Anti-MSR1 antibody and method of use thereof

Abstract

An antibody and an antigen-binding fragment that bind to MSR1 and a method of using the same are provided herein. According to specific embodiments, the antibody binds to human MSR1 with high affinity. In specific embodiments, the antibody binds to MSR1 while not blocking modified LDL binding to MSR1 or blocking less than 90% of it. In some embodiments, the antibody binds to MSR1 expressed on the cell surface and is internalized. The antibody of the present invention may be a complete human antibody. The present invention comprises an anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to a drug or therapeutic compound.

Description

Technology Field

[0001] This application claims priority to U.S. Provisional Patent No. 62 / 669,276, filed May 9, 2018; U.S. Provisional Patent No. 62 / 678,200, filed May 30, 2018; U.S. Provisional Patent No. 62 / 769,946, filed November 20, 2018; U.S. Provisional Patent No. 62 / 789,987, filed January 8, 2019; and U.S. Provisional Patent No. 62 / 821,362, filed March 20, 2019, the full text of which is incorporated herein by reference for all purposes.

[0002] Field of invention

[0003] The present invention relates to an antibody that specifically binds to a trimeric membrane glycoprotein receptor (MSR1) to regulate MSR1 signal transduction, as well as its antigen-binding fragment and an antibody-drug conjugate of such antibody, and a method of using the same.

[0004] Sequence list

[0005] An official copy of the sequence list is submitted via EFS-Web simultaneously with this specification as a paper copy of an ASCII-formatted sequence list with the filename 114581.00244_ST25.TXT, having a creation date of May 30, 2018, and a size of approximately 165 kilobytes. The sequence list contained in this paper copy of the ASCII-formatted document is part of the specification, and the full text thereof is incorporated herein by reference. Background Technology

[0006] Macrophage scavenger receptor 1 (MSR1) is a single-pass, trimeric type II transmembrane glycoprotein pattern recognition receptor that mediates the uptake of a series of negatively charged / multivalent anionic ligands, e.g., modified low-density lipoprotein (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) (Smedsrød et al. 1997. Biochem J. 322(Pt 2):567-573). MSR1 receptors have been implicated in many macrophage-related physiological and pathological processes, e.g., atherosclerosis, Alzheimer's disease, and host defense.

[0007] MSR1 expression was originally considered to be macrophage-specific. However, it has recently been demonstrated that it exists on different classes of dendritic cells (Herber et al. 2010). Nat. Med. 16(8): 880-886). Additionally, MSR1 is thought to be expressed in endothelial cells and smooth muscle cells. It is internalized through coated pits on the cell surface and releases its ligand at acidic pH before being recirculated back from the trans-Golgi apparatus to the cell surface (Doi et al. 1994. Journal of Biological Chemistry ; Mori, T. 1994. Lab Invest. This promotes the conversion of monocyte-derived macrophages into foam cells, which is an important step in the progression of atherosclerosis.

[0008] MSR1 isoforms type 1 and type 2 are functional receptors capable of mediating the endocytosis of modified low-density lipoprotein (LDL). MSR1 isoform type 3 can bind to modified LDL (acetyl-LDL) but appears unable to internalize the bound complex. However, MSR1 also binds to a wide variety of ligands other than modified LDL. These ligands include beta-amyloid proteins, molecular chaperons, extracellular matrix proteins, advanced glycosylated terminal products, apoptotic cells, and activated B cells.

[0009] The liver X receptor (LXR) comprises LXRα and LXRβ, ligand-dependent transcription factors that control the expression of genes related to cholesterol, lipid and glucose homeostasis, inflammation, and intrinsic immunity. LXRα is highly expressed in the liver, intestine, adipose tissue, and differentiated macrophages; LXRβ is ubiquitously expressed. LXR possesses various biological functions, for example, (i) stimulating the expression of cholesterol transporters, such as ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux; and (ii) negatively regulating the expression of macrophage inflammatory genes through the inhibition of NF-kB activation. LXR has also been implicated in atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation. Proliferative disorders include melanoma, 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). et al . 2011; Huang et al . 2015; Cui et al . 2012). Macrophage LXR is known to possess anti-atherogenic activity. LXR agonists are believed to be able to (i) inhibit the initiation of atherosclerosis and delay its progression; (ii) alleviate atherosclerosis and stabilize established atherosclerotic lesions; and (iii) reduce lesional macrophages through apoptosis. The problem to be solved

[0010] The therapeutic efficacy of small molecule LXR modulators is limited, for example, by undesirable modulation of LXR in non-target cells and / or low bioavailability. Modulation of LXR in non-target cells can lead to undesirable side effects, and low bioavailability can manifest for countless reasons, including low solubility, which further exacerbate a poor therapeutic window for treatment. The development of ADCs containing LXR modulators can avoid side effects caused by off-target modulation of LXR by allowing target-specific modulation of LXR. Furthermore, such ADCs can provide improved modulation of biological targets, improved bioavailability, and an improved therapeutic window. Therefore, there is a continuing demand for the effective treatment of metabolic diseases, for example, using antibody-drug conjugates of LXR modulators.

[0011] Glucocorticoids (GCs) are small molecule steroids that bind to glucocorticoid receptors (GRs) and are widely used in anti-inflammatory and immunosuppressive therapies. However, due to the ubiquitous expression of glucocorticoid receptors in many cell types, glucocorticoid therapy is counterproductive to toxicity in most organ systems. Therefore, there is a need for novel glucocorticoids as well as new therapeutic regimens that minimize side effects resulting from glucocorticoid administration, particularly those caused by the activation of glucocorticoid receptors in non-target cells.

[0012] Rifamycin forms a subclass of the ansamicin antibiotic family with an active spectrum against Gram-positive and Gram-negative bacteria and is an antimycobacterial drug commonly prescribed for the treatment of tuberculosis, leprosy, and / or Mycobacterium avium complex (MAC). The rifamycin group of antibiotics "Traditional" rifamycin drug In addition, it includes rifamycin derivatives, e.g., rifampicin (or rifampin), rifabutin, rifapentine, rifalazil, and rifaximin. In particular, antibiotic-resistant strains of bacteria (e.g., methicillin-resistant S. aureus ( S. aureus )(MRSA), vancomycin-resistant S. aureus (VRSA)), multi-drug resistant M. tuberculousis ( M. tuberculosisThe increasing emergence of antibiotic-resistant strains is an ongoing problem. More effective analogs of rifamycin are required. Rifamycin is an intermediate to potent inducer of cytochrome P450 (particularly CYP3A4), which can induce reduced bioavailability and enhanced clearance of some co-administered drugs that undergo metabolism by the cytochrome P450 enzyme system (particularly CYP3A4). While these interactions may be delayed at the onset, they can persist beyond the co-administration of rifamycin. Rifamycin can also induce P-glycoprotein (P-gp) multidrug efflux transporters. Novel therapeutic regimens are required to minimize adverse effects induced by the administration of rifamycin, particularly those resulting from the activation of the cytochrome P450 enzyme system.

[0013] As disclosed in the present application, MSR antibodies can minimize unwanted side effects resulting from systemic administration of these compounds by providing means for specific targeting of therapeutic molecules, e.g., LXR agonists, steroids, and rifamycin. means of solving the problem

[0014] summation

[0015] An antibody that binds to a membrane glycoprotein receptor known as MSR1, an antigen-binding fragment of the antibody, and an antibody-drug conjugate thereof are provided herein. The antibody is particularly useful for targeting cells expressing MSR1, e.g., macrophages. The anti-MSR1 antibody and its antigen-binding site may be used alone in an unmodified form or may be included as part of an antibody-drug conjugate.

[0016] The antibodies disclosed herein may be full-length (e.g., IgG1 or IgG4 antibodies) or may contain only an antigen-binding site (e.g., Fab, F(ab')2 or scFv fragment) and may be modified to affect functionality, for example, by removing residual effector function (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[0017] Embodiments of the anti-MSR1 antibody disclosed herein are listed in Tables 4 and 5. Table 4 shows the amino acid sequence identifiers of the heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain complementarity determining region (HCDR1, HCDR2, and HCDR3), and light chain complementarity determining region (LCDR1, LCDR2, and LCDR3) of the exemplary anti-MSR1 antibody. Table 5 shows the nucleic acid sequence identifiers of the HCVR, LCVR, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of the exemplary anti-MSR1 antibody.

[0018] An antibody or its antigen-binding fragment that specifically binds to MSR1 is provided herein, comprising an HCVR comprising an amino acid sequence selected from any HCVR amino acid sequence shown in Table 4, or an HCVR comprising an amino acid sequence selected from a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0019] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising an LCVR comprising an amino acid sequence selected from any LCVR amino acid sequence shown 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 with respect thereto.

[0020] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising an HCVR and LCVR amino acid sequence pair (HCVR / LCVR) comprising any HCVR amino acid sequence shown in Table 4 paired with any LCVR amino acid sequence shown in Table 4. Specific embodiments relate to an antibody or its antigen-binding fragment comprising an HCVR / LCVR amino acid sequence contained within any exemplary anti-MSR1 antibody 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.

[0021] An antibody or its antigen-binding fragment that specifically binds to MSR1 is provided herein, comprising a heavy chain CDR1 (HCDR1) comprising any HCDR1 amino acid sequence shown in Table 4 or an amino acid sequence selected from a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0022] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising a heavy chain CDR2 (HCDR2) comprising an amino acid sequence selected from any HCDR2 amino acid sequence shown in Table 4 or an amino acid sequence selected from a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0023] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising a heavy chain CDR3 (HCDR3) comprising an amino acid sequence selected from any HCDR3 amino acid sequence shown in Table 4 or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0024] An antibody or its antigen-binding fragment that specifically binds to MSR1 is provided herein, comprising a light chain CDR1 (LCDR1) comprising any LCDR1 amino acid sequence shown 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.

[0025] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising a light chain CDR2 (LCDR2) comprising any LCDR2 amino acid sequence shown 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.

[0026] Also provided herein is an antibody or its antigen-binding fragment that specifically binds to MSR1, comprising a light chain CDR3 (LCDR3) comprising any LCDR3 amino acid sequence shown 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.

[0027] Also provided herein is an antibody or an antigen-binding fragment thereof that specifically binds to MSR1, comprising an HCDR3 and LCDR3 amino acid sequence pair (HCDR3 / LCDR3) comprising any HCDR3 amino acid sequence shown in Table 4 paired with any LCDR3 amino acid sequence shown in Table 4. Certain embodiments relate to an antibody or an antigen-binding fragment thereof comprising an HCDR3 / LCDR3 amino acid sequence pair contained within any exemplary anti-MSR1 antibody shown 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.

[0028] An antibody or an antigen-binding fragment thereof that specifically binds to MSR1, comprising a set of six CDRs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) contained within any exemplary anti-MSR1 antibody shown in Table 4, is provided herein. In a specific embodiment, the set of amino acid sequences of HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 is selected from the group consisting of 4-6-8-12-14-16; 36-38-40-44-46-48; 52-54-56-60-62-64; 100-102-104-108-110-112, and 292-294-296-300-302-304.

[0029] In a related embodiment, an antibody that specifically binds to MSR1, or an antigen-binding fragment thereof, is provided herein, 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 exemplary anti-MSR1 antibody shown in Table 4. For example, the present invention comprises an antibody that specifically binds to MSR1 or an antigen-binding fragment thereof, comprising a set of amino acid sequences, HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3, 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 HCVR and / or LCVR amino acid sequences specified herein. Exemplary conventions that can be used to identify the boundaries of CDRs include, for example, 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 structural loop regions, and the AbM definition is a compromise between the Kabat and Chothia approaches. For example, 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 See 86:9268-9272 (1989). Public databases are also available to identify CDR sequences within antibodies.

[0030] Additionally, a nucleic acid molecule encoding an anti-MSR1 antibody or a site thereof is provided herein. For example, a nucleic acid molecule encoding any HCVR amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any HCVR nucleic acid sequence shown 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 with respect thereto.

[0031] Additionally, a nucleic acid molecule encoding any LCVR amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any LCVR nucleic acid sequence shown in Table 5, or a polynucleotide sequence selected from a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect to the same.

[0032] Additionally, a nucleic acid molecule encoding any HCDR1 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any HCDR1 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0033] Additionally, a nucleic acid molecule encoding any HCDR2 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any HCDR2 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0034] Additionally, a nucleic acid sequence encoding any HCDR3 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any HCDR3 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0035] Additionally, a nucleic acid molecule encoding any LCDR1 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any LCDR1 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0036] Additionally, a nucleic acid molecule encoding any LCDR2 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any LCDR2 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0037] Additionally, a nucleic acid molecule encoding any LCDR3 amino acid sequence shown in Table 4 is provided herein; in a specific embodiment, the nucleic acid molecule comprises a polynucleotide sequence selected from any LCDR3 nucleic acid sequence shown in Table 5, or a substantially similar sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with respect thereto.

[0038] Also provided herein is a nucleic acid molecule encoding HCVR, wherein HCVR comprises a set of three CDRs (i.e., HCDR1-HCDR2-HCDR3), wherein the set of amino acid sequences of HCDR1-HCDR2-HCDR3 is defined as any exemplary anti-MSR1 antibody shown in Table 4.

[0039] Additionally, a nucleic acid molecule encoding LCVR is provided herein, wherein LCVR comprises a set of three CDRs (i.e., LCDR1-LCDR2-LCDR3), wherein the set of LCDR1-LCDR2-LCDR3 amino acid sequences is defined as any exemplary anti-MSR1 antibody shown in Table 4.

[0040] Additionally, a nucleic acid molecule encoding both HCVR and LCVR is provided herein, wherein HCVR comprises an amino acid sequence of any HCVR amino acid sequence shown in Table 4, and LCVR comprises an amino acid sequence of any LCVR amino acid sequence shown in Table 4. In certain embodiments, the nucleic acid molecule comprises a polynucleotide sequence selected from any HCVR nucleic acid sequence shown 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 therewith, and any LCVR nucleic acid sequence shown in Table 5, or a polynucleotide sequence selected from a substantially similar sequence thereof having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity therewith. In certain embodiments, according to this aspect of the invention, the nucleic acid molecule encodes HCVR and LCVR, wherein both HCVR and LCVR are derived from the same anti-MSR1 antibody shown in Table 4.

[0041] Additionally, recombinant expression vectors capable of expressing polypeptides comprising a heavy or light chain variable region of an anti-MSR1 antibody are provided herein. For example, embodiments include recombinant expression vectors comprising any of the aforementioned nucleic acid molecules, namely, recombinant expression vectors comprising nucleic acid molecules encoding any HCVR, LCVR, and / or CDR sequences shown 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 for producing antibodies or regions thereof by culturing the host cells under conditions that allow for the production of antibodies or antibody fragments, and by recovering the antibodies and antibody fragments thus produced.

[0042] Anti-MSR1 antibodies having a modified glycosylation pattern are provided herein. In some embodiments, modifications to remove undesirable glycosylation sites may be useful, for example, for increasing antibody-dependent cytotoxicity (ADCC) function (Ref. Shield et al. (2002) JBC 277:26733). In some embodiments, modifications to provide antibodies lacking fucose moiety present on oligosaccharide chains may be useful, for example, for increasing antibody-dependent cytotoxicity (ADCC) function. In other applications, modifications to glycosylation may be made to modify complement-dependent cytotoxicity (CDC).

[0043] In another aspect, a pharmaceutical composition comprising a recombinant human antibody or a fragment thereof that specifically binds to MSR1 and a pharmaceutically acceptable carrier is provided herein. In a related aspect, the embodiment relates to a composition that is a combination of an anti-MSR1 antibody and a second therapeutic agent. In one embodiment, the second therapeutic agent is any formulation that is advantageously combined with the anti-MSR1 antibody. An antibody-drug conjugate (ADC) comprising an anti-MSR1 antibody conjugated to a drug or therapeutic agent is also provided herein. Exemplary combination therapies, co-formulations, and ADCs comprising an anti-MSR1 antibody are disclosed somewhere in this invention.

[0044] Also provided herein are antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody conjugated to a drug or therapeutic agent, or an MSR1 antigen-binding fragment thereof. Also provided herein are reactive linker-payloads useful for manufacturing ADCs. Also provided herein are modified anti-MSR1 antibodies and modified MSR1 antigen-binding fragments useful for manufacturing ADCs.

[0045] Additionally, a therapeutic method is provided herein comprising administering an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody comprising an antigen-binding site of an MSR1 antibody, or an anti-MSR1 antibody comprising an MSR1 antigen-binding fragment thereof to a subject in need thereof. The therapeutic method comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody comprising an antigen-binding site of an MSR1 antibody, or an anti-MSR1 antibody comprising an MSR1 antigen-binding fragment thereof. The disorder treated is any disease or condition that is improved, alleviated, suppressed, or prevented by targeting MSR1. In some embodiments, the disease or condition is a proliferative disease, a metabolic disease, an inflammation, a neurodegenerative disease, or a disease, disorder, or condition related to glucocorticoid receptor signaling. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, the disease, disorder, or condition related to glucocorticoid receptor signaling is an inflammatory disease, disorder, or condition. In some of these embodiments, adverse effects associated with the administration of an unconjugated steroid payload of the compound are reduced. Additionally, a therapeutic method is provided herein for the treatment and / or prevention of bacterial infection in a subject, comprising the administration of an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody of the antigen-binding site of an MSR1 antibody, or an anti-MSR1 antigen-binding fragment thereof.

[0046] The use of an ADC comprising an anti-MSR1 antibody, an antigen-binding site of an MSR1 antibody, or an MSR1 antigen-binding fragment thereof, described herein for the treatment of any disease, disorder, or condition described herein is provided herein.

[0047] Also provided herein is a method for treating, attenuating, or alleviating atherosclerosis, comprising administering to a subject in need an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody comprising an antigen-binding site of an MSR1 antibody, or an anti-MSR1 antibody comprising an MSR1 antigen-binding fragment thereof. The therapeutic method comprises administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody comprising an antigen-binding site of an MSR1 antibody, or an anti-MSR1 antibody comprising an MSR1 antigen-binding fragment thereof.

[0048] Other embodiments will become apparent from a review of the following detailed description. Brief explanation of the drawing

[0049] Fig. 1 silver P1 and P2B Provides a reaction equation for the synthesis of. Fig. 2 Is LP1 Provides a reaction equation for the synthesis of. Fig. 3 silver LP2 Provides a reaction equation for the synthesis of. Fig. 4 Is LP5 Provides a reaction equation for the synthesis of. Fig. 5 Is LP6 Provides a reaction equation for the synthesis of. Fig. 6 silver LP18 Provides a reaction equation for the synthesis of. Fig. 7 silver LP4 Provides a reaction equation for the synthesis of. Fig. 8 silver LP11 Provides a reaction equation for the synthesis of. Fig. 9 Is LP9 Provides a reaction equation for the synthesis of. Fig. 10 silver LP12 Provides a reaction equation for the synthesis of. Fig. 11 silver P3 and P4 Provides a reaction equation for the synthesis of. Fig. 12 Is LP3 Provides a reaction equation for the synthesis of. Fig. 13 silver LP13 Provides a reaction equation for the synthesis of. Fig. 14 Is LP14 Provides a reaction equation for the synthesis of. Fig. 15 Is LP15 Provides a reaction equation for the synthesis of. Fig. 16 It provides a reaction scheme for the synthesis of antibody-drug conjugates (ADCs). Fig. 17 is a line graph showing the dose-dependent cholesterol efflux percentage within THP-1 macrophages for an exemplary MSR1 antibody-LXR conjugate, its unconjugated counterpart, a homologous control-steroid conjugate, and the corresponding free payload. Fig. 18 The present invention provides a series of bar graphs showing the effects of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on serum lipid levels in a mouse model of atherosclerosis. Fig. 19 The provides a series of bar graphs showing the effects of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on lesion lipid sites and macrophage (CD68) contents in a mouse model of atherosclerosis. Fig. 20 The present invention provides a series of bar graphs showing the effects of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on liver triglyceride and cholesterol levels in a mouse model of atherosclerosis. Fig. 21 The present invention provides a series of bar graphs showing the effects of an exemplary MSR1 antibody-LXR agonist conjugate and its unconjugated counterpart on de novo lipogenesis in a mouse model of atherosclerosis. Fig. 22 The provides reaction schemes for the synthesis of budesonide-spacers containing reactive groups, suc-acids (compound of 1c), carbamate analogs (1d, 1e), THP analogs (1g and 1h), glucose analogs (1i and 1j), phosphate analogs (1k and 1l), and commercially available phosphate analogs (1m). Fig. 23silver payload, compound, and bis-octahydrophenanthrene carboxamide P3B-P9B Provides a reaction equation for the synthesis of. Fig. 24 is a payload, a compound, and bis-octahydrophenanthrene carboxamide P10B-P11B Provides a reaction equation for the synthesis of. Fig. 25 is the linker and linker payload LP1B-LP5B Provides a reaction equation for the synthesis of. Fig. 26 linker and linker payload LP6B Provides a reaction equation for the synthesis of. Fig. 27 linker and linker payload LP7B Provides a reaction equation for the synthesis of. Fig. 28 linker and linker payload LP8B Provides a reaction equation for the synthesis of. Fig. 29 is the linker and linker payload LP9B Provides a reaction equation for the synthesis of. Fig. 30 linker and linker payload LP10B , and LP11B Provides a reaction equation for the synthesis of. Fig. 31 silver payload 12B , linker and linker payload LP12B Provides a reaction equation for the synthesis of. Fig. 32 is cyclodextrin-azide 105a Provides a reaction equation for the synthesis of. Fig. 33 It is azido-PEG4-taurine 105b Provides a reaction equation for the synthesis of. Fig. 34 is Maltos-Azid 105c Provides a reaction equation for the synthesis of. Fig. 35 is S. aureus ( S. aureus This is a plot of the results of the growth inhibition test. Fig. 36 This is a bar graph of the results of the S. aureus intracellular death assay performed using a rifamycin analog. Fig. 37 This is a plot of the results of the S. aureus intracellular death assay performed using a rifamycin analog. Specific details for implementing the invention

[0050] details

[0051] Before describing the present invention, it should be understood that the invention is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the technical terms used herein are for the purpose of describing specific embodiments only, and that the scope of the invention is limited only by the appended claims and is not intended to be limited.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which the present invention pertains. The term “about” as used herein means that, when used by reference to specific cited figures, such values ​​may vary by up to 1% from the cited values. For example, the expression “about 100” as used herein includes 99 and 101 and all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0053] Any method and material similar or identical to that described herein may be used in the practice or testing of the present invention, but preferred methods and materials are described hereafter. All patents, patent applications, and B-patent publications mentioned herein are incorporated herein in their entirety by reference.

[0054] definition

[0055] Expressions "MSR1," "hMSR1," etc., as used herein relate to human signal-pass, trimeric type II transmembrane glycoprotein pattern recognition receptors comprising (i) an amino acid sequence as described in NCBI Accession No. NP_002436.1, (ii) an amino acid sequence as described in NCBI Accession No. NP_619729.1, and / or (iii) an amino acid sequence as described in NCBI Accession No. NP_619730.1, which represent various types and isomorphs of class A macrophage scavenger receptors. The expression "MSR1" includes both monomeric and multimeric MSR1 molecules. As used herein, the expression "monomeric "Human MSR1" does not contain or possess any multimerization domain and It means an MSR1 protein or a site thereof existing as a single MSR1 molecule without direct physical linkage to other MSR1 molecules under normal conditions. An exemplary monomeric MSR1 molecule is the molecule referred herein as "His-hMSR1" comprising the amino acid sequence of SEQ ID NO: 393 (Note: e.g., Example 3 of the present invention).

[0056] All references to proteins, polypeptides, and protein fragments in this application are intended to refer to the human version of each protein, polypeptide, or protein fragment, unless explicitly specified as being from a non-human species. Accordingly, the expression "MSR1" means human MSR1 unless specified as being from a non-human species, e.g., "mouse MSR1," "monkey MSR1," etc.

[0057] As used herein, the expression “cell surface-expressed MSR1” means one or more MSR1 protein(s) or their extracellular domains, which are expressed on the surface of a cell in vitro or in vivo such that at least a portion of the MSR1 protein is exposed to an extracellular portion of the cell membrane and accessible to the antigen-binding site of an antibody. “Cell surface-expressed MSR1” may comprise or consist of an MSR1 protein expressed on the surface of a cell that normally expresses the MSR1 protein. Alternatively, “cell surface-expressed MSR1” may comprise or consist of an MSR1 protein expressed on the surface of a cell that does not normally express human MSR1 on its surface but has been artificially modified to express MSR1 on its surface.

[0058] As used herein, the expression “anti-MSR1 antibody” comprises not only a monovalent antibody having single specificity, but also a bispecific antibody comprising a first arm binding to MSR1 and a second arm binding to a second (target) antigen, wherein the anti-MSR1 arm comprises any HCVR / LCVR or CDR sequence as shown in Table 4 herein. The expression “anti-MSR1 antibody” also comprises an anti-MSR1 antibody conjugated to a drug or therapeutic agent, or an antibody-drug conjugate (ADC) comprising the antigen-binding site thereof. The expression “anti-MSR1 antibody” also comprises an anti-MSR1 antibody conjugated to a radionuclide, or an antibody-radionuclide conjugate (ARC) comprising the antigen-binding site thereof.

[0059] As used herein, the term “antibody” means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a specific antigen (e.g., MSR1). The term “antibody” includes immunoglobulin molecules comprising four polypeptide chains, consisting of two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain is a heavy chain variable region (HCVR or V in this application). H It includes the heavy chain invariant region (abbreviated as ) and the heavy chain invariant region. The heavy chain invariant region consists of three domains, C H 1, C H 2 and C H 3. Each light chain includes a light chain variable region (LCVR or V in this application). L It includes a) and a light chain invariant region. The light chain invariant region is a single domain (C L Includes 1). V H and V L The region can be further subdivided into a more conserved region named the skeletal region (FR) and a highly variable region named the complementarity determination region (CDR). Each V H and V L It consists of three CDRs and four FRs arranged in the following order from amino-terminus to carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the present invention, the FRs of the anti-MSR1 antibody (or their antigen-binding sites) may be identical to human wiring sequences, or may be naturally or artificially modified. The amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0060] As used herein, the term “antibody” also includes an antigen-binding fragment of a complete antibody molecule. As used herein, the terms “antigen-binding site” of an antibody, “antigen-binding fragment” of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. An antigen-binding fragment of an antibody may be derived from a complete antibody molecule using any suitable standard technique, such as proteolytic degradation or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA may be known and / or readily available from, for example, commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or synthesized. DNA can be sequenced and manipulated using chemical or molecular biology techniques to, for example, align one or more variable and / or constant domains to a suitable structure, introduce codons, generate cysteine ​​residues, or modify, add, or delete amino acids, etc.

[0061] Non-limiting examples of antigen-binding fragments include (i) Fab fragment; (ii) F(ab')2 fragment; (iii) Fd fragment; (iv) Fv fragment; (v) single-stranded Fv(scFv) molecule; (vi) dAb fragment; and (vii) a minimal recognition unit consisting of amino acid residues mimicking the hypervariable region of the antibody (e.g., isolated complementarity determining region (CDR), e.g., CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other processed molecules, e.g., domain-specific antibodies, monodomain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodidies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also included within the expression "antigen-binding fragment" as used herein.

[0062] The antigen-binding fragment of the antibody will typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame with one or more backbone sequences. V L V related to the domain H In the antigen-binding fragment having a domain, V H and V L Domains can be located relative to each other in any suitable alignment. For example, a variable domain can be a dimer and V H -V H , V H -V L or V L -V LIt may contain a dimer. Alternatively, the antigen-binding fragment of the antibody is a monomeric V H or V L It may contain a domain.

[0063] In a specific embodiment, the antigen-binding fragment of the antibody may contain at least one variable domain covalently connected to at least one constant domain. Non-limiting, exemplary structures of the variable and constant domains that may be found in the antigen-binding fragment of the antibody of the present invention are: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C LIt includes. In any structure of variable and constant domains comprising any of the exemplary structures listed above, the variable and constant domains may be directly connected to each other or connected by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that create a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody of the present invention comprises one other and / or one or more monomeric V H or V L When non-covalent association with the domain (e.g., by disulfide bond(s)), it may include a homo-dimer or hetero-dimer (or other polymer) of any variable and invariant domain structure listed above.

[0064] Since a complete antibody molecule is used, the antigen-binding fragment may be unispecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, each of which may specifically bind to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody modality, including the exemplary bispecific antibody modality disclosed herein, may be adopted for use in the context of the antigen-binding fragment of the antibody of the present invention using the ordinary techniques available in the art.

[0065] The antibodies of the present disclosure may act via complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the degradation of antigen-expressing cells by the antibody of the present invention in the presence of a complement. "Antibody-dependent cell-mediated cytotoxicity (ADCC) refers to a cell-mediated response in which non-specific cytotoxic cells expressing the Fc receptor (FcR) (e.g., natural killer (NK) cells, neutrophils, and macrophages) induce the degradation of target cells by recognizing antibodies bound to target cells. CDC and ADCC may be measured using assays that are well known and available in the art (see, for example, U.S. Patents No. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95 (652-656). The constant region of an antibody is important for the antibody's ability to anchor complements and mediate cell-dependent cytotoxicity. Therefore, the isoform of an antibody can be selected based on whether this is desirable for the antibody to mediate cytotoxicity.

