and etc. Exemplary fragments include Fv, Fab, Fc, scFv, scFv-Fc, and etc.

[0349] In certain embodiments, the antibody of the conjugate comprises one, two, three, four, five, or six of the CDR sequences described herein. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (VH) described herein. In certain embodiments, the antibody of the conjugate comprises a light chain variable domain (VL) described herein. In certain embodiments, the antibody of the conjugate comprises a heavy chain variable domain (VH) described herein and a light chain variable domain (VL) described herein. In certain embodiments, the antibody of the conjugate comprises a paired heavy chain variable domain and a light chain variable domain described herein (VH - VL pair). In certain embodiments, the antibody of the conjugate comprises a three heavy chain CDRs and three light chain CDRs with sequences consisting of the heavy chain and light chain CDRs of any paired heavy chain variable domain and a light chain variable domain described herein (six CDRs of any VH - Wpair).

[0350] In certain embodiments, the antibody of the conjugate comprises any of the amino acid sequences of the antibodies described herein. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 10 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 9 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 8 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 7 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 6 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 5 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 4 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 3 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 2 amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 1 conservative amino acid substitution. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. For example, in certain embodiments, the antibody comprises any of the amino acid sequences above with up to 10 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 9 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 8 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 7 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 6 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 5 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 4 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 3 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 2 conservative amino acid substitutions. In certain embodiments, the antibody comprises any of the amino acid sequences above with up to 1 conservative amino acid substitution.

[0351] In certain embodiments, the antibody conjugate can be formed from an antibody that comprises one or more reactive groups. In certain embodiments, the antibody conjugate can be formed from an antibody comprising all naturally encoded amino acids. Those of skill in the art will recognize that several naturally encoded amino acids include reactive groups capable of conjugation to a payload or to a linker. These reactive groups include cysteine side chains, lysine side chains, and amino-terminal groups suitable for conjugation. In these embodiments, the antibody conjugate can comprise a payload or linker linked to the residue of an antibody reactive group. In these embodiments, the payload precursor or linker precursor comprises a reactive group capable of forming a bond with an antibody reactive group. Typical reactive groups include maleimide groups, activated carbonates (including but not limited to, p- nitrophenyl ester), activated esters (including but not limited to, N-hydroxysuccinimide, p- nitrophenyl ester, and aldehydes). Particularly usefill reactive groups include maleimide and succinimide, for instance N-hydroxysuccinimide, for forming bonds to cysteine and lysine side chains. Additional reactive groups include alkynes, for example strained alkynes, azides, and aminooxy groups, for forming bonds to non-natural amino acids incorporated in antibody polypeptide chains. Further reactive groups are described in the sections and examples below.

[0352] In certain embodiments, the antibody comprises one or more modified amino acids or non-natural amino acids having a reactive group, as described herein. Typically, the modified amino acid is not a naturally encoded amino acid. These modified amino acids can comprise a reactive group usefill for forming a covalent bond to a linker precursor or to a payload precursor. One of skill in the art can use the reactive group to link the polypeptide to any molecular entity capable of forming a covalent bond to the modified amino acid. Thus, provided herein are conjugates comprising an antibody comprising a modified amino acid residue linked to a payload directly or indirectly via a linker. Exemplary modified amino acids are described in the sections below. Generally, the modified amino acids have reactive groups capable of forming bonds to linkers or payloads with complementary reactive groups.

[0353] The non-natural or modified amino acids are positioned at select locations in a polypeptide chain of the antibody. In certain embodiments, these locations provide optimum sites for substitution with the non-natural or modified amino acids. Each site is capable of bearing a non-natural or modified amino acid with optimum structure, function and / or methods for producing the antibody.

[0354] In certain embodiments, a site-specific position for substitution provides an antibody that is stable. Stability can be measured by any technique apparent to those of skill in the art.

[0355] In certain embodiments, a site-specific position for substitution provides an antibody that has optimal functional properties. For instance, the antibody can show little or no loss of binding affinity for its target antigen compared to an antibody without the site-specific nonnatural or modified amino acid. In certain embodiments, the antibody can show enhanced binding compared to an antibody without the site-specific non-natural or modified amino acid.

[0356] In certain embodiments, a site-specific position for substitution provides an antibody that can be made advantageously. For instance, in certain embodiments, the antibody shows advantageous properties in its methods of synthesis, discussed below. In certain embodiments, the antibody can show little or no loss in yield in production compared to an antibody without the site-specific non-natural amino acid. In certain embodiments, the antibody can show enhanced yield in production compared to an antibody without the site-specific non-natural or modified amino acid. In certain embodiments, the antibody can show little or no loss of tRNA suppression compared to an antibody without the site-specific non-natural or modified amino acid. In certain embodiments, the antibody can show enhanced tRNA suppression in production compared to an antibody without the site-specific non-natural or modified amino acid.

[0357] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous solubility. In certain embodiments, the antibody can show little or no loss in solubility compared to an antibody without the site-specific non-natural or modified amino acid. In certain embodiments, the antibody can show enhanced solubility compared to an antibody without the site-specific non-natural or modified amino acid.

[0358] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous expression. In certain embodiments, the antibody can show little or no loss in expression compared to an antibody without the site-specific non-natural or modified amino acid. In certain embodiments, the antibody can show enhanced expression compared to an antibody without the site-specific non-natural or modified amino acid.

[0359] In certain embodiments, a site-specific position for substitution provides an antibody that has advantageous folding. In certain embodiments, the antibody can show little or no loss in proper folding compared to an antibody without the site-specific non-natural or modified amino acid. In certain embodiments, the antibody can show enhanced folding compared to an antibody without the site-specific non-natural or modified amino acid.

[0360] In certain embodiments, a site-specific position for substitution provides an antibody that is capable of advantageous conjugation. As described below, several non-natural or modified amino acids have side chains or functional groups that facilitate conjugation of theantibody to a second agent, either directly or via a linker. In certain embodiments, the antibody can show enhanced conjugation efficiency compared to an antibody without the same or other non-natural or modified amino acids at other positions. In certain embodiments, the antibody can show enhanced conjugation yield compared to an antibody without the same or other nonnatural or modified amino acids at other positions. In certain embodiments, the antibody can show enhanced conjugation specificity compared to an antibody without the same or other nonnatural or modified amino acids at other positions.

[0361] The one or more non-natural or modified amino acids are located at selected site- specific positions in at least one polypeptide chain of the antibody. The polypeptide chain can be any polypeptide chain of the antibody without limitation, including either light chain or either heavy chain. The site-specific position can be in any domain of the antibody, including any variable domain and any constant domain.

[0362] In certain embodiments, the antibodies provided herein comprise one non-natural or modified amino acid at a site-specific position. In certain embodiments, the antibodies provided herein comprise two non-natural or modified amino acids at site-specific positions. In certain embodiments, the antibodies provided herein comprise three non-natural or modified amino acids at site-specific positions. In certain embodiments, the antibodies provided herein comprise more than three non-natural or modified amino acids at site-specific positions. In certain embodiments, the antibodies provided herein comprise four non-natural or modified amino acids at site-specific positions.

[0363] The site-specific positions for substituting can be described with any antibody nomenclature system known to those of skill in the art. In the Kabat numbering system, these positions are at heavy chain residues HC005, HC023, HC042, HC065, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438. In other words, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from Kabat residues HC005, HC023, HC042,HC065, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438.

[0364] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues HC005, HC023, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC239, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC359, HC375, HC386, HC389, HC392, HC398, HC404, HC420, HC421, and HC438.

[0365] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues HC005, HC023, HC084, HC118, HC119, HC132, HC134, HC136, HC137, HC160, HC162, HC172, HC239, HC241, HC267, HC269, HC270, HC271, HC272, HC282, HC286, HC292, HC293, HC296, HC298, HC329, HC330, HC334, HC335, HC340, HC355, HC359, HC386, HC389, HC404, HC420, HC421, HC438, and HC342.

[0366] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues HC005, HC084, HC118, HC132, HC136, HC239, HC293, HC334, HC355, HC359, and HC389.

[0367] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues HC023, HC074, HC119, HC134, HC135, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, H294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329,HC330, HC332, HC333, HC335, HC337, HC339, HC342, HC344, HC355, HC375, HC386, HC392, HC398, HC404, HC420, HC421, HC340 and HC438.

[0368] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues HC042, HC065, HC138, HC155, HC174, HC176, HC177, HC219, HC238, HC243, HC262, HC264, HC265, HC278, HC342, HC356, HC358, HC360, HC383, HC384 HC404, and HC436.

[0369] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues corresponding to HC292-H301, HC303, andHC305.

[0370] In the Chothia numbering system, these positions are at heavy chain residues HC005, HC023, HC042, HC065, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438. In other words, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from Chothia residues HC005, HC023, HC042, HC065, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438.

[0371] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Chothia residues HC005, HC023, HC074, HC084, HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC239, HC241, HC246, HC267, HC268, HC269,HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC359, HC375, HC386, HC389, HC392, HC398, HC404, HC420, HC421, and HC438.

[0372] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Chothia residues HC005, HC084, HC118, HC132, HC136, HC239, HC293, HC334, HC342, HC355, HC359, HC389 and HC404.

[0373] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Kabat residues corresponding to HC292-H301, HC303, andHC305.

[0374] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Chothia residues HC023, HC074, HC119, HC134, HC135, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC335, HC337, HC339, HC342, HC344, HC355, HC375, HC386, HC392, HC398, HC420, HC421, HC340, HC404, and HC438.

[0375] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from Chothia residues HC042, HC065, HC138, HC155, HC174, HC176, HC177, HC219, HC238, HC243, HC262, HC264, HC265, HC278, HC342, HC356, HC358, HC360, HC383, HC384, HC404, and HC436.

[0376] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from residues HC005, HC023, HC084, HC118, HC119, HC132, HC134, HC136, HC137, HC160, HC162, HC172, HC239, HC241, HC267, HC269, HC270, HC271, HC272, HC282, HC286, HC292, HC293, HC296, HC298, HC329, HC330, HC334, HC335, HC340, HC355, HC359, HC386, HC389, HC404, HC420, HC421, HC438, and HC342, according to the Kabat or Chothia numbering scheme.

[0377] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, LC068, LC109, LC112, LC114, LC144, LC153, LC156,LC157, LC168, LC184, LC202, LC203, and LC206, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, LC068, LC109, LC112, LC114, LC144, LC153, LC156, LC168, LC184, LC202, and LC203, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, LC068, LC109, LC144, LC153, LC156, LC184, LC202, and LC203, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues LC042, LC049, LC056, LC057, LC060, LC067, LC109, LC153, LC202, and LC203, according to the Kabat or Chothia numbering scheme.

