Anti-MSR1 antibodies and methods of using same

Abstract

To provide antibodies or antigen binding fragments that bind to MSR1 and methods of use thereof.SOLUTION: Provided is an antibody that bind to human MSR1 with a high affinity. In an embodiment, the antibody binds to MSR1 without blocking the binding of modified LDL to MSR1 or blocking the binding less than 90%. In some embodiments, the antibody binds to MSR1 expressed on the cell surface and is internalized. The antibody of the invention may be a fully human antibody. The invention includes an anti-MSR1 antibody or antigen binding fragment thereof conjugated to a drug or therapeutic compound.SELECTED DRAWING: Figure 21

Description

[Technical Field]

[0001] This application is filed on May 9, 2018, which is incorporated by reference in its entirety for all purposes. U.S. Provisional Application No. 62 / 669,276 filed May 30, 2018, U.S. Provisional Application No. 62 / 678 filed May 30, 2018, No. 200, filed November 20, 2018; U.S. Provisional Application No. 62 / 769,946, filed January 8, 2019; U.S. Provisional Application No. 62 / 789,987, filed March 20, 2019, and U.S. Provisional Application No. 62 / 821,366, filed March 20, 2019. Priority is claimed for No. 2.

[0002] FIELD OF THE INVENTION The present invention provides a novel antibody that specifically binds to the trimeric membrane glycoprotein receptor (MSR1) and mediates MSR1 signal transduction. Modulating antibodies and antigen-binding fragments thereof, and antibody-drug conjugates of such antibodies - Patents.com and its method of use.

[0003] (Sequence Listing) A copy of the sequence listing is available under the file name 114581.00244_ST25.TXT, created on May 30, 2018, and at The present specification will be available via EFS-Web as a hard copy of the sequence listing in ASCII format, approximately 165 kilobytes in size. The sequence listing contained in this hardcopy ASCII document is submitted simultaneously with the present specification. and is incorporated herein by reference in its entirety. [Background technology]

[0004] (background) Macrophage scavenger receptor 1 (MSR1) mediates the binding of modified low-density lipoprotein (LDL) (Kri Eger, M., 1994. Annu. Rev. Biochem. 63:601-637; Platt, N. and S. Gordon. Literature, 2001. J Clin Invest. 108(5):649-654) and advanced glycation end products of bovine serum albumin (A A series of challenges, including GE-BSA (Smedsrod et al., 1997. Biochem J. 322(Pt 2):567-573), A single-spanning trimeric type II membrane glycoprotein mediating uptake of electrophilic / polyanionic ligands Pattern recognition receptor. MSR1 receptor is involved in atherosclerosis, Alzheimer's disease, involved in many macrophage-related physiological and pathological processes, including macrophage-mediated immune responses and host defense. It is said that there is a relationship.

[0005] MSR1 expression was initially thought to be macrophage-specific. , which has been shown to be present on various classes of dendritic cells (Herber et al., 2002). 010. Nat. Med. 16(8): 880-886). Furthermore, MSR1 is expressed in endothelial cells and smooth muscle cells. It appears to be internalized via coated pits on the cell surface and is activated at acidic pH. After releasing the ligand, it is recycled from the trans-Golgi apparatus back to the cell surface (Doi (Mori, T. 1994. Journal of Biological Chemistry; Mori, T. 1994. Lab Invest.) This is a key step in the progression of atherosclerosis, from monocyte-derived macrophages. Promotes transformation into foam cells.

[0006] MSR1 isoforms 1 and 2 are functional receptors for modified low-density lipoprotein (LDL) MSR1 isoform 3 can mediate the endocytosis of modified LDL (aspartate). cetyl-LDL) but are unable to internalize the bound complex. However, MSR1 also binds to a wide variety of ligands other than modified LDL. These ligands include β-amyloid proteins, molecular chaperones, and extracellular matrices. These include cytoplasmic proteins, advanced glycation end products, apoptotic cells, and activated B cells.

[0007] Liver X receptors (LXRs) are involved in cholesterol, lipid, and glucose homeostasis, inflammation, and LXRα and LXR are ligand-dependent transcription factors that regulate the expression of genes involved in innate immunity. LXRα is highly expressed in the liver, intestine, adipose tissue, and differentiated macrophages. LXRs are expressed as (i) cholesterol transporters, e.g. For example, it stimulates the expression of ABCA1 and ABCG1, both of which mediate cellular cholesterol efflux. and (ii) negatively affect macrophage inflammatory gene expression through the suppression of NF-kB activation. LXRs have various biological functions, including regulating atherosclerosis. It has also been implicated in proliferative disorders, neurodegenerative disorders, and inflammation. These include melanoma, lung cancer, oral squamous cell 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, and Enteritis, Crohn's disease, and arthritis (Anderson et al., 2011; Huang et al., 20 15; Cui et al., 2012). Macrophage LXRs are known to contain anti-atherogenic activity. LXR agonists have been shown to (i) inhibit the initiation of atherosclerosis and slow its progression; (ii) delay atherosclerosis and improve established atherosclerotic lesions; and (iii) reduce lesion macrophage content by apoptosis. It is believed that this will be possible.

[0008] The therapeutic efficacy of small molecule LXR modulators may be enhanced by, for example, undesired modulation of LXRs in non-target cells. Regulation of LXRs in non-target cells is limited by their limited activity and / or low bioavailability. However, poor bioavailability can lead to undesirable side effects, including but not limited to: However, this is occurring for a number of reasons, including low solubility, which exacerbates the inadequate therapeutic window for treatment. If ADCs containing LXR modulators are developed, target-specific LXR regulation will become possible. This would avoid side effects due to off-target regulation of LXRs. Furthermore, such ADCs may offer benefits such as improved modulation of biological targets, increased bioavailability, and Therefore, antibody-drug combinations of LXR modulators may be beneficial in treating rheumatoid arthritis. There is a continuing need for effective treatment of, for example, metabolic diseases using monoconjugates. There are.

[0009] Glucocorticoids (GCs) are small steroids that bind to the glucocorticoid receptor (GR). It is widely used in anti-inflammatory and immunosuppressive therapy. Due to the ubiquitous expression of glucocorticoid receptors in the brain, glucocorticoid treatment is largely It is impaired by toxicity to most organ systems. Side effects arising from glucocorticoid receptor activation in non-target cells, particularly Both new glucocorticoids and new therapies that minimize the side effects associated with steroid use are needed. There are.

[0010] Rifamycins are antibiotics with a spectrum of activity against gram-positive and gram-negative bacteria. They form a subclass of the ansamycin antibiotic family and are used to treat tuberculosis, leprosy, and / or Commonly prescribed for the treatment of Mycobacterium avium complex (MAC) Antimycobacterial drugs. The rifamycin group of antibiotics includes the "classical" rifamycins. rifamycins and rifamycin derivatives, such as rifampicin (or rifampin), rifamycin These include butine, rifapentine, rifalazil, and rifaximin. Antibiotic-resistant bacterial strains in the environment (e.g., methicillin-resistant Staphylococcus aureus (MRSA), The increasing incidence of virulent steroids (VRSA) and multidrug-resistant Mycobacterium tuberculosis (MTB) is an ongoing problem. There is a need for more effective rifamycin analogues. , reduced bioavailability and metabolism by the cytochrome P450 enzyme system (especially CYP3A4). cytochrome P450 enzymes, which can result in enhanced clearance of some co-administered drugs It is a moderate to strong inducer of CYP3A4 and CYP4A5 pathways, particularly CYP3A4. Such interactions are delayed in onset. Although the side effects may be prolonged, they persist beyond the coadministration of rifamycin. It can also induce the multidrug efflux transporter protein (P-gp). Side effects caused by administration, especially side effects caused by activation of the cytochrome P450 enzyme system Novel therapies that minimize this are needed.

[0011] As disclosed in this application, MSR antibodies are produced by systemic administration of such compounds. Therapeutic molecules, e.g., LXR agonists, to minimize unwanted side effects caused by To provide a means for specific targeting of steroids and rifamycins can be done. Summary of the Invention

[0012] (overview) Provided herein are antibodies that bind to the membrane glycoprotein receptor known as MSR1. , antigen-binding fragments of antibodies, and antibody-drug conjugates thereof. This is useful for targeting cells that express MSR1, such as macrophage cells. The anti-MSR1 antibody and its antigen-binding portion can be used alone in an unmodified form. , or as part of an antibody-drug conjugate.

[0013] The antibodies disclosed herein can be full-length (e.g., IgG1 or IgG4 antibodies). or may comprise only the antigen-binding portion (e.g., Fab, F(ab')2, or scFv fragment). and affect functionality, e.g., by eliminating remaining effector functions. (Reddy et al., 2000, J. Immunol. 164:1925-1933).

[0014] Embodiments of anti-MSR1 antibodies disclosed herein are listed in Tables 4 and 5. Table 4 lists: The heavy chain variable region (HCVR), light chain variable region (LCVR), heavy chain complementarity determining region (HVR) of an exemplary anti-MSR1 antibody The amino acid sequence of the light chain complementarity determining region (LCDR1, LCDR2, and LCDR3) and the light chain complementarity determining region (LCDR1, LCDR2, and LCDR3) is Table 5 shows the amino acid sequence identifiers for the HCVR, LCVR, HCDR1, and HCDR2 of exemplary anti-MSR1 antibodies. , HCDR3, LCDR1, LCDR2, and LCDR3 nucleic acid sequence identifiers are shown.

[0015] Provided herein are HCVR amino acid sequences selected from any of the sequences listed in Table 4. or at least 90%, at least 95%, at least HCVRs containing substantially similar sequences having 98% or at least 99% sequence identity. The antibody or antigen-binding fragment thereof specifically binds to MSR1, comprising:

[0016] Also provided herein are any of the LCVR amino acid sequences listed in Table 4. or at least 90%, at least 95%, or at least and substantially similar sequences having at least 98% or at least 99% sequence identity. An antibody or antigen-binding fragment thereof that specifically binds to MSR1, including LCVR.

[0017] Also provided herein are antibodies that can be used with any of the LCVR amino acid sequences listed in Table 4. HCVR and LCVR amino acid sequences containing any of the paired HCVR amino acid sequences listed in Table 4 an antibody or an antigen-binding fragment thereof that specifically binds to MSR1 and contains a nucleotide sequence pair (HCVR / LCVR); Some embodiments include the HCVR / MSR1 antibody of any of the exemplary anti-MSR1 antibodies listed in Table 4. In some embodiments, the present invention relates to an antibody or antigen-binding fragment thereof comprising a LCVR amino acid sequence pair. wherein the HCVR / LCVR amino acid sequence pair is: 2 / 10, 34 / 42 , 50 / 58; 98 / 106 , and 290 / 298 from is selected from the group consisting of:

[0018] Provided herein are HCDR1 amino acid sequences selected from any of the HCDR1 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or heavy chain CDR1 (HCDR1) containing a substantially similar sequence thereof having at least 99% sequence identity The antibody or antigen-binding fragment thereof specifically binds to MSR1, comprising:

[0019] Also provided herein are any of the HCDR2 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or or a heavy chain CDR2 (HCD2) containing a substantially similar sequence thereof having at least 99% sequence identity. R2) or an antigen-binding fragment thereof that specifically binds to MSR1.

[0020] Also provided herein are any of the HCDR3 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or or a heavy chain CDR3 (HCD3) containing a substantially similar sequence thereof having at least 99% sequence identity. R3), or an antigen-binding fragment thereof that specifically binds to MSR1.

[0021] Provided herein are LCDR1 amino acid sequences selected from any of the LCDR1 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or a light chain CDR1 (LCDR1) containing a substantially similar sequence thereof having at least 99% sequence identity thereto; The antibody or antigen-binding fragment thereof specifically binds to MSR1, comprising:

[0022] Also provided herein are any of the LCDR2 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or or a light chain CDR2 (LCD) containing a substantially similar sequence thereof having at least 99% sequence identity. R2) or an antigen-binding fragment thereof that specifically binds to MSR1.

[0023] Also provided herein are any of the LCDR3 amino acid sequences listed in Table 4. or at least 90%, at least 95%, at least 98%, or or a light chain CDR3 (LCD) containing a substantially similar sequence thereof having at least 99% sequence identity. R3), or an antigen-binding fragment thereof that specifically binds to MSR1.

[0024] Also provided herein are antibodies to any of the LCDR3 amino acid sequences listed in Table 4. HCDR3 and LCDR3 amino acid sequences containing any of the paired HCDR3 amino acid sequences listed in Table 4 An antibody or an antigen-binding fragment thereof that specifically binds to MSR1, comprising a HCDR3 / LCDR3 amino acid sequence pair. Some embodiments include the H of any of the exemplary anti-MSR1 antibodies listed in Table 4. Some embodiments relate to antibodies or antigen-binding fragments thereof, comprising a CDR3 / LCDR3 amino acid sequence pair. In embodiments, the HCDR3 / LCDR3 amino acid sequence pairs are: 8 / 16, 40 / 48, 56 / 64; 96 / 104, and 288 / 296.

[0025] Provided herein are antibodies containing any of the exemplary anti-MSR1 antibodies listed in Table 4. MSR1 contains six CDR pairs (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) In one embodiment, the HCDR1-HC is an antibody or antigen-binding fragment thereof that specifically binds to the HCDR1-HC The DR2-HCDR3-LCDR1-LCDR2-LCDR3 amino acid sequence pairs are: 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 Consists of is selected from the group.

[0026] In related embodiments, provided herein are exemplary antibodies listed in Table 4. Six CDs contained in the HCVR / LCVR amino acid sequence pair defined by one of the anti-MSR1 antibodies R set (i.e., HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3) that specifically binds to MSR1. For example, the present invention provides an antibody or an antigen-binding fragment thereof. 34 / 42 , 50 / 58, 98 / 106 , and 290 / 298 HCDR1-HCDR2 contained in an HCVR / LCVR amino acid sequence pair selected from the group consisting of: -An antibody that specifically binds to MSR1, comprising the amino acid sequence HCDR3-LCDR1-LCDR2-LCDR3, or Methods for identifying CDRs contained in HCVR and LCVR amino acid sequences, including antigen-binding fragments. and techniques are well known in the art and are not limited to the specific HCVR and / or LCVR applications disclosed herein. can be used to identify CDRs within the amino acid sequence. Exemplary conventions that can be used include, for example, the Kabat definition, the Chothia definition, and the Ab Generally, the Kabat definition is based on sequence variability, while the Chothia definition is based on The AbM definition is based on the position of the structural loop regions, and the AbM definition is based on the Kabat approach and the Chothia approach. For example, see Kabat's paper, "Protein Immunology of Proteins of Immunological Interest." "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethe sda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin See, e.g., Proc. Natl. Acad. Sci. USA 86:9268-9272 (1989). Databases are also available to identify CDR sequences within antibodies.

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

[0028] Also provided herein are any of the LCVR amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a a polynucleotide sequence selected from any of the LCVR nucleic acid sequences, or at least have 90%, at least 95%, at least 98%, or at least 99% sequence identity with each other. and substantially similar sequences thereof.

[0029] Also provided herein are any of the HCDR1 amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a A polynucleotide sequence selected from any of the HCDR1 nucleic acid sequences, or at least one sequence corresponding thereto. at least 90%, at least 95%, at least 98%, or at least 99% sequence identity and substantially similar sequences thereof having the same structure.

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

[0031] Also provided herein are any of the HCDR3 amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a A polynucleotide sequence selected from any of the HCDR3 nucleic acid sequences, or at least one sequence corresponding thereto. at least 90%, at least 95%, at least 98%, or at least 99% sequence identity and substantially similar sequences thereof having the same structure.

[0032] Also provided herein are any of the LCDR1 amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a A polynucleotide sequence selected from any of the LCDR1 nucleic acid sequences or at least one corresponding thereto have 90%, at least 95%, at least 98%, or at least 99% sequence identity with each other. and substantially similar sequences thereof.

[0033] Also provided herein are any LCDR2 amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a A polynucleotide sequence selected from any of the LCDR2 nucleic acid sequences or at least one corresponding thereto have 90%, at least 95%, at least 98%, or at least 99% sequence identity with each other. and substantially similar sequences thereof.

[0034] Also provided herein are any LCDR3 amino acid sequences listed in Table 4. In certain embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a A polynucleotide sequence selected from any of the LCDR3 nucleic acid sequences or at least one corresponding thereto have 90%, at least 95%, at least 98%, or at least 99% sequence identity with each other. and substantially similar sequences thereof.

[0035] Also provided herein are nucleic acid molecules encoding HCVRs, wherein the HCVRs are , comprising a set of three CDRs (i.e., HCDR1-HCDR2-HCDR3), wherein the HCDR1-HCDR2-HCDR3 The amino acid sequence set is defined by any of the exemplary anti-MSR1 antibodies listed in Table 4. This is exactly what is happening.

[0036] Also provided herein are nucleic acid molecules encoding LCVRs, wherein the LCVRs are , comprising a set of three CDRs (i.e., LCDR1-LCDR2-LCDR3), wherein the LCDR1-LCDR2-LCDR3 The amino acid sequence set is defined by any of the exemplary anti-MSR1 antibodies listed in Table 4. This is exactly what is happening.

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

[0038] Also provided herein are polypeptides comprising the heavy or light chain variable region of an anti-MSR1 antibody. For example, embodiments include a recombinant expression vector capable of expressing the above-mentioned nucleic acid. The nucleic acid molecule, i.e., a nucleic acid molecule containing any of the HCVR, LCVR, and / or CDR sequences listed in Table 4, Also included within the scope of the present invention are recombinant expression vectors containing any of the nucleic acid molecules encoding the Included in the present invention are host cells into which such vectors have been introduced, as well as those capable of infecting the host cells with antibodies. and producing the antibody or portion thereof by culturing the antibody under conditions that permit the production of the antibody or antibody fragment. and a method for recovering the antibodies and antibody fragments thus produced.

[0039] Provided herein are anti-MSR1 antibodies with modified glycosylation patterns. In some embodiments, modifications to remove undesired glycosylation sites are may be useful, for example, to enhance antibody-dependent cellular cytotoxicity (ADCC) function (Shiel (See, e.g., J.D. et al. (2002) JBC 277:26733). In some embodiments, Modifications to provide antibodies lacking an existing fucose moiety can be used in, for example, antibody-dependent cellular cytotoxicity. In other applications, galactosylation may be useful for increasing ADCC function. Modifications can be made to modify complement dependent cytotoxicity (CDC).

[0040] In another aspect, provided herein is a recombinant human antibody that specifically binds to MSR1. A pharmaceutical composition comprising the body or a fragment thereof and a pharmaceutically acceptable carrier. In one embodiment, the composition is a combination of an anti-MSR1 antibody and a second therapeutic agent. In embodiments, the second therapeutic agent is any agent that is advantageously combined with an anti-MSR1 antibody. Also provided herein are anti-MSR1 antibodies, including those conjugated to a drug or therapeutic agent. Exemplary Combination Therapies and Co-Formulations Comprising Anti-MSR1 Antibodies , and ADCs are disclosed elsewhere herein.

[0041] Also provided herein are anti-MSR1 antibodies or The present invention also provides an antibody-drug conjugate (ADC) containing the MSR1 antigen-binding fragment. Provided are reactive linker-payloads useful for generating ADCs. Provided herein are modified anti-MSR1 antibodies and modified MSR1 antigen binding antibodies useful for generating ADCs. It is a fragment.

[0042] Also provided herein are methods for administering an anti-MSR1 antibody, an MSR1 antibody, or a method for administering an anti-MSR1 antibody to a subject in need thereof. or an ADC comprising an anti-MSR1 antibody or an MSR1 antigen-binding fragment thereof. The therapeutic method includes administering an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody to a patient. or administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an ADC containing the MSR1 antigen-binding fragment thereof. The disorder to be treated is improved and ameliorated by targeting MSR1. Any disease or disorder that is ameliorated, inhibited, or prevented. In one embodiment, the disease or condition is a proliferative disease, a metabolic disease, an inflammatory disease, a neurodegenerative disease, or or a disease, disorder, or condition associated with glucocorticoid receptor signaling. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, a disease associated with glucocorticoid receptor signaling, The disorder or disease is an inflammatory disease, disorder, or disease. in association with administration of an unconjugated steroid payload of the compound. Also provided herein are methods for treating and / or administering to a subject a bacterial infection, and / or reducing the side effects of the infection. or a combination of an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody or its MS for prophylaxis. The therapeutic method includes administering an ADC containing the R1 antigen-binding fragment.

[0043] Provided herein are methods for treating any of the diseases, disorders, or conditions described herein. an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody described herein for or the use of an ADC comprising the MSR1 antigen-binding fragment thereof.

[0044] Also provided herein are compounds that can be used to treat, halt, or reverse atherosclerosis. A therapeutic method for improving a patient's condition, comprising administering an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody to a patient. or administering an ADC comprising the MSR1 antigen-binding fragment thereof to a subject in need thereof. The method of treatment includes administering an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody. A therapeutically effective amount of a pharmaceutical composition comprising an ADC comprising an MSR1 antibody or an MSR1 antigen-binding fragment thereof is administered to a subject. This includes administering to

[0045] Other embodiments will become apparent from a review of the following detailed description. [Brief explanation of the drawings]

[0046] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 provides the synthetic scheme for P1 and P2B.

[0047] [Figure 2] Figure 2 provides the synthetic scheme for LP1.

[0048] [Figure 3] Figure 3 provides the synthetic scheme for LP2.

[0049] [Figure 4] Figure 4 provides the synthetic scheme for LP5.

[0050] [Figure 5] Figure 5 provides a synthetic scheme for LP6.

[0051] [Figure 6] Figure 6 provides a synthetic scheme for LP18.

[0052] [Figure 7] Figure 7 provides a synthetic scheme for LP4.

[0053] [Figure 8] Figure 8 provides the synthetic scheme for LP11.

[0054] [Figure 9] Figure 9 provides a synthetic scheme for LP9.

[0055] [Figure 10] Figure 10 provides the synthetic scheme for LP12.

[0056] [Figure 11] Figure 11 provides the synthetic scheme for P3 and P4.

[0057] [Figure 12] Figure 12 provides the synthetic scheme for LP3.

[0058] [Figure 13] Figure 13 provides a synthetic scheme for LP13.

[0059] [Figure 14] Figure 14 provides a synthetic scheme for LP14.

[0060] [Figure 15] Figure 15 provides the synthetic scheme for LP15.

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

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

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

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

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

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

[0067] [Figure 22] Figure 22 provides a synthesis scheme for budesonide-spacer containing reactive groups: suc-acid (compound 1c), carbamate analogs (1d, 1e), THP-analogs (1g and 1h), glucose analogs (1i and 1j), phosphate analogs (1k and 1l), and a commercially available phosphate analog (1m).

[0068] [Figure 23] FIG. 23 provides the payloads, compounds, and synthetic schemes for bis-octahydrophenanthrenecarboxamides P3B-P9B.

[0069] [Figure 24] FIG. 24 provides the payloads, compounds, and synthetic schemes for bis-octahydrophenanthrenecarboxamides P10B-P11B.

[0070] [Figure 25] FIG. 25 provides a synthetic scheme for linkers and linker payloads LP1B-LP5B.

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

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

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

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

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

[0076] [Figure 31] FIG. 31 provides a synthetic scheme for payload 12B, linker, and linker payload LP12B.

[0077] [Figure 32] FIG. 32 provides a synthetic scheme for cyclodextrin-azide 105a.

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

[0079] [Figure 34] Figure 34 provides a synthetic scheme for maltose-azide 105c.

[0080] [Figure 35] FIG. 35 is a plot of the results of a Staphylococcus aureus growth inhibition assay performed with rifamycin analogs.

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

[0082] [Figure 37] FIG. 37 is a plot of the results of an S. aureus intracellular killing assay performed with rifamycin analogs. DETAILED DESCRIPTION OF THE INVENTION

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

[0084] Unless otherwise defined, all technical and scientific terms used herein refer to the The terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. When used, the term "about" when used in reference to a specific recited numerical value means that the value may vary by as little as 1% from the listed value. When used, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 9 99.1, 99.2, 99.3, 99.4, etc.

[0085] Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. Although various methods and materials can be used in the present study, preferred methods and materials are now described. All patents, applications, and non-patent publications mentioned in this document are hereby fully incorporated by reference. be absorbed.

[0086] (definition) As used herein, the expressions "MSR1", "hMSR1", etc. refer to class A macrophage scavenger antigens. (i) NCBI accession numbers representing the various types and isoforms of Benjamin receptors (ii) the amino acid sequence described in NCBI accession number NP_002436.1; and / or (iii) the amino acid sequence set forth in NCBI accession number NP_619730.1 Human single-spanning trimeric type II membrane glycoprotein pattern with described amino acid sequence The term "MSR1" refers to both monomeric and multimeric MSR1 molecules. As used herein, the term "monomeric human MSR1" refers to a monomeric human MSR1 that does not contain a multimerization domain. does not contain or possess, and under normal conditions, is not directly physically connected to another MSR1 molecule, The term "monomer" refers to an MSR1 protein or a portion thereof that exists as a single MSR1 molecule. The MSR1 molecule is designated herein as "His-hMSR1" and comprises the amino acid sequence of SEQ ID NO: 393. (See, for example, Example 3 herein).

[0087] All references herein to proteins, polypeptides, and protein fragments are to non- Unless explicitly identified as being derived from the human species, each protein, polypeptide, It is intended to refer to the human version of a peptide or protein fragment. The term "MSR1" refers to a non-human species, e.g., "mouse MSR1," "monkey MSR1," " or otherwise specified, human MSR1 is meant.

[0088] As used herein, the phrase "cell surface-expressed MSR1" refers to a cell surface-expressed MSR1 protein. At least part of the membrane is exposed on the extracellular surface of the cell, making it accessible to the antigen-binding portion of an antibody. one or more MSR1 proteins expressed on the surface of a cell in vitro or in vivo, "Cell surface-expressed MSR1" refers to the extracellular domain of MSR1. The MSR1 protein may be expressed on the surface of a cell that is Alternatively, "cell surface-expressed MSR1" can consist of a cell that normally displays human MSR1 on its surface. However, it is expressed on the surface of cells that have been artificially modified to express MSR1 on their surface. The compound may comprise or consist of the expressed MSR1 protein. do.

[0089] As used herein, the term "anti-MSR1 antibody" refers to a monovalent antibody having a single specificity. a first arm that binds to MSR1 and a second arm that binds to a second (target) antigen, and a bispecific antibody comprising an anti-MSR1 arm, wherein the anti-MSR1 arm is a polypeptide as set forth in Table 4 herein. The term "anti-MSR1 antibody" refers to a drug or therapeutic and an antibody-drug conjugate comprising an anti-MSR1 antibody or an antigen-binding portion thereof conjugated to a drug. The term "anti-MSR1 antibody" also includes an anti-MSR1 antibody conjugated to a radionuclide. Also included are antibody-radionuclide conjugates (ARC) comprising the SR1 antibody or an antigen-binding portion thereof.

[0090] As used herein, the term "antibody" refers to an antibody that specifically binds to a particular antigen (e.g., MSR1). Any amino acid sequence containing at least one complementarity determining region (CDR) that binds to or specifically interacts with The term "antibody" refers to any antigen-binding molecule or molecular complex. It contains four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by Immunoglobulin molecules include those containing heavy chains and their multimers (e.g., IgM). Each heavy chain contains a heavy chain variable region. region (referred to herein as HCVR or V H The heavy chain constant region contains three domains. Main, C H 1. C H 2, and C H 3. Each light chain comprises a light chain variable region (referred to herein as LCVR or V L The light chain constant region comprises one domain (C L 1) V H Reach BiV L The regions are complementary, interspersed with more conserved regions called framework regions (FR). Each V can be further divided into hypervariable regions called CDRs. H and V L It consists of three CDRs and four FRs, and from the amino terminus to the carboxy terminus, The sequence is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the anti-MSR1 antibody (or antigen-binding portion thereof) are identical to the human germline sequence. The amino acid consensus may be any amino acid, or may be modified naturally or artificially. The sequence can be defined based on comparative analysis of two or more CDRs.

[0091] As used herein, the term "antibody" also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like refer to Any naturally occurring, enzymatically derived, enzyme-derived antibody that specifically binds to an antigen to form a complex. Antigens of antibodies include synthetic, or genetically engineered polypeptides or glycoproteins. Binding fragments can be prepared using any suitable standard technique, such as proteolytic digestion or isolation of antibody variable domains. Recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding the nucleotide sequence and optionally the constant domain. Such DNA can be obtained from whole antibody molecules using methods known in the art and / or For example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), DNA is sequenced and can be readily obtained from or synthesized. engineered chemically or by using molecular biology techniques, e.g., to contain one or more variable and / or Alternatively, the constant domains may be arranged in a suitable position, or a codon may be introduced to replace the cysteine ​​residues. Groups can be generated, amino acids can be modified, added or deleted, and the like.

[0092] Non-limiting examples of antigen-binding fragments include: (i) a Fab fragment; (ii) a F(ab')2 fragment; (iii) a Fd fragment; (iv) (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) amino acid sequences that mimic the hypervariable regions of antibodies. A minimal recognition unit consisting of acid residues (e.g., an isolated complementarity-determining region (CD) such as a CDR3 peptide) R)), or constrained FR3-CDR3-FR4 peptides. Other modified molecules, such as domains Specific antibodies, single domain antibodies, domain deleted antibodies, chimeric antibodies, CDR grafted antibodies, bodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies) nanobody, bivalent nanobody, small modular immune medicine (SMIP), and shark variable IgNAR domain Antigen-binding fragments are also encompassed by the term "antigen-binding fragment" as used herein.

[0093] An antigen-binding fragment of an antibody typically contains at least one variable domain. , may be of any size or amino acid composition, and typically contain one or more framework sequences. V. Contains at least one CDR that is contiguous with or in-frame with it. H Do The main is V L In the antigen-binding fragment associated with the domain, V H Domains and V L The domain is They may be in any suitable configuration relative to each other, for example, the variable regions are dimeric, and V H -V H , V H -V L , or V L -V L Alternatively, the antigen-binding fragment of an antibody may comprise a dimer. , monomeric V H or V L It may contain domains.