[0066] In certain embodiments, the anti-MSR1 antibody disclosed herein is a human antibody. As used herein, the term “recombinant human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibody of the present invention may include, for example, amino acid residues within the CDR and particularly within CDR3 that are not encoded by the human germline immunoglobulin sequence (e.g., mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, e.g., mouse, is transplanted onto a human skeletal sequence.

[0067] The antibodies disclosed herein may, in some embodiments, be recombinant human antibodies. As used herein, the term “recombinant human antibody” refers to an antibody expressed using a recombinant expression vector transfected into a host cell (described further below), an antibody isolated from a recombinant, recombinant human antibody library (described further below), or an antibody isolated from an animal (e.g., mouse) that is transgenic to a human immunoglobulin gene (Note: e.g., Taylor et al. It is intended to include all human antibodies produced, expressed, generated, or isolated by recombinant means, such as antibodies produced, expressed, generated, or isolated by any other means including splicing a human immunoglobulin gene sequence into another DNA sequence (1992) Nucl. Acids Res. 20:6287-6295). Such recombinant human antibodies have variable and constant regions derived from human wiring immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are applied for in vitro mutagenesis (or, in vivo somatic mutagenesis where animals transgenic to the human Ig sequence are used), thereby the V of the recombinant antibody H and V L The amino acid sequence of the region is human wiring V H and V L It is a sequence derived from and related to the sequence, but which may not naturally exist within the human antibody wiring repertoire in vivo.

[0068] Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises four stable chain constructs of approximately 150 to 160 kDa, where the dimers are held together by interchain heavy chain disulfide bonds. In the second form, the dimers are not connected via interchain disulfide bonds, forming a molecule of approximately 75 to 80 kDa consisting of light and heavy chains (half of the antibody) coupled by covalent bonds. This form was extremely difficult to separate, even after affinity purification.

[0069] The frequency of the appearance of the second form in various complete IgG isoforms is attributed to, but is not limited to, structural differences associated with the hinge domain isoforms of the antibody. A single amino acid substitution within the hinge domain of the human IgG4 hinge leads to the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) can be significantly reduced to levels typically observed using a human IgG1 hinge. An embodiment disclosed herein includes a hinge, C, which may be desirable, for example, to enhance the yield of the desired antibody form during production. H 2 or C H It includes antibodies having one or more mutations within 3 regions.

[0070] The antibodies disclosed herein may be isolated antibodies. As used herein, "isolated antibody" means an antibody identified, isolated, and / or recovered from at least one component of its natural environment. For example, an antibody isolated or removed from at least one component of an organism, or from a tissue or cell in which the antibody is naturally present or naturally produced, is an "isolated antibody" for the purposes of the present invention. The isolated antibody is also in a recombinant cell or in a reaction system ( in situ) includes antibodies. The isolated antibody is an antibody applied in at least one purification or isolation step. Depending on a specific embodiment, the isolated antibody may not substantially contain other cellular material and / or chemical substances.

[0071] The anti-MSR1 antibody disclosed herein may include one or more amino acid substitutions, insertions, and / or deletions within the backbone and / or CDR regions of the heavy and light chain variable domains compared with the corresponding wiring sequence from which the antibody is derived. Such mutations can be easily identified by comparing the amino acid sequence disclosed herein with, for example, wiring sequences available in public antibody sequence databases. An embodiment comprises an antibody and an antigen-binding fragment thereof derived from any amino acid sequence disclosed herein, wherein one or more amino acids within one or more backbone and / or CDR regions are mutated into corresponding residue(s) of the wiring sequence from which the antibody is derived, or corresponding residue(s) of another human wiring sequence, or conserved amino acid substitutions of corresponding wiring residue(s) (such sequence changes are collectively referred to herein as “wiring mutations”). A person skilled in the art can easily produce a number of antibodies and antigen-binding fragments comprising one or more individual wiring mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In a specific embodiment, V H and / or V L All back-mutated Once obtained, antibodies and antigen-binding fragments containing one or more wiring mutations can be readily tested for one or more desired properties, such as enhanced binding specificity, increased binding affinity, enhanced or improved antagonistic or efficacious biological properties (as in some cases), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are included within the embodiments disclosed herein.

[0072] An embodiment also comprises an anti-MSR1 antibody comprising a variant of any HCVR, LCVR, and / or CDR amino acid sequence disclosed herein having one or more conservative substitutions. For example, an embodiment comprises an anti-MSR1 antibody having an HCVR, LCVR, and / or CDR amino acid sequence having 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, conservative amino acid substitutions for any HCVR, LCVR, and / or CDR amino acid sequence as shown in Table 4 of the present invention, for example.

[0073] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site within a variable region of an antibody molecule known as a paratope. A single antigen may have one or more epitopes. Therefore, different antibodies may bind to different sites on the antigen and have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are produced by adjacent amino acid residues within the polypeptide chain. In certain circumstances, epitopes may include a moiety of saccharide, phosphoryl group, or sulfonyl group on the antigen.

[0074] Where referring to a nucleic acid or a fragment thereof, the terms “substantial identity” or “substantively identical” mean that when optimally aligned with another nucleic acid (or its complementary strand) with appropriate nucleotide insertions or deletions, there is nucleotide sequence identity at least about 95%, and more preferably at least about 96%, 97%, 98%, or 99%, 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 with respect to a reference nucleic acid molecule, in certain examples, encodes a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0075] As applied to polypeptides, the terms “substantial similarity” or “substantially similar” mean that when optimally aligned, such as by programmed GAP or BESTFIT using default gap weights, two peptide sequences share at least 95% sequence identity, and even more preferably at least 98% or 99% sequence identity. Preferably, non-identical residue positions differ by conservative amino acid substitutions. “Conservative amino acid substitution” is the substitution of an amino acid residue by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitutions will not substantially alter the functional properties of the protein. Where two or more amino acid sequences differ from each other by conservative substitutions, the percentage of sequence identity or the degree of similarity may be synergistically adjusted to compensate for the conservative nature of the substitutions. Means for achieving such adjustments are well known to those skilled in the art. For example, see the literature: Pearson (1994) methods Mol. Biol. 24: 307-331. Examples of a group of amino acids having 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: cysteine ​​and methionine. Preferred conservative or amino acid substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, conservative substitutions are referenced in the literature: Gonnet et al. (1992) Science 256: 1443-1445. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0076] Additionally, sequence similarity for polypeptides referred to as sequence identity is typically measured using sequencing software. Protein analysis software matches similar sequences using a specified measure of similarity for various substitutions, deletions, and other modifications, including conserved amino acid substitutions. For example, GCG software includes programs such as GAP and BESTFIT, which can be used with default parameters to measure sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between wild-type proteins and their mutants. See, for example, GCG Version 6.1. Polypeptide sequences can also be compared using FASTA, a program in GCG Version 6.1, using default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides the alignment of the region of best overlap between the query and search sequences and the percentage of sequence identity (see Pearson (2000) above). When comparing the sequence of the present invention with a database containing multiple sequences from different organisms, another preferred algorithm is the computer program BLAST, in particular BLASTP or TBLASTN using default parameters. For example, Altschul et al.(1990) J. Mol. Biol. 215:403-410 and Altschul et al. Refer to (1997) Nucleic Acids Res. 25:3389-402.

[0077] When referring to the compounds provided herein, the following terms have the following meanings unless otherwise indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art. Even if multiple definitions exist for the terms provided herein, these definitions shall prevail unless otherwise stated.

[0078] As used herein, the singular form (“a” or “an”) means one or more unless the context clearly indicates otherwise.

[0079] As used herein, "alkyl" refers to a monovalent and saturated hydrocarbon radical moiety. The alkyl may be optionally substituted and may be straight-chain, branched-chain, or cyclic, i.e., cycloalkyl. The alkyl are radicals having 1 to 20 carbon atoms, i.e., C 1-20 Alkyl; radicals having 1 to 12 carbon atoms, i.e., C 1-12 Alkyl; radicals having 1 to 8 carbon atoms, i.e., C 1-8 Alkyl; radicals having 1 to 6 carbon atoms, i.e., C 1-6 Alkyl; and radicals having 1 to 3 carbon atoms, i.e., C 1-3 It includes, but is not limited to, alkyl groups. Examples of alkyl moiety are methyl, ethyl, n -profile, i -profile, n -butyl, s -butyl, t -butyl, i- Includes butyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, but is not limited thereto. Pentyl moiety includes n-pentyl and i-pentyl, but is not limited thereto. Hexyl moiety includes n-hexyl, but is not limited thereto.

[0080] As used herein, "alkylene" refers to a divalent alkyl group. Unless otherwise specified, an alkylene comprises 1 to 20 carbon atoms, but is not limited thereto. The alkylene group is optionally substituted for the alkyl as described herein. In some embodiments, the alkylene is unsubstituted. In some embodiments, the alkylene is a divalent branched alkyl group.

[0081] The term "amino" is -NH 2 It means.

[0082] As used herein, and unless otherwise specified, the term "alkylamino" refers to the group -NHR' as defined herein, where R' is C 1-10 It is an alkyl. In some or any embodiment, the alkylamino is C 1-6 It is an alkylamino.

[0083] As used herein, and unless otherwise specified, the term "dialkylamino" is Referring to the group -NR'R', where each R' is independently C as defined herein. 1-10 It is an alkyl. In some or any embodiment, the dialkylamino is di-C 1-6 It is an alkylamino.

[0084] As used herein, and unless otherwise specified, the term “aminoalkyl” refers to an alkyl group as defined herein that is substituted with one or more amino groups. In some or any embodiments, an aminoalkyl is an alkyl group substituted with one -NH2 group (e.g., -R'(NH 2 Here, R' is -C as defined herein 1-10It is an alkyl). In some or any embodiments, the aminoalkyl is an alkyl group substituted with two -NH2 groups. In some embodiments, "aminoalkyl" is aminoC 1-6 It is an alkyl.

[0085] As used herein, and unless otherwise specified, "alkylaminoalkyl" refers to an alkyl group as defined herein, substituted with one or more alkylamino groups as defined herein. In some embodiments, "alkylaminoalkyl" refers to C 1-6 Alkylamino C 1-6 It is an alkyl. In some embodiments, each alkyl in the alkylaminoalkyl group is selected independently.

[0086] As used herein, and unless otherwise specified, “dialkylaminoalkyl” refers to an alkyl group as defined herein, substituted with one or more dialkylamino groups as defined herein. In some embodiments, “dialkylaminoalkyl” refers to a di-C 1-6 Alkylamino C 1-6 It is an alkyl. In some embodiments, each alkyl in the dialkylaminoalkyl is independently selected.

[0087] As used herein, the terms “O-amino acid” or “HO-amino acid” refer to an amino acid in which the natural amino group at the N-terminus of an amino acid or amino acid sequence is replaced by an oxygen or a hydroxyl group, respectively. For example, “O-AAAA” or “HO-AAAA” is intended to represent an amino acid sequence (AAAA) in which the natural amino group at the N-terminus is replaced by an oxygen or a hydroxyl group, respectively (e.g., , where each R is an amino acid side chain). Similarly, the term “O-amino acid residue” or “HO-amino acid residue” refers to a chemical residue within a compound remaining after a chemical reaction. For example, “O-amino acid residue” or “HO-amino acid residue” indicates the product of amine coupling or peptide coupling of an O-amino acid or HO-amino acid to a suitable coupling partner; where, for example, a water molecule is discharged after amide or peptide coupling of an O-amino acid or HO-amino acid to produce a product having an O-amino acid residue or HO-amino acid residue incorporated therein.

[0088] The definition of an amino acid or amino acid residue without specifying its stereochemistry is intended to include the L-form of an amino acid, the D-form of an amino acid, or a racemic mixture thereof.

[0089] As used herein, “haloalkyl” refers to an alkyl as defined above, wherein the alkyl comprises at least one substituent selected from halogens, e.g., fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyls include, but are not limited to, -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0090] 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. The alkenyl may be optionally substituted and may be straight-chain, side-chain, or cyclic. The alkenyls are radicals containing 2 to 20 carbon atoms, i.e., C 2-20 Alkenyl; radicals containing 2 to 12 carbon atoms, i.e., C 2-12 Alkenyl; radicals containing 2 to 8 carbon atoms, i.e., C 2-8 Alkenyl; radicals containing 2 to 6 carbon atoms, i.e., C 2-6Alkenyl; and radicals containing 2 to 4 carbon atoms, i.e., C 2-4 Includes, but is not limited to, alkenyls. Examples of alkenyl moiety include, but are not limited to, vinyl, propenyl, butenyl, and cyclohexenyl.

[0091] 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. The alkynyl may be optionally substituted and may be straight-chain, side-chain, or cyclic. The alkynyl are radicals having 2 to 20 carbon atoms, i.e., C 2-20 Alkynyl; radicals having 2 to 12 carbon atoms, i.e., C 2-12 Alkynyl; radicals having 2 to 8 carbon atoms, i.e., C 2-8 Alkynyl; radicals having 2 to 6 carbon atoms, i.e., C 2-6 Alkynyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Includes, but is not limited to, alkynyl. Examples of alkynyl moiety include, but are not limited to, ethinyl, propynyl, and buthinyl.

[0092] As used herein, "alkoxy" refers to a monovalent and saturated hydrocarbon radical moiety, wherein the hydrocarbon contains a single bond to an oxygen atom and the radical is located on the oxygen atom, for example, in the case of ethoxy, CH3CH2-O. Alkoxy substituents are bonded to the compound they substitute through this oxygen atom of the alkoxy substituent. The alkoxy is optionally substituted and may be straight-chain, side-chain, or cyclic, i.e., cycloalkoxy. The alkoxy consists of those having 1 to 20 carbon atoms, i.e., C 1-20 Alkoxy; those having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; those having 1 to 8 carbon atoms, i.e., C 1-8Alkoxy; those having 1 to 6 carbon atoms, i.e., C 1-6 Alkoxy; and those having 1 to 3 carbon atoms, i.e., C 1-3 Includes, but is not limited to, alkoxy groups. Examples of alkoxy moiety are methoxy, ethoxy, n -Propoxi, i -Propoxi, n -Butoxy, s -Butoxy, t -Butoxy, i - Includes butoxy, pentoxy moiety, hexoxy moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy, but is not limited thereto.

[0093] As used herein, "haloalkoxy" refers to an alkoxy as defined above, wherein the alkoxy comprises at least one substituent selected from halogens, such as F, Cl, Br, or I.

[0094] As used herein, "aryl" refers to a monovalent moiety that is a radical of an aromatic compound in which the ring atom is a carbon atom. The aryl is optionally substituted and may be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of aryl moiety are those having 6 to 20 ring carbon atoms, i.e., C 6-20 Aryl; those having 6 to 15 cyclic carbon atoms, i.e., C 6-15 Aryls, and those having 6 to 10 cyclic carbon atoms, i.e., C 6-10 Includes, but is not limited to, aryls. Examples of aryl moiety include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrenyl.

[0095] 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, that is, the aromatic compound contains a single bond to the alkyl group, and the radical is localized on the alkyl group. The arylalkyl group is bonded to the chemical structure represented by the alkyl group. The arylalkyl is a structure, e.g., It can be represented as, where B is an aromatic moiety, e.g., phenyl. The arylalkyl group is optionally substituted, that is, the aryl group and / or alkyl group may be substituted as disclosed herein. Examples of arylalkyl groups include, but are not limited to, benzyl.

[0096] 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, that is, the aryl compound contains a single bond to an alkyl group, wherein the radical is localized on the aryl group. The alkylaryl group is bonded to the chemical structure represented by the aryl group. The alkylaryl is a structure, It can be represented as, where B is an aromatic moiety, e.g., phenyl. The alkylaryl is optionally substituted, that is, the aryl group and / or alkyl group may be substituted as disclosed herein. Examples of alkylaryls include, but are not limited to, toluyl.

[0097] As used herein, "aryloxy" refers to a monovalent moiety, which is a radical of an aromatic compound, wherein the ring atom is a carbon atom and the ring is substituted with an oxygen radical; that is, the aromatic compound contains a single bond to an oxygen atom and the radical is localized on the oxygen atom, for example, in the case of phenoxy, It is. Aryloxy substituents bond to the compound they substitute through these oxygen atoms. Aryloxy is arbitrarily substituted. Aryloxy is a radical having 6 to 20 ring-carbon atoms, i.e., C 6-20Aryloxy; a radical having 6 to 15 cyclic carbon atoms, i.e., C 6-15 Aryloxy, and a radical having 6 to 10 cyclic carbon atoms, i.e., C 6-10 Includes, but is not limited to, aryloxy. Examples of aryloxy moiety include, but are not limited to, phenoxy, naphthoxy, and anthroxy.

[0098] As used herein, "R a R b "N-aryloxy" refers to the monovalent moiety, which is a radical of an aromatic compound, where the ring atom is a carbon atom and the ring is at least one R a R b It is substituted with an N-substituent and at least one oxygen radical, that is, the aromatic compound is R a R b It includes a single bond to an N-substituent and a single bond to an oxygen atom, wherein the radical is localized on the oxygen atom, for example, is. R a R b N-aryloxy substituents bond to the compounds they substitute through these oxygen atoms. R a R b The N-aryloxy is arbitrarily substituted. R a R b N-aryloxy has 6 to 20 ring atoms, for example, C 6-20 (R a R b N)n-aryloxy, having 6 to 15 cyclic carbon atoms, e.g., C 6-15 (R a R b N)n-aryloxy, and having 6 to 10 cyclic carbon atoms, e.g., C 6-10 (R a R b N) Includes, but is not limited to, n-aryloxy, where n is R a R b Indicates the number of N-substituents. R a Rb An example of an N-aryloxy moiety is 4-(dimethylamino)-phenoxy, Includes, but is not limited to.

[0099] As used herein, "arylene" refers to a divalent moiety of an aromatic compound, wherein the ring atom is only a carbon atom. Arrylenes are optionally substituted and may be monocyclic or polycyclic, e.g., bicyclic or tricyclic. Examples of arylene moiety are those having 6 to 20 carbon atoms, i.e., C 6-20 Arrylene; having 6 to 15 cyclic carbon atoms, i.e., C 6-15 Arrylene, and having 6 to 10 cyclic carbon atoms, i.e., C 6-10 Includes, but is not limited to, arylene.

[0100] As used herein, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkenyl" refers to an alkenyl group in which one or more carbon atoms are replaced by heteroatoms. As used herein, "heteroalkynyl" refers to an alkynyl group 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 groups are optionally substituted. Examples of heteroalkyl moiety include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moiety include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl.

[0101] As used herein, “heteroaryl” refers to a monovalent moiety that is a radical of an aromatic compound, wherein the ring atom contains a carbon atom and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl moiety include, but are not limited to, having 5 to 20 ring atoms; 5 to 15 ring atoms; and 5 to 10 ring atoms. The heteroaryl is optionally substituted.

[0102] As used herein, "heteroarylene" refers to an arylene in which one or more ring atoms of an aromatic ring are replaced by oxygen, sulfur, nitrogen, or phosphorus atoms. Heteroarylenes are optionally substituted.

[0103] 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. Heterocycloalkyls are optionally substituted. Examples of heterocycloalkyl moiety include, but are not limited to, morpholinyl, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl.

[0104] As used herein, "N-containing heterocycloalkyl" refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms, wherein at least one heteroatom is a nitrogen atom. Suitable heteroatoms other than nitrogen include, but are not limited to, oxygen and sulfur atoms. The N-containing heterocycloalkyl is optionally substituted. Examples of N-containing heterocycloalkyl moiety include, but are not limited to, morpholinyl, piperidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, or thiazolidinyl.

[0105] As used herein, “optionally substituted” means that when used to describe radical moiety, e.g., optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylene, and optionally substituted heteroarylene, such moiety is optionally bonded to one or more substituents. Examples of such substituents include halo, cyano, nitro, optionally substituted haloalkyl, azido, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, or Includes, but is not limited to, where R A , R B , and R C is, independently in the presence of each, a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form a saturated or unsaturated carbocyclic ring with the atoms to which they are bonded, wherein the ring is optionally substituted, and one or more ring atoms are optionally replaced with heteroatoms. In certain embodiments, where the radical moiety is optionally substituted with an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted saturated or unsaturated carbocyclic ring, the substituent on the optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted saturated or unsaturated carbocyclic ring is not additionally optionally substituted with additional substituents when they are substituted. In some embodiments, where the group described herein is optionally substituted, the substituent bonded to the group is not substituted unless otherwise specified.

[0106] As used herein, "O-glucose" refers to a monovalent moiety attached via an exocyclic glucose oxygen atom. Suitable O-glucose moiety is not limited to, Includes the back.

[0107] As used herein, "O-PEGn" refers to a monovalent moiety attached through a terminal oxygen atom, where n is 1 to 100. For example, when n is 1, O-PEGn is -O-CH2CH2OH; when n is 2, O-PEGn is -O-CH2CH2O-CH2CH2OH; and when n is 3, O-PEGn is -O-CH2CH2O-CH2CH2O-CH2CH2OH.

[0108] As used herein, "binding agent" refers to any molecule capable of specifically binding to a given binding partner, e.g., an antigen, e.g., a protein or an antibody.

[0109] As used herein, “linker” refers to a divalent, trivalent, or multivalent moiety that covalently links a binder to one or more compounds described herein, for example, a payload compound and / or a hydrophilic group as described herein.

[0110] As used herein, "connector group" or "connector group residue" refers to any group capable of facilitating the release of a payload. A suitable connector group facilitates the release of a payload to which a divalent or polyvalent component is attached in reverse to its original unbonded form, which is hardly derivatized or not derivatized at all. Examples of connector groups are ..., or derivatives thereof, but not limited thereto. In other examples, the connector group am.

[0111] In additional examples, the connector group is a self-immolative group. "Self-immolative group" refers to any such group known to those skilled in the art. In a specific embodiment, the self-immolative group p -Aminobenzyl oxycarbonyl (PAB / PABC), i.e., A person skilled in the art will recognize that a self-sacrificial group may involve a chemical reaction that releases the remaining atoms of the linker from the payload.

[0112] "Connecting linker" (L as used herein) 2 ) or "linking links" are It refers to a divalent group that is either cleavable or non-cleavable. A cleavable linker is a linker that is cleaved by intracellular metabolism after internalization, e.g., by hydrolysis, reduction, or cleavage via enzymatic reactions. A non-cleavable linker is a linker that releases an attached payload through the lysosome degradation of the antibody after internalization. Suitable linking linkers include, but are not limited to, acid-unstable linkers, hydrolysis-unstable linkers, enzymatically cleavable linkers, reduction-unstable linkers, and non-cleavable linkers. Suitable linkers are also, but are not limited to, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, and disulfide units (e.g., -SS-, -SC(R 1b R 2b )-(here R 1b and R 2b (is 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 2, 3, 4, 5, 6, 7, or 8 or more amino acid residues, e.g., but not limited to valine-citrulline residue units or those comprising such units, as used herein, "Caproyl" is -(CH2)5-C(O)- means group

[0113] As used in the present invention, The phrase "reactive group" ("RG") is Antibodies, modified antibodies, or Its antigen-binding fragment Reacting with the reactive site of action group or moiety refers to . In a specific embodiment, the "reactive group" is Reacting with cysteine ​​or lysine residues of antibodies or their antigen-binding fragments action group or moiety (e.g., maleimide or NHS esters) is. In a specific embodiment, the "reactive group" is It is an active group or moiety capable of undergoing a click chemical reaction. In some embodiments of the click chemical reaction, the reactive group comprises an alkyne capable of undergoing a 1,3-cycloaddition with an azide. Such suitable reactive groups include, but are not limited to, strained alkines, e.g., those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes, e.g., cyclooctine, benzannulated alkynes, and alkynes capable of undergoing a 1,3-cycloaddition with an azide in the absence of a copper catalyst. Suitable alkynes are also DIBAC (wherein the -C(O)CH2CH2C(O)- site of the DIBAC moiety is L and / or L 2 It can be represented as), DIBO (where the -O- site of the DIBO moiety is L and / or L 2 can be represented as), BARAC (here, of the BARAC moiety The site is L and / or L 2 It can be represented as), DIFO (where the -O- site is L and / or L 2(can be represented as), substituted alkynes, e.g., fluorinated alkynes, aza-cycloalkynes, BCN, and derivatives thereof, but are not limited thereto. Linker-payloads containing such reactive groups are useful for conjugating antibodies functioned with azido groups. Such functioned antibodies include antibodies functioned with azido-polyethylene glycol groups. In a specific embodiment, such functioned antibodies are induced by reacting an antibody containing at least one glutamine residue, e.g., heavy chain Q295 (EU numbering), with a compound according to the formula H2N-LL-N3 (where LL is a divalent polyethylene glycol group) in the presence of the enzyme transglutaminase.

[0114] In some embodiments, reactive groups ( RG ) is an alkyne, for example, , and this is through click chemistry azide, for example, Reacting with, click chemical products, e.g., , its regioisomer, or a mixture thereof may be formed. In some embodiments, the reactive group is an alkyne, e.g., or (Here, L and / or L 2 is -OCH2C(O)- and this is azide, for example, through click chemistry. Reacting with to form click chemical products, e.g., It can form. In some embodiments, the reactive group is an alkyne, e.g., , and this is through click chemistry azide, for example, Reacting with to form click chemical products, e.g., , its regioisomers, or mixtures thereof may be formed. In some embodiments, the reactive group is a functional group, e.g., and, by reacting with cysteine ​​residues on the antibody or its antigen-binding fragment, binding to it, e.g., (Here, Ab is an antibody or its antigen-binding fragment, and S refers to an S atom on a cysteine ​​residue through which the action group binds to Ab.) forms. In some embodiments, the reactive group is an action group, e.g., and, this reacts with lysine residues on the antibody or its antigen-binding fragment, binding to it, e.g., (Here, Ab is an antibody or its antigen-binding fragment, and N refers to the N atom on the lysine or amino-terminal residue through which the active group binds to Ab.) forms. In some examples, the reactive group And, this reacts with two thiols (e.g., two different chain-bound thiols) of an antibody or its antigen-binding fragment to bind to them, e.g., It forms. In some examples, the reactive group And, this reacts with two thiols (e.g., two different chain-bound thiols) of an antibody or its antigen-binding fragment to bind to them, e.g., forms.

[0115] The phrase "reactive group residue" as used herein is a binder ( comprising a product of click chemistry) BA It refers to the reaction product of the active group within the linker moiety and the reactive site of ). The reactive group residue is formed by the reaction of the reactive group on the amino acid of the binder and is attached to the binder (e.g., antibody) and the linker. In some embodiments, the reactive group residue is a group comprising 1,2,3-tetrazole, that is, formed by the reaction of an alkyne and an azide. In some embodiments, the reactive group residue (a) where S refers to the S atom on the cysteine ​​residue that binds (a) to Ab through this, and this It is formed by the reaction of a cysteine ​​residue on an antibody or its antigen-binding fragment. In some embodiments, the reactive group residue is and here N refers to the N atom on the lysine residue, which is an active group, e.g., It is formed by the reaction of a lysine residue on an antibody or its antigen-binding fragment. Those skilled in the art will recognize that part of the reactive group residue may come from the reactive group, from the antibody, or both. In some examples, the reactive group residue and, where S refers to the S atom on the cysteine ​​residue, which is the functional group or It is formed by the reaction of cysteine ​​residues on antibodies or their antigen-binding fragments.

[0116] "Pharmaceuticalally acceptable salts" as used herein are It refers to any salt suitable for administration to a patient. Suitable salts are referenced in the literature included herein by reference: Berge et al ., "Pharmaceutical Salts", J. Pharm. SciExamples of salts include, but are not limited to, those disclosed in 66:1 of 1977. Examples of salts include, but are not limited to, salts of calcium, magnesium, potassium, sodium, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvate, 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, and salicylic acid, etc., acid-derived, base-derived, organic, inorganic, amine, and alkali or alkaline earth metal salts. In some examples, the payload described herein (e.g., the rifamycin analog described herein) comprises a tertiary amine, wherein the nitrogen atom in the tertiary amine is the atom through which the payload is bonded to the linker or linker-spacer. In these examples, the bonding of the payload to the tertiary amine creates a quaternary amine within the linker-payload molecule. The positive charge on the quaternary amine can be balanced by a counterion (e.g., chloro, bromo, iodo, or any other suitably charged moiety such as those described above).

[0117] Specific groups, moiety, substituents, and atoms are represented by wavy lines. Wavy lines may intersect or cap bonds. By doing so, dashed lines indicate the atoms to which a group, moiety, substituent, or atom bonds. For example, or The phenyl group substituted with the propyl group described as has the following structure: .