[0378] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues HC023, HC084, HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC164, HC195, HC197, HC219, HC282, HC289, HC296, HC330, HC335, HC361, HC400, HC404, HC422, HC440, HC260, HC267, HC268, HC272, HC274, HC292, HC293, HC297, HC298, HC303, HC305, HC332, HC333, HC334, HC340, HC341, HC342, HC343, HC355, HC362, HC386, HC392, HC404, HC424, HC438, HC442 and HC443, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC023, HC084, HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC164, HC195, HC197, HC219, HC282, HC296, HC335, HC361, HC422, HC440, HC267, HC272, HC274, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC342, HC343, HC355, HC362, HC392, HC404, HC424, HC438, HC442 and HC443, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC023, HC084, HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC195, HC197, HC219, HC282, HC296, HC422, HC440, HC267, HC272, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC342, HC355, HC392, HC404, HC424, HC438, HC442 and HC443, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC023, HC084, HC118, HC119, HC135, HC136, HC160, HC162, HC195,HC219, HC282, HC296, HC267, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC392, and HC438, HC442, according to the Kabat or Chothia numbering scheme.

[0379] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC051, HC052, HC053, HC056, HC070, HC082A, HC098, HC100, HC110, HC112, HC121, HC180, HC184, HC190, HC192, HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC052, HC053, HC056, HC070, HC082A, HC100, HC110, HC112, HC121, HC180, HC190, HC192, HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC052, HC070, HC082A, HC100, HC110, HC112, HC121, HC180, HC190, HC192, HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues HC007, HC014, HC019, HC025, HC040, HC043, HC052, HC070, HC100, HC110, HC112, HC121, HC180, HC214, HC216, HC222, HC227, HC230, HC23 1, HC232, and HC236, according to the Kabat or Chothia numbering scheme.

[0380] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues (-)LC001, LC003, LC005, LC007, LC008, LC009, LC010, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, LC107, LC138, LC142, LC143, LC152, LC171, LC182, LC188, LC199, andLC201, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues minus 1, LC003, LC005, LC007, LC008, LC009, LC010, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, LC107, LC142, LC143, LC152, LC171, LC182, LC188, LC199, and LC201, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one ormore non-natural amino acids at one or more positions selected from residues (-)LC001, LC003, LC005, LC007, LC008, LC009, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, LC107, LC142, LC152, LC171, LC182, LC188, and LC199, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from residues minus 1, LC005, LC007, LC008, LC016, LC017, LC018, LC020, LC022, LC027, LC045, LC058, LC063, LC077, LC079, LC107, LC142, LC152, LC182, LC188, and LC199, according to the Kabat or Chothia numbering scheme. In certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from residues (-)LC001, LC016, LC063, and LC199, according to the Kabat or Chothia numbering scheme.

[0381] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues HC019, HC025, HC051, HC070, HC098, HC110, HC112, HC121, HC136, HC180, HC187, HC190, HC214, HC216, HC221, and HC222, according to the Kabat or Chothia numbering scheme.

[0382] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues (-)LC001, LC007, LC008, LC016, LC022, LC063, LC014, LC070, LC138, LC142, LC143 and LC152, according to the Kabat or Chothia numbering scheme.

[0383] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues HC019, HC025, HC051, HC070, HC077, HC079, HC098, HC110, HC112, HC121, HC136, HC180, HC187, HC190, HC214, HC216, HC221, and HC222, according to the Kabat or Chothia numbering scheme.

[0384] In certain embodiments, provided herein are antibodies comprising one or more non- natural amino acids at one or more positions selected from residues (-)LC001, LC007, LC008, LC016, LC022, LC063, LC070, LC138, LC142, LC143, LC152 and LC201, according to the Kabat or Chothia numbering scheme.

[0385] Analysis of the data from TAG screening as presented in the Examples allowed selection of sites which are ideal candidates for making ADCs on the basis of cell killing, expression levels, drug-to-antibody ratio, solvent accessibility and (where available) thermal stability. The most preferred sites have lower solvent accessibility, and higher thermostability than the other tested variants. The preferred sites for nnAA incorporation are listed in Table I,below. Examples of site-specific positions for amino acid substitutions are also provided inTable IA and Table IB.Table I: Preferred Sites for nnAA IncorporationTable IA Examples of site-specific positions for amino acid substitutionPosition (HC Numbering Position in SEQ Position in SEQ Position in SEQ indicates a system ID NO: 7 ID NO: 20 (antiID NO: 12 heavy chain (Trastuzumab tissue factor (Trastuzumab position; LC HC) antibody HC) LC) indicates a light chain position)HC-S113 Kabat 120 120 N / AHC-A118 EU index of 121 12? N / AKabatHC-T120 EU index of 123 123 N / AKabatHC-R121 EU index of 124 124 N / AKabatHC-G138 EU index of 141 141 N / AKabatHC-A140 EU index of 143 143 N / AKabatPosition (HC Numbering Position in SEQ Position in SEQ Position in SEQ indicates a system ID NO: 7 ID NO: 20 (antiID NO: 12 heavy chain (Trastuzumab tissue factor (Trastuzumab position; LC HC) antibody HC) LC) indicates a light chain position) HC-T155 EU index of 158 158 N / AKabatHC-S160 EU index of 163 163 N / AKabatHC-A162 EU index of 165 165 N / AKabatHC-L163 EU index of 166 166 N / AKabatHC-Q196 EU index of 199 199 N / AKabatHC-I199 EU index of 202 202 N / AKabatHC-N203 EU index of 206 206 N / AKabatHC-T209 EU index of 212 212 N / AKabatHC-K210 EU index of 213 213 N / AKabatHC-R222 EU index of 225 225 N / AKabatHC-K246 Eu index of 249 249 N / AKabatHC-E258 EU index of 261 261 N / AKabatHC-K290 EU index of 293 293 N / AKabatHC-E294 EU index of 297 297 N / AKabatHC-Q295 EU index of 298 298 N / AKabatHC-Y296 EU index of 299 299 N / AKabatHC-N297 EU index of 300 300 N / AKabatHC-Y300 EU index of 303 303 N / AKabatHC-V303 EU index of 306 306 N / AKabatHC-V305 EU index of 308 308 N / AKabatHC-E318 EU index of 321 321 N / AKabatPosition (HC Numbering Position in SEQ Position in SEQ Position in SEQ indicates a system ID NO: 7 ID NO: 20 (antiID NO: 12 heavy chain (Trastuzumab tissue factor (Trastuzumab position; LC HC) antibody HC) LC) indicates a light chain position)HC-A330 EU index of 333 333 N / A KabatHC-T335 EU index of 338 338 N / A KabatHC-I336 EU index of 339 339 N / A KabatHC-S337 EU index of 340 340 N / A KabatHC-R344 EU index of 347 347 N / A KabatHC-E345 EU index of 348 348 N / A KabatHC-R355 EU index of 358 358 N / A KabatHC-M358 EU index of 361 361 N / A KabatHC-Q362 EU index of 365 365 N / A KabatHC-E382 EU index of 385 385 N / A KabatHC-E388 EU index of 391 391 N / A KabatHC-N390 EU index of 393 393 N / A KabatHC-Y391 EU index of 394 394 N / A KabatHC-K392 EU index of 395 395 N / A KabatHC-T393 EU index of 396 396 N / A KabatHC-T411 EU index of 414 414 N / A KabatHC- N421 EU index of 424 424 N / A KabatHC-S424 EU index of 427 427 N / A KabatHC-Q438 EU index of 441 441 N / A KabatHC-L443 EU index of 446 446 N / A KabatLC-T109 Kabat N / A N / A 109LC-V110 Kabat N / A N / A 110Position (HC Numbering Position in SEQ Position in SEQ Position in SEQ indicates a system ID NO: 7 ID NO: 20 (antiID NO: 12 heavy chain (Trastuzumab tissue factor (Trastuzumab position; LC HC) antibody HC) LC) indicates a light chain position) LC-A111 Kabat N / A N / A 111 LC-A112 Kabat N / A N / A 112 LC-D122 Kabat N / A N / A 122 LC-Q124 Kabat N / A N / A 124 LC-R126 Kabat N / A N / A 126 LC-S127 Kabat N / A N / A 127 LC-T129 Kabat N / A N / A 129 LC-N138 Kabat N / A N / A 138 LC-R142 Kabat N / A N / A 142 LC-E143 Kabat N / A N / A 143 LC-Q147 Kabat N / A N / A 147 LC-R149 Kabat N / A N / A 149 LC-D151 Kabat N / A N / A 151 LC-A153 Kabat N / A N / A 153 LC-L154 Kabat N / A N / A 154 LC-Q155 Kabat N / A N / A 155 LC-S159 Kabat N / A N / A 159 LC-E165 Kabat N / A N / A 165 LC-Q166 Kabat N / A N / A 166 LC-S168 Kabat N / A N / A 168 LC-R169 Kabat N / A N / A 169 LC-S171 Kabat N / A N / A 171 LC-T172 Kabat N / A N / A 172 LC-T180 Kabat N / A N / A 180 LC-A184 Kabat N / A N / A 184 LC-E187 Kabat N / A N / A 187 LC-H189 Kabat N / A N / A 189 LC-R190 Kabat N / A N / A 190 LC-V191 Kabat N / A N / A 191 LC-E195 Kabat N / A N / A 195 LC-L201 Kabat N / A N / A 201 LC-S202 Kabat N / A N / A 202 LC-S203 Kabat N / A N / A 203 LC-V205 Kabat N / A N / A 205 LC-T206 Kabat N / A N / A 206Table IB. Additional examples of site-specific positions for amino acid substitutionPosition (HC Numbering Position in SEQ Position in SEQ Position in SEQ indicates a system ID NO: 7 ID NO: 20 (antiID NO: 12 heavy chain (Trastuzumab tissue factor (Trastuzumab position; LC HC) antibody HC) LC) indicates a light chain position)Y180 EU index of 183 183 N / AKabat _F241 EU index of 244 244 N / AKabat _F404 EU index of 407 407 N / AKabat _V264 EU index of 267 267 N / AKabat _K42 Kabat N / A N / A 42

[0386] Accordingly, in certain embodiments, provided herein are antibodies comprising one or more non-natural amino acids at one or more positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-R121, HC-Y180, HC-F241, LCC-T22, LCC-S7, LCC-N152, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-R222, HC-R19, HC-Y52, or HC-S70 according to the Kabat or Chothia numbering scheme, or a post- translationally modified variant thereof.

