Anti-MSR1 antibodies and methods of use thereof

Abstract

Provided herein are antibodies and antigen-binding fragments that bind MSR1 and methods of use thereof. According to certain embodiments, the antibodies bind human MSR1 with high affinity. In certain embodiments, the antibodies bind MSR1 without blocking, or blocking less than 90%, of modified LDL binding to MSR1. In some embodiments, the antibodies bind cell surface expressed-MSR1 and are internalized. The antibodies of the invention may be fully human antibodies. The invention includes anti-MSR1 antibodies, or antigen-binding fragments thereof, conjugated to drugs or therapeutic compounds.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 669,276, filed May 9, 2018, U.S. Provisional Application No. 62 / 678,200, filed May 30, 2018, U.S. Provisional Application No. 62 / 769,946, filed November 20, 2018, U.S. Provisional Application No. 62 / 789,987, filed January 8, 2019, and U.S. Provisional Application No. 62 / 821,362, filed March 20, 2019, which are incorporated herein by reference in their entireties for all purposes. FIELD OF THE INVENTION

[0002] The present invention relates to antibodies, and antigen-binding fragments thereof, as well as antibody-drug conjugates of such antibodies, which specifically bind the trimeric membrane glycoprotein receptor (MSR1) and modulate MSR1 signal transduction, and methods of use thereof. SEQUENCE LISTING

[0003] An official copy of the sequence listing is submitted concurrently with the specification via EFS-Web as a paper copy of an ASCII formatted sequence listing with a file name of 114581.00244_ST25.TXT, a creation date of May 30, 2018, and a size of about 165 kilobytes. The sequence listing contained in this paper copy of the ASCII formatted document is part of the specification and is herein incorporated by reference in its entirety. BACKGROUND

[0004] Macrophage scavenger receptor 1 (MSR1) is a single-pass, trimeric type II transmembrane glycoprotein pattern recognition receptor that mediates uptake of a series of negatively charged / polyanionic ligands, including modified low density lipoproteins (LDL) (Krieger, M. 1994. Annu. Rev. Biochem. 63:601-637; Platt, N. and S. Gordon. 2001. J Clin Invest. 108(5):649-654) and advanced glycation end products of bovine serum albumin (AGE-BSA) (Smedsrod et al. 1997. Biochem J. 322(Pt 2):567-573.) MSR1 receptors have been implicated in many macrophage-associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense.

[0005] MSR1 expression was originally considered to be macrophage-specific. However, it has recently been demonstrated to be present on different classes of dendritic cells (Herber et al. 2010. Nat. Med. 16(8): 880-886). In addition, MSR1 appears to be expressed in endothelial cells and smooth muscle cells. It is internalized via coated pits at the cell surface and releases its ligand at acidic pH before being recycled back to the cell surface from the trans-Golgi apparatus (Doi et al. 1994. Journal of Biological Chemistry; Mori, T. 1994. Lab Invest.). It promotes conversion of monocyte-derived macrophages into foam cells, which is a critical step for atherosclerosis progression.

[0006] MSR1 isoforms type 1 and type 2 are functional receptors and are able to mediate endocytosis of modified low density lipoproteins (LDLs). MSR1 isoform type 3 can bind modified LDL (acetyl-LDL) but appears to be incapable of internalizing the bound complex. However, MSR1 also binds to a wide variety of ligands other than modified LDLs. These ligands include beta-amyloid protein, molecular chaperones, extracellular matrix protein, advanced glycation end products, apoptotic cells, and activated B-cells.

[0007] Liver X Receptor (LXR) includes LXRa and LXR£ which are ligand-dependent transcription factors that control the expression of genes involved in cholesterol, lipid and glucose homeostasis, inflammation, and innate immunity. LXRa is highly expressed in liver, intestine, adipose tissue, and differentiated macrophages; and LXR£ is ubiquitously expressed. LXRs have various biological functions including (i) stimulating the expression of cholesterol transporters, for example, ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux; and (ii) negatively regulating macrophage inflammatory gene expression via repression of NF-kB activation. LXRs have also been implicated in atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation. Proliferative disorders include melanomas, lung cancer, oral squamous carcinoma, and prostate cancer. (Pencheva et al. 2004; Wu et al. 2015; Kaneko et al. 2015; Chuu et al. 2006) Neurodegenerative disorders include Alzheimer’s disease and myelin gene expression. (Terwel et al. 2011; Sandoval-Hernandez et al. 2016; Meffre et al. 2014) Inflammation includes inflammatory bowel disease, ulcerative colitis, Crohn’s disease, and arthritis. (Anderson etal. 2011; Huang etal. 2015; Cui et al. 2012). Macrophage LXRs are known to include anti-atherogenic activity. LXR agonists are believed to be capable of (i) inhibiting the initiation and delay the progression of atherosclerosis; (ii) mitigating atherosclerosis and stabilizing established atherosclerotic lesions; and (iii) reducing lesion macrophage content by apoptosis.

[0008] The therapeutic potential of small molecule LXR modulators is limited by, for example, undesired modulation of LXR at non-target cells and / or low bioavailability. Modulation of LXR at non-target cells can lead to undesirable side effects, and low bioavailability may manifest for myriad reasons including, without limitation, low solubility that further exacerbates poor therapeutic windows for treatment. The development of ADCs comprising LXR modulators would allow for target-specific modulation of LXR, thereby avoiding side-effects caused by off-target modulation of LXR. Furthermore, such ADCs would provide improved modulation of biological targets, improved bioavailability, and improved therapeutic window. Therefore, there is a continuing need for effective treatments of, for example, metabolic diseases using antibodydrug conjugates of LXR modulators.

[0009] Glucocorticoids (GCs) are small molecule steroids that bind to glucocorticoid receptors (GRs) and are widely utilized in anti-inflammatory and immunosuppressive therapies. However, due to the ubiquitous expression of glucocorticoid receptors in many cell types, glucocorticoid treatments are compromised by toxicities to most organ systems. Thus, there is need for both novel glucocorticoids as well as novel therapies that minimize the side effects arising from glucocorticoid administration, particularly those arising from activating glucocorticoid receptors in non-target cells.

[0010] Rifamycins form a subclass of the ansamycin antibiotics family with an activity spectrum against gram-positive and gram-negative bacteria, and are commonly prescribed antimycobacterial drugs for the treatment of tuberculosis, leprosy and / or mycobacterium avium complex (MAC). The rifamycin group of antibiotics includes the “classic” rifamycin drugs as well as rifamycin derivatives such as rifampicin (or rifampin), rifabutin, rifapentine, rifalazil and rifaximin. The increasing occurrence of antibiotic resistant strains of bacteria (e.g., methicillin resitant S. aureus (MRSA), vancomycin resistant S. aureus (VRSA)), multi-drug resistant M. tuberculosis), particularly in nosocomial settings, is an ongoing problem. There is a need for more effective analogs of rifamycins. Rifamycins are moderate to potent inducers of the cytochrome P450 enzyme system (notably CYP3A4), which can lead to reduced bioavailability and enhanced clearance of some coadministered drugs undergoing metabolism by the cytochrome P450 enzyme system (notably CYP3A4). Such interactions may be delayed in onset but persist beyond rifamycin coadministration. Rifampin may also induce P-glycoprotein (P-gp) multidrug efflux transporters. There is a need for novel therapies that minimize the side effects arising from administration of rifamycins, particularly those arising from activation of the cytochrome P450 enzyme system.

[0011] As disclosed in this application, MSR antibodies may provide a means for specific targeting of therapeutic molecules such as LXR agonists, steroids and rifamycins to minimize unwanted side effects arising from systemic administration of such compounds. SUMMARY

[0012] Provided herein are antibodies, antigen-binding fragments of antibodies, and antibodydrug conjugates thereof that bind the membrane glycoprotein receptor known as MSR1. The antibodies are useful, inter alia, for targeting cells that express MSR1, such as macrophage cells. The anti-MSR1 antibodies, and antigen-binding portions thereof, can be used alone in unmodified form, or can be included as part of an antibody-drug conjugate. 2019265703  06 Apr 2023

[0013] The antibodies disclosed herein can be full-length (for example, an IgG1 or IgG4 antibody) or can comprise only an antigen-binding portion (for example, a Fab, F(ab’)2 or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[0014] Embodiments of anti-MSR1 antibodies disclosed herein are listed in Tables 4 and 5. Table 4 sets forth the amino acid sequence identifiers of the heavy chain variable regions (HCVRs), light chain variable regions (LCVRs), heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), and light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of the exemplary anti-MSR1 antibodies. Table 5 sets forth the nucleic acid sequence identifiers of the HCVRs, LCVRs, HCDR1, HCDR2 HCDR3, LCDR1, LCDR2 and LCDR3 of the exemplary anti-MSR1 antibodies.

[0015] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising an HCVR comprising an amino acid sequence selected from any of the HCVR amino acid sequences listed in Table 4, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0016] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising an LCVR comprising an amino acid sequence selected from any of the LCVR amino acid sequences listed in Table 4, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0017] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising an HCVR and an LCVR amino acid sequence pair (HCVR / LCVR) comprising any of the HCVR amino acid sequences listed in Table 4 paired with any of the LCVR amino acid sequences listed in Table 4. Certain embodiments relate to antibodies, or antigen-binding fragments thereof, comprising an HCVR / LCVR amino acid sequence pair contained within any of the exemplary anti-MSR1 antibodies listed in Table 4. In some embodiments, the HCVR / LCVR amino acid sequence pair is selected from the group consisting of: 2 / 10, 34 / 42, 50 / 58; 98 / 106, and 290 / 298.

[0018] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a heavy chain CDR1 (HCDR1) comprising an amino acid sequence selected from any of the HCDR1 amino acid sequences listed in Table 4 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0019] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any of the HCDR2 amino acid sequences listed in Table 4 ora substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0020] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any of the HCDR3 amino acid sequences listed in Table 4 ora substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0021] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a light chain CDR1 (LCDR1) comprising an amino acid sequence selected from any of the LCDR1 amino acid sequences listed in Table 4 or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0022] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a light chain CDR2 (LCDR2) comprising an amino acid sequence selected from any of the LCDR2 amino acid sequences listed in Table 4 ora substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0023] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a light chain CDR3 (LCDR3) comprising an amino acid sequence selected from any of the LCDR3 amino acid sequences listed in Table 4 ora substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.

[0024] Also provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising an HCDR3 and an LCDR3 amino acid sequence pair (HCDR3 / LCDR3) comprising any of the HCDR3 amino acid sequences listed in Table 4 paired with any of the LCDR3 amino acid sequences listed in Table 4. Certain embodiments relate to antibodies, or antigen-binding fragments thereof, comprising an HCDR3 / LCDR3 amino acid sequence pair contained within any of the exemplary anti-MSR1 antibodies listed in Table 4. In some embodiments, the HCDR3 / LCDR3 amino acid sequence pair is selected from the group consisting of: 8 / 16, 40 / 48, 56 / 64; 96 / 104, and 288 / 296. 2019265703  06 Apr 2023

[0025] Provided herein are antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any of the exemplary anti-MSR1 antibodies listed in Table 4. In certain embodiments, the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences set is selected from the group consisting of: 4-6-8-12-14-16; 36-38-40-44-46-48; 52-54-56-60-6264; 100-102-104-108-110-112, and 292-294-296-300-302-304.

[0026] In a related embodiment, provided herein are antibodies, or antigen-binding fragments thereof that specifically bind MSR1, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within an HCVR / LCVR amino acid sequence pair as defined by any of the exemplary anti-MSR1 antibodies listed in Table 4. For example, the present invention includes antibodies or antigen-binding fragments thereof that specifically bind MSR1, comprising the HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequences set contained within an HCVR / LCVR amino acid sequence pair selected from the group consisting of: 2 / 10, 34 / 42, 50 / 58, 98 / 106, and 290 / 298. Methods and techniques for identifying CDRs within HCVR and LCVR amino acid sequences are well known in the art and can be used to identify CDRs within the specified HCVR and / or LCVR amino acid sequences disclosed herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, e.g., the Kabat definition, the Chothia definition, and the AbM definition. In general terms, the Kabat definition is based on sequence variability, the Chothia definition is based on the location of the structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. See, e.g., Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin et al., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Public databases are also available for identifying CDR sequences within an antibody.

[0027] Also provided herein are nucleic acid molecules encoding anti-MSR1 antibodies or portions thereof. For example, provided herein are nucleic acid molecules encoding any of the HCVR amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0028] Also provided herein are nucleic acid molecules encoding any of the LCVR amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0029] Also provided herein are nucleic acid molecules encoding any of the HCDR1 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR1 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0030] Also provided herein are nucleic acid molecules encoding any of the HCDR2 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR2 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0031] Also provided herein are nucleic acid molecules encoding any of the HCDR3 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCDR3 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0032] Also provided herein are nucleic acid molecules encoding any of the LCDR1 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR1 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0033] Also provided herein are nucleic acid molecules encoding any of the LCDR2 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR2 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0034] Also provided herein are nucleic acid molecules encoding any of the LCDR3 amino acid sequences listed in Table 4; in certain embodiments the nucleic acid molecule comprises a polynucleotide sequence selected from any of the LCDR3 nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto.

[0035] Also provided herein are nucleic acid molecules encoding an HCVR, wherein the HCVR comprises a set of three CDRs ( / .e., HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 amino acid sequence set is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 4.

[0036] Also provided herein are nucleic acid molecules encoding an LCVR, wherein the LCVR comprises a set of three CDRs ( / .e., LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2-LCDR3 amino acid sequence set is as defined by any of the exemplary anti-MSR1 antibodies listed in Table 4.

[0037] Also provided herein are nucleic acid molecules encoding both an HCVR and an LCVR, wherein the HCVR comprises an amino acid sequence of any of the HCVR amino acid sequences listed in Table 4, and wherein the LCVR comprises an amino acid sequence of any of the LCVR amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule comprises a polynucleotide sequence selected from any of the HCVR nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto, and a polynucleotide sequence selected from any of the LCVR nucleic acid sequences listed in Table 5, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity thereto. In certain embodiments according to this aspect of the invention, the nucleic acid molecule encodes an HCVR and LCVR, wherein the HCVR and LCVR are both derived from the same anti-MSR1 antibody listed in Table 4.

[0038] Also provided herein are recombinant expression vectors capable of expressing a polypeptide comprising a heavy or light chain variable region of an anti-MSR1 antibody. For example, embodiments include recombinant expression vectors comprising any of the nucleic acid molecules mentioned above, i.e., nucleic acid molecules encoding any of the HCVR, LCVR, and / or CDR sequences as set forth in Table 4. Also included within the scope of the present invention are host cells into which such vectors have been introduced, as well as methods of producing the antibodies or portions thereof by culturing the host cells under conditions permitting production of the antibodies or antibody fragments, and recovering the antibodies and antibody fragments so produced.

[0039] Provided herein are anti-MSR1 antibodies having a modified glycosylation pattern. In some embodiments, modification to remove undesirable glycosylation sites, may be useful for example, to increase antibody dependent cellular cytotoxicity (ADCC) function (see Shield et al. (2002) JBC 277:26733). In some embodiments, modification to provide an antibody lacking a fucose moiety present on the oligosaccharide chain, may be useful for example, to increase antibody dependent cellular cytotoxicity (ADCC) function. In other applications, modification of galactosylation can be made in order to modify complement dependent cytotoxicity (CDC).

[0040] In another aspect, provided herein is a pharmaceutical composition comprising a recombinant human antibody or fragment thereof which specifically binds MSR1 and a pharmaceutically acceptable carrier. In a related aspect, embodiments relate to a composition which is a combination of an anti-MSR1 antibody and a second therapeutic agent. In one embodiment, the second therapeutic agent is any agent that is advantageously combined with an anti-MSR1 antibody. Also provided herein are antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody conjugated to a drug or a therapeutic agent. Exemplary combination therapies, co-formulations, and ADCs involving the anti-MSR1 antibodies are disclosed elsewhere herein.

[0041] Also provided herein are antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody, or an MSR1 antigen-binding fragment thereof, conjugated to a drug or a therapeutic agent. Also provided herein are reactive linker-payloads useful for making the ADCs. Further provided herein are modified anti-MSR1 antibodies and modified MSR1 antigen-binding fragments useful for making the ADCs.

[0042] Also provided herein are therapeutic methods comprising administration of an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof, to a subject in need thereof. The therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof to the subject. The disorder treated is any disease or condition which is improved, ameliorated, inhibited or prevented by targeting MSR1. In some embodiments, the disease or condition is a proliferative disease, a metabolic disease, inflammation, a neurodegenerative disease, or disease, disorder, or condition associated with glucocorticoid receptor signaling. In some embodiments the disease or condition is atherosclerosis. In some embodiments, the disease, disorder, or condition associated with glucocorticoid receptor signaling is an inflammatory disease, disorder, or condition. In some of such embodiments, the side effects associated with administration of the unconjugated steroid payload of said compound are reduced. Also provided herein are therapeutic methods comprising administration an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof, for the treatment and / or prevention of bacterial infection in a subject.

[0043] Provided herein is the use of an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof, described herein, for the treatment of any disease disorder or condition described herein.

[0044] Also provided herein are therapeutic methods for treating, attenuating, or ameliorating atherosclerosis, comprising administration of an anti-MSR1 antibody, an antigen-binding portion 2019265703   18 Jun 2026 of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof, to a subject in need thereof. The therapeutic methods comprise administering a therapeutically effective amount of a pharmaceutical composition comprising an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof to the subject. [0044a] In a further aspect, provided herein is an isolated antibody or antigen-binding fragment thereof that binds macrophage scavenger receptor 1 (MSR1), wherein the antibody or antigenbinding fragment comprises: (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 52; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 54; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 56; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 64; (ii) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; (iii) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 36; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 38; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 40; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 46; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 48; (iv) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 100; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 102; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 104; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 108; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 110; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 112; (v) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 292; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 294; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 300; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 302; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 304.

[0045] Other embodiments will become apparent from a review of the ensuing detailed description. BRIEF DESCRIPTION OF THE FIGURES 2019265703   18 Jun 2026

[0046] Figure 1 provides a scheme for the synthesis of P1 and P2B.

[0047] Figure 2 provides a scheme for the synthesis of LP1.

[0048] Figure 3 provides a scheme for the synthesis of LP2.

[0049] Figure 4 provides a scheme for the synthesis of LP5.

[0050] Figure 5 provides a scheme for the synthesis of LP6.

[0051] Figure 6 provides a scheme for the synthesis of LP18.

[0052] Figure 7 provides a scheme for the synthesis of LP4.

[0053] Figure 8 provides a scheme for the synthesis of LP11.

[0054] Figure 9 provides a scheme for the synthesis of LP9.

[0055] Figure 10 provides a scheme for the synthesis of LP12.

[0056] Figure 11 provides a scheme for the synthesis of P3 and P4.

[0057] Figure 12 provides a scheme for the synthesis of LP3.

[0058] Figure 13 provides a scheme for the synthesis of LP13.

[0059] Figure 14 provides a scheme for the synthesis of LP14.

[0060] Figure 15 provides a scheme for the synthesis of LP15.

[0061] Figure 16 provides a scheme for the synthesis of antibody-drug conjugates (ADCs).

[0062] Figure 17 is a line graph illustrating percentage of dose-dependent cholesterol efflux in THP-1 macrophages for an exemplary MSR1 antibody-LXR conjugate, its unconjugated counterpart, an isotype control-steroid conjugate, and the corresponding free payload.

[0063] Figure 18 provides a series of bar graphs illustrating the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on serum lipid levels in a mouse model of atherosclerosis.

[0064] Figure 19 provides a series of bar graphs illustrating the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on lesion lipid area and macrophage (CD68) content in a mouse model of atherosclerosis.

[0065] Figure 20 provides a series of bar graphs illustrating the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on hepatic triglyceride and cholesterol levels in a mouse model of atherosclerosis.

[0066] Figure 21 provides a series of bar graphs illustrating the effect of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on de novo lipogenesis in a mouse model of atherosclerosis.

[0067] Figure 22 provides a scheme for the synthesis of Budesonide-spacers containing the reactive groups, suc-acid (compound 1c), carbamate analogues (1d, 1 e), THP-analogues (1g and 1 h), glucose analogues (1 i and 1 j), phosphate analogues (1 k and 11), and a commercial phosphate analogue (1m).

[0068] Figure 23 provides a scheme for the synthesis of payloads, compounds, and bis-octahydrophenanthrene carboxamides P3B - P9B.

[0069] Figure 24 provides a scheme for the synthesis of payloads, compounds, and bis-octahydrophenanthrene carboxamides P10B - P11B.

[0070] Figure 25 provides a scheme for the synthesis of linkers and linker payloads LP1B -LP5B.

[0071] Figure 26 provides a scheme for the synthesis of linkers and linker payload LP6B.

[0072] Figure 27 provides a scheme for the synthesis of linkers and linker payload LP7B.

[0073] Figure 28 provides a scheme for the synthesis of linkers and linker payload LP8B.

[0074] Figure 29 provides a scheme for the synthesis of linkers and linker payload LP9B.

[0075] Figure 30 provides a scheme for the synthesis of linkers and linker payloads LP10B, and LP11B.

[0076] Figure 31 provides a scheme for the synthesis of payloads 12B, linkers and linker payload LP12B.

[0077] Figure 32 provides a scheme for the synthesis of cyclodextrin-azide 105a.

[0078] Figure 33 provides a scheme for the synthesis of azido-PEG4-taurine 105b.

[0079] Figure 34 provides a scheme for the synthesis of maltose-azide 105c. 2019265703   23 Dec 2025

[0080] Figure 35 is a plot of the results of the S. aureus growth inhibition assay conducted with rifamycin analogs.

[0081] Figure 36 is a bar graph of the results of the S. aureus intracellular killing assay conducted with rifamycin analogs.

[0082] Figure 37 is a plot of the results of the S. aureus intracellular killing assay conducted with rifamycin analogs. DETAILED DESCRIPTION

[0083] Before the present invention is described, it is to be understood that this invention is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0084] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1 %. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1,99.2, 99.3, 99.4, etc.). [0084a] Unless the context requires otherwise, where the terms “comprise”, “comprises”, “comprised” or “comprising” are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

[0085] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entireties. [0085a] A reference herein to a patent document or other matter which is given as prior art is not to be taken as admission that the document or matter was known or that the information it contains was part of the common general knowledge as at the priority date of any of the claims. 2019265703   23 Dec 2025 Definitions

[0086] The expressions "MSR1," "hMSR1" and the like, as used herein, refer to the human single-pass, trimeric type II transmembrane glycoprotein pattern recognition receptor comprising (i) the amino acid sequence as set forth in NCBI accession No. NP_002436.1, (ii) the amino acid sequence as set forth in NCBI accession No. NP_619729.1, and / or (iii) the amino acid sequence as set forth in NCBI accession No. NP_619730.1, which represent the various types and isoforms of class A macrophage scavenger receptors. The expression "MSR1" includes both monomeric and multimeric MSR1 molecules. As used herein, the expression "monomeric human MSR1” means a MSR1 protein or portion thereof that does not contain or possess any multimerizing domains and that exists under normal conditions as a single MSR1 molecule without a direct physical connection to another MSR1 molecule. An exemplary monomeric MSR1 molecule is the molecule referred to herein as "His-hMSR1" comprising the amino acid sequence of SEQ ID NO: 393 (see, e.g., Example 3, herein).

[0087] All references to proteins, polypeptides and protein fragments herein are intended to refer to the human version of the respective protein, polypeptide or protein fragment unless explicitly specified as being from a non-human species. Thus, the expression "MSR1" means human MSR1 unless specified as being from a non-human species, e.g., "mouse MSR1," "monkey MSR1," etc.

[0088] As used herein, the expression "cell surface-expressed MSR1" means one or more MSR1 protein(s), or the extracellular domain thereof, that is / are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a MSR1 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody. A "cell surface-expressed MSR1" can comprise or consist of a MSR1 protein expressed on the surface of a cell which normally expresses MSR1 protein. Alternatively, "cell surface-expressed MSR1" can comprise or consist of MSR1 protein expressed on the surface of a cell that normally does not express human MSR1 on its surface but has been artificially engineered to express MSR1 on its surface.

[0089] As used herein, the expression "anti-MSR1 antibody" includes monovalent antibodies with a single specificity, as well as bispecific antibodies comprising a first arm that binds MSR1 and a second arm that binds a second (target) antigen, wherein the anti-MSR1 arm comprises any of the HCVR / LCVR or CDR sequences as set forth in Table 4 herein. The expression "anti-MSR1 antibody" also includes antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody or antigen-binding portion thereof conjugated to a drug or a therapeutic agent. The expression "anti-MSR1 antibody" also includes antibody-radionuclide conjugates (ARCs) comprising an anti-MSR1 antibody or antigen-binding portion thereof conjugated to a radionuclide.

[0090] The term "antibody", as used herein, means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., MSR1). The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or Vh) and a heavy chain constant region. The heavy chain constant region comprises three domains, Ch1, Ch2 and Ch3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (Cl1). The Vh and Vl regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each Vh and Vl is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-MSR1 antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0091] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0092] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigenbinding fragment," as used herein.

[0093] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a Vh domain associated with a Vl domain, the Vh and Vl domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain Vh-Vh, Vh-Vl or Vl-Vl dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric Vh or Vl domain.

[0094] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigenbinding fragment of an antibody of the present invention include: (i) Vh-Ch1; (ii) Vh-Ch2; (iii) Vh-Ch3; (iv) Vh-Ch1-Ch2; (v) Vh-Ch1-Ch2-Ch3; (vi) Vh-Ch2-Ch3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) Vl-Ch3; (xi) Vl-Ch1-Ch2; (xii) Vl-Ch1-Ch2-Ch3; (xiii) Vl-Ch2-Ch3; and (xiv) Vl-Cl. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homodimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0095] As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.

[0096] The antibodies of the present invention may function through complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complementdependent cytotoxicity" (CDC) refers to lysis of antigen-expressing cells by an antibody of the invention in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" (ADCC) refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and thereby lead to lysis of the target cell. CDC and ADCC can be measured using assays that are well known and available in the art. (See, e.g., U.S. Patent Nos 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95:652656). The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.

[0097] In certain embodiments, the anti-MSR1 antibodies disclosed herein are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0098] The antibodies disclosed herein may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the Vh and Vl regions of the recombinant antibodies are sequences that, while derived from and related to human germline Vh and Vl sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0099] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.

[0100] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human IgG 1 hinge. Embodiments disclosed herein encompass antibodies having one or more mutations in the hinge, Ch2 orCn3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0101] The antibodies disclosed herein may be isolated antibodies. An "isolated antibody," as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present invention. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0102] The anti-MSR1 antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. Embodiments include antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence ( / .e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within embodiments disclosed herein.

[0103] Embodiments also include anti-MSR1 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, embodiments include anti-MSR1 antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences set forth in Table 4 herein.

[0104] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0105] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or GAP, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0106] As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalaninetyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443-1445. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 loglikelihood matrix.

[0107] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as GAP and BESTFIT which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutant thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP orTBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402.

[0108] 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 provided herein, these Definitions prevail unless stated otherwise.

[0109] The terms “a” or “an,” as used in herein means one or more, unless context clearly dictates otherwise.