[0118] As used herein, “amide synthesis conditions” refer to reaction conditions suitable for carrying out the formation of an amide by, for example, the reaction of a carboxylic acid, an activated carboxylic acid, or an acyl halide with an amine. In some embodiments, amide synthesis conditions refer to reaction conditions suitable for carrying out 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. Conditions suitable for carrying out the formation of amides are, with a carboxylic acid and dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotriazole-1-yl)- N,N,N',N' -Tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazole-1-yl)- N,N,N',N' -Tetramethyluronium tetrafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b] Utilizing reagents for carrying out a reaction between an amine and a carboxylic acid, including but not limited to pyridinium 3-oxide 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 (CDI). In some embodiments, the carboxylic acid is first converted to an activated carboxylic ester before the activated carboxylic ester is treated 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 it 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. This activated carboxylic ester for a specific carboxylic acid subsequently becomes more sensitive to nucleophilic attack by the amine than the carboxylic acid before activation. This leads to the formation of an amide bond. Therefore, the carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

[0119] "Amino acid" or "amino acid residue" refers to a naturally occurring amino acid in some embodiments. In other embodiments, the amino acid or amino acid residue refers to a naturally occurring amino acid and / or a non-natural amino acid (e.g., β-amino acid (β- 3 and β 2), homo-amino acids, proline and pyruvate derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, and / or N-methyl amino acids, or any other commercially available non-natural amino acids (e.g., non-natural amino acids available from Sigma-Aldrich). In other embodiments, the amino acid residue may be a residue having a side chain involved in a reaction mediated by transglutaminase, e.g., a transglutaminase-mediated reaction of an amino acid side chain with a primary amine. For example, the reaction of an asparagine and / or glutamine side chain with a primary amine is used in the preparation of the specific ADC described herein. In a specific embodiment, this functioned antibody is derived by reacting an antibody containing at least one glutamine residue, such as heavy chain Q295 (EU numbering), with a compound according to the formula H2N-LL-N3 (where LL is a divalent polyethylene glycol group) in the presence of the enzyme transglutaminase.

[0120] "Taurine," as used herein, is a reagent , or group (Here This refers to the atom that taurine binds to an adjacent group within the chemical formula.

[0121] As used herein, “stereoisomer form” or “stereoisomer” refers to the relative spatial orientation of different groups within a compound. Stereoisomer forms include enantiomers, diastereomers, and / or mixtures thereof.

[0122] As used herein, “reggioisomer,” “reggioisomers,” or “mixture of regioisomers” refers to product(s) of a 1,3-cyclobuga reaction or a modified-promoted alkyne-azide cyclobuga reaction (SPAAC) also known as a click reaction—derived from a suitable azide (e.g., -N3, or PEG-N3-derived antibody) treated with a suitable alkyne. In certain embodiments, for example, a regioisomer and a mixture of regioisomers are characterized by the click reaction products shown below:

[0123]

[0124] As merely an example, the regioisomers of compound A1', namely compounds A2', A3', and A4', are shown below, where each is a bond to the binder; and each is a combination for the payload:

[0125]

[0126] Compound A1′

[0127]

[0128] Compound A2';

[0129]

[0130] Compound A3';

[0131]

[0132] Compound A4'.

[0133] Fc 변이체를 포함하는 항-MSR1 항체

[0134] According to specific embodiments, an anti-MSR1 antibody is provided comprising an Fc domain containing one or more mutations that enhance or weaken antibody binding to the FcRn receptor at acidic pH compared to neutral pH, for example. For example, C of the Fc domain H 2 or C HAnti-MSR1 antibodies comprising mutations within three regions are provided herein, wherein the mutation(s) increase the affinity of the Fc domain for FcRn in an acidic environment (e.g., within an endosome where the pH is in the range of about 5.5 to about 6.0). Such mutations may cause an increase in the serum half-life of the antibody when administered to animals. Non-limiting examples of such Fc modifications include, for example, modifications at position 250 (e.g., E or Q); positions 250 and 428 (e.g., L or F); modifications at positions 252 (e.g., L / Y / F / W or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D or T); or a deformation 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); or a deformation at position 250 and / or 428; or 307 or 308 (e.g., 308F, V308F), and a deformation at position 434. In one embodiment, the deformations include 428L (e.g., M428L) and 434S (e.g., N434S) deformations; 428L, 259I (e.g., V259I), and 308F (e.g., V308F) deformations; 433K (e.g., H433K) and 434 (e.g., 434Y) deformations; Variants of 252, 254, and 256 (e.g., 252Y, 254T, and 256E); 250Q and 428L variants (e.g., T250Q and M428L); and 307 and / or 308 variants (e.g., 308F or 308P).

[0135] For example, an embodiment comprises an anti-MSR1 antibody 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 aforementioned Fc domain mutations and other mutations within the antibody variable domain disclosed herein are considered within the scope of the present invention.

[0136] 항체의 생물학적 특성

[0137] An embodiment comprises an antibody binding to human MSR1 having high affinity and an antigen-binding fragment thereof. For example, the present invention, using a assay mode such as that defined in Example 3 of this application, or a substantially similar assay, K less than about 10 nM as measured by surface plasmon resonance at 25°C or 37°C. DIt includes an anti-MSR1 antibody that binds to the extracellular domain of human MSR1 expressed with an N-terminal nonahistidin tag (e.g., His9-hMSR1). Depending on a specific embodiment, for example, using a calibration mode as defined in Example 3 of the present invention, or a substantially similar calibration, measured by surface plasmon resonance, 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, about K less than 20 pM, or about less than 10 pM D An anti-MSR1 antibody that binds to human MSR1 at 37°C is provided. In some embodiments, the anti-MSR1 antibody disclosed herein is, for example, measured by surface plasmon resonance using a assay mode as defined in Example 3 of this application, or a substantially similar assay, K 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 about 20 pM. D It binds to human MSR1 at 25℃.

[0138] The embodiment also includes an antibody binding to monkey MSR1 having high affinity and an antigen-binding fragment thereof. For example, using a assay mode as defined, for instance, in Example 3 of the present invention, or a substantially similar assay, K less than about 20 nM as measured by surface plasmon resonance at 25°C or 37°C. D An anti-MSR1 antibody that binds to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag (e.g., HMM-mfMSR1) is disclosed herein. Depending on a specific embodiment, using a calibration mode as defined in Example 3 of the present invention, or a substantially similar calibration, measured by surface plasmon resonance, 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, about K less than 60 pM, approximately less than 50 pM, approximately less than 40 pM, approximately less than 30 pM, approximately 20 pM, or approximately less than 10 pM DAn anti-MSR1 antibody that binds to monkey MSR1 at 37°C is provided. In some embodiments, the anti-MSR1 antibody disclosed herein is measured by surface plasmon resonance using a assay mode as defined in Example 3 of this application, or a substantially similar assay, and is 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, about K less than 40 pM, approximately 30 pM, or less than approximately 20 pM D It binds to monkey MSR1 at 25℃.

[0139] The present invention also comprises an antibody that binds to the extracellular domain of human MSR1 expressed with an N-terminal nonahistidin tag (e.g., His9-hMSR1) having a dissociative half-life (t½) of more than about 5 minutes, measured by surface plasmon resonance at 25°C or 37°C using a assay mode as defined in Example 3 of the present invention, or a substantially similar assay, and an antigen-binding fragment thereof. According to a specific embodiment, for example, using a assay mode as defined in Example 3 of the present invention, or a substantially similar assay, an anti-MSR1 antibody is provided that binds to human MSR1 at 37°C with a t½ of about 4 minutes, about 5 minutes, about 6 minutes, about 8 minutes, about 10 minutes, about 12 minutes, about 14 minutes, about 16 minutes, about 18 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 120 minutes, about 150 minutes, about 180 minutes, about 210 minutes, and about 240 minutes, as measured by surface plasmon resonance.

[0140] The embodiment also comprises an antibody capable of binding to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag (e.g., HMM-mfMSR1) with high affinity, and an antigen-binding fragment thereof. For example, the present invention, using a assay modality as defined in Example 3 of the present invention, or a substantially similar assay, or using a substantially similar assay, K less than about 20 nM as measured by surface plasmon resonance at 25°C or 37°C. DIt includes an anti-MSR1 antibody that binds to HMM-mFMSR1. Depending on a specific embodiment, for example, using a calibration mode as defined in Example 3 of the present invention, or a substantially similar calibration, measured by surface plasmon resonance, 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, K of about 60 pM, or less than about 50 pM D An anti-MSR1 antibody that binds to HMM-mfMSR1 at 37°C is provided. In some embodiments, the anti-MSR1 antibody disclosed herein is measured by surface plasmon resonance, for example, using a assay mode as defined in Example 3 of this application, or a substantially similar assay, to be 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 K less than, approximately less than 60 pM, or approximately less than 50 pM D Combine with HMM-mfMSR1 at 25℃.

[0141] The embodiment also includes an antibody and its antigen-binding fragment that binds to the extracellular domain of monkey MSR1 expressed with an N-terminal myc-myc-hexahistidine tag (e.g., HMM-mfMSR1) with a dissociation half-life (t½) of more than about 55 minutes, measured by surface plasmon resonance at 25°C or 37°C, using, for example, a assay mode as defined in Example 3 of the present invention, or a substantially similar assay. According to a specific embodiment, for example, using a assay mode as defined in Example 3 of the present invention, or a substantially similar assay, an anti-MSR1 antibody is provided that binds to dimeric human MSR1 at 37°C with a t½ of about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 8 minutes, about 10 minutes, about 12 minutes, about 14 minutes, about 16 minutes, about 18 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 120 minutes, about 150 minutes, about 180 minutes, and about 210 minutes, as measured by surface plasmon resonance.

[0142] The embodiment also comprises an antibody binding to processed cell-surface expressed hMSR1 and an antigen-binding fragment thereof having a binding ratio of processed hMSR1-expressing cells to non-expressing cells of at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 12 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 30 times, at least about 35 times, at least about 40 times, at least about 45 times, at least about 50 times or more, as measured by an antibody binding assay using, for example, the assay form defined in Example 5 of the present invention, or a substantially similar assay. In some embodiments, an antibody that binds to cells with endogenously expressed hMSR1 having a binding ratio of endogenously expressed hMSR1-expressing cells to non-expressing cells, measured by an antibody binding assay using, for example, a assay mode as defined in Example 5 of the present invention, or a substantially similar assay, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times or more, at least about 12 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 30 times, at least about 35 times, at least about 40 times, at least about 45 times, at least about 50 times or more, is provided herein.In some embodiments, the MSR1 antibody or antigen-binding fragment disclosed herein binds to processed cell-surface mouse MSR1 at a binding ratio of processed mouse MSR1-expressing cells to non-expressing cells of at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 12 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 30 times, at least about 35 times, at least about 40 times, at least about 45 times, at least about 50 times or more, as measured by an antibody binding assay, for example, using a assay mode as defined in Example 5 of the present invention or a substantially similar assay.

[0143] The embodiment also comprises an antibody and its antigen-binding fragment that bind to MSR1 and exhibit maximum inhibition of the uptake of modified low-density lipoprotein (LDL) in cells expressing less than about 95% of human MSR1. For example, the embodiment is measured using a ligand uptake assay, such as using a assay modality as defined, for instance, in Example 8 of the present invention, or a substantially similar assay, with an IC50 of less than about 6.1 nM. 50It includes an anti-MSR1 antibody that exhibits maximum inhibition of the uptake of modified LDL (e.g., oxidized or acetylated) in cells expressing less than 95% of human MSR1. Depending on a specific embodiment, for example, using a calibration modality as defined in Example 8 of the present invention, or a substantially similar calibration, as measured by a ligand absorption assay, ICs 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, and less than about 20 pM are 50 An anti-MSR1 antibody is provided that exhibits maximum inhibition of modified LDL uptake in cells expressing less than about 95% of human MSR1.

[0144] In some embodiments, the anti-MSR1 antibody is measured using a ligand uptake assay, for example, using a assay mode as defined in Example 8 of the present invention, or a substantially similar assay, 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, and less than about 20 pM. 50 As such, it exhibits maximum inhibition of modified LDL uptake in cells expressing less than approximately 90% of human MSR1.

[0145] In some embodiments, the anti-MSR1 antibody is measured using a ligand uptake assay, for example, using a assay mode as defined in Example 8 of the present invention, or a substantially similar assay, 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, and about 20 pM. 50 As such, it represents maximum inhibition of modified LDL uptake in less than 75% of human MSR1-expressing cells.

[0146] In some embodiments, the anti-MSR1 antibody is measured using a ligand uptake assay, for example, using a assay mode as defined in Example 8 of the present invention, or a substantially similar assay, 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, and less than about 20 pM. 50 As such, it exhibits maximum inhibition of modified LDL uptake in cells expressing less than approximately 60% of human MSR1.

[0147] In some embodiments, the anti-MSR1 antibody is measured using a ligand uptake assay, for example, using a assay mode as defined in Example 8 of the present invention, or a substantially similar assay, 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, and less than about 20 pM. 50 As such, it represents maximum inhibition of modified LDL uptake in cells expressing less than 50% of human MSR1.

[0148] The embodiments also include an antibody that binds to MSR1 expressed on the cell surface and is internalized by the cell, and an antigen-binding fragment thereof. For example, an antibody that binds to MSR1 expressed on the cell surface on THP-1 cells and is internalized by the cell is provided herein. For example, the present disclosure includes an anti-MSR1 antibody internalized by the cell at least about 10 percent relative percentage, measured by chemiluminescence using a assay mode as defined, for example, in Example 9 of the present invention, or a substantially similar assay. In a specific embodiment, the anti-MSR1 antibody binds to MSR1 expressed on the cell surface of THP-1 cells and is internalized by the cells at a relative percentage of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, as measured by chemiluminescence using, for example, a assay mode as defined in Example 9 of the present invention, or a substantially similar assay.

[0149] The antibodies disclosed herein may possess one or more of the biological properties mentioned above, or any combination thereof. The foregoing list of the biological properties of the antibodies disclosed herein is not intended to be exhaustive. Other biological properties of the antibodies disclosed herein will become apparent to those skilled in the art from a review of the disclosure, including the working examples thereof.

[0150] 항체-약물 접합체(ADC)

[0151] Antibody-drug conjugates (ADCs) comprising an anti-MSR1 antibody or an antigen-binding fragment thereof conjugated to a drug or therapeutic agent are provided herein. In some embodiments, the therapeutic agent is a liver X receptor (LXR) agonist or a steroid. Reactive linker payloads useful for manufacturing the ADC are also provided herein. Modified anti-MSR1 antibodies and modified MSR1 antibody-binding fragments useful for manufacturing the ADC are also provided herein.

[0152] ADC is generally the chemical formula (I): BA -[(L) 0-1 - PA It has ]n. In the chemical formula, BA is a binder, for example, anti-MSR1, antibody, or its MSR1 antigen-binding fragment. L is a linker described in detail below. PA is a payload. A suitable payload comprises any small molecule capable of providing therapeutic benefits through its delivery to MSR1. In certain embodiments, the payload may be, for example, a steroid, an LXR modulator, or a rifamycin analog. Useful payloads are described in detail below. In the chemical formula, n is an integer from 1 to 30, for example, from 1 to 4, for example, 2 or 4. Each L-PA is covalently bonded to the action group of PA. In some specific embodiments, each L-PA Is BAIt is covalently bonded to the lysine side chain, cysteine ​​side chain, glutamine side chain, or amino terminus.

[0153] Techniques and linkers for conjugating to residues of antibodies or antigen-binding fragments are known in the art. Exemplary amino acid conjugations that may be used in the context of such embodiments are, for example, lysine (Ref.: 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 ​​(cf.: 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 ​​(cf.: e.g., WO 2008 / 122039; and Hofer et al ., Proc. Natl. Acad. Sci., USA, 2008 , 105:12451-12456), formylglycine (Note: e.g., Carrico et al., Nat. Chem. Biol. , 2007, 3:321-322; Agarwal et al., Proc. Natl. Acad. Sci., USA, 2013, 110 : 46-51, and Rabuka et al., Nat. Protocols , 2012, 10:1052-1067), non-natural amino acids (cf.: e.g., WO 2013 / 068874, and WO 2012 / 166559), and acidic amino acids (cf.: e.g., WO 2012 / 05982). The linker also includes carbohydrates to the antigen-binding protein (cf.: e.g., US 2008 / 0305497, WO 2014 / 065661, and Ryan et al., Food & Agriculture Immunol., 2001, 13 : 127-130) and disulfide linkers (Note: e.g., WO 2013 / 085925, WO 2010 / 010324, WO 2011 / 018611, and Shaunak et al., Nat. Chem. Biol., 2006Conjugation can be achieved through attachment to ( , 2:312-313). Site-specific conjugation techniques can also be used to direct conjugation to specific residues of antibodies or antigen-binding proteins (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).

[0154] The linker can be conjugated to one or more glutamine residues via transglutaminase-based chemical-enzyme conjugation (Note: e.g., Dennler et al., 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 may be coupled to a primary amine compound. In summary, 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 enzymatic transglutaminase. The primary amine compound comprises a payload or a linker-payload, which provides an antibody-drug conjugate through transglutaminase-mediated coupling. The primary amine compound also comprises a linker and a spacer functioned as a reactive group capable of subsequently reacting with additional compounds toward the synthesis of the antibody-drug conjugate. An antibody containing a glutamine residue may be isolated from a natural source or processed to contain one or more glutamine residues. The technique for processing glutamine residues into an antibody polypeptide chain (a glutamyl-modified antibody or antigen-binding molecule) is within the skill of those skilled in the art. In a specific embodiment, the antibody is aglycosylated.

[0155] In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises at least one glutamine residue within at least one polypeptide chain sequence. In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises two heavy-chain polypeptides, each having one Gln295 residue. In further embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule comprises one or more glutamine residues at sites other than heavy-chain 295. In some embodiments, the antibody may insert glutamine residues at a site without producing antibody function or binding impaired by site-directed mutagenesis. For example, antibodies having Asn297Gln(N297Q) mutation(s) as described herein are included herein. In some embodiments, an antibody having a Gln295 residue and / or an N297Q mutation contains one or more additional naturally occurring glutamine residues within its variable region, which are accessible via transglutaminase and thus can be conjugated to a linker or linker-payload. An exemplary naturally occurring glutamine residue can be found, for example, at Q55 of the light chain. In such examples, the antibody conjugated via transglutaminase may have a higher DAR value than expected (e.g., a DAR exceeding 4). Any such antibody may be isolated from a natural or artificial source.

[0156] A primary amine compound useful for transglutaminase-mediated coupling of an antibody (or antigen-binding compound) containing glutamine may be any primary amine compound considered useful by a person skilled in the art. Generally, the primary amine compound has the formula H2N-R, where R may be any group compatible with the antibody and reaction conditions. In certain embodiments, R is alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0157] In some embodiments, the primary amine compound comprises a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkyl, thiols, alcohols, ketones, aldehydes, acids, esters, hydrogenides, anilines, and amines. In certain embodiments, the reactive group is selected from the group consisting of azides, alkynes, sulfhydryls, cycloalkyls, aldehydes, and carboxyls.

[0158] In a specific embodiment, the primary amine compound is of the formula H2N- LL-X According to, here LL 2 is a spacer and X is a reactive group or a protected reactive group. In a special embodiment, LL is a divalent polyethylene glycol (PEG) group. In a specific embodiment, X is selected from the group consisting of -SH, -N3, alkynes, aldehydes, and tetrazole. In a special embodiment, X is -N3.

[0159] In a specific embodiment, the primary amine compound corresponds to one of the following chemical formulas:

[0160] H2N-(CH2) n -X;

[0161] H2N-(CH2CH2O) n -(CH) p -X;

[0162] H2N-(CH2) n -N(H)C(O)-(CH2) m -X;

[0163] H2N-(CH2CH2O) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X;

[0164] H2N-(CH2) n -C(O)N(H)-(CH2) m -X;

[0165] H2N-(CH2CH2O) n-C(O)N(H)-(CH2CH2O) m -(CH2) p -X;

[0166] H2N-(CH2) n -N(H)C(O)-(CH2CH2O) m -(CH2) p -X;

[0167] H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X;

[0168] H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and

[0169] H2N-(CH2CH2O) n -C(O)N(H)-(CH2) m -X;

[0170] Here, n is an integer selected from 1 to 12;

[0171] m is an integer selected from 0 to 12;

[0172] p is an integer selected from 0 to 2;

[0173] X is -SH, -N3, -C≡CH, -C(O)H, tetrazole, and any

[0174] It is selected from a group consisting of.

[0175] In the above, any alkyl or alkylene (i.e., -CH2-) group is, for example, C 1-8 It may be optionally substituted with alkyl, methylformyl, or -SO3H. In certain embodiments, the alkyl group is unsubstituted.

[0176] In a specific embodiment, the primary amine compound is selected from the group consisting of the following:

[0177]

[0178] In a specific embodiment, the primary amine compound is am.

[0179] Exemplary conditions for the above reaction are provided in the following examples:

[0180] Accordingly, a modified anti-MSR1 antibody linked to one or more primary amine compounds, and an antigen-binding fragment thereof are provided herein. In a specific embodiment, a modified anti-MSR1 antibody according to the following formula, and an antigen-binding fragment thereof are provided herein:

[0181]

[0182] In the chemical 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 1 to BA It is the number of glutamine residues. In certain embodiments, n is 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 antibody and its antigen-binding fragment are, for example, one or more L-PA It is useful for forming ADCs by linking to molecules.

[0183] In a specific implementation example, BA It comprises 2 to 4 glutamine residues. In a specific embodiment, BA It includes Q295 residues. In a specific embodiment, BA It includes the N297Q mutation. In certain embodiments, BA It includes Q295 and N297Q. In this embodiment, BA Since it can be dimeric, BA Is L-PA It has four glutamine residues for conjugation to the moiety.

[0184] 화합물

[0185] In one embodiment, a compound and / or antibody-drug conjugate comprising any antibody or antigen-binding fragment thereof described herein is optionally conjugated to a payload residue via a linker or a linker-spacer is provided herein.

[0186] In the group of embodiments, the compound and / or antibody-drug conjugate has the chemical formula ( I It has the structure of ):

[0187] Chemical formula ( I )

[0188] Here:

[0189] BA is a binder;

[0190] L is a linker;

[0191] PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin analog residues;

[0192] The subscript n is an integer from 1 to 30.

[0193] In the group of embodiments, the compounds and / or antibody-drug conjugates described above and herein have the formula ( YES It has the structure of ):

[0194] Chemical formula ( YES )

[0195] Here

[0196] SP 1 is absent or a spacer;

[0197] RG 1 is a reactive group residue;

[0198] AA 1 is a divalent or trivalent linker comprising an amino acid residue that is absent or arbitrarily bound directly or indirectly to group HG;

[0199] AA 2 is absent, or is a dipeptide, tripeptide, or tetrapeptide residue;

[0200] Q is a connector group residue if it exists;

[0201] SP is absent or a spacer;

[0202] HG If present, it is a hydrophilic group.

[0203] In the group of embodiments, the compounds and / or antibody-drug conjugates described above and herein have the formula ( IB-1 It has the structure of ):

[0204] Chemical formula ( IB-1 )

[0205] Here

[0206] SP 1 is absent, or is a spacer;

[0207] RG 1 is a reactive group residue;

[0208] Q If it exists,

[0209] Igo

[0210] SP is absent or a spacer;

[0211] Here This indicates that the referenced group represents an atom bonded to an adjacent group within the chemical formula.

[0212] In the group of embodiments, the compounds and / or antibody-drug conjugates described above and herein have the formula ( IB-2 It has the structure of ):

[0213] Chemical formula ( IB-2 )

[0214] Here

[0215] SP 1 is absent, or is a spacer;

[0216] RG 1 is a reactive group residue;

[0217] AA 1 is absent, or group HG It is a divalent or trivalent linker comprising an amino acid residue arbitrarily bonded directly or indirectly to;

[0218] AA 2 is absent, or is a dipeptide, tripeptide, or tetrapeptide residue;

[0219] Q is, if it exists, or And;

[0220] SP is absent, or is a spacer;

[0221] HG If it exists,

[0222] And,

[0223] Here This indicates that the reference group represents an atom bonded to an adjacent group within the chemical formula.

[0224] In the group of embodiments, the compound and / or antibody-drug conjugate described above and herein has the structure of formula (IC), formula (ID), or formula (IE):

[0225] Chemical formula (IC)

[0226] Chemical formula (ID)

[0227] Chemical formula (IE)

[0228] Here

[0229] SP 1 is absent, or is a spacer;

[0230] RG 1 is a reactive group residue;

[0231] SP 2 is absent, or is a spacer;

[0232] RG 2 is a reactive group residue;

[0233] AA 1 is a divalent or trivalent linker containing amino acid residues;

[0234] AA 2 is a dipeptide, tripeptide, or tetrapeptide residue;

[0235] Q is, if it exists, And;

[0236] SP is absent, or is a spacer;

[0237] HG Is

[0238] And,

[0239] Here This indicates that the reference group represents an atom bonded to an adjacent group within the chemical formula. In some or any examples, for any compound and / or antibody-drug conjugate described above and herein, AA 1 -AA 2 is the chemical formula ( LL1 According to ):

[0240]

[0241] Here RAA 1 , RAA 2 , and RAA 3 Each independently, at least one of -(RG 2 )-SP 2 -HG, -(RG 2 )-HG or HG It is an amino acid side chain connected to; here is through this AA 1 -AA 2 represents an atom bonded to an adjacent group within the chemical formula. In some of these embodiments, R AA1 silver HG It is a lysine, glutamine, glutamic acid, or aspartic acid side chain directly or indirectly bound to, and R AA2 and R AA3 These are valine and alanine or citrulline side chains, respectively.

[0242] In some or any example, in the case of any compound and / or antibody-drug conjugate described above and herein, AA 1 -AA 2 Is or and, here is through this AA 1 -AA 2 represents an atom bonded to an adjacent group within the chemical formula.

[0243] In some or any example, in the case of any compound and / or antibody-drug conjugate described above and herein, RG 1 and RG 2 In each case, the residue is independently selected from the following group:

[0244]

[0245]

[0246] And;

[0247] Here is through this RG 1 or RG 2 A residue represents an atom bonded to an adjacent group within the chemical formula.

[0248] In some or any example, in the case of any compound and / or antibody-drug conjugate described above and herein, SP, SP 1 and SP 2 In each case, independently absent, or C 1-6 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 Selected from -, (glycine)4-serine, and combinations thereof, where 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.

[0249] In some or any example, for any compound and / or antibody-drug conjugate described above and herein, n is an integer from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or n is 1, 2, 3, or 4.

[0250] In some or any example, in the case of any compound, linker-payload, and / or antibody-drug conjugate described above and herein, Is

[0251]

[0252]

[0253]

[0254]

[0255] am.

[0256] In some or any embodiment, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or its antigen-binding fragment, is conjugated to a steroid payload through a linker or linker-spacer.

[0257] In some or any embodiment, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or its antigen-binding fragment, is conjugated to an LXR regulator payload via a linker.

[0258] In some or any embodiment, for any compound and / or antibody-drug conjugate described above and herein, the antibody, or its antigen-binding fragment, is conjugated to a rifamycin analog payload via a linker.

[0259] 페이로드

[0260] Chemical formula ( I ) BA -[ L-PA ] n at, PA may be any payload considered useful. Such payloads include small molecules that provide therapeutic benefits through their delivery via MSR1. In certain embodiments, PA is a residue of a molecule selected from the group consisting of steroids, LXR modulators, or rifamycin analogs. 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. An exemplary LXR modulator payload is, for example, published in US No. 2018 / 0334426, the full text of which is incorporated herein by reference, " BUSIt is described in U.S. Patent No. 62 / 508,327, filed on May 18, 2017, under the title "-OCTAHYDROPHENANTHRENE CARBOXAMIDES AND PROTEIN CONJUGATES THEREOF". In some examples PA is a rifamycin analog, comprising any rifamycin analog described herein. In some examples, PA is a rifalogue with the following structure:

[0261]

[0262] In a specific embodiment, chemical formula ( I In a compound of ), the payload is the chemical formula ( A It is a glucocorticoid or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof according to ):

[0263] Chemical formula ( A )

[0264] Here,

[0265] R 1 and R 2 is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halo; or R 1 and R 2 together Forms,

[0266] Here R 4 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl, and

[0267] Here, alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are independently in each case -NR Aa R Ab Arbitrarily substituted as;

[0268] R 3 -OH,R Z -C(O)- X -, heteroalkyl, piperidinyl, -NR Aa R Ab , -oxyaryl -NR Aa R Ab or -Z-A'(R P ) t And;

[0269] R Z is alkyl and;

[0270] X is O or NR Aa And;

[0271] Z is S, S(O), S(O)2, SO2 NR Aa , O, C(O) NR Aa , C(O), or NR Aa And;

[0272] A' is an aryl, arylalkyl, or heteroaryl;

[0273] R P is, independently in each case, a halo, an optionally substituted alkyl, -OH, or -NR Aa R Ab And;

[0274] R Aa and R Ab is, independently in each case, -H, an optionally substituted alkyl, or an optionally substituted aryl;

[0275] Subscript a is an integer from 0 to 19;

[0276] t is an integer from 1 to 3;

[0277] step:

[0278] (1) R 3 (a) R 1 This is -OH or (b) R 1 and R 2 Together (Here, R 4 is C 1-9 alkyl or In the case of forming (is), it is not -OH

[0279] (2) R 3 silver It is not,

[0280] R 5A and R 5B Each is independently a halo or hydrogen atom;

[0281] Here, the group R 3 or R 4 It is combined with the linker.

[0282] In some of these implementations, R 3 is NH2. In some other such implementations, R 3 silver and here is through this R 3 This represents the atoms attached to adjacent groups within this chemical formula (I).