[0387] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, LCC-T22, LCC-S7, LCC- N152, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, andHC-K222 according to the Kabat or Chothia numbering scheme, or a post-translationally modified variant thereof.

[0388] In certain embodiments, provided herein are antibodies comprising one or more nonnatural amino acids at one or more positions selected from the group consisting of heavy chain or light chain residues HC-F404, HC-R121, HC-Y180, HC-F241, LCC-T22, LCC-S7, LCC- N152, and HC-S136 according to the Kabat or Chothia numbering scheme, or a post- translationally modified variant thereof.

[0389] The site-specific positions for substituting can be described with any antibody nomenclature system known to those of skill in the art. In the Kabat numbering system, these positions are at heavy chain or light chain residues LC22, LC7, HC25, HC40, HC19, HC52, HC70, and HC110. In the EU numbering system, these positions are at heavy chain or light chain residues HC404, HC121, HC180, LC152, HC136, HC119, HC190, HC222, and HC221.In other words, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from Kabat residues LC22, LC7, HC25, HC40, HC19, HC52, HC70, and HC110; and EU residues HC404, HC121, HC180, LC152, HC136, HC119, HC190, HC222, and HC221.

[0390] In other embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from EU residues HC404, HC121, HC180, HC136, HC119, HC190, HC222, andHC221; and Kabat residues HC25, HC40, HC19, HC52, HC70, and HCHO.

[0391] In other embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC005, HC023, HC042, HC065, HC074, and HC084; and EU residues HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438.

[0392] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC005, HC023, HC074, and HC084; and EU residues HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC239, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC359, HC375, HC386, HC389, HC392, HC398, HC404, HC420, HC421, and HC438.

[0393] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC005, HC023, and HC084; and EU residues HC118, HC119, HC132, HC134, HC136, HC137, HC160, HC162, HC172, HC239, HC241, HC267, HC269, HC270, HC271, HC272, HC282, HC286,HC292, HC293, HC296, HC298, HC329, HC330, HC334, HC335, HC340, HC355, HC359, HC386, HC389, HC404, HC420, HC421, HC438, and HC342.

[0394] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC005 and HC084; and EU residues HC118, HC132, HC136, HC239, HC293, HC334, HC355, HC359, and HC389.

[0395] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC023 and HC074; and EU residues HC119, HC134, HC135, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC335, HC337, HC339, HC342, HC344, HC355, HC375, HC386, HC392, HC398, HC404, HC420, HC421, HC340 and HC438.

[0396] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat residues HC042 and HC065; and EU residues HC138, HC155, HC174, HC176, HC177, HC219, HC238, HC243, HC262, HC264, HC265, HC278, HC342, HC356, HC358, HC360, HC383, HC384 HC404, and HC436.

[0397] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from EU residues corresponding to HC292-H301, HC303, and HC305.

[0398] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Chothia residues HC005, HC023, HC042, HC065, HC074, and HC084; and EU residues HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299.H300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC404, HC420, HC421, HC436, and HC438.

[0399] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Chothia residues HC005, HC023, HC074, and HC084; and EU residues HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC239, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC342, HC344, HC355, HC359, HC375, HC386, HC389, HC392, HC398, HC404, HC420, HC421, and HC438.

[0400] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Chothia residues HC005 and HC084; and EU residues HC118, HC132, HC136, HC239, HC293, HC334, HC342, HC355, HC359, HC389 and HC404.

[0401] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from EU residues corresponding to HC292-H301, HC303, and HC305.

[0402] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Chothia residues HC023 and HC074; and EU residues HC119, HC134, HC135, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC335, HC337, HC339, HC342, HC344, HC355, HC375, HC386, HC392, HC398, HC420, HC421, HC340, HC404, and HC438.

[0403] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Chothia residues HC042 and HC065; and EU residues HC138, HC155, HC174, HC176, HC177, HC219, HC238, HC243, HC262, HC264, HC265, HC278, HC342, HC356, HC358, HC360, HC383, HC384, HC404, and HC436.

[0404] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from Kabat or Chothia residues HC005, HC023, and HC084; and EU residues HC118, HC119, HC132, HC134, HC136, HC137, HC160, HC162, HC172, HC239, HC241, HC267, HC269, HC270, HC271, HC272,HC282, HC286, HC292, HC293, HC296, HC298, HC329, HC330, HC334, HC335, HC340, HC355, HC359, HC386, HC389, HC404, HC420, HC421, HC438, and HC342.

[0405] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC22 and LC7 according to the Kabat or Chothia numbering schemes, and LC152 according to the EU numbering scheme.

[0406] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC112, LC114, LC144, LC153, LC156, LC157, LC168, LC184, LC202, LC203, and LC206, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC1 12, LC114, LC144, LC153, LC156, LC168, LC184, LC202, and LC203, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC144, LC153, LC156, LC184, LC202, and LC203, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues LC042, LC049, LC056, LC057, LC060, and LC067 according to the Kabat or Chothia numbering schemes; and LC109, LC153, LC202, and LC203, according to the EU numbering scheme.

[0407] In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues HC023 and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC164, HC195, HC197, HC219, HC282, HC289, HC296, HC330, HC335, HC361, HC400, HC404, HC422, HC440, HC260, HC267, HC268, HC272, HC274, HC292, HC293, HC297, HC298, HC303, HC305, HC332, HC333, HC334, HC340, HC341, HC342, HC343, HC355, HC362, HC386, HC392, HC404, HC424, HC438, HC442 and HC443, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positionsselected from residues HC023 and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC164, HC195, HC197, HC219, HC282, HC296, HC335, HC361, HC422, HC440, HC267, HC272, HC274, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC342, HC343, HC355, HC362, HC392, HC404, HC424, HC438, HC442 and HC443, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues HC023 and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC135, HC136, HC137, HC160, HC161, HC162, HC195, HC197, HC219, HC282, HC296, HC422, HC440, HC267, HC272, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC342, HC355, HC392, HC404, HC424, HC438, HC442 and HC443, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues HC023 and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC135, HC136, HC160, HC162, HC195, HC219, HC282, HC296, HC267, HC293, HC297, HC298, HC303, HC305, HC334, HC340, HC341, HC392, and HC438, HC442, according to the EU numbering scheme.

[0408] In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC051, HC052, HC053, HC056, HC070, HC082A, HC098, HC100, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC180, HC184, HC190, HC192, HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC052, HC053, HC056, HC070, HC082A, HC100, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC180, HC190, HC192, HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues HC042, HC003, HC007, HC014, HC016, HC019, HC025, HC040, HC043, HC052, HC070, HC082A, HC100, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC180, HC190, HC192,HC214, HC216, HC221, HC222, HC225, HC227, HC230, HC231, HC232, and HC236, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues HC007, HC014, HC019, HC025, HC040, HC043, HC052, HC070, HC100, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC180, HC214, HC216, HC222, HC227, HC230, HC231, HC232, and HC236, according to the EU numbering scheme.

[0409] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC005, HC023, HC042, HC065, HC074, and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC138, HC139, HC155, HC160, HC162, HC165, HC172, HC174, HC176, HC177, HC191, HC194, HC219, HC238, HC239, HC241, HC243, HC246, HC262, HC264, HC265, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC278, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC344, HC355, HC356, HC358, HC359, HC360, HC375, HC383, HC384, HC386, HC389, HC392, HC398, HC420, HC421, HC436, and HC438 according to the EU numbering scheme.

[0410] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC005, HC023, HC074, and HC084 according to the Kabat or Chothia numbering schemes; and HC118, HC119, HC132, HC134, HC135, HC136, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC239, HC241, HC246, HC267, HC268, HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC293, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC334, HC335, HC337, HC339, HC340, HC344, HC355, HC359, HC375, HC386, HC389, HC392, HC398, HC420, HC421, and HC438 according to the EU numbering scheme.

[0411] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC023 and HC074 according to the Kabat or Chothia numbering schemes; and HC119, HC134, HC135, HC137, HC139, HC160, HC162, HC165, HC172, HC191, HC194, HC241, HC246, HC267, HC268,HC269, HC270, HC271, HC272, HC274, HC275, HC280, HC281, HC282, HC283, HC286, HC289, HC292, HC294, HC295, HC296, HC297, HC298, HC299, HC300, HC301, HC303, HC305, HC317, HC320, HC324, HC326, HC327, HC329, HC330, HC332, HC333, HC335, HC337, HC339, HC340, HC344, HC355, HC375, HC386, HC392, HC398, HC420, HC421, and HC438 according to the EU numbering scheme.

[0412] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC042 and HC065 according to the Kabat or Chothia numbering schemes; and HC138, HC155, HC174, HC176, HC177, HC219, HC238, HC243, HC262, HC264, HC265, HC278, HC356, HC358, HC360, HC383, HC384 and HC436 according to the EU numbering scheme.

[0413] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC019, HC025, HC040, HC052, and HC071 according to the Kabat or Chothia numbering schemes; and HC117, HC119, HC124, HC139, HC183, HC193, HC224, HC225, and HC407 according to the EU numbering scheme.

[0414] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC019, HC025, HC040, HC052, and HC070 according to the Kabat or Chothia numbering schemes; and HC119, HC121, HC136, HC180, HC190, HC222, HC241, and HC404 according to the EU numbering scheme.

[0415] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC025 and HC040 according to the Kabat or Chothia numbering schemes; and HC119, HC121, HC136, HC180, HC190, HC222, HC241, and HC404 according to the EU numbering scheme.

[0416] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC121, HC136, HC180, HC241, and HC404 according to the EU numbering scheme.