[0094] In certain embodiments, the antigen-binding fragment of an antibody comprises at least one constant domain shared by the antibody. The antibody of the present invention may comprise at least one variable domain attached to the antibody. Non-limiting exemplary arrangements of variable and constant domains that may be found within a fragment include: (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 L Variable drive configurations, including any of the above exemplary configurations. In any arrangement of variable and constant domains, the variable and constant domains are directly aligned with each other. They may be joined together or by a complete or partial hinge or linker region. The hinge region may connect adjacent variable domains in a single polypeptide molecule. at least two ( For example, 5, 10, 15, 20, 40, 60, or more amino acids Furthermore, antigen-binding fragments of the antibodies of the present invention may be non-covalently associated with each other. and / or one or more monomers V H Or V L domain (e.g., by a disulfide bond) A homodimer or heterodimer of any of the above variable and constant domain configurations in covalent association. It may comprise a dimer (or other multimer).

[0095] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different Each variable domain binds to a different antigen or to different antigens on the same antigen. The exemplary dual-specific antigens disclosed herein are capable of specifically binding to epitopes comprising: Any multispecific antibody format, including isomeric antibody formats, is available in the art. and (iii) a method for producing a human antibody comprising the steps of: (a) preparing a human antibody; (b) preparing a human antibody comprising the steps of: It is possible.

[0096] The antibodies of the present invention may be used to inhibit complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) is a type of cytotoxicity that occurs in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" refers to the lysis of antigen-expressing cells by the antibodies of the present invention in a cell culture medium. Antibody-directed cytotoxicity (ADCC) is a method for the elimination of antigens from nonspecific cytotoxic cells (e.g., natural killer cells) that express Fc receptors (FcRs). (NK) cells, neutrophils, and macrophages) recognize bound antibodies on target cells, thereby CDC and ADCC refer to cell-mediated reactions that result in the lysis of target cells. These can be measured using assays that are available and available (see, e.g., U.S. Pat. Nos. 5,545,562, 5,545,565 ... and 5,545,565). Nos. 00,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA ) 95:652-656). The constant regions of antibodies fix complement and mediate cell-dependent cytotoxicity. Therefore, the isotype of an antibody is important in determining whether it is capable of cytotoxicity. Selection can be based on the desirability of mediating harm.

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

[0098] The antibodies disclosed herein are, in some embodiments, recombinant human antibodies. As used herein, the term "recombinant human antibody" refers to an antibody prepared by recombinant means. All human antibodies that are produced, expressed, generated, or isolated, e.g., transfected into host cells, Antibodies expressed using transfected recombinant expression vectors (described further below) , antibodies isolated from a recombinant combinatorial human antibody library (described further below) animals that are transgenic for human immunoglobulin genes (e.g., mice); Antibodies isolated from human IgG1-associated antigens (e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) (see ), or any other sequence involving splicing of the human immunoglobulin gene sequence to other DNA sequences. This includes antibodies prepared, expressed, produced, or isolated by any other means. It is contemplated that such recombinant human antibodies may be derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant Human antibodies can be produced by in vitro mutagenesis (or transgenic engineering of human Ig sequences). When using a mouse animal, the mouse is subjected to in vivo somatic mutagenesis (somatic mutagenesis) and therefore Recombinant antibody V H and V L The amino acid sequence of the region is human germline V H and V L Derived from the sequence and related to this, but may not naturally occur within the human antibody germline repertoire in vivo. It is a simple array.

[0099] Human antibodies can exist in two forms related to hinge heterogeneity. In this state, immunoglobulin molecules consist of dimers held together by interchain heavy chain disulfide bonds. In the second form, the dimer is formed by the interchain disulfide bonds, forming a stable four-chain construct of approximately 150-160 kDa. Approximately 100% of the total antibody is composed of covalently linked light and heavy chains (half an antibody), not linked by bond bonds. Molecules of 75-80 kDa are formed. These forms are difficult to separate, even after affinity purification. Extremely difficult.

[0100] The frequency of the second form in various intact IgG isotypes is not limited. This is due to structural differences associated with antibody hinge region isotypes. Single amino acid substitutions in the hinge region of the hinge are commonly observed with human IgG1 hinges. This significantly reduces the occurrence of the second form to levels that are comparable to those observed in the control group (Angal et al., 1993). Molecular Immunology 30:105). The embodiments disclosed herein include a hinge, C H 2, or C H The present invention encompasses antibodies with one or more mutations in three regions, which mutations may be present, for example, in production. It may be desirable to improve the yield of the desired antibody form.

[0101] The antibodies disclosed herein may be isolated antibodies. An "isolated antibody" is an antibody that has been identified and separated from at least one component of its natural environment. "antibody" refers to an antibody isolated and / or recovered from at least one component of an organism, e.g., or isolated or removed from the tissue or cell in which the antibody naturally occurs or is naturally produced. An isolated antibody is an "isolated antibody" for purposes of the present invention. An isolated antibody is an antibody that has been isolated from at least one purified or isolated cell. In one embodiment, the isolated antibody is an antibody that has been subjected to an isolation process. The composition may be substantially free of materials and / or chemicals.

[0102] The anti-MSR1 antibodies disclosed herein have a nucleotide sequence similar to that of the corresponding germline sequence from which the antibody was derived. , one or more amino acid substitutions in the framework and / or CDR regions of the heavy and light chain variable domains. Such mutations may include substitutions, insertions, and / or deletions. The amino acid sequence to be determined is compared to the germline sequence available, for example, from public antibody sequence databases. This can be readily verified by comparing the One or more amino acids within the framework and / or CDR regions correspond to the germline sequence from which the antibody is derived. or to the corresponding residue in another human germline sequence, or to the corresponding germline residue Mutated to conservative amino acid substitutions (such sequence changes are referred to herein as and (collectively referred to as "germline mutations"), any of the amino acid sequences disclosed herein. Those skilled in the art will appreciate that the various antibodies disclosed herein are capable of binding to a wide variety of antigens, including antibodies and antigen-binding fragments thereof derived from any of the above-described antibodies. Starting from the chain and light chain variable region sequences, one or more individual germline mutations or combinations thereof Many antibodies and antigen-binding fragments can be readily produced, including Te, V H and / or V L All framework and / or CDR residues within the domain are mutated. to the residue found in the germline sequence from which the antibody was derived. and only specific residues, e.g., the first eight amino acids of FR1 or the last eight amino acids of FR4. Only mutated residues found in the amino acid or only mutated residues found in CDR1, CDR2, or CDR3 Only the divergent residues are mutated to revert to the original germline sequence. The framework and / or CDR residues above may be altered to match those from different germline sequences (i.e., the sequences from which the antibody is derived). The resulting residues are mutated to the corresponding residues in the germline sequence (which differs from the germline sequence from which it was originally derived). Additionally, antibodies of the invention may be designed to mimic, for example, specific individual residues that are identical to the corresponding residues in a particular germline sequence. While the nucleotide sequence has been mutated to the nucleotide sequence, certain other residues that differ from the original germline sequence have been maintained. A framework amino acid sequence that has been modified or mutated to the corresponding residue in a different germline sequence. The human may contain any combination of two or more germline mutations within the gene and / or CDR regions. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be used, e.g., , improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic activity. The compound may be readily tested for one or more desired properties, such as bioactivity (optionally), reduced immunogenicity, etc. The antibodies and antigen-binding fragments obtained by this general method are disclosed herein. It is within the scope of the embodiments described herein.

[0103] Embodiments include HCVRs, LCVRs, and / or HCVRs disclosed herein with one or more conservative substitutions. Also included are anti-MSR1 antibodies comprising any variant of the CDR amino acid sequences. Examples of such amino acid sequences include those containing the HCVR, LCVR, and / or CDR amino acid sequences set forth in Table 4 herein. Conservative amino acid substitutions such as 10 or less, 8 or less, 6 or less, 4 or less, etc., for either of the sequences The present invention also includes anti-MSR1 antibodies having HCVR, LCVR, and / or CDR amino acid sequences with substitutions.

[0104] The term "epitope" refers to a specific site in the variable region of an antibody molecule known as a paratope. A single antigen may contain multiple epitopes. Thus, different antibodies may bind to different parts of the antigen and have different biological Epitopes can be either conformational or linear. Epitopes are spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are formed by adjacent amino acid residues in a polypeptide chain. In some situations, an epitope is a saccharide, phosphoryl group, or fragment on an antigen. , or a sulfonyl group moiety.

[0105] The terms "substantial identity" or "substantially identical" when referring to a nucleic acid or fragment thereof: Optimally align with another nucleic acid (or its complementary strand) with appropriate nucleotide insertions or deletions. When the sequence is determined, any well-known sequence identity algorithm, such as FA, as discussed below, may be used. at least about 95%, more preferably at least nucleotide sequence identity at about 96%, 97%, 98%, or 99% of the nucleotide bases A nucleic acid molecule that has substantial identity to a reference nucleic acid molecule, in some instances, is a nucleic acid molecule that is substantially identical to the reference a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule; The polypeptide encodes a polypeptide having the

[0106] When applied to polypeptides, the terms "substantial similarity" or "substantially similar" For example, using the default gap weights in the programs GAP or BESTFIT Thus, when optimally aligned, two peptide sequences should have at least 95% sequence identity, and Even more preferably, it means sharing at least 98% or 99% sequence identity. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. "Amino acid substitution" refers to a substitution in which the amino acid residues have similar chemical properties (e.g., charge or hydrophobicity). A substitution is a substitution in which a amino acid residue having a side chain (R group) is replaced by another amino acid residue. The amino acid substitution does not substantially alter the functional properties of the protein. If the sequences differ from each other by conservative substitutions, the percent sequence identity or similarity is Adjustments can be made to compensate for the conservative nature of the substitution. These methods are well known to those skilled in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307 See, for example, U.S. Pat. No. 6,331,431. Examples of groups of amino acids with side chains that have 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 glutamate (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartic acid and glutamic acid; and (7) sulfur-containing side chains of cysteine ​​and methionine. Amino acid substitutions are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine -arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glucan Alternatively, conservative substitutions may be made as described in Gonnet et al. (1992) Science 256: 1443-1445. It is any change with a positive value in the PAM250 log-probability matrix disclosed in An "equally conservative" substitution is any change that has a non-negative value in the PAM250 log-probability matrix. be.

[0107] Sequence similarity of polypeptides, also called sequence identity, is typically determined using sequence analysis software. Protein analysis software can be used to measure various amino acid substitutions, including conservative amino acid substitutions. Match similar sequences using similarity measures assigned to substitutions, deletions, and other modifications For example, the GCG software can identify closely related polypeptides, e.g., polypeptides from different organisms. Alignment between homologous polypeptides from different species, or between a wild-type protein and its mutant To determine homology or sequence identity, use the default parameters. This includes programs such as GAP and BESTFIT. See, for example, GCG version 6.1. The polypeptide sequence is generated using the GCG library with default or recommended parameters. Comparisons can also be made using the program FASTA in Section 6.1. A2 and FASTA3) align the highest overlapping regions between the query and search sequences. The alignment and percent sequence identity are provided (Pearson (2000), supra). Another preferred approach is to compare a sequence to a database containing a large number of sequences from various organisms. The algorithm is based on the computer program BLAST, using default parameters, in particular B LASTP or TBLASTN. See, e.g., Altschul (1990) J. Mol. Biol. 215:403-410 and and Altschul (1997) Nucleic Acids Res. 25:3389-402.

[0108] When referring to the compounds provided herein, the following terms are used interchangeably unless otherwise indicated: Unless otherwise defined, technical and scientific terms used herein have the following meanings: All terms have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are multiple definitions for terms used herein, those definitions shall prevail unless expressly stated otherwise. do.

[0109] As used herein, the terms "a" or "an" shall mean any number of items, provided that the context clearly indicates otherwise. Unless otherwise contradictory, "one" or "more" means "one" or "more."

[0110] As used herein, "alkyl" refers to a monovalent and saturated hydrocarbon radical moiety. Alkyl is optionally substituted and may be linear, branched, or cyclic, i.e., cycloalkenyl. Alkyl can be a radical having 1 to 20 carbon atoms, That is, C 1-20 Alkyl; a radical having 1 to 12 carbon atoms, i.e., C 1-12 Al radicals having 1 to 8 carbon atoms, i.e., C 1-8 Alkyl; 1 to 6 carbon atoms radicals having the formula C 1-6 alkyl; and radicals having 1 to 3 carbon atoms, That is, C 1-3 Examples of alkyl moieties include, but are not limited to, alkyl. The following are examples of methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, i-butyl ethyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, Pentyl moieties include, but are not limited to, n- and cyclohexyl. Examples of hexyl moieties include, but are not limited to, pentyl and i-pentyl. and n-hexyl.

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

[0112] The term "amino" means --NH.sub.2.

[0113] The term "alkylamino," as used herein, unless otherwise specified, , refers to the group -NHR', where R' is C as defined herein. 1-10 It is an alkyl. In any of the above embodiments, alkylamino is C 1-6 It is alkylamino.

[0114] The term "dialkylamino," as used herein, unless otherwise specified, means and refers to the group -NR'R', where each R' is independently a C as defined herein. 1-10 Archi In some or any embodiments, the dialkylamino is di-C 1-6 Al This is Kill Amino.

[0115] The term "aminoalkyl," as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, substituted with one or more amino groups. In one or any embodiment, an aminoalkyl has one —NH group (e.g., —R′(NH), wherein R' is -C as defined herein. 1-10 alkyl) substituted with In some or any embodiments, the aminoalkyl is substituted with two -NH groups. In some embodiments, "aminoalkyl" is an amino C 1-6 It is alkyl.

[0116] "Alkylaminoalkyl," as used herein, unless otherwise specified, substituted with one or more alkylamino groups, as defined herein; In some embodiments, "alkylaminoalkyl" refers to an alkyl group having a C1 -6 Alkylamino C 1-6 In some embodiments, the alkylamino group is Each alkyl in alkyl is independently selected.

[0117] "Dialkylaminoalkyl," as used herein, unless otherwise specified, , as defined herein, substituted with one or more dialkylamino groups, as defined herein. In some embodiments, "dialkylaminoalkyl" refers to an alkyl group. Is Ji-C 1-6 Alkylamino C 1-6 In some embodiments, the alkyl is Each alkyl in alkylaminoalkyl is independently selected.

[0118] As used herein, the term "O-amino acid" or "HO-amino acid" refers to an amino acid. The amino acid or the natural amino group at the N-terminus of the amino acid sequence is converted to an oxygen or a hydroxyl group, respectively. For example, "O-AAAA" or "HO-AAAA" represents the N-terminal amino acid that has been replaced. an amino acid sequence in which the natural amino group is replaced by an oxygen or a hydroxyl group, respectively (AAAA) (e.g., [ka] where each R is intended to represent an amino acid side chain. The terms "acid residue" or "HO-amino acid residue" refer to the chemical moiety in a compound that remains after a chemical reaction. For example, "O-amino acid residue" or "HO-amino acid residue" refers to an O-amino acid or HO- Amide coupling or peptide coupling of an amino acid with a suitable coupling partner where, for example, a water molecule is present in the amino acid of the O-amino acid or the HO-amino acid. After peptide coupling, the O-amino acid residue or the HO- A product is generated into which the amino acid residue is incorporated.

[0119] The designation of an amino acid or amino acid residue without specifying its stereochemistry refers to an L-amino acid, a D-amino acid, It is intended to include any amino acid, or a racemic mixture thereof.

[0120] As used herein, "haloalkyl" refers to an alkyl group as defined above. wherein the alkyl is a halogen, such as fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Examples of haloalkyl include: , -CF3, -CH2CF3, -CCl2F, and -CCl3.

[0121] As used herein, "alkenyl" refers to an alkyl group having at least two carbon atoms and one or more alkyl groups. Alkenyl refers to a monovalent hydrocarbon radical moiety containing a non-aromatic carbon-carbon double bond. Alkenyl is optionally substituted and can be linear, branched, or cyclic. For example, radicals with 2 to 20 carbon atoms, i.e., C 2-20 Alkenyl; 2-12 carbons Radicals with elementary atoms, i.e., C 2-12 Alkenyl; Radicals containing 2 to 8 carbon atoms Cal, i.e., C 2-8Alkenyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 alkenyl; and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkenyl is mentioned. Examples of alkenyl moieties include, but are not limited to, vinyl, propenyl, Examples include, but are not limited to, butenyl and cyclohexenyl.

[0122] As used herein, "alkynyl" refers to an alkyl group having at least two carbon atoms and one or more alkyl groups. Alkynyl refers to a monovalent hydrocarbon radical moiety containing a carbon-carbon triple bond. It can be substituted and linear, branched, or cyclic. Alkynyl includes 2 Radicals with ∼20 carbon atoms, i.e., C 2-20 Alkynyl; 2 to 12 carbon atoms radicals, i.e., C 2-12 Alkynyl; a radical having 2 to 8 carbon atoms, That is, C 2-8 Alkynyl; a radical having 2 to 6 carbon atoms, i.e., C 2-6 Alkini and radicals having 2 to 4 carbon atoms, i.e., C 2-4 Alkynyl is an example Examples of alkynyl moieties include, but are not limited to, ethynyl, propynyl, and bromine. These include, but are not limited to, thionyl.

[0123] 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 For example, in the case of ethoxy, it is CH3CH2-O·. An alkoxy substituent is one that is The alkoxy substituent is attached to the compound it substitutes through this oxygen atom. and may be linear, branched, or cyclic, i.e., cycloalkoxy. The alkoxy includes those having 1 to 20 carbon atoms, i.e., C 1-20 Arco oxy; having 1 to 12 carbon atoms, i.e., C 1-12 Alkoxy; 1 to 8 carbon atoms That is, C 1-8 Alkoxy; 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 Alkoxy is mentioned Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, i-butoxy, pentoxoxy cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0124] As used herein, "haloalkoxy" refers to an alkoxy group as defined above. alkoxy refers to alkoxy, where the alkoxy is selected from halogen, e.g., F, Cl, Br, or I. It contains at least one substituent that is

[0125] As used herein, "aryl" refers to an aromatic compound in which the ring atoms are carbon atoms. Aryl refers to a monovalent moiety that is an optionally substituted, monocyclic or polycyclic Examples of aryl moieties include 6-2 those with 0 ring carbon atoms, i.e., C 6-20 Aryl; having 6 to 15 ring carbon atoms That is, C 6-15 Aryl and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples of aryl moieties include, but are not limited to, fluoro ... phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, and pyrene Examples of suitable amines include, but are not limited to, methylaminobenzoates ...

[0126] As used herein, "arylalkyl" refers to the radical of an alkyl compound. where the alkyl compound is substituted with an aromatic substituent, i.e., That is, the aromatic compound contains a single bond to an alkyl group, and the radical is positioned on the alkyl group. The arylalkyl group is attached to the depicted chemical structure via the alkyl group. Arylalkyl has the structure, for example: [ka] where B is an aromatic moiety, e.g., phenyl. The aryl alkyl is optionally substituted, i.e., the aryl and / or alkyl group is It can be substituted as disclosed herein. Examples of arylalkyl include: Examples include, but are not limited to, benzyl.

[0127] As used herein, "alkylaryl" is a radical of an aryl compound. refers to a monovalent moiety in which the aryl compound is substituted with alkyl substituents, i.e., That is, the aryl compound contains a single bond to an alkyl group, and the radical is attached to the aryl group. The alkylaryl group is linked to the chemical structure shown through the aryl group. Alkylaryl has the structure, for example: [ka] where B is an aromatic moiety, e.g., phenyl. The alkylaryl is optionally substituted, i.e., the aryl and / or alkyl group is It can be substituted as disclosed herein. Examples of alkylaryl include: Examples of suitable amines include, but are not limited to, toluyl.

[0128] As used herein, "aryloxy" refers to an aryl group in which the ring atoms are carbon atoms and the It refers to a monovalent moiety that is a radical of an aromatic compound in which the ring is substituted with an oxygen radical, i.e. That is, the aromatic compound contains a single bond to an oxygen atom, and the radical is positioned on the oxygen atom. For example, in the case of phenoxy, [ka] The aryloxy substituent is attached to the compound it substitutes through this oxygen atom. The aryloxy is optionally substituted. The aryloxy is a group having 6 to 20 rings. Radicals with carbon atoms, i.e., C 6-20 Aryloxy; having 6 to 15 ring carbon atoms That is, C 6-15 Aryloxy and those having 6 to 10 ring carbon atoms, That is, C 6-10 Aryloxy includes, but is not limited to, aryloxy. Examples of moieties include phenoxy, naphthoxy, and anthroxy. Not limited to.

[0129] As used herein, "R a R b"N-aryloxy" means that the ring atoms are carbon atoms, and the ring is at least one R a R b substituted with an N-substituent and at least one oxygen radical refers to a monovalent moiety that is a radical of an aromatic compound that is a R b It contains a single bond to the N-substituent and a single bond to the oxygen atom, and the radical is positioned on the oxygen atom. For example, [ka] R a R b The N-aryloxy substituent is a substituent that is substituted through this oxygen atom in the compound it substitutes. Combine. R a R b N-aryloxy is optionally substituted. a R b N-aryloxy For example, those having 6 to 20 ring carbon atoms, such as C 6-20 (R a R b N) n -aryloxy, 6 those with 15 ring carbon atoms, e.g., C 6-15 (R a R b N) n -aryloxy, and 6 to 10 those having ring carbon atoms of, for example, C 6-10 (R a R b N) n -aryloxy (where n is R a R b N- represents the number of substituents), but is not limited to these. a R b N-aryloxy moiety Examples of moieties include 4-(dimethylamino)-phenoxy, [ka] These include, but are not limited to:

[0130] As used herein, "arylene" refers to an aromatic ring in which the ring atoms are only carbon atoms. Arylene refers to a divalent moiety of a compound that is optionally substituted and is monocyclic or polycyclic, e.g., For example, the arylene moiety may be bicyclic or tricyclic. those having ring carbon atoms of C 6-20 Arylene; having 6 to 15 ring carbon atoms Things, namely, C 6-15 arylene, and those having 6 to 10 ring carbon atoms, i.e., C 6-10 Examples include, but are not limited to, arylene.

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

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

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

[0134] As used herein, "heterocycloalkyl" refers to a group in which one or more carbon atoms are heterocyclic. Suitable heteroatoms include nitrogen, oxygen, and sulfur atoms. Heterocycloalkyls are optionally Examples of heterocycloalkyl moieties include morpholinyl, piperidinyl, and the like. , tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl Examples include lysinyl, dioxolanyl, dithiolanyl, oxanyl, or thianyl, Not limited to these.

[0135] As used herein, an "N-containing heterocycloalkyl" refers to an N-containing heterocycloalkyl group having one or more carbon atoms. Cycloalkyl groups substituted with heteroatoms, at least one of which is a nitrogen atom In addition to nitrogen, suitable heteroatoms include oxygen and sulfur atoms. N-containing heterocycloalkyls include, but are not limited to, optionally substituted N- Examples of heterocycloalkyl-containing moieties include morpholinyl, piperidinyl, pyrrolidinyl, and the like. Examples of the alkyl groups include aryl, imidazolidinyl, oxazolidinyl, and thiazolidinyl. Not limited to.

[0136] As used herein, "optionally" when used to describe a radical moiety "substituted", e.g., optionally substituted alkyl, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted arylene, and optionally substituted heteroaryl "Arylene" means that such moiety is optionally bonded to one or more substituents. Examples of such substituents are halo, cyano, nitro, optionally substituted haloalkyl, azido. alkoxy, epoxy, optionally substituted heteroaryl, optionally substituted heterocycloalkyl Lu, [ka] (where R A , R B , and R C independently at each occurrence, represent a hydrogen atom, an alkyl, an alkenyl, Alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, hetero aryl, or heterocycloalkyl, or R A and R B are combined together with the atoms forming a saturated or unsaturated carbocyclic ring, wherein the ring is optionally substituted and one or more ring atoms are optionally substituted with a heteroatom), In some embodiments, the radical moiety is an optionally substituted heterocyclic group. aryl, optionally substituted heterocycloalkyl, or optionally substituted saturated or When an unsaturated carbocyclic ring is optionally substituted, the optionally substituted heteroaryl, optionally substituted heterocycloalkyl or optionally substituted saturated or unsaturated carbocyclic rings; The substituents, when substituted, are optionally further substituted with further substituents. In some embodiments, any of the groups described herein is not substituted with a substituent. When optionally substituted, the substituents attached to the group are substituted unless otherwise specified. It has not been done.

[0137] As used herein, "O-glucose" refers to a glucose molecule attached via the exocyclic glucose oxygen atom. Suitable O-glucose moieties include, but are not limited to: [ka] These include:

[0138] As used herein, "O-PEG" n " is a monovalent moiety attached via 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.

[0139] As used herein, a "binding agent" refers to a molecule that specifically binds to a given binding partner, e.g., an antigen. It refers to any molecule, such as a protein or antibody, that is capable of heteromeric binding.

[0140] As used herein, a "linker" refers to a linker that connects a binding agent to one or more of the compounds described herein. covalently attached to a compound, e.g., a payload compound and / or hydrophilic group described herein refers to a divalent, trivalent, or multivalent moiety that

[0141] As used herein, a "connector group" or "connector group residue" refers to a group Suitable connector groups include divalent or polyvalent attachment groups. Facilitates release of the load, leaving the original conjugate with little or no derivatization. Examples of connector groups include: [ka] or derivatives thereof. In another example, a connector group teeth, [ka] is.

[0142] In a further example, the connector group is a self-immolative group. In certain embodiments, the self-immolative group is p-aminobenzyloxy. dicarbonyl (PAB / PABC), i.e., [ka] Those skilled in the art will recognize the chemical reaction by which the self-immolative group releases the payload from the remaining atoms of the linker. You will know that it can be done.

[0143] As used herein, a "connecting linker" (L 2 ) or "Connection Linkers" The term refers to a divalent group that is cleavable or non-cleavable. A cleavable linker is a linker that is capable of cleaving the cleaved linker after internalization. A linker that is cleaved by intracellular metabolism, e.g., hydrolysis, reduction, or cleavage via an enzymatic reaction. Non-cleavable linkers are added via lysosomal degradation of the antibody after internalization. Suitable connecting linkers include acid-labile linkers, linkers, hydrolytically labile linkers, enzyme-cleavable linkers, reduction-labile linkers, and Suitable linkers include, but are not limited to, non-cleavable linkers. Glucuronide, succinimide-thioether, polyethylene glycol (PEG) unit, hydra disulfide units (e.g., -SS-, -SC(R 1b R 2b )-(where , R 1b and R 2b are independently hydrogen or hydrocarbyl), carbamate units, a para-amino-benzyl unit (PAB), a phosphate unit, e.g., mono-, bis-, or tri- lys-phosphate units, as well as peptide units, such as, but not limited to, valine-citrate 2, 3, 4, 5, 6, 7, 8 or more amino acids containing phosphorus residue units The peptide unit may be or contain amino acid residues. As used herein, "caproyl" refers to a -(CH2)5-C(O)- group. means.

[0144] As used herein, the phrase "reactive group" ("RG") refers to a group that is attached to an antibody, modified antibody, or It refers to a functional group or moiety that reacts with the reactive portion of the antigen-binding fragment. In this context, a "reactive group" is a group that reacts with a cysteine ​​or lysine residue on an antibody or antigen-binding fragment thereof. A functional group or moiety (e.g., maleimide or NHS ester). Thus, a "reactive group" is a functional group or moiety that can undergo a click chemistry reaction. In some embodiments of the click chemistry reaction, the reactive group is selected from the group consisting of 1,3 cycloaddition with azides. Suitable reactive groups include strained alkynes, which can undergo a reaction. Alkynes, such as those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes For example, cyclooctyne, benzannulated alkynes, and cyclooctynes ​​with alkynes in the absence of a copper catalyst. Alkynes capable of undergoing 1,3 cycloaddition reactions include, but are not limited to: Suitable alkynes include DIBAC (wherein the -C(O)CHCHC(O)- moiety of the DIBAC moiety is L and / or L 2 DIBO (wherein the -O- moiety of the DIBO moiety can be L and / or L 2 BARAC (where the BARAC part [ka] The part is L and / or L 2 DIFO (wherein the -O- moiety can be L and / or L 2 substituted alkynes, such as fluorinated alkynes, aza-cycloalkynes, Also included are, but are not limited to, alkynyl groups, BCN, and derivatives thereof. A linker-payload containing a suitable reactive group can be used to conjugate an antibody functionalized with an azide group. Such functionalized antibodies are useful for coupling azide-polyethyleneglycols. In some embodiments, such functionalized antibodies include antibodies functionalized with a hydroxyl group. The present invention relates to an antibody containing at least one glutamine residue, e.g., heavy chain Q295 (EU numbering), which is cleaved by enzyme transfection. In the presence of transglutaminase, a compound according to the formula H2N-LL-N3, where LL is a divalent polyethylene It is obtained by reacting with a propylene glycol group.

[0145] In some embodiments, the reactive group (RG) is an alkyne, e.g., [ka] which can be converted via click chemistry to azides, e.g. [ka] to produce a click chemistry reaction product, e.g., [ka] It is possible to form positional isomers thereof, or mixtures thereof. , the reactive group is an alkyne, e.g. [ka] (wherein L and / or L 2 is -OCH2C(O)-), which is a via azides, e.g., [ka] to produce a click chemistry reaction product, e.g., [ka] In some embodiments, the reactive group can form an alkyne, e.g., [ka] which can be converted via click chemistry to azides, e.g. [ka] to produce a click chemistry reaction product, e.g., [ka] It is possible to form positional isomers thereof, or mixtures thereof. , the reactive group is a functional group, e.g. [ka] which reacts with cysteine ​​residues on an antibody or antigen-binding fragment thereof to form bonds therewith. For example, [ka] (wherein Ab represents an antibody or an antigen-binding fragment thereof, and S represents the functional group via which the functional group is attached to the Ab. In some embodiments, the reaction The reactive group is a functional group, e.g., [ka] which reacts with and binds to lysine residues on an antibody or antigen-binding fragment thereof; for example, [ka] (wherein Ab represents an antibody or an antigen-binding fragment thereof, and N represents the linker through which the functional group is attached to the Ab. In some instances, the bond forms a lysine or N atom on the amino-terminal residue. , the reactive group is [ka] which is a thiol bond between two thiols (e.g., on two different chains) of an antibody or antigen-binding fragment thereof. thiol) to form bonds with it, e.g. [ka] In some instances, the reactive group forms [ka] which is a thiol bond between two thiols (e.g., on two different chains) of an antibody or antigen-binding fragment thereof. thiol) to form bonds with it, e.g. [ka] Form.