[0283] In a specific implementation example, PA... is a steroid. Exemplary steroid payloads are described, for example, in U.S. Patent No. 62 / 614,905 filed January 8, 2018, titled "STEROIDS AND ANTIBODY CONJEGATES THEREOF," each of which is incorporated herein by reference, and in U.S. Patent No. 15 / 806,197 filed November 7, 2017, titled "STEROIDS AND PROTEIN-CONJUGATE THEREOF," disclosed in U.S. Patent No. 2018 / 0155389. In a specific embodiment, PA is

[0284] or is selected from its pharmaceutically acceptable salts, solvates, or stereoisomers. In specific embodiments according to any of formulas 1110 to 1140, R 3 -O-aryl, -NR Aa R Ab , -alkylene -NR Aa R Ab , -X-arylene-Y -NR Aa R Ab , -X-heteroarylene-Y -NR Aa R Ab , or N-containing heterocycloalkyl; where X is absent, or -N-, -CH2-, or -O-; where Y is absent or -CH2-; R 4 is an alkyl, aryl, alkylaryl, or arylalkyl. In certain embodiments, R 3 -O-arylene -NR Aa R Ab , -O-heteroarylene -NR Aa R Ab and; where the aryl or heteroaryl is optionally substituted with a halogen, deuterium, hydroxyl, or methoxyl. In certain embodiments, R 3 -O-phenyl -NR Aa R Ab , -O-heteroarylene -NR Aa R Ab and; where the phenyl or heteroaryl is optionally substituted with a halogen or deuterium. In certain embodiments, R 4 is an n-profile. In a specific implementation, R Aa and R Ab Each is independently hydrogen or alkyl. In a specific embodiment, R Aa and R Ab One of them is a linker (e.g., L or LL It is replaced by a combination for ). In a specific embodiment, PA Is

[0285] or a pharmaceutically acceptable salt, solvate, or stereoisomer 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. 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. In certain embodiments, PA Is , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this embodiment, the dashed line is a linker (e.g., L or LL Represents the combination for ).

[0286] In a specific implementation example, PA is selected from the following residues:

[0287]

[0288]

[0289]

[0290] or a pharmaceutically acceptable salt or stereoisomer thereof. In a specific embodiment, the primary or secondary amine is a linker L It is connected to form a linker payload, which BA It is connected to form a conjugate. The technician [describes] the bonding to a primary or secondary amine group to which the compound substitutes for H. L You will recognize that it can be combined with.

[0291] In some embodiments, the anti-MSR1 antibody described herein is It is joined to.

[0292] In some embodiments, the antibody-drug conjugate described herein comprises a steroid payload, wherein the steroid payload is selected from the group consisting of the following:

[0293] , or a mixture thereof.

[0294] In a specific implementation, PA is:

[0295] , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0296] , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0297] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0298] In a specific implementation, PA Is:

[0299] , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0300] , or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0301] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0302] In a specific implementation example, PA is liver X receptor ( LXR ) is a regulator. In a specific implementation, PA is the chemical formula ( B ):

[0303] (Chemical formula (B)) or according to its pharmaceutically acceptable salt, solvate, or stereoisomer form, wherein

[0304] W is -CH2-, -N(H)-, or -O-;

[0305] R B1 -H, -OH, -NH2, alkyl, or -OP(O)(O R 6 )2 and;

[0306] R B2 -H, -OH, -CH2NH2, R B3 , R B4 , R B5 , or -O- R B5 and, here R B1 and R B2 is not -H at the same time;

[0307] R B3 is -N(R 6 )2 and;

[0308] R B4 Is -XYZ And;

[0309] X is selected from the group consisting of -O- and -N(H)-;

[0310] Y is selected from the group consisting of alkylenes, substituted alkylenes (including, without limitation, oxo substitution (i.e., =O)), heteroalkylenes, and substituted heteroalkylenes (including, without limitation, oxo substitution (i.e., =O));

[0311] Z is selected from the group consisting of -OH and -NH2;

[0312] R B5 is an alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and comprises at least one -OH and -CH2OH substituent, or comprises at least one primary or secondary nitrogen, e.g., O-glucose;

[0313] Each R 6 In each case, is -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an alkyl;

[0314] Each R 7 Eun, independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, and O-PEG band, where each subscript b is an integer from 0 to 3;

[0315] Here, the group R B1 , R B2 or R 7 It is combined with the linker.

[0316] In a specific embodiment, R B1 or R B2 is a linker (e.g., L or LL It is replaced by a combination for ).

[0317] In a specific implementation example, PA Is:

[0318] Selected from.

[0319] In a specific embodiment, My dashed line is a linker (e.g., L or LL Represents the combination for ).

[0320] In a specific embodiment, chemical formula ( B The payload of ) is selected from the following group:

[0321]

[0322]

[0323] or a pharmaceutically acceptable stereoisomer form thereof.

[0324] In a specific implementation example, PA Is:

[0325] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0326] In a specific implementation example, PA Is:

[0327] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0328] In a specific implementation example, PA Is:

[0329] , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0330] In some embodiments, the anti-MSR1 antibody described herein is conjugated to the following:

[0331]

[0332] In some implementations, PA is the chemical formula ( B-1 It is a liver X receptor (LXR) modulator depending on ) or its pharmaceutically acceptable salt, solvate, or stereoisomer form:

[0333] Chemical formula ( B-1 ),

[0334] Here

[0335] R B1 -N(H) R 8 or -N( R 9 )2 and;

[0336] R B2 is -N(H) R 8 And;

[0337] Each R 8 ...is, independently in each case, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety, or an alkyl;

[0338] R 9 is an alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and, if substituted, comprises at least one -OH and -CH2OH, or at least one primary or secondary nitrogen;

[0339] Each R 7 is independently Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG b and, where each subscript b is an integer from 0 to 3;

[0340] Here, the group R B1 , R B2 or R 7 It is combined with the linker.

[0341] In some examples, chemical formula ( B-1 The compound of ) is selected from the group consisting of the following:

[0342]

[0343]

[0344]

[0345] or a pharmaceutically acceptable salt or solvate thereof.

[0346] In a specific embodiment, R B1 or R B2 is a linker (e.g., L or LL It is replaced by a combination for ).

[0347] In a specific implementation example, PA Is

[0348] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0349] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0350] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is:

[0351] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is

[0352] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is

[0353] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is

[0354] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is

[0355] or a pharmaceutically acceptable salt or stereoisomer thereof. In certain embodiments, PA Is

[0356] or a pharmaceutically acceptable salt or stereoisomer thereof. In some of these embodiments, P10B The carboxylic acid group is bonded to the linker via an amide linkage as indicated above. In a specific embodiment, PA Is

[0357] or a pharmaceutically acceptable salt or stereoisomer thereof. In some of these embodiments, P11BThe carboxylic acid group is bonded to the linker via an amide linkage as shown above. In a specific embodiment, PA Is P3B , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0358] In the case of any embodiment described in this paragraph, In this context, the dashed line is a linker as described herein (e.g., L or LL Represents the combination for ).

[0359] In a group of embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided herein:

[0360] Chemical formula ( III );

[0361] Here:

[0362] R 34 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl;

[0363] R x Both are hydrogen; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1 -(Here X 1 is the chemical formula ( III )at L' is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( III )at L' is attached to), -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( III )at L' is attached to), (Here, the attachment point on the right side (i.e., at N) is the chemical formula ( III )at L' It is attached to), -CH2-NH-(where N is the chemical formula ( III )at L' is attached to), (Here, N is the chemical formula ( III )at L' Attached to, where Ar is an arbitrarily substituted arylene or an arbitrarily substituted heteroarylene, -(C1-C 10 -alkylene)- NR 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)- NR 50a -(Here N R 50a is the chemical formula ( III )at L' Attached to and here each C1-C 10 -alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 35 )-C1-C 10 -alkylene-C(O)NH- X 2 -(Here X 2 is the chemical formula ( III )at L' is attached to), or (Here X 4 is the chemical formula ( III )at L' (is attached to) or;

[0364] R x Both are fluoro, and; SPis -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1b -(Here X 1b is the chemical formula ( III )at L' is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)- X 1b -(Here X 1b is the chemical formula ( III )at L' is attached to), (Here, the attachment point on the right side (i.e., at N) is the chemical formula ( III )at L' It is attached to), -CH2-NH-(where N is the chemical formula ( III )at L' is attached to), (Here, N is the chemical formula ( III )at L' Attached to and here Ar is an arbitrarily substituted arylene or an arbitrarily substituted heteroarylene), -(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' Attached to and here each C1-C 10-alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 35 )-(C1-C 10 -alkylene)-C(O)NH- X 2 -(Here X 2 is the chemical formula ( III )at L' is attached to), or (Here X 4 is the chemical formula ( III )at L' is attached to) and;

[0365] X 1 is -N(C 1-6 alkyl)- and;

[0366] X 1b is -S-, -NH-, or -N(C 1-6 alkyl)- and;

[0367] X 2 is -NH- and;

[0368] X 3 is -CH2- and, X 3 -CH2-O-(C1-C 10 -alkylene)-C(O)-(where C(O is X 4 is attached to) or X 3 is -C(O)- and;

[0369] X 4 is -O- and;

[0370] R 35 is H, -OH, -OCH3, or C 1-6 It is alkyl;

[0371] R 50 and R 50a is independently hydrogen or C1-C6-alkyl; R d , R e , and R f is independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH2O R g and, here, each R g is independently -CH2C(O)OH or -CH2C(O)O(alkyl);

[0372] mm is 0 or 1;

[0373] n is an integer selected from 1 to 30 (including boundaries);

[0374] L' is a linker;

[0375] BA is a binder.

[0376] In some embodiments, in a compound of formula (III), R x Both are hydrogen, and SP , BA , L' , R 34 , and n ...is as defined herein in some or any embodiments. In some embodiments, in the compound of formula (III), R x Both are fluoro, and SP , BA , L' , R 34 , and n ...is as defined herein in some or any embodiment. In some embodiments, R 34 is an R-structure. In some implementations, R 34 is an S-structure. In some embodiments, R 34 is a mixture of R- and S-structures. In some embodiments, R 34 is a mixture of R- and S-structures, where 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.

[0377] In some embodiments, chemical formula ( III It is a compound of ) and here

[0378] R x Both are hydrogen; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1 -(Here X 1 is the chemical formula ( III )at L' is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( III )at L' is attached to), -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( III )at L' is attached to), -(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L'Attached to and here each C1-C 10 -alkylene is independently substituted with one or more hydroxyl groups), -C(O)-N( R 5 )-C1-C 10 -alkylene-C(O)NH- X 2 -(Here X 2 is the chemical formula ( III )at L' is attached to), or (Here X 4 is the chemical formula ( III )at L' (is attached to) or;

[0379] R x Both are fluoro, and; SP is -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1b -(Here X 1b is the chemical formula ( III )at L' is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)- X 1b -(Here X 1b is the chemical formula ( III )at L' is attached to), (Here, the attachment point on the right side (i.e., N) is the chemical formula ( III )at L' is attached to), -(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( III )at L' Attached to and here each C1-C 10 -alkylene is independently optionally substituted with one or more hydroxyl groups), or -C(O)-N( R 5 )-(C1-C 10 -alkylene)-C(O)NH- X 2 -(Here X 2 is the chemical formula ( III )at L' It is attached to)

[0380] In some embodiments, chemical formula ( I The compound of ) has the chemical formula ( 3000 ): BA-(L'-SP-D ) n Chemical formula ( 3000 It is a compound of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,

[0381] Here

[0382] D is selected from the following a) and b):

[0383] a) Chemical formula (a),

[0384] Here, from chemical formula (a) R x is hydrogen; R 34 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1 -(Here X 1 is the chemical formula ( 3000(Attached to L' in ), -C(O)-N(H)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( 3000 (Attached to L' in ), -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( 3000 It is attached to L' in ), (Here, the attachment point on the right side (i.e., N) is the chemical formula ( 3000 )at L' is attached to), (Here, N is the chemical formula ( 3000 )at L' Attached to and here Ar is an arbitrarily substituted arylene (in some embodiments ) or any substituted heteroarylene, -(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( 3000 )at L' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a - and (here N R 50a is the chemical formula ( 3000 )at L' Attached to and here each C1-C 10 -alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 35 )-C1-C 10 -alkylene-C(O)NH- X 2 -(Here X 2 is the chemical formula ( 3000 )at L'is attached to), or (Here X 4 is the chemical formula ( 3000 )at L' is attached to), or

[0385] Here, from chemical formula (a) R x Both are fluoro, and; R 34 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1b -(Here X 1b is the chemical formula ( 3000 )at L' is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)- X 1b -(Here X 1b is the chemical formula ( 3000 )at L' is attached to), (Here, the attachment point on the right side (i.e., N) is the chemical formula ( 3000 )at L' It is attached to), -CH2-NH-(where N is the chemical formula ( 3000 )at L' is attached to), (Here, N is the chemical formula ( 3000 )at L Attached to where Ar is an arbitrarily substituted arylene (in some embodiments) ) or any substituted heteroarylene, -(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( 3000 )atL' is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( 3000 )at L' Attached to and here each C1-C 10 -alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 35 )-(C1-C 10 -alkylene)-C(O)NH- X 2 -(Here X 2 is the chemical formula ( 3000 )at L' is attached), or (Here X 4 is the chemical formula ( 3000 )at L' attached); and / or

[0386] b) Compounds in Table A below, wherein the compounds in Table A are formed through the hydroxyl group of the -C(O)CH2OH group, i.e., -C(O)CH2-O-0- SP-L' -by, or through the hydroxyl of Mapracolat, i.e., -O- SP-L' Chemical formula by ( III of the compound of ) BA Connected to;

[0387] X 1 is -N(C 1-6 alkyl)- and;

[0388] X 1b is -S-, -NH-, or -N(C 1-6 alkyl)- and;

[0389] X 2 is -NH- and;

[0390] X 3 is -CH2- or, X 3 -CH2-O-(C1-C 10 -alkylene)-C(O)-(where C(O) is X 4 (is attached to) or, X 3 is -C(O)- and;

[0391] X 4 is -O- and;

[0392] R 35 is H, -OH, -OCH3, or C 1-6 It is alkyl;

[0393] R 50 and R 50a is independently hydrogen or C1-C6-alkyl;

[0394] R d , R e , and R f is independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH2O R g and, here, each R g is independently -CH2C(O)OH or -CH2C(O)O(alkyl);

[0395] mm is 0 or 1;

[0396] n is an integer selected from 1 to 30;

[0397] L' is a linker;

[0398] BA is a binder.

[0399] Chemical formula ( 3000 In some examples of ), Dis budesonide or any other steroid shown in Table A. Chemical formula ( 3000 In some examples of ), D is any budesonide analogue described herein. In Table A, the compounds are formed through the hydroxyl group of the -C(O)CH2OH group, i.e., -C(O)CH2-O- SP-L′ -by, or through the hydroxyl of mapracolat, i.e., -OS PL Chemical formula by ( III of the compound of ) BA It connects to. Chemical formula ( 3000 In some examples of ), moiety SP-D (or H-SP-D ) is referred to herein as "budesonide-spacer" and, for example, the example paragraph and 표 22 Reaction scheme 1 includes the budesonide-spacer shown in Table B.

[0400] [Table A]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406] [Table B]

[0407]

[0408]

[0409]

[0410]

[0411] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some examples, in each of the above structures The n-profile of, that is, exists as an R-structure at the carbon indicated by an asterisk. In some examples, at each of the above structures The n-profile of, that is, exists as an S-structure at the carbon indicated by an asterisk. In some examples, at each of the above structures The n-profile is, that is, a mixture of R- and S-structures at the carbon indicated by an asterisk. In some examples, each of the above structures The n-profile of is, that is, a mixture of R- and S-structures at the carbon indicated by an asterisk, where 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.

[0412] In various implementations, Ab-L'-SP-D of -SP-D or chemical formula ( 3000 )of Is

[0413]

[0414]

[0415] Selected from, and here is a combination for the linker.

[0416] In some examples, in each of the above structures The n-profile of, that is, exists as an R-structure at the carbon indicated by an asterisk. In some examples, at each of the above structures The n-profile of, that is, exists as an S-structure at the carbon indicated by an asterisk. In some examples, at each of the above structures The n-profile is, that is, a mixture of R- and S-structures at the carbon indicated by an asterisk. In some examples, in each of the above structures The n-profile of is, that is, a mixture of R- and S-structures at the carbon indicated by an asterisk, where 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.

[0417] In various implementations, is selected from Table B, , or Selected from.

[0418] In some embodiments, the payload is a chemical formula ( C It is a rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof;

[0419] Chemical formula ( C )

[0420] Here:

[0421] X 1c -O-, -S-, and -N R 5c Selected from;

[0422] R 1c is hydrogen; amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; di-C 1-6 Alkylamino C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-OC 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-SC 1-6 Alkyl; heterocycloalkyl or heterocycloalkyl-C 1-6 It is an alkyl; where the heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from O, N, and S; where the heterocycloalkyl is a halo, C 1-6 Alkyl, -OH, =O, or -N( R 5c )2 is arbitrarily substituted;

[0423] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected independently from;

[0424] R ac -F; -Cl; -Br; -I; -OH; -NH2; and C 1-6 Selected from alkoxy;

[0425] R bc is hydrogen in each existence;

[0426] R 5c is hydrogen in the presence of each; and C 1-6 Independently selected from alkyls;

[0427] step, R 1c is not an n-butyl group;

[0428] step X 1c In the case of -O-, R 1c is not hydrogen;

[0429] Here, the group R 1c It is combined with the linker.

[0430] In some embodiments, the payload is a chemical formula ( C-1 It is a rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof:

[0431] Chemical formula ( C-1 )

[0432] Here:

[0433] X 1c -S-; -O- and -N R 5c Selected from;

[0434] R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; di-C 1-6 Alkylamino C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-OC 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-SC 1-6 Alkyl; heterocycloalkyl or heterocycloalkyl-C 1-6 It is an alkyl; where the heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from O, N, and S; where the heterocycloalkyl is a halo, C 1-6 Alkyl, -OH, =O, or -N( R 5c )2 is arbitrarily substituted;

[0435] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected independently from; each R ac -F; -Cl; -Br; -I; -OH; -NH2; and C are present. 1-6 Independently selected from alkoxy;

[0436] R 5c is independently, hydrogen in the presence of each; and C 1-6 Selected from alkyls;

[0437] Here, the group R 1c It is combined with the linker.

[0438] In some embodiments, the payload is a chemical formula ( C-2 It is a rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof:

[0439] Chemical formula ( C-2 )

[0440] Here:

[0441] X 1c -S-; -O- and -NR 5c Selected from;

[0442] R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; di-C 1-6 Alkylamino C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-OC 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-SC 1-6 Alkyl; heterocycloalkyl or heterocycloalkyl-C 1-6 It is an alkyl; where the heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from O, N, and S; where the heterocycloalkyl is a halo, C 1-6 Alkyl, -OH, =O, or -N( R 5c )2 is arbitrarily substituted;

[0443] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from;

[0444] R ac and R bc -F; -Cl; -Br; -I; -OH; -NH2; and C 1-6 Independently selected from alkoxy;

[0445] R 5c is, in the presence of each, hydrogen; and C 1-6 Independently selected from alkyls;

[0446] Here, the group R 1c It is combined with the linker.

[0447] In some embodiments, the payload is a chemical formula ( C-3 It is a rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof:

[0448] Chemical formula ( C-3 )

[0449] Here:

[0450] R 1c is D-C 1-6 Alkylamino C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N(R 5c )-C 1-6 Alkyl; heterocycloalkyl or heterocycloalkyl-C 1-6 It is an alkyl; where the heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from O, N, and S; where the heterocycloalkyl is a halo, C 1-6Alkyl, -OH, =O, or -N( R 5c )2 is arbitrarily substituted;

[0451] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from;

[0452] R 5c is hydrogen and C 1-6 Selected from alkyls;

[0453] Here, the group R 1c It is combined with the linker.

[0454] In some embodiments, the payload is a chemical formula ( C-4 It is a rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof:

[0455] Chemical formula ( C-4 )

[0456] Here:

[0457] R 1c Is or And;

[0458] Here, Y is C or N and;

[0459] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from;

[0460] R 5c is hydrogen and C 1-6 Selected from alkyls;

[0461] Here, the group R 1c is a dashed line It is bonded to the linker through the nitrogen atom represented by.

[0462] Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), R bc is hydrogen and / or R ac is hydrogen. Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), R 2c is methyl, ethyl, propyl, or isopropyl, preferably methyl. Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), R 3c is a CH3-(C=O)-(acetyl) group, CH3CH2-(C=O)-, CH3CH2CH2-(C=O)-, or (CH3)2CH-(C=O)-; preferably, it is acetyl. Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), R 4c is hydrogen.

[0463] Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), -O R 1c Is or It is one or more of the following. Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), -O R 1c Is and / or am.

[0464] Chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 In some or any implementation of ), X 1c is O and -O R 1c comprises a tertiary amine, and the tertiary amine changes into a quaternary amine after being bonded to a linker. In some such embodiments, -O R 1c Is or is. In this embodiment, where a quaternary amine is formed, a suitable counterion is present, namely, the rifamycin analog is a pharmaceutically acceptable salt comprising a positively charged quaternary amine, and the salt, for example, a negatively charged counterion that balances the charge (e.g., I - , Br - , Cl - or exists as any other suitable counterion.

[0465] In some embodiments, chemical formula ( C-1 ) and / or ( C-2 ) and / or ( C-3 ) and / or ( C-4 The compound of ) is selected from the group consisting of the following:

[0466]

[0467] ,

[0468] Here is a combination for the linker.

[0469] 링커

[0470] Chemical formula ( I ), ( III ), or ( 3000 In some implementations of ), L -L 1 -L 2 -(L 3 ) 0-1 - including L 2 Is

[0471]

[0472]

[0473] -OCH2C(O)-, or cyclodextrin residue( CD ); or includes a combination thereof. In some embodiments, L silver - L 1 - L 2 -( L 3 ) 0-1 - including L 2 Is , or CD , or a combination thereof. In some embodiments, L silver - L 1 - L 2 -( L 3 ) 0-1 - including L 2 Is CD Includes. In some embodiments, L and / or L 2 go CD If including, CD is selected from the following groups:

[0474]

[0475]

[0476] Chemical formula ( I ), ( III ), or ( 3000 In some implementations of ), L silver - L 1 - L 2 -( L 3 ) 0-1 - including L 2 is as described herein HG Includes. In some embodiments, L and / or L 2 Is Includes. In some embodiments, L and / or L 2 Is Includes

[0477] Chemical formula ( I ), ( III ), or ( 3000 In some implementations of ), L silver - L 1 - L 2 -( L 3 ) 0-1 - including, L 1 silver or its regioisomer or mixture of isomers; or comprising a stereoisomer thereof or a mixture of stereoisomers (wherein S is a reactive group residue therethrough BA Refers to the S atom on the cysteine ​​residue attached to); and (Here, N is the reactive group residue through this BA It is selected from (referring to the N atom on the lysine residue attached to).

[0478] In some implementations, L is as described herein - L 1 - L 2 -( L 3 ) 0-1 - and - L 2 -( L 3 ) 0-1 Includes -. In some embodiments, L is the chemical formula ( III ) and chemical formula ( 3000 As described regarding ) The -SP is. In some implementations L It includes the following:

[0479]

[0480]

[0481]

[0482]

[0483]

[0484] In some examples, chemical formula ( I ) or ( III ) or ( 3000 The compound of )

[0485] or selected from its stereoisomer form, or its regioisomer, or a mixture of its regioisomers, and

[0486] Here

[0487] Each Ab is an anti-MSR1 antibody, or its antigen-binding fragment;

[0488] Each n is an integer from 1 to 4.

[0489] In some examples, chemical formula ( I ) or ( III ) or ( 3000 The compound of )

[0490]

[0491]

[0492]

[0493]

[0494]

[0495] or selected from its stereoisomer form, or its regioisomer, or a mixture of its regioisomers, and

[0496] Here

[0497] Each Ab is an anti-MSR1 antibody, or its antigen-binding fragment;

[0498] Each BA Is and, here Ab 1 is an anti-MSR1 antibody, or its antigen-binding fragment; R C 2-4 - It is an alkylene; nn is an integer selected from 2 to 4 (including boundaries) and

[0499] Each n is an integer from 1 to 4.

[0500] In some additional embodiments, the ADC described herein may include a linker described in US No. 9,951,141 B2, filed November 29, 2016 and granted April 24, 2018, which is incorporated herein by reference. In some examples, the linker (Here, b is an integer from 2 to 8 and ...is a binding to the binder) includes. In some embodiments, the linker includes two reactive groups and can form a binding with a thiol on two different chains of, for example, an antibody or its antigen-binding fragment: (where b is an integer from 2 to 8). In a further embodiment, the linker comprises two reactive groups and can form a bond with a thiol on two different chains on, for example, an antibody or its antigen-binding fragment: (where b is an integer from 2 to 8). In some other embodiments, the linker comprises two reactive groups and may form a bond with a thiol on two different chains on, for example, an antibody or its antigen-binding fragment: (Here, b is an integer from 2 to 8, and R N It is a hydrogen atom or an alkyl, and R M is an alkyl. In a further embodiment, the linker comprises two reactive groups and can form a bond with a thiol on two different chains of, for example, an antibody or its antigen-binding fragment: (where b is an integer from 2 to 8). In a specific embodiment, the linker comprises two reactive groups and can form a bond with a thiol on two different chains on, for example, an antibody or its antigen-binding fragment: (where b is an integer from 2 to 8). In some embodiments, the linker comprises two reactive groups and can form a bond with a thiol on two different chains of, for example, an antibody or its antigen-binding fragment: (Here, b is an integer from 2 to 8; R N It is a hydrogen atom or an alkyl; R M is an alkyl).

[0501] Chemical formula described herein ( I ), ( YES ), ( 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 / or BA-[(L) 0-1 -PA] n at PA is any linker considered suitable L together with BA It may be connected to. The linker may be connected to the antibody or antigen-binding protein described herein and a therapeutic moiety, e.g., a steroid or LXR It is any group or moiety that links, connects, or combines the regulators. Suitable linkers are, for example, 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, JL, Eds.; Springer International Publishing, 2015, the full text of which is incorporated herein by reference. In general, a conjugate linker suitable for the antibody conjugate described herein is sufficiently stable to utilize the circulating half-life of the antibody and, at the same time, capable of releasing its payload after antigen-mediated internalization of the conjugate. The linker may be cleavable or non-cleavable. A cleavable linker comprises a linker that is cleaved by intracellular metabolism after internalization, e.g., by hydrolysis, reduction, or cleavage via enzymatic reactions. A non-cleavable linker comprises a linker that releases the attached payload through lysosome degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-unstable linkers, hydrolysis-unstable linkers, enzymatically cleavable linkers, reduction-unstable linkers, self-sacrificial linkers / groups, and non-cleavable linkers. Suitable linkers also include, but are not limited to, peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, and para-aminobenzyl (PAB) units or units thereof.

[0502] The ADC of the present disclosure may be generated or constructed using any linker molecule or linker technique known in the art. In a specific embodiment, the linker is a cleavable linker. According to another embodiment, the linker is a non-cleavable linker. Exemplary linkers that may be used in the context of the present disclosure include, for example, MC (6-maleimidocaproyl), MP (maleimidopropanoyl), val-cit (valine-citrulline), val-ala (valine-alanine), a protease-cleavable dipeptide site within the linker, ala-phe (alanine-phenylalanine), a protease-cleavable dipeptide site within the 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, or linkers composed thereof. Examples of linkers that may be used in the context of the present disclosure are, for instance, US No. 7,754,681 and Ducry, Bioconjugate Chem. Provided in , 2010, 21:5-13, and the references cited therein, the full text of which is incorporated herein by reference.

[0503] In certain embodiments, the linker is stable under physiological conditions. In certain embodiments, the linker is cleavable, for example, may release at least the payload site in the presence of an enzyme or in a specific pH range or value. In some embodiments, the linker comprises an enzyme-cleavable moiety. Exemplary enzyme-cleavable moietys include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages. In some embodiments, the linker comprises a cathepsin-cleavable linker.

[0504] In some embodiments, the linker includes a non-cuttable moiety.

[0505] Suitable linkers also include, but are not limited to, single linkers, e.g., chemically bonded to two cysteine ​​residues of the antibody. Such linkers may be provided to mimic the disulfide bonds of the antibody that are destroyed as a result of the conjugation process.

[0506] In some embodiments, the linker comprises one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteogenic or non-proteogenic, and L- or D-α-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, derivatives thereof, or combinations thereof. In certain embodiments, one or more side chains of the amino acid are linked to the side chain groups 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 includes valine and alanine.

[0507] In some embodiments, the linker comprises a self-sacrificial group. The self-sacrificial group may be any such group known to the skilled person. In specific embodiments, the self-sacrificial group is p-aminobenzyl (PAB) or a derivative thereof. In some embodiments, the self-sacrificial group is p-aminobenzyloxy. In some embodiments, the self-sacrificial group comprises a cleavable disulfide group. Useful derivatives include p-aminobenzyloxycarbonyl (PABC). The skilled person will recognize that the self-sacrificial group may perform a chemical reaction that releases the remaining atoms of the linker from the payload.

[0508] In some implementations, the linker is and, here is binding to an antibody or antigen-binding protein (e.g., via a lysine residue) and is a combination for the payload. In some implementations, the linker is and here is binding to an antibody or antigen-binding protein (e.g., via a lysine residue) and is a combination for the payload. In a specific implementation, the linker is am.

[0509] In a specific implementation, the linker am.

[0510] In some embodiments, the linker is maleimidylmethyl-4-trans-cyclohexanecarboxysuccinate: It originates from.