[0417] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues (-)LC001, LC003, LC005, LC007, LC008, LC009, LC010, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, and LC107 according to the Kabat or Chothia numbering schemes; and LC138, LC142, LC143, LC152, LC171, LC182, LC188, LC199, and LC201 according to the EU numbering scheme. In certainembodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues minus 1, LC003, LC005, LC007, LC008, LC009, LC010, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, and LC107 according to the Kabat or Chothia numbering schemes; and LC142, LC143, LC152, LC171, LC182, LC188, LC199, and LC201, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues (-)LC001, LC003, LC005, LC007, LC008, LC009, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, and LC107 according to the Kabat or Chothia numbering schemes; and LC142, LC152, LC171, LC182, LC188, and LC199, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues minus 1, LC005, LC007, LC008, LC016, LC017, LC018, LC020, LC022, LC027, LC045, LC058, LC063, LC077, LC079, and LC 107 according to the Kabat or Chothia numbering schemes; and LC 142, LC 152, LC182, LC188, and LC199, according to the EU numbering scheme. In certain embodiments, provided herein are antibodies comprising two or more non-natural amino acids at least one or more positions selected from residues (-)LC001 , LCO 16, and LC063 according to the Kabat or Chothia numbering schemes; and LC199 according to the EU numbering scheme.

[0418] In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC112, LC114, LC144, LC153, LC156, LC168, LC184, LC202, and LC203 according to the EU numbering scheme.

[0419] In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues minus LC001, LC003, LC005, LC007, LC008, LC009, LC016, LC017, LC018, LC020, LC022, LC026, LC027, LC045, LC058, LC063, LC065, LC066, LC070, LC077, LC079, and LC107 according to the Kabat or Chothia numbering schemes; and LC142, LC152, LC171, LC182, LC188, and LC199 according to the EU numbering scheme.

[0420] In certain embodiments, provided herein are antibodies comprising two or more non- natural amino acids at least one or more positions selected from residues minus LC001, LC005, LC007, LC008, LC016, LC017, LC018, LC020, LC022, LC027, LC045, LC058, LC063,LC077, LC079, and LC107 according to the Kabat or Chothia numbering schemes; and LC142, LC152, LC182, LC188, and LC199 according to the EU numbering scheme.

[0421] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues minus LC001, LC016, and LC063 according to the Kabat or Chothia numbering schemes; and LC199 according to the EU numbering scheme.

[0422] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues minus LC001, LC007, LC008, LC014, LC016, LC022, LC063, and LC070 according to the Kabat or Chothia numbering schemes; and LC138, LC142, LC143 and LC152 according to the EU numbering scheme.

[0423] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues minus LC001, LC007, LC008, LC016, LC022, LC063, and LC070 according to the Kabat or Chothia numbering schemes; and LC138, LC142, LC143, LC152, and LC201 according to the EU numbering scheme.

[0424] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC112, LC114, LC144, LC153, LC156, LC157, LC168, LC184, LC202, LC203, and LC206 according to the EU numbering scheme.

[0425] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; andLC109, LC112, LC144, LC153, LC156, LC168, LC184, LC202, and LC203 according to the EU numbering scheme.

[0426] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC042, LC043, LC049, LC056, LC057, LC060, LC067, and LC068 according to the Kabat or Chothia numbering schemes; and LC109, LC144, LC153, LC156, LC184, LC202, and LC203 according to the EU numbering scheme.

[0427] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues LC049, LC056,LC057, LC060, and LC067 according to the Kabat or Chothia numbering schemes; and LC109, LC153, LC202, and LC203 according to the EU numbering scheme.

[0428] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC019, HC025, HC051, HC070, HC098, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC136, HC180, HC187, HC190, HC214, HC216, HC221, and HC222, according to the EU numbering scheme.

[0429] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues (-)LC001, LC007, LC008, LC016, LC022, LC063, LC014, and LC070 according to the Kabat or Chothia numbering schemes; and LC138, LC142, LC143 and LC152, according to the EU numbering scheme.

[0430] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues HC019, HC025, HC051, HC070, HC077, HC079, HC098, HC110, and HC112 according to the Kabat or Chothia numbering schemes; and HC121, HC136, HC180, HC187, HC190, HC214, HC216, HC221, and HC222, according to the EU numbering scheme.

[0431] In certain embodiments, provided herein are antibodies comprising two or more nonnatural amino acids at least one or more positions selected from residues (-)LC001, LC007, LC008, LC016, LC022, LC063, and LC070 according to the Kabat or Chothia numbering schemes; and LC138, LC142, LC143, LC152 and LC201, according to the EU numbering scheme.

[0432] In one aspect, the present disclosure provides an antibody comprising one or more nonnatural amino acid residues at one or more positions selected from the group consisting of HC- S113 according to Kabat numbering, HC-A118, HC-T120, HC-K121, HC-G138, HC-A140, HC-T155, HC-S160, HC-A162, HC-L163, HC-Q196, HC-I199, HC-N203, HC-T209, HC- K210, HC-E258, HC-K290, HC-Y296, HC-T335, HC-I336, HC-S337, HC-R344, HC-E345, HC-R355, HC-M358, HC-Q362, HC-E382, HC-E388, HC-N390, HC-Y391, HC-K392, HC- T393, HC-T411, HC- N421, HC-S424, HC-Q438, HC-L443 according to EU index of Kabat, LC-T109, LC-V110, LC-A111, LC-A112, LC-D122, LC-Q124, LC-K126, LC-S127, LC- T129, LC-N138, LC-R142, LC-E143, LC-Q147, LC-K149, LC-D151, LC-A153, LC-L154, LC-Q155, LC-S159, LC-E165, LC-Q166, LC-S168, LC-K169, LC-S171, LC-T172, LC-T180, LC-A184, LC-E187, LC-H189, LC-K190, LC-V191, LC-E195, LC-L201, LC-S202, LC-S203,LC-V205, and LC-T206 according to Kabat numbering, or a post-translationally modified variant thereof.

[0433] In some embodiments, the antibody further comprises one or more additional non- natural amino acid residues at one or more additional positions selected from the group consisting of 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, and HC-S70 according to EU index of Kabat. In some embodiments, the one or more additional non-natural amino acid residues is at one or more positions selected from the group consisting of HC-Y180, HC-F241, HC-F404 HC, and LC-K42 according to EU index of Kabat.

[0434] In certain embodiments, the antibodies provided herein comprise one or more nonnatural or modified amino acids each at a position 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. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC- F404, HC-Y180, HC-F241, HC-Y391, LC-K42, and LC-E161, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F404, HC-Y180, HC-F241, HC-Y391, and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F404, HC-F241, and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F404 and HC-F241, according to the Kabat or Chothia or EU numbering scheme, or a post- translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions selected from the groupconsisting of heavy chain or light chain residues HC-F404 and HC-F241, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F404 and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise one or more non-natural or modified amino acids each at a position selected from the group consisting of heavy chain or light chain residues HC-F241 and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post- translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position HC-F404 according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position HC-F241 according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position HC-Y180, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions HC-F404 and HC-Y180, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position HC-F241 according to the Kabat or Chothia or EU numbering scheme, or a post- translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position LC-K42 according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise a non-natural or modified amino acid at position LC-E161 according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions HC-F404, HC- Y180, and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post- translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions HC-F404, HC-Y180, LC- K42, and LC-E161, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions HC-F404, HC-Y180, and HC-F241, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise nonnatural or modified amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In certain embodiments, the antibodies provided herein comprise non-natural or modified amino acids at positions HC-F404, HC-Y180, HC-F241, and LC-K42, according to the Kabat or Chothia or EU numbering scheme, or a post-translationally modified variant thereof. In these designations, HC indicates a heavy chain residue, and LC indicates a light chain residue.

[0435] The parent antibody can be any antibody known to those of skill in the art, or later discovered, without limitation. The parent antibody may be substantially encoded by an antibody gene or antibody genes from any organism, including but not limited to humans, mice, rats, rabbits, camels, llamas, dromedaries, monkeys, particularly mammals and particularly human and particularly mice and rats. In one embodiment, the parent antibody may be fully human, obtained for example from a patient or subject, by using transgenic mice or other animals (Bruggemarm& Taussig, 1997, Curr. Opin. Biotechnol. 8:455-458) or human antibody libraries coupled with selection methods (Griffiths & Duncan, 1998, Curr. Opin. Biotechnol. 9:102-108). The parent antibody may be from any source, including artificial or naturally occurring. For example, parent antibody can be an engineered antibody, including but not limited to chimeric antibodies and humanized antibodies (Clark, 2000, Immunol. Today 21:397-402) or derived from a combinatorial library. In addition, the parent antibody may be an engineered variant of an antibody that is substantially encoded by one or more natural antibody genes. For example, in one embodiment the parent antibody is an antibody that has been identified by affinity maturation.

[0436] The parent antibody can have affinity to any antigen known to those of skill in the art, or later discovered. Virtually any substance may be an antigen for a parent antibody, or an antibody of the present description. Examples of useful antigens include, but are not limited to, alpha- 1 antitrypsin, angiostatin, antihemolytic factor, antibodies, apolipoprotein, apoprotein, atrial natriuretic factor, atrial natriuretic polypeptide, atrial peptides, C-X-C chemokines (e.g., T39765, NAP-2, ENA-78, Gro-a, Gro-b, Gro-c, IP-10, GCP-2, NAP-4, SDF-1, PF4, MIG), calcitonin, CC chemokines (e.g., monocyte chemoattractant protein- 1, monocytechemoattractant protein-2, monocyte chemoattractant protein-3, monocyte inflammatory protein-1 alpha, monocyte inflammatory protein-1 beta, RANTES, 1309, R83915, R91733, HCC1, T58847, D31065, T64262), CD40 ligand, C-kit ligand, collagen, colony stimulating factor (CSF), complement factor 5a, complement inhibitor, complement receptor 1, cytokines, (e.g., epithelial neutrophil activating peptide-78, GRO / MGSA, GRO, GRO, MIP-1, MIP-1, MCP-1), epidermal growth factor (EGF), erythropoietin ("EPO"), exfoliating toxins A and B, factor IX, factor VII, factor Vm, factor X, fibroblast growth factor (FGF), fibrinogen, fibronectin, G-CSF, GM-CSF, glucocerebrosidase, gonadotropin, growth factors, hedgehog proteins (e.g., Sonic, Indian, Desert), hemoglobin, hepatocyte growth factor (HGF), hirudin, human serum albumin, insulin, insulin-like growth factor (IGF), interferons (e.g., IFN-o, IFN- , IFN-y), interleukins (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, etc.), keratinocyte growth factor (KGF), lactoferrin, leukemia inhibitory factor, luciferase, neurturin, neutrophil inhibitory factor (NIF), oncostatin M, osteogenic protein, parathyroid hormone, PD-ECSF, PDGF, peptide hormones (e.g., human growth hormone), pleiotropin, protein A, protein G, pyrogenic exotoxins A, B, and C, relaxin, renin, SCF, soluble complement receptor I, soluble I-CAM 1, soluble interleukin receptors (IL-1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15), soluble TNF receptor, somatomedin, somatostatin, somatotropin, streptokinase, superantigens, i.e., staphylococcal enterotoxins (SEA, SEB, SEC1, SEC2, SEC3, SED, SEE), superoxide dismutase, toxic shock syndrome toxin (TSST-1), thymosin alpha 1, tissue plasminogen activator, tumor necrosis factor (TNFP), tumor necrosis factor receptor (TNFR), tumor necrosis factor-alpha (TNFa), vascular endothelial growth factor (VEGF), urokinase and others. These antigens can be obtained by methods known to those of skill in the art, for example, from commercial sources or from published polypeptide or polynucleotide sequences (e.g. Genbank).