[0110] As used herein, "alkyl" refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkyl. Alkyl includes, but is not limited to, those radicals having 1-20 carbon atoms, i.e., Ci.2O alkyl; 112 carbon atoms, i.e., Ci-i2 alkyl; 1-8 carbon atoms, i.e., Ci.8 alkyl; 1-6 carbon atoms, i.e., Ci.6 alkyl; and 1-3 carbon atoms, i.e., C1.3 alkyl. Examples of alkyl moieties include, but are not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl, a pentyl moiety, a hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A pentyl moiety includes, but is not limited to, n-pentyl and i-pentyl. A hexyl moiety includes, but is not limited to, n-hexyl.

[0111] As used herein, "alkylene" refers to a divalent alkyl group. Unless specified otherwise, alkylene includes, but is not limited to, 1-20 carbon atoms. The alkylene group is optionally substituted as described herein for alkyl. In some embodiments, alkylene is unsubstituted. In some embodiments, alkylene is a divalent branched alkyl group.

[0112] The term “amino” means -NH2.

[0113] The term “alkylamino,” as used herein, and unless otherwise specified, refers to the group -NHR' where R' is Ci-walkyl, as defined herein. In some or any embodiments, the alkylamino is Ci-ealkylamino.

[0114] The term “dialkylamino,” as used herein, and unless otherwise specified, refers to the group -NR'R'where each R' is independently Ci-walkyl, as defined herein. In some or any embodiments, the dialkylamino is di-Ci-ealkylamino.

[0115] The term “aminoalkyl,” as used herein, and unless otherwise specified, refers to an alkyl group, as defined herein, which is substituted with one or more amino groups. In some or any embodiments, the aminoalkyl is an alkyl group substituted with one -NH2 group (e.g., -R’(NH2) where R’ is -Ci-walkyl, as defined herein). In some or any embodiments, the aminoalkyl is an alkyl group substituted with two -NH2 groups. In some embodiments, “aminoalkyl” is aminoCi-ealkyl

[0116] An “alkylaminoalkyl,” as used herein, and unless otherwise specified, refers to an alkyl group, as defined herein, which is substituted with one or more alkylamino groups as defined herein. In some embodiments, an “alkylaminoalkyl” is Ci-6alkylaminoCi.6alkyl. In some embodiments, each alkyl in alkylaminoalkyl is independently selected.

[0117] A “dialkylaminoalkyl” as used herein, and unless otherwise specified, refers to an alkyl group, as defined herein, which is substituted with one or more dialkylamino groups as defined herein. In some embodiments, “dialkylaminoalkyl” is di-Ci-ealkylaminoCi-ealkyl. In some embodiments, each alkyl in dialkylaminoalkyl is independently selected.

[0118] As used herein, the term “O-amino acid” or “HO-amino acid” designates an amino acid wherein the native amino group at the N-terminus of an amino acid or an amino acid sequence has been replaced with an oxygen or hydroxyl group, respectively. For example, “O-AAAA” or “HO-AAAA” is intended to designate an amino acid sequence (AAAA) wherein the native amino group at the N-terminus has been replaced with an oxygen or hydroxyl group, respectively (e.g., , where each R is an amino acid side chain). Similarly, the terms “O-amino acid residue” or “HO-amino acid residue” refers to the chemical moiety within a compound that remains after a chemical reaction. For example, “O-amino acid residue” or “HO-amino acid residue” refers to the product of an amide coupling or peptide coupling of an O- amino acid or a HO-amino acid to a suitable coupling partner; wherein, for example, a water molecule is expelled after the amide or peptide coupling of the O-amino acid or a HO-amino acid, resulting in the product having the O-amino acid residue or a HO-amino acid residue incorporated therein.

[0119] Designation of an amino acid or amino acid residue without specifying its stereochemistry is intended to encompass the L form of the amino acid, the D form of the amino acid, or a racemic mixture thereof.

[0120] As used herein, "haloalkyl" refers to alkyl, as defined above, wherein the alkyl includes at least one substituent selected from a halogen, for example, fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl include, but are not limited to, -CF3, -CH2CF3, -CCI2F, and -CCI3.

[0121] As used herein, "alkenyl" refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. Alkenyl is optionally substituted and can be linear, branched, or cyclic. Alkenyl includes, but is not limited to, those radicals having 2-20 carbon atoms, i.e., C2-20 alkenyl; 2-12 carbon atoms, i.e., C2-12 alkenyl; 2-8 carbon atoms, i.e., C2-8alkenyl; 2-6 carbon atoms, i.e., C2-6 alkenyl; and 2-4 carbon atoms, i.e., C2-4 alkenyl. Examples of alkenyl moieties include, but are not limited to vinyl, propenyl, butenyl, and cyclohexenyl.

[0122] As used herein, "alkynyl" refers to a monovalent hydrocarbon radical moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. Alkynyl is optionally substituted and can be linear, branched, or cyclic. Alkynyl includes, but is not limited to, those radicals having 2-20 carbon atoms, i.e., C2-20 alkynyl; 2-12 carbon atoms, i.e., C2-12 alkynyl; 2-8 carbon atoms, i.e., C2-8 alkynyl; 2-6 carbon atoms, i.e., C2-6 alkynyl; and 2-4 carbon atoms, i.e., C2.4 alkynyl. Examples of alkynyl moieties include, but are not limited to ethynyl, propynyl, and butynyl.

[0123] As used herein, "alkoxy" refers to a monovalent and saturated hydrocarbon radical moiety wherein the hydrocarbon includes a single bond to an oxygen atom and wherein the radical is localized on the oxygen atom, e.g., CH3CH2-O for ethoxy. Alkoxy substituents bond to the compound which they substitute through this oxygen atom of the alkoxy substituent. Alkoxy is optionally substituted and can be linear, branched, or cyclic, i.e., cycloalkoxy. Alkoxy includes, but is not limited to, those having 1-20 carbon atoms, i.e., C1.20 alkoxy; 1-12 carbon atoms, i.e., C1.12 alkoxy; 1-8 carbon atoms, i.e., C1.8 alkoxy; 1-6 carbon atoms, i.e., C1.6 alkoxy; and 1-3 carbon atoms, i.e., C1.3 alkoxy. Examples of alkoxy moieties include, but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, a pentoxy moiety, a hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0124] As used herein, "haloalkoxy" refers to alkoxy, as defined above, wherein the alkoxy includes at least one substituent selected from a halogen, e.g., F, Cl, Br, or I.

[0125] As used herein, "aryl" refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms. Aryl is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of aryl moieties include, but are not limited to, those having 6 to 20 ring carbon atoms, i.e., C6-20 aryl; 6 to 15 ring carbon atoms, i.e., Ce-15 aryl, and 6 to 10 ring carbon atoms, i.e., Ce-w aryl. Examples of aryl moieties include, but are not limited to phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.

[0126] As used herein, "arylalkyl" refers to a monovalent moiety that is a radical of an alkyl compound, wherein the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound includes a single bond to an alkyl group and wherein the radical is localized on the alkyl group. An arylalkyl group bonds to the illustrated chemical structure via the alkyl group. An arylalkyl can be represented by the structure, e.g., CH2                        / OH I AH ^OH2                  ,                    or B               CH2 >            ’                                                    , wherein B is an aromatic moiety, e.g., phenyl. Arylalkyl is optionally substituted, i.e., the aryl group and / or the alkyl group, can be substituted as disclosed herein. Examples of arylalkyl include, but are not limited to, benzyl.

[0127] As used herein, "alkylaryl" refers to a monovalent moiety that is a radical of an aryl compound, wherein the aryl compound is substituted with an alkyl substituent, i.e., the aryl compound includes a single bond to an alkyl group and wherein the radical is localized on the aryl group. An alkylaryl group bonds to the illustrated chemical structure via the aryl group. An alkylaryl can be represented by the structure, e.g., wherein B is an aromatic moiety, e.g., phenyl. Alkylaryl is optionally substituted, i.e., the aryl group and / or the alkyl group, can be substituted as disclosed herein. Examples of alkylaryl include, but are not limited to, toluyl.

[0128] As used herein, "aryloxy" refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms and wherein the ring is substituted with an oxygen radical, i.e., the aromatic compound includes a single bond to an oxygen atom and 0 wherein the radical is localized on the oxygen atom, e.g., for phenoxy. Aryloxy substituents bond to the compound which they substitute through this oxygen atom. Aryloxy is optionally substituted. Aryloxy includes, but is not limited to, those radicals having 6 to 20 ring carbon atoms, i.e., C6-20 aryloxy; 6 to 15 ring carbon atoms, i.e., Ce-is aryloxy, and 6 to 10 ring carbon atoms, i.e., Ce-w aryloxy. Examples of aryloxy moieties include, but are not limited to phenoxy, naphthoxy, and anthroxy.

[0129] As used herein, "RaRbN-aryloxy" refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms are carbon atoms and wherein the ring is substituted with at least one RaRbN - substituent and at least one oxygen radical, i.e., the aromatic compound includes a single bond to an RaRbN - substituent and a single bond to an RbRaN              . oxygen atom and wherein the radical is localized on the oxygen atom, e.g.,              . RaRbN -aryloxy substituents bond to the compound which they substitute through this oxygen atom. RaRbN -aryloxy is optionally substituted. RaRbN -aryloxy includes, but is not limited to, those having 6 to 20 ring carbon atoms, for example, C6-20 (RaRbN)n-aryloxy, 6 to 15 ring carbon atoms, for example, Ce-is (RaRbN)n-aryloxy, and 6 to 10 ring carbon atoms, for example, Ce-w (RaRbN)n-aryloxy, wherein n represents the number of RaRbN - substituents. An example of an h,cn1J I RaRbN -aryloxy moiety includes, but is not limited to 4-(dimethylamino)-phenoxy, CH3 .

[0130] As used herein, "arylene" refers to a divalent moiety of an aromatic compound wherein the ring atoms are only carbon atoms. Arylene is optionally substituted and can be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of arylene moieties include, but are not limited to those having 6 to 20 ring carbon atoms, i.e., C6-20 arylene; 6 to 15 ring carbon atoms, i.e., Ce-is arylene, and 6 to 10 ring carbon atoms, i.e., Ce-w arylene.

[0131] As used herein, "heteroalkyl" refers to an alkyl in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkenyl" refers to an alkenyl in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkynyl" refers to an alkynyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl is optionally substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.

[0132] As used herein, "heteroaryl" refers to a monovalent moiety that is a radical of an aromatic compound wherein the ring atoms contain carbon atoms and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl moieties include, but are not limited to those having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. Heteroaryl is optionally substituted.

[0133] As used herein, "heteroarylene" refers to an arylene in which one or more ring atoms of the aromatic ring are replaced with an oxygen, sulfur, nitrogen, or phosphorus atom. Heteroarylene is optionally substituted.

[0134] As used herein, "heterocycloalkyl" refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocycloalkyl is optionally substituted. Examples of heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.

[0135] As used herein, "N-containing heterocycloalkyl," refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms and wherein at least one heteroatom is a nitrogen atom. Suitable heteroatoms in addition to nitrogen, include, but are not limited to oxygen and sulfur atoms. N-containing heterocycloalkyl is optionally substituted. Examples of N-containing heterocycloalkyl moieties include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.

[0136] As used herein, "optionally substituted," when used to describe a radical moiety, for example, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylene, and optionally substituted heteroarylene, means that such moiety is optionally bonded to one or more substituents. Examples of such substituents include, but are not limited to, halo, cyano, nitro, optionally substituted haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, -|-°rA, "bSR O      O       O              O      NH nrarb 4^rA -^ORA 4-U—NRARB -|-NrC—Ra -|^NrArB NH                          R< s „ II A D                       .                     N 0 S -?-NRC--U--NRArB —I—S(O)-RA ~S(O)q-RA jJxlvx. JVVV jvLL. .    . .-.A         . f-jC s                        ? n s i2           ii , ii , or ii , wherein RA, R, and Rc are, independently at each occurrence, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or RA and RB together with the atoms to which they are bonded, form a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted, and wherein one or more ring atoms is optionally replaced with a heteroatom. In certain embodiments, when a radical moiety is optionally substituted with an optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, the substituents on the optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted with substituents which are further optionally substituted with additional substituents. In some embodiments, when a group described herein is optionally substituted, the substituent bonded to the group is unsubstituted unless otherwise specified.

[0137] As used herein, “O-glucose” refers to a monovalent moiety attached via an exocyclic glucose oxygen atom. Suitable O-glucose moieties include, without limitation, OH

[0138] As used herein, “O-PEGn” refers to a monovalent moiety attached via the terminal oxygen atom, where n is from 1 to 100. For example, when n is 1, then O-PEGn is -O-CH2CH2OH; when n is two, then O-PEGn is -O-CH2CH2O-CH2CH2OH; and when n is three, then O-PEGn is -O-CH2CH2O-CH2CH2O-CH2CH2OH.

[0139] As used herein, "binding agent" refers to any molecule, e.g., protein or antibody, capable of binding with specificity to a given binding partner, e.g., antigen.

[0140] As used herein, "linker" refers to a divalent, trivalent, or multivalent moiety that covalently links the binding agent to one or more compounds described herein, for instance payload compounds and / or a hydrophilic group, as described herein.

[0141] As used herein, a “connector group” or a “connector group residue” refers to any group which may facilitate a release of a payload. Suitable connector groups facilitate the release of divalent or multivalent appended payloads back to the original unconjugated forms with little or no derivatization. Examples of connector groups include and are not limited to H , or derivatives thereof. In another example, a connector group is

[0142] In further examples, a connector group is a self immolative group. A “self-immolative group" refers to any such group known to those of skill in the art. In particular embodiments, the self-immolative group is p-aminobenzyloxycarbonyl (PAB / PABC), i.e. Those of skill will recognize that a self-immolative group is capable of carrying out a chemical reaction which releases the remaining atoms of a linker from a payload.

[0143] As used herein, “connecting linker” (L2) or “connecting linkers” refers to divalent groups which are cleavable or non-cleavable. Cleavable linkers are linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction. Non-cleavable linkers are linkers that release an attached payload via lysosomal degradation of the antibody following internalization. Suitable connecting linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction labile linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, disulfide units (e.g., -S-S-, -S-C(R1bR2b)-, wherein R1b and R2b are independently hydrogen or hydrocarbyl), carbamate units, para-amino-benzyl units (PAB), phosphate units, e.g., mono-, bis-, or tris- phosphate units, and peptide units, e.g., peptide units containing two, three four, five, six, seven, eight, or more amino acid residues, including but not limited to valine—citrulline residue units. As used herein, “caproyl” means a -(CH2)s-C(O)- group.

[0144] As used herein, the phrase “reactive group” (“RG”), refers to a functional group or moiety that reacts with a reactive portion of an antibody, modified antibody, or antigen binding fragment thereof. In certain embodiments, the “reactive group” is a functional group or moiety (e.g., maleimide or NHS ester) that reacts with a cysteine or lysine residue of an antibody or antigen-binding fragment thereof. In certain embodiments, the “reactive group” is a functional group or moiety that is capable of undergoing a click chemistry reaction. In some embodiments of said click chemistry reaction, the reactive group comprises an alkyne that is capable of undergoing a 1,3 cycloaddition reaction with an azide. Such suitable reactive groups include, but are not limited to, strained alkynes, e.g., those suitable for strain-promoted alkyne-azide cycloadditions (SPAAC), cycloalkynes, e.g., cyclooctynes, benzannulated alkynes, and alkynes capable of undergoing 1,3 cycloaddition reactions with azides in the absence of copper catalysts. Suitable alkynes also include, but are not limited to, DI BAO (where the -C(O)CH2CH2C(O)- portion of DIBAC moiety can be represented by L and / or L2), DIBO (where the -O- portion of DIBO moiety can be represented by L and / or L2), BARAC (where the V                  O~4 [ \ / \ / x portion of BARAC moiety can be represented by L and / or L2), DIFO (where the -O- portion can be represented by L and / or L2), substituted alkynes, e.g., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof. Linker-payloads comprising such reactive groups are useful for conjugating antibodies that have been functionalized with azido groups. Such functionalized antibodies include antibodies functionalized with azido-polyethylene glycol groups. In certain embodiments, such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue, e.g., heavy chain Q295 (EU numbering), with a compound according to the formula H2N-LL-N3, wherein LL is a divalent polyethylene glycol group, in the presence of the enzyme transglutaminase.

[0145] In some embodiments, the reactive group (RG) is an alkyne, e.g., , which can react via click chemistry with an azide, e.g., N , to form a click chemistry product, e.g., , its regioisomer, or mixture thereof. In some embodiments, the reactive group is an alkyne, e.g., (where L and / or L2 encompasses -OCH2C(O)-), which can react via click chemistry with an azide, e.g.,            to form a click chemistry product, e.g., . In some embodiments, the reactive group is an alkyne, e.g., CH , which can react via click chemistry with an azide, e.g., N , to form a click chemistry product, e.g., , its regioisomer, or mixture thereof. In some embodiments, the reactive group is a functional group, e.g., O , which reacts with a cysteine residue on Ab ~ \S o o an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., O , wherein Ab refers to an antibody or antigen-binding fragment thereof and S refers to the S atom on a cysteine residue through which the functional group bonds to the Ab. In some ,O / 4 o V-K JL H o v embodiments, the reactive group is a functional group, e.g., °           , which reacts with a lysine residue on an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g., A, * , wherein Ab refers to an antibody or antigen-binding fragment thereof and N refers to the N atom on, e.g., a lysine or an amino terminus residue through which the functional group bonds to the Ab. In some instances, a reactive group is which reacts with two thiols (e.g., thiols on two different chains) of an antibody or antigen-binding fragment thereof, to Ab form a bond thereto e.g., In some instances, a reactive group is , which reacts with two thiols (e.g., thiols on two different chains) of an antibody or antigen-binding fragment thereof, to form a bond thereto, e.g.,

[0146] As used herein, the phrase “reactive group residue” refers to a product of the reaction of a functional group in the linker moiety with the reactive portion of a binding agent (BA), including the product of click chemistry. The reactive group residue is formed by the reaction of a reactive group on an amino acid of the binding agent, and is attached to the binding agent (e.g. antibody) and to the linker. In some embodiments, the reactive group residue is a group which comprises 1,2,3-tetrazole, i.e. is formed by the reaction of an alkyne with an azide. In O X? ,4 y r 44 n some embodiments, the reactive group residue is            (a) wherein S refers to the S atom on a cysteine residue through which (a) bonds to the Ab, and which is formed by the reaction of O with a cysteine residue on an antibody or antigen-binding fragment thereof. O In some embodiments, the reactive group residue is ' wherein N refers to the N atom on / O / \ o V-n, JL . v o y a lysine residue, and which is formed by the reaction of a functional group, e.g., O           , with a lysine residue on an antibody or antigen-binding fragment thereof. Those of skill in the art will recognize that portions of the reactive group residue may come from the reactive group, Ss 0 from the antibody, or both. In some instances the reactive group residue is *          , where S refers to the S atom on a cysteine residue, and which is formed by the reaction of a functional Br^. O Br^. O group '    / or Br X with a cysteine residue on an antibody or antigen-binding fragment thereof.

[0147] As used herein, “pharmaceutically acceptable salt” refers to any salt suitable for administration to a patient. Suitable salts include, but are not limited to, those disclosed in. Berge etal., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1, incorporated herein by reference. Examples of salts include, but are not limited to, acid-derived, base-derived, organic, inorganic, amine, and alkali or alkaline earth metal salts, including but not limited to calcium salts, magnesium salts, potassium salts, sodium salts, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some examples, a payload described herein (e.g., a rifamycin analog described herein) comprises a tertiary amine, where the nitrogen atom in the tertiary amine is the atom through which the payload is bonded to a linker or a linker-spacer. In such instances, bonding to the tertiary amine of the payload yields a quarternary amine in the linker-payload molecule. The positive charge on the quarternary amine can be balanced by a counter ion (e.g., chloro, bromo, iodo, or any other suitably charged moiety such as those described above).

[0148] Certain groups, moieties, substituents, and atoms are depicted with a wavy line. The wavy line can intersect or cap a bond or bonds. The wavy line indicates the atom through which the groups, moieties, substituents, or atoms are bonded. For example, a phenyl group that is substituted with a propyl group depicted as: CH3 ^CH3 ch3 or ch3 has the following structure:

[0149] As used herein, "amide synthesis conditions" refers to reaction conditions suitable to effect the formation of an amide, e.g., by the reaction of a carboxylic acid, activated carboxylic acid, or acyl halide with an amine. In some examples, amide synthesis conditions refer to reaction conditions suitable to effect the formation of an amide bond between a carboxylic acid and an amine. In some of these examples, the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with an amine to form an amide. Suitable conditions to effect the formation of an amide include, but are not limited to, those utilizing reagents to effect the reaction between a carboxylic acid and an amine, including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), (benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-l-yl)-N,N,N',N’-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N’-tetramethyluronium tetrafluoroborate (TBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazole (GDI). In some examples, a carboxylic acid is first converted to an activated carboxylic ester before treating the activated carboxylic ester with an amine to form an amide bond. In certain embodiments, the carboxylic acid is treated with a reagent. The reagent activates the carboxylic acid by deprotonating the carboxylic acid and then forming a product complex with the deprotonated carboxylic acid as a result of nucleophilic attack by the deprotonated carboxylic acid onto the protonated reagent. The activated carboxylic esters for certain carboxylic acids are subsequently more susceptible to nucleophilic attack by an amine than the carboxylic acid is before it is activated. This results in amide bond formation. As such, the carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

[0150] “Amino acid” or “amino acid residue" refers, in some embodiments, to naturally occurring amino acids. In other embodiments, an amino acid or amino acid residue may be a naturally occurring amino acid and / or an unnatural amino acid (e.g., P-amino acids (P3 and P2), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, and / or / V-methyl amino acids, or any other commercially available unnatural amino acid (e.g., unnatural amino acids available from Sigma-Aldrich)). In other embodiments, an amino acid residue may be a residue having a side chain involved in a reaction mediated by a transglutaminase, e.g., a transglutaminase-mediated reaction of an amino acid side chain with a primary amine. For example, a reaction of an asparagine and / or glutamine side chain with a primary amine is used for preparation of certain ADCs described herein. In certain embodiments, such functionalized antibody is derived by reacting an antibody comprising at least one glutamine residue, e.g., heavy chain Q295 (EU numbering), with a compound according to the formula H2N-LL-N3, wherein LL is a divalent polyethylene glycol group, in the presence of the enzyme transglutaminase. H2N^so h

[0151] As used herein, "taurine" refers to the reagent             3 or group H where indicates the atom through which the taurine is bonded to the adjacent groups in the formula.

[0152] As used herein, "stereoisomeric form" or “stereoisomer” refers to the relative spatial orientation of different groups in a compound. Stereoisomeric forms include enantiomers, diasteromers, and / or mixtures thereof.

[0153] As used herein, "regioisomer," "regioisomers," or "mixture of regioisomers" refers to the product(s) of 1,3-cycloadditions or strain-promoted alkyne-azide cycloadditions (SPAACs) -otherwise known as click reactions - that derive from suitable azides (e.g., -N3, or PEG-N3 derivitized antibodies) treated with suitable alkynes. In certain embodiments, for example, regioisomers and mixtures of regioisomers are characterized by the click reaction products shown below:

[0154] By way of example only, regioisomers of compound A1 i.e., compounds A2’, A3’, A4', are shown below, wherein each 5 to the payload: Q ? h n" Ji )       o A \J □          O       H N> 1   )      0 N 7= / o Q s h N' 1   )      0 N^s^rZ A VJ HOaS^ B <f7 9 H N— / N      n     o N' A 2      0 V# ho3s^ is a bond to the binding agent; and each 5 is a bond 0 H O Y H ? \    \Anh2 1 o / LA /          o o 7=\                                    II 'n'                                         h compound A1' 0 \    ^Anh2 hL° AAA          u nN^0^0^0^0^N^S0sH 'N                                     H compound A2'; 0 \ v». I 0 / HN~^ / 7=\ 0 compound A3'; 0 \ \Anh2 I o / \H HN-Y' <    1 y   \Z          \z N 0 compound A4’. Anti-MSR1 Antibodies Comprising Fc Variants

[0155] According to certain embodiments, anti-MSR1 antibodies are provided comprising an Fc domain comprising one or more mutations which enhance or diminish antibody binding to the FcRn receptor, e.g., at acidic pH as compared to neutral pH. For example, provided herein are anti-MSR1 antibodies comprising a mutation in the Ch2 ora Ch3 region of the Fc domain, wherein the mutation(s) increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Such mutations may result in an increase in serum half-life of the antibody when administered to an animal. Nonlimiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / WorT), 254 (e.g., S orT), and 256 (e.g., S / R / Q / E / D or T); or a modification at position 428 and / or 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., H / F or Y); ora modification at position 250 and / or428; ora modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and / or 308 modification (e.g., 308F or 308P).

[0156] For example, embodiments include anti-MSR1 antibodies comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (e.g., M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F). All possible combinations of the foregoing Fc domain mutations, and other mutations within the antibody variable domains disclosed herein, are contemplated within the scope of the present invention. Biological Characteristics of the Antibodies

[0157] Embodiments include antibodies and antigen-binding fragments thereof that bind human MSR1 with high affinity. For example, the present invention includes anti-MSR1 antibodies that bind human MSR1 extracellular domain expressed with an N-terminal nonahistidine tag (e.g., His9-hMSR1) with a Kd of less than about 10 nM as measured by surface plasmon resonance at 25°C or 37°C, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that bind human MSR1 at 37°C with a Kd of less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. In some embodiments, the anti-MSR1 antibodies disclosed herein bind human MSR1 at 25°C with a Kd of less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay.

[0158] Embodiments also include antibodies and antigen-binding fragments thereof that bind monkey MSR1 with high affinity. For example, disclosed herein are anti-MSR1 antibodies that bind monkey MSR1 extracellular domain expressed with an N-terminal myc-myc-hexahistidine tag (e.g., HMM-mfMSR1) with a KD of less than about 20 nM as measured by surface plasmon resonance at 25°C or 37°C, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that bind monkey MSR1 at 37°C with a Kd of less than about 20 nM, less than about 18 pM, less than about 15 nM, less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. In some embodiments, the anti-MSR1 antibodies disclosed herein bind monkey MSR1 at 25°C with a Kd of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay.

[0159] The present invention also includes antibodies and antigen-binding fragments thereof that bind human MSR1 extracellular domain expressed with an N-terminal nonahistidine tag (e.g., His9-hMSR1) with a dissociative half-life (1½) of greater than about 5 minutes as measured by surface plasmon resonance at 25°C or 37°C, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that bind human MSR1 at 37°C with a 1½ of greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, greater than about 240 minutes, or longer, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay.

[0160] Embodiments also include antibodies and antigen-binding fragments thereof that can bind monkey MSR1 extracellular domain expressed with an N-terminal myc-myc-hexahistidine tag (e.g. HMM-mfMSR1) with high affinity. For example, the present invention includes anti-MSR1 antibodies that bind HMM-mfMSR1 with a Kd of less than about 20 nM as measured by surface plasmon resonance at 25°C or 37°C, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that bind HMM-mfMSR1 at 37°C with a Kd of less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. In some embodiments, the anti-MSR1 antibodies disclosed herein bind HMM-mfMSR1 at 25°C with a Kd of less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM, or less than about 50 pM, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay.