[0511] In some implementations, the linker is: and, here is binding to an antibody or antigen-binding protein (e.g., via a lysine residue) and is combined with the payload.

[0512] In some implementations, L is a cleavable linker. In some embodiments, L is a non-truncatable linker. In some embodiments, L It includes a dipeptide. In some embodiments, L silver PAB Includes moiety. In some embodiments, L It contains a disulfide moiety.

[0513] In some implementations, L It includes a moiety having the following structure:

[0514] .

[0515] In some implementations, L It includes a moiety having the following structure:

[0516] .

[0517] In some embodiments, L includes a moiety having the following structure:

[0518] .

[0519] In some embodiments, L includes a moiety having the following structure:

[0520] .

[0521] In a specific embodiment, the linker comprises a cyclodextrin group. In a specific embodiment, the linker has the chemical formula ( She Provides an ADC based on ):

[0522]

[0523] Chemical formula ( She )at, BA is an anti-MSR1 antibody, or its antigen-binding fragment, and LL is a trivalent linker, and RG is a reactive linker residue, and SP is, independently in each case, an absent or spacer group, and a subscript n is an integer from 1 to 30; PA is the payload. In a specific implementation example, n is from 1 to 4. In a specific embodiment, n is 4. In a specific implementation, n is 2. In a specific implementation, n is 1. In a specific implementation, n It is 3.

[0524] In a specific embodiment, the linker comprises a cyclodextrin group. In a specific embodiment, the linker has the chemical formula ( Id Provides an ADC based on ):

[0525]

[0526] Chemical formula ( Id )at, BA is an anti-MSR1 antibody, or its antigen-binding fragment; RG is a reactive group residue; SP 1 and SP 2 is, respectively, independently in each case, an absent or spacer group residue, where SP 1 It includes a trivalent linker; AA 1 is a trivalent linker containing amino acid residues; AA 2 is a dipeptide residue; PEG is a polyethylene glycol residue; PAB Is and, here is through this PAB represents an atom bonded to an adjacent group within the chemical formula, CD is, independently in each case, an absent or cyclodextrin residue, wherein at least one CD is exists, and subscript n is an integer from 1 to 30; the subscript m is an integer from 0 to 5; and the subscript p is 0 or 1; and PA is a payload moiety. In this example, the subscript m is 0, 1, 2, 3, 4, or 5. In some examples, the subscript m is 0. In some examples, the subscript m is 1. In some examples, the subscript m is 2. In some examples, the subscript m It is 3. In some examples, the subscript m is 4. In some examples, the subscript m is 5. In some examples, the subscript p is 0. In some examples, the subscript p is 1. In some examples, AA 1 or AA 2 Any one of the following comprises, independently in each case, 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, derivatives thereof, or combinations thereof. In certain embodiments, AA 1 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, derivatives thereof, or combinations thereof. In certain embodiments, AA 1 It is lysine. In a specific embodiment, AA 1 is lysine or a derivative of lysine. In certain embodiments, AA 2 is valine-citrulline. In some embodiments, AA 2 is citrulline-valine. In some embodiments, AA 2 is valine-alanine. In some embodiments, AA 2 is alanine-valine. In some embodiments, AA 2 is valine-glycine. In some embodiments, AA 2 is glycine-valine. In some embodiments, AA 1 -AA 2 is glutamine-valine-citrulline. In some embodiments, AA 1 -AA 2 is glutamine-valine-citrulline. In some embodiments, AA 1 -AA 2 is lysine-valine-alanine. In some embodiments, AA 1 -AA 2 is lysine-valine-citrulline. In some embodiments, AA 1 -AA 2 is glutamine-valine-citrulline. In certain embodiments, lysine is L-lysine. In certain embodiments, lysine is D-lysine. In some examples, SP 1 is independently in each case, C 1-6 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 Selected from -, and combinations thereof, where the subscript e is an integer from 0 to 4, and the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8. In some examples, SP 2 is independently in each case, C 1-6 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 Selected from the group consisting of -, and combinations thereof, where the subscript e is an integer from 0 to 4, and the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8.

[0527] In a specific embodiment, chemical formula ( I ), ( YES ), ( 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 In the case of ), the linker is

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539] and

[0540] Selected from.

[0541] In addition, these examples include pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, regioisomers thereof, or mixtures of regioisomers thereof, wherein each is a bond to the binder; and each is a combination for the payload.

[0542] In a specific embodiment, the linker comprises a terminal hydrophilic group (HG). In a specific embodiment, the linker comprises a taurine group. In a specific embodiment, the linker comprises a terminal sulfonic acid group. In a specific embodiment, the linker is of the chemical formula ( CHEAT Provides an ADC according to ):

[0543]

[0544] Here, chemical formula ( CHEAT )at, BA is a binder; LL is a trivalent linker; RG 1 and RG 2 is a reactive group residue; SP 1 and SP 2 is, independently in each case, an absent or spacer group residue; HG is a hydrophilic residue; PA is a payload residue; subscript n is an integer from 1 to 30; subscript q is 0 or 1. In some examples, one or more trivalent linkers LL This may exist. In some examples, n is an integer from 1 to 4. In some examples n is 1. In some examples n is 2. In some examples n It is 3. In some examples n It is 4. In some examples, HG is a terminal hydrophilic group. In some examples, HGIt includes a single terminal sulfonic acid group or a salt thereof. In other examples, HG It comprises one or more terminal sulfonic acid groups or salts thereof. In some examples, HG It includes a single terminal phosphonic acid group or a salt thereof. In other examples, HG It comprises one or more terminal phosphonic acid groups or salts thereof. In some examples, HG It comprises a single terminal tertiary amine group or a salt thereof. In other examples, HG It comprises one or more terminal tertiary amine groups or salts thereof. In some examples, HG It comprises a single terminal polyol (e.g., glucose, maltose) or a derivative thereof. In other examples, HG It comprises one or more terminal polyols (e.g., glucose, maltose) or derivatives thereof.

[0545] In another example, chemical formula ( CHEAT The compound of ) has the chemical formula ( FULL It depends on the compound of ):

[0546] ( FULL ).

[0547] Chemical formula ( FULL )at, BA, RG 1 , SP 1 , RG 2 , SP 2 and HG is as defined above, and AA 1 is a trivalent linker containing amino acid residues; AA 2 is a dipeptide residue; PAB Is and, here is through this PAB α represents an atom bonded to an adjacent group in the chemical formula; subscript p is 0 or 1 and; subscript qis 0 or 1. In some examples, the subscript p is 0 and the subscript q is 0. In some examples, the subscript p is 1 and; subscript q is 0. In some examples, the subscript p is 0 and; subscript q is 1. In some examples, the subscript p is 1 and; and subscript q is 1. In some examples SP 1 It contains 0 to 5 polyethylene glycol (PEG) residues. In some examples SP 2 It contains 0 to 5 PEG residues. In some examples, SP 1 is independently in each case, C 1-6 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 Selected from the group consisting of -, and combinations thereof, where the subscript e is an integer from 0 to 4, and the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8. In some examples, SP 2 is independently in each case, C 1-6 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 Selected from the group consisting of -, and combinations thereof, where the subscript e is an integer from 0 to 4, and the subscript uis an integer from 1 to 8, and the subscript v is an integer from 1 to 8. In some examples, AA 1 or AA 2 Any one of the following comprises, independently in each case, 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, derivatives thereof, or combinations thereof. In certain embodiments, AA 1 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, derivatives thereof, or combinations thereof. In certain embodiments, AA 1 It is lysine. In a specific embodiment, AA 1 is lysine or a derivative of lysine. In certain embodiments, AA 1 is glutamic acid. In a specific embodiment, AA 2 is valine-citrulline. In some embodiments, AA 2 is citrulline-valine. In some embodiments, AA 2 is valine-alanine. In some embodiments, AA 2 is alanine-valine. In some embodiments, AA 2 is valine-glycine. In some embodiments, AA 2 is glycine-valine. In some embodiments, AA 1 -AA 2 is glutamine-valine-citrulline. In some embodiments, AA 1 -AA 2 is lysine-valine-citrulline. In some embodiments, AA 1 -AA 2 is lysine-valine-alanine. In some embodiments, AA 1 -AA 2 is glutamine-valine-alanine. In certain embodiments, lysine is L-lysine. In certain embodiments, lysine is D-lysine.

[0548] In a specific embodiment, chemical formula ( I ), ( YES ), ( 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 In the case of ), the linker is

[0549]

[0550] or is selected from its stereoisomer form, or its regioisomer, or a mixture of its regioisomers, wherein

[0551] Each is a bond to the binder;

[0552] Each is a combination for the payload residue.

[0553] In some examples, moiety L-PA is a reactive group ( RG Attached to ) RG-L-PA It forms (e.g., the linker payload shown in Table 3). In some examples, BA (or BA Modified forms of, for example, as shown in Table 2 PEG - Modified Ab , or Ab 1 ) interacts with the linker payload as described in Tables 1 and 2 ADC It forms. Also, within the scope of the embodiments shown herein, manufactured from any linker payload described in Tables 5A and 5B. ADC is considered.

[0554] 링커 페이로드

[0555] Chemical formula ( 2000 Linker-steroid according to ) RG - L 2 -( L 3 ) 0-1 - SP-D Or, pharmaceutically acceptable salts, solvates, or stereoisomers thereof are considered herein; which are useful for the preparation of antibody-drug conjugates, and

[0556] Here

[0557] D is selected from the following a) and / or b):

[0558] a) Chemical formula ( a ),

[0559] Here, the chemical formula ( a )my R X Both are hydrogen; R 34 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; SP is -C(O)-C1-C 10-alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1 -(Here X 1 is the chemical formula ( 2000 In (L 3 ) 0-1 is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)-S-(here) S is the chemical formula ( 2000 In (L 3 ) 0-1 is attached to), -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S-(here) S is the chemical formula ( 2000 In (L 3 ) 0-1 is attached to), (Here, the attachment point on the right side (i.e., N) is the chemical formula ( 2000 In (L 3 ) 0-1 This is about), -CH2-NH-(where N is the chemical formula ( 2000 In (L 3 ) 0-1 is attached to), (Here, N is the chemical formula ( 2000 In (L 3 ) 0-1 Attached to and here Ar is an optionally substituted arylene (in some embodiments, )is) or any substituted heteroarylene, -(C1-C 10 -alkylene)-N R 5 0 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a - is a chemical formula ( 2000 In (L 3 ) 0-1 is attached to), -C(O)-(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here NR 50a is the chemical formula ( 2000 In (L 3 ) 0-1 Attached to and each C1-C 10 -alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 5 )-C1-C 10 -alkylene-C(O)NH- X 2 -(Here X 2 is the chemical formula ( 2000 In (L 3 ) 0-1 is attached to), or (Here X 4 is the chemical formula ( 2000 In (L 3 ) 0-1 (is attached to) or;

[0560] Chemical formula ( a )at R x Both are fluoro, and; R 34 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1b -(Here X 1b is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to), -C(O)-N(H)-(C1-C 10 -alkylene)- X 1b -(Here X 1b is the chemical formula (2000 )at ( L 3 ) 0-1 is attached to), (Here, the attachment point on the right side (i.e., N) is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to), -CH2-NH-(here N is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to), (Here N is the chemical formula ( 2000 )at ( L 3 ) 0-1 Attached to and here Ar is an optionally substituted arylene (in some embodiments, ) or is an arbitrarily substituted heteroarylene), -(C1-C 10 -alkylene)-N R 5 0 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to), -C(O)-(C1-C 10 -alkylene)-N R 50 C(O)-(C1-C 10 -alkylene)-N R 50a -(Here N R 50a is the chemical formula ( 2000 )at ( L 3 ) 0-1 Attached to and here each C1-C 10 -alkylene is independently and optionally substituted with one or more hydroxyl groups), -C(O)-N( R 5 )-(C1-C10 -alkylene)-C(O)NH- X 2 -(Here X 2 is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to), or (Here X 4 is the chemical formula ( 2000 )at ( L 3 ) 0-1 is attached to) and / or;

[0561] b) The compound in Table A above, wherein the compound in Table A is through the hydroxyl group of the -C(O)CH2OH group, i.e., -C(O)CH2-O-SP-(L 3 ) 0-1 -by, or through the hydroxyl group of mafracolate, i.e., -O- SP -( L 3 ) 0-1 Chemical formula by ( 2000 Connected to the RG of the compound of ):

[0562] X 1 is -N(C 1-6 alkyl)- and;

[0563] X 1b is -S-, -NH-, or -N(C 1-6 alkyl)- and;

[0564] X 2 is -NH- and;

[0565] X 3 is -CH2- or, X 3 -CH2-O-(C1-C 10 -alkylene)-C(O)-(where C(O) is X 4 is attached to) or X 3 is -C(O)- and;

[0566] X 34 is -O- and;

[0567] R 35 is H, -OH, -OCH3, or C 1-6 It is alkyl;

[0568] R 50 and R 50a is independently hydrogen or C1-C6-alkyl;

[0569] R d , R e , and R f is independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH2O R g (Here, each R g is independently -CH2C(O)OH or -CH2C(O)O(alkyl) and;

[0570] mm is 0 or 1;

[0571] RG is a reactive group residue;

[0572] L 2 is a connecting linker;

[0573] L 3 If present, it is a self-sacrificial group.

[0574] Chemical formula useful for the manufacture of antibody-drug conjugates ( 4000 A linker-LXR-regulator according to ) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided herein:

[0575] RG-LE Chemical formula ( 4000 )

[0576] Here

[0577] E Is

[0578] a) Chemical formulas described above and herein ( B Compounds of ); and / or

[0579] b) Chemical formulas described above and herein ( B-1 Compounds of ); and / or

[0580] c) of this institution 표 C Selected from the payload described in;

[0581] L is the linker described herein;

[0582] RG is any reactive group residue described herein.

[0583] In some implementations, the LXR payload is is. In some implementations, the LXR payload is am.

[0584] In some embodiments, chemical formula ( 4000 The linker-payload of ) is the chemical formula ( 4001 ), ( 4002 ), ( 4003 ), or ( 4004 It has the structure of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0585] Chemical formula ( 4001 )

[0586] Chemical formula ( 4002 )

[0587] Chemical formula ( 4003 ) or

[0588] Chemical formula ( 4004 )

[0589] Here SP 1 and SP 2 is, where present, a spacer group as described herein in some and optional embodiments;

[0590] Each AA is an amino acid residue;

[0591] p is an integer from 1 to 10;

[0592] RG is a reactive group residue;

[0593] R B1 , R B2 , R 7 and b is as defined herein in some or any embodiment.

[0594] In some embodiments, chemical formula ( 4001 ), ( 4002 ), ( 4003 ), or ( 4004 The linker-payload of ) is selected from the linker-payloads in Table 3.

[0595] Chemical formula ( 7000 A linker-rifamycin analog according to ), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided herein;

[0596] RG-LF Chemical formula ( 7000 )

[0597] Here F is a rifamycin analogue;

[0598] L is the linker described herein;

[0599] RG is any reactive group residue described herein.

[0600] In some implementations, F is a rifamycin analog described herein. In some embodiments, F is Repalog: is. In some implementations, F is rifampicin: am.

[0601] Also, chemical formula ( DA linker payload according to ) is provided herein:

[0602] Chemical formula ( D ).

[0603] A linker-steroid is provided herein, wherein the steroid conjugated to an antibody, or its antigen-binding fragment, via a linker or linker-spacer is of the formula ( A-1 It is a compound of ) or its pharmaceutically acceptable salt, solvate, or stereoisomer form:

[0604] Chemical formula ( A-1 )

[0605] Here

[0606] R 1 and R 2 is, independently, -H, alkyl, alkyl-C(O)-O-, -OH, or halo; R 1 and R 2 together Forming;

[0607] Here R 4 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl, and

[0608] Here, alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are, in each case independently, -N R Aa R Ab Arbitrarily substituted as;

[0609] R 3 -O, R Z -C(O)- X -, -heteroalkyl, -piperidinyl, -N R Aa R Ab , -oxyaryl-N R Aa R Ab or -FLUID P ) t And;

[0610] R Z is alkyl and;

[0611] X is O or N R Aa And;

[0612] Z is S, S(O), S(O)2, SO2N R Aa , O, C(O) NR Aa , C(O), or N R Aa And;

[0613] A' is an aryl, arylalkyl, or heteroaryl;

[0614] R p is, independently in each case, a halo, an arbitrarily substituted alkyl, -OH, or -N R Aa R Ab And;

[0615] R Aa and R Ab is, independently in each case, -H, an optionally substituted alkyl, or an optionally substituted aryl;

[0616] Subscript a is an integer from 0 to 19;

[0617] t is an integer from 1 to 3;

[0618] R 5A and R 5B Each is independently a halo or hydrogen atom;

[0619] Here, the group R 3 or R 4 It is combined with the linker.

[0620] chemical formula Ab-L'-SP-D or BA-L'-SP-D An antibody-drug conjugate of is provided herein, where D is a budesonide prodrug or a prodrug of a budesonide analog or derivative (including fluorinated analogs and derivatives), where Ab, BA, L' , and SP is as defined in any embodiment described herein. In some embodiments, SP Is D or It is a moiety capable of releasing. In some embodiments, under physiological conditions, L class SP The bond between them is severed, resulting in a steroid prodrug, i.e., H-SP-D or Releasing, SP and D The connection between, or SP and The bond between them is subsequently cleaved, releasing a biologically active steroid.

[0621] In some examples, chemical formula ( I ), ( YES ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( III ), or ( 3000 The ADC of ) is the ADC 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 or , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0622] Chemical formula described herein ( 5001 ), ( 5002 ), ( 5003 ), or ( 5004Antibody-drug conjugates of any LXR-regulator compound of ) or pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, or regioisomers thereof, or mixtures thereof are provided herein:

[0623] Chemical formula ( 5001 )

[0624] Chemical formula ( 5002 )

[0625] Chemical formula ( 5003 ) or

[0626] Chemical formula ( 5004 )

[0627] Here L is any linker described herein in some or any embodiment;

[0628] n is an integer from 1 to 30;

[0629] BA is a binder or a PEG-modified binder;

[0630] R B1 , R B2 , R 7 and b is as defined herein in some or any embodiment.

[0631] Chemical formula ( 6001 ), ( 6002 ), ( 6003 ), or ( 6004 Antibody-drug conjugates of any LXR-regulatory factor compound described herein, or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein:

[0632] Chemical formula ( 6001 )

[0633] Chemical formula (6002 )

[0634] Chemical formula ( 6003 ) or

[0635] Chemical formula ( 6004 );

[0636] Here SP 1 and SP is, where present, a spacer group as defined herein in some and optional embodiments;

[0637] Each AA is an amino acid residue;

[0638] p is an integer from 1 to 10;

[0639] n is an integer from 1 to 30;

[0640] BA is a binder or a PEG-modified binder;

[0641] R B1 , R B2 , R 7 and b is as defined herein in some or any embodiment.

[0642] Chemical formula ( 6005 Antibody-drug conjugates of any LXR-regulatory factor compound described herein, or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein:

[0643] Chemical formula ( 6005 )

[0644] Here R B1 , R B2 , R 7 , b, BA, RG 1 , SP 1 , AA 1 and AA 2 is as defined herein in some or any embodiment.

[0645] In some examples, chemical formula ( I ), ( YES ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 5001 ), ( 5002 ), ( 5003 ), ( 5004 ), ( 6001 ), ( 6002 ), ( 6003 ), ( 6004 ), or ( 6005 The ADC of ) is the ADC described in Table 1 and / or Table 2 and the Examples section. In some embodiments, the LXR regulator payload in any antibody-drug conjugate described herein is or ; or a pharmaceutically acceptable salt or solvate thereof.

[0646] Antibody-drug conjugates of any rifamycin analog having the structure of formula (7001) as described herein, or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein:

[0647] Chemical formula ( 7001 )

[0648] Here:

[0649] X 1c -S-; -O- and -N R 5c Selected from;

[0650] R 1c is amino-C 1-6 Alkyl; C 1-6Alkylamino C 1-6 Alkyl; di-C 1-6 Alkylamino C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-OC 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-SC 1-6 Alkyl; heterocycloalkyl or heterocycloalkyl-C 1-6 It is an alkyl; where the heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from O, N, and S; where the heterocycloalkyl is a halo, C 1-6 Optionally substituted with alkyl, -OH, or =O;

[0651] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected independently from;

[0652] Each R ac is, if present, -F; -Cl; -Br; -I; -OH; -NH2; and C 1-6 Independently selected from alkoxy;

[0653] R 5c is hydrogen in the presence of each; and C 1-6 Independently selected from alkyls;

[0654] L is a linker;

[0655] BA is a binder;

[0656] Subscript n is an integer from 1 to 30.

[0657] Chemical formula described herein ( 7002 An antibody-drug conjugate of any rifamycin analog having the structure of ) or a pharmaceutically acceptable salt, solvate, stereoisomer form thereof, or a regioisomer thereof, or a mixture thereof is provided herein:

[0658]

[0659] Chemical formula ( 7002 );

[0660] Here BA, RG 1 , SP 1 , AA 1 , AA 2 , R 1c , R bc , R ac , X 1c , R 2c , R 3c , R 4c and n ...is as defined herein in some or any embodiment.

[0661] An antibody-rifamycin analog conjugate having the structure of formula (7003) or a pharmaceutically acceptable salt, solvate, stereoisomer form thereof, or a regioisomer thereof, or a mixture thereof is provided herein:

[0662] Chemical formula ( 7003 )

[0663] Here:

[0664] X 1c is selected from -S-; -O- and c;

[0665] R 1cIs, or and; here Y is C or N and;

[0666] R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from;

[0667] R 5c is, in the presence of each, independently absent, hydrogen; and C 1-6 Selected from alkyls;

[0668] Each AA is independently selected from amino acids;

[0669] SP 1 is absent, or is a spacer;

[0670] RG 1 is a reactive group residue;

[0671] BA is an anti-MSR1 antibody or its antigen-binding fragment;

[0672] Subscript n is an integer from 1 to 30;

[0673] Subscript w is 2, 3, or 4;

[0674] Here, R 1c is a dashed line As shown, it is bonded to the linker through nitrogen atoms.

[0675] Chemical formula ( 7003 In various implementations of ), SP 1 , RG 1 and AA is as defined herein in some and / or special embodiments.

[0676] Chemical formula ( 7003In some implementations of ), X 1c is O. Chemical formula ( 7003 In some implementations of ), X 1c is S. Chemical formula ( 7003 In some implementations of ), X 1c is C, chemical formula ( 7003 In some implementation examples of ) X 1c is N R 5c am.

[0677] Chemical formula ( 7003 In some implementations of ), BA is an anti-MSR1 antibody containing the N297Q mutation or its antigen-binding fragment.

[0678] Chemical formula ( 7003 In some implementations of ), the subscript w is 2.

[0679] Chemical formula ( 7003 In some implementations of ), (AA) 2 is valine-citrulline.

[0680] Chemical formula ( 7003 In some implementations of ), SP 1 silver Includes. Chemical formula ( 7003 In some implementations of ), SP 1 silver Includes

[0681] Chemical formula ( 7003 In some implementations of ), RG 1 silver Includes

[0682] Chemical formula ( 7003 In some implementations of ),

[0683] X 1c is O and;

[0684] R 1c Is or and; here Y is C or N and; here R 1c Is R 1c It is bonded to the linker through the quaternary nitrogen atom;

[0685] R 5c is C 1-6 It is alkyl;

[0686] R 6c is a counterion.

[0687] In some of these implementations, R 1c Is , or is. In some of these implementations, R 1c Is is. In some of these implementations, R 1c Is is. In some of these implementations, R 6c is I - , Cl - or Br - and, in some examples, R 6c is I - am.

[0688] Chemical formula ( 7003 In some embodiments of ), the rifamycin analog is or am.

[0689] Chemical formula ( 7003 In some embodiments of ), the rifamycin analog is It is. Chemical formula ( 7003 In some embodiments of ), the rifamycin analog is am.

[0690] Chemical formula ( 7004 An antibody-drug conjugate comprising a rifamycin compound (e.g., rifampicin) according to ) is further provided herein:

[0691]

[0692] Chemical formula ( 7004 ).

[0693] Chemical formula ( 7005 An antibody-drug conjugate comprising a rifamycin compound (e.g., rifampicin) according to ) is also provided herein:

[0694] Chemical formula ( 7005 );

[0695] Here L and BA is as defined herein in some or any embodiment.

[0696] In some examples, chemical formula ( I ), ( YES ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 7001 ) ( 7002 ), ( 7003 ), ( 7004 ), and / or ( 7005 The ADC of ) is the ADC described in Table 2 and / or the Examples paragraph.

[0697] In addition, these examples of ADCs include their pharmaceutically acceptable salts, solvates, stereoisomer forms, their regioisomers, or mixtures of their regioisomers, wherein each is a bond to the binder; and each is a combination for the payload.

[0698] In a specific embodiment, a linker-payload selected from the group consisting of the anti-MSR1 antibody disclosed herein or its antigen-binding fragment, or a PEG-modified anti-MSR1 antibody or its antigen-binding fragment and the linker-payload of Table 3, or its stereoisomer form, or its regioisomer, or a mixture of its regioisomers ( LP An ADC comprising ) is provided herein.

[0699] In addition, an antibody-radionuclide conjugate (ARC) comprising an anti-MSR1 antibody conjugated to one or more radionuclides is provided herein. Exemplary radionuclides that may be used in the context of this disclosure are, for example, 225 Ac, 212 Bi, 213 Bi, 131 I, 186 Re, 227 Th, 222 Rn, 223 Ra, 224 Ra, and 90 Includes, but is not limited to, Y.

[0700] [Table 1]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709] In the ADC of Table 1, Ab is the anti-MSR1 antibody provided herein, or an antigen-binding fragment thereof. In a specific embodiment, Ab The PEG group on the glutamine side chain described herein It is modified into (referred herein to as a PEG-modified antibody). In certain embodiments, the PEG group is terminated by an azido group to facilitate reaction with the linker payload described herein (e.g., the linker payload described in Table 3 and the Examples). In certain embodiments, the PEG group is linked to the linker payload via a triazole or a triazole derivative as described herein. In an ADC, nis an integer from 1 to 10, for example, 1, 2, 3, or 4. In the PEG group, nn is an integer from 1 to 10, for example, 1, 2, 3, 4, or 5. In another embodiment, each of the ADCs in Table 1 BA Is and here Ab 1 is an anti-MSR1 antibody, or its antigen-binding fragment; R C 2-4 - It is an alkylene; nn is an integer selected from 2 to 4 (including boundaries), and each n is, for example, an integer from 1 to 10, for example, 1, 2, 3, or 4.

[0710] In a specific embodiment, a linker-payload selected from the group consisting of the antibody disclosed herein and the linker-payload in Table 2, or its stereoisomer form, or its regioisomer, or a mixture of its regioisomers ( LP An ADC comprising ) is provided herein.

[0711] [Table 2]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738] In the ADC of Table 2, Ab is the anti-MSR1 antibody provided herein, or its antigen-binding fragment. In a specific embodiment, Ab is modified with a PEG group on the glutamine side chain as described herein. In the ADC, n is an integer from 1 to 10, e.g., 1, 2, 3, or 4.

[0739] payload An anti-MSR1 antibody conjugated to, or its antigen-binding fragment, or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof is provided herein. In some embodiments, the anti-MSR1 antibody, or its antigen-binding fragment, comprises the N297Q mutation.

[0740] The payload includes the six Complementarity Determination Regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 An anti-MSR1 antibody conjugated to, or its antigen-binding fragment, or its pharmaceutically acceptable salt, solvate, or stereoisomer form is provided herein. In some embodiments, the anti-MSR1 antibody, or its antigen-binding fragment, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and the N297Q mutation.

[0741] Heavy chain complementarity determining region (HCDR)-1 containing sequence number: 52; HCDR2 containing sequence number: 54; HCDR3 containing sequence number: 56; light chain complementarity determining region (LCDR)-1 containing sequence number: 60; LCDR2 containing sequence number: 62; and LCDR3 containing sequence number: 64, comprising a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or an antigen-binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ No. 52; an HCDR2 comprising SEQ No. 54; an HCDR3 comprising SEQ No. 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ No. 60; an LCDR2 comprising SEQ No. 62; and an LCDR3 comprising SEQ No. 64, and an N297Q mutation.

[0742] A payload including a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a set of the variable region heavy chain variable region (HCVR) and a set of the light chain variable region (LCVR) from Table 4, and the N297Q mutation.

[0743] The payload includes a heavy chain variable region (HCVR) containing SEQ ID NO: 50 and a light chain variable region (LCVR) containing SEQ ID NO: 58 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58, and an N297Q mutation.

[0744] chemical formula

[0745] and / or

[0746] A body-drug conjugate (ADC) or a pharmaceutically acceptable salt, solvate, stereoisomer form, or regioisomer thereof, or a mixture thereof, according to [the invention] is provided herein, wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment comprises the N297Q mutation.

[0747] chemical formula

[0748] and / or

[0749] Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein, wherein the antibody is an anti-MSR1 antibody comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises a set of complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and the N297Q mutation.