[0437] Additional antigens include, but are not limited to, transcriptional and expression activators. Exemplary transcriptional and expression activators include genes and proteins that modulate cell growth, differentiation, regulation, or the like. Expression and transcriptional activators are found in prokaryotes, viruses, and eukaryotes, including fungi, plants, and animals, including mammals, providing a wide range of therapeutic targets. It will be appreciated that expression and transcriptional activators regulate transcription by many mechanisms, e.g., by binding to receptors, stimulating a signal transduction cascade, regulating expression of transcription factors, binding to promoters and enhancers, binding to proteins that bind to promoters and enhancers, unwinding DNA, splicing pre-mRNA, polyadenylatingRNA, and degrading RNA. Antigens include, but are not limited to, expression activators such as cytokines, inflammatory molecules, growth factors, their receptors, and oncogene products, e.g., interleukins (e.g., IL-1, IL-2, IL-8, etc.), interferons, FGF, IGF-I, IGF-II, FGF, PDGF, TNF, TGF-o, TGF-P, EGF, KGF, SCF / c-Kit, CD40L / CD40, VLA-4VCAM-1, ICAM-l / LFA- 1, and hyalurin / CD44; signal transduction molecules and corresponding oncogene products, e.g., Mos, Ras, Raf, and Met; and transcriptional activators and suppressors, e.g., p53, Tat, Fos, Myc, Jim, Myb, Rel, and steroid hormone receptors such as those for estrogen, progesterone, testosterone, aldosterone, the LDL receptor ligand and corticosterone.

[0438] Vaccine proteins may be antigens including, but not limited to, proteins from infectious fungi, e.g., Aspergillus, Candida species; bacteria, particularly E. coli, which serves a model for pathogenic bacteria, as well as medically important bacteria such as Staphylococci (e.g., aureus), or Streptococci (e.g., pneumoniae); protozoa such as sporozoa (e.g., Plasmodia), rhizopods (e.g., Entamoeba) and flagellates (Trypanosoma, Leishmania, Trichomonas, Giardia, etc.); viruses such as (+) RNA viruses (examples include Poxviruses e.g., vaccinia; Picomaviruses, e.g. polio; Togaviruses, e.g., rubella; Flaviviruses, e.g., HCV; and Coronaviruses), (-) RNA viruses (e.g., Rhabdoviruses, e.g., VSV; Paramyxoviruses, e.g., RSV; Orthomyxoviruses, e.g., influenza; Bunyaviruses; and Arenaviruses), dsDNA viruses (Reoviruses, for example), RNA to DNA viruses, i.e., Retroviruses, e.g., HIV and HTLV, and certain DNA to RNA viruses such as Hepatitis B.

[0439] Antigens may be enzymes including, but not limited to, amidases, amino acid racemases, acylases, dehalogenases, dioxygenases, diarylpropane peroxidases, epimerases, epoxide hydrolases, esterases, isomerases, kinases, glucose isomerases, glycosidases, glycosyl transferases, haloperoxidases, monooxygenases (e.g., p450s), lipases, lignin peroxidases, nitrile hydratases, nitrilases, proteases, phosphatases, subtilisins, transaminase, and nucleases.

[0440] Agriculturally related proteins such as insect resistan...

Claims

1. CLAIMSWhat is claimed is:

1. An antibody conjugate comprising: a. an antibody, or antigen binding fragment thereof, that comprises one or more non-natural amino acid residues; and b. one or more payloads, wherein at least one of the payloads is linked to at least one of the one or more non-natural amino acid residues; c. wherein the antibody conjugate has a payload to antibody ratio of greater than 8.

2. The antibody conjugate of claim 1, wherein the payload to antibody ratio is at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, or at least 30.

3. The antibody conjugate of claim 1 or 2, wherein the payload to antibody ratio is at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 22.

4. The antibody conjugate of any of the preceding claims, wherein the payload to antibody ratio is up to 30.

5. The antibody conjugate of any of the preceding claims, wherein the payload to antibody ratio is up to 24.

6. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1 to 14 non-natural amino acids.The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1 to 8 non-natural amino acids.

8. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1 to 7 non-natural amino acids.

9. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 4 to 6 non-natural amino acids.

10. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 non-natural amino acids.

11. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1, 2, 3, 4, 5, 6, 7, or 8 non-natural amino acids.

12. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, comprises 1, 2, 3, 4, 5, 6, or 7 non-natural amino acids.

13. The antibody conjugate of any of the previous claims, further comprising at least one payload linked to a natural amino acid residue of the antibody, or antigen binding fragment thereof.

14. The antibody conjugate of any of claim 6, wherein the at least one payload linked to a natural amino acid residue of the antibody, or antigen binding fragment thereof, is linked to a residue selected from a cysteine residue, glutamine residue, lysine residue, and amino-terminal residue.

15. The antibody conjugate of any of the preceding claims, wherein at the one or more non- natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sites selected from the group consisting of heavy chain or light chain residues H005, H023, H042, H065, H074, H084, Hl 18, Hl 19, H132, H134, H135, H136, H137, H138, H139, H155, H160, H162, H165, H172, H174, H176, H177, H191, H194, H219, H238, H239, H241, H243, H246, H262, H264, H265, H267, H268, H269, H270, H271, H272, H274, H275, H278, H280, H281, H282, H283, H286, H289, H292, H293, H294, H295, H296, H297, H298, H299.H300, H301, H303, H305, H317, H320, H324, H326, H327, H329, H330, H332, H333, H334, H335, H337, H339, H340, H342, H344, H355, H356, H358, H359, H360, H375, H383, H384, H386, H389, H392, H398, H404, H420, H421, H436, H438, (-)LC001, L003, LOOS, L007, LOOS, L009, L010, LOW, L017, L018, L020, L022, L026, L027, L042, L043, L045, L049, L056, L057, LOSS, L060, L063, L065, L066, L067, L068, L070, L077, L079, L107, L109, LI 12, LI 14, L138, L142, L143, L144, L152, L153, L156, L157, L168, L171, L182, L184, LISS, L199, L201, L202, L203, and L206, according to the Kabat, EU, or Chothia numbering scheme.

16. The antibody conjugate of any of the preceding claims, wherein at least one and up to all of the non-natural amino acids residues are at specific antibody, or antigen binding fragmentthereof, sites selected from the group consisting of heavy chain or light chain residues H404, H121, H136, H180, H241, L22, L7, L42, L152, H25, H40, Hl 19, H190, H222, H19, H52, and H70, according to the Kabat, EU, or Chothia numbering scheme.

17. The antibody conjugate of any of the preceding claims, wherein at least one and up to all of the non-natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sites selected from the group consisting of heavy chain or light chain residues HC-113, HC-A118, HC-T120, HC-R121, HC-G138, HC-A140, HC-T155, HC-S160, HC-A162, HC- L163, HC-Q196, HC-I199, HC-N203, HC-T209, HC-R210, HC-E258, HC-R290, HC-Y296, HC-T335, HC-I336, HC-S337, HC-R344, HC-E345, HC-R355, HC-M358, HC-Q362, HC- E382, HC-E388, HC-N390, HC-Y391, HC-R392, HC-T393, HC-T411, HC- N421, HC-S424, HC-Q438, HC-L443 according to EU index of Kabat, LC-T109, LC-V110, LC-A111, LC- A112, LC-D122, LC-Q124, LC-R126, LC-S127, LC-T129, LC-N138, LC-R142, LC-E143, LC-Q147, LC-R149, LC-D151, LC-A153, LC-L154, LC-Q155, LC-S159, LC-E165, LC- Q166, LC-S168, LC-R169, LC-S171, LC-T172, LC-T180, LC-A184, LC-E187, LC-H189, LC-R190, LC-V191, LC-E195, LC-L201, LC-S202, LC-S203, LC-V205, and LC-T206, according to the Kabat, EU, or Chothia numbering scheme.

18. The antibody conjugate of any of the preceding claims, wherein at least one and up to all of the non-natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sites selected from the group consisting of heavy chain or light chain residues HC- A118, HC-T120, HC-R121, HC-G138, HC-A140, HC-T155, HC-S160, HC-A162, HC-L163, HC-Q196, HC-I199, HC-N203, HC-T209, HC-R210, HC-E258, HC-R290, HC-Y296, HC- T335, HC-I336, HC-S337, HC-R344, HC-E345, HC-R355, HC-M358, HC-Q362, HC-E382, HC-E388, HC-N390, HC-Y391, HC-K392, HC-T393, HC-T411, HC- N421, HC-S424, HC- Q438, HC-L443 according to EU index of Kabat, LC-T109, LC-V110, LC-A111, LC-A112, LC-D122, LC-Q124, LC-K126, LC-S127, LC-T129, LC-N138, LC-R142, LC-E143, LC- Q147, LC-K149, LC-D151, LC-A153, LC-L154, LC-Q155, LC-S159, LC-E165, LC-Q166, LC-S168, LC-K169, LC-S171, LC-T172, LC-T180, LC-A184, LC-E187, LC-H189, LC-K190, LC-V191, LC-E195, LC-L201, LC-S202, LC-S203, LC-V205, and LC-T206, according to theKabat, EU, or Chothia numbering scheme.

19. The antibody conjugate of any of the preceding claims, wherein the one or more non- natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sitesselected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-S113, HC-A140, HC-Y180, HC-F241, HC-221, HC-Y391, LC-T22, LC-S7, LC-N152, LC-K42, LC-E161, LC-D170, HC-S136, HC-S25, HC-A40, HC-S119, HC-S190, HC-Q196, HC-K222, HC-R19, HC-Y52, HC-S70, and HC-Q362 according to the Kabat, EU, or Chothia numbering scheme.