[0146] As used herein, the phrase "reactive group residue" includes the products of click chemistry. This refers to the product of the reaction between a functional group in the linker moiety and a reactive moiety in the binding agent (BA). The group is formed by reaction of reactive groups on amino acids of the binding agent, and In some embodiments, the reactive group residue is a 1,2,3-tetrazole. It contains a hydroxyl group, i.e., a group formed by the reaction of an alkyne with an azide. In an embodiment of the present invention, the reactive group residue is [ka] where S represents the S atom on the cysteine ​​residue through which (a) binds to the Ab. And [ka] with cysteine ​​residues on an antibody or its antigen-binding fragment. In an embodiment of the present invention, the reactive group residue is [ka] where N represents the N atom on the lysine residue and a functional group such as [ka] with lysine residues on the antibody or antigen-binding fragment thereof. It will be appreciated that the reactive residue portion may be derived from the reactive group, the antibody, or both. In some instances, the reactive group residue is [ka] where S represents the S atom on a cysteine ​​residue and is a functional group [ka] with cysteine ​​residues on the antibody or antigen-binding fragment thereof.

[0147] As used herein, a "pharmaceutically acceptable salt" refers to any compound suitable for administration to a patient. Suitable salts include those described in Berge et al., which is incorporated herein by reference. "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1. Examples of salts include, but are not limited to, acid-derived salts. Amines derivatized with groups, organic amines, inorganic amines, and, but not limited to, calcium Salt, magnesium salt, potassium salt, sodium salt, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid , phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, Succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, ethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Some examples include, but are not limited to, potassium or alkaline earth metal salts. In the present invention, a payload described herein (e.g., a refurbished The tertiary amine (an analogue of the tertiary amine) contains a tertiary amine, wherein the nitrogen atom in the tertiary amine is The atom where the payload is attached to the linker or linker-spacer. In an example, the bond between the tertiary amine and the payload is not formed by adding a quaternary amine to the linker-payload molecule. The positive charge on the quaternary amine is then substituted with a counter ion (e.g., chloro, bromo, or iodine). or other suitably charged moieties, such as those mentioned above). Cut.

[0148] Certain groups, moieties, substituents, and atoms are shown with wavy lines. A bond or bonds may be crossed or a ... A wavy line indicates the bond between a group, moiety, substituent, or atom. For example, the propyl group shown below: [ka] A phenyl group substituted with has the following structure: [ka] .

[0149] As used herein, "amide synthesis conditions" refers to, for example, carboxylic acids, activated carboxylic acids, to achieve amide formation by reaction of carboxylic acids or acyl halides with amines. In some instances, "amide synthesis conditions" refer to suitable reaction conditions for the synthesis of a carboxylic acid and an amide. Some of these examples refer to reaction conditions suitable for achieving the formation of an amide bond between the amines. In some cases, the carboxylic acid is first converted to an activated carboxylic acid, and then the activated carboxylic acid is reacted with the activated carboxylic acid. The carboxylic acid reacts with the amine to form an amide. The conditions include, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropyl Dicarboxylic acid (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphatase Sulfonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)trifluoromethyl Pyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazo (1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), O-(benzotri Azol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU ), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoro Borate (TBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine Dinium 3-oxide hexafluorophosphate (HATU), N-ethoxycarbonyl-2-ethoxy hydroxy-1,2-dihydroquinoline (EEDQ), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide Imide (EDC), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (C IP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazoline These include the use of reagents to effect the reaction of carboxylic acids with amines, including CDI. In some examples, the carboxylic acid is first activated. carboxylic acid ester, and then treating the activated carboxylic acid ester with an amine to give , to form an amide bond. In some embodiments, the carboxylic acid is treated with a reagent. deprotonates the carboxylic acid, followed by protonation by the deprotonated carboxylic acid. Nucleophilic attack on the protonated reagent results in a product complex with the deprotonated carboxylic acid. The carboxylic acid is activated by forming a bond. The activated carboxylic acid ester is more susceptible to nucleophilic attack by amines than before the carboxylic acid is activated. This results in amide bond formation. The phosphoric acid is described as activated. Exemplary reagents include DCC and DIC. do.

[0150] An "amino acid" or "amino acid residue" refers, in some embodiments, to a naturally occurring amino acid. In other embodiments, the amino acid or amino acid residue refers to a naturally occurring amino acid and / or Unnatural amino acids (e.g., β-amino acids (β 3 and β 2 ), homo-amino acids, proline and pyridine vinic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanines and rosine derivatives, linear core amino acids, and / or N-methyl amino acids, or any other Commercially available unnatural amino acids (e.g., unnatural amino acids available from Sigma-Aldrich) In another embodiment, the amino acid residues are mediated by transglutaminase. reactions involving the transglutaminase-mediated reaction of amino acid side chains with primary amines. It may also be a residue with a participating side chain, e.g., asparagine and / or glutamine Reaction of the side chain with a primary amine is used for the preparation of certain ADCs described herein. In certain embodiments, such functionalized antibodies have at least one glutamine residue. For example, an antibody comprising heavy chain Q295 (EU numbering) can be combined with a compound according to the formula H2N-LL-N3, where LL is a bivalent polypeptide. The reaction is carried out in the presence of the enzyme transglutaminase. It is obtained by:

[0151] As used herein, "taurine" refers to a reagent [ka] or base [ka] (where, [ka] indicates the atom through which taurine is attached to the adjacent group in the formula).

[0152] As used herein, "stereoisomeric forms" or "stereoisomers" refer to different forms in a compound. refers to the relative spatial orientation of groups. Stereoisomeric forms include enantiomers, diastereomers, and / or mixtures thereof.

[0153] As used herein, "positional isomer," "positional isomers," or "positional isomers" refers to a group of isomers that are heterocyclic or heterocyclic. A "mixture of isomers" refers to the reaction of a suitable azide (e.g., -N3, or PE) with a suitable alkyne. 1,3-cycloaddition or strain-promoted alkyne-azide cycloaddition (S-G-N3 derivatized antibody) derived from In one embodiment, the term "PAAC" refers to the product of a click reaction. For example, positional isomers and mixtures of positional isomers can be synthesized by the click reaction products shown below. It is characterized by: [ka] .

[0154] By way of example only, the positional isomers of compound A1', i.e., compounds A2', A3', and A4', are shown below: where each [ka] is the bond with the binder; and each [ka] Here is the binding with the payload: [ka] .

[0155] (Anti-MSR1 antibodies containing Fc variants) In some embodiments, for example, the binding of FcRn receptors at acidic pH compared to neutral pH is reduced. The present invention provides an anti-MSR1 antibody comprising an Fc domain containing one or more mutations that enhance or reduce antibody binding. For example, provided herein are C of the Fc domain. H 2 or C H Sudden changes in the three regions an anti-MSR1 antibody comprising a mutation, wherein the mutation inhibits the activity of the MSR1 antibody in an acidic environment (e.g., a pH range of in endosomes, where the FcRn affinity is about 5.5 to about 6.0), increasing the affinity of the Fc domain for FcRn. Such mutations may result in an increase in the serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, for example, modifications at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L / Y / F / W or T), 254 (e.g., S) or T), and modifications at positions 256 (e.g., S / R / Q / E / D or T); or modifications at positions 428 and / or in 433 (e.g., H / L / R / S / P / Q or K) and / or 434 (e.g., H / F or Y) or modifications at positions 250 and / or 428; or modifications at positions 307 or 308 (e.g., 30 In one embodiment, the modification is at 428L (e.g., V308F, V308F) and 434. M428L) and 434S (e.g., N434S) modifications; 428L, 259I (e.g., V259I), and 308F (e.g., 433K (e.g., H433K) and 434 (e.g., 434Y) modifications; 252, 254, and 25 6 (e.g., 252Y, 254T, and 256E) modifications; 250Q and 428L modifications (e.g., T250Q and M428L); and and 307 and / or 308 modifications (e.g., 308F or 308P).

[0156] For example, embodiments include 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T, and 25 6E (e.g., M252Y, S254T, and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F): or a group thereof. All possible combinations of other mutations within the antibody variable domains disclosed herein are included in the present invention. It is contemplated within the scope of the invention.

[0157] (Biological characteristics of antibodies) Embodiments include antibodies and antigen-binding fragments thereof that bind to human MSR1 with high affinity For example, the present invention provides a method for detecting chromatin-binding proteins using an assay format, such as that defined in Example 3 herein. measured by surface plasmon resonance at 25°C or 37°C, or a substantially similar assay When the nucleotide sequence is expressed, human MSR1 expressed with an N-terminal nonahistidine tag (e.g., His9-hMSR1) is expressed. K of less than approximately 10 nM for the extracellular domain D In one embodiment, the anti-MSR1 antibody binds to For example, surface plasmon resonance imaging using the assay format defined in Example 3 herein. less than about 10 nM, less than about 9 nM at 37°C when measured by a fluorine-containing iodide (FVII) or a substantially similar assay , 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 40 Less than 0 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 K of less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM D in Anti-MSR1 antibodies that bind to human MSR1 are provided. In some embodiments, the antibodies described herein The disclosed anti-MSR1 antibodies can be used in the assay format defined in Example 3 herein. Approximately 6 nM at 25°C as measured by surface plasmon resonance or a substantially similar assay 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, K of less than about 40 pM, less than about 30 pM, or less than about 20 pM D It binds to human MSR1.

[0158] Embodiments also include antibodies and antigen-binding fragments thereof that bind with high affinity to monkey MSR1. For example, disclosed herein are, for example, those defined in Example 3 herein. Surface plasmon resonance at 25°C or 37°C using an assay format, or a substantially similar assay K less than about 20 nM as measured by the D with an N-terminal myc-myc-hexahistidine tag Anti-MSR1 antibodies that bind to the co-expressed monkey MSR1 extracellular domain (e.g., HMM-mfMSR1) In one embodiment, the assay format defined in Example 3 herein is used. At 37°C, approximately less than 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 9 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 less than about pM, less than about 200 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 60 pM , less than about 50 pM, less than about 40 pM, less than about 30 pM, less than about 20 pM, or less than about 10 pM D Binds to monkey MSR1 In some embodiments, the anti-MSR1 antibodies provided herein are The R1 antibody was assayed using surface plasmon resonance imaging using the assay format defined in Example 3 herein. less than about 12 nM, less than about 10 nM at 25°C as measured by resonance or a substantially similar assay 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 50 Less than 0 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, about 80 pM K of less than about 70 pM, less than about 60 pM, less than about 50 pM, less than about 40 pM, less than about 30 pM, or less than about 20 pM D It binds to monkey MSR1.

[0159] The present invention relates to a method for detecting β-glucan-containing compounds, for example, at 25°C using the assay format defined in Example 3 herein. or as measured by surface plasmon resonance at 37°C, or a substantially similar assay , dissociation half-life (t 1 / 2) human MSR expressed with an N-terminal nonahistidine tag The present invention also includes antibodies and antigen-binding fragments thereof that bind to the extracellular domain of hMSR1 (e.g., His9-hMSR1). According to one embodiment, the surface is prepared using the assay format defined in Example 3 herein. at 37°C for more than about 4 minutes, as measured by plasmon resonance, or a substantially similar assay. More than about 5 minutes, more than about 6 minutes, more than about 8 minutes, more than about 10 minutes, more than about 12 minutes, more than about 14 minutes, more than about 16 minutes, more than about 18 minutes, about 2 More than 0 minutes, more than about 30 minutes, more than about 40 minutes, more than about 50 minutes, more than about 60 minutes, more than about 70 minutes, more than about 80 minutes, more than about 90 minutes, about 1 More than 20 minutes, more than about 150 minutes, more than about 180 minutes, more than about 210 minutes, more than about 240 minutes, or longer 1 / 2 for human MS Anti-MSR1 antibodies that bind to R1 are provided.

[0160] In one embodiment, the nucleotide sequence of ... Antibodies capable of binding with high affinity to the exodomain (e.g., HMM-mfMSR1) and their antigens For example, the present invention relates to a method for producing a medicament comprising the steps of: Surface plasmon resonance at 25°C or 37°C using an assay format similar to the one described above, or a substantially similar assay format. K of less than about 20 nM as measured by the assay D Contains anti-MSR1 antibodies that bind to HMM-mfMSR1 In one embodiment, the assay format defined in Example 3 herein is used. Approximately 20 nM at 37°C as measured by surface plasmon resonance or a substantially similar assay 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 80 Less than 0 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 , or a K of about 50 pM D In some embodiments, an anti-MSR1 antibody that binds to HMM-mfMSR1 is provided. In the present specification, the anti-MSR1 antibody is defined in Example 3 herein. measured by surface plasmon resonance using an assay format, or a substantially similar assay At 25°C, less than about 12 nM, less than about 10 nM, less than about 9 nM, less than about 8 nM, less than about 7 nM, less than about 6 nM , less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM , less than about 200 pM, less than about 150 pM, less than about 100 pM, less than about 90 pM, less than about 80 pM, less than about 70 pM, less than about 6 K less than 0 pM or about 50 pM D binds to HMM-mfMSR1.

[0161] Embodiments include, for example, a 2D assay using the assay format defined in Example 3 herein. Measured by surface plasmon resonance at 5°C or 37°C, or a substantially similar assay When the dissociation half-life (t 1 / 2) and expressed with an N-terminal myc-myc-hexahistidine tag. Antibodies that bind to the expressed monkey MSR1 extracellular domain (e.g., HMM-mfMSR1) and their antigen binding In one embodiment, the assay as defined in Example 3 herein is also included. When measured by surface plasmon resonance using the above format, or a substantially similar assay, At 37°C, more than about 1 minute, more than about 2 minutes, more than about 3 minutes, more than about 4 minutes, more than about 5 minutes, more than about 6 minutes, more than about 8 minutes, more than about 10 minutes , more than about 12 minutes, more than about 14 minutes, more than about 16 minutes, more than about 18 minutes, more than about 20 minutes, more than about 30 minutes, more than about 40 minutes, more than about 50 minutes , more than about 60 minutes, more than about 70 minutes, more than about 80 minutes, more than about 90 minutes, more than about 120 minutes, more than about 150 minutes, more than about 180 minutes, about 210 minutes or longer 1 Anti-MSR1 antibodies that bind to dimeric human MSR1 at / 2 are provided.

[0162] Embodiments include, for example, using the assay format defined in Example 5 herein. At least about 2-fold as measured by an antibody binding assay or a substantially similar assay , 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 The binding ratio of modified hMSR1-expressing cells to non-expressing cells was 1:1. In some embodiments, the antibodies provided herein and antigen-binding fragments thereof are also included. For example, antibody binding using the assay format defined in Example 5 herein. At least about 2-fold less when measured by the assay, or a substantially similar assay 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 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 Binds to cells with endogenously expressed hMSR1 at the binding ratio of endogenous hMSR1 expressing cells to non-expressing cells In some embodiments, the MSR1 antibody or antigen-binding The fragments may be assayed for antibody binding using, for example, the assay format defined in Example 5 herein. At least about 2-fold less when measured by the assay, or a substantially similar assay 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-fold, at least about 45-fold, at least about 50-fold, or more, of the modified mouse Binds to engineered cell surface-expressed mouse MSR1 at a binding ratio of MSR1-expressing cells to non-expressing cells .

[0163] In an embodiment, a modified low density liposome in cells that bind to MSR1 and express human MSR1 is used. Also included are antibodies and antigen-binding fragments thereof that exhibit a maximal inhibition of uptake of LDL protein of less than about 95%. For example, embodiments may include the use of an assay format defined in Example 8 herein. When measured using a ligand uptake assay, or a substantially similar assay, the IC<1nM 50 In cells expressing human MSR1, modified LDL (e.g., oxidized or acetylated LDL) was observed. In some embodiments, the anti-MSR1 antibodies exhibit a maximal inhibition of uptake of the MSR1 antibody (e.g., a cytosine-1-phosphate dehydrogenase inhibitor) by less than about 95%. According to an embodiment, ligand capture is performed using the assay format defined in Example 8 herein. less than about 6.1 nM, about 5 nM, when measured using a phosphodiesterase assay, or a substantially similar assay 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 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 20 IC of less than 0 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 So, human MS Anti-MSR1 antibodies that show maximal inhibition of modified LDL uptake by approximately 95% in cells expressing MSR1 are provided. It is served.

[0164] In some embodiments, the anti-MSR1 antibody is as defined in Example 8 herein. Assay format, or a substantially similar assay. When measured, the concentration is 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, and 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 Less than pM, IC of approximately 20 pM 50 Approximately 90% of modified LDL uptake in cells expressing human MSR1 was The maximum inhibition of

[0165] In some embodiments, the anti-MSR1 antibody is as defined in Example 8 herein. Assay format, or a substantially similar assay. When measured, the concentration is 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, and 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 Less than pM, IC of approximately 20 pM 50 , approximately 75% of modified LDL uptake in cells expressing human MSR1 The maximum inhibition of

[0166] In some embodiments, the anti-MSR1 antibody is as defined in Example 8 herein. Assay format, or a substantially similar assay. When measured, the concentration is 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, and 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 Less than pM, IC of approximately 20 pM 50 , approximately 60% of the modified LDL uptake in cells expressing human MSR1 The maximum inhibition of

[0167] In some embodiments, the anti-MSR1 antibody is as defined in Example 8 herein. Assay format, or a substantially similar assay. When measured, the concentration is 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, and 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 Less than pM, IC of approximately 20 pM 50 , approximately 50% of the modified LDL uptake in cells expressing human MSR1 The maximum inhibition of

[0168] Embodiments include antibodies and their binding to cell surface-expressed MSR1 and internalization by the cell. For example, antigen-binding fragments of MSR1 that bind to the cell surface of THP-1 cells and Provided herein are antibodies that become internalized by cells. For example, the present disclosure provides A compound that binds to cell surface-expressed MSR1 on THP-1 cells and is defined in Example 9 herein. When measured using a chemiluminescence assay format, or a substantially similar assay, Anti-MSR1 becomes internalized by the cells at a relative percentage of at least about 10%. In one embodiment, the antibody binds to cell surface-expressed MSR1 on THP-1 cells and Chemiluminescence using the assay format defined in Example 9 herein, or substantially similar. at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative percentage of the protein to be internalized by the cells. Anti-MSR1 antibody.

[0169] The antibodies disclosed herein may have one or more of the above biological characteristics, or The antibodies may possess any combination of the biological characteristics disclosed herein. The foregoing list is not intended to be exhaustive. The biological characteristics of the present invention will be apparent to those skilled in the art upon review of this disclosure, including the working examples herein. There will be.

[0170] (Antibody-drug conjugates (ADCs)) Provided herein are anti-MSR1 antibodies or their derivatives conjugated to drugs or therapeutic agents. In some embodiments, the antibody-drug conjugate (ADC) comprises an antigen-binding fragment of The therapeutic agent is a liver X receptor (LXR) agonist or a steroid. Provided are reactive linker-payloads useful for generating ADCs. Provided herein are modified anti-MSR1 antibodies and modified MSR1 antibodies useful for generating ADCs. SR1 antigen-binding fragment.

[0171] ADCs typically have the formula (I): BA-[(L) 0-1 -PA] n where BA is a binding agent, e.g., an anti-MSR 1 antibody, or an MSR1 antigen-binding fragment thereof. L is a linker, as described in detail below. PA is a payload. A preferred payload is a compound that, when delivered to MSR1, can provide therapeutic benefit. In some embodiments, the present invention is directed to a payload or a small molecule that can provide therapeutic benefit. The load may be, for example, a steroid, an LXR modulator, or a rifamycin analog. Useful payloads are described in detail below, where n is an integer between 1 and 30, e.g. For example, 1 to 4, for example, 2 or 4. Each L-PA is covalently bonded to a functional group of PA. In some specific embodiments, each L-PA comprises a lysine side chain, a cysteine ​​side chain, a glutamic acid side chain, and a glutamic acid side chain of BA. It is covalently attached to the glutamine side chain or amino terminus.

[0172] Techniques and linkers for conjugating to residues of antibodies or antigen-binding fragments are well known in the art. Exemplary amino acid residues that can be used in connection with this embodiment are known in the art. In addition, for example, lysine (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 201 3 / 0101546; and US 2012 / 0585592), cysteine ​​(see, e.g., US 2007 / 0258987; WO 2013 / 055993; WO 2013 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / No. 130598; US 2013 / 0101546; and US 7,750,116), selenocysteine ​​(e.g., WO 2008 / 122039; and Hofer et al., Proc. Natl. Acad. Sci., USA, 2008, 105: 1245 1-12456), formylglycine (see, 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 See Rabuka et al., Nat. Protocols, 2012, 10:1052-1067), unnatural amino acids (e.g. , WO 2013 / 068874 and WO 2012 / 166559), and acidic amino acids (see, for example, WO 201 The linker may be a carbohydrate (see, e.g., US 2008 / 0305497, WO 2014 / 065661). See, for example, Ryan et al., Food & Agriculture Immunol., 2001, 13:127-130) and and disulfide linkers (e.g., WO 2013 / 085925, WO 2010 / 010324, WO 2011 / 01861 1, and Shaunak et al., Nat. Chem. Biol., 2006, 2:312-313). They can also be conjugated to antigen-binding proteins via site-specific conjugation. Conjugation to specific residues of antibodies or antigen-binding proteins is achieved using immunolabeling techniques. It can also be derived (e.g., Schumacher et al., J Clin Immunol (2016) 36(Suppl 1): 1 00). Site-specific conjugation techniques include transglutaminase-mediated glutamine conjugation (e.g., Schibli Angew Chemie Inter Ed. 2010, 49 ,9995).

[0173] The linker is conjugated via transglutaminase-based chemoenzymatic conjugation. can be conjugated to one or more glutamine residues (see, e.g., Dennler et al. (See Bioconjugate Chem. 2014, 25, 569-578 and WO 2017 / 147542). In the presence of glutaminase, one or more glutamine residues of the antibody are converted to a primary amine. Briefly, in some embodiments, Antibodies containing glutamine residues (e.g., Gln295 residue) are subjected to transglutaminase in the presence of the enzyme In the presence of a primary amine compound, the primary amine compound is treated with a primary amine compound, which is described in more detail below. The compound contains an antibody drug conjugate via transglutaminase-mediated coupling. Directly delivering the payload or linker-payload is included. Primary amine compounds can be subsequently reacted with additional compounds for the synthesis of antibody drug conjugates. Also included are linkers and spacers that are functionalized with reactive groups containing glutamine residues. The antibody may be isolated from a natural source or modified to contain one or more glutamine residues. Glutamine residues in the antibody polypeptide chain (glutaminyl-modified antibodies or antigen-binding molecules) Techniques for artificially creating an antibody (antibody) are within the capabilities of one of ordinary skill in the art. The body is aglycosylated.

[0174] In certain embodiments, the antibody or glutaminyl-modified antibody or antigen-binding molecule At least one polypeptide chain sequence contains at least one glutamine residue. In an embodiment, the antibody or glutaminyl-modified antibody or antigen-binding molecule each has one G In a further embodiment, the antibody or The glutaminyl-modified antibody or antigen-binding molecule has one or more glutaminyl residues at a site other than 295 of the heavy chain. In some embodiments, the antibody has impaired antibody function or binding. This was prepared by site-directed mutagenesis to insert a glutamine residue at a certain site without causing any side effects. For example, included herein are those containing the Asn297Gl In some embodiments, the antibody comprises a Gln295 residue and a n(N297Q) mutation. and / or an antibody with the N297Q mutation can access transglutaminase, Therefore, one or more further linkers that can be conjugated to a linker or linker-payload are The variable region contains native glutamine residues consisting of: For example, it can be found at Q55 of the light chain. Antibodies conjugated via ELISA have higher than expected DAR values ​​(e.g., DAR greater than 4). Any such antibody may be isolated from natural or artificial sources. Cut.

[0175] Transglutaminase-mediated coupling of glutamine-containing antibodies (or antigen-binding compounds) The primary amine compounds useful in the method include any primary amine compounds that are deemed useful by those skilled in the art. Typically, the primary amine compound has the formula HN-R, where R is It can be any group that is compatible with the antibody and reaction conditions. In some embodiments, R is , alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.

[0176] In some embodiments, the primary amine compound has a reactive group or a protected reactive group. Useful reactive groups include azides, alkynes, cycloalkynes, thiols, alcohols, and the like. Alkyl, ketone, aldehyde, acid, ester, hydride La J Do, a D R hmm, and amines. In certain embodiments, the reactive group is an azide, alkyne, sulfhydryl, cycloalkenyl, or cycloalkenyl. The alkyl group is selected from the group consisting of alkylene, aldehyde, and carboxyl.

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

[0178] In certain embodiments, the primary amine compound is according to one of the following formulas: R: H2N-(CH2) n -X; H2N-(CH2CH2O) n -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2) m -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2) n -C(O)N(H)-(CH2) m -X; H2N-(CH2CH2O) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; H2N-(CH2) n -N(H)C(O)-(CH2CHO) m -(CH2) p -X; H2N-(CH2CH2O) n -N(H)C(O)-(CH2) m -X; H2N-(CH2) n -C(O)N(H)-(CH2CH2O) m -(CH2) p -X; and H2N-(CH2CH2O) n -C(O)N(H)-(CH2) m -X; (wherein n is an integer selected from 1 to 12; m is an integer selected from 0 to 12; p is an integer selected from 0 to 2; and X is -SH, -N3, -C≡CH, -C(O)H, tetrazole, and [ka] (selected from the group consisting of:

[0179] In the above, either the alkyl or alkylene (i.e., -CH2-) group can be, for example, , C 1-8 It may be optionally substituted with alkyl, methylformyl, or -SO3H. In embodiments, the alkyl group is unsubstituted.

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

[0181] In certain embodiments, the primary amine compound is [ka] is.

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

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

[0184] In the formula, BA is an anti-MSR1 antibody or an antigen-binding fragment thereof. The variable n is an integer from 1 to 30. In some embodiments, n is from 1 to the number of glutamine residues in the BA. In aspects, 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 antibodies and antigen-binding fragments thereof can be, for example, linked to one or more L-PA molecules to form A It is useful for generating DCs.

[0185] In some embodiments, the BA comprises two or four glutamine residues. In some embodiments, the BA comprises a Q295 residue. In some embodiments, the BA comprises a N297Q mutation. In some embodiments, the BA comprises Q295 and N297Q. Since it can be a dimer, BA has four glutamines for conjugation to the L-PA moiety. It has a residue.

[0186] (compound) In one aspect, provided herein are compounds and / or compounds, optionally via a linker, or via a linker-spacer to a payload moiety. An antibody-drug conjugate comprising any of the antibodies or antigen-binding fragments thereof described herein. is.

[0187] In one group of embodiments, the compound and / or the antibody-drug conjugate has the structure of formula (I): It has the following structure: [ka] (In the formula: BA is a binder; L is a linker; PA consists of steroid residues, LXR modulator residues, or rifamycin analog residues. a payload moiety selected from the group consisting of: The subscript n is an integer from 1 to 30.

[0188] In one group of embodiments, the compounds and / or antibody-drug conjugates described above and herein The carboxylate has the structure of formula (IA): [ka] (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or optionally an amino acid residue directly or indirectly bonded to the group HG. a bivalent or trivalent linker comprising a group; AA 2 is absent or a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, is a connector group residue; SP is absent or a spacer; and HG, if present, is a hydrophilic group).

[0189] In one group of embodiments, the compounds and / or antibody-drug conjugates described above and herein The carboxylate has the structure of formula (IB-1): [ka] (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; Q, if present, [ka] and SP is absent or a spacer; where: [ka] indicates the atom through which the referred group is attached to the adjacent group in the formula).

[0190] In one group of embodiments, the compounds and / or antibody-drug conjugates described above and herein The carboxylate has the structure of formula (IB-2): [ka] (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1is absent or optionally an amino acid residue directly or indirectly bonded to the group HG. a bivalent or trivalent linker comprising a group; AA 2 is absent or a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, [ka] and; SP is absent or a spacer; and HG, if present, [ka] where: [ka] indicates the atom through which the referred group is attached to the adjacent group in the formula).

[0191] In one group of embodiments, the compounds and / or antibody-drug conjugates described above and herein The compound has a structure of formula (IC), (ID), or (IE): [ka] (In the formula, 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 bivalent or trivalent linker comprising an amino acid residue; AA 2 is a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, [ka] and; SP is absent or a spacer; and HG is [ka] (It is).

[0192] where: [ka] indicates the atom through which the referred group is bonded to the adjacent group in the formula. and some of the compounds and / or antibody-drug conjugates herein. or in any instance, AA 1 -AA 2 is according to formula (LL1): [ka] (In the formula, R AA1 , R AA2 , and R AA3 are each independently at least one of which is -(RG 2 )-SP 2 -HG,- (RG 2 )-HG, or an amino acid side chain linked to HG; [ka] AA through it 1 -AA 2 indicates the atom bonded to the adjacent group in the formula). In some embodiments, R AA1 is a lysine bound directly or indirectly to HG, glutamine, glutamic acid, or aspartic acid side chain, and R AA2 and R AA3 Is that Either valine and alanine or valine and citrulline side chains, respectively.

[0193] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any instances, AA 1 -AA 2 teeth, [ka] where: [ka] AA through it 1 -AA 2 indicates the atom bonded to the adjacent group in the formula.

[0194] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any of the examples, RG 1 and R.G. 2 The residues are, independently in each case: [ka] selected from the group consisting of: where: [ka] Through it, the RG 1 or RG 2 The residue indicates the atom that is attached to the adjacent group in the formula.

[0195] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any examples, SP, SP 1 , and SP 2 is non-existent in each case independently. 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 -, (glycine) 4-serine, and and combinations thereof, wherein the subscript e is an integer from 0 to 4, and the subscript u is is an integer from 1 to 8, and the subscript v is an integer from 1 to 8.