[0750] Chemical formula:

[0751] and / or

[0752] Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody 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, or an anti-MSR1 antibody comprising an antigen-binding fragment thereof, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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, DAR is 4. In some embodiments, the anti-MSR1 antibody, or its antigen-binding fragment comprises a heavy chain complementarity determining region (HCDR)-1 containing sequence number: 52; an HCDR2 containing sequence number: 54; an HCDR3 containing sequence number: 56; a light chain complementarity determining region (LCDR)-1 containing sequence number: 60; an LCDR2 containing sequence number: 62; and an LCDR3 containing sequence number: 64, and an N297Q mutation.

[0753] Chemical formula:

[0754] and / or

[0755] Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibodies are a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and the N297Q mutation.

[0756] Chemical formula:

[0757] and / or

[0758] An antibody-drug conjugate according to [the invention] or a pharmaceutically acceptable salt, solvate, stereoisomer form, or stereoisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, and an N297Q mutation.

[0759] payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises the N297Q mutation.

[0760] Includes a set of six complementarity determination regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the 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.

[0761] Heavy chain complementarity determining region (HCDR)-1 containing sequence number 52; HCDR2 containing sequence number 54; HCDR3 containing sequence number 56; light chain complementarity determining region (LCDR)-1 containing sequence number 60; LCDR2 containing sequence number 62; and LCDR3 containing sequence number 64, comprising a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to a pharmaceutically acceptable salt, solvate, or stereoisomer form is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ No. 52; an HCDR2 comprising SEQ No. 54; an HCDR3 comprising SEQ No. 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ No. 60; an LCDR2 comprising SEQ No. 62; and an LCDR3 comprising SEQ No. 64, and an N297Q mutation.

[0762] A payload including a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a set of the variable region heavy chain variable region (HCVR) and a set of the light chain variable region (LCVR) from Table 4, and the N297Q mutation.

[0763] The payload includes a heavy chain variable region (HCVR) containing SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58, and an N297Q mutation.

[0764] chemical formula

[0765] and / or

[0766] An antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt, solvate, stereoisomer form, or regioisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment comprises the N297Q mutation.

[0767] Chemical formula:

[0768] and / or

[0769] Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody comprising a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises a set of six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and the N297Q mutation.

[0770] Chemical formula:

[0771] and / or Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody comprising a heavy chain complementarity determining region (HCDR)-1 of SEQ ID NO: 54; an HCDR2 of SEQ ID NO: 54; an HCDR3 of 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, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises the heavy chain complementarity determining region (HCDR)-1 of sequence number: 52; the HCDR2 of sequence number: 54; the HCDR3 of sequence number: 56; the light chain complementarity determining region (LCDR)-1 of sequence number: 60; the LCDR2 of sequence number: 62; and the LCDR3 of sequence number: 64; and the N297Q mutation.

[0772] Chemical formula:

[0773] and / or

[0774] Antibody-drug conjugates (ADCs) or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody comprising a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and the N297Q mutation.

[0775] Chemical formula:

[0776] and / or

[0777] An antibody-drug conjugate (ADC) according to [the invention] or a pharmaceutically acceptable salt, solvate, stereoisomer form, or regioisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, and an N297Q mutation.

[0778] payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises the N297Q mutation.

[0779] The payload includes a set of six complementarity determination regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3), and the N297Q mutation.

[0780] Heavy chain complementarity determining region (HCDR)-1 containing sequence number 52; HCDR2 containing sequence number 54; HCDR3 containing sequence number 56; light chain complementarity determining region (LCDR)-1 containing sequence number 60; LCDR2 containing sequence number 62; and LCDR3 containing sequence number 64, comprising a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ No. 52; an HCDR2 comprising SEQ No. 54; an HCDR3 comprising SEQ No. 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ No. 60; an LCDR2 comprising SEQ No. 62; and an LCDR3 comprising SEQ No. 64, and an N297Q mutation.

[0781] A payload including a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a set of the variable region heavy chain variable region (HCVR) and a set of the light chain variable region (LCVR) from Table 4, and the N297Q mutation.

[0782] Comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, and a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58, and an N297Q mutation.

[0783] Chemical formula:

[0784] and / or

[0785] An antibody-drug conjugate (ADC) or a pharmaceutically acceptable salt, solvate, stereoisomer form, or regioisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment comprises the N297Q mutation.

[0786] Chemical formula:

[0787] and / or

[0788] Antibody-drug conjugates (ADCs) according to [the invention] or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody comprising a set of six complementarity determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3), or an antigen-binding fragment thereof is provided herein. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises a set of six complementary determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0789] Chemical formula:

[0790] and / or

[0791] An antibody-drug conjugate (ADC) according to [the invention] or a pharmaceutically acceptable salt, solvate, stereoisomer form, or regioisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody comprising a heavy chain complementarity determining region (HCDR)-1 containing SEQ ID NO: 52; an HCDR2 containing SEQ ID NO: 54; an HCDR3 containing SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 containing SEQ ID NO: 60; an LCDR2 containing SEQ ID NO: 62; an LCDR3 containing SEQ ID NO: 64; or an antigen-binding fragment thereof is provided herein. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment, comprises a heavy chain complementarity determining region (HCDR)-1 comprising sequence number: 52; a HCDR2 comprising sequence number: 54; a HCDR3 comprising sequence number: 56; a light chain complementarity determining region (LCDR)-1 comprising sequence number: 60; an LCDR2 comprising sequence number: 62; an LCDR3 comprising sequence number: 64; and an N297Q mutation.

[0792] Chemical formula:

[0793] and / or

[0794] Antibody-drug conjugates (ADCs) or pharmaceutically acceptable salts, solvates, stereoisomer forms, or regioisomers thereof, or mixtures thereof are provided herein; wherein the antibody is an anti-MSR1 antibody comprising a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and the N297Q mutation.

[0795] Chemical formula:

[0796] and / or

[0797] An antibody-drug conjugate (ADC) according to [the invention] or a pharmaceutically acceptable salt, solvate, stereoisomer form thereof, or a regioisomer thereof, or a mixture thereof is provided herein; wherein the antibody is an anti-MSR1 antibody comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58, and an N297Q mutation.

[0798] payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises the N297Q mutation.

[0799] It includes a set of six complementarity determination regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) from Table 4, and a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is included herein. In some embodiments, the anti-MSR1 antibody, or an antigen-binding fragment thereof, comprises a set of six complementarity determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3), and the N297Q mutation.

[0800] Heavy chain complementarity determining region (HCDR)-1 containing sequence number 52; HCDR2 containing sequence number 54; HCDR3 containing sequence number 56; light chain complementarity determining region (LCDR)-1 containing sequence number 60; LCDR2 containing sequence number 62 and LCDR3 containing sequence number 64, and a payload An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ No. 52; an HCDR2 comprising SEQ No. 54; an HCDR3 comprising SEQ No. 56; a light chain complementarity determining region (LCDR)-1 comprising SEQ No. 60; an LCDR2 comprising SEQ No. 62; and an LCDR3 comprising SEQ No. 64, and an N297Q mutation.

[0801] A payload including a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a set of the variable region heavy chain variable region (HCVR) and a set of the light chain variable region (LCVR) from Table 4, and the N297Q mutation.

[0802] The payload includes a heavy chain variable region (HCVR) containing SEQ ID NO: 50 and a light chain variable region (LCVR) containing SEQ ID NO: 58 An anti-MSR1 antibody, or an antigen-binding fragment thereof, conjugated to, or to a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof, is provided herein. In some embodiments, the anti-MSR1 antibody, or the antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, and an N297Q mutation.

[0803] Chemical formula:

[0804] Antibody-drug conjugates (ADCs) according to or pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, or regioisomers thereof, or mixtures thereof are provided herein; wherein X - is a pharmaceutically acceptable counterion, where the antibody is an anti-MSR1 antibody or its antigen-binding fragment. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment contains the N297Q mutation.

[0805] Chemical formula:

[0806] Antibody-drug conjugates (ADCs) according to or pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, or regioisomers thereof, or mixtures thereof are provided herein; wherein X - is a pharmaceutically acceptable counterion, and the antibody is an anti-MSR1 antibody or its antigen-binding fragment comprising a set of six complementary determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3). In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 its antigen-binding fragment comprises a set of six complementary determining regions (CDRs) from Table 4 (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0807] Chemical formula:

[0808] Antibody-drug conjugates (ADCs) according to or pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, or regioisomers thereof, or mixtures thereof are provided herein; wherein X - is a pharmaceutically acceptable counterion, and the antibody is an anti-MSR1 antibody, or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR)-1 containing SEQ ID NO: 52; an HCDR2 containing SEQ ID NO: 54; an HCDR3 containing SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 containing SEQ ID NO: 60; an LCDR2 containing SEQ ID NO: 62; and an LCDR3 containing SEQ ID NO: 64. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a heavy chain complementarity determining region (HCDR)-1 containing SEQ ID NO: 52; an HCDR2 containing SEQ ID NO: 54; HCDR3 containing sequence number: 56; light chain complementarity determining region (LCDR)-1 containing sequence number: 60; LCDR2 containing sequence number: 62; and LCDR3 containing sequence number: 64, and N297Q mutation.

[0809] Chemical formula:

[0810] Antibody-drug conjugates (ADCs) according to or pharmaceutically acceptable salts, solvates, stereoisomer forms, or stereoisomers, or mixtures thereof, are provided herein; wherein X -is a pharmaceutically acceptable counterion, and the antibody is an anti-MSR1 antibody, or an antigen-binding fragment thereof, comprising a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a set of variable region heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) from Table 4, and the N297Q mutation.

[0811] Chemical formula:

[0812] Antibody-drug conjugates (ADCs) according to or pharmaceutically acceptable salts, solvates, stereoisomer forms thereof, or regioisomers thereof, or mixtures thereof are provided herein; wherein X - is a pharmaceutically acceptable counterion, and the antibody is an anti-MSR1 antibody comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) comprising SEQ ID NO: 58, or an antigen-binding fragment thereof. In some of these embodiments, the drug-antibody ratio (DAR) is 1 to 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 an antigen-binding fragment thereof, comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50; a light chain variable region (LCVR) comprising SEQ ID NO: 58 and an N297Q mutation.

[0813] As used herein, in certain embodiments, amino acids are, for example, moiety -SP 1 -AA 1 -AA 2 - my spacers SP 1 When combined with, amino acid AA 1 Silver is a spacer through its amino group SP 1 It is bound to. The spacer residue contains the site of the functional group that forms a bond with the amino group within the amino acid. Just as an example, in the following structure:

[0814] , valine residues as shown SP 1 It is combined with and in the relevant example SP 1 The residue contains a (C=O) moiety. Also, in the example, SP 1 The residue includes an active group suitable for forming a bond with a reactive group. SP 1 The residue contains an -NH- moiety. Those skilled in the art will recognize that similar groupings can be applied to all other chemical formulas described herein.

[0815] The antibody-drug conjugates described herein may be prepared using conjugation conditions known to those skilled in the art (see, for example, Doronina et al. Nature Biotechnology 2003, 21, 7, 778, the full text of which is incorporated herein by reference). In some embodiments, the ADC is prepared by contacting an anti-MSR1 antibody or its antigen-binding fragment with a compound comprising the described linker and payload, wherein the linker has a moiety reactive with the antibody or antigen-binding protein, for example, at a desired residue of the antibody or antigen-binding protein. Exemplary conditions are described in the following examples.

[0816] 젭체-약물 접합체의 제조

[0817] In some embodiments, a method for preparing an antibody-drug conjugate is provided herein, 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. Additionally, an antibody-drug conjugate prepared by conjugating an anti-MSR1 antibody, 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, or a stereoisomer form thereof, or a regioisomer thereof, or a mixture thereof isomer thereof is prepared herein.

[0818] [Table 3]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833] The compounds in the table above can be prepared as described in the examples herein.

[0834] A method for preparing a rifamycin analog (e.g., rifampicin) antibody-drug conjugate is also provided herein, comprising the step of contacting an anti-MSR1 antibody, or its antigen-binding fragment, with a linker payload according to formula (D) under conditions suitable for forming a bond between the anti-MSR1 antibody, or its antigen-binding fragment:

[0835] Chemical formula (D).

[0836] 에피토프 맵핑(mapping) 및 관련 기술

[0837] The epitope to which the antibody of the present invention binds may consist of a single continuous sequence of three or more amino acids of the MSR1 protein (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more). Alternatively, the epitope may consist of a number of non-consecutive 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 the modified LDL-binding domain of MSR1 at a location that does not interfere with modified-LDL binding to MSR1 when the antibody binds to this epitope.

[0838] Whether an antibody interacts with "one or more amino acids" within a polypeptide or protein can be determined using various techniques known to those skilled in the art. Exemplary techniques include, for example, the literature: AntibodiesThis includes conventional cross-blocking assays as described in Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY), alanine scanning mutation analysis, peptide blot analysis (Reineke, 2004, Methods Mol Biol 248:443-463), and peptide cleavage analysis. Additionally, methods such as epitope cleavage, epitope extraction, and chemical modification of antigens may be used (Tomer, 2000, Protein Science 9:487-496). Another method that can be used to identify amino acids within a polypeptide with which the antibody interacts is hydrogen / deuterium exchange measured by mass spectrometry. In general terms, the hydrogen / deuterium exchange method comprises the step of deuterium-labeling the target protein, followed by the step of binding an antibody to the deuterium-labeled protein. Next, the protein / antibody complex is transferred to water to allow hydrogen-deuterium exchange, so that it is present on all residues except those protected by the antibody (which remains deuterium-labeled). After dissociating the antibody, the target protein is subjected to protease cleavage and mass spectrometry analysis to reveal deuterium-labeled residues corresponding to the specific amino acids with which the antibody interacts. For example, Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73 Refer to :256A-265A.

[0839] An embodiment comprises an anti-MSR1 antibody that binds to the same epitope as any specific and exemplary antibody described herein (e.g., an antibody comprising any amino acid sequence as shown in Table 4 of this invention). Similarly, an embodiment also comprises an anti-MSR1 antibody that competes for binding to MSR1 with any specific and exemplary antibody described herein (e.g., an antibody comprising any amino acid sequence as shown in Table 4 of this invention).

[0840] It is easy to determine whether an antibody binds to the same epitope as the reference anti-MSR1 antibody or competes for binding with the reference anti-MSR1 antibody by using conventional methods known in the art, for example, as exemplified in Example 7 of this invention. For example, to determine whether a test antibody binds to the same epitope as the reference anti-MSR1 antibody disclosed herein, the reference antibody is bound to the MSR1 protein. Next, the ability of the test antibody to bind to the MSR1 molecule is evaluated. If the test antibody can saturately bind to the reference anti-MSR1 antibody after binding to MSR1, it can be concluded that the test antibody binds to an epitope different from that of the reference anti-MSR1 antibody. On the other hand, if the test antibody cannot saturately bind to the reference anti-MSR1 antibody following the MSR1 molecule, the test antibody may bind to the same epitope as that bound by the reference anti-MSR1 antibody of the present invention. Further conventional experiments (e.g., peptide mutation and binding analysis) may be subsequently performed to determine whether the observed lack of binding of the test antibody is due to binding to the same epitope as the reference antibody or whether steric blockage (or other phenomena) is involved in the observed lack of binding. These types of experiments may be performed using ELISA, RIA, Biacore, flow cytometry, or any other quantitative or qualitative antibody-binding assay available in the field. According to a specific embodiment of the present invention, two antibodies bind to the same (or overlapping) epitope, for example, a 1-, 5-, 10-, 20-, or 100-fold excess of one antibody inhibits the 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, if all amino acid mutations within an antigen that reduce or eliminate the binding of one antibody essentially reduce or eliminate the binding of another, the two antibodies are considered to have bound to the same epitope. If only a subset of amino acid mutations that reduce or eliminate the binding of an antibody reduces or eliminates the binding of another, the two antibodies are considered to have an "overlapping epitope."

[0841] If the antibody competes for (or cross-competes for) binding with the reference anti-MSR1 antibody, the binding methodology described above is performed in two orientations. In the first orientation, the reference antibody is allowed to bind to the MSR1 protein under saturation conditions, and then the binding of the test antibody to the MSR1 molecule is evaluated. In the second orientation, the test antibody is allowed to bind to the MSR1 molecule under saturation conditions, and then the binding of the reference antibody to the MSR1 molecule is evaluated. In both orientations, if only the first (saturated) antibody is able to bind to the MSR1 molecule, it is concluded that the test antibody and the reference antibody are competing for binding to MSR1. As will be recognized by a person skilled in the art, the antibody competing for binding to the reference antibody may not necessarily bind to the same epitope as the reference antibody, but may sterically block the binding of the reference antibody by binding to an overlapping or adjacent epitope.

[0842] 사람 항체의 제조

[0843] The anti-MSR1 antibody disclosed herein may be a complete human antibody. Methods for producing monoclonal antibodies, for example, complete human monoclonal antibodies, are known in the art. Any of these known methods may be used in the context of the present invention to produce a human antibody that specifically binds to human MSR1.

[0844] For example, VELOCIMMUNE™Using the technology or any other similar known method for generating a complete human monoclonal antibody, a high-affinity chimeric antibody against MSR1 having a human variable region and a mouse constant region is initially isolated. As in the experimental paragraph below, the antibody is characterized and selected for desired characteristics, e.g., affinity, ligand blocking activity, selectivity, epitope, etc. If necessary, the mouse constant region is replaced with the desired human constant region, e.g., wild-type or modified IgG1 or IgG4, to generate a complete human anti-MSR1 antibody. The selected constant region may vary depending on the specific application, but the high-affinity antigen-binding and target-specific characteristics remain within the variable region. In a specific example, the complete human anti-MSR1 antibody is isolated directly from antigen-positive B cells.

[0845] 생물동등성(bioequivalent)

[0846] The anti-MSR1 antibodies and antibody fragments disclosed herein comprise proteins having amino acid sequences that differ from those of the target antibody but possess the ability to bind to human MSR1. These variant antibodies and antibody fragments include one or more additions, deletions, or substitutions of amino acids when compared to the parent sequence, but exhibit essentially equivalent biological activity to that of the described antibody. Similarly, the anti-MSR1 antibody-coding DNA sequences disclosed herein include sequences encoding an anti-MSR1 antibody or antibody fragment that include one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but are essentially bioequivalent to the anti-MSR1 antibody or antibody fragment disclosed herein. Examples of such variant amino acid and DNA sequences are discussed above.

[0847] Two antigen-binding proteins or antibodies are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives that do not show a significant difference when administered as a single or multiple doses at the same molar dose under experimental conditions where their absorption rates and extents of absorption are similar. Some antibodies will be considered equivalents or pharmaceutical substitutes if they are equivalent in extents of absorption but not in absorption rates, and may still be considered bioequivalent if this difference in absorption rates is intentional and reflected in labeling, and is not considered medically significant for the specific drug studied, for example, and is not essential for obtaining an effective body drug concentration in chronic use.

[0848] In one embodiment, the two antigen-binding proteins are bioequivalent as there is no clinically significant difference in their safety, purity, and efficacy.

[0849] In one embodiment, the two antigen-binding proteins are bioequivalent if the patient can switch between the reference product and the biological product one or more times without adverse effects, e.g., clinically significant changes in immunogenicity, or a predicted increase in the risk of reduced efficacy compared to a continuous therapy regimen without such switching.

[0850] In one embodiment, two antigen-binding proteins are bioequivalent if both of them act by a general mechanism or mechanism of action for the conditions of use or conditions to the extent that such mechanism is known.

[0851] Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence can be demonstrated, for example, by (a) in vivo testing in humans or other mammals in which the concentration of an antibody or its metabolite is measured as a function of time in blood, plasma, serum, or other biological fluids; (b) in vitro testing that is related to or a sufficient prediction of human in vivo bioavailability data; (c) in vivo testing 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) well-controlled clinical testing to establish the safety, efficacy, or bioavailability or bioequivalence of the antibody.

[0852] Bioequivalent variants of the anti-MSR1 antibody disclosed herein may be constructed, for example, by making various substitutions of residues or sequences, or by deleting terminal or internal residues or sequences that are not necessary for biological activity. For example, by deleting cysteine ​​residues that are not essential for biological activity or replacing them with other amino acids, the formation of intramolecular disulfide bridges that are not essential or incorrect upon renaturation may be prevented. In another context, the bioequivalent antibody may include an anti-MSR1 antibody variant comprising amino acid changes that modify the glycosylation properties of the antibody, such as mutations that eliminate or delete glycosylation.

[0853] 종 선택성 및 종 교차-반응성

[0854] According to specific embodiments, an anti-MSR1 antibody that binds to human MSR1 but not to MSR1 from other species is provided herein. Embodiments also include an anti-MSR1 antibody that binds to human MSR1 and to MSR1 from one or more non-human species. For example, the anti-MSR1 antibody disclosed herein may or may not bind to mouse, rat, guinea pig, hamster, gerbil, pig, cat, dog, rabbit, goat, sheep, cattle, horse, camel, cynomologous, marmoset, rhesus, or chimpanzee MSR1, where present and can bind to human MSR1. According to specific exemplary embodiments, human MSR1 and cynomologous monkey (e.g., Macama pasquicularis ( Macaca fascicularis An anti-MSR1 antibody that specifically binds to MSR1 is provided. Other anti-MSR1 antibodies disclosed herein bind to human MSR1 but do not bind to cynomolgus monkey MSR1, or bind only weakly.

[0855] 다중특이적인 항체

[0856] The antibodies disclosed herein may be unispecific or multispecific (e.g., bispecific). Multispecific antibodies may be specific to different epitopes of a single target polypeptide or may contain antigen-binding domains specific to one or more target polypeptides. For example, Tutt et al. , 1991, J. Immunol . 147:60-69; Kufer et al ., 2004, Trends BiotechnolSee 22:238-244. The anti-MSR1 antibodies disclosed herein may be linked to or co-expressed with other active molecules, e.g., other peptides or proteins. For example, an antibody or a fragment thereof may be functionally linked to one or more other molecular entities, e.g., other antibodies or antibody fragments (e.g., chemical coupling, genetic fusion, non-covalent association, or others) to produce bispecific or multispecific antibodies having a second binding specificity.

[0857] An embodiment comprises a bispecific antibody, wherein one arm of the immunoglobulin binds to human MSR1, and the other arm of the immunoglobulin is specific to a second antigen. The MSR1-binding arm may comprise any HCVR / LCVR or CDR amino acid sequence as shown in Table 4 of the present invention. In a specific embodiment, the MSR1-binding arm binds to human MSR1 and blocks modified LDL binding to MSR1. In another embodiment, the MSR1-binding arm binds to human MSR1 but does not block modified LDL binding to MSR1. In some embodiments, the MSR1 binds to human MSR1 and activates MSR1 signaling. In another embodiment, the MSR1-binding arm blocks MSR1-mediated receptor stimulation. An embodiment also includes a bispecific antibody, wherein one arm of the antibody binds to the first epitope of human MSR1 and the other arm of the antibody binds to the second apparent epitope of human MSR1.

[0858] An exemplary bispecific antibody modality that can be used in the context of the present invention is a first immunoglobulin (Ig) C H 3 domains and the second Ig C H It includes the use of 3 domains, wherein the first and second Ig C HThe three domains differ from each other by at least one amino acid, wherein one or more amino acid differences reduce the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking amino acid differences. In one embodiment, the first Ig C H The 3rd domain binds to protein A and the second Ig C H The 3 domain contains mutations that reduce or discard protein A binding, e.g., H95R modifications (by IMGT exon numbering; H435R by EU numbering). The 2nd C H 3 additionally includes a Y96F variant (according to IMGT; Y436F according to EU). 2 C H Additional variations that may be found within 3 include: D16E, L18M, N44S, K52N, V57M, and V82I for IgG1 antibodies (according to IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU); N44S, K52N, and V82I for IgG2 antibodies (according to IMGT; N384S, K392N, and V422I by EU); and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I for IgG4 antibodies (according to IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU). Variations in the bispecific antibody forms described above are considered within the scope of the present invention.

[0859] Other exemplary bispecific modalities that may be used in the context of the present invention include, for example, scFv-based or diabodic bispecific modalities, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-into-holes, common light chains (e.g., common light chains having knobs-into-holes), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual-acting Fab(DAF)-IgG, and Mab 2 Includes, but is not limited to, double-specific forms (Note: for example, in the case of the preceding consideration of forms, Klein et al . 2012, mAbs 4:6, 1-11, and the references cited therein). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugates, for example, here using non-natural amino acids with ortho-chemical reactivity to generate site-specific antibody-oligonucleotide conjugates, which are then self-assembled into multimeric complexes with a subsequently defined composition, valence, and geometry. (Note: e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012 ]).

[0860] 치료학적 제형 및 투여

[0861] Embodiments relate to pharmaceutical compositions comprising the anti-MSR1 antibody disclosed herein or an antigen-binding fragment thereof. Pharmaceutical compositions of the present invention are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, etc. Suitable formulation sizes can be found in formulas known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. Such formulations are, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, and lipids (cationic or anionic). Containing vesicle (e.g., LIPOFECTIN™, Life Technologies, Carlsbad, California), DNA It comprises a conjugate, an anhydrous absorbent paste, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycol of various molecular weights), a semi-solid gel, and a semi-solid mixture comprising carbowax. Additionally, Powell et al . See “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-311.

[0862] The dose of the antibody administered to a patient may vary depending on the patient's age and physique, target disease, condition, route of administration, etc. The preferred dose is typically calculated based on body weight or body surface area. In adult patients, it may be advantageous to administer the antibody of the present invention intravenously as a single dose generally 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 duration of treatment may be adjusted. Effective dosage and schedule for administering the anti-MSR1 antibody can be determined experimentally; for example, patient progression can be monitored through periodic evaluations, and the dose can be adjusted accordingly. Furthermore, interspecies scaling of the dosage can be performed using methods well known in the art (e.g., Mordenti et al. , 1991, Pharmaceut. Res . 8:1351).

[0863] Various delivery systems, e.g., liposomal encapsulation, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptor-mediated endocytosis, are known and may be used to administer the pharmaceutical composition disclosed herein (Note: e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, dura mater, and oral routes. The composition may be administered by any convenient route, e.g., by infusion or bolus injection, by absorption through an epithelial or mucocutaneous lining (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered in combination with other biologically active agents. Administration may be systemic or local.

[0864] Pharmaceutical compositions as disclosed herein may be delivered subcutaneously or intravenously using standard needles and syringes. Additionally, regarding subcutaneous delivery, pen delivery devices are applicable for delivering the pharmaceutical compositions of the present invention. Such pen delivery devices may be reusable or single-use. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. In single-use pen delivery devices, there is no replaceable cartridge. Rather, the single-use pen delivery device is pre-filled with the pharmaceutical composition maintained in a reservoir within the device. Once the pharmaceutical composition in the reservoir is emptied, the empty device is discarded.

[0865] Many reusable pens and auto-injector delivery devices have applications in the subcutaneous delivery of the pharmaceutical compositions disclosed herein. To mention just a few examples, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Berdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, Indiana), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, New Jersey), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany)Includes, but is not limited to. Examples of disposable pen delivery devices having an application for subcutaneous delivery of the pharmaceutical composition of the present invention are, to mention only a few: SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK TM Automatic Injector (Amgen, Thousand Oaks, Canada), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TM Includes, but not limited to, Penn (Abbott Labs, Appfort Park, Illinois).

[0866] In certain circumstances, the pharmaceutical composition may be delivered to a controlled release system. In one embodiment, a pump may be used (see: Langer, cit.; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In other embodiments, polymeric materials may be used; see: Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. Still in other embodiments, only a fraction of the systemic dose may be required by positioning the controlled release system adjacent to the target of the composition (see: e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled emission systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0867] Injectable preparations may include forms such as intravenous, subcutaneous, intracutaneous, and intramuscular injection doses, drip infusions, etc. Such injectable preparations may be prepared by publicly known methods. For example, injectable preparations may be prepared, for instance, by dissolving, suspending, or emulsifying the aforementioned antibody or its salt in a sterile aqueous or oily medium commonly used for injection. As an aqueous medium for injection, for example, physiological saline, an isotonic solution containing glucose and other adjuvants, etc., may be used together with a suitable solubilizer, for example, alcohol (e.g., ethanol), polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactant (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil), etc. As an oily medium, for example, sesame oil, soybean oil, etc., may be used, and may be used together with a solubilizer, for example, benzyl benzoate, benzyl alcohol, etc. The injection solution thus prepared is preferably filled into a suitable ampoule.

[0868] Advantageously, the oral or parenteral pharmaceutical composition described above is prepared in a unit dose formulation suitable for matching the dosage of the active ingredient. Such unit dose formulations include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforementioned antibody contained in the unit dose is generally about 5 to about 500 mg per dose, particularly in the injection form; and it is preferable that the aforementioned antibody be contained in about 5 to about 100 mg and about 10 to about 250 mg for other dosage forms.

[0869] Therapeutic Uses of Antibodies

[0870] An embodiment comprises a method comprising the step of administering to a subject requiring this 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 an ADC comprising any HCVR / LCVR or CDR sequence as shown in Table 4 herein). The therapeutic composition comprises any anti-MSR1 antibody disclosed herein, its antigen-binding fragment, or an ADC (e.g., 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 It may include an ADC), and a pharmaceutically acceptable carrier or excipient.

[0871] The antibodies and ADCs disclosed herein are particularly useful for the treatment, prevention, and / or alleviation of any disease or disorder associated with or mediated by MAR1 expression or activity, or for treatment by binding to MAR1 without competing for modified LDL, and / or promoting MSR1 receptor internalization and / or reducing the number of cell surface receptors. For example, the antibodies and ADCs disclosed herein are useful for the treatment, attenuation, or alleviation of atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation by targeting cells that express MAR1 and / or respond to MAR1-mediated signaling, such as macrophages.