[0161] Embodiments also include antibodies and antigen-binding fragments thereof that bind monkey MSR1 extracellular domain expressed with an N-terminal myc-myc-hexahistidine tag (e.g. HMM-mfMSR1) with a dissociative half-life (1½) of greater than about 55 minutes as measured by surface plasmon resonance at 25°C or 37°C, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that bind dimeric human MSR1 at 37°C with a 1½ of greater than about 1 minute, greater than about 2 minutes, greater than about 3 minutes, greater than about 4 minutes, greater than about 5 minutes, greater than about 6 minutes, greater than about 8 minutes, greater than about 10 minutes, greater than about 12 minutes, greater than about 14 minutes, greater than about 16 minutes, greater than about 18 minutes, greater than about 20 minutes, greater than about 30 minutes, greater than about 40 minutes, greater than about 50 minutes, greater than about 60 minutes, greater than about 70 minutes, greater than about 80 minutes, greater than about 90 minutes, greater than about 120 minutes, greater than about 150 minutes, greater than about 180 minutes, greater than about 210 minutes, or longer, as measured by surface plasmon resonance, e.g., using an assay format as defined in Example 3 herein, or a substantially similar assay.

[0162] Embodiments also include antibodies and antigen-binding fragments thereof that bind engineered cell-surface expressed hMSR1 with binding ratios of engineered hMSR1-expressing cells to non-expressing cells of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40fold, at least about 45-fold, at least about 50-fold, or greater, as measured by antibody binding assay, e.g., using an assay format as defined in Example 5 herein, or a substantially similar assay. In some embodiments, provided herein are antibodies that bind cells with endogenously-expressed hMSR1 with binding ratios of endogenous hMSR1-expressing cells to nonexpressing cells of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, or greater at least about 12-fold, at least about 15-fold, at least about 20fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, or greater, as measured by antibody binding assay, e.g., using an assay format as defined in Example 5 herein, ora substantially similar assay. In some embodiments, an MSR1 antibody or antigen binding fragment disclosed herein bind engineered cell-surface expressed mouse MSR1 with binding ratios of engineered mouse MSR1-expressing cells to non-expressing cells of at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 12-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 30-fold, at least about 35-fold, at least about 40-fold, at least about 45-fold, at least about 50-fold, or greater, as measured by antibody binding assay, e.g., using an assay format as defined in Example 5 herein, or a substantially similar assay.

[0163] Embodiments also include antibodies and antigen-binding fragments thereof that bind MSR1 and exhibit maximum inhibition of uptake of modified low-density lipoprotein (LDL) in cells expressing human MSR1 of less than about 95%. For example, embodiments include anti-MSR1 antibodies that exhibit maximum inhibition of uptake of modified LDL (e.g., oxidized or acetylated) in cells that express human MSR1 of less than about 95%, with an IC50 of less than about 6.1 nM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay. According to certain embodiments, anti-MSR1 antibodies are provided that exhibit maximum inhibition of modified LDL uptake in cells expressing human MSR1 of less than about 95%, with an IC50 of less than about 6.1 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.0 nM, less than about 900 pM, less than about 800 pM, less than about 600 pM, less than about 400 pM, less than about 200 pM, less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay.

[0164] In some embodiments, the anti-MSR1 antibodies exhibit maximum inhibition of modified LDL uptake in cells expressing human MSR1 of less than about 90%, with an IC50 of less than about 6.1 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.0 nM, less than about 900 pM, less than about 800 pM, less than about 600 pM, less than about 400 pM, less than about 200 pM, less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay.

[0165] In some embodiments, the anti-MSR1 antibodies exhibit maximum inhibition of modified LDL uptake in cells expressing human MSR1 of less than about 75%, with an IC50 of less than about 6.1 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.0 nM, less than about 900 pM, less than about 800 pM, less than about 600 pM, less than about 400 pM, less than about 200 pM, less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay.

[0166] In some embodiments, the anti-MSR1 antibodies exhibit maximum inhibition of modified LDL uptake in cells expressing human MSR1 of less than about 60%, with an IC50 of less than about 6.1 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.0 nM, less than about 900 pM, less than about 800 pM, less than about 600 pM, less than about 400 pM, less than about 200 pM, less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay.

[0167] In some embodiments, the anti-MSR1 antibodies exhibit maximum inhibition of modified LDL uptake in cells expressing human MSR1 of less than about 50%, with an IC50 of less than about 6.1 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1.5 nM, less than about 1.4 nM, less than about 1.3 nM, less than about 1.2 nM, less than about 1.0 nM, less than about 900 pM, less than about 800 pM, less than about 600 pM, less than about 400 pM, less than about 200 pM, less than about 100 pM, less than about 80 pM, less than about 60 pM, less than about 40 pM, less than about 20 pM as measured using a ligand uptake assay, e.g., using an assay format as defined in Example 8 herein, or a substantially similar assay.

[0168] Embodiments also include antibodies and antigen-binding fragments thereof that bind cell surface-expressed MSR1 and are internalized by the cells. For example, antibodies that bind to cell surface-expressed MSR1 on THP-1 cells and become internalized by the cells are provided herein. For example, the instant disclosure includes anti-MSR1 antibodies that bind to cell surface-expressed MSR1 on THP-1 cells and become internalized by the cells with a relative percentage of at least about 10%, as measured by chemiluminescence, e.g., using an assay format as defined in Example 9 herein, or a substantially similar assay. In certain embodiments, anti-MSR1 antibodies that bind to cell surface-expressed MSR1 on THP-1 cells and become internalized by the cells with a relative percentage of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, as measured by chemiluminescence, e.g., using an assay format as defined in Example 9 herein, or a substantially similar assay.

[0169] The antibodies disclosed herein may possess one or more of the aforementioned biological characteristics, or any combination thereof. The foregoing list of biological characteristics of the antibodies disclosed herein is not intended to be exhaustive. Other biological characteristics of the antibodies disclosed herein will be evident to a person of ordinary skill in the art from a review of the present disclosure including the working Examples herein. Antibody-Drug Conjugates (ADCs)

[0170] Provided herein are antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody or antigen-binding fragment thereof conjugated to a drug or a therapeutic agent. In some embodiments, the therapeutic agent is a liver X receptor (LXR) agonist or a steroid. Also provided herein are reactive linker-payloads useful for making the ADCs. Further provided herein are modified anti-MSR1 antibodies and modified MSR1 antigen-binding fragments useful for making the ADCs.

[0171] The ADCs generally have the Formula (I): BA - [(L)o-i - PA]n. In the formula, BA is a binding agent, for instance, an anti-MSR1, antibody, or an MSR1 antigen-binding fragment thereof. L is a linker, described in detail below. PA is a payload. Suitable payloads include any small molecule that can provide a therapeutic benefit through its delivery to MSR1. In certain embodiments, a payload may be, for instance, a steroid, an LXR modulator, or a rifamycin analog. Useful payloads are described in detail below. In the formula, n is an integer from 1 to 30, for instance from 1 to 4, e.g., 2 or 4. Each L - PA is covalently bonded to a functional group of PA. In some particular embodiments, each L - PA is covalently bonded to a lysine side chain, a cysteine side chain, a glutamine side chain, or an amino terminus of BA.

[0172] Techniques and linkers for conjugating to residues of an antibody or antigen binding fragment are known in the art. Exemplary amino acid attachments that can be used in the context of this aspect, e.g., lysine (see, e.g., US 5,208,020; US 2010 / 0129314; Hollander et al., Bioconjugate Chem., 2008, 19:358-361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / 0585592), cysteine (see, e.g., US 2007 / 0258987; WO 2013 / 055993; WO 2013 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 0101546; and US 7,750,116), selenocysteine (see, e.g., WO 2008 / 122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 705:12451-12456), formyl glycine (see, e.g., Carrico et al., Nat. Chem. Biol., 2007, 3:321-322; Agarwal etal., Proc. Natl. Acad. Sci., USA, 2013, 7 70:46-51, and Rabuka et al., Nat. Protocols, 2012, 70:1052-1067), non-natural amino acids (see, e.g., \NO 2013 / 068874, and WO 2012 / 166559), and acidic amino acids (see, e.g., \NO 2012 / 05982). Linkers can also be conjugated to an antigen-binding protein via attachment to carbohydrates (see, e.g., US 2008 / 0305497, WO 2014 / 065661, and Ryan et al., Food & Agriculture Immunol., 2001, 73:127130) and disulfide linkers (see, e.g., \NO 2013 / 085925, WO 2010 / 010324, WO 2011 / 018611, and Shaunak et al., Nat. Chem. Biol., 2006, 2:312-313). Site specific conjugation techniques can also be employed to direct conjugation to particular residues of the antibody or antigen binding protein (see, e.g., Schumacher et al. J Clin Immunol (2016) 36(Suppl 1): 100). Site specific conjugation techniques, include, but are not limited to glutamine conjugation via transglutaminase (see e.g., Schibli, Angew Chemie Inter Ed. 2010, 49 ,9995).

[0173] Linkers can be conjugated to one or more glutamine residues via transglutaminasebased chemo-enzymatic conjugation (see, e.g., Dennler eta / ., Bioconjugate Chem. 2014, 25, 569-578, and WO 2017 / 147542). For example, in the presence of transglutaminase, one or more glutamine residues of an antibody can be coupled to a primary amine compound. Briefly, in some embodiments, an antibody having a glutamine residue (e.g., a Gln295 residue) is treated with a primary amine compound, described in more detail below, in the presence of the enzyme transglutaminase. Primary amine compounds include payloads or linker-payloads, which directly provide antibody drug conjugates via transglutaminase-mediated coupling. Primary amine compounds also include linkers and spacers that are functionalized with reactive groups that can be subsequently reacted with further compounds towards the synthesis of antibody drug conjugates. Antibodies comprising glutamine residues can be isolated from natural sources or engineered to comprise one or more glutamine residues. Techniques for engineering glutamine residues into an antibody polypeptide chain (glutaminyl-modified antibodies or antigen binding molecules) are within the skill of the practitioners in the art. In certain embodiments, the antibody is aglycosylated.

[0174] In certain embodiments, the antibody or a glutaminyl-modified antibody or antigen binding molecule comprises at least one glutamine residue in at least one polypeptide chain sequence. In certain embodiments, the antibody or a glutaminyl-modified antibody or antigen binding molecule comprises two heavy chain polypeptides, each with one Gln295 residue. In further embodiments, the antibody or a glutaminyl-modified antibody or antigen binding molecule comprises one or more glutamine residues at a site other than a heavy chain 295. In some embodiments, an antibody can be prepared by site-directed mutagenesis to insert a glutamine residue at a site without resulting in disabled antibody function or binding. For example, included herein are antibodies bearing Asn297Gln (N297Q) mutation(s) as described herein. In some embodiments, an antibody having a Gln295 residue and / or an N297Q mutation contains one or more additional naturally occurring glutamine residues in their variable regions, which can be accessible to transglutaminase and therefore capable of conjugation to a linker or a linker-payload. An exemplary naturally occurring glutamine residue can be found, e.g., at Q55 of the light chain. In such instances, the antibody conjugated via transglutaminase can have a higher than expected DAR value (e.g., a DAR higher than 4). Any such antibodies can be isolated from natural or artificial sources.

[0175] The primary amine compound useful for the transglutaminase mediated coupling of an antibody (or antigen binding compound) comprising a glutamine can be any primary amine compound deemed useful by the practitioner of ordinary skill. Generally, the primary amine compound has the formula H2N-R, where R can be any group compatible with the antibody and reaction conditions. In certain embodiments, R is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0176] In some embodiments, the primary amine compound comprises a reactive group or protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, ketones, aldehydes, acids, esters, hydrazides, analines, and amines. In certain embodiments, the reactive group is selected from the group consisting of azide, alkyne, sulfhydryl, cycloalkyne, aldehyde, and carboxyl.

[0177] In certain embodiments, the primary amine compound is according to the formula H2N-LL-X, where LL is a divalent spacer and X is a reactive group or protected reactive group. In particular embodiments, LL is a divalent polyethylene glycol (PEG) group. In certain embodiments, X is selected from the group consisting of-SH, -N3, alkyne, aldehyde, and tetrazole. In particular embodiments, X is-Ns.

[0178] In certain embodiments, the primary amine compound is according to one of the following formulas: H2N-(CH2)n-X; H2N-(CH2CH2O)n-(CH2)p-X; H2N-(CH2)n-N(H)C(O)-(CH2)m-X; H2N-(CH2CH2O)n-N(H)C(O)-(CH2CH2O)m-(CH2)p-X; H2N-(CH2)n-C(O)N(H)-(CH2)m-X; H2N-(CH2CH2O)n-C(O)N(H)-(CH2CH2O)m-(CH2)p-X; H2N-(CH2)n-N(H)C(O)-(CH2CH2O)m-(CH2)p-X; H2N-(CH2CH2O)n-N(H)C(O)-(CH2)m-X; H2N-(CH2)n-C(O)N(H)-(CH2CH2O)m-(CH2)p-X; and H2N-(CH2CH2O)n-C(O)N(H)-(CH2)m-X; where n is an integer selected from 1 to 12; m is an integer selected from 0 to 12; p is an integer selected from 0 to 2; and X is selected from the group consisting of-SH, -N3, -C=CH, -C(O)H, tetrazole, and any of

[0179] In the above, any of the alkyl or alkylene ( / .e., -CH2-) groups can optionally be substituted, for example with Ci-salkyl, methylformyl, or-SOsH. In certain embodiments, the alkyl groups are unsubstituted.

[0180] In certain embodiments, the primary amine compound is selected from the group consisting of:

[0181] In particular embodiments, the primary amine compound is H2N                          n3

[0182] Exemplary conditions for the above reactions are provided in the Examples below:

[0183] Accordingly, provided herein are modified anti-MSR1 antibodies, and antigen-binding fragments thereof, linked to one or more primary amine compounds. In particular embodiments, provided herein are modified anti-MSR1 antibodies, and antigen-binding fragments thereof, according to the formula:

[0184] In the formula, BA is an anti-MSR1 antibody, or an antigen binding fragment thereof. The variable n is an integer from 1 to 30. In certain embodiments, n is from 1 to the number of glutamine residues in BA. In certain embodiments, n is from 1 to 4. In certain embodiments, n is 1,2,3, or 4. In some embodiments, n is 2. In some embodiments, n is 4. The modified anti-MSR1 antibodies, and antigen-binding fragments thereof, are useful, for example, for linking to one or more L - PA molecules to form an ADC.

[0185] In certain embodiments, BA comprises two or four glutamine residues. In certain embodiments, BA comprises a Q295 residue. In certain embodiments, BA comprises an N297Q mutation. In certain embodiments, BA comprises Q295 and N297Q. In such embodiments, because BA can be dimeric, BA has four glutamine residues for conjugation to L - PA moieties. Compounds

[0186] In one aspect, provided herein is a compound and / or an antibody-drug conjugate comprising any antibody, or antigen-binding fragment thereof, described herein conjugated to a payload residue optionally through a linker or through a linker-spacer,

[0187] In a group of embodiments, the compound and / or the antibody-drug conjugate has the structure of Formula (I): BA PA n Formula (I) wherein: BA is a binding agent; L is a linker; PA is a payload moiety selected from the group consisting of a steroid residue, a LXR modulator residue, or a rifamycin analog residue; and subscript n is an integer from 1 to 30.

[0188] In a group of embodiments, a compound and / or antibody-drug conjugate described above and herein has the structure of Formula (IA): BA--RG1--SP1---AA1----AA2----(Q)01----SP----PA n Formula (IA) wherein SP1 is absent, or a spacer; RG1 is a reactive group residue; AA1 is absent, or a divalent or trivalent linker comprising an amino acid residue which is optionally bonded directly or indirectly to a group HG; AA2 is absent, ora dipeptide, tripeptide, or tetrapeptide residue; Q, when present, is a connector group residue; SP is absent, or a spacer; and HG, when present, is a hydrophilic group.

[0189] In a group of embodiments, a compound and / or antibody-drug conjugate described above and herein has the structure of Formula (IB-1): BA--RG1---SP1---(Q)O-1----SP-----PA n Formula (IB-1) wherein SP1 is absent, or a spacer; RG1 is a reactive group residue; Q, when present, is O H                 , H              , or H            ; oA s s and SP is absent, or a spacer; wherein the indicates the atoms through which the referenced group is bonded to the adjacent groups in the formula.

[0190] In a group of embodiments, a compound and / or antibody-drug conjugate described above and herein has the structure of Formula (IB-2): BA--RG1--SP1---AA1----AA2----(Q)^----SP----PA n Formula (IB-2) wherein SP1 is absent, or a spacer; RG1 is a reactive group residue; AA1 is absent, or a divalent or trivalent linker comprising an amino acid residue which is optionally bonded directly or indirectly to a group HG; AA2 is absent, ora dipeptide, tripeptide, or tetrapeptide residue; r N Q, when present, is H SP is absent, or a spacer; and HG, when present, is HO wherein the \ indicates the atoms through which the referenced group is bonded to the adjacent groups in the formula.

[0191] In a group of embodiments, a compound and / or antibody-drug conjugate described above and herein has the structure of Formula (IC), Formula (ID), or Formula (IE): BA--RG1--SP1---AA1----AA2----(Qh^----SP----PA I                                                                          n RG2 SP2 HG                                 Formula (IC) BA--RG1---SP1---AA1-----AA2-----(Q)o-i RG2 HG SP----PA Formula (ID) BA--RG1---SP1---AA1- AA2-----(Q)o-1-----SP-----PA HG n Formula (IE) wherein SP1 is absent, or a spacer; RG1 is a reactive group residue; SP2 is absent, or a spacer; RG2 is a reactive group residue; AA1 is a divalent or trivalent linker comprising an amino acid residue; AA2 is a dipeptide, tripeptide, or tetrapeptide residue; Q, when present, is SP is absent, or a spacer; and

[0192] wherein the indicates the atoms through which the referenced group is bonded to the adjacent groups in the formula. In some or any instances, for any compound and / or antibody-drug conjugate described above and herein, AA1-AA2 is according to Formula (LL1): (LL1) wherein RAA1, RAA2, and RAA3 are each, independently, amino acid side chains, at least one of which is bonded to -(RG2)-SP2-HG, -(RG2)-HG or HG; wherein the indicates the atoms through which AA1-AA2 is bonded to the adjacent groups in the formula. In some of such embodiments, RAA1 is a lysine, glutamine, glutamic acid or aspartic acid side chain bonded directly or indirectly to HG, and RAA2 and RAA3 are either valine and alanine or valine and citrulline sidechains respectively.

[0193] In some or any instances, for any compound and / or antibody-drug conjugate described wherein the indicates the atoms through which AA1-AA2 is bonded to the adjacent groups in the formula.

[0194] In some or any instances, for any compound and / or antibody-drug conjugate described above and herein, the RG1 and RG2 residues are independently, in each instance, selected from the group consisting of: wherein the ' indicates the atom through which the RG1 or RG2 residue is bonded to the adjacent groups in the formula.

[0195] In some or any instances, for any compound and / or antibody-drug conjugate described above and herein, SP, SP1 and SP2 are independently, in each instance, absent, or selected from the group consisting of C1.6 alkylene, -NH-, -S-, -O-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)u-C(O)-, -C(O)-NH-(CH2)v-, (glycine)4-serine, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

[0196] In some or any instances, for any compound and / or antibody-drug conjugate described above and herein, n is an integer from 1 to 10, from 1 to 8, from 1 to 6, from 1 to 4, or n is 1, 2, 3, or 4.

[0197] In some or any instances, for any compound, linker-payload, and / or antibody-drug SP1---AA1----AA2----(Q)0.i----SP— conjugate described above and herein, ’                                       5 is

[0198] In some or any embodiments, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or antigen-binding fragment thereof, is conjugated to a steroid payload through a linker or a linker-spacer.

[0199] In some or any embodiments, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or antigen-binding fragment thereof, is conjugated to a LXR modulator payload through a linker.

[0200] In some or any embodiments, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or antigen-binding fragment thereof, is conjugated to a rifamycin analog payload through a linker. Payloads

[0201] In the Formula (I) BA - [L - PA]n, PA can be any payload deemed useful. Such payloads include small molecules that provide a therapeutic benefit through their delivery via MSR1. In certain embodiments, PA is the residue of a molecule selected from the group consisting of a steroid,an LXR modulator, or a rifamycin analog. In some cases, PA is a steroid. In some cases, PA is an LXR modulator. In some cases, PA is an LXR agonist. In some embodiments, PA is an LXR antagonist. Exemplary LXR modulator payloads are described, e.g., in U.S. Application No. 62 / 508,327, filed May 18, 2017, entitled “BIS-OCTAHYDROPHENANTHRENE CARBOXAMIDES AND PROTEIN CONJUGATES THEREOF,” published as US 2018 / 0334426, which is incorporated herein by reference in its entirety. In some instances PA is a rifamycin analog, including any rifamycin analog described herein. In some instances, PA is rifalogue, having the following structure:

[0202] In certain embodiments, the payloads in compounds of Formula (I) are glucocorticoids according to Formula (A): R5A Formula (A) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein R1 and R2 are, independently, -H, alkyl, alkyl-C(O)-O-, -OH, or halo; or R1 and R4 O^O R2 together form , wherein R4is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl, wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are, independently in each instance, optionally substituted with -NRAaRAb; R3 is-OH, RZ-C(O)-X-, heteroalkyl, piperidinyl, -NRAaRAb, -oxyaryl-NRAaRAb or -Z-A'(Rp)t; Rz is alkyl; X is O or NRAa; Z is S, S(O), S(O)2, SO2NRAa, O, C(O)NRAa, 0(0), or NRAa; A' is aryl, arylalkyl, or heteroaryl; Rp is, independently in each instance, halo, optionally substituted alkyl, -OH, or -NRAaRAb; RAa and RAb are, independently in each instance, -H, optionally substituted alkyl, or optionally subtitued aryl; subscript a is an integer from 0-19; and t is an integer from 1-3; with the proviso that: R4 (1) R3 is not -OH (a) when R1 is -OH or (b) when R1 and R2 together form , wherein R4 is Ci.galkyl or (2) R3 is not and R5A and R5B are each, independently, halo or a hydrogen atom; wherein the group R3 or R4 is bonded to the linker.

[0203] In some of such embodiments, R3 is NH2. In some other of such embodiments, R3 is nh2 wherein indicates the atom through which R3 is attached to the adjacent groups in Formula (I).

[0204] In certain embodiments, PA is a steroid. Exemplary steroid payloads are described, e.g., in U.S. Application No. 62 / 614,905, filed January 8, 2018, entitled “STEROIDS AND ANTIBODY CONJUGATES THEREOF,” and U.S. Application No. 15 / 806,197, filed November 7, 2017, entitled “STEROIDS AND PROTEIN-CONJUGATES THEREOF,” published as US 2018 / 0155389, each of which is incorporated herein by reference in its entirety. In certain embodiments, PA is selected from 1110                   1120 1130                   1140 ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments according to any of Formulas 1110-1140, R3 is -O-aryl, -NRAaRAb, -alkylene-NRAaRAb, -X-arylene-Y-NRAaRAb, -X-heteroarylene-Y-NRAaRAb, or N-containing heterocycloalkyl; wherein X is absent, -N-, -CH2-, or-O-; wherein Y is absent or-CH2-; and R4is alkyl, aryl, alkylaryl, or arylalkyl. In certain embodiments, R3 is -O-arylene-NRAaRAb, -O-heteroarylene-NRAaRAb; wherein aryl or heteroaryl is optionally substituted with halogen, deuterium, hydroxyl, or methoxyl. In certain embodiments, R3 is -O-phenyl-NRAaRAb, -O-heteroarylene-NRAaRAb; wherein phenyl or heteroaryl is optionally substituted with halogen or deuterium. In certain embodiments, R4 is n-propyl. In certain embodiments, RAaand RAb are each independently hydrogen or alkyl. In particular embodiments, one of RAaand RAbis substituted with a bond to the linker (e.g., L or LL). In certain embodiments, PA is ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, , or a pharmaceutically acceptable salt, solvate, or stereoisomer HN thereof In certain embodiments, PA is                        , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof In certain embodiments, PA is or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments, PA is f               , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In such embodiments, the wavy line indicates a bond to the linker (e.g., L or LL).

[0205] In certain embodiments, PA is selected from residues of the following: or a pharmaceutically acceptable salt or stereoisomer thereof. In particular embodiments, a primary or secondary amine is linked to a linker L to form a linker payload, which is linked to BA to form a conjugate. Those of skill will recognize that the above compounds can be linked to L with a bond to a primary or secondary amine group, substituting for an H.

[0206] In some embodiments, the anti-MSR1 antibodies described herein are conjugated to:

[0207] In some embodiments, the antibody-drug conjugates described herein comprise a steroid payload, wherein the steroid payload is selected from the group consisting of:

[0208] In certain embodiments, PA is: F                 , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is: f                 , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is: f                 , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0209] In certain embodiments, PA is: certain embodiments, PA is: or a pharmaceutically acceptable salt or stereoisomer thereof In certain embodiments, PA is:

[0210] In certain embodiments, PA is a liver X receptor (LXR) modulator. In certain embodiments, PA is according to Formula (B): Formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein W is -CH2-, -N(H)-, or -O-; RB1 is-H, -OH, -NH2, alkyl, or-OP(O)(OR6)2; RB2 is -H, -OH, -CH2NH2, RB3, RB4, RB5, or-O-RB5, wherein RB1 and RB2 are not simultaneously -H; RB3 is -N(R6)2; RB4 is -X-Y-Z; X is selected from the group consisting of-O- and -N(H)-; Y is selected from the group consisting of alkylene, substituted alkylene (including, without limitation, oxo substitution, i.e., =O)), heteroalkylene, and substituted heteroalkylene (including, without limitation, oxo substitution (i.e., =O)); Z is selected from the group consisting of-OH and -NH2; RB5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl includes one, two, or three heteroatoms selected from nitrogen and oxygen, and includes at least one -OH and -CH2OH substituent, or at least one primary or secondary nitrogen, for instance, O-glucose; each R6 is in each instance, -H, an amino acid residue, an / V-alkyl amino acid residue, a peptide, or alkyl; and each R7 is, independently, halo, Ci-e alkyl, Ci-e alkoxy, -ON, O-glucose, O-amino acid residue, and O-PEGb, wherein each subscript b is an integer from 0-3; wherein the group RB1, RB2 or R7 is bonded to the linker.

[0211] In particular embodiments, RB1 or RB2 is substituted with a bond to the linker (e.g., L or LL).

[0212] In certain embodiments, PA is selected from:

[0213] In particular embodiments, the wavy line in 5 indicates a bond to the linker (e.g., L or LL).

[0214] In certain embodiments, the payload of Formula (B) is selected from the group consisting of: OH or a pharmaceutically acceptable stereoisomeric form thereof.

[0215] In certain embodiments, PA is: OH or a pharmaceutically acceptable salt or stereoisomer thereof.

[0216] In certain embodiments, PA is: OH or a pharmaceutically acceptable salt or stereoisomer thereof.

[0217] In certain embodiments, PA is: OH or a pharmaceutically acceptable salt or stereoisomer thereof.