20. The antibody conjugate of any of the preceding claims, wherein the one or more non- natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sites selected from the group consisting of heavy chain or light chain residues HC-F404, HC-K121, HC-Y180, HC-F241, HC-221, HC-Y391, 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, and HC-S70 according to the Kabat, EU, or Chothia numbering scheme.

21. The antibody conjugate of any of the preceding claims, wherein the one or more non- natural amino acids residues are at specific antibody, or antigen binding fragment thereof, sites selected from the group consisting of heavy chain or light chain residues HC-404, HC-180, HC-391, HC-241, LC-42, LC-161, LC-170, according to the Kabat, EU, or Chothia numbering scheme.

22. The antibody conjugate of any of the preceding claims, wherein each of the one or more non-natural amino acid residues comprises a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, and tetrazine.

23. The antibody conjugate of any of the preceding claims, wherein each of the one or more non-natural amino acid residues comprises an azide moiety.

24. The antibody conjugate of any of the preceding claims, wherein each of the one or more non-natural amino acid residues comprises an acetyl moiety.

25. The antibody conjugate of any of the preceding claims, wherein each of the one or more non-natural amino acid residues comprises a tetrazine moiety.

26. The antibody conjugate of any of the preceding claims, wherein each of the one or more non-natural amino acid residues is according to the formula:wherein each L is independently a divalent linker; each R is independently a residue of a functional group; and each wavy line indicates a bond that connects to remainder of a polypeptide chain of the antibody.

27. The antibody conjugate of claim 26, wherein R is a residue of a reactive group selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, and tetrazine.

28. The antibody conjugate of claim 27, wherein L is a divalent linker selected from the group consisting of a bond, alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarlyene and substituted heteroarylene.

29. The antibody conjugate of any one of the preceding claims, wherein the one or more non-natural amino acid residues are selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine.

30. The antibody conjugate of any one of the preceding claims, wherein the one or more non-natural amino acid residues are 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-phenylalanine.

31. The antibody conjugate of any one of the preceding claims, wherein at least one of the one or more non-natural amino acid residues is p-azidomethyl-L-phenylalanine.

32. The antibody conjugate of any one of the preceding claims, wherein at least one of the one or more non-natural amino acid residues is p-azido-L-phenylalanine.

33. The antibody conjugate of any one of the preceding claims, wherein at least one of the one or more non-natural amino acid residues is p-acetyl-L-phenylalanine.

34. The antibody conjugate of any one of the preceding claims, wherein at least one and up to all of the payloads are therapeutic moieties.

35. The antibody conjugate of claim 34, wherein one or more therapeutic moieties are selected from immunomodulatory agents, alkylating agents, DNA-crosslinking agents, antitumor antibiotics, anti-metabolites, anti-mitotic agents, DNA damage response inhibitors, histone-deacetylase (HD AC) inhibitors, telomerase inhibitors, immunogenic cell death agents, tubulin inhibitors, and topoisomerase inhibitors.

36. The antibody conjugate of claim 35, wherein one or more therapeutic moieties are topoisomerase I inhibitors selected from the group consisting of camptothecin, irinotecan, SN- 38, topotecan, exatecan, and derivatives thereof.

37. The antibody conjugate of claim 36, wherein at least one of the one or more therapeutic moieties is exatecan.

38. The antibody conjugate of claim 35, wherein at least one of the one or more therapeutic moieties is hemiasterlin.

39. The antibody conjugate of claim 35, wherein at least one of the one or more therapeutic moieties is 3-aminophenyl hemiasterlin.

40. The antibody conjugate of claim 35, wherein at least one of the one or more therapeutic moieties is an immunomodulatory agent.

41. The antibody conjugate of claim 40, wherein at least one of the one or more therapeutic moieties is a STING agonist.

42. The antibody conjugate of claim 40, wherein at least one of the one or more therapeutic moieties is a Toll-like receptor (TLR) agonist.

43. The antibody conjugate of claim 42, wherein the TLR agonist is a TLR 7 / 8 agonist.

44. The antibody conjugate of claim 35, wherein the DNA damage response inhibitor is a poly (ADP-ribose) polymerase (PARP) inhibitor.

45. The antibody conjugate of any of claims 1-34, wherein at least one of the one or more payloads is a labeling moiety.

46. The antibody conjugate of any of the previous claims, wherein the antibody, or antigen binding fragment thereof, is linked to at least one of the one or more payloads via one or more linkers.

47. The antibody conjugate of claim 46, wherein at least one of the one or more linkers is hydrolytically stable.

48. The antibody conjugate of claim 46, wherein at least one of the one or more linkers is cleavable.

49. The antibody conjugate of claim 46, wherein at least one of the linkers is a protease cleavable linker, an enzyme cleavable linker, a pH-sensitive linker, or a non-cleavable linker.

50. The antibody conjugate of claim 46, wherein at least one of the linkers is branched.

51. The antibody conjugate of any one of the previous claims, wherein the antibody conjugate 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 the antibody, or antigen-binding fragment thereof; each L* is a linker; each PAY is a payload; and subscript n is an integer selected from 2 to 30; wherein each L* is the same or different, and wherein each PAY is the same or different.

52. The antibody conjugate of claim 51, wherein n is an integer selected from 2 to 24.

53. The antibody conjugate of any one of the previous claims represented by the structure of Formula (la-1), (la-2), or (la-3):Formula (la-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is the same or different; each m is an integer selected from 1 to 30; each SP1, SP2, and SP3is independently, at each occurrence, absent or a divalent spacer group; each W1is independently, at each occurrence, absent,, wherein the -NH- is bound toW2and each indicates a point of attachment to the rest of the formula; each W2is independently, at each occurrence, absent, CH2, CH, NH, N, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP2group; each HP1, is independently, at each occurrence, absent or a divalent hydrophilic group;each HP2, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, optionally substituted Ci-ealkyl wherein the Ci-ealkyl is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy; each RT is independently, at each occurrence, absent or a release trigger group; each RL is a reactive linker residue; y is an integer independently selected from 0, 1, and 2; and z is an integer independently selected from 0 and 1.

54. The antibody conjugate of claim 53, wherein m an integer selected from 2 to 24.

55. The antibody conjugate of any one of claims 1-51, represented by Formula (Ib-1), (Ib- 2), or (Ib-3):Formula (Ib-2)Formula (Ib-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is independently, at each occurrence, a payload residue and is the same or different;L2is -Ci-6 alkylene- optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-io alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; each Y* is, independently, at each occurrence, -X^i-e alkylene-P^-Ci-e alkylene]a-[X1]b-, -X^M alkenylene-[X1-C2-6 alkenylene]a-[X1]b-, or-X1-C2-6 alkynylene-fX1^^ alkynyleneJa-P^Jb-, wherein at least one alkylene, alkenylene, or alkynylene in Y* is substituted with one or more substituents independently selected from R50, and wherein the alkylene, alkenylene, or alkynylene in Yais further optionally substituted with one or more substituents independently selected from R51;R50is -C1-6 alkylene-X^Ci-e alkylene]c-HP2, -C2-6 alkenylene-X2-[C2-6 alkenylene]c-HP2, or -C2-6 alkynylene-X2-[C2-6 alkynylene]c-HP2, wherein each alkylene, alkenylene, or alkynylene of R50is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -NfR10^, - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6HS, CI-IO alkyl, C2-io alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;R51is independently selected from halogen, -CN, -NO2, -OH, -NQt10}?, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2. 10 alkenyl, C2-io alkynyl, C3-U carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;X1and X2are independently selected from -N(R10)-, -C(O)-, and - N(R10)C(O)-;R10is independently selected at each occurrence from hydrogen, Ci-io alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-10 haloalkyl; a is an integer selected from zero, one, two, and three; b is an integer selected from zero and one; c is an integer selected from zero and one; Su is a hexose form of a monosaccharide;X is -C1-C10 alkylene-X1-, -X^Ci-Cio alkylene-X1-, -C1-C10 alkylene-X1-R2-, -X^i.Cio alkylene-X1-R2-, -X^Ci-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene- X1-, -[POLY]-Ci-Cio alkylene-X1-, -C2-C10 alkenylene-X1-, -X1-C2-Cio alkenylene-X1- , -C2-C10 alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1- R2-X1-[POLY]-C2-CIO alkenylene-X1-, -[POLY]-C2-CIO alkenylene-X1-C2-C10 alkynylene-X1-, -X1-C2-Cio alkynylene-X1-, -C2-C10 alkynylene-X1-R2-, -X1-C2-Cio alkynylene-X1-R2-, -X1-C2-Cio alkynylene-X1-R2-X1-[POLY]-C2-CIO alkynylene-X1-, or -[POLY]-C2-CIO alkynylene-X1-, wherein the alkylene, alkenylene, or alkynylene of X is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6H5, - NHC(O)OCH2C6HS, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and CMO haloalkyl; each X1is independently selected from -NQt1)-, -C(O)-, and -QOJNCR1)-; each Y** is independently -[POLY]-CI-C6 alkylene- Y1-, -[POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-, -[POLY]-CI-C6alkylene- Y1-R2-Y1-CI-C6alkylene-Y1- -[POLY]-C2-C6 alkenylene- Y1-, -[POLYJ-C2-C6 alkenylene- Y1-C2-Ce alkenylene- Y1-, -[POLY]-C2-C6 alkenylene-Y1-R2-Y1-C2-C6 alkenylene- Y1-, -[POLY]-C2-C6 alkynylene- Y1-, -[POLYJ-C2-C6 alkynylene- Y1-C2-Ce alkynylene- Y1-, -[POLY]-C2-C6 alkynylene-Y1-R2-Y1-C2-C6 alkynylene- Y1-, wherein the alkylene, alkenylene, or alkynylene of Y1* is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, - C(O)OCH2C6HS, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;each Y1is independently selected from -N(R10)-, -C(0)-, and -C(O)N(R10)-; each Z is independently -Ci-Cio alkylene-; each R10is independently hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl,C3-12 caibocycle, 3- to 12-membered heterocycle, or Ci-2ohaloalkyl;R2is whereineach R3is independently an amino acid side chain or a non-amino acid side chain; each POLY is a divalent water-soluble polymer; aa is an integer from one to five; and each m is an integer selected from 1 to 30.