[0196] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any examples, 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.

[0197] Any of the compounds described above and herein, linker-payload, and / or antibody-drug complexes In some or any examples of conjugates, [ka] teeth, [ka] TIFF0007824992000070.tif230170TIFF0007824992000071.tif223170TIFF0007824992000072.tif181170TIFF0007824992000073.tif214170.

[0198] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any embodiments, the antibody or antigen-binding fragment thereof does not include a linker or linker. It is conjugated to a steroid payload via an anchor-spacer.

[0199] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any embodiments, the antibody or antigen-binding fragment thereof is linked via a linker. and conjugated to an LXR modulator payload.

[0200] Any of the compounds and / or antibody-drug conjugates described above and herein In some or any embodiments, the antibody or antigen-binding fragment thereof is linked via a linker. and conjugated to a rifamycin analogue payload.

[0201] (payload) Formula (I) BA-[L-PA] n In this case, the PA can be any payload that is deemed useful. Such payloads include small molecules that provide therapeutic benefit through their delivery via MSR1. In some embodiments, the PA is a steroid, an LXR modulator, or In some cases, the residue is a molecule selected from the group consisting of rifamycin analogs. In some cases, the PA is a steroid. In some cases, the PA is an LXR modulator. In some embodiments, the PA is an LXR agonist. wherein PA is an LXR antagonist. Exemplary LXR modulator payloads include, for example, See, for example, "Patent Document 1," published as US 2018 / 0334426, which is incorporated herein by reference in its entirety. Bis-octahydrophenanthrenecarboxamide and its protein conjugates (BI (S-OCTAHYDROPHENANTHRENE CARBOXAMIDES AND PROTEIN CONJUGATES THEREOF) No. 62 / 508,327, filed May 18, 2017. Some examples wherein PA is a rifamycin analog, including any of the rifamycin analogs described herein. In some instances, the PA is a rifalog having the structure : [ka] .

[0202] In certain embodiments, the payload in the compound of Formula (I) is a glucocorticoid according to Formula (A): ide: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula, R 1 and R 2 is independently —H, alkyl, alkyl-C(O)—O—, —OH, or halo; or R 1 and R 2 together, [ka] Forming where R 4 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl It is a kill, wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl is, independently in each occurrence, -NR Aa R Ab optionally substituted with; R 3 is -OH, R Z -C(O)-X-, heteroalkyl, piperidinyl, -NR Aa R Ab , -oxyaryl -NR Aa RAb , or -Z-A'(R P ) t and; R Z is alkyl; X is O or NR Aa and; Z is S, S(O), S(O)2, SO2NR Aa , O, C(O)NR Aa , C(O), or NR Aa and; A' is aryl, arylalkyl, or heteroaryl; R P is independently in each occurrence halo, optionally substituted alkyl, —OH, or —NR Aa R Ab in can be; R Aa and R Ab is independently in each occurrence -H, optionally substituted alkyl, or optionally substituted is an aryl; the subscript a is an integer from 0 to 19; and t is an integer from 1 to 3; however: (1)R 1 is —OH, or (b) R 1 and R 2 together, [ka] (where R 4 is C 1-9 Alkyl or [ka] ) is formed, R 3 is not -OH(a), and (2)R 3 teeth, [ka] Not and R 5A and R 5Bare each independently a halo or a hydrogen atom; where the group R 3 or R 4 is attached to the linker).

[0203] In some such embodiments, R 3 is NH2. In some such embodiments In a few other things, R 3 teeth, [ka] where: [ka] is R 3 indicates the atom bonded to the adjacent group in formula (I).

[0204] In certain embodiments, the PA is a steroid. Exemplary steroid payloads include: See, for example, US Pat. No. 6,299,999, filed Jan. 8, 2018, each of which is incorporated herein by reference in its entirety. "STEROIDS AND ANTIBODY CONJUGATES THER" No. 62 / 614,905, entitled "Potentially Induced Inflammation of a Polysaccharide in a Polysaccharide-Based Organism," and published as US 2018 / 0155389. "STEROIDS AND PROTEIN-CONJUGATES THEREFOR" No. 15 / 806,197, filed November 7, 2017, entitled "EREOF" In one embodiment, the PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In certain embodiments according to any of 10 to 1140, R 3is -O-aryl, -NR Aa R Ab , -Al Kiren-NR Aa R Ab , -X-arylene-Y-NR Aa R Ab , -X-heteroarylene-Y-NR Aa R Ab , or N-containing wherein X is absent, -N-, -CH2-, or -O-; wherein Y is absent or -CH-; and R 4 is alkyl, aryl, alkylaryl, or arylalkyl. In certain embodiments, R 3 is -O-arylene-NR Aa R Ab ,- O-Heteroarylene-NR Aa R Ab wherein aryl or heteroaryl is halogen , deuterium, hydroxyl, or methoxyl. Te, R 3 is -O-phenyl-NR Aa R Ab , -O-heteroarylene-NR Aa R Ab where Pheny The aryl or heteroaryl is optionally substituted with halogen or deuterium. Hey, R 4 is n-propyl. In certain embodiments, R Aa and R Ab are each independently is hydrogen or alkyl. In certain embodiments, R Aa and R Ab One of them is the linker In some embodiments, PA is substituted with a bond to - (e.g., L or LL). [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this, PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this, PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this, PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this, PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In this, PA is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In embodiments, the wavy line indicates a bond to a linker (eg, L or LL).

[0205] In certain embodiments, PA comprises the following residues: [ka] TIFF0007824992000090.tif206170TIFF0007824992000091.tif95170 or a pharmaceutically acceptable salt or stereoisomer thereof. wherein a primary or secondary amine is linked to the linker L to form the linker payload. , which is linked to a BA to form a conjugate. Alternatively, L may be linked to a primary or secondary amine group. You will be aware of this.

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

[0207] In some embodiments, the antibody-drug conjugates described herein are and a steroid payload, wherein the steroid payload comprises: [ka] or a mixture thereof.

[0208] In one embodiment, the PA comprises: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0209] In one embodiment, the PA comprises: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0210] In certain embodiments, the PA is a liver X receptor (LXR) modulator. wherein PA is according to formula (B) or a pharmaceutically acceptable salt, solvate or is the stereoisomeric form: [ka] (In the formula, W is -CH2-, -N(H)-, or -O-; R B1 is -H, -OH, -NH2, alkyl, or -OP(O)(OR 6 )2; R B2 -H, -OH, -CH2NH2, R B3 , R B4 , R B5 , or -OR B5 where R B1 and R B2 teeth , but not simultaneously -H; R B3 is -N(R 6 )2; R B4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is alkylene, substituted alkylene (including but not limited to oxo-substituted, i.e., =O). heteroalkylene, and substituted heteroalkylene (including but not limited to oxo-substituted (i.e. i.e., ═O); Z is selected from the group consisting of -OH and -NH; R B5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl is selected from nitrogen and oxygen; containing one, two, or three selected heteroatoms and at least one -OH and -CHOH substitution group or at least one primary or secondary nitrogen, e.g., O-glucose; Each R 6 represents in each case -H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; and Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues and O-PEG b where each subscript b is an integer from 0 to 3; where the group R B1 , R B2 , or R 7 is attached to the linker).

[0211] In certain embodiments, R B1 or R B2 is replaced by a bond to a linker (e.g., L or LL) It has been done.

[0212] In one embodiment, the PA comprises: [ka] is selected from.

[0213] In certain embodiments, [ka] The wavy line in the middle indicates a bond to a linker (eg, L or LL).

[0214] In some embodiments, the payload of formula (B) is: [ka] TIFF0007824992000104.tif234170 or a pharmaceutically acceptable stereoisomeric form thereof.

[0215] In one embodiment, the PA comprises: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0216] In one embodiment, the PA comprises: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0217] In one embodiment, the PA comprises: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof.

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

[0219] In some embodiments, the PA is a liver X receptor (LXR) modulator according to Formula (B-1): or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: [ka] (In the formula, R B1 is -N(H)R 8 or -N(R 9 )2; R B2 is -N(H)R 8 and; Each R 8 is independently in each occurrence hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety, or an alkyl; R 9 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocyclic alkyl. wherein each heterocycloalkyl or substituted heterocycloalkyl alkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and is substituted; When the alkyl group is a cyclic alkyl group, it contains at least one of -OH and -CH2OH or at least one primary or Contains secondary nitrogen; Each R 7 are independently halo, C 1-6 Alkyl, C 1-6 Alkoxy, -CN, O-glucose, O- Amino acid residues, or O-PEG b (wherein each subscript b is an integer from 0 to 3); where the group R B1 , R B2 , or R 7 is attached to the linker).

[0220] In some examples, the compound of formula (B-1) is: [ka] TIFF0007824992000111.tif188170TIFF0007824992000112.tif232170TIFF0007824992000113.tif55170 or a pharmaceutically acceptable salt or solvate thereof.

[0221] In certain embodiments, R B1 or R B2 is replaced by a bond to a linker (e.g., L or LL) It has been done.

[0222] In one embodiment, the PA is [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth: [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In one embodiment, PA teeth, [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some cases, the carboxylic acid group of P10B is linked to the lysine via an amide bond as shown above. In one embodiment, the PA is [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. In some cases, the carboxylic acid group of P11B is linked to the lysine via an amide bond as shown above. In one embodiment, the PA is [ka] or a pharmaceutically acceptable salt or stereoisomer thereof. For any embodiment, [ka] The wavy line in the middle indicates a bond to a linker (eg, L or LL) as described above.

[0223] In a group of embodiments, provided herein are compounds of formula (III) or medicaments thereof and an acceptable salt, solvate, or stereoisomer thereof: [ka] (In the formula: R 34 is alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl can be; Both R x is hydrogen; and SP is —C(O)—C—C 10 -Alkylene-C(O)-, -C(O)-N(C 1-6 Al Kill)-C1-C 10 -Alkylene-X 1 -(where X 1 is attached to L' in formula (III), -C(O)- N(H)-(C1-C 10 -alkylene)-S- (wherein S is attached to L' in formula (III)), -C(O)-N (C 1-6 Alkyl)-(C1-C 10 -alkylene)-S- (wherein S is attached to L' in formula (III) ), [ka] (where the point of attachment to the right (i.e., at N) is to L' in formula (III) -CH2-NH- (where N is attached to L' in formula (III)), [ka] where N is attached to L' in formula (III) and Ar is an optionally substituted aryl. -(C-C 10 -alkylene)-NR 50 C(O)-(C1 -C 10 -alkylene)-NR 50a -(where NR 50a is attached to L' in formula (III), -C(O)-( C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a is represented by formula (III) and each C1-C 10 -Alkylene is independently one or more hydroxyl optionally substituted), -C(O)-N(R 35 )-C1-C 10 -Alkylene-C(O)NH-X 2 -(where X 2 teeth, attached to L' in formula (III), or [ka] (where X 4 is attached to L' in formula (III); or Both R x is fluoro; and SP is —C(O)—C—C 10 -Alkylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1b -(where X 1b is attached to L in formula (III), - C(O)-N(H)-(C1-C 10 -alkylene)-X 1b -(where X 1b is attached to L' in formula (III) , [ka] (where the point of attachment to the right (i.e., at N) is to L' in formula (III) -CH2-NH- (where N is attached to L' in formula (III)), [ka] where N is attached to L' in formula (III) and Ar is an optionally substituted aryl. -(C-C 10 -alkylene)-NR 50 C(O)-(C1 -C 10 -alkylene)-NR 50a -(where NR 50a is attached to L' in formula (III), -C(O)-( C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a is represented by formula (III) and each C1-C 10 -Alkylene is independently one or more hydroxyl optionally substituted), -C(O)-N(R 35 )-(C1-C 10 -alkylene)-C(O)NH-X 2 -(where X 2 teeth , attached to L' in formula (III), or [ka] (where X 4 is attached to L' in formula (III); and X 1 is -N(C 1-6 alkyl)-; X 1b is -S-, -NH-, or -N(C 1-6 alkyl)-; X 2 is -NH-; X 3is -CH2- or X 3 is -CH2-O-(C1-C 10 -alkylene)-C(O)- (wherein C(O) is X 4 (attached to a 3 is -C(O)-; X 4 is -O-; R 35 is H, -OH, -OCH3, or C 1-6 is alkyl; R 50 and R 50a are independently hydrogen or C1-C6-alkyl; R d , R e , and R f are, independently, -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CHOR g and Here, each R g is independently —CHC(O)OH or —CHC(O)O(alkyl); and mm is 0 or 1; n is an integer selected from 1 to 30; L' is a linker; and BA is a binder).

[0224] In some embodiments, in the compound of Formula (III), both R x is hydrogen, and SP, B A, L', R 34 and n may, in some or any embodiment, be any of the groups described herein. In some embodiments, in the compound of Formula (III), both R x is full Oro and SP, BA, L', R 34 and n is, in some or any embodiment, As described herein. In some embodiments, R 34 is the R-configuration In some embodiments, R 34 is in the S-configuration. In the embodiment, R 34 is a mixture of R- and S-configurations. , R 34 is a mixture of R- and S-configurations, 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.

[0225] In some embodiments, the compound is of Formula (III), wherein: Both R x is hydrogen; and SP is —C(O)—C—C 10 -Alkylene-C(O)-, -C(O)-N(C 1-6 a Rukill)-C1-C 10 -Alkylene-X 1 -(where X 1 is attached to L' in formula (III), -C(O )-N(H)-(C1-C 10 -alkylene)-S- (wherein S is attached to L' in formula (III)), -C(O) -N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S- (wherein S is attached to L' in formula (III) ), -(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a teeth, attached to L' in formula (III), -C(O)-(C-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -Al Kiren)-NR 50a -(where NR 50ais attached to L' in formula (III) and each of C1-C 10 - alkylene is optionally substituted independently with one or more hydroxy), —C(O)—N(R 5 )-C1-C 10 -Alkylene-C(O)NH-X 2 -(where X 2 is attached to L' in formula (III), or [ka] (where X 4 is attached to L' in formula (III); or Both R x is fluoro; and SP is —C(O)—N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1b -(where X 1b is attached to L' in formula (III), -C(O)-N(H)-(C-C 10 -Alkylene )-X 1b -(where X 1b is attached to L' in formula (III), [ka] (where the point of attachment to the right (i.e., at N) is to L' in formula (III) ), -(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a teeth, attached to L' in formula (III), -C(O)-(C-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -Al Kiren)-NR 50a -(where NR50a is attached to L' in formula (III) and each of C1-C 10 - alkylene is optionally substituted independently with one or more hydroxy), or —C(O)—N(R 5 )-(C1-C 10 -alkylene)-C(O)NH-X 2 -(where X 2 is attached to L' in formula (III) be.

[0226] In some embodiments, the compound of formula (I) is a compound of formula (3000) or a pharmaceutical thereof: and optionally acceptable salts, solvates, or stereoisomers thereof: BA-(L′-SP-D) n Expression(3000) (In the formula, D is a) [ka] (wherein both R x is hydrogen; R 34 is an alkyl, aryl, or aryl group. alkyl, or N-containing heterocycloalkyl; and SP is —C(O)—C—C 10 -Alkylene-C (O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1 -(where X 1 is added to L' in equation (3000). -C(O)-N(H)-(C1-C 10 -alkylene)-S- (wherein S represents L' in formula (3000) -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -alkylene)-S- (wherein S is a group represented by the formula (30 00) attached to L'), [ka] (where the point of attachment on the right (i.e., at N) is to L' in formula (3000). -CH2-NH- (wherein N is attached to L' in formula (3000)), [ka] (wherein N is attached to L' in formula (3000), and Ar is an optionally substituted aryl group. (In some embodiments, [ka] ) or optionally substituted heteroarylene), -(C-C 10 -alkylene)-NR 50 C(O)- (C1-C 10 -alkylene)-NR 50a -(where NR 50a is added to L' in formula (3000), -C( O)-(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a is expressed as (3 000) and each C1-C 10 -Alkylene independently represents one or more hydro -C(O)-N(R 35 )-C1-C 10 -Alkylene-C(O)NH-X 2 -(where X 2 is attached to L' in formula (3000), or [ka] (where X 4is attached to L' in formula (3000); or Here, both R in formula (a) x is fluoro; R 34 is alkyl, aryl, aryl and SP is —C(O)—C—C 10 -Archile -C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1b -(where X 1b is in equation (3000). attached to L'), -C(O)-N(H)-(C1-C 10 -alkylene)-X 1b -(where X 1b is the formula (300 0) attached to L'), [ka] (where the point of attachment on the right (i.e., at N) is to L' in formula (3000). -CH2-NH- (wherein N is attached to L' in formula (3000), [ka] (wherein N is attached to L' in formula (3000), and Ar is an optionally substituted arylene. In some embodiments, [ka] ) or optionally substituted heteroarylene)), -(C-C 10 -alkylene)-NR 50 C(O) -(C1-C 10 -alkylene)-NR 50a -(where NR 50a is attached to L' in formula (3000), -C (O)-(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a is the formula ( 3000) and each C1-C 10 -Alkylene independently represents one or more hydroxyl groups. -C(O)-N(R 35 )-(C1-C 10 -alkylene)-C(O)NH-X 2 -(here So, X 2 is attached to L' in formula (3000), or [ka] (where X 4 is attached to L' in formula (3000); and / or b) a compound in Table A below (wherein the compound in Table A is a compound selected from the group consisting of hydroxy groups of -C(O)CHOH, , i.e., by -C(O)CH2-O-SP-L'- or via the hydroxy of the maplart i.e., linked to BA of the compound of formula (III) by -O-SP-L'-; X 1 is -N(C 1-6 alkyl)-; X 1b is -S-, -NH-, or -N(C 1-6 alkyl)-; X 2 is -NH-; X 3 is -CH2- and X 3 is -CH2-O-(C1-C 10 -alkylene)-C(O)- (wherein C(O) is X 4 to (attached) or X 3 is -C(O)-; X 4is -O-; R 35 is H, -OH, -OCH3, or C 1-6 is alkyl; R 50 and R 50a are independently hydrogen or C1-C6-alkyl; R d , R e , and R f are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, - C(O)OH or -CH2OR g where each R g are independently -CH2C(O)OH or -CH2C(O)O( alkyl); and mm is 0 or 1; n is an integer selected from 1 to 30; L' is a linker; and BA is a binder).

[0227] In some examples of formula (3000), D is budesonide or any other compound shown in Table A. In some examples of formula (3000), D is any of the steroids described herein. The compounds in Table A are all budesonide analogs via the hydroxy of the -C(O)CHOH group. That is, by -C(O)CH2-O-SP-L'- or through the hydroxy of the maplart, i.e. That is, it is linked to BA of the compound of formula (III) by -O-SP-L'-. In examples, the moiety SP-D (or H-SP-D) is referred to herein as a "budesonide-spacer." and is shown, for example, in Table B, the Examples section, and in Scheme 1 of FIG. 22. spacer or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Table A. [Table 1] TIFF0007824992000145.tif229170TIFF0007824992000146.tif229170TIFF0007824992000147.tif229170TIFF0007824992000148.tif166170Table B. Budesonide-Spacer (Budesonide-SP) [Table 2] TIFF0007824992000150.tif231170TIFF0007824992000151.tif240170TIFF0007824992000152.tif228170TIFF0007824992000153.tif146170In some instances, in each of the above structures [ka] n-propyl is in the R-configuration, i.e., at the carbon indicated by the asterisk In some instances, in each of the above structures [ka] n-propyl is in the S-configuration, i.e., at the carbon indicated by the asterisk In some instances, in each of the above structures [ka] n-propyl is a mixture of R- and S-configuration, i.e., the carbon indicated by the asterisk. In some instances, in each of the above structures [ka] n-propyl is a mixture of R- and S-configuration, i.e., the carbon indicated by the asterisk. wherein the R:S mixture is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, or about 10:1.

[0228] In various embodiments, Ab-L′-SP-D or -SP-D of formula (3000) [ka] teeth, [ka] Selected from TIFF0007824992000160.tif225170 and TIFF0007824992000161.tif90170, where: [ka] is the bond to the linker.

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

[0230] In various embodiments, [ka] is selected from Table B, or [ka] is selected from.

[0231] In some embodiments, the payload is a rifamycin having the structure of Formula (C): analogue: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula: X 1c -O-, -S-, and -NR 5c Selected from; R 1c is hydrogen; amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; Di-C 1-6 Archi Amino C 1-6 Alkyl; Hydroxy-C 1-6 Alkyl; HS-C 1-6 Alkyl; (R 5c )2N-C 1-6 Archi Ren-N(R 5c )-C 1-6 Alkyl; (R 5c )2N-C 1-6Alkylene-OC 1-6 Alkyl; (R 5c )2N-C 1-6 Al Killen-SC 1-6 Alkyl; heterocycloalkyl, or heterocycloalkyl-C 1-6 Archi wherein heterocycloalkyl is one, two, or three selected from O, N, and S. and wherein the heteroatom is nine Roarke Lu is , Haro, C 1-6 Alkyl, -OH, =O, or -N(R 5c )2 optionally substituted; R 2c , R 3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; R ac -F; -Cl; -Br; -I; -OH; -NH2; and C 1-6 selected from alkoxy; R bc Each occurrence of is hydrogen; and R 5c is independently at each occurrence hydrogen; and C 1-6 alkyl; However, R 1c is not an n-butyl group; and Furthermore, however, X 1c When is -O-, R 1c is not hydrogen; where the group R 1c is attached to the linker).

[0232] In some embodiments, the payload is a rifamycin having the structure of formula (C-1): Analogue: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula: X 1c -S-; -O- and -NR 5c Selected from; R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; Di-C 1-6 Alkylamine No.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 wherein heterocycloalkyl is selected from 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein heteroatoms are nine Roarke Lu is , Haro, C 1-6 Alkyl, -OH, =O, or -N(R 5c )2 optionally substituted; R 2c , R 3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; Each R ac are, if present, independently -F; -Cl; -Br; -I; -OH; -NH; and C 1-6 Arco selected from: R 5cis independently at each occurrence hydrogen; and C 1-6 alkyl; where the group R 1c is attached to the linker).

[0233] In some embodiments, the payload is a rifamycin having the structure of formula (C-2): Analogue: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula: X 1c -S-; -O- and -NR 5c Selected from; R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; Di-C 1-6 Alkylamine No.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 wherein heterocycloalkyl is selected from 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein heteroatoms are nine Roarke Lu is , Haro, C 1-6 Alkyl, -OH, =O, or -N(R 5c)2 optionally substituted; R 2c , R 3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; R ac and R bc are independently -F; -Cl; -Br; -I; -OH; -NH; and C 1-6 Selected from alkoxy and R 5c is independently at each occurrence hydrogen; and C 1-6 alkyl; where the group R 1c is attached to the linker).

[0234] In some embodiments, the payload is a rifamycin having the structure of formula (C-3): Analogue: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula: R 1c Is Ji-C 1-6 Alkylamino C 1-6 Alkyl; (R 5c )2N-C 1-6 Alkylene-N(R 5c )-C 1-6 a alkyl; heterocycloalkyl, or heterocycloalkyl-C 1-6 alkyl; Heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from O, N, and S. and here, heterocysteine nine Roarke Lu is , Haro, C 1-6 Alkyl, -OH, =O, or -N(R 5c )2 is optionally substituted with; and R 2c , R3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; t R 5c is hydrogen and C 1-6 alkyl; where the group R 1c is attached to the linker).

[0235] In some embodiments, the payload is a rifamycin having the structure of formula (C-4): Analogue: or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof; [ka] (In the formula: R 1c teeth, [ka] and; where Y is C or N; R 2c , R 3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; t R 5c is hydrogen and C 1-6 alkyl; where the group R 1c is a wavy line [ka] (which is attached to the linker via a nitrogen atom indicated by

[0236] Some or any embodiments of formula (C-1) and / or (C-2) and / or (C-3) and / or (C-4) In the same way, R bc is hydrogen, and / or Rac is hydrogen. Formula (C-1) and / or (C-2) and / or (C-3) and / or (C-4), in some or any of the embodiments, R 2c Is Methi The formula (C-1) and / or the formula (C-2) are each independently methyl, ethyl, propyl, or isopropyl, and preferably methyl. In some or any of the embodiments of (C-2) and / or (C-3) and / or (C-4), R 3c teeth , CH3-(C=O)-(acetyl) group, CH3CH2-(C=O)-, CH3CH2CH2-(C=O)-, or (CH3)2CH-(C=O)-; Preferred is acetyl. In some or any embodiments, R 4c is hydrogen.

[0237] In some embodiments of formula (C-1) and / or (C-2) and / or (C-3) and / or (C-4), , -OR 1c teeth, [ka] One or more of the formulae (C-1) and / or (C-2) and / or (C-3) and / or (C-4) In some embodiments, -OR 1c teeth, [ka] is.

[0238] Some or any embodiments of formula (C-1) and / or (C-2) and / or (C-3) and / or (C-4) In your opinion, X 1c is O and -OR 1c contains a tertiary amine, and the tertiary amine is a phosphorus After attachment to the car, the -O R 1c teeth, [ka] In such embodiments, when a quaternary amine is formed, a suitable counterion is There are drugs that contain quaternary amines that carry a positive charge, i.e., rifamycin analogs. and salts, such as salts containing negatively charged charge-balancing counterions (e.g. , I - , Br - , Cl - , or any other suitable counterion).

[0239] In some embodiments, the compounds of formula (C-1) and / or (C-2) and / or (C-3) and / or (C-4) The compound is: [ka] TIFF0007824992000180.tif164170; where: [ka] is the bond to the linker.

[0240] (Linker) In some embodiments of Formula (I), (III), or (3000), L is -L 1 -L 2 -(L 3 ) 0-1 -Includes Mikatsu L 2 teeth, [ka] -OCH2C(O)-, or a cyclodextrin residue (CD); or a combination thereof. In one embodiment, L is -L 1 -L 2 -(L 3 ) 0-1 - and L 2 teeth, [ka] or CD, or a combination thereof. In some embodiments, L is -L 1 -L 2 -(L 3 ) 0-1 - and L 2 In some embodiments, L and / or L 2 Contains CD If so, the CD [ka] TIFF0007824992000185.tif98170.

[0241] In some embodiments of Formula (I), (III), or (3000), L is -L 1 -L 2 -(L 3 ) 0-1 -Includes Mikatsu L 2 In some embodiments, L and / or HG are as described herein. L 2 teeth, [ka] In some embodiments, L and / or L 2 teeth, [ka] Includes:

[0242] In some embodiments of Formula (I), (III), or (3000), L is -L 1 -L2 -(L 3 ) 0-1 -Includes Mikatsu L 1 teeth, [ka] or a positional isomer or mixture of isomers thereof; [ka] or a stereoisomer or a mixture of stereoisomers thereof (wherein S is a group that is connected to a reactive group residue via represents the S atom on the cysteine ​​residue to which the group is attached to BA); and [ka] (where N represents the N atom on the lysine residue through which the reactive group residue is attached to the BA) (The following is selected from the list:

[0243] In some embodiments, L is -L as described herein. 1 -L 2 -(L 3 ) 0-1 - and -L 2 -(L 3 ) 0-1 In some embodiments, L includes any of the groups described herein for Formula (III) and Formula (3000). In some embodiments, L is L'-SP as described in the document: [ka] Includes TIFF0007824992000192.tif224170TIFF0007824992000193.tif223170TIFF0007824992000194.tif182170TIFF0007824992000195.tif216170.

[0244] In some examples, the compound of formula (I) or (III) or (3000) is [ka] or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof Selected, where: each Ab is an anti-MSR1 antibody or an antigen-binding fragment thereof; and Each n is an integer from 1 to 4.

[0245] In some examples, the compound of formula (I) or (III) or (3000) is [ka] TIFF0007824992000198.tif211170TIFF0007824992000199.tif234170TIFF0007824992000200.tif207170TIFF0007824992000201.tif222170TIFF0007824992000202.tif131170 or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof Selected, where: each Ab is an anti-MSR1 antibody or an antigen-binding fragment thereof; Each BA is [ka] where Ab 1 is an anti-MSR1 antibody or an antigen-binding fragment thereof; R is C 2-4 -Archile and nn is an integer selected from 2 to 4, and Each n is an integer from 1 to 4.

[0246] In some further embodiments, the ADCs described herein are and the linker described in U.S. Patent No. 9,951,141 B2, filed on April 24, 2018. Some examples include: wherein the linker is: [ka] wherein b is an integer from 2 to 8; and [ka] is a bond to a binding agent. In some embodiments, the linker has two reactive groups and, for example, binding to thiols on two different chains of an antibody or antigen-binding fragment thereof Can form: [ka] wherein b is an integer from 2 to 8. In a further embodiment, the linker is a compound selected from the group consisting of two reactants: groups and can be bonded to, for example, thiols on two different chains of an antibody or antigen-binding fragment thereof. The combination can be formed: [ka] where b is an integer from 2 to 8. In some other embodiments, the linker comprises two and, for example, thiols on two different chains of an antibody or antigen-binding fragment thereof. You can form a bond with: [ka] where b is an integer from 2 to 8, and R N is a hydrogen atom or alkyl, and R M Is, Al In further embodiments, the linker comprises two reactive groups and is, for example, For example, it is possible to form bonds with thiols on two different chains of an antibody or antigen-binding fragment thereof. Can: [ka] Here, b is an integer of 2 to 8. In certain embodiments, the linker has two reactive groups. and for example, binding to thiols on two different chains of an antibody or antigen-binding fragment thereof. Can be formed: [ka] Here, b is an integer of 2 to 8. In some embodiments, the linker comprises two anti- reactive groups and can be linked, for example, to thiols on two different chains of an antibody or antigen-binding fragment thereof. Bonds can be formed: [ka] where b is an integer from 2 to 8; R N is a hydrogen atom or alkyl; and R M Is, Archi It is.