[0218] In some embodiments, the anti-MSR1 antibodies described herein are conjugated to:

[0219] In some embodiments, PA is a liver X receptor (LXR) modulator according to Formula (B-1): Formula (B-1) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein RB1 is -N(H)R8or-N(R9)2; RB2 is -N(H)R8; each R8 is, independently in each instance, hydrogen, an amino acid residue, an / V-alkyl amino acid residue, a peptide residue, a biodegradable moiety, or alkyl; R9 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and when substituted includes at least one -OH and -CH2OH, or at least one primary or secondary nitrogen; each R7 is independently halo, C1.6 alkyl, C1.6 alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEGb, wherein each subscript b is an integer from 0-3; wherein the group RB1, RB2 or R7 is bonded to the linker.

[0220] In some instances, a compound of Formula (B-1) is selected from the group consisting of: H2N P3B; or a pharmaceutically acceptable salt or solvate thereof.

[0221] LL).

[0222] In particular embodiments, RB1 or RB2 is substituted with a bond to the linker (e.g., L or In certain embodiments, PA is P4B, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is: HO^ P5B, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is: or stereoisomer thereof. In certain embodiments, PA is: or stereoisomer thereof. In certain embodiments, PA is or stereoisomer thereof. In certain embodiments, PA is P12B, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is —                P2B, or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA is or a pharmaceutically acceptable salt or stereoisomer thereof. In some of such embodiments, the carboxylic acid group of P10B is bonded to the linker through an amide linkage as shown above. In certain embodiments, PA is P11B, or a pharmaceutically acceptable salt or stereoisomer thereof. In some of such embodiments, the carboxylic acid group of P11B is bonded to the linker through an amide linkage as shown above. In certain embodiments, PA is stereoisomer thereof. For any embodiments described in this paragraph, the wavy line in indicates a bond to the linker (e.g., L or LL) as described herein.

[0223] In a group of embodiments, provided herein are compounds of Formula (III): Formula (III); or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R34is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; both Rx are hydrogen; and SP is -C(0)-Ci-Cio-alkylene-C(0)-, -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1- where X1 is attached to L' in Formula (III), -C(0)-N(H)-(Ci-Cio-alkylene)-S-where S is attached to L' in Formula (III), -C(0)-N(Ci-6alkyl)-(Ci-Cio-alkylene)-S- where S is O k / Ny attached to L in Formula (III),                where the point of attachment on the right hand side ( / .e. at N) is to L’ in Formula (III), -CH2-NH- where the N is attached to L’ in j        H Formula (III), O           where the N is attached to L'in Formula (III) and where Ar is optionally substituted arylene or optionally substituted heteroarylene, -(Ci-Cw-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III), -C(O)-(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(0)-N(R35)-Ci-Cio-alkylene-C(0)NH-X2- where X2 is attached to L' in Formula Re | 'J mm X4—d (III), or ?                           where X4 is attached to L' in Formula (III); or both Rx are fluoro; and SP is -C(O)-Ci-Ci0-alkylene-C(O)-, -C(0)-N(Ci.6alkyl)-Ci-Cio-alkylene-X1b- where X1b is attached to L in Formula (III), -C(0)-N(H)-(Ci-Cio-alkylene)-X1b- where X1b O is attached to L in Formula (III),              e where the point of attachment on the right hand side ( / .e. at N) is to L' in Formula (III), -CH2-NH- where the N is attached to L' in 5        H Formula (III), O           where the N is attached to L'in Formula (III) and where Ar is optionally substituted arylene or optionally substituted heteroarylene, -(Ci-Cw-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III), -C(O)-(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(0)-N(R35)-(Ci-Cio-alkylene)-C(0)NH-X2- where X2 is attached to L' in Formula Re (III), or ’                          where X4 is attached to L' in Formula (III); and X1 is-N(Ci.6alkyl)-; X1b is -S-, -NH-, or -N(Ci-6alkyl)-; X2is-NH-; X3 is -CH2-, X3 is -CH2-0-(Ci-Cio-alkylene)-C(0)- where the C(O) is attached to X4, or X3 is -C(O)-; X4 is -O-; R35 is H, -OH, -OCH3, or Ci.6alkyl; R50 and R50a are independently hydrogen or Ci-Ce-alkyl;Rd, Re, and Rf are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or-CH2OR9, where each R9 is independently -CH2C(O)OH or-CH2C(O)O(alkyl); and mm is 0 or 1; n is an integer selected from 1-30, inclusive; L' is a linker; and BA is a binding agent.

[0224] In some embodiments, in a compound of Formula (III), both Rx are hydrogen, and SP, BA, L', R34, and n are as described herein in some or any embodiments. In some embodiments, in a compound of Formula (III), both Rx are fluoro, and SP, BA, L', R34, and n are as described herein in some or any embodiments. In some embodiments, R34 is in the R-configuration. In some embodiments, R34is in the S-configuration. In some embodiments, R34is a mixture of the R- and S-configurations. In some embodiments, R34is a mixture of the R- and S-configurations, wherein the R:S mixture is about 1:1, about 2:1, about 3;1, about 4:1, about 5:1, about 6; 1, about 7:1, about 8:1, about 9:1, or about 10:1.

[0225] In some embodiments are compounds of Formula (III) where both Rx are hydrogen; and SP is -C(0)-Ci-Cio-alkylene-C(0)-, -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1- where X1 is attached to L' in Formula (III), -C(0)-N(H)-(Ci-Cio-alkylene)-S-where S is attached to L' in Formula (III), -C(0)-N(Ci.6alkyl)-(Ci-Cio-alkylene)-S- where S is attached to L' in Formula (III), -(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III), -C(0)-(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(O)-N(R5)-Ci-Ci0-alkylene- Re | 'J 'mm ,       ,                             H X4-X3 X) C(O)NH-X - where X2 is attached to L' in Formula (III), or ?                       where X4 is attached to L' in Formula (III); or both Rx are fluoro; and SP is -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1b- where X1b is attached to L' in Formula (III), -C(0)-N(H)-(Ci-Cio-alkylene)-X1b- where X1b is attached to L' in Formula O (III),              e where the point of attachment on the right hand side ( / .e. at N) is to L in Formula (III), -(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L'in Formula (III), -C(0)-(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (III) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, or -C(0)-N(R5)-(Ci-Cio-alkylene)-C(0)NH-X2- where X2 is attached to L' in Formula (III).

[0226] In some embodiments, a compound of Formula (I) is a compound of Formula (3000): BA-(L'-SP-D)n Formula (3000) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein D is selected from where both Rx in Formula (a) are hydrogen; R34is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; and SP is -C(O)-Ci-Ci0-alkylene-C(O)-, -C(0)-N(Ci.6alkyl)-Ci-Cio-alkylene-X1- where X1 is attached to L' in Formula (3000), -C(O)-N(H)-(Ci-Ci0-alkylene)-S- where S is attached to L' in Formula (3000), -C(0)-N(Ci.6alkyl)-(Ci-Cio-alkylene)-S- where S is attached to L' in Formula (3000), where the point of attachment on the right hand side ( / .e. at N) is to L' in Formula (3000), -CH2-NH- where j        H the N is attached to L'in Formula (3000),   0           where the N is attached to L'in Formula (3000) and where Ar is optionally substituted arylene (in some embodiments Xa ) or optionally substituted heteroarylene, -(Ci-Cio-alkylene)-NR50C(0)-(Ci-Cio-alkylene)-NR5Oa- where NR50a is attached to L' in Formula (3000), -C(O)-(Ci-Cw-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (3000) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(0)-N(R35)-Ci-Cio-alkylene-C(0)NH-X2- where X2 is attached to L' in Re | 'J mm x4-x3^o^^        , Formula (3000), or ?                       where X4 is attached to L' in Formula (3000); or where both Rx in Formula (a) are fluoro; R34is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; and SP is -C(O)-Ci-Ci0-alkylene-C(O)-, -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1b- where X1b is attached to L' in Formula (3000), -C(0)-N(H)-(Ci-Cio- alkylene)-X1b- where X1b is attached to L' in Formula (3000), point of attachment on the right hand side ( / .e. at N) is to L' in Formula (3000), -CH2-NH- , H where the N is attached to L' in Formula (3000), O           where the N is attached to L in Formula (3000) and where Ar is optionally substituted arylene (in some LX embodiments             ) or optionally substituted heteroarylene, -(Ci-Cio-alkylene)- NR50C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (3000), - C(0)-(Ci-Cio-alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L' in Formula (3000) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -0(0)-N(R35)-(Ci-Cio-alkylene)-C(0)NH-X2- where Re | 'J 'mm ,                         |-X4-X3^O^ /         , X2 is attached to L in Formula (3000), or ’                       where X4 is attached to L' in Formula (3000); and / or b) the compounds in Table A below, where the compounds in Table A are linked to BA of the Compound of Formula (III) through the hydroxy of the -C(O)CH2OH group, i.e. by -C(O)CH2-O-SP-L'-, or through the hydroxy of Mapracorat, i.e. by -O-SP-L'-; X1 is-N(Ci.6alkyl)-; X1b is -S-, -NH-, or -N(Ci-6alkyl)-; X2is-NH-; X3 is -CH2-, X3 is -CH2-0-(Ci-Cio-alkylene)-C(0)- where the C(O) is attached to X4, or X3 is -C(O)-; X4 is -O-; R35 is H, -OH, -OCH3, or Ci.6alkyl; R50 and R50a are independently hydrogen or Ci-C6-alkyl; Rd, Re, and Rf are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or-CH2OR9, where each R9 is independently -CH2C(O)OH or-CH2C(O)O(alkyl); and mm is 0 or 1; n is an integer selected from 1-30, inclusive; L' is a linker; and BA is a binding agent.

[0227] In some instances of Formula (3000), D is budesonide or any other steroid shown in Table A. In some instances of Formula (3000), D is any budesonide analog described herein. The compounds in Table A are linked to BA of the Compound of Formula (III) through the hydroxy of the -C(O)CH2OH group, i.e. by -C(O)CH2-O-SP-L'-, or through the hydroxy of Mapracorat, i.e. by -O-SP-L'-. In some instances of Formula (3000), the moiety SP-D (or H-SP-D) is refererred to herein as a “budesonide-spacer” and includes, e.g., budesonide-spacers shown in Table B, in the examples section and in Scheme 1 in FIG. 22. Table A. Trade name Structure Hydrocortisone butyrate Locoid® H < | H 1 ) | J H s H Halometasone Sicorten® / (C-48401-Ba) o p % / X ■1.....0 TV- ( T|:A-----Z ..... k A”° : / "o Betamethasone Celestone® / Rinderon® / Diprosone® (NSC-39470; Sch-4831) . s M : >— Trade name Structure Fluclorolone Acetonide Cutanit® / T opicon® (RS-2252) Q A V Q T>" < '.....X > O ■X'A.....7 'yc' Q x i Fluocinolone Acetonide Flucort® / Fluonid® / lluvien® / Retisert® / Syn alar® / Synalar-HP® / Synemol® (NSC-92339; DF-277) ...J Flunisolide (RS-3999; RS-1320) HO / O »Ov-jS<OT‘ j J H : H Cloprednol (RS-4691) HO £ ,OH s > H i > Cl Triamcinolone Aristocort® / Kenacort® „QH ... । X? x Trade name Structure Budesonide OH Flurandrenolide Co rd ran® OH .... .1, j J $ I $ F Desoximetasone Topicort® (DSXS) o. / \ / )-.....Q (\—f \.....\ 0 PH X ; f Betamethasone benzoate Uticort® (W-5975) X O f          \          /    fi       X--Q'“X / b ( \ / \ > O x ■ / b Desonide Desonate® (D-2083) HO ,.P      ( HO*. ^jS^T" Ah I V0 H 1 J Trade name Structure Meprednisone (NSC-527579; Sch-4358) HO     ..OH %— £ : H[  >— / J H j H Prednisolone Delta-Cortef® (NCS-9120) Triamcinolone Acetonide '"'H o,„ >■-. T           J. > ( Z*7..... 0    X     /   \ I              J' O ..... X / \\ / ’b Methylprednisolone Depo-Medrol; Medrol; Urbason® (NSC-19987) hok _.Uom x^r Prednisone Decortin® / Deltasone® / Lodotra® / Meticorte n® / Rayos® (NSC-10023) ^1454-? A A । Trade name Structure Dexamethasone Decadron® (FT-4145; ENV-1105; IBI-10090; ISV-305; OTO-104) HO _ ,.-, j fn f >..... J J — Hydrocortisone valerate Westcort® HO ..... . i H :    ? 0 i J A i H Mapracorat (BOL-242X; BOL-303242-X; ZK-245186; BAY-865319; BOL-303242-X) x5c ?h xx f'^k Ui f^f Benzodrocortisone H0 - ZZ X / h" / 4W 0 : H s H Table B. Budesonide-spacer (Budesonide-SP) Compound No. Structure 1a (Budesonide) z (  °   1 \ \_Ut q / I ■XT3' Cx o 1c I o X0 ° \ \ ° I ( V \ o vJ \ 1 ■Xl1 ex o Compound No. Structure 1d z —z Ay ( 0^0 i xl I I MJ o 1e o (M MmS □A?*1 T p 7% ~Z.T. / z CM T ig .. \_ / y y-v h 5= I I OJA H Aa / =° HO^o^ox J / M Z ^^0 OH 1h / k\ °v / • o °A o H / —\ W H >=\ aZ / tvD^° %  OH 1i tMynM / 0 HO''        / QH OH 1j i^H H / -\ h°T0T^0 °h ho"M"oh OH 1k -x,°4tTv MMq=o / X,OJzOx A —<H *x= / h2n        p            VOH OH Compound No. Structure 11 H           \ __ o-~YyX X=\ AA \ !     Ao n ° I A C- I * 9 OH o-p=o / -- / OH h2n 1m <A'H / —\ I / 7\   / =\ H°77vV7\= / ° + Ox °      OH Na ' ’O \\ Na+ O 100 H H A —. o4a / \ \_ / ( AX f >=\ ° iAV7\- / ° HO^XX * ° OH 101a F H H H / —\ Y ^^^O  *0H 1           O 101b F H H H / —\ 1 N O    * —v HN'^ / Y ^^O OH 1           O 101c \ 0 101d o XX i rX1 / ° i U X—' / Ac* / ° o Av Y° \ / —'    o /     >o / —z -Z.—' I Compound No. Structure 102c —\   0,.___vH / —i ' \ I XX H V-. oTZ h XX \ / / XX ° H 1° OH 0 102d ' ( 1 XX H H X- / V J / v- / / \==z° 1   1^° OH HS—NY° O 102e F --\  °'' rA -H / —A ' ( 1 XX F \=x oxx h x / v h 1   0 OH HS—V 0 102f F —\   0 / ,.H .—£ ' X X / 7\ F h x~y \ 1     1    ° OH HS—NY° O 103a o fj Jyy '7^ O X z CN I 103b ” o°KXb=° H2N / Y       ° OH 0 104a A ° r / , hXX°YiXy'f hX<S x"x> or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some instances, the in each of the above structures is in the R-configuration, i.e. at the carbon indicated by the asterisk. In some instances, the n-propyl of in each of the above structures is in the S-configuration, i.e. at the carbon indicated by the asterisk. In some -A P- / instances, the n-propyl of               in each of the above structures is a mixture of the R and S-configurations, i.e. at the carbon indicated by the asterisk. In some instances, the n- propyl of               in each of the above structures is a mixture of the R- and S configurations, i.e. at the carbon indicated by the asterisk, wherein the R:S mixture is about 1:1, about 2:1, about 3;1, about 4:1, about 5:1, about 6; 1, about 7:1, about 8:1, about 9:1, or about 10:1.

[0228] In various embodiments, -SP-D of Ab-L'-SP-D or

[0229] In some instances, the n-propyl of         oA jn each of the above structures is in the R-configuration, i.e. at the carbon indicated by the asterisk. In some instances, the n-propyl of         oA in each of the above structures is in the S-configuration, i.e. at the carbon indicated by the asterisk. In some instances, the n-propyl of         oA jn each of the above structures is a mixture of the R- and S-configurations, i.e. at the carbon indicated by the asterisk. In some instances, the n-propyl of         oA jn each of the above structures is a mixture of the R- and S-configurations, i.e. at the carbon indicated by the asterisk, wherein the R:S mixture is about 1:1, about 2:1, about 3; 1, about 4:1, about 5:1, about 6; 1, about 7:1, about 8:1, about 9:1, or about 10:1.

[0230] B, or is selected from

[0231] In some embodiments, the payload is a rifamycin analog having the structure of Formula (C): or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein: X1c is selected from -O-, -S—, and -NR5c; R1c is hydrogen; amino-Ci-ealkyl; Ci-ealkylaminoCi-ealkyl; di-Ci-ealkylaminoCi-ealkyl; hydroxy-Ci.6alkyl; HS-Ci.6alkyl; (R5c)2N-Ci.6alkylene-N(R5c)-Ci.6alkyl; (R5c)2N-Ci. 6alkylene-O-Ci-6alkyl; (R5c)2N-Ci-6alkylene-S-Ci-6alkyl; heterocycloalkyl or heterocycloalkyl-Ci-ealkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci-ealkyl, -OH, =O, or-N(R5c)2; R2c, R3c, and R4c are independently selected from hydrogen, Ci-ealkyl, and -(C=O)-R5c; Rac is selected from -F; -Cl; -Br; -I; -OH; -NH2; and Ci-ealkoxy; Rbc is hydrogen at each occurrence; and R5c is independently, at each occurrence, selected from hydrogen; and Ci-ealkyl; with a proviso that R1c is not an n-butyl group; and a further proviso that when X1c is -O-, R1c is not hydrogen; wherein the group R1c is bonded to the linker.

[0232] In some embodiments, the payload is a rifamycin analog having the structure of Formula (C-1): or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein: X1c is selected from -S-; -O- and -NR5c; R1c is amino-Ci.6alkyl; Ci.6alkylaminoCi.6alkyl; di-Ci.6alkylaminoCi.6alkyl; hydroxy-Ci.6alkyl; HS-Ci.6alkyl; (R5c)2N-Ci.6alkylene-N(R5c)-Ci.6alkyl; (R5c)2N-Ci.6alkylene-O-Ci.6alkyl; (R5c)2N-Ci.6alkylene-S-Ci-6alkyl; heterocycloalkyl or heterocycloalkyl-Ci.6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci-ealkyl, -OH, =0, or-N(R5c)2; R2c, R3c, and R4c are independently selected from hydrogen, Ci-ealkyl, and -(C=O)-R5c; each Rac, when present, is independently selected from -F; -Cl; -Br; -I; -OH; -NH2; and Ci-ealkoxy; and R5c is independently, at each occurrence, selected from hydrogen; and Ci-ealkyl; wherein the group R1c is bonded to the linker.

[0233] In some embodiments, the payload is a rifamycin analog having the structure of Formula (C-2): ,ch3 h3c? ,or3c Formula (C-2) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein: X1c is selected from -S-; -O- and -NR5c; R1c is amino-Ci-ealkyl; Ci-ealkylaminoCi-ealkyl; di-Ci-ealkylaminoCi-ealkyl; hydroxy-Ci-ealkyl; HS-Ci.6alkyl; (R5c)2N-Ci.6alkylene-N(R5c)-Ci.6alkyl; (R5c)2N-Ci.6alkylene-O-Ci.6alkyl; (R5c)2N-Ci-6alkylene-S-Ci-6alkyl; heterocycloalkyl or heterocycloalkyl-Ci-ealkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci-ealkyl, -OH, =O, or-N(R5c)2; R2c, R3c, and R4c are independently selected from hydrogen, Ci-ealkyl, and -(C=O)-R5c; Racand Rbc are independently selected from -F; -Cl; -Br; -I; -OH; -NH2; and Ci.6alkoxy; and R5c is independently, at each occurrence, selected from hydrogen; and Ci-ealkyl; wherein the group R1c is bonded to the linker.

[0234] In some embodiments, the payload is a rifamycin analog having the structure of Formula (C-3): Formula (C-3) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein: R1c is di-Ci.6alkylaminoCi.6alkyl; (R5c)2N-Ci.6alkylene-N(R5c)-Ci-6alkyl; heterocycloalkyl or heterocycloalkyl-Ci.6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci.6alkyl, -OH, =O, or-N(R5c)2; and R2c, R3c, and R4c are independently selected from hydrogen, Ci.6alkyl, and -(C=O)-R5c; and R5c is selected from hydrogen and Ci-ealkyl; wherein the group R1c is bonded to the linker.

[0235] In some embodiments, the payload is a rifamycin analog having the structure of Formula (C-4): or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein: wherein Y is C or N; R2c, R3c, and R4c are independently selected from hydrogen, Ci-ealkyl, and -(C=O)-R5c; and R5c is selected from hydrogen and Ci-ealkyl; wherein the group R1c is bonded to the linker via the nitrogen atom as indicated by the wavy line

[0236] In some or any embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), Rbc is hydrogen and / or Rac is hydrogen. In some or any embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), R2c is methyl, ethyl, propyl or isopropyl, preferably methyl. In some or any embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), R3c is CH3-(C=O)- (acetyl) group, CH3CH2-(C=O)-. CH3CH2CH2-(C=O)-, or (CH3)2CH-(C=O)-; preferably acetyl. In some or any embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), R4c is hydrogen.

[0237] In some embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), -OR1c is one or more of In some embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), -OR1cis

[0238] In some or any embodiments of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4), X1c is O, and -OR1c comprises a tertiary amine, said tertiary amine, after bonding to a linker, changes to a quarternary amine. In some of such embodiments, -OR1c is or In such embodiments, where a quarternary amine is formed, a suitable counter ion is present, i.e., the rifamycin analog is present as a pharmaceutically acceptable salt comprising a quarternary amine bearing a positive charge, and, as a salt, for instance, a chargebalancing negatively charged counter ion (e.g., I", Br , Cl" or any other suitable counter ion).

[0239] In some embodiments, a compound of Formula (C-1) and / or (C-2) an / or (C-3) and / or (C-4) is selected from the group consisting of: >_____ wherein the * is the bond to the linker. Linkers

[0240] In some embodiments of Formula (I), (III), or (3000), L comprises -L1-L2-(L3)0-i- and L2 comprises -OCH2C(O)-, or cyclodextrin residue (CD); or combinations thereof. In some embodiments, L comprises -L1-L2-(L3)o-i- and L2 comprises thereof. In some embodiments, L comprises -L1-L2-(L3)o-i- and L2 comprises CD. In some embodiments, where L and / or L2 comprises CD, CD is selected from the group consisting of HO          P HO / / 0H          HO\ r-OH \\ UZ°H            Vo PZ             OH / HO—AA            niP \OH           Py ? OH    H0 OH / / oH oAtoh ho \ \T u A-—o \ / vo /    oA HO           / HO and d N--7 HO 0^ _-S^Ov OH £ /          OI1 I 0 / HO            Q / / oh       H0Jr0H A^-oh          \\ °~7\oh                  / \P 0 /                 OH / H0 \°H d   HOHoOHe H svotedVo HO       O / / HO               . stereoisomers thereof, where S refers to the S atom on a cysteine residue through which the O reactive group residue is attached to BA; and ’ r where N refers to the N atom on a lysine residue through which the reactive group residue is attached to BA.

[0243] In some embodiments, L comprises -L1-L2-(L3)o-i- and -L2-(L3)o-i- as described herein. In some embodiments, L is L'-SP as described herein for Formula (III) and Formula (3000). In some embodiments L comprises:

[0244] In some instances, a compound of Formula (I) or (III) or (3000), is selected from or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein each Ab is an anti-MSR1 antibody, or an antigen binding fragment thereof; and each n is an integer from 1 to 4.

[0245] In some instances, a compound of Formula (I) or (III) or (3000), is selected from or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein each Ab is an anti-MSR1 antibody, or an antigen binding fragment thereof; where Ab1 is an anti-MSR1 antibody, or an antigen binding fragnment thereof; R is C2-4-alkylene; and nn is an integer selected from 2 to 4, inclusive. and each n is an integer from 1 to 4.

[0246] In some additional embodiments, the ADCs described herein may comprise linkers described in US 9,951,141 B2, filed November 29, 2016, and issued on April 24. 2018, which linkers are incorporated herein by reference. In some instances, the linker comprises: bond to the binding agent. In some embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen O^NH2 NH Br—\ 9 u O □ O \ ^^N-(CH2)b^-N N H C^CHH ° binding fragment thereof:                          3        3             ; wherein b is an integer from 2 to 8. In further embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen binding 2 to 8. In some other embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen binding 2 to 8, RN is a hydrogen atom or alkyl, and RM is alkyl. In additional embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen binding fragment thereof: O^NH2 NH Br—\             0 u 0 f" B^N_(CH2)biN^ x o H3C CH3             . wherejn b is an integer form 2 to 8. In certain embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen binding fragment thereof: O^NH2 NH Br—\ Q      0.,0  \ 0 H C CH 3 on3            . herein b is an integer from 2 to 8. In some embodiments, the linker comprises two reactive groups and can form bonds with, for example, thiols on two different chains of an antibody, or antigen binding fragment thereof: 0<yNH2 NH R\ rm Br^ Oy O u O f B^0X(CH2)b^N^ X 0 H3C CH3             . wherein b is an integer from 2 to 8; RN is a hydrogen atom or alkyl; and RM is alkyl.

[0247] In the Formulae (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7003), (7004), and / or (7005) described herein, and / or in BA - [(L)o-i - PA]n, PA can be linked to BA with any linker L deemed suitable. Linkers are any group or moiety that links, connects, or bonds the antibody or antigen-binding proteins described herein with a therapeutic moiety, e.g. a steroid or an LXR modulator. Suitable linkers may be found, for example, in Antibody-Drug Conjugates and Immunotoxins-, Phillips, G. L., Ed.; Springer Verlag: New York, 2013; Antibody-Drug Conjugates’, Ducry, L., Ed.; Humana Press, 2013; Antibody-Drug Conjugates’, Wang, J., Shen, W.-C., and Zaro, J. L., Eds.; Springer International Publishing, 2015, the contents of each incorporated herein in their entirety by reference. Generally, suitable binding agent linkers for the antibody conjugates described herein are those that are sufficiently stable to exploit the circulating halflife of the antibody and, at the same time, capable of releasing its payload after antigen- mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable. Cleavable linkers include linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction. Non-cleavable linkers include linkers that release an attached payload via lysosomal degradation of the antibody following internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction labile linkers, self-immolative linkers / groups, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citruline units, and para-aminobenzyl (PAB) units.

[0248] Any linker molecule or linker technology known in the art can be used to create or construct an ADC of the present disclosure. In certain embodiments, the linker is a cleavable linker. According to other embodiments, the linker is a non-cleavable linker. Exemplary linkers that can be used in the context of the present disclosure include, linkers that comprise or consist of e.g., MC (6-maleimidocaproyl), MP (maleimidopropanoyl), val-cit (valine-citrulline), val-ala (valine-alanine), dipeptide site in protease-cleavable linker, ala-phe (alanine-phenylalanine), dipeptide site in protease-cleavable linker, PAB (p-aminobenzyloxycarbonyl), SPP (N-Succinimidyl 4-(2-pyridylthio) pentanoate), SMCC (N-Succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate), SIAB (N-Succinimidyl (4-iodo-acetyl)aminobenzoate), and variants and combinations thereof. Additional examples of linkers that can be used in the context of the present disclosure are provided, e.g., in US 7,754,681 and in Ducry, Bioconjugate Chern., 2010, 27:5-13, and the references cited therein, the contents of which are incorporated by reference herein in their entireties.