56. The antibody conjugate of claim 55, represented by Formula (Ib-1), (Ib-2), or (Ib-3):Formula (Ib-3) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is independently, at each occurrence, a payload residue;L2is -Ci-6 alkylene- optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, - C(S)-, -C(OX)CH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-io alkenyl, CMO alkynyl, €3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; each Y* is, independently, at each occurrence, -X^i-e alkylene-P^-Ci-e alkylene]a-[X1]b-, -X^M alkenylene-[X1-C2-6 alkenylene]a-[X1]b-, or-X1-C2-6 alkynylene-fX1^^ alkynyleneJa-P^Jb-, wherein at least one alkylene, alkenylene, or alkynylene in Y is substituted with one or more substituents selected from R50, and wherein the alkylene, alkenylene, or alkynylene in Y is optionally substituted with one or more substituents selected from R51;R50is -C1-6 alkylene-X^Ci-e alkylene]c-HP2, -C2-6 alkenylene-X2-[C2-6 alkenylene]c- HP2, or -C2-6 alkynylene-X2-[C2-6 alkynylene]c- HP2, wherein each alkylene, alkenylene, or alkynylene of R50is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-io alkenyl, C2-io alkynyl, €3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;R51is independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2. 10 alkenyl, C2-io alkynyl, Cs-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;X1and X2are independently selected from -N(R10)-, -C(O)-, and - N(R10)C(O)-;R10is independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-io alkenyl, C2-io alkynyl, Cs-12 carbocycle, 3- to 12-membered heterocycle, and Ci-10 haloalkyl; a is an integer selected from zero, one, two, and three; b is an integer selected from zero and one;c is an integer selected from zero and one;Su is a hexose form of a monosaccharide;X is -C1-C10 alkylene-X1-, -X^i-Cio alkylene-X1-, -C1-C10 alkylene-X1-R2-, -X^i.Cio alkylene-X^R2-, -XM^i-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene- X1-, -C2-C10 alkenylene-X1-, -X1-C2-Cio alkenylene-X1-, -C2-C10 alkenylene-X1^2-, -X1-C2-Cio alkenylene-X^R2-, -XMkCio alkenylene-X1-R2-X1-[POLY]-C2-Cio alkenylene-X1-, -C2-C10 alkynylene-X1-, -X1-C2-Cio alkynylene-X1-, -C2-C10 alkynylene-X1^2-, -X1-C2-Cio alkynylene-X1-R2-, or -X1-C2-Cio alkynylene-X1-R2- X1-[POLY]-C2-CIO alkynylene-X1-, wherein the alkylene, alkenylene, or alkynylene of X is optionally substituted with one or more substituents selected from halogen, - CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6H5, -NHC(OX)CH2C6H5, Cl. 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 caibocycle, 3- to 12-membered heterocycle, and Ci-iohaloalkyl; each X1is independently selected from --; each Ybis independently -[POLY]-CI-C6 alkylene- Y1-, -[POLY]-CI-C6 alkylene- Y1-CI-C6 alkylene- Y1-,[POLYJ-Ci-Ce alkylene- Y1-R2-Y1-Ci-C6alkylene-Y1-, -[POLY]-C2-C6 alkenylene- Y1-, -[POLY]-C2-C6 alkenylene- Y1-C2-Ce alkenylene-Y1-, -[POLY]-C2-Ce alkenylene- Y1-R2-Y1-C2-C6 alkenylene- Y1-,-[POLY]-C2-C6 alkynylene- Y1-, -[POLY]-C2-C6 alkynylene- Y1-C2-Ce alkynylene-Y1-, -[POLY]-C2-Ce alkynylene- Y1-R2-Y1-C2-C6 alkynylene-Y1-, wherein the alkylene, alkenylene, or alkynylene of Y is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6H5, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 caibocycle, 3- to 12-membered heterocycle, and Ci-iohaloalkyl; each Y1is independently selected from -N(R10)-, -C(O)-, and -C(O)N(R10)-; each Z is independently -C1-C10 alkylene-; each R10is independently hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-12 caibocycle, 3- to 12-membered heterocycle, or Ci-2ohaloalkyl; whereineach R3is independently an amino acid side chain or a non-amino acid side chain; each POLY is a divalent water-soluble polymer; aa is an integer from one to five; and each m is an integer selected from 1 to 30.

57. The antibody conjugate of any one of claims 1-50, represented by Formula (Ic-1) or (Ic-2):Formula (Ic-2) or a pharmaceutically acceptable salt, solvate, stereoisomer, regioisomer, or mixture of regioisomers thereof; wherein:Ab is the antibody, or antigen-binding fragment thereof; each PAY is independently, at each occurrence, a payload residue and is the same or different;L2is -Ci-6 alkylene- optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-ioalkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; each Y* is, independently, at each occurrence, -X^i-e alkylene-P^-Ci-e alkylene]a-[X1]b-, -X1-C2-6 alkenylene-[X1-C2-6 alkenylene]a-[X1]b-, or-X1-C2-6 alkynylene-[X1-C2-6 alkynyleneJa-P^Jb-, wherein at least one alkylene, alkenylene, or alkynylene in Y* is substituted with one or more substituents independently selected from R50, and wherein the alkylene, alkenylene, or alkynylene in Yais further optionally substituted with one or more substituents independently selected from R51;R50is -C1-6 alkylene-X^Ci-e alkylene]c-HP2, -C2-6 alkenylene-X2-^^ alkenylene]c- HP2, or -C2-6 alkynylene-X2-[C2-6 alkynylene]c- HP2, wherein each alkylene, alkenylene, or alkynylene of R50is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, CI-IO alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;R51is independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(OX)CH2C6H5, CI-IO alkyl, C2- 10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl;X1and X2are independently selected from -N(R10)-, -C(O)-, and - N(R10)C(O)-;R10is independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-10 haloalkyl; a is an integer selected from zero, one, two, and three; b is an integer selected from zero and one; c is an integer selected from zero and one;Su is a hexose form of a monosaccharide;X is -C1-C10 alkylene-X1-, -X^Ci-Cio alkylene-X1-, -C1-C10 alkylene-X1-R2-, -X^i.Cio alkylene-X1-R2-, -X^Ci-Cio alkylene-X1-R2-X1-[POLY]-Ci-Cio alkylene- X1-, -[POLY]-Ci-Cio alkylene-X1-, -C2-C10 alkenylene-X1-, -X1-C2-Cio alkenylene-X1- , -C2-C10 alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1-R2-, -X1-C2-Cio alkenylene-X1-R2-X1-[POLY]-C2-CIO alkenylene-X1-, -[POLY]-C2-CIO alkenylene-X1-C2-C10 alkynylene-X1-, -X1-C2-Cio alkynylene-X1-, -C2-C10 alkynylene-X1-R2-, -X1-C2-Cio alkynylene-X1-R2-, -X1-C2-Cio alkynylene-X1-R2-X1-[POLY]-C2-CIO alkynylene-X1-, or -[POLY]-C2-CIO alkynylene-X1-, wherein the alkylene, alkenylene, or alkynylene of X is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)OCH2C6H5, - NHC(O)OCH2C6HS, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and Ci-iohaloalkyl; each X1is independently selected from --; each Ybis independently -[POLY]-CI-C6 alkylene- Y1-,-[POLY]-CI-C6 alkylene- Y^i-Ce alkylene- Y1-, -[POLY]-CI-C6alkylene- Y1-R2-Y1-CI-C6alkylene-Y1- -[POLY]-C2-C6 alkenylene- Y1-, -[POLYJ-C2-C6 alkenylene- Y1-C2-Ce alkenylene- Y1-, -[POLY]-C2-C6 alkenylene-Y1-R2-Y1-C2-C6 alkenylene- Y1-,-[POLY]-C2-C6 alkynylene- Y1-, -[POLYJ-C2-C6 alkynylene- Y1-C2-Ce alkynylene- Y1-, -[POLY]-C2-C6 alkynylene-Y1-R2-Y1-C2-C6 alkynylene- Y1-, wherein the alkylene, alkenylene, or alkynylene of Y** is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, - C(O)OCH2C6HS, -NHC(OX)CH2C6H5, Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-iohaloalkyl; each Y1is independently selected from -N(R10)-, -C(O)-, and -C(O)N(R10)-; each Z is independently -C1-C10 alkylene-; each R10is independently hydrogen, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, or Ci-2ohaloalkyl;R2iswherein each R3is independently an amino acid side chain or a non-amino acid side chain; each POLY is a divalent water-soluble polymer; aa is an integer from one to five;each SP1, SP2, and SP3is independently, at each occurrence, absent or a divalent spacer group; each W1is independently, at each occurrence, absent, wherein the -NH- is bound toW2and each indicates a point of attachment to the rest of the formula; each W2is independently, at each occurrence, absent, CH2, CH, NH, N, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP2group; each HP1, is independently, at each occurrence, absent or a divalent hydrophilic group; each HP2, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, optionally substituted Ci-ealkyl wherein the Ci-ealkyl is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy; each RT is independently, at each occurrence, absent or a release trigger group; each RL is a reactive linker residue; y is an integer independently selected from 0, 1, and 2; z is an integer independently selected from 0 and 1; each n is an integer selected from 1 to 30; and each m is an integer selected from 1 to 30.

58. The antibody conjugate of claim 53 or 57, wherein SP2and SP3are independently absent or selected from -Ci-ealkylene-, -C(O)-, -Ci-6alkylene-C(O)- wherein the -C(O)- is bound to W2or HP1, respectively, -C(O)-Ci-6alkylene-C(O)-, -C(O)(Ci-6alkylene)NR1C(O)- , -C(OXCi-6alkylene)OC(O)-, and -C(OXCi-6alkylene)SC(O)-; wherein R1is hydrogen or optionally substituted Ci^alkyl; and the Ci-ealkylene of SP2or SP3, alone or part of anothergroup, is optionally substituted with one, two, or three substituents selected from halogen, alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy.

59. The antibody conjugate of any one of claims 53 and 57-58, wherein SP3is independently absent or -C(O)-Ci-6alkylene-C(O)-.

60. The antibody conjugate of any one of claims 53 and 57-59, wherein SP3is absent.

61. The antibody conjugate of any one of claims 53 and 57-60, wherein SP2is independently absent or -Ci-6alkylene-C(O)- wherein the -C(O)- is bound to W2.

62. The antibody conjugate of any one of claims 53 and 57-61, wherein SP2is independently -Ci-2alkylene-C(O)-.

63. The antibody conjugate of any one of claims 53 and 57-62, wherein HP1is independentlywherein R2is hydrogen or methyl and xl is an integer between1 and 50, inclusive; and each is the point of attachment to the rest of the compound.