[0247] Formulas (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III) as described herein , (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 In the formula, PA can be linked to BA via any suitable linker L. The linker can be used to link the antibodies or antigen binding proteins described herein to therapeutic linked or connected to a moiety, such as a steroid or an LXR modulator; Suitable linkers are, for example, those described in the respective texts by reference. Antibody-drug conjugates and immunotoxins (Antibody-Drug Conjugates) rug Conjugates and Immunotoxins); edited by Phillips, GL; Springer Verlag: New York, 2013; Antibody-Drug Conjugates; Ducry, L. (ed.); Humana Pres s, 2013;Antibody-Drug Conjugates; Wang, J., Shen, W.-C. , and Zaro, JL (eds.); Springer International Publishing, 2015 Generally, suitable binder linkers for the antibody conjugates described herein are Stable enough to utilize the body's circulating half-life and at the same time, antigen-mediated It is capable of releasing its payload after internalization of the conjugate. The linker can be cleavable or non-cleavable. Cleavable linkers include those that are capable of cleaving the cellular target protein after internalization. Linkers that are cleaved by endogenous metabolism, e.g., hydrolysis, reduction, or cleavage via enzymatic reactions. Non-cleavable linkers include those that allow the addition of a non-cleavable linker via lysosomal degradation of the antibody after internalization. Suitable linkers include acid-labile linkers that release the attached payload. Linkers, hydrolytically unstable linkers, enzyme-cleavable linkers, reduction-labile linkers, Examples include, but are not limited to, cleavable linkers / groups and non-cleavable linkers. Suitable linkers include peptides, glucuronides, succinimide-thioethers, and polyethers. ethylene glycol (PEG) units, hydrazones, malto-caproyl units, dipeptide units, para-citrulline units and para-aminobenzyl (PAB) units, or containing these These include, but are not limited to:

[0248] Any linker molecule or linker technology known in the art can be used to make the ADCs of the disclosure. In some embodiments, the linker is a cleavable linker. In other embodiments, the linker is a non-cleavable linker. Exemplary linkers that can be used in the Prooyl), MP (Maleimidopropanoyl), val-cit (Valine-Citrulline), val-ala (Vali dipeptide moiety in the protease-cleavable linker, ala-phe (alanine-phe) dipeptide moiety in the protease-cleavable linker, PAB (p-aminophenylalanine), SPP (N-succinimidyl 4-(2-pyridylthio)pentanoate) , SMCC (N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate SIAB (N-succinimidyl (4-iodo-acetyl) aminobenzoate), and its derivatives Linkers that include or consist of variants and combinations thereof. Further examples of linkers that can be used in the present invention are described, for example, in No. 7,754,681 and Ducry, Bioconjugate Chem., 1999, which are incorporated herein in their entireties. 2010, 21:5-13, and the references cited therein.

[0249] In certain embodiments, the linker is stable under physiological conditions. Thus, the linker is cleavable, e.g., in the presence of an enzyme or at a particular pH range or value. In some embodiments, the receptor can release at least the payload portion. The anchor comprises an enzyme-cleavable moiety. Exemplary enzyme-cleavable moieties include a peptide bond, an endonucleaser, an enantiomer, an amino acid ... These include, but are not limited to, ester linkages, hydrazone linkages, and disulfide linkages. In some embodiments, the linker comprises a cathepsin-cleavable linker.

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

[0251] Suitable linkers include those that chemically bond to two cysteine ​​residues of a single binding agent, e.g., an antibody. Such linkers include, but are not limited to, those that are bonded in a manner that is Mimics the disulfide bonds in antibodies that are broken as a result of the conjugation process can do the work.

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

[0253] In some embodiments, the linker comprises a self-immolative group. In certain embodiments, the self-immolative group is p- aminobenzyl (PAB) or a derivative thereof. In some embodiments, the self-immolative group is , p-aminobenzyloxy. In some embodiments, the self-immolative group is a cleavable diaminobenzyloxy. Contains a sulfide group. Useful derivatives include p-aminobenzyloxycarbonyl (PABC) Those skilled in the art will appreciate that the self-immolative group is a chemical group that releases the remaining atoms of the linker from the payload. You will know that you can make a reaction.

[0254] In some embodiments, the linker is: [ka] where: [ka] is the binding to an antibody or antigen-binding protein (e.g., via a lysine residue), and [ka] is the bond to the payload. In some embodiments, the linker is: [ka] where: [ka] is the binding to an antibody or antigen-binding protein (e.g., via a lysine residue), and [ka] is the bond to the payload. In some embodiments, the linker is: [ka] is.

[0255] In some embodiments, the linker is: [ka] is.

[0256] In some embodiments, the linker is maleimidylmethyl-4-trans-cyclohexyl Xanthan Gum Carboxysuccinate: [ka] It comes from.

[0257] In some embodiments, the linker is: [ka] where: [ka] is the binding to an antibody or antigen-binding protein (e.g., via a lysine residue), and [ka] is the binding with the payload.

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

[0259] In some embodiments, L comprises a moiety having the structure: [ka] .

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

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

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

[0263] In certain embodiments, the linker comprises a cyclodextrin group. wherein the linker provides an ADC according to formula (Ia): [ka] .

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

[0265] In certain embodiments, the linker comprises a cyclodextrin group. wherein the linker provides an ADC according to formula (Id): [ka] .

[0266] In formula (Id), BA is an anti-MSR1 antibody or an antigen-binding fragment thereof; RG is a reactive group residue. Yes; SP 1 and SP 2 are each, independently in each occurrence, absent or a spacer group residue; Here, SP 1 comprises 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 [ka] where: [ka] indicates the atom through which PAB is bonded to the adjacent group in the formula, and CD indicates the atom through which each group is bonded to the adjacent group in the formula. and independently in each case, absent or a cyclodextrin residue, wherein at least one CD is where subscript n is an integer from 1 to 30; subscript m is an integer from 0 to 5; and subscript p is 0 or 1; and PA is the payload portion. In these examples, the subscript m is 0 , 1, 2, 3, 4, or 5. In some instances, 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 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 instances, the subscript p is 1. In some instances, AA 1 or AA 2 Noi one of which is, independently in each occurrence, alanine, valine, leucine, isoleucine, methyl Onine, tryptophan, phenylalanine, proline, serine, threonine, cysteine tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, an amino acid selected from arginine, histidine, or citrulline, or a derivative thereof; or a combination thereof. In some embodiments, AA 1 are alanine, valine, leucine, Isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, Serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparagine an amino acid selected from the group consisting of glutamic acid, lysine, arginine, histidine, and citrulline; In one embodiment, the AA 1 is lysine In one embodiment, AA 1is lysine or a derivative of lysine. In AA 2 is valine-citrulline. In some embodiments, AA 2 Is, Shi In some embodiments, AA 2 is valine-alanine In some embodiments, AA 2 is alanine-valine. Hey, AA 2 is valine-glycine. In some embodiments, AA 2 Grisi In some embodiments, AA 1 -AA 2 is glutamine-valine-citrate In some embodiments, AA 1 -AA 2 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 an embodiment, AA 1 -AA 2 is glutamine-valine-citrulline. In some embodiments, the lysine is L-lysine. In some embodiments, the lysine is D-lysine. In some instances, SP 1 is, in each case independently, 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 -, and combinations thereof, wherein the subscript e is an integer from 0 to 4. where the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8. Hey, SP 2 is, in each case independently, 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 - and its and combinations thereof, wherein the subscript e is an integer from 0 to 4 and the subscript u is 1 is an integer between 1 and 8, and the subscript v is an integer between 1 and 8.

[0267] Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5 002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7 In certain embodiments of (7003), (7004), and / or (7005), the linker is: [ka] TIFF0007824992000233.tif212170TIFF0007824992000234.tif187170TIFF0007824992000235.tif 172170TIFF0007824992000236.tif166170TIFF0007824992000237.tif206170TIFF000782499200023 8.tif213170TIFF0007824992000239.tif210170TIFF0007824992000240.tif243170TIFF0007824992000241.tif168170TIFF0007824992000242.tif222170TIFF0007824992000243.tif184170. Also included in these examples are pharmaceutically acceptable salts, solvates thereof, a compound, stereoisomeric form, positional isomer thereof, or a mixture of positional isomers thereof, wherein each Many [ka] is the bond with the binder; and each [ka] is the binding with the payload.

[0268] In certain embodiments, the linker comprises a terminal hydrophilic group (HG). In some embodiments, the linker comprises a terminal sulfo In certain embodiments, the linker comprises a phosphate group. In certain embodiments, the linker provides an ADC according to Formula (II): [ka] wherein in formula (II), BA is a binding agent; LL is a trivalent linker; RG 1 and R.G. 2 is a reactive group residue; SP 1 and SP 2is, independently in each occurrence, absent or a spacer group residue HG is a hydrophilic residue; PA is a payload residue; and the subscript n is 1 to 30. and the subscript q is 0 or 1. In some examples, multiple trivalent linkers -LL may be present. 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 is 3. In some examples, n is 4. In some examples, HG is the terminal parent In some examples, HG comprises one terminal sulfonic acid group or a salt thereof. In other examples, HG contains multiple terminal sulfonic acid groups or salts thereof. In other examples, HG includes one terminal phosphonic acid group or a salt thereof. In some examples, HG comprises one terminal tertiary amine group or a salt thereof. In another example, HG comprises a plurality of terminal tertiary amine groups or salts thereof. In some instances, HG comprises one terminal polyol (e.g., glucose, maltose, ) or derivatives thereof. In another example, HG comprises multiple terminal polyols (e.g., glycosaminoglycans, Contains saccharides such as maltose and maltose or their derivatives.

[0269] In another example, the compound of formula (II) is according to formula (IV): [ka] .

[0270] In formula (IV), BA, RG 1 , SP 1 , R.G. 2 , SP 2 , and HG are as defined above and AA 1 is a trivalent linker comprising amino acid residues; AA 2 is a dipeptide residue ; and PAB [ka] where: [ka] represents the atom through which PAB is attached to the adjacent group in the formula; the subscript p is 0 or 1; and subscript q is 0 or 1. In some examples, subscript p is 0, and subscript q is 0. In some examples, subscript p is 1; and subscript q is In some instances, the subscript p is 0; and the subscript q is 1. In some examples, the subscript p is 1; and the subscript q is 1. , SP 1 contains 0 to 5 polyethylene glycol (PEG) residues. In some examples, SP 2 contains 0 to 5 PEG residues. 1 is, in each case independently, 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 -, and combinations thereof, wherein The subscript e is an integer from 0 to 4, the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8. In some cases, SP 2 is, in each case independently, C 1-6Alkylene, -NH -, -C(O)-, (-CH2-CH2-O) e , -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C (O)-NH-(CH2) v -, -, and combinations thereof, wherein the subscript e is from 0 to 4. where the subscript u is an integer between 1 and 8, and the subscript v is an integer between 1 and 8. In that example, AA 1 or AA 2 any one of, independently in each occurrence, alanine, valine , leucine, isoleucine, methionine, tryptophan, phenylalanine, proline , serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparagi selected from phosphate, glutamic acid, lysine, arginine, histidine, or citrulline In one embodiment, the amino acid AA 1 Is, A Leucine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine Nine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine , glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, if or citrulline, a derivative thereof, or a combination thereof. In an embodiment, AA 1 is lysine. In some embodiments, AA 1 is lysine or lysine In one embodiment, AA 1 is glutamic acid. Hey, AA 2 is valine-citrulline. In some embodiments, AA 2Ha, Shito In some embodiments, AA 2 is valine-alanine. In some embodiments, AA 2 is alanine-valine. AA 2 is valine-glycine. In some embodiments, AA 2 is glycine- In some embodiments, AA is valine. 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 the embodiment of AA 1 -AA 2 is glutamine-valine-alanine. In some embodiments, the lysine is L-lysine. In some embodiments, the lysine is D-lysine. .

[0271] Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (III), (3000), (5001), (5 002), (5003), (5004), (6001), (6002), (6003), (6004), (6005), (7001), (7002), (7 In certain embodiments of (7003), (7004), and / or (7005), the linker is: [ka] or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof is selected, where Each [ka] is a bond with a binder; and Each [ka] is the bond to the payload residue.

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

[0273] (Linker payload) Provided herein are compounds useful in the preparation of antibody-drug conjugates; 000) or a pharmaceutically acceptable salt, solvate thereof, or are stereoisomers; RG-L 2 -(L 3 ) 0-1 -SP-D (In the formula, D is a) [ka] (wherein both R x is hydrogen; R 34 is an alkyl, aryl, or aryl group. alkyl, or N-containing heterocycloalkyl; and SP is —C(O)—C—C 10 -Archile -C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1 -(where X 1 is in equation (2000). (L 3 ) 0-1 -C(O)-N(H)-(C1-C 10 -alkylene)-S- (wherein S is a group represented by the formula (2000 ) in (L 3 ) 0-1 attached to -C(O)-N(C 1-6 Alkyl)-(C1-C 10 -Alkylene)-S-(here And S is (L 3 ) 0-1 (attached to [ka] (where the attachment point on the right (i.e., at N) is (L 3 ) 0-1 Also for (where N is the group represented by (L 3 ) 0-1 (attached to [ka] (where N is the (L 3 ) 0-1 and wherein Ar is optionally substituted substituted arylenes (in some embodiments, [ka] ) or optionally substituted heteroarylene), -(C-C 10 -alkylene)-NR 50 C(O)- (C1-C 10 -alkylene)-NR 50a -(where NR 50a is (L 3 ) 0-1 (attached to , -C(O)-(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a teeth , (L 3 ) 0-1 and wherein each C1-C 10 -Alkylene is a optionally substituted with one or more hydroxy groups, -C(O)-N(R 5 )-(C1-C 10 -alkylene)- C(O)NH-X 2 -(where X 2 is (L 3 ) 0-1 (attached to [ka] (where X 4 is (L 3 ) 0-1 (appended to the Here, both R in formula (a) x is fluoro; R 34 is alkyl, aryl, aryl and SP is —C(O)—C—C 10 -Al Xylene-C(O)-, -C(O)-N(C 1-6 Alkyl)-C1-C 10 -Alkylene-X 1b -(where X 1b is the formula (200 0) in (L 3 ) 0-1-C(O)-N(H)-(C1-C 10 -alkylene)-X 1b -(where X 1b is (L 3 ) 0-1 (attached to [ka] (where the attachment point on the right (i.e., at N) is (L 3 ) 0-1 Also for (where N is the group represented by (L 3 ) 0-1 (attached to [ka] (where N is the (L 3 ) 0-1 and wherein Ar is optionally substituted substituted arylenes (in some embodiments, [ka] ) or optionally substituted heteroarylene), -(C-C 10 -alkylene)-NR 50 C(O)- (C1-C 10 -alkylene)-NR 50a -(where NR 50a is (L 3 ) 0-1 (attached to , -C(O)-(C1-C 10 -alkylene)-NR 50 C(O)-(C1-C 10 -alkylene)-NR 50a -(where NR 50a teeth , (L 3 ) 0-1and wherein each C1-C 10 -Alkylene is a optionally substituted with one or more hydroxy groups, -C(O)-N(R 5 )-(C1-C 10 -alkylene)- C(O)NH-X 2 -(where X 2 is (L 3 ) 0-1 (attached to [ka] (where X 4 is (L 3 ) 0-1 (attached to); and / or b) the compounds of Table A above (wherein the compounds of Table A are all hydroxyl groups of the -C(O)CHOH group) That is, -C(O)CH2-O-SP-(L 3 ) 0-1 - or through the hydroxyl of mapracorate That is, -O-SP-(L 3 ) 0-1 - linked to BA of the compound of formula (2000) by Selected from: X 1 is -N(C 1-6 alkyl)-; X 1b is -S-, -NH-, or -N(C 1-6 alkyl)-; X 2 is -NH-; X 3 is -CH2- or X 3 is -CH2-O-(C1-C 10 -alkylene)-C(O)- (wherein C(O) is X 4 (attached to a 3 is -C(O)-; X 34 is -O-; R 35 is H, -OH, -OCH3, or C 1-6 is alkyl; R 50 and R 50a are independently hydrogen or C1-C6-alkyl; R d , R e , and R f are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, - C(O)OH or -CH2OR g where each R g are independently -CH2C(O)OH or -CH2C(O)O( alkyl); and mm is 0 or 1; RG is a reactive group residue; L 2 is the connecting linker; and L 3 is a self-immolative group, if present).

[0274] Provided herein are compounds of the formula (I), which are useful in preparing antibody-drug conjugates. 4000) or a pharmaceutically acceptable salt or solvate thereof, or are stereoisomers; RG-LE type (4000) (In the formula, E is a) a compound of formula (B) as described above and herein; and / or b) a compound of formula (B-1) as described above and herein; and / or c) Payloads described in Table C herein Selected from; L is a linker described herein; and RG is any reactive group residue described herein).

[0275] In some embodiments, the LXR payload is [ka] In some embodiments, the LXR payload is [ka] is.

[0276] In some embodiments, the linker-payload of Formula (4000) is selected from the group consisting of formulas (4001), (4002), or a pharmaceutically acceptable salt, solvate, or isoform thereof. have isomeric forms; [ka] (In the formula, SP 1 and SP 2 When present, in some and optional embodiments, is a spacer group defined as Each AA is an amino acid residue; p is an integer from 1 to 10; RG is a reactive group residue; and R B1 , R B2 , R 7 and b are, in some and optional embodiments, as defined herein. (As stated).

[0277] In some embodiments, a phosphorus group of formula (4000), (4001), (4002), (4003), or (4004) is The linker-payload is selected from the linker-payloads in Table 3.

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

[0279] In some embodiments, F is a rifamycin analog described herein. In some embodiments, F is a reference amino acid: [ka] In some embodiments, F is rifampicin: [ka] is.

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

[0281] Provided herein are antibodies or their derivatives linked via a linker or linker-spacer. The steroid conjugated to the antigen-binding fragment is a compound of formula (A-1) or a pharmaceutical thereof a linker-steroid, which is a suitably acceptable salt, solvate, or stereoisomeric form thereof; ru; [ka] (In the formula, R 1 and R 2 is independently —H, alkyl, alkyl-C(O)—O—, —OH, or halo; or R 1 and R 2 together, [ka] Forming where R 4 is an alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl It is a kill, wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl is, independently in each occurrence, -NR Aa R Ab optionally substituted with; R 3 is -O,R Z -C(O)-X-, -heteroalkyl, -piperidinyl, -NR Aa R Ab , -oxyary Lu-NR Aa R Ab , or -Z-A'(R P ) t and; R Z is alkyl; X is O or NR Aa and; Z is S, S(O), S(O)2, SO2NR Aa , O, C(O)NR Aa , C(O), or NR Aa and; A' is aryl, arylalkyl, or heteroaryl; R P is independently in each occurrence halo, optionally substituted alkyl, —OH, or —NR Aa R Ab in can be; R Aa and R Ab is independently in each occurrence -H, optionally substituted alkyl, or optionally substituted is an aryl; the subscript a is an integer from 0 to 19; and t is an integer from 1 to 3; and R 5A and R 5B are each independently a halo or a hydrogen atom; where the group R 3or R 4 is attached to the linker).

[0282] Provided herein are antibody-drug conjugates of the formula Ab-L'-SP-D or BA-L'-SP-D where D is a budesonide prodrug or a budesonide analog or derivative (e.g., and wherein Ab, BA, L', and S are prodrugs of P is as defined in any embodiment described herein. In some embodiments, SP is D or [ka] In some embodiments, under physiological conditions, L and SP is cleaved to give a steroid prodrug, i.e., H-SP-D or [ka] and then release the bond between SP and D, or SP and [ka] The bond between is cleaved, releasing the biologically active steroid.

[0283] In some examples, the compounds of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (II) I), or (3000) ADCs are those listed in Table 1 and / or Table 2 and in the Examples section. In some embodiments, in any of the antibody drug conjugates described herein The steroid payload of [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0284] Provided herein are compounds of formula (5001), (5002), (5003), or (5004) as described herein. an antibody-drug conjugate of any LXR-modulator compound: or a pharmaceutical thereof Acceptable salts, solvates, stereoisomeric forms, or positional isomers thereof, or mixtures thereof is; [ka] wherein L, in some or any embodiment, is any phosphorus group described herein. Carr; n is an integer from 1 to 30; BA is a binding agent or a PEG-modified binding agent; and R B1 , R B2 , R 7 and b are, in some and optional embodiments, as defined herein. (As stated).

[0285] Provided herein are compounds of formula (6001), (6002), (6003), or (6004) as described herein. an antibody-drug conjugate of any LXR-modulator compound: or a pharmaceutical thereof Acceptable salts, solvates, stereoisomeric forms, or positional isomers thereof, or mixtures thereof is; [ka] (In the formula, SP 1 and SP, when present, may in some or any embodiment be used herein is a spacer group defined by Each AA is an amino acid residue; p is an integer from 1 to 10; n is an integer from 1 to 30; BA is a binding agent or a PEG-modified binding agent; and R B1 , R B2 , R 7 and b are, in some and optional embodiments, as defined herein. (As stated).

[0286] Provided herein is any LXR-modulator described herein of formula (6005): -Antibody-drug conjugates of the compounds: or pharmaceutically acceptable salts, solvates, steric forms thereof isomeric forms, or positional isomers thereof, or mixtures thereof; [ka] (In the formula, R B1 , R B2 , R 7 , b, BA, RG 1 , SP 1 , A.A. 1 , and A.A. 2 In some or any embodiment (as defined herein in the context of the specification).

[0287] In some examples, the compounds of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (50 01), (5002), (5003), (5004), (6001), (6002), (6003), (6004), or (6005) ADCs In some embodiments, the ADC is an ADC described in Table 1 and / or Table 2 and in the Examples section. , an LXR modulator payload in any antibody drug conjugate described herein Do is [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0288] Provided herein are any of the compounds described herein and having the structure of formula (7001): an antibody-drug conjugate of a rifamycin analog, or a pharmaceutically acceptable salt thereof; solvates, stereoisomeric forms, or positional isomers thereof, or mixtures thereof; [ka] (In the formula: X 1c -S-; -O- and -NR 5c Selected from; R 1c is amino-C 1-6 Alkyl; C 1-6 Alkylamino C 1-6 Alkyl; Di-C 1-6 Alkylamine No.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 wherein heterocycloalkyl is one, two, or three hetero atoms selected from O, N, and S; and wherein nine Roarke Lu is , Haro, C 1-6 alkyl, -OH, or Optionally substituted with =O; R 2c , R 3c , and R 4care independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; Each R ac are, if present, independently -F; -Cl; -Br; -I; -OH; -NH; and C 1-6 Arco selected from: R 5c is independently at each occurrence hydrogen; and C 1-6 alkyl; L is a linker; BA is a binder; and The subscript n is an integer from 1 to 30.

[0289] Provided herein are any of the compounds described herein and having the structure of formula (7002): Antibody-drug conjugates of rifamycin analogs: or pharmaceutically acceptable salts thereof, solvates, stereoisomeric forms, or positional isomers thereof, or mixtures thereof; [ka] (Wherein, BA, RG 1 , SP 1 , A.A. 1 , A.A. 2 , R 1c , R bc , R ac , X 1c , R 2c , R 3c , R 4c , and n are In some or any embodiments, as defined herein).

[0290] Provided herein are antibody-rifamycin analog complexes having the structure of formula (7003): or a pharmaceutically acceptable salt, solvate, stereoisomeric form thereof, or or a mixture thereof; [ka] (In the formula: X 1c is selected from -S-; -O-; and c; R 1c teeth, [ka] where Y is C or N; R 2c , R 3c , and R 4c are independently hydrogen, C 1-6 Alkyl, and -(C=O)-R 5c Selected from; R 5c is, independently at each occurrence, absent or hydrogen; and C 1-6 Selected from alkyl Re; each AA is an independently selected amino acid; SP 1 is absent or a spacer; RG 1 is a reactive group residue; BA is an anti-MSR1 antibody or an antigen-binding fragment thereof; The subscript n is an integer from 1 to 30; The subscript w is 2, 3, or 4; where R 1c is a wavy line [ka] (which is attached to the linker via a nitrogen atom indicated by

[0291] In various embodiments of formula (7003), SP 1 , R.G. 1 , and AA are some and / or any In certain embodiments of, as defined herein.

[0292] In some embodiments of Formula (7003), X 1cis O. Some embodiments of formula (7003) In your opinion, X 1c is S. In some embodiments of Formula (7003), X 1c teeth C The formula is In some embodiments of (7003), X 1c is NR 5c is.

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

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

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

[0296] In some embodiments of Formula (7003), SP 1 teeth, [ka] In some embodiments of Formula (7003), SP 1 teeth, [ka] Includes:

[0297] In some embodiments of Formula (7003), RG 1 teeth, [ka] Includes:

[0298] In some embodiments of Formula (7003), X 1c is O; R 1c teeth, [ka] where Y is C or N; where R 1c is R 1c via the quaternary nitrogen atom of phosphorus It is bound to the KA; R 5c is C 1-6 alkyl; and R 6c is the counter ion.

[0299] In some such embodiments, R 1c teeth, [ka] In some such embodiments, R 1c teeth, [ka] In some such embodiments, R 1c teeth, [ka] In some such embodiments, R 6c I - , Cl - , or Br - And In some examples, R 6c I - is.

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

[0301] [ka] In some embodiments of Formula (7003), the rifamycin analog is: [ka] is.

[0302] Further provided herein are rifamycin compounds according to formula (7004) (e.g., rifamycin and fampicin): [ka] .

[0303] Further provided herein are rifamycin compounds according to formula (7005) (e.g., rifamycin and fampicin): [ka] wherein L and BA are, in some or any embodiment, as defined herein. (This is the street.)

[0304] In some examples, the compounds of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (70 The ADCs of (7001), (7002), (7003), (7004), and / or (7005) are listed in Table 2 and / or in the Examples section. It is an ADC that is used.

[0305] Also included in these examples of ADCs are pharmaceutically acceptable salts, solvates, and steric forms thereof. isomeric forms, positional isomers thereof, or mixtures of positional isomers thereof, wherein each [ka] is the bond with the binder; and each [ka] is the binding with the payload.

[0306] In certain embodiments, provided herein are anti-MSR1 antibodies disclosed herein. or an antigen-binding fragment thereof, or a PEG-modified anti-MSR1 antibody or an antigen-binding fragment thereof and an ADC comprising a linker-payload (LP) selected from the group consisting of: is a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof.

[0307] Also provided herein are anti-MSR1 antibodies conjugated to one or more radionuclides. In the context of this aspect of the disclosure, the antibody-radionuclide conjugate (ARC) comprises Exemplary radionuclides that can be used include, for example, 225 Ac, 212 Bi, 213 Bi, 1 31 I, 186 Re, 227 Th, 222 Rn, 223 Ra, 224 Ra, and 90 These include, but are not limited to, Y. do not have. Table 1: List of ADCs and their structures [Table 3] TIFF0007824992000298.tif207170TIFF0007824992000299.tif219170TIFF0007824992000300.tif244170TIFF0007824992 000301.tif241170TIFF0007824992000302.tif243170TIFF0007824992000303.tif233170TIFF0007824992000304.tif43170

[0308] In the ADCs of Table 1, Ab is an anti-MSR1 antibody or antigen-binding fragment thereof provided herein. In certain embodiments, the Ab has a PEG group on the glutamine side chain described herein. [ka] (referred to herein as a PEG-modified antibody). In one embodiment, PEG The group terminates in an azide group and can be a linker-payload as described herein (e.g., Table 3 and In some embodiments, the linker (or payload) is reacted with the hydroxyl group to form a linker payload. The PEG group may be attached to the phosphorus via a triazole or triazole derivative as described herein. In the ADC, n is an integer between 1 and 10, for example, 1, 2, 3, or is 4. In the PEG group, nn is an integer from 1 to 10, for example, 1, 2, 3, 4, or 5. In one embodiment, each BA in the ADC of Table 1 is [ka] where Ab 1 is an anti-MSR1 antibody or an antigen-binding fragment thereof; R is C 2-4 -Archile and nn is an integer selected from 2 to 4, and each n is an integer from 1 to 10. , for example, 1, 2, 3, or 4.

[0309] In some embodiments, provided herein are antibodies and antibodies disclosed herein. an ADC comprising a linker-payload (LP) selected from the group consisting of: or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof . Table 2: List of ADCs and their structures [Table 4] TIFF0007824992000308.tif214170TIFF0007824992000309.tif201170TIFF0007824992000310.tif211170TIF F0007824992000311.tif213170TIFF0007824992000312.tif226170TIFF0007824992000313.tif239170TIFF000 7824992000314.tif244170TIFF0007824992000315.tif207170TIFF0007824992000316.tif231170TIFF0007824 992000317.tif207170TIFF0007824992000318.tif213170TIFF0007824992000319.tif194170TIFF00078249920 00320.tif198170TIFF0007824992000321.tif183170TIFF0007824992000322.tif228170TIFF00078249920003 23.tif237170TIFF0007824992000324.tif241170TIFF0007824992000325.tif241170TIFF0007824992000326.t if183170TIFF0007824992000327.tif176170TIFF0007824992000328.tif181170TIFF0007824992000329.tif23 0170TIFF0007824992000330.tif229170TIFF0007824992000331.tif244170TIFF0007824992000332.tif167170

[0310] In the ADCs of Table 2, Ab is an anti-MSR1 antibody or antigen-binding fragment thereof provided herein. In certain embodiments, the Ab is a PEG group on a glutamine side chain as described herein. In the ADC, n is an integer from 1 to 10, for example, 1, 2, 3, or 4.

[0311] Provided herein are payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0312] Provided herein are six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, L) of Table 4. CDR1, LCDR2, LCDR3) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is an acceptable salt, solvate, or stereoisomeric form of The anti-MSR1 antibody or its antigen-binding fragment has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3) shown in Table 4. It contains a set of LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0313] Provided herein are heavy chain complementarity determining regions (HCDR)-1 comprising SEQ ID NO: 52; SEQ ID NO: 5 HCDR2 comprising SEQ ID NO: 4; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; LCDR2 comprising sequence number 62; and LCDR3 comprising sequence number 64, and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR) comprising SEQ ID NO: 60 -1; LCDR2 comprising SEQ ID NO: 62; and LCDR3 comprising SEQ ID NO: 64, and the N297Q mutation.