[0249] In certain embodiments, the linkers are stable in physiological conditions. In certain embodiments, the linkers are cleavable, for instance, able to release at least the payload portion in the presence of an enzyme or at a particular pH range or value. In some embodiments, a linker comprises an enzyme-cleavable moiety. Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages. In some embodiments, the linker comprises a cathepsin-cleavable linker.

[0250] In some embodiments, the linker comprises a non-cleavable moiety.

[0251] Suitable linkers also include, but are not limited to, those that are chemically bonded to two cysteine residues of a single binding agent, e.g., antibody. Such linkers can serve to mimic the antibody’s disulfide bonds that are disrupted as a result of the conjugation process.

[0252] In some embodiments, the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D- a-amino acids. In some embodiments, the linker comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or combination thereof. In certain embodiments, one or more side chains of the amino acids is linked to a side chain group, described below. In some embodiments, the linker comprises valine and citrulline. In some embodiments, the linker comprises lysine, valine, and citrulline. In some embodiments, the linker comprises lysine, valine, and alanine. In some embodiments, the linker comprises valine and alanine.

[0253] In some embodiments, the linker comprises a self-immolative group. The self-immolative group can be any such group known to those of skill. In particular embodiments, the self-immolative group is p-aminobenzyl (PAB), or a derivative thereof. In some embodiments, the self-immolative group is p-aminobenzyloxy. In some embodiments the self-immolative group comprises a cleavable di-sulfide group. Useful derivatives include p-aminobenzyloxycarbonyl (PABC). Those of skill will recognize that a self-immolative group is capable of carrying out a chemical reaction which releases the remaining atoms of a linker from a payload.

[0254] In some embodiments, the linker is: wherein is a bond to the antibody or antigen-binding protein (e.g., via lysine residue) and * is a bond to the payload. In some embodiments, the linker is: »A wherein * is a bond to the antibody or antigen-binding protein (e.g., via lysine residue) and * is a bond to the payload. In certain embodiments, the linker is:

[0255] In certain embodiments, the linker is: a O

[0256] In some embodiments, the linker is derived from maleimidylmethyl-4-trans-cyclohexanecarboxysuccinate:

[0257] In some embodiments, the linker is: »A wherein * is a bond to the antibody or antigen-binding protein (e.g., via lysine residue) and * is a bond to the payload.

[0258] In some embodiments, L is a cleavable linker. In some embodiments, L is a non-cleavable linker. In some embodiments, L comprises a dipeptide. In some embodiments, L comprises a PAB moiety. In some embodiments, L comprises a disulfide moiety.

[0259] In some embodiments, L comprises a moiety having the following structure: o

[0260] In some embodiments, L comprises a moiety having the following structure:

[0261] In some embodiments, L comprises a moiety having the following structure:

[0262] In some embodiments, L comprises a moiety having the following structure:

[0263] In certain embodiments, the linker comprises a cyclodextrin group. In certain embodiments, the linker provides an ADC according to Formula (la): (la)

[0264] In Formula (la), BA is an anti-MSR1 antibody, or an antigen-binding fragment thereof, LL is a trivalent linker, RG is a reactive linker residue, SP is, independently in each instance, absent or a spacer group, subscript n is an integer from 1 to 30; and PA is a payload. In certain embodiments, n is from 1 to 4. In certain embodiments, n is 4. In certain embodiments, n is 2. In certain embodiments, n is 1. In certain embodiments, n is 3.

[0265] In certain embodiments, the linker comprises a cyclodextrin group. In certain embodiments, the linker provides an ADC according to Formula (Id): BA-RG—SP14PEG)^j-SP2—AA1-AA2-(PAB)-PA CD            CD        P L                                            Jn (Id)

[0266] In Formula (Id), BA is an anti-MSR1 antibody, or an antigen-binding fragment thereof; RG is a reactive group residue; SP1 and SP2 are each, independently in each instance, absent or a spacer group residue, and wherein SP1 comprises a trivalent linker; AA1 is a trivalent linker comprising an amino acid residue; AA2 is a di-peptide residue; PEG is a polyethylene glycol o residue; PAB is h            , wherein the x indicates the atom through which the PAB is bonded to the adjacent groups in the formula, CD is, independently in each instance, absent or a cyclodextrin residue, wherein at least one CD is present, subscript n is an integer from 1 to 30; subscript m is an integer from 0 to 5; subscript p is 0 or 1; and PA is a payload moiety. In these examples, subscript m is 0, 1,2, 3, 4, or 5. In some examples, subscript m is 0. In some examples, subscript m is 1. In some examples, subscript m is 2. In some examples, subscript m is 3. In some examples, subscript m is 4. In some examples, subscript m is 5. In some examples, subscript p is 0. In some examples, subscript p is 1. In some examples, any one of AA1 or AA2 comprises, independently in each instance, an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or a combination thereof. In certain embodiments, AA1 is an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or a combination thereof. In certain embodiments, AA1 is lysine. In certain embodiments, AA1 is lysine or a derivative of lysine. In certain embodiments, the AA2 is valine-citrulline. In some embodiments, the AA2 is citrulline-valine. In some embodiments, the AA2 is valine-alanine. In some embodiments, the AA2 is alanine-valine. In some embodiments, the AA2 is valine-glycine. In some embodiments, the AA2 is glycine-valine. In some embodiments, the AA1-AA2 glutamine-valine-citrulline. In some embodiments, the AA1-AA2is glutamine-valine-citrulline. In some embodiments, the AA1-AA2is lysine-valine-alanine. In some embodiments, the AA1-AA2 is lysine-valine-citrulline. In some embodiments, the AA1-AA2is glutamine-valine-citrulline. In certain embodiments, the lysine is L-lysine. In certain embodiments, the lysine is D-lysine. In some examples, SP1 is independently in each instance, selected from the group consisting of Ci.6 alkylene, -NH-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)u-C(O)-, -C(O)-NH-(CH2)v-, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some examples, SP2 is independently in each instance, selected from the group consisting of Ci.6 alkylene, -NH-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)U-C(O)-, -C(O)-NH-(CH2)v-, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

[0267] In certain embodiments, for Formulas (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7003), (7004), and / or (7005), the linker is selected from: OH O OH O OH OH OH o OH OH OH OH OH OH OH OH OH Also included in these examples, is a pharmaceutically acceptable salt, solvate, stereoisomeric Y-form thereof, a regioisomer thereof, or mixture of regioisomers thereof, wherein each * is a P bond to the binding agent; and each ' is a bond to the payload.

[0268] In certain embodiments, the linker comprises a terminal hydrophilic group (HG). In certain embodiments, the linker comprises a taurine group. In certain embodiments, the linker comprises a terminal sulfonic acid group. In certain embodiments, the linker provides an ADC according to Formula (II): BA RG1—SP1 LL----PA (RG2)q SP2 I HG (II) wherein, in Formula (II), BA is a binding agent; LL is a trivalent linker; RG1 and RG2 are reactive group residues; SP1 and SP2 are independently, in each instance, absent, or a spacer group residue; HG is a hydrophilic residue; PA is a payload residue; subscript n is an integer from 1 to 30; and subscript q is 0 or 1. In some instances more than one trivalent linker LL may be present. In some instances, n is an integer from 1 to 4. In some instances n is 1. In some instances n is 2. In some instances n is 3. In some instances n is 4. In some instances, HG is a terminal hydrophilic group. In some instances, HG comprises one terminal sulfonic acid group or a salt thereof. In other instances, HG comprises more than one terminal sulfonic acid groups or salts thereof. In some instances, HG comprises one terminal phosphonic acid group or a salt thereof. In other instances, HG comprises more than one terminal phosphonic acid groups or salts thereof. In some instances, HG comprises one terminal tertiary amine group or a salt thereof. In other instances, HG comprises more than one terminal tertiary amine groups or salts thereof. In some instances, HG comprises one terminal polyol (e.g., glucose, maltose) or a derivative thereof. In other instances, HG comprises more than one terminal polyol (e.g., glucose, maltose) or derivatives thereof.

[0269] In another example, the compound of Formula (II) is according to Formula (IV): BA RG1—SP1--AA1---AA2---(PAB)p---PA (RG2)q SP2 I HG (IV).

[0270] In Formula (IV), BA, RG1, SP1, RG2, SP2 and HG are as defined above, AA1 is a trivalent linker comprising an amino acid residue; AA2 is a dipeptide residue; and PAB is o a             X h             , wherein the x indicates the atom through which the PAB is bonded to the adjacent groups in the formula; subscript p is 0 or 1; and subscript q is 0 or 1. In some instanes, subscript p is 0 and subscript q is 0. In some instances, subscript p is 1; and subscript q is 0. In some instances, subscript p is 0; and subscript q is 1. In some instances, subscript p is 1; and subscript q is 1. In some instances SP1 comprises from 0-5 polyethylene glycol (PEG) residues. In some instances SP2 comprises from 0-5 PEG residues. In some examples, SP1 is independently in each instance, selected from the group consisting of Ci-6 alkylene, -NH-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)U-C(O)-, -C(O)-NH-(CH2)v-, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some examples, SP2 is independently in each instance, selected from the group consisting of Ci.6 alkylene, -NH-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)U-C(O)-, -C(O)-NH-(CH2)v-, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some examples, any one of AA1 or AA2 comprises, independently in each instance, an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, ora combination thereof. In certain embodiments, AA1 is an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, ora combination thereof. In certain embodiments, AA1 is lysine. In certain embodiments, AA1 is lysine or a derivative of lysine. In certain embodiments, AA1 is glutamic acid. In certain embodiments, the AA2is valine-citrulline. In some embodiments, the AA2is citrulline-valine. In some embodiments, the AA2 is valine-alanine. In some embodiments, the AA2 is alanine-valine. In some embodiments, the AA2 is valine-glycine. In some embodiments, the AA2 is glycine-valine. In some embodiments, the AA1-AA2isglutamine-valine-citrulline. In some embodiments, the AA1-AA2is lysine-valine-citrulline. In some embodiments, the AA1-AA2 is lysine-valine-alanine. In some embodiments, the AA1-AA2is glutamine-valine-alanine. In certain embodiments, the lysine is L-lysine. In certain embodiments, the lysine is D-lysine.

[0271] In certain embodiments, for Formulas (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7003), (7004), and / or (7005), the linker is selected from: or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, wherein Al— each * is a bond to the binding agent; and P each * is a bond to the payload residue.

[0272] In some instances, the moiety L-PA is attached to a reactive group (RG) to form RG-L-PA (e.g., linker payloads shown in Table 3). In some instances, BA (or a modified from of BA, e.g., PEG-modified Ab, as shown in Table 2, or Ab1) reacts with linker payloads to form the ADCs described in Table 1 and Table 2. Also contemplated within the scope of embodiments presented herein are ADCs prepared from any linker payloads described in Table 5A and Table 5B. Linker payloads

[0273] Provided herein are linker-steroids according to Formula (2000), RG-L2-(L3)0-i-SP-D or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; which are useful in the preparation of antibody-drug conjugates, wherein D is selected from where both Rx in formula (a) are hydrogen; R34is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; and SP is -C(O)-Ci-Ci0-alkylene-C(O)-, -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1- where X1 is attached to (L3)o-i in Formula (2000), -C(0)-N(H)-(Ci-Cio-alkylene)-S- where S is attached to (L3)o-i in Formula (2000), -C(0)-N(Ci-6alkyl)-(Ci-Cio- O alkylene)-S- where S is attached to (L3)o-i in Formula (2000),                where the point of attachment on the right hand side ( / .e. at N) is to (L3)o-i in Formula (2000), -CH2- 5        H NH-where N is attached to (L3)o-i in Formula (2000),   0           where the N is attached to (L3)o-i in Formula (2000) and where Ar is optionally substituted arylene (in UL some embodiments,            ) or optionally substituted heteroarylene, -(C1-C10- alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to (L3)o-i in Formula (2000), -C(O)-(Ci-Ci0-alkylene)-NR50C(O)-(Ci-Ci0-alkylene)-NR50a- where NR50a is attached to (L3)o-i in Formula (2000) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(O)-N(R5)-Ci-Ci0-alkylene-C(O)NH- Re R^Jj.Rf) ] 'J 'mm |—x4—x3S) X2- where X2 is attached to (L3)o-i in Formula (2000), or ’                         where X4 is attached to (L3)o-i in Formula (2000); or where both Rx in formula (a) are fluoro; R34is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; and SP is -C(O)-Ci-Ci0-alkylene-C(O)-, -C(0)-N(Ci-6alkyl)-Ci-Cio-alkylene-X1b- where X1b is attached to (L3)o-i in Formula (2000), -C(0)-N(H)-(Ci-Cio- O alkylene)-X1b-where X1b is attached to (L3)o-i in Formula (2000),                where the point of attachment on the right hand side ( / .e. at N) is to (L3)0-i in Formula (2000), - j        H CH2-NH-where N is attached to (L3)o-i in Formula (2000),   0           where the N is attached to (L3)0-i in Formula (2000) and where Ar is optionally substituted arylene (in Y1 some embodiments,          e ) or optionally substituted heteroarylene, -(C1-C10- alkylene)-NR5°C(0)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to (L3)o-i in Formula (2000), -C(O)-(Ci-Ci0-alkylene)-NR50C(O)-(Ci-Ci0-alkylene)-NR50a- where NR50a is attached to (L3)o-i in Formula (2000) and where each Ci-Cw-alkylene is independently optionally substituted with one or more hydroxy, -C(0)-N(R5)-(Ci-Cio-alkylene)-C(0)NH- X2- where X2 is attached to (L3)o-i in Formula (2000), or X4 is attached to (L3)o-i in Formula (2000); and / or Re mm where b) the compounds in Table A above, where the compounds in Table A are linked to RG of the Compound of Formula (2000) through the hydroxy of the -C(O)CH2OH group, i.e. by -C(0)CH2-0-SP-(L3)o-i -, or through the hydroxy of Mapracorat, i.e. by -0-SP-(L3)o-i -: X1 is-N(Ci.6alkyl)-; X1b is -S-, -NH-, or -N(Ci-6alkyl)-; X2is-NH-; X3 is -CH2-, X3 is -CH2-0-(Ci-Cio-alkylene)-C(0)- where the C(O) is attached to X4, or X3 is -C(O)-; X34 is -O-; R35 is H, -OH, -OCH3, or Ci.6alkyl; R50 and R50a are independently hydrogen or Ci-Ce-alkyl; Rd, Re, and Rf are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or-CH2OR9, where each R9 is independently -CH2C(O)OH or-CH2C(O)O(alkyl); and mm is 0 or 1; RG is a reactive group residue; L2 is a connecting linker; and L3, when present, is a self-immolative group.

[0274] Provided herein are linker-LXR-modulators according to Formula (4000), RG-L-E Formula (4000) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; which are useful in the preparation of antibody-drug conjugates, wherein E is selected from a) compounds of Formula (B) described above and herein; and / or b) compounds of Formula (B-1) described above and herein; and / or c) payloads described in Table C herein; L is a linker described herein; and RG is any reactive group residue described herein.

[0275] In some embodiments, the LXR payload is

[0276] In some embodiments, linker-payloads of Formula (4000) have the structures of Formula (4001), (4002), (4003), or (4004): Formula (4001) Formula (4002) SP2—(AA)„—SP1---RG c . ,AnnA. ' 'p              Formula (4004) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein SP1 and SP2, when present, are spacer groups as defined herein in some and any embodiments; each AA is an amino acid residue; p is an integer from 1 to 10; RG is a reactive group residue; and RB1, RB2, R7 and b are as defined herein in some or any embodiments.

[0277] In some embodiments, linker-payloads of Formula (4000), (4001), (4002), (4003), or (4004) are selected from linker-payloads in Table 3.

[0278] Provided herein are linker-rifamycin analogs according to Formula (7000), RG-L-F Formula (7000) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein F is a rifamycin analog; L is a linker described herein; and RG is any reactive group residue described herein.

[0279] In some embodiments, F is a rifamycin analog described herein. In some

[0280] Also provided herein is a linker payload according to Formula (D):

[0281] Provided herein are linker-steroids wherein the steroid conjugated to the antibody, or antigen-binding fragment thereof, through a linker or a linker-spacer is a compound of Formula (A-1) Formula (A-1) or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein R1 and R2 are, independently, -H, alkyl, alkyl-C(O)-O-, -OH, or halo; or R1 and R2 together form , wherein R4is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl, wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are, independently in each instance, optionally substituted with -NRAaRAb; R3 is -O, RZ-C(O)-X-, -heteroalkyl, -piperidinyl, -NRAaRAb, -oxyaryl-NRAaRAb or -Z-A’(Rp)t; Rz is alkyl; X is O or NRAa; Z is S, S(O), S(O)2, SO2NRAa, O, C(O)NRAa, C(O), or NRAa; A' is aryl, arylalkyl, or heteroaryl; Rp is, independently in each instance, halo, optionally substituted alkyl, -OH, or -NRAaRAb; RAa and RAb are, independently in each instance, -H, optionally substituted alkyl, or optionally subtitued aryl; subscript a is an integer from 0-19; and t is an integer from 1-3; and R5A and R5B are each, independently, halo or a hydrogen atom; wherein the group R3 or R4 is bonded to the linker.

[0282] Provided herein are antibody-drug conjugates of formula Ab-L'-SP-D or BA-L'-SP-D, where D is a budesonide prodrug or a prodrug of a budesonide analog or derivative (including fluorinated analogs and derivatives), and where Ab, BA, L', and SP are as defined in any embodiment described herein. In some embodiments, SP is a moiety capable of releasing D or In some embodiments, under physiological conditions the bond between L and SP is cleaved to release a steroid prodrug, i.e. H-SP-D or and the bond between SP and D, or between SP and steroid. is subsequently cleaved to release a biologically active

[0283] In some instances, ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), or (3000), are ADCs described in Table 1 and / or Table 2 and the Examples section. In some embodiments, the steroid payload in any antibody drug conjugate described herein is solvate, or stereoisomer thereof.

[0284] Provided herein are antibody-drug conjugates of any LXR-modulator compounds described herein of Formula (5001), (5002), (5003), or (5004): n Formula (5002) or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein L is any linker described herein in some or any embodiments; n is an integer from 1 to 30; BA is a binding agent or a PEG-modified binding agent; and RB1, RB2, R7 and b are as defined herein in some or any embodiments.

[0285] Provided herein are antibody-drug conjugates of any LXR-modulator compounds described herein of Formula (6001), (6002), (6003), or (6004): Formula (6001) n Formula (6002) Formula (6003) or n Formula (6004) or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein SP1 and SP, when present, are spacer groups as defined herein in some and any embodiments; each AA is an amino acid residue; p is an integer from 1 to 10; n is an integer from 1 to 30; BA is a binding agent or a PEG-modified binding agent; and RB1, RB2, R7 and b are as defined herein in some or any embodiments.

[0286] Provided herein are antibody-drug conjugates of any LXR-modulator compounds described herein of Formula (6005): n Formula (6005) or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein RB1, RB2, R7, b, BA, RG1, SP1, AA1 and AA2 are as defined herein in some or any embodiments.

[0287] In some instances, ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), or (6005), are ADCs described in Table 1 and / or Table 2 and the Examples section. In some embodiments, the LXR modulator payload in any antibody drug conjugate described herein is or a pharmaceutically acceptable salt or solvate thereof.

[0288] Provided herein are antibody-drug conjugates of any rifamycin analogs described herein and having the structure of Formula (7001) n Formula (7001) or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein: X1c is selected from -S-; -O- and -NR5c; R1c is amino-Ci-ealkyl; Ci-ealkylaminoCi-ealkyl; di-Ci-ealkylaminoCi-ealkyl; hydroxy-Ci-ealkyl; HS-Ci.6alkyl; (R5c)2N-Ci.6alkylene-N(R5c)-Ci.6alkyl; (R5c)2N-Ci.6alkylene-O-Ci.6alkyl; (R5c)2N-Ci.6alkylene-S-Ci-6alkyl; heterocycloalkyl or heterocycloalkyl-Ci.6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci-ealkyl, -OH, or=O; R2c, R3c, and R4c are independently selected from hydrogen, Ci.6alkyl, and -(C=O)-R5c; each Rac, when present, is independently selected from -F; -Cl; -Br; -I; -OH; -NH2; and Ci-ealkoxy; and R5c is independently, at each occurrence, selected from hydrogen; and Ci-ealkyl; L is a linker; BA is a binding agent; and subscript n is an integer from 1 to 30.

[0289] Provided herein are antibody-drug conjugates of any rifamycin analogs described herein and having the structure of Formula (7002): Formula (7002); or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein BA, RG1, SP1, AA1, AA2, R1c, Rbc, Rac, X1c, R2c, R3c, R4c and n are as defined herein in some or any embodiments.

[0290] Provided herein are antibody-rifamycin analog conjugates having the structure of Formula (7003): —                                                                Formula (7003) or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or regioisomer thereof, or mixtures thereof; wherein: X1c is selected from -S-; -O- and c; R2c, R3c, and R4c are independently selected from hydrogen, Ci-ealkyl, and -(C=O)-R5c; 2019265703  06 Apr 2023 R5c is independently, at each occurrence, absent, or selected from hydrogen; and C1-6alkyl; each AA is an independently selected amino acid; SP1 is absent, or a spacer; RG1 is a reactive group residue; BA is an anti-MSR1 antibody or antigen binding fragment thereof; subscript n is an integer from 1 to 30; subscript w is 2, 3, or 4; wherein R1c is bonded to the linker via a nitrogen atom as indicated by the wavy line

[0291] In various embodiments of Formula (7003), SP1, RG1 and AA are as defined herein in some and / or any particular embodiments.

[0292] In some embodiments of Formula (7003), X1c is O. In some embodiments of Formula (7003), X1c is S. In some embodiments of Formula (7003), X1c is C. In some embodiments of Formula (7003), X1c is NR5c.

[0293] In some embodiments of Formula (7003), BA is an anti-MSR1 antibody or antigen binding fragment thereof; comprising an N297Q mutation.

[0294] In some embodiments of Formula (7003), subscript w is 2.

[0295] In some embodiments of Formula (7003), (AA)2 is valine-citrulline.

[0296] In some embodiments of Formula (7003), SP1 comprises             4-10 . In some embodiments of Formula (7003), SP1 comprises

[0297] In some embodiments of Formula (7003), RG1 comprises

[0298] In some embodiments of Formula (7003), X1c is O; wherein R1c is bonded to the linker via the quarternary nitrogen atom of R1c; R5c is Ci.6alkyl; and R6c is a counter ion.

[0299] In some of such embodiments, R1c is In some of such embodiments, R1c is is I". In some of such embodiments, R6c is I", Cl" or Br, and in some instances, R6c

[0300] In some embodiments of Formula (7003), the rifamycin analog is: In some embodiments of Formula (7003), the rifamycin analog is: (7003), the rifamycin analog is:

[0302] Further provided herein is an antibody-drug conjugate comprising a rifamycin compound (e.g., rifampicin), according to Formula (7004): Formula (7004).

[0303] Further provided herein is an antibody-drug conjugate comprising a rifamycin compound (e.g., rifampicin), according to Formula (7005): wherein L and BA are as defined herein in some or any embodiments.

[0304] In some instances, ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (7001) (7002), (7003), (7004), and / or (7005) are ADCs described in Table 2 and / or the Examples section.

[0305] Also included in these examples of ADCs, is a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, a regioisomer thereof, or mixture of regioisomers thereof, wherein each I— * is a bond to the binding agent; and each P is a bond to the payload.

[0306] In certain embodiments, provided herein is an ADC comprising an anti-MSR1 antibody or an antigen binding fragment thereof, or a PEG-modified anti-MSR1 antibody or an antigen binding fragment thereof, disclosed herein and a linker-payload (LP) selected from the group consisting of the linker-payloads in Table 3, or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof.

[0307] Also provided herein are antibody-radionuclide conjugates (ARCs) comprising Anti-MSR1 antibodies conjugated to one or more radionuclides. Exemplary radionuclides that can be used in the context of this aspect of the disclosure include, but are not limited to, e.g., 225Ac, 212Bi, 213Bi, 1311, 186Re, 227Th, 222Rn, 223Ra, 224Ra, and 90Y. Table 1: List of ADCs and their structures OH OH OH

[0308] In the ADCs of Table 1, Ab is an anti-MSR1 antibody provided herein, or an antigenbinding fragment thereof. In particular embodiments, Ab is modified with a PEG group nn on a glutamine side chain described herein (referred to herein as a PEG-modified antibody). In certain embodiments, the PEG group terminates with an azido group, facilitating reaction with linker-payloads described here (e.g., linker payloads described in Table 3 and in the examples). In certain embodiments, the PEG group is linked to a linker-payload through a triazole or triazole derivative as described herein. In the ADCs, n is an integer from 1 to 10, for instance, 1, 2, 3, or 4. In the PEG group, nn is an integer from 1-10, for instance, 1, 2, 3, 4, or 5. In other embodiments, each BA in the ADCs in Table 1 is where Ab1 is an anti-MSR1 antibody, or an antigen-binding fragnment thereof; R is C2-4- alkylene; and nn is an integer selected from 2 to 4, inclusive, and each n is an integer from 1 to 10, for instance, 1,2,3, or 4.

[0309] In certain embodiments, provided herein is an ADC comprising an antibody disclosed herein and a linker-payload (LP) selected from the group consisting of the linker-payloads in Table 2, or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof. Table 2: List of ADCs and their structures and or a mixture thereof or a mixture thereof or a mixture thereof or a mixture thereof

[0310] In the ADCs in Table 2, Ab is an anti-MSR1 antibody provided herein, or an antigenbinding fragment thereof. In particular embodiments, Ab is modified with a PEG group on a glutamine side chain as described herein. In the ADCs, n is an integer from 1 to 10, for instance, 1, 2, 3, or 4.

[0311] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, conjugated to the payload solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0312] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 and conjugated to the payload , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0313] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64 and conjugated to the stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0314] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 and conjugated to the payload O, or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0315] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58 and conjugated to the payload O, or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0316] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0317] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0318] An antibody-drug conjugate (ADC) according to the formulas: or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0319] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodimets, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0320] An antibody-drug conjugate (ADC) according to the formulas: or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0321] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, nh2 conjugated to the payload , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0322] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 and conjugated to the payload , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0323] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64 and conjugated to the payload                                , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0324] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 and conjugated to the payload or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0325] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58 and conjugated to the payload nh2 or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0326] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0327] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0328] An antibody-drug conjugate (ADC) according to the formulas: and / or OH or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0329] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0330] An antibody-drug conjugate (ADC) according to the formulas: and / or or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0331] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, OH N H conjugated to the payload , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0332] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 and conjugated to the payload OH N H , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0333] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64 and conjugated to the OH payload                                   , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0334] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 and conjugated to the payload or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0335] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58 and conjugated to the payload or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0336] An antibody-drug conjugate (ADC) according to the formulas: OH and / or OH or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0337] An antibody-drug conjugate (ADC) according to the formulas: or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0338] An antibody-drug conjugate (ADC) according to the formulas: OH and / or OH or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0339] An antibody-drug conjugate (ADC) according to the formulas: OH and / or OH or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0340] An antibody-drug conjugate (ADC) according to the formulas: OH and / or OH or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In som embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0341] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0342] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 and conjugated to the payload stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0343] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64 and conjugated to the payload stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0344] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 and conjugated to the payload or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0345] Provided herein is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58 and conjugated to the payload , or pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58, and an N297Q mutation.