64. The antibody conjugate of claim 63, wherein R2is hydrogen.

65. The antibody conjugate of claim 63 or 64, wherein xl is independently an integer between 1 and 10, inclusive.

66. The antibody conjugate of any one of claims 63-65, wherein xl is independently an integer between 1 and 5, inclusive.

67. The antibody conjugate of claim 66, wherein xl is 4.

68. The antibody conjugate of any one of claims 53 and 57-62, wherein HP1is absent.

69. The antibody conjugate of any one of claims 53 and 57-68, wherein W2is absent.

70. The antibody conjugate of any one of claims 53 and 57-68, wherein W2is independently an amino acid residue or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP2.

71. The antibody conjugate of any one of claims 53, 57-68, and 70, wherein W2is independently a peptide residue and the peptide residue comprises at least one non-natural amino acid residue and the peptide residue is optionally substituted with HP2.

72. The antibody conjugate of claim 71, wherein the at least one non-natural amino acid residue is selected from 3 -sulfoalanine, hydroxyproline (Hyp), citrulline (Cit), ornithine (Om), 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.

73. The antibody conjugate of any one of claims 53 and 57-68, wherein W2is independently an amino acid residue and the amino acid residue is a beta-amino acid.

74. The antibody conjugate of claim 73, wherein the beta-amino acid is beta-alanine.

75. The antibody conjugate of any one of claims 51 and 55-66, wherein W2is independently selected from -(C(O)CHR3NR4)a-, -(C(O)CH2CHR3NR4)b-, -(C(O)CHR3CH2NR4)b-, -(C^CftCHR’NR^^C^JCHR’NR4),-, <C(O)CHR3CH2NR4)b- (CCOKHR’NR4),-, -(CCOKHR’NRVCCCOJCftCHR’NR4^-, and -(C(O)CHR3NR4)a- (C(O)CHR3CH2NR4)b-; wherein R3is independently an amino acid sidechain residue optionally substituted withHP2;R4is independently hydrogen or Ci-6 alkyl; each of a and b is an integer independently an integer between 1 and 10, inclusive; and the -C(O)- of W2is bound to W1.

76. The antibody conjugate of any one of claims 53, 57-68, and 75, wherein W2is independently -(C(O)CHR3NR4),-.

77. The antibody conjugate of any one of claims 53, 57-68, and 75, wherein W2is independently -(C(O)CH2CHR3NR4)b-.

78. The antibody conjugate of any one of claims 53, 57-68, and 75, wherein W2is independently -(C(O)CH2CHR3NR4)b-(C(O)CHR3NR4)a-.

79. The antibody conjugate of any one of claims 75-78, wherein R3is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, 3- sulfoalanine and 2,3-diaminopropionate.

80. The antibody conjugate of any one of claims 75-79, wherein R4is hydrogen.

81. The antibody conjugate of any one of claims 75-80, wherein a is independently an integer between 1 and 3, inclusive.

82. The antibody conjugate of any one of claims 75-81, wherein b is 1.

83. The antibody conjugate of any one of claims 53 and 57-68, wherein W2is independently of the formula:; and each isthe point of attachment to the rest of the compound.

84. The antibody conjugate of any one of claims 53, 57-68, and 83, wherein W2is independently of the formula:or85. The antibody conjugate of any one of claims 53 and 57-68, wherein W2is independently of the formula each is the pointof attachment to the rest of the compound.

86. The antibody conjugate of any of claims 53, 57-68, 70-71, 75-78, and 85, wherein HP2is independently wherein R2is hydrogen or methyl and x2 is an integerbetween 1 and 50, inclusive; and each is the point of attachment to the rest of thecompound.

87. The antibody conjugate of claim 86, wherein x2 is independently an integer between 10 and 20, inclusive.

88. The antibody conjugate of claim 86 or 87, wherein x2 is 12.

89. The antibody conjugate of any one of claims 53 and 57-88, wherein W1is absent.

90. The antibody conjugate of any one of claims 53 and 57-88, wherein W1is independently91. The antibody conjugate of claim 90, wherein y is 0.

92. The antibody conjugate of any one of claims 90-91, wherein z is 0.

93. The antibody conjugate of any one of claims 90-91, wherein z is 1.

94. The antibody conjugate of any one of claims 53 and 57-93, wherein RT is a P~ glucuronidase-cleavable β-glucuronide.

95. The antibody conjugate of any one of claims 53 and 57-94, wherein RT is and is the point of attachment to the rest of the compound.

96. The antibody conjugate of any one of claims 53 and 57-95, wherein RT is97. The antibody conjugate of any one of claims 53 and 57-96, wherein SP1is absent.

98. The antibody conjugate of any one of claims 53 and 57-96, wherein SP1is independently absent or selected from -NR5CH2- and -NR4-arylene-CH2- wherein R5is Ci- 6alkyl-OCH3 and R4is hydrogen or Ci-6 alkyl.

99. The antibody conjugate of claim 98, wherein SP1is independently -NR5CH2-.

100. The antibody conjugate of claim 98, wherein SP1is -N(CH2CH2OCH3KH2-.

101. The antibody conjugate of claim 98, wherein SP1is independently -NR4-arylene-CH2-102. The antibody conjugate of claim 98, wherein SP1is ; and eachis the point of attachment to the rest of the compound.

103. The conjugate of any one of claims 55-102, wherein Su i whereinrepresents attachment to the remainder of the compound.

104. The conjugate of any one of claims 55-103, wherein Su is , whereinrepresents attachment to the remainder of the compound.

105. The conjugate of any one of claims 55-104, wherein L2is -C1-3 alkylene-.

106. The conjugate of any one of claims 55-104, wherein Y* is -X'-C^ alkylene-P^-CM alkyleneJ.-X1-, wherein at least one alkylene in Yais substituted with one or more substituents independently selected from R50.

107. The conjugate of any one of claims 55-106, wherein Y* is -X1-CM alkylene-X1-CM alkylene-X1-CM alkylene-X1-, wherein at least one alkylene in Y is substituted with one or more substituents independently selected from R50.

108. The conjugate of any one of claims 55-106, wherein Y* is -X*-Ci4 alkylene-X1-CM alkylene-X1-, wherein at least one alkylene in Yais substituted with one or more substituents independently selected from R50.

109. The conjugate of any one of claims 55-108, wherein R50 is-CM alkylene-alkylene]c-HP2, wherein each alkylene of R50is optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(OX)CH2C6H5, CI-IO alkyl,C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and Ci-10 haloalkyl.

110. The conjugate of any one of claims 55-108, wherein c is one.

111. The conjugate of any one of claims 55-110, wherein HP2is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), polypropylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(7V-acryloylmorpholine), polysarcosine, or a combination thereof.

112. The conjugate of claim 111, wherein HP2comprises a polyethylene glycol (PEG) or methoxypolyethylene glycol (mPEG).

113. The conjugate of any one of claims 51-112, wherein PAY is independently a residue of an immunomodulatory agent, alkylating agent, DNA-crosslinking agent, anti-tumor antibiotic, anti-metabolite, anti-mitotic agent, DNA damage response inhibitor, histone-deacetylase (HDAC) inhibitor, telomerase inhibitor, immunogenic cell death agent, tubulin inhibitor, or topoisomerase inhibitor.

114. The conjugate of any one of claims 51-113, wherein PAY is independently a residue of a topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN- 38, topotecan, and exatecan.

115. The conjugate of any one of claims 51-114, wherein PAY is a residue of exatecan.

116. The conjugate of any one of claims 51-113, wherein PAY is a residue of hemiasterlin.

117. The conjugate of any one of claims 51-113 and 116, wherein PAY is a residue of 3- aminophenyl hemiasterlin.

118. The conjugate of any one of claims 51-113, wherein PAY is a residue of an auristatin.

119. The conjugate of any one of claims 51-113 and 118, wherein PAY is a residue of monomethyl auristatin E (MMAE).

120. The conjugate of any one of claims 51-113, wherein PAY is a residue of an immunomodulatory agent.

121. The conjugate of any one of claims 51-113 and 120, wherein PAY is a residue of a STING agonist.

122. The conjugate of any one of claims 51-113 and 120, wherein PAY is a residue of a Tolllike receptor (TLR) agonist.

123. The conjugate of any one of claims 51-113, 120, and 122, wherein the TLR agonist is a TLR 7 / 8 agonist.

124. The conjugate of any one of claims 51-113, 120, and 122-123, wherein the TLR agonist is a TLR 7 agonist.

125. The conjugate of any one of claims 51-113, wherein PAY is a residue of a DNA damage response inhibitor.

126. The conjugate of any one of claims 51-113 and 125, wherein PAY is a residue of a PARP inhibitor.

127. A pharmaceutical composition comprising an antibody conjugate of any one of the previous claims and a pharmaceutically acceptable carrier, excipient, or diluent.

128. A method for treating or preventing a disease or condition in a subject in need thereof comprising administering to the subject an effective amount of an antibody conjugate of any one of claims 1-126 or the pharmaceutical composition of 127.

129. A method of diagnosing a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of an antibody conjugate of any one of claims 1-126 or the pharmaceutical composition of 127.

130. The method of claim 128 or 129, wherein the disease or condition is a cancer or inflammatory disease or condition.

131. The method of claim 130, wherein the disease or condition is cancer.

132. Use of an effective amount of an antibody conjugate of any one of claims 1-126 or the pharmaceutical composition of 127 in the preparation of a medicament for treating or preventing a disease or condition in a subject in need thereof.

133. Use of an effective amount of an antibody conjugate of any one of claims 1-126 or the pharmaceutical composition of 126 in the preparation of a medicament for diagnosing a disease or condition in a subject in need thereof.

134. The use of claim 132 or 133, wherein the disease or condition is a cancer or inflammatory disease or condition.

135. The use of claim 134, wherein the disease or condition is cancer.

136. A kit comprising the antibody conjugate of any one of claims 1-126, and instructions for use.

137. The kit of claim 136, wherein the antibody conjugate is lyophilized.

138. The kit of claim 136, further comprising a fluid for reconstitution of the lyophilized antibody conjugate.

139. A process for preparing an antibody conjugate of any one of claims 1-126, comprising a. optionally, conjugating at least one PAY residue with the light chain (LC) of the antibody or antigen binding fragment thereof; b. conjugating at least one PAY residue with the heavy chain (HC) of the antibody or antigen binding fragment thereof; c. contacting the LC with the HC under conditions suitable for forming the antibody conjugate, wherein the total number of conjugated PAY residues provides the payload antibody ratio.

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