[0314] Provided herein are sets of heavy chain variable regions (HCVRs) and light chain variable regions (HCVRs) that are the variable regions of Table 4. Contains a set of variable regions (LCVRs) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof has a set of heavy chain variable regions (HCVRs) and a light chain variable region (LCVR) shown in Table 4. It contains a set of chain variable regions (LCVRs) and the N297Q mutation.

[0315] Provided herein is a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (HCVR) of SEQ ID NO: 58. Contains a chain variable region (LCVR) and a payload [ka] Conjugated to Anti-MSR1 antibody or its antigen-binding fragment, or a pharmaceutically acceptable salt, solvate, or In some embodiments, the anti-MSR1 antibody or its antigen-binding The fragment comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58, as well as and N297Q mutation.

[0316] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug-antibody ratio (DAR) is 1 to 4. In some embodiments, the DAR is 1 or In some embodiments, the DAR is 2. In some embodiments, the DAR is In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. , the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0317] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2) in Table 4. An anti-MSR1 antibody or antigen-binding fragment thereof comprises a set of MSR1, LCDR2, LCDR3). In some, 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 R is 3. In some embodiments, DAR is 4. In some embodiments, The anti-MSR1 antibody or antigen-binding fragment thereof has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, It contains a set of HCDR3, LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0318] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; a heavy chain complementarity determining region (HCDR)-2 ​​comprising SEQ ID NO: 54; R2; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; and an LCDR3 comprising SEQ ID NO: 64. In some such 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 antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 52. Complementarity determining region (HCDR)-1; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising: an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. as well as the N297Q mutation.

[0319] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] Here, the antibody has a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) that are variable regions in Table 4. ) and the like. In some 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-MS The R1 antibody or its antigen-binding fragment has a set of heavy chain variable regions (HCVRs) and a set of light chain variable regions (HCVRs) which are variable regions in Table 4. It contains a set of variable regions (LCVRs) as well as the N297Q mutation.

[0320] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region of SEQ ID NO: 58 (LCVR). In some 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-MS The R1 antibody or antigen-binding fragment thereof has a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a heavy chain variable region (HCVR) comprising SEQ ID NO: 58. It contains the light chain variable region (LCVR), as well as the N297Q mutation.

[0321] Provided herein are payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof conjugated to In some embodiments, the anti-MS The R1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0322] Provided herein are six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, L) of Table 4. CDR1, LCDR2, LCDR3) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or its antigen-binding fragment has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3) shown in Table 4. 3, LCDR1, LCDR2, LCDR3) set and N297Q mutation.

[0323] Provided herein are heavy chain complementarity determining regions (HCDR)-1 comprising SEQ ID NO: 52; SEQ ID NO: 5 HCDR2 comprising SEQ ID NO: 4; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; LCDR2 comprising sequence number 62; and LCDR3 comprising sequence number 64, and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR) comprising SEQ ID NO: 60 -1; LCDR2 comprising SEQ ID NO: 62; and LCDR3 comprising SEQ ID NO: 64, and the N297Q mutation.

[0324] Provided herein are sets of heavy chain variable regions (HCVRs) and light chain variable regions (HCVRs) that are the variable regions of Table 4. Contains a set of variable regions (LCVRs) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof has a set of heavy chain variable regions (HCVRs) and a light chain variable region (LCVR) shown in Table 4. It contains a set of chain variable regions (LCVRs) and the N297Q mutation.

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

[0326] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug-antibody ratio (DAR) is 1 to 4. In some embodiments, the DAR is 1 or In some embodiments, the DAR is 2. In some embodiments, the DAR is In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. , the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0327] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2) in Table 4. An anti-MSR1 antibody or antigen-binding fragment thereof comprises a set of MSR1, LCDR2, LCDR3). In some, 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 R is 3. In some embodiments, DAR is 4. In some embodiments, The anti-MSR1 antibody or antigen-binding fragment thereof has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, It contains a set of HCDR3, LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0328] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; a heavy chain complementarity determining region (HCDR)-2 ​​comprising SEQ ID NO: 54; R2; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; and an LCDR3 comprising SEQ ID NO: 64. In some such 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 antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 52. Complementarity determining region (HCDR)-1; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising: an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. as well as the N297Q mutation.

[0329] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] Here, the antibody has a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) that are variable regions in Table 4. ) and the like. In some 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-MS The R1 antibody or its antigen-binding fragment has a set of heavy chain variable regions (HCVRs) and a set of light chain variable regions (LCVRs) shown in Table 4. It contains a set of variable regions (LCVRs) as well as the N297Q mutation.

[0330] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region of SEQ ID NO: 58 (LCVR). In some 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-MS The R1 antibody or antigen-binding fragment thereof has a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a heavy chain variable region (HCVR) comprising SEQ ID NO: 58. It contains the light chain variable region (LCVR), as well as the N297Q mutation.

[0331] Provided herein are payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0332] Provided herein are six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, L) of Table 4. CDR1, LCDR2, LCDR3) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or its antigen-binding fragment has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3) shown in Table 4. 3, LCDR1, LCDR2, LCDR3) set and N297Q mutation.

[0333] Provided herein are heavy chain complementarity determining regions (HCDR)-1 comprising SEQ ID NO: 52; SEQ ID NO: 5 HCDR2 comprising SEQ ID NO: 4; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; LCDR2 comprising sequence number 62; and LCDR3 comprising sequence number 64, and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR) comprising SEQ ID NO: 60 -1; LCDR2 comprising SEQ ID NO: 62; and LCDR3 comprising SEQ ID NO: 64, and the N297Q mutation.

[0334] Provided herein are sets of heavy chain variable regions (HCVRs) and light chain variable regions (HCVRs) that are the variable regions of Table 4. Contains a set of variable regions (LCVRs) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof has a set of heavy chain variable regions (HCVRs) and a light chain variable region (LCVR) shown in Table 4. It contains a set of chain variable regions (LCVRs) and the N297Q mutation.

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

[0336] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody is an anti-MSR1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug-antibody ratio (DAR) is 1 to 4. In some embodiments, the DAR is 1 or In some embodiments, the DAR is 2. In some embodiments, the DAR is In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. , the anti-MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0337] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2) in Table 4. An anti-MSR1 antibody or antigen-binding fragment thereof comprises a set of MSR1, LCDR2, LCDR3). In some, 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 R is 3. In some embodiments, DAR is 4. In some embodiments, The anti-MSR1 antibody or antigen-binding fragment thereof has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, It contains a set of HCDR3, LCDR1, LCDR2, LCDR3) and the N297Q mutation.

[0338] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; a heavy chain complementarity determining region (HCDR)-2 ​​comprising SEQ ID NO: 54; R2; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; and an LCDR3 comprising SEQ ID NO: 64. In some such 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 antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 52. Complementarity determining region (HCDR)-1; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; a light chain complementarity determining region (LCDR)-1 comprising: an LCDR2 comprising SEQ ID NO: 62; and an LCDR3 comprising SEQ ID NO: 64. as well as the N297Q mutation.

[0339] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] Here, the antibody has a set of heavy chain variable regions (HCVR) and a set of light chain variable regions (LCVR) that are variable regions in Table 4. ) and the like. In some 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-MS The R1 antibody or its antigen-binding fragment has a set of heavy chain variable regions (HCVRs) and a set of light chain variable regions (LCVRs) shown in Table 4. It contains a set of variable regions (LCVRs) as well as the N297Q mutation.

[0340] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] wherein the antibody comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region of SEQ ID NO: 58 (LCVR). In some 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-MS The R1 antibody or antigen-binding fragment thereof has a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a heavy chain variable region (HCVR) comprising SEQ ID NO: 58. It contains the light chain variable region (LCVR), as well as the N297Q mutation.

[0341] Provided herein are payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises an N297Q mutation.

[0342] Provided herein are six complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, L) of Table 4. CDR1, LCDR2, LCDR3) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or its antigen-binding fragment has six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3) shown in Table 4. 3, LCDR1, LCDR2, LCDR3) set and N297Q mutation.

[0343] Provided herein are heavy chain complementarity determining regions (HCDR)-1 comprising SEQ ID NO: 52; SEQ ID NO: 5 HCDR2 comprising SEQ ID NO: 4; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; LCDR2 comprising sequence number 62; and LCDR3 comprising sequence number 64, and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (LCDR) comprising SEQ ID NO: 60 -1; LCDR2 comprising SEQ ID NO: 62; and LCDR3 comprising SEQ ID NO: 64, and the N297Q mutation.

[0344] Provided herein are sets of heavy chain variable regions (HCVRs) and light chain variable regions (HCVRs) that are the variable regions of Table 4. Contains a set of variable regions (LCVRs) and a payload [ka] an anti-MSR1 antibody or an antigen-binding fragment thereof, or a pharmaceutically acceptable salt thereof, conjugated to In some embodiments, the compound is a salt, solvate, or stereoisomeric form of the compound. The MSR1 antibody or antigen-binding fragment thereof has a set of heavy chain variable regions (HCVRs) and a light chain variable region (LCVR) shown in Table 4. It contains a set of chain variable regions (LCVRs) and the N297Q mutation.

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

[0346] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] where X - is a pharmaceutically acceptable counterion, and wherein the antibody is an anti-MSR1 antibody. In some such embodiments, the drug-antibody ratio (D In some embodiments, DAR is 1. In some embodiments, 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 The fragment contains the N297Q mutation.

[0347] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] where X - is a pharmaceutically acceptable counterion, and wherein the antibody is one of the six antibodies of Table 4. Anti-MSR1 antibody containing a set of complementarity determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) In some such embodiments, the drug-antibody ratio is (DAR) is 1 to 4. In some embodiments, 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 The fusion fragments consist of six complementarity-determining regions (CDRs) (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3) in Table 4. ) and the N297Q mutation.

[0348] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] where X - is a pharmaceutically acceptable counterion, and wherein the antibody is heavy chain complementarity determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; Light chain complementarity determining region (LCDR)-1 comprising SEQ ID NO: 60; LCDR2 comprising SEQ ID NO: 62; and SEQ ID NO: 64 In some such embodiments, the anti-MSR1 antibody or antigen-binding fragment thereof comprises an LCDR3 comprising: In some, 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 R is 3. In some embodiments, DAR is 4. In some embodiments, , the anti-MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity-determining region (HCDR)-1 comprising SEQ ID NO: 52; HCDR2 comprising SEQ ID NO: 54; HCDR3 comprising SEQ ID NO: 56; light chain complementarity determining region (L) comprising SEQ ID NO: 60 CDR)-1; LCDR2 comprising SEQ ID NO: 62; and LCDR3 comprising SEQ ID NO: 64, and comprising the N297Q mutation. nothing.

[0349] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] where X - is a pharmaceutically acceptable counterion, and wherein the antibody is an anti-MSR1 antibody or a combination thereof, each of which comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), is an antigen-binding fragment thereof. In some such embodiments, the drug-antibody ratio (DAR) is 1 to 4. In some embodiments, DAR is 1. In some embodiments, In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody or antigen-binding fragment thereof represents a set of heavy chain variable regions (HCVRs) and a set of light chain variable regions (LCVRs) that are variable regions in Table 4, and N Contains the 297Q mutation.

[0350] An antibody-drug conjugate (ADC) according to the formula: any substance, stereoisomeric form, or positional isomer, or mixture thereof; [ka] where X - is a pharmaceutically acceptable counterion, and wherein the antibody is an anti-MSR1 antibody or a light chain variable region (LCVR) comprising a heavy chain variable region (HCVR) comprising SEQ ID NO: 50 and a light chain variable region (LCVR) of SEQ ID NO: 58; is an antigen-binding fragment thereof. In some such embodiments, the drug-antibody ratio (DAR) is 1 to 4. In some embodiments, DAR is 1. In some embodiments, In some embodiments, the DAR is 2. In some embodiments, the DAR is 3. In some embodiments, the DAR is 4. In some embodiments, the anti-MSR1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 50; a light chain variable region (LCVR) of SEQ ID NO: 58; and N297Q Including mutations.

[0351] As used herein, in certain embodiments, an amino acid is a nucleotide, e.g., a nucleotide, such as the moiety -SP 1 -A A 1 -AA 2 -Middle spacer SP 1 When bound to the amino acid AA 1 through its amino group , Spacer SP 1 The spacer residue binds to the amino group in the amino acid. By way of example only, the following structure: [ka] In the example, the valine residue is SP as shown. 1 binds to SP 1 The residues in this example are , (C=O) moiety. Also, in this example, SP 1 The residue is used to form a bond with the reactive group. containing suitable functional groups and SP 1 The residue contains an -NH- moiety. Those skilled in the art will appreciate the similar classifications described herein. It will be appreciated that the same may be applied to all other formulas described in the document.

[0352] The antibody drug conjugates described herein can be prepared using any conjugation method known to those skilled in the art. can be prepared using conditions (see, for example, (See Doronina et al., Nature Biotechnology 2003, 21, 7, 778). In some embodiments, the ADC comprises an anti-MSR1 antibody or antigen-binding fragment thereof coupled to a desired linker and payload. The linker is prepared by reacting the antibody or antibody-containing compound with the a portion that reacts with the original binding protein, e.g., at a desired residue of the antibody or antigen binding protein; Exemplary conditions are described in the Examples below.

[0353] (Preparation of antibody-drug conjugates) In some embodiments, provided herein are antibody-drug conjugates A process for preparing an anti-MSR1 antibody or a PEG-modified anti-MSR1 antibody or an antigen-binding The fragment is joined with a linker-payload or linker-spacer-payload selected from Table 3. Also provided herein is a process for producing an anti-MSR1 antibody or or a PEG-modified anti-MSR1 antibody or antigen-binding fragment thereof, with a linker payload or antibody drug prepared by conjugating with a linker-spacer-payload Conjugates or stereoisomeric forms thereof or positional isomers thereof or positional isomers thereof It is a mixture of Table 3: List of linker-payload (LP) and their structures [Table 5] TIFF0007824992000375.tif216170TIFF0007824992000376.tif218170TIFF0007824992000377.tif210170TIFF000 7824992000378.tif216170TIFF0007824992000379.tif238170TIFF0007824992000380.tif244170TIFF00078249920 00381.tif223170TIFF0007824992000382.tif233170TIFF0007824992000383.tif185170TIFF0007824992000384.t if228170TIFF0007824992000385.tif221170TIFF0007824992000386.tif234170TIFF0007824992000387.tif211170

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

[0355] Also provided herein are rifamycin analogues (e.g., rifampicin) and their anti-inflammatory properties. A method for preparing an antibody-drug conjugate, comprising: A linker payload according to formula (D): [ka] and under conditions suitable for forming a bond between the anti-MSR1 antibody or antigen-binding fragment thereof. The method includes the step of:

[0356] (Epitope mapping and related techniques) The epitopes to which the antibodies of the present invention bind may be three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) amino acids Alternatively, the epitope may consist of multiple discontinuous sequences of MSR1. In some embodiments, the epitope can consist of an amino acid (or amino acid sequence). In another embodiment, the epitope is located at or near the modified LDL-binding domain of MSR1. The epitope may be located outside the modified LDL-binding domain of MSR1, for example, so that the antibody can target such an epitope. It is located on the surface of MSR1 at a position that, when bound to the peptide, does not interfere with the binding of modified LDL to MSR1. Place.

[0357] Antibodies can be generated using a variety of techniques known to those skilled in the art to identify "one or more" polypeptides or proteins. Exemplary techniques include: For example, routine cross-blocking assays, e.g., Harlow and Lane, Antibodies s) (Cold Spring Harbor Press, Cold Spring Harb., NY), Scanning mutation analysis, peptide blot analysis (Reineke, 2004, Methods Mo Biol 248:443-463) and peptide cleavage analysis. Methods such as excision, epitope extraction, and chemical modification are available (Tomer et al., 2004). (2000, Protein Science 9:487-496). Amino acids in the polypeptide with which the antibody interacts. Another method that can be used to identify the Generally, the hydrogen / deuterium exchange method is performed by This involves deuterium-labeling a protein and then binding an antibody to the deuterium-labeled protein. , the protein / antibody complex is transferred to water to isolate the residues protected by the antibody (deuterium-labeled After antibody dissociation, the target protein undergoes hydrogen-deuterium exchange at all residues except the target protein (which remains the same). The protein was subjected to protease cleavage and mass spectrometry analysis, whereby the antibody Identify deuterium-labeled residues corresponding to specific interacting amino acids. For example, Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) See Anal. Chem. 73:256A-265A.

[0358] In embodiments, specific exemplary antibodies described herein (e.g., those listed in Table 4 herein) are included. Antibody containing any of the amino acid sequences shown Similarly, embodiments include antibodies that bind to MSR1, such as those described herein.

[0033] Different exemplary antibodies (e.g., antibodies comprising any of the amino acid sequences shown in Table 4 herein) are also suitable. Also included are anti-MSR1 antibodies that compete with either the MSR1 antibody or the MSR1 antibody.

[0359] Routine methods known in the art and exemplified herein, e.g., in Example 7, are also known. By using the method, it is possible to determine whether the antibody binds to the same epitope as the reference anti-MSR1 antibody. It can be readily determined whether the antibody competes for binding with the target or reference anti-MSR1 antibody. For example, whether the test antibody binds to the same epitope as the reference anti-MSR1 antibody disclosed herein. The reference antibody is then allowed to bind to the MSR1 protein to determine whether the test antibody binds to the MSR1 protein. The ability of the test antibody to bind to the MSR1 molecule is evaluated. After saturation binding with the reference anti-MSR1 antibody, If the test antibody can bind to a different epitope than the reference anti-MSR1 antibody, On the other hand, it can be concluded that after saturation binding with the reference anti-MSR1 antibody, the test antibody binds to the MSR1 molecule. If the test antibody is unable to bind to the antibody, then the test antibody is not bound by the reference anti-MSR1 antibody of the present invention. The antibody can then bind to the same epitope as the one being tested. Experiments (e.g., peptide mutagenesis and binding analysis) are performed to determine the observed binding of the test antibody. Whether the lack is in fact due to binding to the same epitope as the reference antibody or not To determine whether body block (or another phenomenon) is responsible for the observed lack of binding. This type of experiment can be performed using ELISA, RIA, Biacore, flow cytometry, and other methods available in the art. This can be performed using immunohistochemistry, immunohistochemistry, immunohistochemistry, immunohistochemistry, immunohistochemistry - cy ... In some embodiments of the present invention, for example, when measured in a competitive binding assay, , 1, 5, 10, 20, or 100-fold excess of one antibody inhibits binding of the other by at least 50%, However, preferably, two antibodies are considered to be identical ( or overlapping) epitopes (see, e.g., Junghans et al., Cancer Res. 1990:50: Alternatively, essentially all of the antigen may be present, reducing or eliminating binding of one antibody. Two antibodies may be considered to have the same binding if all amino acid mutations reduce or eliminate binding of the other. The amino acid sequence that reduces or eliminates binding of one antibody to the other is considered to bind to the epitope. Two antibodies are considered "antibodies" if only a subset of the natural mutations reduces or abolishes binding of the other. These are considered to have "overlapping epitopes."

[0360] Whether the antibody competes for binding (or cross-competes for binding) with a reference anti-MSR1 antibody To determine whether the binding method is effective, the above binding method is performed in two directions. In the first direction, the reference The antibody is allowed to bind to the MSR1 protein under saturating conditions, and then the binding of the test antibody to the MSR1 molecule is measured. In the second orientation, the test antibody is allowed to bind to the MSR1 molecule under saturating conditions, and then Binding of the reference antibody to the MSR1 molecule is assessed. In both directions, the first (saturating) antibody binds to the MSR1 molecule. If the test antibody and reference antibody are able to bind to the molecule, they compete for binding to MSR1. As will be understood by those skilled in the art, the binding of a specific antibody to a reference antibody can be determined by the following equation: The antibody that binds to the reference antibody may not necessarily be able to bind to the same epitope as the reference antibody. sterically blocking the binding of a reference antibody by binding to overlapping or adjacent epitopes. It is possible.

[0361] (Preparation of human antibodies) The anti-MSR1 antibodies disclosed herein can be fully human antibodies. Methods for producing monoclonal antibodies, including clonal antibodies, are known in the art. Any such known method may be used in the context of the present invention to produce a human MSR1-specific antibody. Human antibodies can be generated that bind to

[0362] For example, VELOCIMMUNE™ technology, or for generating fully human monoclonal antibodies Any other similar known method can be used to construct MSR1 with human variable regions and mouse constant regions. High affinity chimeric antibodies against the IgG1 gene are first isolated. As seen in the experimental section below, the antibodies are specifically Characterization is performed to identify desired characteristics, including affinity, ligand blocking activity, selectivity, epitope, etc. If necessary, the mouse constant region is replaced with a desired human constant region, e.g., wild-type or The constant region is replaced with a modified IgG1 or IgG4 to generate a fully human anti-MSR1 antibody. Although this may vary depending on the specific application, high affinity antigen binding and target specificity characteristics reside in the variable region. In some instances, fully human anti-MSR1 antibodies are isolated directly from antigen-positive B cells.

[0363] (biological equivalent) The anti-MSR1 antibodies and antibody fragments disclosed herein may be prepared by combining the amino acid sequences of the described antibodies with the It includes proteins with amino acid sequences that differ from those of human MSR1 but retain the ability to bind to human MSR1. Such variant antibodies and antibody fragments may have one or more amino acid substitutions when compared to the parent sequence. and the like, but which have essentially equivalent biological activity to the described antibodies. Similarly, the DNA sequences encoding the anti-MSR1 antibodies disclosed herein are Contains one or more additions, deletions, or substitutions of nucleotides when compared to the sequence shown. is an anti-MSR1 antibody or antibody fragment essentially biologically equivalent to the anti-MSR1 antibody or antibody fragment disclosed herein. Such variant amino acid and DNA sequences include sequences encoding the R1 antibody or antibody fragment. Examples of columns are discussed above.

[0364] For example, two antigen binding proteins or antibodies may have similar rates and extents of absorption. Under experimental conditions, significant differences were observed when administered at the same molar dose, either in single or multiple doses. If there are no differences between the two pharmaceutical equivalents or substitutes, they are considered to be bioequivalent. Some antibodies have equivalent levels of absorption, but not equivalent rates of absorption. If not, they are considered equivalents or pharmaceutical substitutes and are considered bioequivalent. Because such differences in absorption rates are intentional and not contrary to labeling, are not essential for achieving effective drug concentrations in the body during long-term use. and is not considered medically significant for the particular drug being tested.

[0365] In one embodiment, the two antigen binding proteins are identical in terms of safety, purity, and potency. If there are no clinically significant differences in

[0366] In one embodiment, continuous therapy without one or more switches between the reference product and the biological product is administered. The risk of adverse effects, including clinically significant changes in immunogenicity or reduced efficacy, compared with the It may be possible to allow patients to make such a switch without a predicted increase in risk. In this case, the two antigen-binding proteins are biologically equivalent.

[0367] In one embodiment, the two antigen binding proteins are To the extent that mechanisms are known, identify a common mechanism(s) of action for the condition(s) of use. They are bioequivalent if they act by one or more of the following:

[0368] Bioequivalence can be demonstrated by in vivo and in vitro methods. Examples of measures of therapeutic equivalence include: (a) the concentration of an antibody or its metabolite in blood, plasma, or serum; In humans or other mammals, measured as a function of time in erythrocytes, erythrocytes, or other biological fluids. (b) in vivo studies that correlate with and support human in vivo bioavailability data; (c) in vitro tests that reasonably predict the appropriate acute pharmacological effect of the antibody (or its target) over time; (d) in vivo testing in humans or other mammals, measured as a function of antibody safety. well-controlled studies to establish efficacy, bioavailability or bioequivalence Clinical trials include:

[0369] Biologically equivalent variants of the anti-MSR1 antibodies disclosed herein include, for example, variants of the residues or Various substitutions of the sequence may be made, or terminal or internal residues or residues not required for biological activity may be omitted. can be constructed by deleting sequences, e.g., sequences that are not essential for biological activity. Cysteine ​​residues are deleted or replaced with other amino acids to eliminate unnecessary or incorrect amino acids during refolding. This prevents the formation of accurate intramolecular disulfide bridges. Antibodies equivalent to the present invention may also include amino acid changes that modify the glycosylation characteristics of the antibody, e.g., glycosylation The antibody may include an anti-MSR1 antibody variant containing a mutation that abolishes or eliminates the activity of MSR1.

[0370] (Species selectivity and species cross-reactivity) In some embodiments, provided herein are antibodies that bind to human MSR1 but not to other species-derived antibodies. In some embodiments, the antibody binds to human MSR1 and one or more non-human species. Also included are anti-MSR1 antibodies that bind to MSR1 derived from the MSR1. For example, the anti-MSR1 antibodies disclosed herein can bind to human MSR1, and optionally to mouse, rat, guinea pig, hamster Tar, gerbil, pig, cat, dog, rabbit, goat, sheep, cow, horse, camel, macaque, marmoset, rhesus monkey, or chimpanzee MSR1 According to an exemplary embodiment, human MSR1 and macaque Anti-MSR1 antibodies that specifically bind to monkey (e.g., cynomolgus monkey (Macaca fascicularis)) MSR1 Other anti-MSR1 antibodies disclosed herein bind to human MSR1 but do not bind to macaque MSR1. It does not bind or only weakly binds to monkey MSR1.

[0371] (multispecific antibody) The antibodies disclosed herein may be monospecific or multispecific (e.g., bispecific). Multispecific antibodies can be specific for different epitopes of a single target polypeptide. or may contain antigen-binding domains specific for multiple target polypeptides. See, e.g., Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004 See, Trends Biotechnol. 22:238-244. The anti-MSR1 antibodies disclosed herein are , linked to or combined with another functional molecule, for example, another peptide or protein. For example, antibodies or fragments thereof can be co-expressed (e.g., by chemical coupling). , genetic fusion, non-covalent association, or otherwise) to one or more other molecular entities, e.g., Bispecific or antibody fragments operably linked to another antibody or antibody fragment with a second binding specificity Multispecific antibodies can be produced.

[0372] In one embodiment, one arm of the immunoglobulin binds to human MSR1, and the other arm of the immunoglobulin binds to human MSR1. The other arm is specific for a second antigen. The amino acid sequence may comprise any of the HCVR / LCVR or CDR amino acid sequences shown in Table 4 herein. In one embodiment, the MSR1-binding arm binds to human MSR1 and can bind to MSR1. In another embodiment, the MSR1-binding arm binds to human MSR1 and blocks modified LDL binding. In some embodiments, the modified LDL binds to MSR1 but does not block the binding of the modified LDL to MSR1. The arm binds to human MSR1 and activates MSR1 signaling. The MSR1-binding arm blocks MSR1-mediated receptor stimulation. The antibody binds to a first epitope of human MSR1, and the other arm of the antibody binds to a second epitope of human MSR1. Also included are bispecific antibodies that bind to different epitopes.

[0373] Exemplary bispecific antibody formats that can be used in the context of the present invention are , the first immunoglobulin (Ig) C H 3 domain and second Ig C H 3 domains, including the use of and the first and second Ig C H The three domains differ from each other by at least one amino acid, and wherein at least one amino acid difference is present in a bispecific antibody compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the binding of the bispecific antibody to Protein A is reduced when compared to that of the bispecific antibody to Protein A. The first Ig C H The 3 domain binds to protein A and the second Ig C H 3 domains are pro Mutations that reduce or eliminate tein A binding, such as the H95R modification (according to the IMGT exon numbering) ; H435R according to EU numbering). H 3 is Y96F modified (according to IMGT; according to EU , Y436F). HFurther modifications that may be found within 3 include: For IgG1 antibodies, D16E, L18M, N44S, K52N, V57M, and V82I (according to IMGT; D3 according to EU) 56E, L358M, N384S, K392N, V397M, and V422I for IgG2 antibodies; N44S, K52N, and V82 I (IMGT; N384S, K392N, and V422I according to EU); and for IgG4 antibodies, Q15R, N44S, K52 N, V57M, R69K, E79Q, and V82I (according to IMGT; Q355R, N384S, K392N, V397M, according to EU) R409K, E419Q, and V422I). Relations are contemplated within the scope of the present invention.

[0374] Other exemplary bispecific formats that can be used in the context of the present invention include: Examples include, but are not limited to, scFv-based or diabody bispecific formats. IgG-scFv fusion, dual variable domain (DVD)-Ig, quadroma, knob-in knobs-into-holes, common light chain (e.g., with knobs-into-holes) Common light chain, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, duobody ( Duobody), IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab 2 Bispecific format (see above) For a review of formats, see, e.g., Klein et al., 2012, mAbs 4:6, 1-11, and (See references cited therein). Bispecific antibodies include, for example: Unnatural amino acids with orthogonal chemical reactivity are used to create compounds with defined composition, valence, and Site-specific antibody-oligonucleotide complexes that subsequently self-assemble into shape-defining multimeric complexes They can also be constructed using peptide / nucleic acid conjugation to generate conjugates. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0375] Therapeutic Formulations and Administration Embodiments include pharmaceutical compositions comprising the anti-MSR1 antibodies or antigen-binding fragments thereof disclosed herein. The pharmaceutical composition of the present invention is a suitable compound that provides improved transfer, delivery, tolerability, etc. They are formulated with carriers, excipients, and other drugs. Many suitable formulations are available to every pharmacist. Known Formularies: Remington's Pharmaceutical Sciences, Mack Pub These formulations can be found at the Liquor Company, Easton, PA. For example, powders, pastes, ointments, gels, waxes, oils, lipids, lipids (cationic or anionic) ionic)-containing vesicles (e.g., LIPOFECTIN™, Life Technologies, Carlsbad, CA), DNA Conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, Carbowak emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and carbon dioxide. Powell et al., "Excipients for Parenteral Formulations," "Compendium of excipients for parenteral formulations," PDA literature (19 98) See also J Pharm Sci Technol 52:238-311.

[0376] The dose of antibody administered to a patient depends on factors such as the age and size of the patient, the target disease, condition, and route of administration. The preferred dose is usually calculated according to body weight or body surface area. In adult patients, the antibody of the present invention is typically administered at a dose of about 0.01 to about 20 mg / kg body weight, more preferably Intravenously administered at a single dose of 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 disease, the frequency and duration of treatment can be adjusted. The effective dosage and schedule for administering the anti-MSR1 antibody can be experimentally determined. for example, by monitoring the patient's progress through regular assessments and adjusting the dose accordingly. Additionally, interspecies scaling of dosages can be performed using methods well known in the art. (See, e.g., Mordenti et al., 1991, Pharmaceut. Res. 8: 1351).