[0346] An antibody-drug conjugate (ADC) according to the formula: cAnh2 or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein X"is a pharmaceutically acceptable counter ion and wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises an N297Q mutation.

[0347] An antibody-drug conjugate (ADC) according to the formula: o^nh2 or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein X"is a pharmaceutically acceptable counter ion and wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and an N297Q mutation.

[0348] An antibody-drug conjugate (ADC) according to the formula: cAnh2 or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein X"is a pharmaceutically acceptable counter ion and wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; an HCDR2 comprising SEQ ID NO: 54; an HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64, and an N297Q mutation.

[0349] An antibody-drug conjugate (ADC) according to the formula: o^nh2 or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein X"is a pharmaceutically acceptable counter ion and wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a set of variable regions heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and an N297Q mutation.

[0350] An antibody-drug conjugate (ADC) according to the formula: o^nh2 or pharmaceutically acceptable salt, solvate, stereoisomeric form, or regioisomer thereof, or mixtures thereof; wherein X"is a pharmaceutically acceptable counter ion and wherein the antibody is an anti-MSR1 antibody, or antigen binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) SEQ ID NO: 58. In some of such embodiments, the drug antibody ratio (DAR) is from 1-4. In some embodiments, the DAR is 1. In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody, or antigen binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50; a light chain variable region (LCVR) SEQ ID NO: 58; and an N297Q mutation.

[0351] As used herein, in certain embodiments, where an amino acid is bonded to the spacer SP1, e.g., in the moiety -SP1-AA1-AA2-, the amino acid AA1 is bonded via its amino group to the spacer SP1. The spacer residue includes portions of a functional group that formed the bond with the amino group in the amino acid. By way of example only, in the following structure: AA1-AA2 the valine residue is bonded to SP1 as shown, and the SP1 residue, in this example, comprises a (C=O) moiety. Also, in this example, the SP1 residue comprises a functional group suitable for forming a bond with the reactive group and the SP1 residue comprises a -NH- moiety. Those of skill in the art will recognize that similar groupings can apply to all other formulae described herein.

[0352] The antibody drug conjugates described herein can be prepared using conjugation conditions known to those of ordinary skill in the art, (see, e.g., Doronina et al. Nature Biotechnology 2003, 21, 7, 778, which is incorporated herein by reference in its entirety). In some embodiments an ADC is prepared by contacting an anti-MSR1 antibody or an antigenbinding fragment thereof with a compound comprising the desired linker and payload, wherein said linker possesses a moiety that is reactive with the antibody or antigen-binding protein, e.g., at the desired residue of the antibody or antigen-binding protein. Exemplary conditions are described in the Examples below. Preparation of antibody-drug conjugates

[0353] In some embodiments, provided herein are processes for preparing an antibody-drug conjugate comprising contacting an anti-MSR1 antibody, or a PEG-modified anti-MSR1 antibody, or an antigen binding fragment thereof with a linker-payload or a linker-spacer-payload selected from Table 3. Also provided herein is an antibody drug conjugate prepared by conjugating an anti-MSR1 antibody ora PEG-modified anti-MSR1 antibody, or an antigen binding fragment thereof, with a linker payload, or a linker-spacer-payload, or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, selected from Table 3. Table 3: List of linker-payloads (LPs) and their structures LP1 / =\ O    H                   H 9 Y H 9 o                     o J h o > h     kk H kk 1                  ho hny° O ^XOH   VX n yyUM       oh 9 / \             HO\ \OH           Vq iho        hoy—0H H0 okatbio^^ OH LP2 / =\ ? h               h 9 Y h 9 YYX'hA asOlX t / k'^^o^YY0Y t NV i N / Ak0H °           o < H ° H MHM HN^O / X HO O>kOH        H0>0 j^OH / OH                 951 H0Xy k X OH LP5 jQ hhT 1 0 r°H , n °yP O    H                   H O    H O r^Y^O^M 7fN' / kV7;CYNH k )  0          oLh^^H V#                         1     SH HN^O k NH2 0       ' N     X-O PH v 0Y0H Oktx hto          H0>0 9           AK-oh Ho-YyOH        Hl^ W opHOY0 0H OH LP4B €3* 9 H                  H 9 Y H 9 TYT >H ? 9 H \V> o                o I H o < H0 M H M V /                         S     ^N^NH, N .~N N                                     N 0    O LP5B nh2 .a ''Th UH           H 9 Vh 9 nO-T 0 °                  0 ^T H 0 H Aj HN^O / X I 1 / HQ PH H0 OH 0 / \ / —( N. ,N.....(  )-0-( / "OH 'N 0-(    0-( '—OH HO LP6B Vr °^~u y© IZ o o o Q XZ / o=\ ' ZI zz / a '—A ' / =° zz \^° < \ 1 zz T z z LP7B / =\                                             0         u 0 0 „         O fr~T^ o              o Y h 0 AY^o^n^^AaTnTtTA^n^^NH2 \= /    0     H                       H i 1 Ho I A N NH2 H LP8B 9 H -..Tlx H / ==) ? h               h 9Yh 9 TIT0 H^^NTTTr^NXHTjf^ v# -N;i^fN^Q^o^o^o^rNYXNJYN'-rXNj^     °       0 0 V- / } 0              o L H 0 Y '—'                                  >       ^N^NH, , ,„ hnt°Oh °< 0 )=(  ^0^^6^9 oh T A TA H0 okotbiOT^ OH LP10 B OH

[0354] The compounds in the tables above can be prepared as described in the Examples herein.

[0355] Also provided herein is a method of preparing an antibody-drug conjugate of a rifamycin analog (e.g., rifampicin), comprising the step of contacting an anti-MSR1 antibody, or antigen-binding fragment thereof, with a linker payload according to Formula (D): under conditions suitable for forming a bond between anti-MSR1 antibody, or antigen-binding fragment thereof. Epitope Mapping and Related Technologies

[0356] The epitope to which the antibodies of the present invention bind may consist of a single contiguous sequence of 3 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more) amino acids of an MSR1 protein. Alternatively, the epitope may consist of a plurality of non-contiguous amino acids (or amino acid sequences) of MSR1. In some embodiments, the epitope is located on or near the modified LDL-binding domain of MSR1. In other embodiments, the epitope is located outside of the modified LDL-binding domain of MSR1, e.g., at a location on the surface of MSR1 at which an antibody, when bound to such an epitope, does not interfere with modified-LDL binding to MSR1.

[0357] Various techniques known to persons of ordinary skill in the art can be used to determine whether an antibody "interacts with one or more amino acids" within a polypeptide or protein. Exemplary techniques include, e.g., routine cross-blocking assay such as that described Antibodies, Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutational analysis, peptide blots analysis (Reineke, 2004, Methods Mol Biol 248:443-463), and peptide cleavage analysis. In addition, methods such as epitope excision, epitope extraction and chemical modification of antigens can be employed (Tomer, 2000, Protein Science 9:487-496). Another method that can be used to identify the amino acids within a polypeptide with which an antibody interacts is hydrogen / deuterium exchange detected by mass spectrometry. In general terms, the hydrogen / deuterium exchange method involves deuterium-labeling the protein of interest, followed by binding the antibody to the deuterium-labeled protein. Next, the protein / antibody complex is transferred to water to allow hydrogen deuterium exchange to occur at all residues except for the residues protected by the antibody (which remain deuterium-labeled). After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis, thereby revealing the deuterium-labeled residues which correspond to the specific amino acids with which the antibody interacts. See, e.g., Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73.25QA-2Q5A.

[0358] Embodiments include anti-MSR1 antibodies that bind to the same epitope as any of the specific exemplary antibodies described herein (e.g. antibodies comprising any of the amino acid sequences as set forth in Table 4 herein). Likewise, embodiments also include anti-MSR1 antibodies that compete for binding to MSR1 with any of the specific exemplary antibodies described herein (e.g. antibodies comprising any of the amino acid sequences as set forth in Table 4 herein).

[0359] One can easily determine whether an antibody binds to the same epitope as, or competes for binding with, a reference anti-MSR1 antibody by using routine methods known in the art and exemplified herein at, e.g., Example 7. For example, to determine if a test antibody binds to the same epitope as a reference anti-MSR1 antibody disclosed herein, the reference antibody is allowed to bind to a MSR1 protein. Next, the ability of a test antibody to bind to the MSR1 molecule is assessed. If the test antibody is able to bind to MSR1 following saturation binding with the reference anti-MSR1 antibody, it can be concluded that the test antibody binds to a different epitope than the reference anti-MSR1 antibody. On the other hand, if the test antibody is not able to bind to the MSR1 molecule following saturation binding with the reference anti-MSR1 antibody, then the test antibody may bind to the same epitope as the epitope bound by the reference anti-MSR1 antibody of the invention. Additional routine experimentation (e.g., peptide mutation and binding analyses) can then be carried out to confirm whether the observed lack of binding of the test antibody is in fact due to binding to the same epitope as the reference antibody or if steric blocking (or another phenomenon) is responsible for the lack of observed binding. Experiments of this sort can be performed using ELISA, RIA, Biacore, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art. In accordance with certain embodiments of the present invention, two antibodies bind to the same (or overlapping) epitope if, e.g., a 1-, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50% but preferably 75%, 90% or even 99% as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502). Alternatively, two antibodies are deemed to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other. Two antibodies are deemed to have "overlapping epitopes" if only a subset of the amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.

[0360] To determine if an antibody competes for binding (or cross-competes for binding) with a reference anti-MSR1 antibody, the above-described binding methodology is performed in two orientations. In a first orientation, the reference antibody is allowed to bind to a MSR1 protein under saturating conditions followed by assessment of binding of the test antibody to the MSR1 molecule. In a second orientation, the test antibody is allowed to bind to a MSR1 molecule under saturating conditions followed by assessment of binding of the reference antibody to the MSR1 molecule. If, in both orientations, only the first (saturating) antibody is capable of binding to the MSR1 molecule, then it is concluded that the test antibody and the reference antibody compete for binding to MSR1. As will be appreciated by a person of ordinary skill in the art, an antibody that competes for binding with a reference antibody may not necessarily bind to the same epitope as the reference antibody, but may sterically block binding of the reference antibody by binding an overlapping or adjacent epitope. Preparation of Human Antibodies

[0361] The anti-MSR1 antibodies disclosed herein can be fully human antibodies. Methods for generating monoclonal antibodies, including fully human monoclonal antibodies are known in the art. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to human MSR1.

[0362] Using VELOCIMMUNE™ technology, for example, or any other similar known method for generating fully human monoclonal antibodies, high affinity chimeric antibodies to MSR1 are initially isolated having a human variable region and a mouse constant region. As in the experimental section below, the antibodies are characterized and selected for desirable characteristics, including affinity, ligand blocking activity, selectivity, epitope, etc. If necessary, mouse constant regions are replaced with a desired human constant region, for example wildtype or modified IgG 1 or lgG4, to generate a fully human anti-MSR1 antibody. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region. In certain instances, fully human anti-MSR1 antibodies are isolated directly from antigen-positive B cells. Bioequivalents

[0363] The anti-MSR1 antibodies and antibody fragments disclosed herein encompass proteins having amino acid sequences that vary from those of the described antibodies but that retain the ability to bind human MSR1. Such variant antibodies and antibody fragments comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antibodies. Likewise, the anti- MSR1 antibody-encoding DNA sequences disclosed herein encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an anti-MSR1 antibody or antibody fragment that is essentially bioequivalent to an anti-MSR1 antibody or antibody fragment disclosed herein. Examples of such variant amino acid and DNA sequences are discussed above.

[0364] Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

[0365] In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0366] In one embodiment, two antigen-binding proteins are bioequivalent if a patient can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

[0367] In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

[0368] Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

[0369] Bioequivalent variants of anti-MSR1 antibodies disclosed herein may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include anti-MSR1 antibody variants comprising amino acid changes which modify the glycosylation characteristics of the antibodies, e.g., mutations which eliminate or remove glycosylation. Species Selectivity and Species Cross-Reactivity

[0370] According to certain embodiments, provided herein are anti-MSR1 antibodies that bind to human MSR1 but not to MSR1 from other species. Embodiments also include anti-MSR1 antibodies that bind to human MSR1 and to MSR1 from one or more non-human species. For example, the anti-MSR1 antibodies disclosed herein may bind to human MSR1 and may bind or not bind, as the case may be, to one or more of mouse, rat, guinea pig, hamster, gerbil, pig, cat, dog, rabbit, goat, sheep, cow, horse, camel, cynomologous, marmoset, rhesus or chimpanzee MSR1. According to certain exemplary embodiments, anti-MSR1 antibodies are provided which specifically bind human MSR1 and cynomolgus monkey (e.g., Macaca fascicularis) MSR1. Other anti-MSR1 antibodies disclosed herein bind human MSR1 but do not bind, or bind only weakly, to cynomolgus monkey MSR1. Multispecific Antibodies

[0371] The antibodies disclosed herein may be monospecific or multispecific (e.g., bispecific). Multispecific antibodies may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for more than one target polypeptide. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kuferefa / ., 2004, Trends Biotechnol. 22:238-244. The anti-MSR1 antibodies disclosed herein can be linked to or co-expressed with another functional molecule, e.g., another peptide or protein. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bispecific or a multispecific antibody with a second binding specificity.

[0372] Embodiments include bispecific antibodies wherein one arm of an immunoglobulin binds human MSR1, and the other arm of the immunoglobulin is specific for a second antigen. The MSR1-binding arm can comprise any of the HCVR / LCVR or CDR amino acid sequences as set forth in Table 4 herein. In certain embodiments, the MSR1-binding arm binds human MSR1 and blocks modified LDL binding to MSR1. In other embodiments, the MSR1-binding arm binds human MSR1 but does not block modified LDL binding to MSR1. In some embodiments, the MSR1 binding arm binds human MSR1 and activates MSR1 signaling. In other embodiments, the MSR1 binding arm blocks MSR1-mediated receptor stimulation. Embodiments also include bispecific antibodies wherein one arm of an antibody binds a first epitope of human MSR1, and the other arm of said antibody binds a second distinct epitope of human MSR1.

[0373] An exemplary bispecific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (Ig) Ch3 domain and a second Ig Ch3 domain, wherein the first and second Ig Ch3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second Ch3 may further comprise a Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG 1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of lgG4 antibodies. Variations on the bispecific antibody format described above are contemplated within the scope of the present invention.

[0374] Other exemplary bispecific formats that can be used in the context of the present invention include, without limitation, e.g., scFv-based ordiabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, lgG1 / lgG2, dual acting Fab (DAF)-lgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, fora review of the foregoing formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry. (See, e.g., Kazane etal., J. Am. Chem. Soc. [Epub'. Dec. 4, 2012]). Therapeutic Formulation and Administration

[0375] Embodiments relate to pharmaceutical compositions comprising the anti-MSR1 antibodies or antigen-binding fragments thereof disclosed herein. The pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0376] The dose of antibody administered to a patient may vary depending upon the age and the size of the patient, target disease, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. In an adult patient, it may be advantageous to intravenously administer the antibody of the present invention normally at a single dose of about 0.01 to about 20 mg / kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg / kg body weight. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted. Effective dosages and schedules for administering anti-MSR1 antibodies may be determined empirically; for example, patient progress can be monitored by periodic assessment, and the dose adjusted accordingly. Moreover, interspecies scaling of dosages can be performed using well-known methods in the art (e.g., Mordenti etal., 1991, Pharmaceut. Res. 8:1351).

[0377] Various delivery systems are known and can be used to administer the pharmaceutical compositions disclosed herein, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu etal., 1987, J. Biol. Chern. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[0378] A pharmaceutical composition as disclosed herein can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0379] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition disclosed herein. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park IL), to name only a few.

[0380] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0381] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

[0382] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms. Therapeutic Uses of Antibodies

[0383] Embodiments include methods comprising administering to a subject in need thereof a therapeutic composition comprising an anti-MSR1 antibody or an antibody-drug conjugate comprising an anti- MSR1 antibody (e.g., an anti- MSR1 antibody or ADC comprising any of the HCVR / LCVR or CDR sequences as set forth in Table 4 herein). The therapeutic composition can comprise any of the anti- MSR1 antibodies, antigen-binding fragments thereof, or ADCs disclosed herein (e.g., ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7003), (7004) and / or (7005)), and a pharmaceutically acceptable carrier or diluent.

[0384] The antibodies and ADCs disclosed herein are useful, inter alia, for the treatment, prevention and / or amelioration of any disease or disorder associated with or mediated by MSR1 expression or activity, or treatable by binding MSR1 without competing against modified LDL, or and / or promoting MSR1 receptor internalization and / or decreasing cell surface receptor number. For example, the antibodies and ADCs disclosed herein are useful for the treatment, attenuation, or amelioration of atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation by targeting cells that express MSR1 and / or that respond to MSR1-mediated signaling, e.g., macrophages.

[0385] In the context of the methods of treatment described herein, the anti-MSR1 antibody, or an ADC thereof, may be administered as a monotherapy ( / .e., as the only therapeutic agent) or in combination with one or more additional therapeutic agents (examples of which are described elsewhere herein).

[0386] Provided herein is a method of treating a proliferative disease, a metabolic disease, inflammation, a neurodegenerative disease, or disease, disorder, or condition associated with glucocorticoid receptor signaling, in a subject comprising administering to the subject an effective treatment amount of a compound described herein (e.g., an anti-MSR1 ADC), or a pharmaceutical composition comprising a compound described herein.

[0387] In some embodiments, where the payload is a steroid, the disease, disorder, or condition is allergic state, including but not limited to asthma, atopic dermatitis, contact dermatitis, allergic dermatitis, drug hypersensitivity reactions, anaphylactic rhinitis, perennial or seasonal allergic rhinitis, and serum sickness; dermatologic diseases and conditions, including but not limited to skin itching, seborrheic dermatitis, neurodermatitis, eczema, bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme (Stevens-Johnson syndrome); endocrine disorders, including but not limited to primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; gastrointestinal diseases; hematologic disorders, including but not limited to acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults, pure red cell aplasia, and secondary thrombocytopenia; trichinosis; tuberculous meningitis with subarachnoid block or impending block; neoplastic diseases, including but not limited to leukemias and lymphomas; nervous system disorders, including but not limited to acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumor, craniotomy, or head injury; ophthalmic diseases, including but not limited to sympathetic ophthalmia, temporal arteritis, uveitis, xerophthalmia, and ocular inflammatory conditions unresponsive to topical corticosteroids; renal diseases, including but not limited to for inducing a diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus; respiratory diseases, including but not limited to berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis; and Rheumatic disorders, including but not limited to use as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriaticarthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis, and for use in dermatomyositis, polymyositis, stomatitis, and systemic lupus erythematosus. In certain embodiments, provided herein are methods of treating or preventing arthritis.

[0388] In some embodiments, set forth herein is a method for treating a disease, disorder, or condition selected from an autoimmune disease, an allergy, arthritis, asthma, a breathing disorder, a blood disorder, a cancer, a collagen disease, a connective tissue disorders, a dermatological disease, an eye disease, an endocrine problem, an immunological disease, an inflammatory disease, an intestinal disorders, a gastrointestinal disease, a neurological disorder, an organ transplant condition, a rheumatoid disorder, a skin disorder, a swelling condition, a wound healing condition, and a combination thereof comprising administering a steroid payload or conjugate thereof described herein.

[0389] In some embodiments, the autoimmune disorder is selected from multiple sclerosis, autoimmune hepatitis, shingles, systemic lupus erythematosus (i.e., lupus), myasthenia gravis, Duchenne muscular dystrophy, and sarcoidosis. In some embodiments, the breathing disorder is selected from asthma, chronic respiratory disease, chronic obstructive pulmonary disease, bronchial inflammation, and acute bronchitis. In some embodiments, the cancer is selected from leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma (NHL), and multiple myeloma. In some embodiments, the collagen disease is systemic lupus erythematosus. In some embodiments, the eye disease is keratitis. In some embodiments, the endocrine problem is selected from Addison's Disease, adrenal insufficiency, adrenal cortical dysfunction, adrenocortical, and congenital adrenal hyperplasia. In some embodiments, the inflammatory disease is selected from inflammation after cataract surgery, joint inflammation, immune inflammation, tendon inflammation, bursitis, epicondylitis, Crohn's disease, inflammatory bowels disease, lipid pneumonitis thyroiditis, urticaria (hives), pericarditis, nephrotic syndrome, and uveitis. In some embodiments, the intestinal disorder is selected from collagenous colitis, ulcerative colitis, Crohn’s disease, and inflammatory bowels disease. In some embodiments, the rheumatoid disorder is selected from rheumatoid arthritis, polymyalgia rheumatic, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus. In some embodiments, the skin disorder is selected from psoriasis, eczema, and poison ivy. In some embodiments, the neurological disorder is chronic inflammatory demyelinating polyradiculoneuropathy.

[0390] In some embodiments, the compounds described herein are administered to a patient to treat an acute inflammatory event, including but not limited to shock, brain edema, and graft- vs-host disease. In some embodiments, the compounds described herein are administered to treat lympholytic effects, including but not limited to those associated with hematological malignancies, e.g., leukemias, lymphomas, and myelomas.

[0391] In some embodiments, set forth herein is a method for reducing inflammation in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein. In some embodiments, set forth herein is a method for modulating the immune system in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein. In some embodiments, set forth herein is a method for modulating cortisol levels in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein. In some embodiments, set forth herein is a method of reducing lymphocyte migration in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of a steroid or conjugate thereof described herein. In some embodiments, set forth herein is a method of treating hypercalcemia due to cancer, Meniere's disease, a migraine headache, a cluster headache, a severe aphthous ulcer, laryngitis, severe tuberculosis, a Herxheimer reaction to syphilis, a decompensated heart failure, allergic rhinitis or nasal polyps, comprising administering to a subject in need thereof a steroid payload or conjugate thereof described herein. In some embodiments, the compounds disclosed herein can be used for treating inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the disease, disorder, or condition is a chronic inflammatory condition, including but not limited to asthma, skin infections, and ocular infections. In some embodiments, compounds described herein are used for immunosuppression in patients undergoing organ transplantation.

[0392] In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a nervous disorder associated with GR signaling, including but not limited to psychiatric disorders such as schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), and mood disorders, substance abuse, stress, and anxiety.

[0393] In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a visual system disorder, including but not limited to ocular inflammation (e.g., conjunctivitis, keratitis, uveitis), macular edema, and macular degeneration. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a cardiovascular disorder. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a glucose and / or liver metabolism disorder. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a musculoskeletal system disorder. In some embodiments, the steroid payloads and conjugates thereof described herein are administered to a patient to treat a cutaneous inflammatory condition, such as eczema and psoriasis.

[0394] The protein conjugates described herein provide a means for targeted delivery of its steroid payload to particular cells or organ systems, thereby reducing or preventing side effects that result from administration of the free unconjugated steroid payload. Examples of such potential side effects to be reduced or prevented include those listed in the approved drug label for Decadron® (dexamethasome), which is incorporated herein by reference in its entirety. In some embodiments, the side effect to be reduced or prevented is selected from elevation of blood pressure; sodium retention; water / fluid retention (edema, angioedema, pulmonary edema); increased excretion of potassium; reversible hypothalamic-pituitary adrenal (HPA) axis suppression; potential corticosteroid insufficiency after withdrawal of treatment; susceptibility to infecctions; exacerbation of systemic fungal infections; worsening of severity of chickenpox in pediatric and adult patients; worsening of severity of measles in pediatric and adult patients; posterior subcapsular cataracts; glaucoma with possible damage to the optic nerves; enhancement of the establishment of secondary ocular infections due to bacteria, fungi, or viruses; increase in new episodes of optic neuritis; Kaposi’s sarcoma; drug-induced secondary adrenocortical insufficiency; increased risk of a perforation when active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, are present; peritoneal irritation following gastrointestinal perforation; decreased bone formation; increased bone resorption; inhibition of osteoblast function; inhibition of bone growth in pediatric patients; development of osteoporosis at any age; acute myopathy (possibly involving ocular and respiratory muscles, and potentially resulting in quadriparesis); elevation of creatinine kinase; psychic derangements, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations; aggravation of existing emotional instability or psychotic tendencies; elevated intraocular pressure; bradycardia; cardiac arrest; cardiac arrhythmias; cardiac enlargement; circulatory collapse; congestive heart failure; fat embolism; hypertension; hypertrophic cardiomyopathy in premature infants; myocardial rupture following recent myocardial infarction; syncope; tachycardia; thromboembolism; thrombophlebitis; vasculitis; acne; allergic dermatitis; dry scaly skin; ecchymoses and petechiae; erythema; impaired wound healing; increased sweating; rash; striae; suppression of reactions to skin tests; thin fragile skin; thinning scalp hair; urticarial; decreased carbohydrate and glucose tolerance; development of Cushingoid state; hyperglycemia; glycosuria; hirsutism; hypertrichosis; increased requirements for insulin or oral hypoglycemic agents in diabetes (insulin resistance); manifestations of latent diabetes mellitus; menstrual irregularities; secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress; as in trauma; surgery; or illness); suppression of growth in pediatric patients; congestive heart failure in susceptible patients; fluid retention; hypokalemic alkalosis; potassium loss; sodium retention; abdominal distention; elevation in serum liver enzyme levels (usually reversible upon discontinuation); hepatomegaly; increased appetite; nausea; pancreatitis; peptic ulcer with possible perforation and hemorrhage; perforation of the small and large intestine (particularly in patients with inflammatory bowel disease); ulcerative esophagitis; negative nitrogen balance due to protein catabolism; aseptic necrosis of femoral and humeral heads; loss of muscle mass; muscle weakness; osteoporosis; pathologic fracture of long bones; steroid myopathy; tendon rupture; vertebral compression fractures; convulsions; depression; emotional instability; euphoria; headache; increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment; insomnia; mood swings; neuritis; neuropathy; paresthesia; personality changes; psychic disorders; vertigo; exophthalmos; glaucoma; increased intraocular pressure; posterior subcapsular cataracts; abnormal fat deposits; decreased resistance to infection; hiccups; increased or decreased motility and number of spermatozoa; malaise; moon face; and weight gain; and and those side effects associated with drug-drug interactions. In some embodiments, the side effect to be reduced or prevented are those associated with drug-drug interactions. In some embodiments, the side effect to be reduced or prevented is associated with drug-drug interactions from the use of a corticosteroid with aminoglutethimide including diminishment of adrenal suppression by corticosteroids; amphotericin B injection and potassium-depleting agents, including development of hypokalemia, cardiac enlargement, and congestive heart failure; antibiotics including a significant decrease in corticosteroid clearance; anticholinesterases including producing severe weakness in patients with myasthenia gravis; oral anticoagulants including inhibition of response to warfarin; antidiabetics including increased blood glucose concentrations; antitubercular drugs including decreased serum concentrations of isoniazid; cholestyramine including increased clearance of corticosteroids; cyclosporine including increased activity of both cyclosporine and corticosteroids, and incidence of convulsions; dexamethasone suppression test (DST) interference including false-negative results in patients being treated with indomethacin; digitalis glycosides including increased risk of arrhythmias due to hypokalemia; ephedrine including enhancement of the metabolic clearance of corticosteroids, resulting in decreased blood levels and lessened physiologic activity; estrogens, including oral contraceptives, including decreased hepatic metabolism of certain corticosteroids and associated increase in their effect; hepatic enzyme inducers, inhibitors and substrates (drugs which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity e.g., barbiturates, phenytoin, carbamazepine, rifampin), including enhancing of metabolism of corticosteroids; drugs which inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as erythromycin), including the potential for increased plasma concentrations of corticosteroids; drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin), including increase in their clearance, resulting in decreased plasma concentration; ketoconazole including decreased metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects, and inhibition of adrenal corticosteroid synthesis potentially causing adrenal insufficiency during corticosteroid withdrawal; nonsteroidal anti-inflammatory agents (NSAIDS), including increased risk of gastrointestinal side effects and increased clearance of salicylates; phenytoin, including increases or decreases in phenytoin level, altered seizure control; skin tests, including suppression of reactions to skin tests; thalidomide including toxic epidermal necrolysis; and vaccines including a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response or potentiation of the replication of some organisms contained in live attenuated vaccines).