[0872] In the context of the treatment methods described herein, an anti-MSR1 antibody, or its ADC, may be administered as monotherapy (i.e., as the only therapeutic agent) or in combination with one or more additional therapeutic agents (e.g., those described elsewhere in this invention).

[0873] A method for treating a proliferative disease, metabolic disease, inflammation, neurodegenerative disease, or disease, disorder, or condition related to glucocorticoid receptor signaling in a subject is provided herein, comprising administering to the subject an effective therapeutic amount of the compound described herein (e.g., anti-MSR1 ADC) or a pharmaceutical composition comprising the compound described herein.

[0874] In some embodiments, where the payload is a steroid, asthma, atopic dermatitis, contact dermatitis, allergic dermatitis, drug hypersensitivity reaction, anaphylactic rhinitis, perennial or seasonal allergic rhinitis, and serum sickness; skin diseases and conditions, e.g., 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, e.g., but not limited to, primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis; gastrointestinal disease;Hematologic disorders, e.g., 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 grade 2 thrombocytopenia; trichinosis; tuberculous meningitis with subarachnoid block or impending block; neoplastic diseases, e.g., but not limited to leukemia and lymphoma; neurological disorders, e.g., but not limited to Acute exacerbations of multiple sclerosis, cerebral edema associated with a primary or metastatic brain tumor, craniotomy, or head injury; ophthalmic diseases, e.g., but not limited to sympathetic ophthalmia, temporal arteritis, uveitis, xerophthalmia, and ocular inflammatory conditions unresponsive to topical corticosteroids; renal diseases, e.g., but not limited to induction of diuresis or resolution of proteinuria due to idiopathic nephrotic syndrome or lupus erythematosus;Respiratory disease, e.g., but not limited to, when used concurrently with appropriate antituberculosis chemotherapy; beryllium poisoning (berylliosis), fulminating or disseminated pulmonary tuberculosis, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis; and use as an adjuvant therapy for short-term administration (to prevent an acute episode or exacerbation in the patient) in rheumatic disorders, e.g., but not limited to acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, e.g., juvenile rheumatoid arthritis, and in dermatomyositis, polymyositis, stomatitis, and systemic lupus erythematosus. In certain embodiments, a method for treating or preventing arthritis is provided herein.;

[0875] In some embodiments, a method for treating a disease, disorder, or condition selected from autoimmune disease, allergy, arthritis, asthma, breathing disorder, blood disorder, cancer, collagen disease, connective tissue disorder, dermatological disease, eye disease, endocrine problem, immunological disease, inflammatory disease, intestinal disorder, gastrointestinal disease, neurological disorder, organ transplant condition, rheumatoid disorder, skin disorder, swelling condition, wound healing condition, and combinations thereof is provided herein, including administering the steroid payload or conjugate thereof described herein.

[0876] 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 respiratory 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 bowel disease, lipid pneumonitis thyroiditis, urticaria (hives), pericarditis, nephrotic syndrome, and uveitis. In some embodiments, the intestinal disorder is collagenous colitis. Ulcerative colitis, Crohn's disease, and inflammatory bowel disease It is selected from. In some embodiments, the rheumatic 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 selected from chronic inflammatory demyelinating polyradiculoneuropathy.

[0877] In some embodiments, the compound described herein is administered to a patient to treat acute inflammatory phenomena, such as shock, cerebral edema, and graft-vs-host disease, for example, but not limited to. In some embodiments, the compound described herein is administered to treat lympholytic effects associated with hematological malignancies, such as leukemia, lymphoma, and multiple myeloma, for example, but not limited to.

[0878] In some embodiments, a method for reducing inflammation in a subject in need is provided herein, comprising administering a therapeutically effective amount of the steroid or conjugate thereof described herein to a subject in need thereof. In some embodiments, a method for modulating the immune system in a subject in need thereof is provided herein, comprising administering a therapeutically effective amount of the steroid or conjugate thereof described herein to a subject in need thereof. In some embodiments, a method for modulating cortisol levels in a subject in need thereof is provided herein, comprising administering a therapeutically effective amount of the steroid or conjugate thereof described herein to a subject in need thereof. In some embodiments, a method for reducing lymphocyte migration in a subject in need thereof is provided herein, comprising administering a steroid payload or conjugate thereof described herein to a subject in need thereof. In some embodiments, a method for treating hypercalcemia due to cancer, Meniere's disease, migraine, cluster headache, severe aphthous ulcer, laryngitis, severe tuberculosis, Herxheimer reaction to syphilis, decompensated heart failure, allergic rhinitis, or nasal polyp is provided herein, comprising administering the steroid payload or conjugate thereof described herein to a subject in need thereof. In some embodiments, the compound disclosed herein may be used to treat inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the disease, disorder, or condition is a chronic inflammatory condition, e.g., but not limited to asthma, skin infection, and eye infection.In some embodiments, the compound described herein is used for immunosuppression in patients undergoing organ transplantation.

[0879] In some embodiments, the steroid payload and conjugate thereof described herein are administered to a patient to treat neurological disorders associated with GR signaling, e.g., but not limited to psychiatric disorders, e.g., schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), and mood disorders, substance abuse, stress, and anxiety.

[0880] In some embodiments, the steroid payload and its conjugate described herein are administered to a patient to treat visual system disorders, such as, but not limited to, ocular inflammation (e.g., conjunctivitis, keratitis, uveitis), macular edema, and macular degeneration. In some embodiments, the steroid payload and its conjugate described herein are administered to a patient to treat cardiovascular disorders. In some embodiments, the steroid payload and its conjugate described herein are administered to a patient to treat glucose and / or liver metabolic disorders. In some embodiments, the steroid payload and its conjugate described herein are administered to a patient to treat musculoskeletal disorders. In some embodiments, the steroid payload and its conjugate described herein are administered to a patient to treat subcutaneous inflammatory conditions, such as eczema and psoriasis.

[0881] The protein conjugates described herein reduce or prevent adverse effects resulting from the administration of free, unconjugated steroid payloads by providing means for targeted delivery of their steroid payloads to specific cells or organ systems. Examples of such reduced or prevented adverse effects include those listed in the approved drug label for Decadron® (dexamethasone), the full text of which is incorporated herein by reference. In some embodiments, the adverse effects to be reduced or prevented are: elevated blood pressure; sodium retention; water / fluid retention (edema, angioedema, pulmonary edema); increased potassium excretion; reversible hypohalamic-pituitary adrenal (HPA) axis suppression; potential corticosteroid deficiency after discontinuation of treatment; susceptibility to infection; exacerbation of systemic fungal infection; Worsening of the severity of chickenpox in pediatric and adult patients; worsening of measles in pediatric and adult patients; posterior subcapsular cataracts; glaucoma with possible damage to the optic nerve; improvement in the establishment of a grade 2 eye infection caused by bacteria, fungi, or viruses; increased incidence of a new episode of optic neuritis; Kaposi's sarcoma; drug-induced secondary adrenocortical insufficiency; increased risk of perforation in the presence of active or latent gastric ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis; peritoneal irritation after 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, potentially causing quadriparesis); elevation of creatinine kinase; euphoria, insomnia, mood swings, personality changes, and psychic derangement ranging from severe depression to frank psychotic manifestations; worsening of existing emotional instability or psychotic tendency; 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 after recent myocardial infarction; syncope; tachycardia; thromboembolism; thrombophlebitis; vasculitis; acne; allergic dermatitis; dry scaly skin;Echymose and petechiae; erythema; impaired wound healing; increased sweating; rash; striae; suppression of reactions to skin tests; thin and fragile skin; thinning scalp hair; urticaria; decreased carbohydrate and glucose tolerance; development of a Cushingoid state; hyperglycemia; glycosuria; hirsutism; hypertrichosis; increased demand for insulin or oral hypoglycemic agents in diabetes (insulin resistance); manifestation of latent diabetes mellitus; menstrual irregularity; Grade II adrenal cortex and pituitary non-responsiveness (especially during stress; trauma; surgery; or disease); growth inhibition in pediatric patients; congestive heart failure in susceptible patients; fluid retention; hypokalemic alkalosis; potassium loss; sodium retention; abdominal distention; increased serum liver enzyme levels (generally reversible upon discontinuation); hepatomegaly; increased appetite; nausea; pancreatitis; peptic ulcer with possible perforation and hemorrhage; perforation of the small and large intestines (especially in patients with inflammatory bowel disease);Ulcerative esophagitis; negative nitrogen balance due to protein catabolism; aseptic necrosis of the femoral and humeral heads; loss of muscle mass; muscle weakness; osteoporosis; pathologic fracture of long bone; steroid myopathy; tendon rupture; vertebral compression fracture; convulsion; depression; emotional instability; euphoria; headache; increased intracranial pressure with papilledema (pseudotumor cerebri), generally after discontinuation of treatment; insomnia; mood swing; neuritis; neuropathy; paresthesia; Personality changes; mental disorders; vertigo; exophthalmos; glaucoma; increased intraocular pressure; suboccipital cataracts; abnormal fat deposits; decreased tolerance to infection; hiccups; increased or decreased motility and number of spermatozoa; malaise; moon face; and weight gain;and is selected from side effects associated with drug-drug interactions. In some embodiments, the side effects to be reduced or prevented are those associated with drug-drug interactions. In some embodiments, the side effects to be reduced or prevented are drug-drug interactions from the use of corticosteroids and aminoglutesimide, e.g., reduction of adrenal suppression by corticosteroids; amphotericin B injection and potassium-depleting agents, e.g., development of hypokalemia, cardiac enlargement, and congestive heart failure; antibiotics, e.g., significant reduction in corticosteroid clearance; anticholinesterases, e.g., development of severe weakness in patients with myasthenia gravis; inhibition of response to oral anticoagulants, e.g., warfarin; antidiabetic agents, e.g., increased blood glucose concentration; Antituberculosis drugs, e.g., increased serum concentrations of isoniazid; cholestyramine, e.g., increased clearance of corticosteroids; cyclosporines, e.g., increased activity of both cyclosporine and corticosteroids, and incidence of convulsion; interference with the dexamethasone suppression test (DST), e.g., false-negative results in patients being treated with indomethacin; digitalis glycoside, e.g., increased risk of arrhythmia due to hypokalemia; ephedrine, e.g., enhanced metabolic clearance of corticosteroids causing reduced blood levels and decreased physiological activity; estrogen, e.g., oral contraceptives, e.g., reduced hepatic metabolism of certain corticosteroids and associated increases in their effects;Enhancement of metabolism of hepatic enzyme inducers, inhibitors, and substrates (drugs inducing cytochrome P450 3A4 (CYP 3A4) enzyme activity, e.g., barbiturates, phenytoin, carbamazepine, rifamycin), e.g., corticosteroids; potential for increased plasma concentrations of drugs inhibiting CYP 3A4 (e.g., ketoconazole, macrolide antibiotics, e.g., erythromycin), e.g., corticosteroids; increased clearance of drugs metabolized by CYP 3A4 (e.g., indinavir, erythromycin), e.g., causing reduced plasma concentrations; reduced metabolism of certain corticosteroids, e.g., ketoconazole, up to 60%, resulting in an increased risk of corticosteroid side effects; and inhibition of adrenal corticosteroid synthesis, potentially causing adrenal insufficiency during corticosteroid clearance; Non-steroidal anti-inflammatory drugs (NSAIDs), e.g., an increased risk of gastrointestinal side effects and increased clearance of salicylates; phenytoin, e.g., an increase or decrease in phenytoin levels, altered seizure control; skin tests, e.g., suppression of the response to a skin test; thalidomide, e.g., toxic epidermal necrosis; and vaccines, e.g., live or inactivated vaccines, which are associated with a reduced response to toxoids and suppression of antibody responses or the enhancement of replication of certain organisms contained in live attenuated vaccines.;

[0882] Therefore, chemical formula ( I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), chemical formula ( III ) or chemical formula ( 3000A method for treating a disease, disorder, or condition associated with a glucocorticoid receptor is provided herein, comprising administering a conjugate of ) to a patient having the disease, disorder, or condition, wherein side effects associated with the administration of a free steroid payload of said conjugate are reduced. Additionally, a method for delivering a compound of formula (III) or a compound of formula (3000) to said cell is provided herein, comprising contacting said cell with a protein conjugate formula (3000) or a compound of formula (III), wherein the protein conjugate comprises an antibody or an antigen-binding fragment thereof that binds to a surface antigen of said cell.

[0883] In some examples, where the payload is an LXR regulator, a therapeutically effective amount of a compound and / or ADC (e.g., chemical formula ( I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 5001 ), ( 5002 ), ( 5003 ), ( 5004 ), ( 6001 ), ( 6002 ), ( 6003 ), ( 6004 ), or ( 6005 A method for treating a disease, disorder, or condition is provided herein, including administering an ADC of ) or a pharmaceutical composition thereof.

[0884] In some examples, a therapeutically effective amount of a compound and / or ADC (e.g., formula ( I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), (5001 ), ( 5002 ), ( 5003 ), ( 5004 ), ( 6001 ), ( 6002 ), ( 6003 ), ( 6004 ), or ( 6005 A method for preventing a disease, disorder, or condition is provided herein, including administering an ADC of ) or a pharmaceutical composition thereof.

[0885] In some examples, methods for treating or preventing any disease, disorder, or condition that is responsive to the regulation of LXR signaling are provided herein. In some examples, the disease or disorder is related to LXR function, LXR polymorphism, LXR agonist activity, or LXR antagonist activity. In some examples, methods for treating or preventing a disease, disorder, or condition selected from the group consisting of proliferative disorders, neurodegenerative disorders, immunological disorders, autoimmune diseases, inflammatory disorders, skin diseases, metabolic diseases, cardiovascular diseases, and gastrointestinal diseases are provided herein.

[0886] Proliferative disorders may be any proliferative disorder known to the skilled technician. In certain embodiments, proliferative disorders include, but are not limited to, tumor disorders, wherein tumor disorders may be any cancer disorders known to the skilled technician. In certain embodiments, a method for treating or preventing melanoma is provided herein. In certain embodiments, a method for treating or preventing metastatic melanoma is provided herein. In certain embodiments, a method for treating or preventing lung cancer is provided herein. In certain embodiments, a method for treating or preventing EGFR-tyrosine kinase inhibitor-resistant lung cancer is provided herein. In certain embodiments, a method for treating or preventing oral cancer is provided herein. In certain embodiments, a method for treating or preventing oral squamous cell carcinoma is provided herein. In certain embodiments, a method for treating or preventing prostate cancer is provided herein. In certain embodiments, a method for treating or preventing Hodgkin lymphoma is provided herein. In certain embodiments, a method for treating or preventing breast cancer is provided herein.

[0887] Neurodegenerative disorders may be any neurodegenerative disorder known to the skilled technician. In certain embodiments, a method for treating or preventing Alzheimer's disease is provided herein. In certain embodiments, a method for treating or preventing Parkinson's disease is provided herein. In certain embodiments, a method for treating or preventing Huntington's disease is provided herein. In certain embodiments, a method for treating or preventing amyotrophic lateral sclerosis is provided herein. In certain embodiments, a method for treating or preventing myelin gene expression is provided herein. In certain embodiments, a method for treating or preventing myelin and demyelination states, diseases, or disorders is provided herein.

[0888] The immunological disorder may be any immunological disorder known to the technician. In certain embodiments, a method for treating or preventing inflammatory bowel disease is provided herein. In certain embodiments, a method for treating or preventing ulcerative colitis is provided herein. In certain embodiments, a method for treating or preventing Crohn's disease is provided herein.

[0889] Inflammatory disorders may be any inflammatory disorder known to the technician. In certain embodiments, a method for treating or preventing arthritis is provided herein. In certain embodiments, a method for treating or preventing rheumatoid arthritis is provided herein.

[0890] The metabolic disease may be any metabolic disease known to the skilled person. In a specific embodiment, the metabolic disease is dyslipidemia. The dyslipidemia may be any dyslipidemia known to the skilled person. In a specific embodiment, the dyslipidemia is hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and cardiovascular disease, e.g., coronary artery disease (including the treatment and prevention of, e.g., angina, myocardial infarction, and sudden cardiac death); atherosclerosis (including, e.g., the treatment and prevention of atherosclerosis); It is selected from the group consisting of and restenosis (including, for example, the prevention or treatment of atherosclerotic plaques that develop as a result of medical procedures such as balloon angioplasty). In a specific embodiment, a method for treating or preventing diabetes mellitus is provided herein.

[0891] Cardiovascular disease may be any cardiovascular disease known to the skilled technician. In certain embodiments, a method for treating or preventing atherosclerosis is provided herein. In certain embodiments, a method for treating or preventing atherosclerosis resulting from abnormal macrophage processing is provided herein. In certain embodiments, a method for treating or preventing atherosclerosis resulting from the formation of oxidized low-density lipoprotein (oxLDL) is provided herein, wherein macrophages do not process oxLDL. In certain embodiments, a method for treating or preventing ischemic heart disease is provided herein. In certain embodiments, a method for treating or preventing stroke is provided herein. In certain embodiments, a method for treating or preventing hypertensive heart disease is provided herein. In certain embodiments, a method for treating or preventing aortic aneurysm is provided herein. In certain embodiments, a method for treating or preventing endocarditis is provided herein. In a specific embodiment, a method for treating or preventing peripheral artery disease is provided herein. In a specific embodiment, a method for treating or preventing any combination of diseases provided in this paragraph is provided herein.

[0892] In some examples, methods for modulating the function of nuclear receptors are provided herein. As non-limiting examples, such function may be selected from inflammatory mediators (e.g., cytokines, chemokines), cholesterol regulation, cholesterol uptake, cholesterol efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation, apoptosis, migration, chemotaxis, gene transcription, and protein expression.

[0893] In some examples, a therapeutically effective amount of the chemical formula (for patients with the above disorder)I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 7001 ), ( 7002 ), ( 7003 ), ( 7004 ), and / or ( 7005 A method for preventing a disease, disorder, or condition is provided herein, including administering a compound of ) and / or an ADC, or a pharmaceutical composition thereof.

[0894] S. Aureus S. aureus ) is a special (facultative) intracellular bacterium capable of surviving phagocytosis by macrophages and other cell types (Horn, J., et al., Inside job: Staphylococcus aureus host-pathogen 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 act as reservoirs, where S. aureus replicates and then seeds other organs during infection (Surewaard, BG, 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, e.g., macrophages, very well, which indicates that intracellular S. aureus reservoirs can evade treatment with standard management antibiotics (Lehar, SM, et al., Novel Antibiotic composite eliminates intracellular S. aureus.Nature, 2015. 527(7578): p. 323-8). However, liposomal formulations of vancomycin increased the penetration of the antibiotic into macrophages, thereby reducing the burden on the organs of S. aureus more effectively than standard-administered vancomycin (Surewaard, BG, et al.). Identification and treatment of the Staphylococcus aureus reservoir in vivo. J Exp Med, 2016. 213(7): p. 1141-51). In addition, these data indicate that delivering antibiotics to macrophages may be an effective method to remove intracellular S. aureus reservoirs.

[0895] Antibiotic-resistant S. aureus remains a public health problem, and approximately 40% of bloodstream infections in the United States are caused by methicillin-resistant S. aureus (MRSA). Few FDA authorities have demonstrated the existence of treatment options for MRSA bloodstream infections, and vancomycin remains the antibiotic choice. Despite appropriate antibiotic treatment, the mortality rate from S. aureus is approximately 18%, which drives research into combinations that could improve treatment.

[0896] Antibiotics of the rifamycin class inhibit bacterial RNA polymerase (RNAP) and exhibit potent activity against S. aureus. However, monotherapy using this class of antibiotics can lead to the selection of resistance populations during treatment. Therefore, rifamycin antibiotics can be used in combination with first-line antibiotics to generally improve outcomes in infections involving prosthetics or external devices.

[0897] The ADCs described herein containing rifamycin derivatives are useful for preventing or treating bacterial growth and / or bacterial infection in subjects. In some examples, the bacteria are Gram-positive bacteria (Gram-positive bacteria are the cause of bacterial infection). In some examples, the bacteria are penicillin-resistant bacteria (penicillin-resistant bacteria are the cause of bacterial infection). In some examples, the bacteria are Staphylococcus aureus ( Staphylococcus aureus ), methicillin-resistant Staphylococcus aureus (MRSA) bacteria (MRSA bacteria are the cause of bacterial infection). In some cases, the bacteria are methicillin-susceptible Staphylococcus aureus (MSSA) bacteria (MSSA bacteria are the cause of bacterial infection). In some cases, the bacteria are vancomycin-resistant Staphylococcus aureus (VRSA) bacteria (VRSA bacteria are the cause of bacterial infection). In some cases, the bacteria are multidrug-resistant M. tuberculous ( M. tuberculosis )(Multi-drug resistant M. tuberculous bacteria are the cause of bacterial infections). In additional examples, the bacteria are, for instance, Chlamydia trachomatis resistant to azithromycin ( Chlamydia trachomatis ) is (e.g., Chlamydia trachomatis resistant to azithromycin is a cause of bacterial infection). In additional examples, the bacteria are, for instance, Clostridium difficile resistant to metronidazole, vancomycin, and / or fidaxomycin ( Clostridium difficile )is (e.g., Clostridium difficile resistant to metronidazole, vancomycin, and / or fidaxomycin is a cause of bacterial infection).

[0898] An effective therapeutic dose of rifamycin analogue (e.g., chemical formula ( I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 7001 ), ( 7002 ), ( 7003 ), ( 7004 ) and / or ( 7005Cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, 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, comprising administering an antibody-drug conjugate comprising an ADC) to a subject A method for preventing or treating (associated with an implant) is provided herein. In addition, an effective therapeutic dose of a rifamycin analog (e.g., ( I ), ( IA ), ( IB ), ( IB-1 ), ( IB-2 ), ( IC ), ( ID ), ( IE ), ( 7001 ), ( 7002 ), ( 7003 ), ( 7004 ) and / or ( 7005A method for preventing or treating intracellular bacterial infection in a subject is provided herein, comprising administering an antibody-drug conjugate containing an antibody-drug conjugate comprising an ADC of ).

[0899] In some examples, a therapeutic method is provided herein comprising administering an ADC comprising an anti-MSR1 antibody, an anti-MSR1 antibody of the antigen-binding site of an MSR1 antibody, or an anti-MSR1 antibody of the MSR1 antigen-binding fragment thereof to a subject in need, which is useful for the treatment and / or prevention of a disease, disorder, or condition associated with a bacterial infection and / or Staphylococcus infection, e.g., S. aureus infection, and / or alleviation of at least one symptom associated with such disease, disorder, or condition. Such disease, disorder, or condition may be cellulitis, bacteremia, necrosis of the skin, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, burn-like skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, or suppurative arthritis. In some examples, the subject has a prosthetic joint, and the antibody disclosed herein is S. It is used to treat and / or prevent S. aureus infection. In some examples, the subject has a catheter, and the antibody disclosed herein is used to treat and / or prevent S. aureus infection of the catheter and / or tissues surrounding the catheter. In some examples, the subject has an implanted foreign body, and the antibody disclosed herein is used to treat and / or prevent S. aureus infection of the foreign body and / or tissues surrounding the foreign body. In some examples, the subject has mastitis, and the antibody disclosed herein is useful for treating mastitis.

[0900] In some examples, rifamycin analogs and / or their anti-MSR1 ADCs are administered together with one or more additional antibiotics (e.g., antibiotics that can be used for MRSA infections), e.g., vancomycin, trimethoprim-sulfamethoxazole, tetracycline, doxycycline / minocycline, clindamycin, cephalosporin (e.g., cephalexin), naficillin, fidaxomycin, linezolid, etc., and / or any other suitable antibiotic(s). In some examples, the ADCs described herein containing rifamycin analogs are administered together with vancomycin and are useful for preventing or treating bacterial infections in subjects.

[0901] Combination therapy and formulations

[0902] An embodiment includes a composition and a therapeutic formulation comprising any anti-MSR1 antibody described herein together with one or more additional therapeutically active components, and a therapeutic method comprising administering such combination to a subject in need thereof.

[0903] The anti-MSR1 antibody disclosed herein may be co-formulated and / or administered with one or more additional therapeutically active components selected from the group consisting of cytokine inhibitors, e.g., small-molecule cytokine inhibitors, and antibodies binding to 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 their respective receptors.

[0904] The anti-MSR1 antibody disclosed herein may also be administered and / or co-formulated with anti-inflammatory agents, immunomodulators, analgesics, corticosteroids, steroids, antioxidants, COX inhibitors, cardioprotective agents, metal chelators, IFN-gamma, and / or NSAIDs. In some embodiments, the anti-MSR1 antibody may be administered and / or co-formulated with anti-PCSK9 antibodies, anti-ANGPTL3 antibodies, statins, ezetimibes, and other lipid-lowering therapies.

[0905] Additional therapeutically active component(s), e.g., any of the formulations listed above or derivatives thereof, may be administered before, together with, or immediately after administration of the anti-MSR1 antibody disclosed herein; (for the purposes of this disclosure, such administration regimens consider the administration of the anti-MSR1 antibody "together with additional therapeutically active component(s)"). An embodiment comprises a pharmaceutical composition in which the anti-MSR1 antibody disclosed herein is co-administered with one or more additional therapeutically active component(s) as described elsewhere in this invention.

[0906] Administration therapy

[0907] According to specific embodiments, multiple doses of anti-MSR1 antibodies (a pharmaceutical composition comprising a combination of an ADC or anti-MSR1 antibody and any additional therapeutically active agent described herein) may be administered to a subject over a defined time course. The method comprises the step of sequentially administering multiple doses of the anti-MSR1 antibody disclosed herein to a subject. As used herein, “sequentially administering” means that each dose of the anti-MSR1 antibody is administered to the subject at different times, for example, on different days separated by scheduled intervals (e.g., hours, days, weeks, or months). An embodiment comprises a method comprising sequentially administering to a patient a single initial dose of the anti-MSR1 antibody, followed by one or more second doses of the anti-MSR1 antibody, and optionally one or more third doses of the anti-MSR1 antibody.

[0908] The terms “initial dose,” “second dose,” and “third dose” refer to the transient sequence of administration of the anti-MSR1 antibody disclosed herein. Thus, the “initial dose” is the dose administered at the start of the therapeutic regimen (also referred to as the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the administration of the second dose. The initial, second, and third doses may all contain the same amount of anti-MSR1 antibody, but may generally differ from each other in terms of the frequency of administration. In certain embodiments, however, the amount of anti-MSR1 antibody contained in the first, second, and / or third doses varies from one another during the course of treatment (e.g., appropriately up- or down-adjusted). In a specific embodiment, two or more doses (e.g., 2, 3, 4, or 5) are administered as a “loading dose” at the start of the therapeutic regimen, followed by a subsequent dose (e.g., a “maintenance dose”) administered at a less common standard.

[0909] In certain exemplary embodiments, each second and / or third dose is given for 1 to 26 weeks after the immediately preceding dose (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, It is administered at 25½, 26, and 26½ weeks or later. As used herein, the phrase “immediately preceding dose” refers to the dose of anti-MSR1 antibody administered to the patient immediately before the administration of the next dose in the sequence, without an intervening dose, in a sequence of multiple doses.

[0910] A method according to this aspect of the present invention may comprise administering any number of second and / or third doses of anti-MSR1 antibodies to a patient. For example, in a specific embodiment, a single second dose is administered to the patient. In another embodiment, two or more second doses (e.g., two, three, four, five, six, seven, eight or more) are administered to the patient. Similarly, in a specific embodiment, a single third dose is administered to the patient. In another embodiment, two or more third doses (e.g., two, three, four, five, six, seven, eight or more) are administered to the patient. The administration regimen may be performed indefinitely over the lifetime of the subject in question, or until such treatment is no longer therapeutically required or beneficial.

[0911] In an embodiment comprising multiple second doses, each second dose may be administered at the same frequency as other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks or 1 to 2 months after the immediate previous dose. Similarly, in an embodiment comprising multiple third doses, each third dose may be administered at the same frequency as other third doses. For example, each third dose may be administered to the patient 2 to 12 weeks after the immediate previous dose. In certain embodiments, the frequency at which the second and / or third doses are administered to the patient may vary over the course of the treatment regimen. The frequency of administration may also be adjusted by the attending physician during the course of treatment according to the individual patient's needs after the clinical trial.

[0912] An embodiment includes a dosing regimen in which 2 to 6 loading doses are administered to a patient at a first frequency (e.g., once per week, once per two weeks, once per three weeks, once per month, once per two months, etc.), and then 2 or more maintenance doses are administered to the patient at a frequency that is rarely common. For example, according to this aspect of the present invention, when the loading dose is administered at a frequency of once per month, the maintenance dose may be administered to the patient once every six weeks, once every two months, once every two months, once every three months, etc.