[0377] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions disclosed herein. The delivery system can include, for example, encapsulation in liposomes, microparticles, and microcapsules. Recombinant cells capable of expressing mutant viruses enter the host through receptor-mediated endocytic pathways. (e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432). These include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, including, but not limited to, , by infusion or bolus injection, into epithelial or mucocutaneous layers (e.g., oral mucosa, rectum, and can be administered by absorption through the intestinal mucosa and in combination with other biologically active agents Administration can be systemic or local.

[0378] The pharmaceutical compositions disclosed herein can be delivered subcutaneously or intravenously with a standard needle and syringe. Additionally, for subcutaneous delivery, a pen delivery device may be used to deliver the pharmaceutical compositions of the present invention. Such pen delivery devices may be reusable or disposable. Reusable pen delivery devices typically include a replaceable cartridge containing the pharmaceutical composition. The cartridge is emptied after the pharmaceutical composition in the cartridge is completely administered. Once this occurs, immediately discard the empty cartridge and replace it with a new one containing the pharmaceutical composition. The pen delivery device can then be reused. The pen delivery device does not have a replaceable cartridge. Rather, it is a disposable pen delivery device. The device comes pre-filled with a pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0379] Many reusable pen and autoinjector delivery devices are disclosed herein. Applications include subcutaneous delivery of pharmaceutical compositions. Examples include AUTOPEN (trademark), to name a few. ) (Owen Mumford, Woodstock, UK), DISETRONIC™ Pen (Disetronic Medical System s, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMAL IN 70 / 30(TM) pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN(TM) I, II, and and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Cop enhagen, Denmark), BD™ Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ( trademark), OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-ave The pharmaceutical compositions of the present invention include, but are not limited to, the following: Examples of disposable pen delivery devices that are applied to the subcutaneous delivery of substances include, to name a few: SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (trademark) (Eli Lilly), SURECLICK (trademark) Autoinjector (Amgen, Thousand Oaks, CA), PENLET ( (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA pens (Abbott Labs, Abbott Park IL).

[0380] In some situations, the pharmaceutical composition can be delivered in a controlled release system. A pump may be used (Langer, supra; Sefton, 1987, CRC Crit. R ef. Biomed. Eng. 14:201). In another embodiment, polymeric materials are used. Medical Applications of Controlled Release, Lange See, e.g., r. and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In embodiments, a controlled release system can be placed in proximity to the target of the composition, thereby allowing systemic Only a small fraction of the dose is needed (e.g., controlled release medical applications). ions of Controlled Release, supra, Vol. 2, pp. 115-138, Goodson, 1984 Other controlled-release systems are reviewed by Langer, 1990, Science 249:1527-1533. It is being considered.

[0381] Injectable preparations include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, infusions, etc. These injectable preparations can be prepared by known methods. For example, the injectable preparation may be prepared by injecting the above-mentioned antibody or a salt thereof into a conventional injection syringe. The bacteria are prepared by dissolving, suspending, or emulsifying them in an aqueous or oily medium. As an aqueous medium for injection, for example, an alcohol (e.g., ethanol) can be used. alcohols), polyalcohols (e.g., propylene glycol, polyethylene glycol), non-isopropyl alcohols ionic surfactants [e.g., polyoxyethylene of polysorbate 80, HCO-50 (hydrogenated castor oil)] Physiological saline, Glycerin, etc., which may be used in combination with a suitable solubilizer, such as ethylene (50 mol) adduct. Examples of oily vehicles include isotonic solutions containing glucose and other auxiliaries. Sesame oil, which may be used in combination with a solubilizer such as benzyl maltate or benzyl alcohol; Soybean oil, etc. are used. The injections prepared in this manner are preferably prepared with an appropriate It is filled into the pool.

[0382] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are suitable for the dosage of the active ingredient. The dosage form is prepared into a unit dose suitable for combining the two. Examples of the formulation include tablets, pills, injections (ampoules), suppositories, etc. The amount of the active ingredient is usually about 5 to about 500 mg per unit dose; particularly in the form of an injection, The antibody is preferably contained in an amount of about 5 to about 100 mg, and in other dosage forms, about 10 to about 250 mg. It's nice.

[0383] Therapeutic Uses of Antibodies In some embodiments, a subject in need thereof is administered an anti-MSR1 antibody or an antibody-containing anti-MSR1 antibody. Drug conjugates (e.g., any of the HCVR / LCVR or CDR sequences set forth in Table 4 herein) and administering to a subject a therapeutic composition comprising an anti-MSR1 antibody or ADC comprising either of the above. The therapeutic composition may comprise an anti-MSR1 antibody, an antigen-binding fragment thereof, or an ADC (e.g., For example, 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) ADC), and a pharmaceutically acceptable A carrier or diluent may be included.

[0384] The antibodies and ADCs disclosed herein may be used to detect, among other things, MSR1 expression or activity. or mediated by MSR1 expression or activity, or by competing for modified LDL <Binding to MSR1 and / or promoting MSR1 receptor internalization and / or cell Treatment of any disease or disorder treatable by reducing the number of surface receptors; For example, the antibodies and ADCs disclosed herein are useful for preventing and / or ameliorating MSR1 Cells that express and / or respond to MSR1-mediated signaling, e.g., macrophages Atherosclerosis, proliferative disorders, neurodegenerative disorders, and inflammation by targeting The present invention is useful for treating, arresting, or ameliorating

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

[0386] Provided herein are methods for treating a proliferative disorder, metabolic disorder, inflammation, neurodegenerative disorder, or The present invention relates to a method for treating a disease, disorder, or illness associated with glucocorticoid receptor signaling. The method comprises administering to the subject a compound described herein (e.g., an anti-MSR1 ADC), or administering an effective therapeutic amount of a pharmaceutical composition comprising a compound described herein. be.

[0387] In some embodiments, when the payload is a steroid, the disease, disorder, or Diseases include, but are not limited to, asthma, atopic dermatitis, contact dermatitis, allergic skin inflammation, drug hypersensitivity reactions, anaphylactic rhinitis, perennial or seasonal allergic rhinitis, and Allergic conditions, including but not limited to serum sickness; pruritus, seborrheic dermatitis, neurodermatitis, and eczema rash, bullous herpetic dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, and severe erythema multiforme ( Skin disorders, including but not limited to Stevens-Johnson syndrome; primary or secondary Adrenal insufficiency, congenital adrenal hyperplasia, hypercalcemia associated with cancer, and nonsuppurative thyroiditis Endocrine disorders, including erysipelas, gastrointestinal disorders, including but not limited to acquired (autoimmune) hemolytic anemia, Congenital (erythroblastic) aplastic anemia (Diamond-Blackfan anemia), adult idiopathic platelet Blood disorders, including purpura, pure red cell aplasia, and secondary thrombocytopenia; trichinellosis; subarachnoid Tuberculous meningitis with block or impending block; including, but not limited to, leukemia and lymphoma Neoplastic diseases, including but not limited to acute exacerbation of multiple sclerosis, primary or metastatic brain tumors nervous system disorders, including but not limited to cerebral edema, craniotomy, or head injury associated with Ophthalmitis, temporal arteritis, uveitis, xerophthalmia, and eyes refractory to topical corticosteroids ophthalmologic diseases, including, but not limited to, inflammatory conditions in idiopathic nephrotic syndrome; For diuresis or induction of remission of proteinuria, or for the treatment of proteinuria due to lupus erythematosus Renal disease, including for diuresis or to induce remission; including but not limited to beryllium disease; Fulminant or disseminated pulmonary tuberculosis, idiopathic eosinophilic tuberculosis when used concomitantly with appropriate antituberculous chemotherapy Respiratory diseases, including pneumonia and symptomatic sarcoidosis; and acute gouty Arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis. Short-term use (to help patients get through an acute episode or exacerbation) in rheumatoid arthritis, including for administration and in dermatomyositis, polymyositis, stomatitis, and systemic lupus erythematosus In one embodiment, the present invention is directed to a rheumatic disorder, including as an adjunct therapy for the treatment of rheumatic disorders. Thus, provided herein are methods for treating or preventing arthritis.

[0388] In some embodiments, the compounds described herein are useful for treating autoimmune diseases, allergies, , arthritis, asthma, respiratory disorders, blood disorders, cancer, collagen diseases, connective tissue disorders, skin diseases, eye diseases, Endocrine disorders, immune disorders, inflammatory diseases, intestinal disorders, gastrointestinal diseases, neurological disorders, organ transplant diseases, A disease selected from a rheumatoid disorder, a skin disorder, a swelling condition, a wound healing condition, and a combination thereof. A method of treating a disease, disorder, or condition, comprising administering to a subject a steroid payload described herein. The method comprises administering a compound or a conjugate thereof to a patient.

[0389] Autoimmune diseases include multiple sclerosis, autoimmune hepatitis, shingles, and 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 In some embodiments, the pulmonary artery disease is selected from chronic obstructive pulmonary disease, bronchial inflammation, and acute bronchitis. In this regard, cancers include leukemia, lymphoblastic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and Selected from blastic 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. Secretory disorders include Addison's disease, adrenal insufficiency, adrenal cortical insufficiency, adrenal hyperplasia, and congenital adrenal In some embodiments, the inflammatory disease is selected from inflammation after cataract surgery. Inflammation, joint inflammation, immune inflammation, tendon inflammation, bursitis, epicondylitis, Crohn's disease, inflammatory bowel disease, Lipid pneumonitis, thyroiditis, urticaria (hives), pericarditis, nephrotic syndrome In some embodiments, the bowel disease is selected from collagenous colonic ulcers, In some embodiments, the inflammatory bowel disease is selected from ulcerative colitis, Crohn's disease, and inflammatory bowel disease. In Japan, rheumatoid disorders include rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthritis, and severe rheumatoid arthritis. In some embodiments, the inflammatory bowel disease is selected from the group consisting of orthotopic spondylitis, and systemic lupus erythematosus. In some embodiments, the skin disorder is selected from psoriasis, eczema, and poison ivy. In this case, the neurological disorder is a chronic inflammatory demyelinating polyneuropathy.

[0390] In some embodiments, the compounds described herein include, but are not limited to, serotonin. It is administered to patients to treat acute inflammatory events, including cerebrovascular disease, cerebral edema, and graft-versus-host disease. In some embodiments, the compounds described herein are administered without limitation. including those associated with hematological malignancies, such as leukemia, lymphoma, and myeloma; It is administered to treat lymphocytolytic effects.

[0391] In some embodiments, the present invention provides a method for treating a subject in need thereof. The present invention relates to a method for reducing inflammation in a subject, the method comprising administering to a subject in need thereof ... The method comprises administering a therapeutically effective amount of a steroid or a conjugate thereof. In some embodiments, described herein are methods for administering a therapeutic agent to a subject in need thereof. A method of modulating the immune system comprises administering to a subject in need thereof a steroid hormone as described herein. The method comprises administering a therapeutically effective amount of a steroid or a conjugate thereof. In some embodiments, described herein is a method for administering a cholangiocarcinoma to a subject in need thereof. 2. A method for regulating thymidine levels in a subject in need thereof, comprising administering to a subject a compound as described herein. a therapeutically effective amount of a steroid or a conjugate thereof, In some embodiments, the present invention provides a method for treating a patient in need thereof. 1. A method of reducing lymphocyte migration in an elephant, comprising administering to a subject in need thereof a compound as described herein. a method comprising administering a therapeutically effective amount of the steroid or conjugate thereof described. In some embodiments, the present invention provides a method for treating hypercalcemia caused by cancer. Hemoglobinemia, Meniere's disease, migraine, cluster headache, severe aphthous ulcers, laryngitis, severe tuberculosis, Herxheimer reaction to venom, decompensated heart failure, allergic rhinitis, or nasal polyps The present invention relates to a method for treating a steroid-related condition, comprising administering to a subject in need thereof a steroid-related condition, comprising administering to the subject a steroid-related condition, the steroid-related condition, or a steroid-related condition, as described herein. The method includes administering a therapeutically effective amount of a medicament or a conjugate thereof. In embodiments, the compounds disclosed herein are useful in treating inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the disease or disorder can be used to treat ulcerative colitis. or diseases, including, but not limited to, chronic inflammatory diseases, including asthma, skin infections, and eye infections. In some embodiments, the compounds described herein are useful in treating patients who have received an organ transplant. It is used for immunosuppression in patients with

[0392] In some embodiments, the steroid payloads and their co- Conjugates are used to treat, but are not limited to, schizophrenia, drug addiction, and post-traumatic stress disorder (PTS). D) and GR signaling, including psychiatric disorders such as mood disorders, substance abuse, stress, and anxiety. The compounds are administered to patients to treat neurological disorders associated with neurotransmission.

[0393] In some embodiments, the steroid payloads and their co- Conjugates are useful in treating, but not limited to, eye inflammation (e.g., conjunctivitis, keratitis, uveitis), jaundice, and eczema. It is administered to patients to treat visual system disorders, including macula edema, and macular degeneration. In some embodiments, the steroid payloads and conjugates thereof described herein In some embodiments, the compound is administered to a patient to treat a cardiovascular disorder. The steroid payloads and conjugates thereof described herein are capable of transporting glucose and and / or administered to a patient to treat a liver metabolic disorder. The steroid payloads and conjugates thereof described herein are useful for treating musculoskeletal disorders. In some embodiments, the compounds described herein are administered to a patient to treat the condition. Steroid payloads and their conjugates are used to treat inflammatory skin conditions such as eczema and psoriasis. It is administered to a patient to treat the condition.

[0394] The protein conjugates described herein are capable of expressing specific steroid payloads. The present invention provides a means for targeted delivery of free conjugated Reduce or prevent side effects resulting from administration of an untreated steroid payload. Examples of such potential side effects to be prevented or prevented include those disclosed herein by reference. Fully incorporated Decadron® (dexamethasone) hmm ) listed on approved drug labels In some embodiments, the side effect to be reduced or prevented is Uses include increased blood pressure; sodium retention; water / fluid retention (edema, angioedema, pulmonary edema); and potassium excretion. increased excretion; reversible hypothalamic-pituitary-adrenal (HPA) axis suppression; potential corticosteroid effects after withdrawal of treatment steroid deficiency; susceptibility to infections; exacerbation of systemic fungal infections; chickenpox in children and adults Worsening of the severity of measles in children and adults; posterior subcapsular cataracts; potential damage to the optic nerve Glaucoma with scarring; promotion of the establishment of secondary bacterial, fungal, or viral ocular infections; optic neuritis increased new episodes of rheumatoid arthritis; Kaposi's sarcoma; drug-induced secondary adrenal insufficiency; active or If there is latent peptic ulcer, diverticulitis, fresh bowel anastomosis, and nonspecific ulcerative colitis Increased risk of gastrointestinal perforation; peritoneal irritation after gastrointestinal perforation; decreased bone formation; increased bone resorption; osteoblastic mechanisms Impaired bone growth in pediatric patients; development of osteoporosis at any age; acute myopathy (and Possibly involving the eyes and respiratory muscles, potentially causing quadriplegia); creatinine elevated levels of hydroxybenzoates; psychosis evident in euphoria, insomnia, mood swings, personality changes, and severe depression mental confusion with periodic manifestations; aggravation of existing emotional instability or psychotic tendencies; increased intraocular pressure; bradycardia; cardiac Cardiac arrest; cardiac arrhythmia; cardiac hypertrophy; circulatory collapse; congestive heart failure; fat embolism; hypertension; hypertrophic heart in preterm infants Myopathy; cardiac rupture after subacute myocardial infarction; syncope; tachycardia; thromboembolism; thrombophlebitis; vasculitis; acne; allergies Allergic dermatitis; Sharkey skin; Ecchymoses and petechiae; Erythema; Impaired wound healing; Hyperhidrosis; Rash; Striae; Skin Depressed skin test response; thin, brittle skin; thinning scalp hair; hives; carbohydrate and gluten-related skin reactions. Decreased tolerance to courses; development of Cushingoid state; hyperglycemia; diabetes; hirsutism; hypertrichosis Hypertrichosis: Increased insulin or oral hypoglycemic drug requirements in diabetes Phosphate resistance; signs of latent diabetes; menstrual irregularities; secondary adrenal and pituitary refractoriness (especially in times of stress; trauma; surgery; or illness; growth restriction in pediatric patients; in susceptible patients Congestive heart failure in patients with fluid retention; hypokalemic alkalosis; potassium loss; nat sodium retention; abdominal distension; elevated serum liver enzyme levels (usually reversible upon discontinuation); hepatomegaly; increased appetite nausea; pancreatitis; peptic ulcers with possible perforation and bleeding; perforation of the small and large intestine (especially inflammation) patients with ulcerative colitis; patients with ulcerative esophagitis; patients with negative nitrogen balance due to protein catabolism; patients with ulcerative colitis ... Aseptic necrosis of the humeral head; muscle mass loss; muscle weakness; osteoporosis; pathological fractures of long bones; steroid myopathy -; Tendon rupture; Spinal compression fractures; Convulsions; Depression; Emotional lability; Euphoria; Headache; Usually after discontinuation of treatment Increased intracranial pressure with edema (pseudotumor cerebri); insomnia; mood swings; neuritis; neuropathy; paresthesia; human Changes in mood; mental disorders; vertigo; exophthalmos; glaucoma; increased intraocular pressure; posterior subcapsular cataract; abnormal fat accumulation Decreased resistance to infection; hiccups; increased or decreased sperm motility and count; fatigue; anticholinergic esterase agents; and weight gain; and side effects associated with drug-drug interactions. In some embodiments, the side effect to be reduced or prevented is associated with a drug-drug interaction. In some embodiments, the side effect to be reduced or prevented is Corticosteroids and aminoglutethimide, including attenuation of adrenal suppression by corticosteroids Drug-drug interactions with the use of Drug-drug interactions due to the use of amphotericin B injection and potassium depleting agents; corticosterone Drug-drug interactions with antibiotic use, including a marked decrease in steroid clearance; myasthenia gravis Drug use with anticholinesterase drugs, including those causing severe weakness in patients with rheumatoid arthritis Drug-drug interactions with oral anticoagulant use, including inhibition of response to warfarin Actions: Drug-drug interactions with antidiabetic agents, including increased blood glucose levels; serum isoniazid Drug-drug interactions with antituberculous drugs, including decreased concentrations; clearing of corticosteroids Drug-drug interactions with cholestyramine use, including increased risk of cholestyramine; The use of cyclosporine has been associated with both steroid activity and an increased incidence of seizures. Drug-drug interactions due to: Drug-drug interactions due to the use of dexamethasone suppression test (DST) interference; hypokalemia Drug-drug interactions with the use of digitalis glycosides, including an increased risk of arrhythmias; blood levels Increased metabolic clearance of corticosteroids resulting in decreased blood flow and reduced physiological activity Drug-drug interactions with ephedrine use, including hepatic metabolism of certain corticosteroids The effects of estrogen-containing oral contraceptives, including a reduction in side effects and a concomitant increase in their effectiveness, Drug-drug interactions include increased metabolism of corticosteroids and hepatic enzyme inducers, inhibitors, and and substrates (drugs that induce cytochrome P450 3A4 (CYP 3A4) enzyme activity, e.g., barbiturates) Drug-drug interactions due to the use of methadone, phenytoin, carbamazepine, and rifampin; Drugs that inhibit CYP 3A4 (e.g., ketoconazole), including the potential for increased plasma concentrations of corticosteroids Drug-drug interactions due to the use of benzodiazepines, macrolide antibiotics, e.g., erythromycin metabolized by CYP 3A4, including increased clearance, resulting in decreased plasma concentrations Drug-drug interactions due to the use of drugs that are known to cause steroid use (e.g., indinavir, erythromycin); Up to 60% of certain corticosteroids result in an increased risk of corticosteroid side effects Adrenal corticosteroids may cause metabolic decline and adrenal insufficiency during corticosteroid withdrawal Drug-drug interactions with ketoconazole, including inhibition of corticosteroid synthesis; gastrointestinal side effects nonsteroidal anti-inflammatory drugs, including increased risk of side effects and increased clearance of salicylates Drug-drug interactions with the use of anti-inflammatory drugs (NSAIDS): increased or decreased phenytoin levels, seizure control Drug-drug interactions with phenytoin use, including changes in the immune system; reduced skin test response Drug-drug interactions with the use of skin tests, including toxic epidermal necrolysis; thalidomide, including toxic epidermal necrolysis drug-drug interactions due to the use of drugs; and inhibition of antibody responses or the presence of drugs in live attenuated vaccines. The response to toxoids and live or inactivated vaccines by enhancing the replication of certain organisms. associated with drug-drug interactions with vaccine use, including a decrease

[0395] Thus, provided herein are methods for treating diseases associated with the glucocorticoid receptor, A method for treating a disorder or disease, comprising administering to a patient a compound of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), ( (ID), (IE), Formula (III), or Formula (3000) to treat a patient suffering from the disease, disorder, or condition. wherein the free steroid payload of the conjugate is Further provided herein are methods for reducing side effects associated with the administration of , Formula (III) or Formula (3000) into a cell, comprising administering to the cell a compound of Formula (III) or with a protein conjugate of a compound of formula (3000), wherein the protein the protein conjugate comprises an antibody or antigen-binding fragment thereof that binds to a surface antigen of the cell; It is a method.

[0396] In some examples where the payload is an LXR modulator, The present invention relates to a method of treating a disease, disorder, or illness, comprising administering to a patient having the disorder a compound and and / or ADCs (e.g., compounds of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (500 1), (5002), (5003), (5004), (6001), (6002), (6003), (6004), or (6005) ADC) or a method comprising administering a therapeutically effective amount of the pharmaceutical composition.

[0397] In some instances, described herein are compounds that prevent a disease, disorder, or illness. The method comprises administering to a patient having the disorder a compound and / or an ADC (e.g., a compound represented by Formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), (IE), (5001), (5002), (5003), (5004), (6001), administering a prophylactically effective amount of the ADC of (6002), (6003), (6004), or (6005) or a pharmaceutical composition thereof; The method includes:

[0398] In some instances, described herein are antibodies that are responsive to modulation of LXR signaling. In some examples, the present invention is a method for treating or preventing any disease, disorder, or condition of The disease or disorder may involve an alteration in LXR function, an LXR polymorphism, an LXR agonist activity, or an LXR antagonist activity. In some instances, the methods described herein are associated with proliferative disorders, neurodegenerative disorders, and the like. disorders, immunological disorders, autoimmune diseases, inflammatory disorders, skin diseases, metabolic diseases, cardiovascular diseases, and gastrointestinal disorders. be.

[0399] The proliferative disorder can be any proliferative disorder known to those of skill in the art. In this context, proliferative disorders include, but are not limited to, oncology disorders. wherein the oncological disorder can be any cancer disorder known to those skilled in the art. In embodiments, provided herein are methods of treating or preventing melanoma. In certain embodiments, provided herein are methods for treating or preventing metastatic melanoma. In certain embodiments, provided herein are methods for treating or preventing lung cancer. In one embodiment, provided herein is a method for preventing EGFR-tyrosine In one embodiment, the present invention provides a method for treating or preventing kinase inhibitor-resistant lung cancer. Provided herein are methods for treating or preventing oral cancer. Provided herein are methods for treating or preventing oral squamous cell carcinoma. In certain embodiments, provided herein are methods for treating or preventing prostate cancer. In some embodiments, provided herein are methods for treating or preventing Hodgkin's lymphoma. In some embodiments, provided herein are methods for treating or preventing breast cancer. is a preventative method.

[0400] The neurodegenerative disorder can be any neurodegenerative disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing Alzheimer's disease. In certain embodiments, provided herein are methods for treating or preventing Parkinson's disease. In some embodiments, provided herein are methods for treating Huntington's disease. In one embodiment, provided herein are methods for treating or preventing muscle atrophy. In one embodiment, the method comprises administering to a subject a compound provided herein, the compound being administered to a subject ... Provided are methods for treating or preventing myelin gene expression. Provided herein are methods for treating or preventing diseases, disorders, or disorders of myelination and remyelination. It is a preventative method.

[0401] The immunological disorder can be any immunological disorder known to those of skill in the art. In accordance with the present invention, provided herein are methods for treating or preventing inflammatory bowel disease. In certain embodiments, provided herein are methods for treating or preventing ulcerative colitis. In certain embodiments, provided herein are methods for treating or preventing Crohn's disease. It is a way to prevent this.

[0402] The inflammatory disorder can be any inflammatory disorder known to those of skill in the art. In one embodiment, provided herein is a method for treating or preventing arthritis. In accordance with the present invention, provided herein are methods for treating or preventing rheumatoid arthritis.

[0403] The metabolic disorder can be any metabolic disorder known to those of skill in the art. In the present invention, the metabolic disorder is dyslipidemia. Dyslipidemia can be any lipid abnormality known to those skilled in the art. In some embodiments, the dyslipidemia can be hyperlipidemia, hypercholesterolemia, or cholesterolemia, hypertriglyceridemia, hyperlipoproteinemia, HDL deficiency, ApoA-I deficiency, and cardiovascular diseases, such as coronary artery disease (e.g., angina pectoris, myocardial infarction, and sudden cardiac death). including the treatment and prevention of atherosclerosis; and prevention); and restenosis (e.g., as a result of medical procedures such as balloon angioplasty). and (including the treatment or prevention of atherosclerotic plaques resulting from the In certain embodiments, provided herein are methods for treating or preventing diabetes. It is the law.

[0404] The cardiovascular disease can be any cardiovascular disease known to those of skill in the art. Provided herein is a method for treating or preventing atherosclerosis, In certain embodiments, provided herein are methods for treating abnormal macrophage processes. The present invention is a method for treating or preventing atherosclerosis resulting from vasoconstriction. In the present invention, a method for treating oxLDL in macrophages is provided. Atherosclerosis resulting from the formation of oxidized low-density lipoprotein (oxLDL) that cannot be oxidized In one embodiment, provided herein is a method for treating or preventing a deficiency. In one embodiment, the method for treating or preventing ischemic heart disease is a method for treating or preventing ischemic heart disease. In one embodiment, the method provided herein is for treating or preventing stroke. Contemplated is a method for treating or preventing hypertensive heart disease. Provided herein are methods for treating or preventing aortic aneurysms. Provided herein are methods for treating or preventing endocarditis. In accordance with the present invention, provided herein is a method for treating or preventing peripheral arterial disease. In embodiments, provided herein are methods for treating any of the diseases provided in this paragraph. The present invention is a method for treating or preventing any of the above-mentioned combinations.

[0405] In some instances, described herein are methods for modulating the function of a nuclear receptor. As a non-limiting example, the function is to inhibit inflammatory mediators (e.g., cytokines). , chemokine) expression / secretion, cholesterol regulation, cholesterol uptake, cholesterol Efflux, cholesterol oxidation, migration, chemotaxis, apoptosis and necrosis, inflammatory activity, lipid regulation The effect may be selected from: apoptosis, migration, chemotaxis, gene transcription, and protein expression.

[0406] In some instances, described herein are compounds that prevent a disease, disorder, or illness. The method comprises administering to a patient having the disorder a compound represented by formula (I), (IA), (IB), (IB-1), (IB-2), (IC), (ID), ), (IE), (7001), (7002), (7003), (7004), and / or (7005) compounds and / or ADCs, or administering a therapeutically effective amount of the pharmaceutical composition.

[0407] Staphylococcus aureus survives phagocytosis by macrophages and other cell types It is a facultative intracellular bacterium that can infect the host (Horn, J. et al., Insider Crime: Staphylococcus aureus Pathogen interactions (Inside job: Staphylococcus aureus host-pathogen interactions). In J Med Microbiol, 2018. 308(6): pp. 607-624; Jubrail, J. et al., Staphylococcus aureus The inability of β-lactamases to sustain intraphagolysosomal killing contributes to bacterial persistence in macrophages. Inability to sustain intraphagolysosomal killing of Staphylococcus aureus reus predisposes to bacterial persistence in macrophages). Cell Microbiol, 2016. 18(1): pp. 80-96). Intravital imaging revealed that macrophages are able to inhibit Staphylococcus aureus. can act as a reservoir that replicates and subsequently disseminates to other organs during infection It has been shown (Surewaard, BG et al., Identification of an in vivo S. aureus reservoir) Identification and treatment of the Staphylococcus aureus reservoir in J Exp Med, 2016. 213(7): p. 1141-51). Most antibiotics inhibit macrophages. It does not penetrate cells containing HIV-1, and the intracellular S. aureus reservoir is not easily penetrated by standard-of-care antibiotics. (Lehar, SM et al., Novel Antibody-Antibody Bioconjugates eliminate intracellular Staphylococcus aureus (Novel antibody-antibiotic conjugate eliminates intracellular S. aureus). Nature, 2015. 527(7578): p. 323- 8) However, liposomal formulations of vancomycin have not been shown to significantly improve the delivery of the antibiotic to macrophages. Increased penetration and reduced organ burden of Staphylococcus aureus more effectively than standard-of-care vancomycin (Surewaard, BG et al., Identification and Treatment of Staphylococcus aureus Reservoirs In Vivo) (Identification and treatment of the Staphylococcus aureus reservoir in vivo). J Exp Med, 2016. 213(7): pp. 1141-51). Taken together, these data suggest that macrophages Delivery of antibiotics to the endothelium may be an effective way to eliminate intracellular S. aureus reservoirs. This indicates that

[0408] Antibiotic-resistant Staphylococcus aureus continues to be a public health problem in the United States. Approximately 40% of bloodstream infections are caused by methicillin-resistant Staphylococcus aureus (MRSA). FDA-approved treatment options are few and far between for MRSA bloodstream infections. Coimycin remains the antibiotic of choice. However, the mortality rate from S. aureus bloodstream infections is ~18%, and there are currently no combinations that could improve treatment. It encourages research.