[0395] Thus, provided herein are methods for treating a disease, disorder, or condition associated with the glucocorticoid receptor comprising administering a conjugate of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), Formula (III) or Formula (3000), to a patient having said disease, disorder, or condition, wherein the side effects associated with administration of the free steroid payload of said conjugate is reduced. Furthermore, provided herein are methods of delivering a compound of Formula (III), or Formula (3000), to a cell comprising contacting said cell with a protein conjugate the compound of Formula (3000), or Formula (III), wherein the protein conjugate comprises an antibody or antigen binding fragment thereof that binds a surface antigen of said cell.

[0396] In some examples, where the payload is an LXR modulator, set forth herein is a method of treating a disease, disorder or condition comprising administering to a patient having said disorder a therapeutically effective amount of a compound and / or an ADC (e.g., ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), or (6005)) or a pharmaceutical composition thereof.

[0397] In some examples, set forth herein is a method of preventing a disease, disorder or condition comprising administering to a patient having said disorder a prophylactically effective amount of a compound and / or an ADC (e.g., ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (5001), (5002), (5003), (5004), (6001), (6002), (6003), (6004), or (6005), ora pharmaceutical composition thereof.

[0398] In some examples, set forth herein are methods for treating or preventing any disease, disorder, or condition responsive to modulation of LXR signaling. In some examples, the disease or disorder is associated with LXR function, LXR polymorphisms, LXR agonist activity, or LXR antagonist activity. In some examples, set forth herein is a method of treating or preventing a disease, disorder, or condition selected from the group consisting of a proliferative disorder, a neurodegenerative disorder, an immunological disorder, an autoimmune disease, an inflammatory disorder, a dermatological disease, a metabolic disease, cardiovascular disease, and a gastrointestinal disease.

[0399] The proliferative disorder can be any proliferative disorder known to those of skill. In certain embodiments, proliferative disorders include, without limitation, oncology disorders, where the oncology disorder can be any cancer disorder known to those of skill. In certain embodiments, provided herein are methods of treating or preventing a melanoma. In certain embodiments, provided herein are methods of treating or preventing metastatic melanoma. In certain embodiments, provided herein are methods of treating or preventing lung cancer. In certain embodiments, provided herein are methods of treating or preventing EGFR-tyrosine kinase inhibitor resistant lung cancer. In certain embodiments, provided herein are methods of treating or preventing oral cancer. In certain embodiments, provided herein are methods of treating or preventing oral squamous cell carcinoma. In certain embodiments, provided herein are methods of treating or preventing prostate cancer. In certain embodiments, provided herein are methods of treating or preventing Hodgkin’s lymphoma. In certain embodiments, provided herein are methods of treating or preventing breast cancer.

[0400] The neurodegenerative disorder can be any neurodegenerative disorder known to those of skill. In certain embodiments, provided herein are methods of treating or preventing Alzheimer’s disease. In certain embodiments, provided herein are methods of treating or preventing Parkinson’s disease. In certain embodiments, provided herein are methods of treating or preventing Huntington’s disease. In certain embodiments, provided herein are methods of treating or preventing amyotrophic lateral sclerosis. In certain embodiments, provided herein are methods of treating or preventing myelin gene expression. In certain embodiments, provided herein are methods of treating or preventing myelination and remyelination conditions, diseases, or disorders.

[0401] The immunological disorder can be any immunological disorder known to those of skill. In certain embodiments, provided herein are methods of treating or preventing imflammatory bowel disease. In certain embodiments, provided herein are methods of treating or preventing ulcerative colitis. In certain embodiments, provided herein are methods of treating or preventing Crohn’s disease.

[0402] The inflammatory disorder can be any inflammatory disorder known to those of skill. In certain embodiments, provided herein are methods of treating or preventing arthritis. In certain embodiments, provided herein are methods of treating or preventing rheumatoid arthritis.

[0403] The metabolic disease can be any metabolic disease known to those of skill. In certain embodiments, the metabolic disease is dyslipidemia. Dyslipidemia can be any dyslipidemia known to those of skill. In certain embodiments, dyslipidemia is selected from the group consisting of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-l deficiency, and cardiovascular disease such as coronary artery disease (including, for example, treatment and prevention of angina, myocardial infarction, and sudden cardiac death); atherosclerosis (including, for example, treatment and prevention of atherosclerosis); and restenosis (including, for example, preventing or treating atherosclerotic plaques which develop as a consequence of medical procedures such as balloon angioplasty). In certain embodiments, provided herein are methods of treating or preventing diabetes.

[0404] The cardiovascular disease can be any cardiovascular disease known to those of skill. In certain embodiments, provided herein are methods of treating or preventing atherosclerosis. In certain embodiments, provided herein are methods of treating or preventing atherosclerosis derived from abnormal macrophage processing. In certain embodiments, provided herein are methods of treating or preventing atherosclerosis derived from the formation of oxidized low-density lipoproteins (oxLDLs), where marcrophages fail to process oxLDLs. In certain embodiments, provided herein are methods of treating or preventing ischemic heart disease. In certain embodiments, provided herein are methods of treating or preventing stroke. In certain embodiments, provided herein are methods of treating or preventing hypertensive heart disease. In certain embodiments, provided herein are methods of treating or preventing aortic aneurysm. In certain embodiments, provided herein are methods of treating or preventing endocarditis. In certain embodiments, provided herein are methods of treating or preventing peripheral artery disease. In certain embodiments, provided herein are methods of treating or preventing combinations of any of the diseases provided in this paragraph.

[0405] In some examples, set forth herein is a method for modulating the function of a nuclear receptor. By way of non-limiting example, the function may be selected from expression / secretion of inflammatory mediators (e.g. cytokines, chemokines), cholesterol regulation, cholesterol intake, cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, an inflammatory activity, lipid regulation, apoptosis, migration, chemotaxis, gene transcription, and protein expression.

[0406] In some examples, set forth herein herein is a method of preventing a disease, disorder or condition comprising administering to a patient having said disorder a therapeutically effective amount of a compound and / or an ADC of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (7001), (7002), (7003), (7004), and / or (7005), ora pharmaceutical composition thereof.

[0407] S. aureus is a facultative intracellular bacterium that can survive phagocytosis by macrophages and other cells types (Horn, J., et al., Inside job: Staphylococcus aureus hostpathogen interactions. Int J Med Microbiol, 2018. 308(6): p. 607-624; Jubrail, J., et al., Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages. Cell Microbiol, 2016. 18(1): p. 80-96). Intravital imaging has demonstrated that macrophages can serve as a reservoir where S. aureus replicates and then seeds other organs during infection (Surewaard, B.G., et al., Identification and treatment of the Staphylococcus aureus reservoir in vivo. J Exp Med, 2016. 213(7): p. 1141-51). Most antibiotics do not penetrate cells, including macrophages, very well, indicating that the intracellular S. aureus reservoir can evade treatment with standard of care antibiotics (Lehar, S.M., et al., Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature, 2015. 527(7578): p. 3238). However, liposomal formulation of vancomycin increased penetration of the antibiotic into macrophages and reduced S. aureus organ burden more effectively than standard of care vancomycin (Surewaard, B.G., et al., Identification and treatment of the Staphylococcus aureus reservoir in vivo. J Exp Med, 2016. 213(7): p. 1141-51). Together, these data indicate that delivering an antibiotic to macrophages may be an effective method to eliminate the intracellular S. aureus reservoir.

[0408] Antibiotic resistant S. aureus remains a public health problem and roughly 40% blood stream infections are caused by methicillin-resistant S. aureus (MRSA) in the USA. Few FDA approved treatment options exist for MRSA blood stream infections, with vancomycin remaining an antibiotic of choice. In spite of appropriate antibiotic treatment, mortality from S. aureus blood stream infections is ~18%, prompting investigation into combinations that can improve treatment.

[0409] The rifamycin class of antibiotics inhibit bacterial RNA polymerase (RNAP) and have potent activity against S. aureus. Monotherapy with this class of antibiotics, however, can lead to selection of a resistant population during treatment. Therefore, rifamycin antibiotics can be used in combination with first line antibiotics to improve outcomes, commonly in infections involving prostheses or foreign devices.

[0410] The ADCs described herein comprising rifamycin analogs are useful for preventing or treating growth of a bacterium and / or bacterial infection in a subject. In some instances, the bacterium is a gram positive bacterium (a gram positive bacterium is the cause of the bacterial infection). In some instances, the bacterium is a pencillin-resistant bacterium (a penicillin-resistant bacterium is the cause of the bacterial infection). In some instances, the bacterium is a Staphylococcus aureus, methiciliin resistant Staphylococcus aureus (MRSA) bacterium (a MRSA bacterium is the cause of the bacterial infection). In some instances, the bacterium is a methicillin susceptible Staphylococcus aureus (MSSA) bacterium (a MSSA bacterium is the cause of the bacterial infection). In some instances, the bacterium is a vancomycin-resistant Staphylococcus aureus (VRSA) bacterium (a VRSA bacterium is the cause of the bacterial infection). In some instances, the bacterium is multi-drug resistant M. tuberculosis (a multi-drug resistant M. tuberculosis bacterium is the cause of the bacterial infection). In further instances, the bacterium is Chlamydia trachomatis resistant to, e.g., azithromycin (Chlamydia trachomatis resistant to, e.g., azithromycin is the cause of the bacterial infection). In more instances, the bacterium is Clostridium difficile resistant to, e.g., metronidazole, vancomycin, and / or fidaxomicin (Clostridium difficile resistant to, e.g., metronidazole, vancomycin, and / or fidaxomicin is the cause of the bacterial infection).

[0411] Provided herein is a method of preventing or treating cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, septicemia, toxic shock syndrome, septic arthritis, mastitis, infection associated with a prosthetic joint, infection associated with a catheter, or infection associated with an implant, in a subject comprising administering to the subject an effective treatment amount of an antibody-drug conjugate comprising a rifamycin analog (e.g., ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (7001), (7002), (7003), (7004) and / or (7005)). Also provided herein is a method of preventing or treating an intracellular bacterial infection in a subject comprising administering to the subject an effective treatment amount of an antibody-drug conjugate of an antibody-drug conjugate comprising a rifamycin analog (e.g., ADCs of Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (7001), (7002), (7003), (7004) and / or (7005)).

[0412] In some instances, provided herein are therapeutic methods comprising administration an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an ADC comprising an anti-MSR1 antibody of MSR1 antigen-binding fragment thereof, to a subject in need thereof are useful for the treatment, and / or prevention of bacterial infection in a subject, and / or a disease or disorder or condition associated with Staphylococcal infection, for example, a S. aureus infection infection and / or for ameliorating at least one symptom associated with such disease, disorder or condition. Such disease, disorder or condition can be cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, septicemia, toxic shock syndrome, or septic arthritis. In some instances, the subject has a prosthetic joint and the antibodies disclosed herein are used for treating and / or preventing S. aureus infection of the tissue surrounding the prosthetic joint. In some instances, the subject has a catheter and the antibodies disclosed herein are used for treating and / or preventing S. aureus infection of the catheter and / or the tissue surrounding the catheter. In some instances, the subject has a foreign body implanted, and the antibodies disclosed herein are used for treating and / or preventing S. aureus infection of the foreign body and / or the tissue surrounding the foreign body. In some instances, the subject has mastitis, and the antibodies disclosed herein are useful for treating mastitis.

[0413] In some instances, the rifamycin analogs and / or anti-MSR1 ADCs thereof are administered in combination with one or more additional antibiotics (e.g., antibiotics that may be used for MRSA infections) such as vancomycin, trimethoprim-sulfamethoxazole, tetracycline, doxycycline / minocycline, clindamycin, cephalosporins (e.g. cephalexin), naficillin, fidaxomicin, linezolid, and the like, and / or any other suitable antibiotic(s). In some instances, the ADCs described herein comprising rifamycin analogs are administered in combination with vancomycin and are useful for preventing or treating bacterial infection in a subject. Combination Therapies and Formulations

[0414] Embodiments include compositions and therapeutic formulations comprising any of the anti-MSR1 antibodies described herein in combination with one or more additional therapeutically active components, and methods of treatment comprising administering such combinations to subjects in need thereof.

[0415] The anti-MSR1 antibodies disclosed herein may be co-formulated with and / or administered in combination with one or more additional therapeutically active component(s) selected from the group consisting of: cytokine inhibitors, including small-molecule cytokine inhibitors and antibodies that bind to cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-11, IL-12, IL-13, IL-17, IL-18, or to their respective receptors.

[0416] The anti-MSR1 antibodies disclosed herein may also be administered and / or coformulated in combination with anti-inflammatory agents, immunomodulatory agents, analgesics, corticosteroids, steroids, antioxidants, COX inhibitors, cardioprotectants, metal chelators, IFN-gamma, and / or NSAIDs. In some embodiments, the anti-MSR1 antibodies can be administered and / or co-formulated in combination with anti-PCSK9 antibodies, anti-ANGPTL3 antibodies, statins, ezetimibe and other lipid lowering therapies.

[0417] The additional therapeutically active component(s), e.g., any of the agents listed above or derivatives thereof, may be administered just prior to, concurrent with, or shortly after the administration of an anti-MSR1 antibody disclosed herein; (for purposes of the present disclosure, such administration regimens are considered the administration of an anti-MSR1 antibody "in combination with" an additional therapeutically active component). Embodiments include pharmaceutical compositions in which an anti-MSR1 antibody disclosed herein is co-formulated with one or more of the additional therapeutically active component(s) as described elsewhere herein. Administration Regimens

[0418] According to certain embodiments, multiple doses of an anti-MSR1 antibody (or an ADC or a pharmaceutical composition comprising a combination of an anti-MSR1 antibody and any of the additional therapeutically active agents mentioned herein) may be administered to a subject over a defined time course. The methods comprise sequentially administering to a subject multiple doses of an anti-MSR1 antibody disclosed herein. As used herein, "sequentially administering" means that each dose of anti-MSR1 antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). Embodiments include methods which comprise sequentially administering to the patient a single initial dose of an anti-MSR1 antibody, followed by one or more secondary doses of the anti-MSR1 antibody, and optionally followed by one or more tertiary doses of the anti-MSR1 antibody.

[0419] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the anti-MSR1 antibody disclosed herein. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of anti-MSR1 antibody, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of anti-MSR1 antibody contained in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses").

[0420] In certain exemplary embodiments, each secondary and / or tertiary dose is administered 1 to 26 (e.g., 1, 1½. 2, 2½. 3, 3½. 4, 4½. 5, 5½. 6, 6½. 7, 7½. 8, 8½. 9, 9½. 10, 10½. 11, 11½. 12, 12½. 13, 13½. 14, 14½. 15, 15½. 16, 16½. 17, 17½. 18, 18½. 19, 19½. 20, 20½. 21,21½. 22, 22½. 23, 23½. 24, 24½. 25, 25½. 26, 26½. or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of anti-MSR1 antibody which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

[0421] The methods according to this aspect of the invention may comprise administering to a patient any number of secondary and / or tertiary doses of an anti-MSR1 antibody. For example, in certain embodiments, a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient. The administration regimen may be carried out indefinitely over the lifetime of a particular subject, or until such treatment is no longer therapeutically needed or advantageous.

[0422] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 12 weeks after the immediately preceding dose. In certain embodiments, the frequency at which the secondary and / or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

[0423] Embodiments include administration regimens in which 2 to 6 loading doses are administered to a patient at a first frequency (e.g., once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by administration of two or more maintenance doses to the patient on a less frequent basis. For example, according to this aspect of the invention, if the loading doses are administered at a frequency of once a month, then the maintenance doses may be administered to the patient once every six weeks, once every two months, once every three months, etc. Diagnostic Uses of the Antibodies

[0424] The anti-MSR1 antibodies disclosed herein may also be used to detect and / or measure MSR1, or MSR1-expressing cells in a sample, e.g., for diagnostic purposes. For example, an anti-MSR1 antibody, or fragment thereof, may be used to diagnose a condition or disease characterized by aberrant expression (e.g., over-expression, under-expression, lack of expression, etc.) of MSR1. Exemplary diagnostic assays for MSR1 may comprise, e.g., contacting a sample, obtained from a patient, with an anti-MSR1 antibody disclosed herein, wherein the anti-MSR1 antibody is labeled with a detectable label or reporter molecule. Alternatively, an unlabeled anti-MSR1 antibody can be used in diagnostic applications in combination with a secondary antibody which is itself detectably labeled. The detectable label or reporter molecule can be a radioisotope, such as 3H, 14C, 32P, 35S, or 125l; a fluorescent or chemiluminescent moiety such as fluorescein, or rhodamine; or an enzyme such as alkaline phosphatase, beta-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that can be used to detect or measure MSR1 in a sample include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immuno-PET (e.g., 89Zr, 64Cu, etc.), and fluorescence-activated cell sorting (FACS).

[0425] Samples that can be used in MSR1 diagnostic assays according to the present invention include any tissue or fluid sample obtainable from a patient which contains detectable quantities of MSR1 protein, or fragments thereof, under normal or pathological conditions. Generally, levels of MSR1 in a particular sample obtained from a healthy patient (e.g., a patient not afflicted with a disease or condition associated with abnormal MSR1 levels or activity) will be measured to initially establish a baseline, or standard, level of MSR1. This baseline level of MSR1 can then be compared against the levels of MSR1 measured in samples obtained from individuals suspected of having a MSR1-related disease or condition. EXAMPLES

[0426] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions provided herein, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. The examples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects.

[0427] As used herein, the symbols and conventions used in the processes, and Examples, herein, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry unless specified otherwise to the contrary. Specifically, but without limitation, the following abbreviations may be used in the Examples and throughout the specification: Abbreviation Term ADC Antibody-drug conjugate Abbreviation Term Aglycosylated antibody Antibody does not have any glycan aq Aqueous BARAC Biarylazacyclooctynone BCN (1 R,8S,9s)-Bicyclo[6.1,0]non-4-yn-9-yl Boc N-tert-butoxycarbonyl BupHTM Thermo Scientific Prod# 28372, containing 100 mM sodium phosphate and 150 mM sodium chloride, potassium free, pH was adjusted from 7.2 to 7.6-7.8 MQ, unless otherwise noted. CD Cyclodextrin COT Cyclooctynol Da Dalton DAR Drug to antibody ratio. DCM Dichloromethane DIBAC Dibenz[b,f]azocine, 11,12-didehydro-5,6-dihydro- or Dibenzocyclooctyne or Dibenz[b,f]azocine-5(6H)-butanoic acid, 11,12-didehydro DIBAC-Suc Dibenz[b,f]azocine-5(6H)-butanoic acid, 11,12-didehydro DIBACT 3H-Benzo[c]-1,2,3-triazolo[4,5-e][1]benzazocine, 8,9-dihydro- DIBO Dibenzocyclooctyne DIFO Difluorinated cyclooctyne DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO Dimethylsulfoxide ESI Electrospray ionization g Gram HATU 2-(7-Aza-1 H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HC Heavy chain of immunoglobulin HEK Human embryonic kidney (cells) HPLC High performance liquid chromatography hr or hrs Hours LC Light chain of immunoglobulin LC Liquid chromatography MC Maleimidocaproyl mg Milligrams min Minutes mL Milliliters mM Millimolar MMAE Monomethyl auristatin E MS Mass spectrometry Abbreviation Term MSD Mass-selective detector MTG Microbial transglutaminase MW Molecular weight ncADC Non-Cytotoxic antibody drug conjugation NHS N-hydroxy succinimide nM nanomolar NMR Nuclear magnetic resonance NOESY Nuclear Overhauser effect spectroscopy PAB Para-aminobezyloxy(carbonyl) PBS 10 mM sodium phosphate buffer and 150 mM sodium chloride PBSg 10 mM phosphate, 150 mM sodium chloride, 5% glycerol PEG Polyethyleneglycol ppm Parts per million (chemical shift) RP Reversed phase RT or rt Room temperature SDS-PAGE Sodium dodecylsulfate polyacrylamide gel electrophoresis SEC Size exclusion chromatography Sue Succinic acid TCEP Tris(2-carboxyethyl)phosphine hydrochloride TEA Triethylamine TFA Trifluoroacetic acid TG Transglutaminase THF Tetra hydrofuran TOF Time-of-flight UPLC Ultra Performance Liquid Chromatography UV Ultraviolet VA Valine-Aniline VC Valine-citrulline pL Microliters pM micromolar

[0428] Reagents and solvents were obtained from commercial sources such as Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other vendors, unless explicitly stated otherwise.

[0429] 1H NMR and other NMR spectra were recorded on a Bruker AVIII 400 or Bruker AVIII 500. The data were processed with Nuts software or MestReNova software, measuring proton shifts in parts per million (ppm) downfield from an internal standard tetramethylsilane (TMS).

[0430] HPLC-MS measurements were run on an Agilent 1200 HPLC / 6100 SQ System using the follow conditions:

[0431] Method A for HPLC-MS measurements included, as the Mobile Phase: A: Water (0.01% trifluoroacetic acid (TFA)), B: acetonitrile (0.01% TFA); Gradient Phase: 5% of B increased to 95% of B within 15 minutes (min); Flow Rate: 1.0 mL / min; Column: SunFire C18, 4.6x50 mm, 3.5 pm; Column Temperature: 50 °C. Detectors: Analog to Digital Converter (ADC) Evaporative Light-scattering Detector (ELSD), Diode array detector (DAD) (214 nm and 254 nm), electrospray ionization-atmospheric ionization (ES-API).

[0432] Method B for HPLC-MS measurements included, as the Mobile Phase: A: Water (10 mM NH4HCO3), B: acetonitrile; Gradient Phase: 5% to 95% of B within 15 min; Flow Rate: 1.0 mL / min; Column: XBridge C18, 4.6x50 mm, 3.5 pm; Column Temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), mass selective detector (MSD) (ES-API).

[0433] LC-MS measurements were run on an Agilent 1200 HPLC / 6100 SQ System using the following conditions:

[0434] Method A for LC-MS measurements included, as the Instrument: WATERS 2767; column: Shimadzu Shim-Pack, PRC-ODS, 20x250mm, 15 pm, two connected in series; Mobile Phase: A: Water (0.01% TFA), B: acetonitrile (0.01% TFA); Gradient Phase: 5% of B increased to 95% of B within 3 min; Flow Rate: 1.8 - 2.3 mL / min; Column: SunFire C18, 4.6x50 mm, 3.5 pm; Column Temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), ES-API.

[0435] Method B for LC-MS measurement included, as the Instrument: Gilson GX-281; column: Xbridge Prep C18 10 pm OBD, 19x250 mm; Mobile Phase: A: Water (10 mM NH4HCO3), B: Acetonitrile; Gradient Phase: 5% to 95% of B within 3 min; Flow Rate: 1.8 -2.3 mL / min; Column: XBridge C18, 4.6x50 mm, 3.5 pm; Column Temperature: 50 °C. Detectors: ADC ELSD, DAD (214 nm and 254 nm), MSD (ES-API).

[0436] Preparative high-pressure liquid chromatography (Prep-HPLC) in an acidic or basic solvent system was utilized on a Gilson GX-281 instrument. The acidic solvent system used a Waters SunFire 10 pm C18 column (100A, 250x19 mm), and solvent A for prep-HPLC was water / 0.05% TFA and solvent B was acetonitrile. The elution conditions were a linear gradient increase of solvent B from 5% to 100% over a time period of 20 min at a flow rate of 30 mL / min. The basic solvent system included a Waters Xbri...

Claims

1. An isolated antibody or antigen-binding fragment thereof that binds macrophagescavenger receptor 1 (MSR1), wherein the antibody or antigen-binding fragment comprises:(i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 52; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 54; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 56; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 64;(ii) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 12; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 14; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 16;(iii) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 36; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 38; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 40; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 46; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 48;(iv) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 100; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 102; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 104; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 108; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 110; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 112;(v) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 292; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 294; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 300; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 302; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 304.2019265703   18 Jun 20262.     The isolated antibody or antigen-binding fragment thereof of claim 1, wherein theantibody or antigen-binding fragment thereof comprises:(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2 and a light chain comprising the amino acid sequence of SEQ ID NO:10; or(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 34 and a light chain comprising the amino acid sequence of SEQ ID NO: 42; or(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 50 and a light chain comprising the amino acid sequence of SEQ ID NO: 58; or(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 98 and a light chain comprising the amino acid sequence of SEQ ID NO: 106; or(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 290 and a light chain comprising the amino acid sequence of SEQ ID NO: 298.

3. An antibody-drug conjugate comprising the antibody, or antigen-binding fragmentthereof, of claim 1 or claim 2 conjugated to a payload residue.

4. An antibody-drug conjugate comprising the antibody, or antigen-binding fragmentthereof, of claim 1 or claim 2 conjugated to a payload residue optionally through a linker or through a linker-spacer.

5. The antibody-drug conjugate of claim 3 or claim 4, having the structure of Formula (I):BAFormula (I)or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, a regioisomer thereof, or mixtures of regioisomers thereof;wherein:BA is a binding agent;L is a linker;PA is a payload moiety selected from the group consisting of a steroid residue, a LXR modulator residue, or a rifamycin analog residue; andsubscript n is an integer from 1 to 30.2019265703   18 Jun 20266.     The antibody-drug conjugate of any one of claims 3-5, having the structure of Formula(IA):BA RG1 S P1---AA1-----AA2----(QSP----PAn Formula (IA)whereinSP1 is absent, or a spacer;RG1 is a reactive group residue;AA1 is absent, or a divalent or trivalent linker comprising an amino acid residue which is optionally bonded directly or indirectly to a group HG;AA2 is absent, or a dipeptide, tripeptide, or tetrapeptide residue;Q, when present, is a connector group residue;SP is absent, or a spacer; andHG, when present, is a hydrophilic group.