[0913] Diagnostic uses of antibodies

[0914] The anti-MSR1 antibody disclosed herein may also be used to detect and / or measure MSR1 or MSR1-expressing cells in a sample, for example, for diagnostic purposes. For example, the anti-MSR1 antibody or a fragment thereof may be used to diagnose abnormal expression of MAR1 (e.g., over-expression, under-expression, lack of expression, etc.). An exemplary diagnostic test for MSR1 comprises, for example, contacting a sample obtained from a patient with the 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 may be used in a diagnostic application together with a second antibody that is itself detectably labeled. The detectable label or reporter molecule is a radioisotope, for example, 3 H, 14 C, 32 P, 35 S, or 125 I; a fluorescent or chemiluminescent moiety, e.g., fluorescein, or rhodamine; or an enzyme, e.g., alkaline phosphatase, beta-galactosidase, horseradish peroxidase, or luciferase. Specific exemplary assays that may be used to detect or measure MSR1 in a sample are enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immuno-PET (e.g., 89 Zr, 64 Includes Cu et al.), and fluorescence-activated cell sorting (FACS).

[0915] Samples that can be used for the MSR1 diag...

Claims

Claim 1 An antibody or an antigen-binding fragment thereof that binds to a macrophage scavenger receptor 1 (MSR1), wherein the antibody or the antigen-binding fragment thereof comprises: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO: 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID NO: 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID NO:

10. Claim 2 The antibody or its antigen-binding fragment according to claim 1, wherein the antibody or its antigen-binding fragment exhibits one or more of the following characteristics: a. K less than 1.4 nM as measured by surface plasmon resonance. D a. Binds to human MSR1 at 37°C; b. Binds to human MSR1 at 37°C with a half-life t½ greater than 4 minutes as measured by surface plasmon resonance; c. IC50 less than 10 nM as measured by ligand uptake assay. 50 d. Shows maximum inhibition of LDL uptake modified by human MSR1 of less than 90%; d. Blocks < 50% of modified LDL binding to human MSR1 as measured by competitive ELISA assay; and / or e. Shows binding of human MSR1 and internalization of 10% or more of the bound complex as measured by binding in THP-1 cells. Claim 3 The antibody or its antigen-binding fragment comprising the following, wherein: a. HCDR1 consisting of the amino acid sequence of SEQ ID NO: 52; HCDR2 consisting of the amino acid sequence of SEQ ID NO: 54; HCDR3 consisting of the amino acid sequence of SEQ ID NO: 56; LCDR1 consisting of the amino acid sequence of SEQ ID NO: 60; LCDR2 consisting of the amino acid sequence of SEQ ID NO: 62; and LCDR3 consisting of the amino acid sequence of SEQ ID NO: 64; or b. HCDR1 consisting of the amino acid sequence of SEQ ID NO: 4; HCDR2 consisting of the amino acid sequence of SEQ ID NO: 6; HCDR3 consisting of the amino acid sequence of SEQ ID NO: 8; LCDR1 consisting of the amino acid sequence of SEQ ID NO: 12; LCDR2 consisting of the amino acid sequence of SEQ ID NO: 14; and LCDR3 consisting of the amino acid sequence of SEQ ID NO:

16. Claim 4 In paragraph 3, an antibody or its antigen-binding fragment comprising: (i) HCVR comprising the amino acid sequence of SEQ ID NO: 50; and LCVR comprising the amino acid sequence of SEQ ID NO: 58; or (ii) HCVR comprising the amino acid sequence of SEQ ID NO: 2; and LCVR comprising the amino acid sequence of SEQ ID NO:

10. Claim 5 An antibody-drug conjugate (ADC) comprising an antibody according to claim 1 or an antigen-binding fragment thereof conjugated to a payload residue via a linker or a linker-spacer. Claim 6 In claim 5, an antibody-drug conjugate having the structure of chemical formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer form thereof, a regioisomer thereof, or a mixture of regioisomers thereof: Chemical formula ( I Here: BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; L is a linker; PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin residues. Claim 7 In paragraph 5, chemical formula ( IA Antibody-drug conjugate having the structure of: Chemical formula ( IA Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or HG It is a divalent or trivalent linker comprising amino acid residues directly or indirectly bound to; AA 2 is absent or is a dipeptide, tripeptide, or tetrapeptide residue; Q is a connector group residue if it exists; SP is absent or a spacer; HG If present, it is a hydrophilic group; PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin residues. Claim 8 In paragraph 5, chemical formula ( IB-1 Antibody-drug conjugate having the structure of: Chemical formula ( IB-1 Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; Q If it exists, or And; SP is absent or a spacer; PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin residues; where This indicates an atom in which the referenced group is bonded to an adjacent group within the chemical formula. Claim 9 In paragraph 5, chemical formula ( IB-2 Antibody-drug conjugate having the structure of: Chemical formula ( IB-2 Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or HG It is a divalent or trivalent linker comprising amino acid residues directly or indirectly bound to; AA 2 is absent or is a dipeptide, tripeptide, or tetrapeptide residue; Q is, if it exists, or And; SP is absent or a spacer; HG If it exists, And, PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin residues; where This indicates an atom bonded to an adjacent group within the chemical formula of the group mentioned therein. Claim 10 In paragraph 5, chemical formula ( IC ), chemical formula ( ID ), or chemical formula ( IE Antibody-drug conjugate having the structure of: Chemical formula ( IC ) Chemical formula ( ID ) Chemical formula ( IE Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; SP 2 is absent or a spacer; RG 2 is a reactive group residue; AA 1 is a divalent or trivalent linker containing amino acid residues; AA 2 is a dipeptide, tripeptide, or tetrapeptide residue; Q is, if it exists, And; SP is absent or a spacer; HG Is And, PA is a payload moiety selected from the group consisting of steroid residues, LXR modulator residues, or rifamycin residues; where This indicates an atom bonded to an adjacent group within the chemical formula of the group mentioned therein. Claim 11 In Paragraph 7, CHALLENGE ACCEPTED 1 -CHALLENGE ACCEPTED 2 chemical formula ( LL1 Antibody-drug conjugate according to ): Here DAY 1 , YES 2 , and RAA 3 Each of these independently, at least one of them HG It is an amino acid side chain connected to; here is through this CHALLENGE ACCEPTED 1 -CHALLENGE ACCEPTED 2 represents an atom bonded to an adjacent group within the chemical formula. Claim 12 In Paragraph 11, R AA1 this HG It is a lysine, glutamine, glutamic acid, or aspartic acid side chain directly or indirectly bound to, and R AA2 and R AA3 Antibody-drug conjugates that are valine and alanine side chains or valine and citrulline side chains, respectively. Claim 13 In Paragraph 7, CHALLENGE ACCEPTED 1 -CHALLENGE ACCEPTED 2 go or and, here Through this CHALLENGE ACCEPTED 1 -CHALLENGE ACCEPTED 2 Antibody-drug conjugate, in which represents an atom bonded to an adjacent group within the chemical formula. Claim 14 In any one of paragraphs 7 through 10, RG 1 Antibody-drug conjugate, wherein the residue is independently selected from the following group in each case: ;Here is through this RG 1 A residue represents an atom bonded to an adjacent group within the chemical formula. Claim 15 In Paragraph 10, RG 2 Antibody-drug conjugate, wherein the residue is independently selected from the following group in each case: ;Here is through this RG 2 A residue represents an atom bonded to an adjacent group within the chemical formula. Claim 16 In any one of paragraphs 7 through 10, SP and SP 1 In each of these cases, independently absent or C 1-6 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 Independently selected from the group consisting of -, (glycine)4-serine, and combinations thereof, where the subscript e g is an integer from 0 to 4, and the subscript u a is an integer from 1 to 8, and the subscript v An antibody-drug conjugate in which α is an integer from 1 to 8. Claim 17 In Paragraph 10, SP 2 a, in each case, independently absent or C 1-6 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 Independently selected from the group consisting of -, (glycine)4-serine, and combinations thereof, where the subscript e g is an integer from 0 to 4, and the subscript u a is an integer from 1 to 8, and the subscript v An antibody-drug conjugate in which α is an integer from 1 to 8. Claim 18 In Paragraph 7, Antibody-drug conjugate, any one of the following: Claim 19 An antibody-drug conjugate according to paragraph 5, wherein the antibody or its antigen-binding fragment is conjugated to a steroid payload through a linker or linker-spacer. Claim 20 An antibody-drug conjugate according to claim 5, wherein the antibody or its antigen-binding fragment is conjugated to an LXR regulatory factor payload through a linker. Claim 21 An antibody-drug conjugate according to paragraph 5, wherein an antibody or its antigen-binding fragment is conjugated to a rifamycin payload through a linker. Claim 22 In paragraph 19, a steroid conjugated to an antibody or its antigen-binding fragment via a linker or linker-spacer has the chemical formula ( A-1 Antibody-drug conjugates that are compounds of ) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof: Chemical formula ( A-1 );here R 1 and R 2 is, independently, hydrogen, C1-C 20 Alkyl, C1-C 20 Alkyl-C(O)-O-, -OH, or a halo selected from bromo, chloro, fluoro, and iodine; R 1 and R 2 together Forming; here R 4 is C1-C 20 Alkyl, C6-C 20 Aryl, C6-C 20 Arylalkyl, 5- or 6-membered N-containing heterocycloalkyl, C1-C 20 Alkylene, C6-C 20 Arrylene, C6-C 20 It is an arylalkylene, or a 5- or 6-membered N-containing heterocycloalkylene, and R 3 -O-, R Z -C(O)- X -, -C1-C 20 Heteroalkylene, piperidinylene, 5- or 6-membered N-containing heterocycloalkylene, -N R Aa - , -Oxy C6-C 20 Aryl-N R Aa - , or - ZA ( R P ) t And; R Z is C1-C 20 It is an alkylene; X is -O- or -N( R Aa )-and; Z -S-, -S(O)-, -S(O)2-, -SO2N( R Aa )-, -O-, -C(O)N( R Aa )-, -C(O)-, or -N( R Aa )-and; A' is C6-C 20 Arrylene, C6-C 20 It is an arylalkylene, or a 5- to 20-membered heteroarylene; R p is, independently in each case, a halo selected from bromo, chloro, fluoro, and iodine; R Aa is hydrogen; t is an integer from 1 to 3; R 5A and R 5B Each is independently a halo selected from bromo, chloro, fluoro, and iodine, or hydrogen; where R 3 or R 4 It is combined with the linker. Claim 23 In paragraph 19, chemical formula ( 3000 ) or an antibody-drug conjugate having a structure in the form of a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: BA-(L'-SP-D ) n Chemical formula ( 3000 Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; D is selected from the following a) and / or b): a) Chemical formula (a), where in chemical formula (a) R x Both are hydrogen; R 34 is C1-C 20 Alkyl, C6-C 20 Aryl, C6-C 20 It is an arylalkyl, or a 5- or 6-membered N-containing heterocycloalkyl; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1 -(Here X 1 is the chemical formula ( 3000 Attached to L' in ), -C(O)-N(H)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( 3000 Attached to L' in ), -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S-(where S is the chemical formula ( 3000 Attached to L' in ), (Here, the attachment point at the terminal nitrogen of piperazine is the chemical formula ( 3000 )at L' (is in), -CH2-NH-(where nitrogen is the chemical formula ( 3000 Attached to L' in ), or (Here, nitrogen is the chemical formula ( 3000 )at L' (attached to) or, where in chemical formula (a) R x Both are fluoro, and; R 34 is C1-C 20 Alkylene, C1-C 20 Arrylene, C6-C 20 It is an arylalkylene, or a 5- or 6-membered N-containing heterocycloalkylene; SP is -C(O)-C1-C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -alkylene- X 1b -(Here X 1b is the chemical formula ( 3000 )at L' Attached to), -C(O)-N(H)-(C1-C 10 -alkylene)- X 1b -(Here X 1b is the chemical formula ( 3000 )at L' (attached to), (Here, the attachment point at the terminal nitrogen of peperazine is the chemical formula ( 3000 )at L' (is in), -CH2-NH-(where nitrogen is the chemical formula ( 3000 )at L' Attached to), or (Here, nitrogen is the chemical formula ( 3000 )at L (attached to); b) a compound selected from the following: Here, the compound of b) has the chemical formula (through the hydroxyl group of the -C(O)CH2OH group or through the hydroxyl group of the mapracolat 3000 )of BA Connected to; X 1 is -N(C 1-6 alkyl)- and; X 1b is -S-, -NH-, or -N(C 1-6 alkyl)- and; n is an integer selected from 1 to 30 (including boundaries); L' is a linker; BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ No.

10. Claim 24 In paragraph 19, an antibody-drug conjugate in which the steroid payload is selected from the group consisting of the following: Here is a combination for the linker. Claim 25 In paragraph 19, an antibody-drug conjugate in which the steroid payload is selected from the group consisting of the following: and , or a mixture thereof. Claim 26 In paragraph 20, an antibody-drug conjugate in which the LXR regulator conjugated to the antibody or its antigen-binding fragment via a linker is a compound of formula (B) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Chemical formula ( B Here W is -CH2-, -N(H)-, or -O-; R B1 is hydrogen, -OH, -O-, -NH2, -N(H)-, alkyl, alkylene, -OP(O)(O R 6 )2, or -OP(O)(O R 6 )O R 6 - and; R B2 is hydrogen, -OH, -O-, -CH2NH2, -CH2N(H)-, R B3 , R B4 , R B5 , or -O- R B5 and, here R B1 and R B2 is not hydrogen at the same time; R B3 is -N( R 6 )2 or -N( R 6 )- R 6 - and; R B4 Is -XYZ or - X - Y - Z - and; X is selected from the group consisting of -O- and -N(H)-; Y is C1-C 20 Alkylene, substituted C1-C 20 Alkylene, C1-C 20 Heteroalkylene, and substituted C1-C 20 Selected from the group consisting of heteroalkylenes, wherein the substituents are halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; Z is selected from the group consisting of -OH, -NH2, -O-, and -N(H)-; R B5 is C1-C 20 Alkyl, C2-C 20 Heterocycloalkyl, substituted C2-C 20 Heterocycloalkyl, C1-C 20 Alkylene, C2-C 20 Heterocycloalkylene, or substituted C2-C 20 It is a heterocycloalkylene, wherein each of the heterocycloalkyl, heterocycloalkylene, substituted heterocycloalkyl, or substituted heterocycloalkylene comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, comprises at least one -OH and -CH2OH substituent or comprises at least one primary or secondary nitrogen, wherein the substituent is a halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, where R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; each of R 6 In each case, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide containing two or more amino acids, C1-C 20 alkyl, or C1-C 20 It is an alkylene; and each of R 7 Eun, independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG b and, here, each subscript b is an integer from 0 to 3; where group R B1 or R B2 It is combined with the linker. Claim 27 In paragraph 20, the LXR regulator conjugated to an antibody or its antigen-binding fragment via a linker has the chemical formula ( B-1 Antibody-drug conjugates that are compounds of ) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof: Chemical formula ( B-1 ),here: R B1 -N(H) R 8 or -N( R 9 )2 and; R B2 is -N(H) R 8 and; each R 8 Silver, independently in each case, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue comprising two or more amino acid residues, or C1-C 20 It is alkyl; R 9 is C1-C 20 Alkyl, C6-C 20 Aryl, C6-C 20 Arylalkyl, C2-C 20 Heterocycloalkyl, or substituted C2-C 20 It is a heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and, when substituted, comprises at least one -OH and -CH2OH, or at least one primary or secondary nitrogen; each of R 7 is independently Halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG b and, here, each subscript b is an integer from 0 to 3; where group R B1 or R B2 It is combined with the linker. Claim 28 In paragraph 5, chemical formula ( 6005 Antibody-drug conjugate having the structure of: Chemical formula ( 6005 Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or HG It is a divalent or trivalent linker comprising amino acid residues directly or indirectly bound to; AA 2 is absent or is a dipeptide, tripeptide, or tetrapeptide residue; R B1 is hydrogen, -OH, -O-, -NH2, -N(H)-, alkyl, alkylene, -OP(O)(O R 6 )2, or -OP(O)(O R 6 )O R 6 - and; R B2 is hydrogen, -OH, -O-, -CH2NH2, -CH2N(H)-, R B3 , R B4 , R B5 , or -O- R B5 and, here R B1 and R B2 is not hydrogen at the same time; R B3 -N( R 6 )2 or -N( R 6 )- R 6 - and; R B4 Is -XYZ or - X - Y - Z - and; X is selected from the group consisting of -O- and -N(H)-; Y is C1-C 20 Alkylene, substituted C1-C 20 Alkylene, C1-C 20 Heteroalkylene, and substituted C1-C 20 Selected from the group consisting of heteroalkylenes, wherein the substituents are halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; Z is selected from the group consisting of -OH, -NH2, -O-, and -N(H)-; R B5 is C1-C 20 Alkyl, C2-C 20 Heterocycloalkyl, substituted C2-C 20 Heterocycloalkyl, C1-C 20 Alkylene, C2-C 20 Heterocycloalkylene, or substituted C2-C 20 It is a heterocycloalkylene, wherein each of the heterocycloalkyl, heterocycloalkylene, substituted heterocycloalkyl, or substituted heterocycloalkylene comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, comprises at least one -OH and -CH2OH substituent or comprises at least one primary or secondary nitrogen, wherein the substituent is a halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, where R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; each of R 6 In each case, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide containing two or more amino acids, C1-C 20 alkyl, or C1-C 20 It is an alkylene; and each of R 7 Eun, independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG b and, here, each subscript b is an integer from 0 to 3; where group R B1 or R B2 It is combined with the linker. Claim 29 In paragraph 20, an antibody-drug conjugate in which the LXR modulator is selected from the group consisting of the following: and Here, is a combination for the linker. Claim 30 In paragraph 20, an antibody-drug conjugate in which the LXR modulator is selected from the group consisting of the following: Here, is a combination for the linker. Claim 31 In paragraph 20, an antibody-drug conjugate in which the LXR modulator is any one of the following: or Here is a combination for the linker. Claim 32 In paragraph 21, rifamycin has the chemical formula ( C-1 Antibody-drug conjugates that are compounds of ) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof: Chemical formula ( C-1 Here: X 1c -S-, -O-, and -N R 5c Selected from; R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino; C 1-6 Alkyl; di-C 1-6 Alkylamino; C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-OC 1-6 Alkyl; ( R 5c )2N-C 1-6 Alkylene-SC 1-6 Alkyl; C 2- C 20 Heterocycloalkyl; or C 2-20 It is a heterocycloalkyl; where C 2- C 20 Heterocycloalkyl comprises 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur; R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from; each R ac is present in the presence of fluoro, chloro, bromo, iodine, -OH, -NH2, and C 1-6 Independently selected from alkoxy; R 5c is independently, in each case, hydrogen and C 1-6 Selected from alkyls; where R 1c It is combined with the linker. Claim 33 In paragraph 21, rifamycin has the chemical formula ( C-2 Antibody-drug conjugates that are compounds of ) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof: Chemical formula ( C-2 Here: X 1c -S-, -O-, and -N R 5c Selected from; R 1c is absent, or -amino-C 1-6 Alkylene; C 1-6 Alkylene-amino-; C 1-6 Alkylene; -di-C 1-6 Alkylamino C 1-6 Alkylene; -OC 1-6 Alkylene; -SC 1-6 Alkylene; - R 5c -( R 5c )NC 1-6 Alkylene-N( R 5c )-C 1-6 Alkylene; - R 5c -( R 5c )NC 1-6 Alkylene-OC 1-6 Alkylene; - R 5c -( R 5c )NC 1-6 Alkylene-SC 1-6 Alkylene; C2-C 20 Heterocycloalkyl heterocycloalkylene; or C2-C 20 Heterocycloalkyl-C 1-6 It is an alkylene; here, C2-C 20 Heterocycloalkylene comprises one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur; R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from; R ac and R bc is fluoro, chloro, bromo, iodine, -OH, -NH2, and C 1-6 Independently selected from alkoxy; R 5c In each case, hydrogen and C 1-6 Independently selected from alkyls; where R 1c It is combined with the linker. Claim 34 In paragraph 21, rifamycin has the chemical formula ( C-3 Antibody-drug conjugates that are compounds of ) or pharmaceutically acceptable salts, solvates, or stereoisomers thereof: Chemical formula ( C-3 Here: R 1c is D-C 1-6 Alkylamino C 1-6 Alkylene; ( R 5c )2N-C 1-6 Alkylene-N( R 5c )-C 1-6 Alkylene; C2-C 20 Heterocycloalkylene or C2-C 20 Heterocycloalkyl-C 1-6 It is an alkylene; here, C2-C 20 Heterocycloalkylene comprises one, two, or three heteroatoms selected from oxygen, nitrogen, and sulfur; R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from; R 5c is hydrogen and C 1-6 Selected from alkyls; where R 1c It is combined with the linker. Claim 35 In paragraph 21, rifamycin has the chemical formula ( C-4 A compound of ) or a pharmaceutically acceptable salt, solvate, or stereoisomer form thereof. Antibody-drug conjugate: Chemical formula ( C-4 Here: R 1c Is or and; here Y is carbon or nitrogen; R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from; R 5c In each case, independently absent, hydrogen and C 1-6 Selected from alkyls; where R 1c Is It is bonded to the linker through the nitrogen atom represented by. Claim 36 In paragraph 5, chemical formula ( 7002 Antibody-drug conjugate having the structure of: Chemical formula ( 7002 Here BA is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; n is 1, 2, 3, or 4; SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or HG It is a divalent or trivalent linker comprising an amino acid residue directly or indirectly bound to; AA 2 is absent or is a dipeptide, tripeptide, or tetrapeptide residue; R B1 is hydrogen, -OH, -O-, -NH2, -N(H)-, alkyl, alkylene, -OP(O)(O R 6 )2, or -OP(O)(O R 6 )O R 6 - and; R B2 is hydrogen, -OH, -O-, -CH2NH2, -CH2N(H)-, R B3 , R B4 , R B5 , or -O- R B5 and, here R B1 and R B2 is not hydrogen at the same time; R B3 is -N( R 6 )2 or -N( R 6 )- R 6 - and; R B4 Is -XYZ or - X - Y - Z - and; X is selected from the group consisting of -O- and -N(H)-; Y is C1-C 20 Alkylene, substituted C1-C 20 Alkylene, C1-C 20 Heteroalkylene, and substituted C1-C 20 Selected from the group consisting of heteroalkylenes, wherein the substituents are halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; Z is selected from the group consisting of -OH, -NH2, -O-, and -N(H)-; R B5 is C1-C 20 Alkyl, C2-C 20 Heterocycloalkyl, substituted C2-C 20 Heterocycloalkyl, C1-C 20 Alkylene, C2-C 20 Heterocycloalkylene, or substituted C2-C 20 It is a heterocycloalkylene, wherein each of the heterocycloalkyl, heterocycloalkylene, substituted heterocycloalkyl, or substituted heterocycloalkylene comprises 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, comprises at least one -OH and -CH2OH substituent or comprises at least one primary or secondary nitrogen, wherein the substituent is a halo, cyano, nitro, haloalkyl, azido, epoxy, heteroaryl, heterocycloalkyl, , , , , , , , , , , , , , or Selected from a group consisting of, where R A , R B , and R C is, independently in each case, hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R A and R B They form saturated or unsaturated carbocyclic or heterocyclic rings together with the atoms to which they are bonded; each of R 6 In each case, hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide containing two or more amino acids, C1-C 20 alkyl, or C1-C 20 It is an alkylene; and each of R 7 Eun, independently, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O-amino acid residue, or O-PEG b and, here, each subscript b is an integer from 0 to 3; where group R B1 or R B2 It is combined with the linker. Claim 37 In paragraph 5, an antibody-drug conjugate in which rifamycin is selected from the group consisting of the following: Here, is a combination for the linker. Claim 38 Chemical formula ( 7003 ) or an antibody-rifamycin conjugate having a structure in the form of a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Chemical formula ( 7003 Here: X 1c -S-, -O-, and -N R 5c Selected from; R 1c Is , ; , ; or and; here Y is carbon or nitrogen; R 2c , R 3c , and R 4c is hydrogen, C 1-6 Alkyl, and -(C=O)- R 5c Selected independently from; R 5c is, in each case, independently absent or hydrogen and C 1-6 Selected from alkyls; each of AA is an independently selected amino acid residue; SP 1 is absent or a spacer; RG 1 is a reactive group residue; BA is the antibody of claim 1 or its antigen-binding fragment; n is an integer from 1 to 30; w is 2, 3, or 4; here R 1c is a dashed line It is bonded to the linker through the nitrogen atom represented by; R 6c is a counterion. Claim 39 In Paragraph 38, X 1c antibody-rifamycin conjugate containing oxygen. Claim 40 An antibody-rifamycin conjugate according to claim 38 or 39, wherein the antibody or its antigen-binding fragment contains the N297Q mutation. Claim 41 In Paragraph 38, w A 2-person, antibody-rifamycin conjugate. Claim 42 In Paragraph 38, (AA)2 antibody-rifamycin conjugate in which valine-citrulline is present. Claim 43 In Paragraph 38, SP 1 this An antibody-rifamycin conjugate comprising Claim 44 In Paragraph 38, SP 1 this An antibody-rifamycin conjugate comprising Claim 45 In Paragraph 38, RG 1 this An antibody-rifamycin conjugate comprising Claim 46 In Paragraph 38, X 1c is oxygen; R 1c go or and; here Y is carbon or nitrogen; here R 1c Is R 1c It is bonded to the linker through the quaternary nitrogen atom; R 5c is C 1-6 It is alkyl; R 6c is an antibody-rifamycin conjugate that is a counterion. Claim 47 In paragraph 38, an antibody-rifamycin conjugate in which rifamycin is any one of the following: or . Claim 48 In paragraph 5, an antibody-drug conjugate selected from the group consisting of the following or its stereoisomer forms, or its regioisomers, or mixtures of its regioisomers: Here, each Ab is the antibody of claim 1 or its antigen-binding fragment; and each of BA Is and here Ab 1 is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; R C 2-4 It is an alkylene; nn is an integer from 2 to 4 (including boundaries), and each of n is an integer from 1 to 4. Claim 49 Antibody-drug conjugate selected from the following or its stereoisomer forms, or its regioisomers, or mixtures of its regioisomers: Here, each of Ab is the antibody of claim 1 or its antigen-binding fragment; and each of n is an integer from 1 to 4. Claim 50 Antibody-drug conjugates according to one of the following chemical formulas or its stereoisomer form, its regioisomer, or a mixture of its regioisomers: Here, each Ab is the antibody of claim 1 or its antigen-binding fragment; and each of BA Is and, here Ab 1 is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ ID No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ ID No. 10; R C 2-4 - It is an alkylene; nn is an integer from 2 to 4 (including boundaries), and each of n is an integer from 1 to 4. Claim 51 In paragraph 5, chemical formula ( 7004 Antibody-drug conjugate according to ): Chemical formula ( 7004 Here Ab is an antibody or its antigen-binding fragment comprising: (i) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ No. 50; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ No. 58; or (ii) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the heavy chain variable region (HCVR) amino acid sequence of SEQ No. 2; and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the light chain variable region (LCVR) amino acid sequence of SEQ No.

10. Claim 52 An antibody-drug conjugate prepared by conjugating an anti-MSR1 antibody or a PEG-modified anti-MSR1 antibody to a linker payload selected from the following groups, or a stereoisomer form thereof, a regioisomer thereof, or a mixture of regioisomers thereof, wherein the anti-MSR1 antibody is an antibody according to claim 1 or an antigen-binding fragment thereof: Claim 53 In paragraph 5, the anti-MSR1 antibody or PEG-modified anti-MSR1 antibody is of the formula ( D An antibody-drug conjugate prepared by contacting a linker payload according to ), or a stereoisomer form thereof, or a regioisomer thereof, with the antibody or its antigen-binding fragment under conditions suitable for forming a binding between them, wherein the anti-MSR1 antibody is the antibody according to claim 1 or its antigen-binding fragment: Chemical formula ( D ). Claim 54 An antibody according to claim 1 or an antigen-binding fragment thereof, comprising, and a pharmaceutically acceptable carrier, for inflammation, atherosclerosis, arthritis, dyslipidemia, bacterial infection, intracellular bacterial infection, cellulitis, bacteremia, dermonecrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, 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 A pharmaceutical composition for preventing or treating joint), catheter-associated infection, or implant-associated infection. Claim 55 A pharmaceutical composition for preventing or treating inflammation, atherosclerosis, arthritis, dyslipidemia, bacterial infection, intracellular bacterial infection, cellulitis, bacteremia, necrosis of the skin, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, boil, burn-like skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, suppurative arthritis, mastitis, infection associated with a prosthetic joint, infection associated with a catheter, or infection associated with an implant, comprising an antibody-drug conjugate according to claim 5 and a pharmaceutically acceptable carrier. Claim 56 A pharmaceutical composition according to claim 54 or 55, wherein side effects associated with the administration of an unconjugated steroid payload of the compound are reduced. Claim 57 In paragraph 54 or 55, the bacteria are Gram-positive bacteria, penicillin-resistant bacteria Staphylococcus aureus ( Staphylococcus aureus ), methicillin-resistant Staphylococcus aureus (methiciliin resistant Staphylococcus aureus : MRSA), methicillin-sensitive Staphylococcus aureus (methicillin susceptible Staphylococcus aureus : MSSA) or vancomycin-resistant Staphylococcus aureus Staphylococcus aureus : VRSA), or multi-drug resistant Mycobacterium tuberculousis (multi-drug resistant Mycobacterium tuberculosis )Pharmaceutical composition. Claim 58 A pharmaceutical composition administered together with vancomycin in paragraph 57. Claim 59 delete Claim 60 delete Claim 61 delete Claim 62 delete Claim 63 delete Claim 64 delete Claim 65 delete Claim 66 delete Claim 67 delete Claim 68 delete Claim 69 delete

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