[0409] Rifamycin class antibiotics inhibit bacterial RNA polymerase (RNAP) and cause the production of yellow buds. However, monotherapy with this class of antibiotics is not recommended. This method can lead to the selection of resistant populations during treatment. in combination with first-line antibiotics for the treatment of infections commonly associated with prosthetic or exogenous devices. It can improve outcomes.

[0410] The ADCs described herein, which include rifamycin analogs, can be used to treat bacterial growth and / or bacterial infection in a subject. or is useful for preventing or treating a bacterial infection. In some instances, the bacteria is Gram Gram-positive bacteria are responsible for bacterial infections. The bacteria D Siri Resistant to (Penicillin-resistant bacteria are the cause of bacterial infections). In some instances, the bacteria is Staphylococcus aureus, a methicillin-resistant Staphylococcus aureus (MRSA) bacterium. (MRSA bacteria are the cause of bacterial infections.) In some cases, the bacteria The most common bacterial infections are caused by MSSA bacteria (MSSA bacteria are responsible for bacterial infections). In this study, the bacteria was vancomycin-resistant Staphylococcus aureus (VRSA) bacteria (VRSA bacteria are cells In some instances, the bacteria is a multidrug-resistant tuberculosis bacterium (multidrug-resistant tuberculosis bacterium). In a further example, the bacteria is, for example, azithromycin. Chlamydia trachomatis resistant to methicillin (e.g. , Chlamydia trachomatis resistant to azithromycin is the cause of the bacterial infection). In further examples, the bacteria are treated with, for example, metronidazole, vancomycin, and / or Clostridium difficile resistant to fidaxomicin le) (e.g., metronidazole, vancomycin, and / or fidaxomicin (The bacterial infection is caused by Clostridium difficile resistant to antibiotics).

[0411] Provided herein are methods for treating cellulitis, bacteremia, skin necrosis, eyelid infections, eye infections, and the like in a subject. rash, neonatal conjunctivitis, osteomyelitis, impetigo, inflammatory boils, scalded skin syndrome, food poisoning, pneumonia , surgical infections, urinary tract infections, post-burn infections, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis, prosthetic joint-related infections, catheter-related infections or a method for preventing or treating an infection associated with an implant, comprising administering to the subject a lift Antibody-drug conjugates containing amicycline analogs (e.g., those represented by formulas (I), (IA), (IB), (IB-1) , (IB-2), (IC), (ID), (IE), (7001), (7002), (7003), (7004), and / or (7005) ADCs Also provided herein are methods for treating atopic dermatitis, the methods comprising administering a therapeutically effective amount of 1. A method for preventing or treating an intracellular bacterial infection in an elephant, comprising administering to the subject a rifamycin analog. and antibody-drug conjugates comprising (e.g., compounds of formula (I), (IA), (IB), (IB-1), (IB-2), (IC), ( administering a therapeutically effective amount of an ADC of (7001), (7002), (7003), (7004), and / or (7005) It is a method that includes providing

[0412] In some instances, provided herein are methods for treating a bacterial infection and / or budworm in a subject. Treatment of a disease or disorder or illness associated with a Staphylococcus infection, e.g., a Staphylococcus aureus infection. the treatment and / or prevention, and / or at least the prevention of such diseases or disorders or illnesses; and an anti-MSR1 antibody, an antigen-binding portion of an MSR1 antibody, or an anti-MSR1 antibody, which is also useful for improving one or more symptoms. and administering an ADC containing the antibody or MSR1 antigen-binding fragment thereof to a subject in need thereof. Such diseases, disorders, or conditions include cellulitis, bacteremia, skin rash, and the like. Death, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, inflammatory boils, burns Skin syndrome, food poisoning, pneumonia, surgical infections, urinary tract infections, post-burn infections, meningitis, endocarditis, It can be sepsis, toxic shock syndrome, or septic arthritis. In the present invention, the subject has an artificial joint, and the antibody disclosed herein is administered to the tissue surrounding the artificial joint. In some instances, it is used to treat and / or prevent Staphylococcus aureus infections of the tissues. wherein the subject has a catheter, and the antibodies disclosed herein are administered to the catheter and / or is used to treat and / or prevent Staphylococcus aureus infection of the tissue surrounding the catheter. In some instances, the subject has an implanted foreign body and is treated with the methods disclosed herein. The antibodies treat and / or prevent Staphylococcus aureus infection of the foreign body and / or tissue surrounding the foreign body. In some instances, the subject has mastitis and is treated with the methods disclosed herein. The resulting antibodies are useful in treating mastitis.

[0413] In some instances, the rifamycin analog and / or its anti-MSR1 ADC may comprise one or more additional Additional antibiotics (e.g., antibiotics that can be used for MRSA infections), such as vancomycin, trimethoprim-peptide Methoprim-sulfamethoxazole...

Claims

1. An isolated antibody or antigen-binding fragment thereof that binds to macrophage scavenger receptor 1 (MSR1), wherein the antibody or antigen-binding fragment thereof is: (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 36; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 38; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 40; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 44; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 46; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 48; or (ii) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 100; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 102; an HCDR3 comprising the amino acid sequence of SEQ ID NO: 104; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 108; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 110; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 112; or (iii) HCDR1 comprising the amino acid sequence of SEQ ID NO: 292; HCDR2 comprising the amino acid sequence of SEQ ID NO: 294; HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; LCDR1 comprising the amino acid sequence of SEQ ID NO: 300; LCDR2 comprising the amino acid sequence of SEQ ID NO: 302; and LCDR3 comprising the amino acid sequence of SEQ ID NO: 304 The isolated antibody or antigen-binding fragment thereof, comprising:

2. The isolated antibody or antigen-binding fragment thereof of claim 1, which binds to macrophage scavenger receptor 1 (MSR1), wherein the antibody or antigen-binding fragment thereof has one of the following properties: (i) binds to human MSR1 with a KD of less than about 1.4 nM at 37°C as measured by surface plasmon resonance; (ii) binds to human MSR1 with a half-life t1 / 2 of greater than about 4 minutes at 37°C as measured by surface plasmon resonance; (iii) exhibiting less than about 90% maximal inhibition of modified LDL uptake by human MSR1 with an IC 50 of less than about 10 nM as measured by a ligand uptake assay; (iv) blocking modified LDL binding to human MSR1 by <50% as measured by a competitive ELISA assay; and / or (v) exhibiting binding of human MSR1 and internalization of greater than about 10% of the bound complex when assayed by binding in THP-1 cells; The isolated antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment exhibits one or more of the following:

3. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof blocks the inhibition of modified LDL uptake by MSR1 by less than 60% with an IC 50 of less than 3.5 nM.

4. The antibody or antigen-binding fragment thereof, (i) an HCVR comprising the amino acid sequence of SEQ ID NO: 34; and an LCVR comprising the amino acid sequence of SEQ ID NO: 42; or (ii) an HCVR comprising the amino acid sequence of SEQ ID NO: 98; and an LCVR comprising the amino acid sequence of SEQ ID NO: 106; or (iii) an HCVR comprising the amino acid sequence of SEQ ID NO: 290; and an LCVR comprising the amino acid sequence of SEQ ID NO:

298. The anti-MSR1 antibody or antigen-binding fragment thereof according to claim 1, comprising:

5. An antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 4, optionally conjugated to a payload moiety via a linker or via a linker-spacer.

6. The antibody-drug conjugate of claim 5, having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomeric form, positional isomer, or mixture of positional isomers thereof: 【Chemistry 1】 (In the formula: BA is a binder; L is a linker; PA is a payload moiety selected from the group consisting of a steroid residue, an LXR modulator residue, or a rifamycin residue; and The subscript n is an integer from 1 to 30.

7. The antibody-drug conjugate of claim 5 or claim 6, having the structure of formula (IA): 【Chemistry 2】 (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or a bivalent or trivalent linker comprising an amino acid residue optionally bonded directly or indirectly to a group HG; AA 2 is absent or a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, is a connector group residue; SP is absent or a spacer; and HG, if present, is a hydrophilic group).

8. The antibody-drug conjugate of any one of claims 5 to 7, having a structure of formula (IB-1): 【Transformation 3】 (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; Q, if present, 【Chemistry 4】 and SP is absent or a spacer; where: 【Transformation 5】 indicates the atom through which the referred group is attached to the adjacent group in the formula).

9. The antibody-drug conjugate of any one of claims 5 to 7, having a structure of formula (IB-2): 【Transformation 6】 (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; AA 1 is absent or a bivalent or trivalent linker comprising an amino acid residue optionally bonded directly or indirectly to a group HG; AA 2 is absent or a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, 【Transformation 7】 and; SP is absent or a spacer; and HG, if present, 【Transformation 8】 and where: 【Chemistry 9】 indicates the atom through which the referred group is attached to the adjacent group in the formula).

10. The antibody-drug conjugate of any one of claims 5 to 7 and 9, having a structure of Formula (IC), Formula (ID), or Formula (IE): 【Chemistry 10】 (In the formula, SP 1 is absent or a spacer; RG 1 is a reactive group residue; SP2 is absent or a spacer; RG 2 is a reactive group residue; AA 1 is a bivalent or trivalent linker comprising an amino acid residue; AA 2 is a dipeptide, tripeptide, or tetrapeptide residue; Q, if present, 【Chemistry 11】 and; SP is absent or a spacer; and HG is 【Chemistry 12】 and where: 【Chemistry 13】 indicates the atom through which the referred group is attached to the adjacent group in the formula).

11. The antibody-drug conjugate of any one of claims 7, 9 and 10, wherein AA 1 -AA 2 is according to formula (LL1): 【Chemistry 14】 wherein R AA1 , R AA2 , and R AA3 are each independently an amino acid side chain, at least one of which is linked to -(RG 2 )-SP 2 -HG, -(RG 2 )-HG, or HG; 【Chemistry 15】 indicates the atom through which AA 1 -AA 2 is attached to the adjacent group in the formula).

12. The antibody-drug conjugate of claim 11, wherein R AA1 is a lysine, glutamine, glutamic acid, or aspartic acid side chain directly or indirectly bound to HG, and R AA2 and R AA3 are either valine and alanine or valine and citrulline side chains, respectively.

13. AA 1 -AA 2 is 【Chemistry 16】 where: 【Chemistry 17】 The antibody-drug conjugate of any one of claims 7 and 9 to 12, wherein represents the atom through which AA 1 -AA 2 is attached to the adjacent group in said formula.

14. The RG 1 and RG 2 residues are, independently in each occurrence: [Chemistry 18] selected from the group consisting of: where: 【Chemistry 19】 The antibody-drug conjugate of any one of claims 7 to 13, wherein represents the atom through which the RG 1 or RG 2 residue is attached to the adjacent group in the formula.

15. An antibody-drug conjugate described in any one of claims 7 to 14, wherein SP, SP 1, and SP 2 are, independently in each occurrence, absent or selected from the group consisting of C 1-6 alkylene, -NH-, -S-, -O-, -C(O)-, (-CH 2 -CH 2 -O) e , -NH-CH 2 -CH 2 -(-O-CH 2 -CH 2 ) e -C(O)-, -C(O)-(CH 2 ) u -C(O)-, -C(O)-NH-(CH 2 ) v -, (glycine) 4 -serine, and combinations thereof, wherein the subscript e is an integer from 0 to 4, the subscript u is an integer from 1 to 8, and the subscript v is an integer from 1 to 8.

16. An antibody-drug conjugate described in any one of claims 5 to 15, wherein n is 1, 2, 3, or 4. 【Request Item 17】 【Chemistry 20】 but, 【Chemistry 21】 【change】 【change】 【change】 【change】 The antibody-drug conjugate of any one of claims 7 to 16, wherein 18. The antibody-drug conjugate of claim 5, wherein the antibody or antigen-binding fragment thereof is conjugated to a steroid payload via a linker or linker-spacer.

19. The antibody-drug conjugate of claim 5, wherein the antibody or antigen-binding fragment thereof is conjugated to an LXR modulator payload via a linker.

20. The antibody-drug conjugate of claim 5, wherein the antibody or antigen-binding fragment thereof is conjugated to a rifamycin payload via a linker.

21. The antibody-drug conjugate of claim 18, wherein the steroid conjugated to the antibody or antigen-binding fragment thereof via a linker or linker-spacer is a compound of formula (A-1): 【Chemistry 22】 (In the formula, R 1 and R 2 are independently —H, alkyl, alkyl-C(O)—O—, —OH, or halo; or R 1 and R 2 together are 【Chemistry 23】 Forming wherein R 4 is alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocycloalkyl are independently in each occurrence optionally substituted with -NR Aa R Ab ; R 3 is —O, R Z —C(O)—X—, -heteroalkyl, -piperidinyl, —NR Aa R Ab , -oxyaryl-NR Aa R Ab , or —Z-A′(RP ) t ; RZ is alkyl; X is O or NR Aa ; Z is S, S(O), S(O)2, SO2NR Aa , O, C(O)NR Aa , C(O), or NR Aa ; A' is aryl, arylalkyl, or heteroaryl; R P is independently at each occurrence halo, optionally substituted alkyl, —OH, or —NR Aa R Ab ; R Aa and R Ab are, independently at each occurrence, —H, optionally substituted alkyl, or optionally substituted aryl; the subscript a is an integer from 0 to 19; and t is an integer from 1 to 3; and R 5A and R 5B are each independently a halo or a hydrogen atom; where the group R 3 or R 4 is attached to the linker).

22. The antibody-drug conjugate of claim 18, having the structure of Formula (3000), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: BA-(L′-SP-D) n formula (3000) (In the formula, D is a) 【Chemistry 24】 wherein both R x in formula (a) are hydrogen; R 34 is alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; and SP is -C(O)-C 1 -C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 alkyl)-C 1 -C 10 -alkylene-X 1 - (wherein X 1 is attached to L' in formula (3000)), -C(O)-N(H)-(C 1 -C 10 -alkylene)-S- (wherein S is attached to L' in formula (3000)), -C(O)-N(C 1-6 alkyl)-(C 1 -C 10 -alkylene)-S- (wherein S is attached to L' in formula (3000)), 【Chemistry 25】 (wherein the point of attachment to the right (i.e., at N) is to L' in formula (3000)), -CH2-NH- (wherein N is attached to L' in formula (3000)), 【Chemistry 26】 wherein N is attached to L′ in formula (3000), and wherein Ar is an optionally substituted arylene (in some embodiments, 【Chemistry 27】 ) or optionally substituted heteroarylene), -(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- (wherein NR50a is attached to L' in formula (3000)), -C(O)-(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- (wherein NR50a is attached to L' in formula (3000) and where each C1-C10-alkylene is independently optionally substituted with one or more hydroxy), -C(O)-N(R35)-C1-C10-alkylene-C(O)NH-X2- (wherein X2 is attached to L' in formula (3000), or 【Chemistry 28】 (wherein X 4 is attached to L′ in formula (3000)); or wherein both R x in formula (a) are fluoro; R 34 is alkyl, aryl, arylalkyl, or N-containing heterocycloalkyl; and SP is -C(O)-C 1 -C 10 -alkylene-C(O)-, -C(O)-N(C 1-6 alkyl)-C 1 -C 10 -alkylene-X 1b - (wherein X 1b is attached to L' in formula (3000)), -C(O)-N(H)-(C 1 -C 10 -alkylene)-X 1b - (wherein X 1b is attached to L' in formula (3000)), 【Chemistry 29】 (wherein the point of attachment to the right (i.e., at N) is to L' in formula (3000)), -CH2-NH- (wherein N is attached to L' in formula (3000)), 【Transformation 30】 wherein N is attached to L′ in formula (3000), and wherein Ar is an optionally substituted arylene (in some embodiments, 【Chemistry 31】 ) or optionally substituted heteroarylene), -(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- (wherein NR50a is attached to L' in formula (3000)), -C(O)-(C1-C10-alkylene)-NR50C(O)-(C1-C10-alkylene)-NR50a- (wherein NR50a is attached to L' in formula (3000) and where each C1-C10-alkylene is independently optionally substituted with one or more hydroxy), -C(O)-N(R35)-(C1-C10-alkylene)-C(O)NH-X2- (wherein X2 is attached to L' in formula (3000), or 【Chemistry 32】 (wherein X 4 is attached to L′ in formula (3000)); and / or b) a compound consisting of: Table 1 【change】 【change】 【change】 【change】 (wherein the compound is linked to BA of the compound of formula (III) via the hydroxy of the -C(O)CH2OH group or via the hydroxy of the maplacorat) Selected from; X 1 is —N(C 1-6 alkyl)-; X 1b is -S-, -NH-, or -N(C 1-6 alkyl)-; X 2 is —NH—; X 3 is —CH 2 —, X 3 is —CH 2 —O—(C 1 -C 10 -alkylene)-C(O)— (wherein C(O) is bonded to X 4 ) or X 3 is —C(O)—; X 4 is —O—; R 35 is H, —OH, —OCH 3 , or C 1-6 alkyl; R 50 and R 50a are independently hydrogen or C 1 -C 6 -alkyl; R d , R e , and R f are independently -H, -OH, hydroxyalkyl, alkoxycarbonyl, -C(O)OH, or -CH 2 OR g , where each R g is independently -CH 2 C(O)OH or -CH 2 C(O)O(alkyl); and mm is 0 or 1; n is an integer selected from 1 to 30; L' is a linker; and BA is a binder).

23. The steroid payload of claim 22, wherein: 【Transformation 33】 【change】 【change】 is selected from the group consisting of where: 【Transformation 34】 The antibody-drug conjugate of claim 18, wherein: is the bond to the linker.

24. The steroid payload of claim 23, wherein: 【Chemistry 35】 or a mixture thereof.

25. The antibody-drug conjugate of claim 19, wherein the LXR modulator conjugated to the antibody or antigen-binding fragment thereof via a linker is a compound of Formula (B): 【Transformation 36】 (In the formula, W is -CH2-, -N(H)-, or -O-; R B1 is -H, -OH, -NH 2 , alkyl, or -OP(O)(OR 6 ) 2 ; R B2 is —H, —OH, —CH 2 NH 2 , R B3 , R B4 , R B5 , or —OR B5 , where R B1 and R B2 are not simultaneously —H; R B3 is —N(R 6 ) 2 ; R B4 is -XYZ; X is selected from the group consisting of -O- and -N(H)-; Y is selected from the group consisting of alkylene, substituted alkylene (including but not limited to, oxo-substituted, i.e., =0)), heteroalkylene, and substituted heteroalkylene (including but not limited to, oxo-substituted (i.e., =0)); Z is selected from the group consisting of -OH and -NH2; R B5 is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen and contains at least one —OH and —CH 2 OH substituent or at least one primary or secondary nitrogen, e.g., O-glucose; each R 6 , at each occurrence, is —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or an alkyl; and each R 7 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, —CN, O-glucose, O-amino acid residue, and O-PEG b (where each subscript b is an integer from 0 to 3); where a group R B1 or R B2 is attached to the linker).

26. The antibody-drug conjugate of claim 19, wherein the LXR modulator conjugated to the antibody or antigen-binding fragment thereof via a linker is a compound of formula (B-1): 【Chemistry 37】 (In the formula: R B1 is —N(H)R 8 or —N(R 9 ) 2 ; R B2 is —N(H)R 8 ; each R 8 , independently at each occurrence, is hydrogen, an amino acid residue, an N-alkyl amino acid residue, a peptide residue, a biodegradable moiety, or alkyl; R 9 is alkyl, aryl, arylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, where each heterocycloalkyl or substituted heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, and when substituted, contains at least one —OH and —CH 2 OH, or contains at least one primary or secondary nitrogen; 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 (where each subscript b is an integer from 0 to 3); where a group R B1 or R B2 is attached to the linker).

27. The antibody-drug conjugate of any one of claims 5 to 17, 19, 25, and 26, having the structure of formula (6005): 【Transformation 38】 。 28. The LXR modulator of claim 27, wherein: 【Chemistry 39】 is selected from the group consisting of where: 【Chemistry 40】 20. The antibody-drug conjugate of claim 19, wherein: is the bond to the linker.

29. The LXR modulator of claim 29, wherein: 【Chemistry 41】 【change】 【change】 【change】 is selected from the group consisting of where: 【Chemistry 42】 20. The antibody-drug conjugate of claim 19, wherein: is the bond to the linker.

30. The LXR modulator of claim 1, 【Chemistry 43】 and; where: 【Chemistry 44】 20. The antibody-drug conjugate of claim 19, wherein: is the bond to the linker.

31. The antibody-drug conjugate of claim 20, wherein the rifamycin is a compound of formula (C-1), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: 【Chemistry 45】 (In the formula: X 1c is selected from -S-; -O- and -NR 5c ; R 1c is amino-C 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkyl; di-C 1-6 alkylaminoC 1-6 alkyl; hydroxy-C 1-6 alkyl; HS-C 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-N(R 5c )—C 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-OC 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-SC 1-6 alkyl; heterocycloalkyl, or heterocycloalkyl-C 1-6 alkyl; wherein heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein heterocycloalkyl is halo, C 1-6 alkyl, —OH, ═O, or —N(R 5c ) 2 optionally substituted with; R 2c , R 3c , and R 4c are independently selected from hydrogen, C 1-6 alkyl, and —(C═O)—R 5c ; each R ac , if present, is independently selected from: -F; -Cl; -Br; -I; -OH; -NH 2 ; and C 1-6 alkoxy; and R 5c at each occurrence is independently selected from hydrogen; and C 1-6 alkyl; where the group R 1c is attached to the linker).

32. The antibody-drug conjugate of claim 20, wherein the rifamycin is a compound of formula (C-2), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: 【Chemistry 46】 (In the formula: X 1c is selected from -S-; -O- and -NR 5c ; R 1c is amino-C 1-6 alkyl; C 1-6 alkylaminoC 1-6 alkyl; di-C 1-6 alkylaminoC 1-6 alkyl; hydroxy-C 1-6 alkyl; HS-C 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-N(R 5c )—C 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-OC 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-SC 1-6 alkyl; heterocycloalkyl, or heterocycloalkyl-C 1-6 alkyl; wherein heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein heterocycloalkyl is halo, C 1-6 alkyl, —OH, ═O, or —N(R 5c ) 2 optionally substituted with; R 2c , R 3c , and R 4c are independently selected from hydrogen, C 1-6 alkyl, and —(C═O)—R 5c ; R ac and R bc are independently selected from: -F; -Cl; -Br; -I; -OH; -NH 2 ; and C 1-6 alkoxy; and R 5c at each occurrence is independently selected from hydrogen; and C 1-6 alkyl; where the group R 1c is attached to the linker).

33. The antibody-drug conjugate of claim 20, wherein the rifamycin is a compound of formula (C-3), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: 【Chemistry 47】 (In the formula: R 1c is di-C 1-6 alkylaminoC 1-6 alkyl; (R 5c ) 2 NC 1-6 alkylene-N(R 5c )—C 1-6 alkyl; heterocycloalkyl, or heterocycloalkyl-C 1-6 alkyl; wherein heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from O, N, and S; and wherein heterocycloalkyl is optionally substituted with halo, C 1-6 alkyl, —OH, ═O, or —N(R 5c ) 2 ; and R 2c , R 3c , and R 4c are independently selected from hydrogen, C 1-6 alkyl, and —(C═O)—R 5c ; and R 5c is selected from hydrogen and C 1-6 alkyl; where the group R 1c is attached to the linker).

34. The antibody-drug conjugate of claim 20, wherein the rifamycin is a compound of formula (C-4), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: 【Chemistry 48】 (In the formula: R 1c is 【Chemistry 49】 where Y is C or N; R 2c , R 3c , and R 4c are independently selected from hydrogen, C 1-6 alkyl, and —(C═O)—R 5c ; and R 5c at each occurrence is independently absent or selected from hydrogen and C 1-6 alkyl; where the group R 1c is represented by a wavy line [Transformation 50] is attached to the linker via a nitrogen atom indicated by 35. The antibody-drug conjugate of any one of claims 5-7, 9, 13-17, 20, and 31-34, having the structure of formula (7002): 【Chemistry 51】 。 36. The rifamycin comprising: 【Chemistry 52】 【change】 is selected from the group consisting of where: 【Chemistry 53】 The antibody-drug conjugate of any one of claims 6, 7, 9, 13-17, 20, and 31-35, wherein: is the bond to the linker.

37. An antibody-rifamycin conjugate having the structure of Formula (7003), or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof: 【Chemistry 54】 (In the formula: X 1c is selected from -S-; -O- and -NR 5c ; R 1c is 【Transformation 55】 where Y is C or N; R 2c , R 3c , and R 4c are independently selected from hydrogen, C 1-6 alkyl, and —(C═O)—R 5c ; R 5c at each occurrence is independently selected from: absent or hydrogen; and C 1-6 alkyl; each AA is an independently selected amino acid; SP 1 is absent or a spacer; RG 1 is a reactive group residue; The BA is the anti-MSR1 antibody or antigen-binding fragment thereof according to claim 1; The subscript n is an integer from 1 to 30; The subscript w is 2, 3, or 4; Here, R 1c is represented by a wavy line 【Transformation 56】 is attached to the linker via a nitrogen atom indicated by 38. The antibody-rifamycin conjugate of claim 37, wherein X 1c is O.

39. An antibody-rifamycin conjugate described in claim 37 or claim 38, wherein BA is an anti-MSR1 antibody or an antigen-binding fragment thereof comprising an N297Q mutation.

40. An antibody-rifamycin conjugate described in any one of claims 37 to 39, wherein the subscript w is 2.

41. The antibody-rifamycin conjugate of any one of claims 37 to 40, wherein (AA) 2 is valine-citrulline.

42. SP 1 is 【Chemistry 57】 42. The antibody-rifamycin conjugate of any one of claims 37 to 41, comprising:

43. SP 1 is 【Chemistry 58】 42. The antibody-rifamycin conjugate of any one of claims 37 to 41, comprising:

44. RG 1 is 【Chemistry 59】 44. The antibody-rifamycin conjugate of any one of claims 37 to 43, comprising:

45. X 1c is O; R 1c is 【Transformation 60】 wherein Y is C or N; and wherein R 1c is attached to the linker via the quaternary nitrogen atom of R 1c ; R 5c is C 1-6 alkyl; and R 6c is a counter ion; The antibody-rifamycin conjugate of any one of claims 37 to 43.

46. ​​The rifamycin comprising: 【Chemistry 61】 46. ​​The antibody-rifamycin conjugate of any one of claims 37 to 45, wherein 47. The following: 【Transformation 62】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 wherein: each Ab is an anti-MSR1 antibody or an antigen-binding fragment thereof; Each BA 【Transformation 63】 and wherein Ab 1 is an anti-MSR1 antibody or an antigen-binding fragment thereof; R is C 2-4 -alkylene; and nn is an integer selected from 2 to 4, inclusive; and each n is an integer from 1 to 4; 21. The antibody-drug conjugate of any one of claims 5 to 20, or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof.

48. The following: 【Chemistry 64】 is selected from, where: each Ab is an anti-MSR1 antibody or antigen-binding fragment thereof according to claim 1; and each n is an integer from 1 to 4; An antibody-drug conjugate or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof.

49. An antibody-drug conjugate according to one of the following formulas or a stereoisomeric form thereof or a positional isomer thereof or a mixture of positional isomers thereof: 【Transformation 65】 【change】 【change】 【change】 【change】 (In the formula, Each Ab is an anti-MSR1 antibody or an antigen-binding fragment thereof according to claim 1; Each BA is 【Chemical Formula 66】 wherein Ab 1 is an anti-MSR1 antibody or an antigen-binding fragment thereof; R is C 2-4 -alkylene; and nn is an integer selected from 2 to 4, inclusive; and Each n is an integer from 1 to 4).

50. The antibody-drug conjugate of any one of claims 5, 6 and 20 according to formula (7004): 【Transformation 67】 。 51. An antibody-drug conjugate prepared by conjugating the anti-MSR1 antibody or PEG-modified anti-MSR1 antibody or antigen-binding fragment thereof according to claim 1 with a linker payload selected from the group consisting of: 【Transformation 68】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 。

52. The anti-MSR1 antibody, PEG-modified anti-MSR1 antibody, or antigen-binding fragment thereof is reacted with a compound of formula (D): 【Transformation 69】 6. The antibody-drug conjugate of claim 5, prepared by contacting a linker payload according to the formula: or a stereoisomeric form or positional isomer thereof with an anti-MSR1 antibody or an antigen-binding fragment thereof under conditions suitable for forming a bond between the linker payload according to the formula:

53. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof described in any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

54. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 5 to 50 and a pharmaceutically acceptable carrier.

55. A pharmaceutical composition according to claim 53 or 54 for treating a subject's proliferative disease, metabolic disease, inflammation, neurodegenerative disease, or disease, disorder, or condition associated with glucocorticoid receptor signaling.

56. The pharmaceutical composition of claim 55 for treating atherosclerosis.

57. The pharmaceutical composition of claim 55, wherein the disease, disorder, or condition associated with glucocorticoid receptor signaling is an inflammatory disease, disorder, or condition.

58. A pharmaceutical composition according to claim 55 for treating arthritis.

59. The pharmaceutical composition of claim 55, which reduces side effects associated with administration of a steroid payload that is not conjugated to an antibody.

60. The pharmaceutical composition of claim 55, wherein the metabolic disease is dyslipidemia.

61. A pharmaceutical composition described in claim 53 or 54 for preventing or treating a bacterial infection in a subject.

62. The pharmaceutical composition of claim 61, wherein the bacterium is a gram-positive bacterium, penicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive Staphylococcus aureus (MSSA), or vancomycin-resistant Staphylococcus aureus (VRSA), or multidrug-resistant Mycobacterium tuberculosis.

63. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is administered in combination with vancomycin.

64. A pharmaceutical composition as described in claim 53 or 54 for preventing or treating cellulitis, bacteremia, skin necrosis, eyelid infection, eye infection, neonatal conjunctivitis, osteomyelitis, impetigo, inflammatory boils, scalded skin syndrome, food poisoning, pneumonia, surgical infection, urinary tract infection, post-burn infection, meningitis, endocarditis, sepsis, toxic shock syndrome, septic arthritis, mastitis, infections associated with artificial joints, infections associated with catheters, or infections associated with implants in a subject.

65. A pharmaceutical composition according to claim 53 or 54 for preventing or treating an intracellular bacterial infection in a subject.

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