7. The antibody-drug conjugate of any one of claims 3-6, having the structure ofFormula (IB-1):BA--RG1---SP1---(Q)o-1-----SP-----PAn Formula (IB-1)whereinSP1 is absent, or a spacer;RG1 is a reactive group residue;Q, when present, isSP is absent, or a spacer;wherein the x indicates the atoms through which the referenced group is bonded tothe adjacent groups in the formula.2019265703   18 Jun 20268.     The antibody-drug conjugate of any one of claims 3-6, having the structure of Formula(IB-2):BA--RG1--SP1---AA1----AA2----(Q)^SP----PAn Formula (IB-2)whereinSP1 is absent, or a spacer;RG1 is a reactive group residue;AA1 is absent, or a divalent or trivalent linker comprising an amino acid residue which is optionally bonded directly or indirectly to a group HG;AA2 is absent, or a dipeptide, tripeptide, or tetrapeptide residue;Q, when present, isSP is absent, or a spacer; andHG, when present, isN HHOOHHOHO,0OH"OHOH‘O'HOHOOHHOOH■"OHOHSO3H,orHOX / .S / / 00 \NN H,0wherein the      indicates the atoms through which the referenced group is bonded tothe adjacent groups in the formula.2019265703   18 Jun 20269.     The antibody-drug conjugate of any one of claims 3-6 and 8, having the structure of Formula (IC), Formula (ID), or Formula (IE): BA — -RG1 SP1 AA1-----AA2-----(0)0.,-----SP-----PA 1 2 RG2 1 n 1 , SP2 1 1 HG Formula (IC) BA — RG1 SP1 AA1----AA2----(Q)01----SP----PA 2 RG2 HG Formula (ID) BA — -RG1 SP1 AA1----AA2--------SP----PA HG Formula (IE)whereinSP1 is absent, or a spacer;RG1 is a reactive group residue;SP2 is absent, or a spacer;RG2 is a reactive group residue;AA1 is a divalent or trivalent linker comprising an amino acid residue;AA2 is a dipeptide, tripeptide, or tetrapeptide residue;Q, when present, isN HSP is absent, or a spacer; andHG is2019265703   18 Jun 2026HOOHHO,0OH"OHHO‘O'0H HOHOOHHO■"OHOHSO3H,orHOX / .S / / 0OH0,09' ^0 H\\0wherein the      indicates the atoms through which the referenced group is bonded tothe adjacent groups in the formula.

10. The antibody-drug conjugate of any one of claims 6, and 8-9, wherein AA1-AA2 is according to Formula (LL1):Raa1rAA3(LL1)wherein RAA1, RAA2, and RAA3 are each, independently, amino acid side chains, at leastone of which is bonded to -(RG2)-SP2-HG, -(RG2)-HG or HG; wherein theindicates the atoms through which AA1-AA2 is bonded to the adjacent groups in the formula.

11. The antibody-drug conjugate of claim 10, wherein RAA1 is a lysine, glutamine, glutamic acid or aspartic acid side chain bonded directly or indirectly to HG, and RAA2 and RAA3 are either valine and alanine or valine and citrulline sidechains respectively.2019265703   18 Jun 202612. The antibody-drug conjugate of any one of claims 6, and 8-11, wherein AA1-AA2 isorwherein theindicatesthe atoms through which AA1-AA2 is bonded to the adjacent groups in the formula.

13. The antibody-drug conjugate of any one of claims 6-12, wherein the RG1 and RG2 residues are independently, in each instance, selected from the group consisting of:, or2019265703   18 Jun 2026andwherein the      indicates the atom through which the RG1 or RG2 residue is bondedto the adjacent groups in the formula.

14. The antibody-drug conjugate of any one of claims 6-13, wherein SP, SP1 and SP2 are independently, in each instance, absent, or selected from the group consisting of C1-6 alkylene, -NH-, -S-, -O-, -C(O)-, (-CH2-CH2-O)e, -NH-CH2-CH2-(-O-CH2-CH2)e-C(O)-, -C(O)-(CH2)u-C(O)-, -C(O)-NH-(CH2)v-, (glycine)4-serine, and combinations thereof, wherein subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

15. The antibody-drug conjugate of any one of claims 5-14, wherein n is 1, 2, 3, or 4.

16. The antibody-drug conjugate of any one of claims 6-15, whereinSP1--AA1----AA2----(Q)^----sp—$ is5545555565572019265703   18 Jun 202617. The antibody-drug conjugate molecule of claim 3, wherein the antibody, or antigenbinding fragment thereof, is conjugated to a steroid payload through a linker or a linkerspacer.

18. The antibody-drug conjugate molecule of claim 3, wherein the antibody, or antigenbinding fragment thereof, is conjugated to a LXR modulator payload through a linker.

19. The antibody-drug conjugate molecule of claim 3, wherein the antibody, or antigenbinding fragment thereof, is conjugated to a rifamycin analog payload through a linker.

20. The antibody-drug conjugate molecule of claim 17, wherein the steroid conjugated to the antibody, or antigen-binding fragment thereof, through a linker or a linker-spacer is a compound of Formula (A-1)Formula (A-1)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof;whereinR1 and R2 are, independently, -H, alkyl, alkyl-C(O)-O-, -OH, or halo; or R1 andR40^0R2 together form         ,wherein R4 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl,wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are, independently in each instance, optionally substituted with -NRAaRAb;R3 is -O, RZ-C(O)-X-, -heteroalkyl, -piperidinyl, -NRAaRAb, -oxyaryl-NRAaRAb or-Z-A‘(RP)t;2019265703   18 Jun 2026RZ is alkyl;X is O or NRAa;Z is S, S(O), S(O)2, SO2NRAa, O, C(O)NRAa, C(O), or NRAa;A’ is aryl, arylalkyl, or heteroaryl;RP is, independently in each instance, halo, optionally substituted alkyl, -OH, or -NRAaRAb;RAa and RAb are, independently in each instance, -H, optionally substituted alkyl, or optionally subtitued aryl;subscript a is an integer from 0-19; andt is an integer from 1-3;andR5A and R5B are each, independently, halo or a hydrogen atom;wherein the group R3 or R4 is bonded to the linker.

21. The antibody-drug conjugate of claim 17, having the structure of Formula (3000):BA-(L‘-SP-D)n Formula (3000)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof;whereinD is selected fromFormula (a),where both Rx in Formula (a) are hydrogen; R34 is alkyl, aryl, arylalkyl, or an N-containingheterocycloalkyl; and SP is -C(O)-C1-C10-alkylene-C(O)-, -C(O)-N(C1-6alkyl)-C1-C10-alkylene-X1- where X1 is attached to L‘ in Formula (3000), -C(O)-N(H)-(C1-C10-alkylene)-S- where S is attached to L‘ in Formula (3000), -C(O)-N(C1-6alkyl)-(C1-Cw-alkylene)-S-where S is attached to L‘ in Formula (3000),where the point ofattachment on the right hand side (i.e. at N) is to L‘ in Formula (3000), -CH2-NH- where2019265703   18 Jun 2026the N is attached to L‘ in Formula (3000),where the N is attached to L‘in Formula (3000) and where Ar is optionally substituted arylene (in some embodiments) or optionally substituted heteroarylene, -(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- where NR50a is attached to L‘ in Formula (3000), -C(O)-(Ci-Cio-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- where NR50a is attached to L‘ in Formula (3000) and where each C1-C10-alkylene is independently optionally substituted with one or more hydroxy, -C(O)-N(R35)-C1-C10-alkylene-C(O)NH-X2- where X2 is attached to L‘ inFormula (3000), or                        where X4 is attached to L‘ in Formula(3000); orwhere both Rx in Formula (a) are fluoro; R34 is alkyl, aryl, arylalkyl, or an N-containing heterocycloalkyl; and SP is -C(O)-C1-C10-alkylene-C(O)-, -C(O)-N(C1-6alkyl)-C1-C10-alkylene-X1b- where X1b is attached to L‘ in Formula (3000), -C(O)-N(H)-(Ci-Cio-Oalkylene)-X1b- where X1b is attached to L‘ in Formula (3000),                where thepoint of attachment on the right hand side (i.e. at N) is to L‘ in Formula (3000), -CH2-NH-where the N is attached to L‘ in Formula (3000),   0           where the N is attachedto L‘ in Formula (3000) and where Ar is optionally substituted arylene (in someLXembodiments             ) or optionally substituted heteroarylene, -(Ci-Cio-alkylene)-NR50C(O)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L‘ in Formula (3000), -C(O)-(Ci-Cio-alkylene)-NR50C(O)-(Ci-Cio-alkylene)-NR50a- where NR50a is attached to L‘ in Formula (3000) and where each C1-C10-alkylene is independently optionallysubstituted with one or more hydroxy, -C(O)-N(R35)-(C1-C10-alkylene)-C(O)NH-X2- where2019265703   18 Jun 2026X2 is attached to L‘ in Formula (3000), or «                        where X4 is attachedto L‘ in Formula (3000); and / orb) the compounds in Table A, where the compounds in Table A are linked to BA of the Compound of Formula (III) through the hydroxy of the -C(O)CH2OH group, or through the hydroxy of Mapracorat;X1 is -N(C1-6alkyl)-;X1b is -S-, -NH-, or -N(C1-6alkyl)-;X2 is -NH-;X3 is -CH2-, X3 is -CH2-O-(C1-C10-alkylene)-C(O)- where the C(O) is attached to X4, or X3 is -C(O)-;X4 is -O-;R35 is H, -OH, -OCH3, or C1-6alkyl;R50 and R50a are independently hydrogen or C1-C6-alkyl;Rd, Re, and Rf are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH2ORg, where each Rg is independently -CH2C(O)OH or -CH2C(O)O(alkyl); andmm is 0 or 1;n is an integer selected from 1-30, inclusive;L‘ is a linker; andBA is a binding agent.

22. The antibody-drug conjugate of claim 17, wherein the steroid payload is selected from the group consisting of:5622019265703   18 Jun 20262019265703   18 Jun 2026F0o, andS’__________ wherein the * is the bond to the linker.2019265703   18 Jun 202623. The antibody-drug conjugate of claim 17, wherein the steroid payload is selected from the group consisting of:

24. The antibody-drug conjugate of claim 18, wherein the LXR modulator conjugated to the antibody, or antigen-binding fragment thereof, through a linker is a compound of Formula (B):Formula (B)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form, whereinW is -CH2-, -N(H)-, or -O-;RB1 is -H, -OH, -NH2, alkyl, or-OP(O)(OR6)2;RB2 is -H, -OH, -CH2NH2, RB3, RB4, RB5, or -O-RB5, wherein RB1 and RB2 are not simultaneously -H;RB3 is -N(R6)2;RB4 is -X-Y-Z;X is selected from the group consisting of -O- and -N(H)-;Y is selected from the group consisting of alkylene, substituted alkylene (including, without limitation, oxo substitution, i.e., =O)), heteroalkylene, and substituted heteroalkylene (including, without limitation, oxo substitution (i.e., =O));Z is selected from the group consisting of -OH and -NH2;RB5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl includes one, two, or three heteroatoms selected from nitrogen2019265703   18 Jun 2026and oxygen, and includes at least one -OH and -CH2OH substituent, or at least one primary or secondary nitrogen, for instance, O-glucose;each R6 is in each instance, -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; andeach R7 is, independently, halo, C1-6 alkyl, C1-6 alkoxy, -CN, O-glucose, O-amino acid residue, and O-PEGb, wherein each subscript b is an integer from 0-3;wherein the group RB1 or RB2 is bonded to the linker.

25. The antibody-drug conjugate of claim 18, wherein the LXR modulator conjugated to the antibody, or antigen-binding fragment thereof, through a linker is a compound of FormulaFormula (B-1)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof;wherein:RB1 is -N(H)R8 or -N(R9)2;RB2 is -N(H)R8;each R8 is, independently in each instance, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety, or alkyl;R9 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and when substituted includes at least one -OH and -CH2OH, or at least one primary or secondary nitrogen;each R7 is independently halo, C1-6 alkyl, C1-6 alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEGb, wherein each subscript b is an integer from 0-3;wherein the group RB1 or RB2 is bonded to the linker.2019265703   18 Jun 202626. The antibody-drug conjugate of any one of claims 3-16, 18, and 24-25, having the structure of Formula (6005)BA— RG1—SP1—AA1—AA2—RB127.rB2n Formula (6005)The antibody-drug conjugate of claim 18, wherein the LXR modulator is selected from the group consisting of:HO O, and NH2HO_wherein the * is the bond to the linker.2019265703   18 Jun 202628.The antibody-drug conjugate of claim 18, wherein the LXR modulator is selected from the group consisting of:P5B;P6B;568T) to 00P8B;569O I")P2B;2019265703   18 Jun 2026P11B; and>_____wherein the * is the bond to the linker.

29. The antibody-drug conjugate of claim 18, wherein the LXR modulator is>_____wherein the * is the bond to the linker.2019265703   18 Jun 202630. The antibody-drug conjugate of claim 19, wherein the rifamycin analog is a compound of Formula (C-1):.OR30Formula (C-1)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein:X1c is selected from -S-; -O- and -NR5c;R1c is amino-C1-6alkyl; C1-6alkylaminoC1-6alkyl; di-C1-6alkylaminoC1-6alkyl; hydroxy-C1-6alkyl; HS-C1-6alkyl; (R5c)2N-C1-6alkylene-N(R5c)-C1-6alkyl; (R5c)2N-C1-6alkylene-O-C1-6alkyl; (R5c)2N-C1-6alkylene-S-C1-6alkyl; heterocycloalkyl or heterocycloalkyl-C1-6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci—6alkyl, -OH, =O, or -N(R5c)2;R2c, R3c, and R4c are independently selected from hydrogen, C1-6alkyl, and -(C=O)-R5c; each Rac, when present, is independently selected from -F; -Cl; -Br; -I; -OH; -NH2; and C1-6alkoxy; andR5c is independently, at each occurrence, selected from hydrogen; and C1-6alkyl; wherein the group R1c is bonded to the linker.2019265703   18 Jun 202631. The antibody-drug conjugate of claim 19, wherein the rifamycin analog is a compound of Formula (C-2):,or3cFormula (C-2)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein:X1c is selected from -S-; -O- and -NR5c;R1c is amino-C1-6alkyl; C1-6alkylaminoC1-6alkyl; di-C1-6alkylaminoC1-6alkyl; hydroxy-C1-6alkyl; HS-C1-6alkyl; (R5c)2N-C1-6alkylene-N(R5c)-C1-6alkyl; (R5c)2N-C1-6alkylene-O-C1-6alkyl;(R5c)2N-C1-6alkylene-S-C1-6alkyl; heterocycloalkyl or heterocycloalkyl-C1-6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, C1-6alkyl, -OH, =O, or -N(R5c)2;R2c, R3c, and R4c are independently selected from hydrogen, C1-6alkyl, and -(C=O)-R5c;Racand Rbc are independently selected from -F; -Cl; -Br; -I; -OH; -NH2; and C1-6alkoxy; and R5c is independently, at each occurrence, selected from hydrogen; and C1-6alkyl;wherein the group R1c is bonded to the linker.2019265703   18 Jun 202632. The antibody-drug conjugate of claim 19, wherein the rifamycin analog is a compound ofFormula (C-3):Formula (C-3)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein:R1c is di-C1-6alkylaminoC1-6alkyl; (R5c)2N-C1-6alkylene-N(R5c)-C1-6alkyl; heterocycloalkyl or heterocycloalkyl-C1-6alkyl; wherein heterocycloalkyl includes one, two, or three heteroatoms selected from O, N, and S; and wherein heterocyloalkyl is optionally substituted with halo, Ci-6alkyl, -OH, =O, or -N(R5c)2; andR2c, R3c, and R4c are independently selected from hydrogen, C1-6alkyl, and -(C=O)-R5c; andR5c is selected from hydrogen and C1-6alkyl; wherein the group R1c is bonded to the linker.33.The antibody-drug conjugate of claim 19, wherein the rifamycin analog is a compound ofFormula (C-4):Formula (C-4)or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; wherein:2019265703   18 Jun 2026R'< X3 . R5< X3 _     .I                          Y S'                 / Y (CH2)2.6—>o1 . X W" \ Yf * u KlR1c is     -           r ,            1-3     ; or           1-3                ; wherein y is C or N;R2c, R3c, and R4c are independently selected from hydrogen, C1-6alkyl, and -(C=O)-R5c; andR5c is independently, at each occurrence, absent, or selected from hydrogen and C1-6alkyl; wherein the group R1c is bonded to the linker via a nitrogen atom as indicated by the wavy line         .

34. The antibody-drug conjugate of any one of claims 3-6, 8, 12-16, 19 and 30-33, having the structure of Formula (7002):BA--RG1--SPl--AA1---AA2--NH35.Formula (7002).The antibody-drug conjugate of any one of claims 3-6, 8, 12-16, 19 and 30-34, wherein the rifamycin analog is selected from the group consisting of:2019265703   18 Jun 20262019265703   18 Jun 2026, and_wherein the * is the bond to the linker.

36. An antibody drug conjugate which is an antibody-rifamycin analog conjugate having the structure of Formula (7003):BA--RG1--SP1--(AA)W---NHor a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof;wherein:X1c is selected from -S-; -O- and -NR5c;2019265703   18 Jun 2026R1c isor; wherein Y is C or N;R2c, R3c, and R4c are independently selected from hydrogen, C1-6alkyl, and -(C=O)-R5c;R5c is independently, at each occurrence, absent, or selected from hydrogen; and C1-6alkyl;each AA is an independently selected amino acid;SP1 is absent, or a spacer;RG1 is a reactive group residue;BA is the anti-MSR1 antibody or antigen binding fragment thereof of claim 1 or claim 2;subscript n is an integer from 1 to 30;subscript w is 2, 3, or 4;wherein R1c is bonded to the linker via a nitrogen atom as indicated by the wavy line      .37.38.39.40.41.42.43.44.The antibody-drug conjugate of claim 36, wherein X1c is O.The antibody-drug conjugate of claim 36 or claim 37, wherein BA comprises an N297Q mutation.The antibody-drug conjugate of any one of claims 36-38, wherein subscript w is 2.The antibody-drug conjugate of any one of claims 36-39, wherein (AA)2 is valinecitrulline.The antibody-drug conjugate of any one of claims 36-40, wherein SP1 comprisesThe antibody-drug conjugate of any one of claims 36-40, wherein SP1 comprisesThe antibody-drug conjugate of any one of claims 36-42, wherein RG1 comprisesThe antibody-drug conjugate of any one of claims 36-42, whereinX1c is O;2019265703   18 Jun 20261-3                                / \1-3r5c       R5<+ / H, ,    R\+Z\          ,I              / N    Y— £-    , / N Y (CH2)2.6—<Xr6^Y s Vr6<?MR1c is      r6c      ^,           1-3     ; or          13               ; wherein Y is C or N;wherein R1c is bonded to the linker via the quarternary nitrogen atom of R1c;R5c is C1-6alkyl; andR6c is a counter ion.

45. The antibody-drug conjugate of any one of claims 36-44, wherein the rifamycin analog is:,,.,0 MeOAc*\0H'ch3,,,0 MeOAc.<»0H^CH:CH3 h3c^OHh3cHO,%CH3^ h3c;OHH3CH0 / „or2019265703   18 Jun 202646. The antibody-drug conjugate of any one of claims 3-19, selected from the group consisting of:580L / l 005825835845852019265703   18 Jun 2026a mixture thereof;n orNH °^NH2or a stereoisomer or mixture of stereoisomers thereof;a mixture thereof;2019265703   18 Jun 2026or a stereoisomer or mixture of stereoisomers thereof;or a stereoisomer or mixture of stereoisomers thereof;2019265703   18 Jun 2026OHHOor a mixture thereof2019265703   18 Jun 2026or a mixture thereofor a stereoisomer or mixture of stereoisomers thereofor a mixture thereof2019265703   18 Jun 2026or a mixture thereofor a mixture thereof2019265703   18 Jun 2026or a mixture thereof2019265703   18 Jun 2026or a mixture thereof2019265703   18 Jun 2026or a mixture thereof2019265703   18 Jun 2026or a mixture thereof5955965975985996006026032019265703   18 Jun 2026or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, whereineach Ab is an anti-MSR1 antibody, or an antigen binding fragment thereof;each BA is                     n where Ab1 is an anti-MSR1 antibody, or an antigenbinding fragnment thereof; R is C2-4-alkylene; and nn is an integer selected from 2 to 4, inclusive. andeach n is an integer from 1 to 4.2019265703   18 Jun 202647. An antibody-drug conjugate of any one of claims 3-5 and 19, according to Formula (7004):Formula (7004).

48. An antibody drug conjugate prepared by conjugating the anti-MSR1 antibody of claim 1or claim 2, optionally wherein the anti-MSR1 antibody is PEG-modified,or an antigen binding fragment thereof, with a linker payload, or a stereoisomeric form thereof, or a regioisomer thereof, or a mixture of regioisomers thereof, selected from the group consisting of:6062019265703   18 Jun 2026LP4LP11LP9LP12LP36086092g KJ —h 2b 2a LP15 — -- Oxyb °^ / b z —L O I i Z-W zO\ / 0 \ '1 WV-z 7 ( ° b ^0 / ° \ CM bo \ ZI IZ IZ / 0 0 IZ    Z o / =O o TZ / \ °=( \ 0 o O=^^\ o ZI Il / / \ 0 ZT / =° o o IZ   IZ O   __ / >o Ox 0 ( o \ Z^ O o \ 5 Q °4 / I              )__, > \ ZT < / > >O r \\ bo 0 -r / ---'    ?=O IZ    / / Izu >° IZ , ob \ 0=0 0 / oz xo ob ZI )—-\        ZT / ° ZI °= / o b O \ / "7 o r - / >o zzbb   >0 I NJ IZ o °v o V / — / bo I1 b / —7x OO \__ / X 00 / / \ / " zx Vrz iz / Vo \OQl b J          0 °\ )=° bl oOJ / >° o7 / IZ / ) J o         / 9        o= / ob ° / ( v \ V1 \ O^o-^ \ N. ° J / ~O \   1 AV 7 Oo1 ; ao 0*0 \ / osu -.- ^ / \   / 7 K / —-S, 1 >° vO / -^ / V x IZ       cf     -n b \ ) °^0 o oz 0, Oh6102m ro K) 7T ±? H H H / —\ 9      H JYh J fYoACN7°a° OH M-      S I H S S H n >          N NH2 1                       H HN^O          H0 “it. OH H HHr-x o-Vya _      ?   .   N O               o   H o ^y^0^N^NY     OH / —-vXo'^N^^                              ° / y h                       h o \ h y NH O^NH2 Y-^z. o \ o / \ ZI >"'Vo IZ O= /  '--K o ZI  z^ p ■ J o M z — X O           / o=\o \ \ X p i     X / o^y \ c / 7-' y~\ )1 cr z —y / o / =° X o ^'"yo 1 s y >° IZ ZI °-> IZ >° o 1  o=\ o      / - °x^\ F \ / 'Y^"^ > T i jy-o J T^i±2019265703   18 Jun 20262n H H o Y h 9 hY'^nYn^n^V     0 n3^ A h o k h N^O        A O H             I A N NH2 H or a mixture thereof 2q h H4AAV0 yY , o                    0 \ T yY A   °Yh I   -ijv y N       --N           O 0          H O  \ o nAh2 H . LP1A F H HH- f) °            0 V h 0 PPoAYNYO'^ooh ANyA^N-A / Ox / xo / xj)^o,~J<N.YANA      0 O 0 H              Y 1 H kNH cAnh2 LP2A F H HH- if}   0              o Y H 0 fY^O^'N^Y0'0^^^ O o    H                    H    1 H kNH cAnh2 LP3A YY                                                   / H HH,—x ZA                             -- \ pAAA y / ? o                       o ^^YAtOYA0 / : 'N ' / A N'' --O                  A N 9 AY0 N ^ 'I0   0 OH U o H o / .MjyY - 0 kNH OA'NH2LP4A2019265703   18 Jun 2026LP5ALP6ALP7ALP8ALP9A2019265703   18 Jun 2026LP10ALP11ALP12ALP13ALP18ALP19A2019265703   18 Jun 2026LP20ALP21ALP22 ALP23 ALP24 ALP25 A2019265703   18 Jun 2026LP26 ALP27 AOHLP28 ALP29 ALP30 A2019265703   18 Jun 2026LP31 ALP1BLP2B2019265703   18 Jun 2026LP3BLP4BLP5BLP6BLP7B2019265703   18 Jun 2026LP8BLP9BLP10 BLP11 BLP12 BR20OHand2019265703   18 Jun 202649. An antibody-drug conjugate of claim 3, prepared by contacting an anti-MSR1 antibody or a PEG-modified anti-MSR1 antibody, or antigen-binding fragment thereof, with a linker payload, or a stereoisomeric form thereof, or a regioisomer thereof, according to Formula (D):Formula (D).under conditions suitable for forming a bond between anti-MSR1 antibody, or antigenbinding fragment thereof.

50. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 2, and a pharmaceutically acceptable carrier.

51. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 3 to 49, and a pharmaceutically acceptable carrier.

52. Use of an effective treatment amount of an antibody-drug conjugate of any one of claims 1-18, 20-29, and 46, or a pharmaceutical composition of any one of claims 50-51, for treating a proliferative disease, a metabolic disease, inflammation, a neurodegenerative disease, or disease, disorder, or condition associated with glucocorticoid receptor signaling, in a subject.

53. The use of claim 52, wherein the use is for treating atherosclerosis.2019265703   18 Jun 202654. The use of claim 52, wherein the disease, disorder, or condition associated with glucocorticoid receptor signaling is an inflammatory disease, disorder, or condition.

55. The use of claim 52, wherein the use is for treating arthritis.

56. The use of claim 52, wherein side effects associated with administration of theunconjugated steroid payload of said compound are reduced.

57. The use of claim 52, wherein the metabolic disease is dyslipidemia.

58. Use of an effective treatment amount of an antibody-drug conjugate of any one of claims1-16, 19, 30-45, and 47, or a pharmaceutical composition of any one of claims 50-51 for preventing or treating bacterial infection in a subject comprising administering to the subject.

59. The use of claim 58, wherein the bacterium is a gram positive bacterium, pencillin-resistant bacterium Staphylococcus aureus, methiciliin resistant Staphylococcus aureus (MRSA), methicillin susceptible Staphylococcus aureus (MSSA), or vancomycin-resistant Staphylococcus aureus (VRSA), or multi-drug resistant Mycobacterium tuberculosis.

60. The use of claim 58, wherein the antibody-drug conjugate of any one of claims 1-16, 19, 30-45, and 47, or a pharmaceutical composition of any one of claims 50-51, is administered in combination with vancomycin.

61. Use of an effective treatment amount of an antibody-drug conjugate of any one of claims 6-16, 19, 30-45, and 47,or a pharmaceutical composition of any one of claims 50-51 for preventing or treating cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, septicemia, toxic shock syndrome, septic arthritis, mastitis, infection associated with a prosthetic joint, infection associated with a catheter, or infection associated with an implant, in a subject comprising administering to the subject.

62. Use of any one of claims 6-16, 19, 30-45, and 47, or a pharmaceutical composition of any one of claims 50-51 for preventing or treating an intracellular bacterial infection in a subject comprising administering to the subject an effective treatment amount of an antibody-drug conjugate.

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