Anti-CD36 antibody for treatment of liver diseases

Abstract

This disclosure provides compositions and methods for treating liver diseases with an anti-CD36 antibody or fragment thereof.

Description

Attorney Docket No.: 92EW-395024-WOANTI-CD36 ANTIBODY FOR TREATMENT OF LIVER DISEASESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of the United States Provisional Application Serial No. 63 / 709,774, filed October 21, 2025, the content of which is hereby incorporated by reference in its entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (395024. xml; Size: 10,279 bytes; and Date of Creation: October 15, 2025) is herein incorporated by reference in its entirety.BACKGROUND

[0003] Liver disease is generally classified as acute or chronic based upon the duration of the disease. Liver disease may be caused by infection, injury, exposure to drugs or toxic compounds, alcohol, impurities in foods, and the abnormal build-up of normal substances in the blood, an autoimmune process, a genetic defect (such as haemochromatosis), or unknown cause(s).Common liver diseases include cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cryptogenic steatotic liver disease, hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), and hepatitis.

[0004] Liver disease is a leading cause of death world-wide. In particular, it has been seen that a diet high in fat damages the liver in ways that are surprisingly similar to hepatitis. The American Liver Foundation estimates that more than 20 percent of the population has nonalcoholic fatty liver disease (NAFLD). It is suggested that obesity, unhealthy diets, and sedentary lifestyles may contribute to the high prevalence of NAFLD. When left untreated, NAFLD can progress to non-alcoholic steatohepatitis (NASH), causing serious adverse effects. Once NASH is developed, it would cause the liver to swell and scar over time. More recently, NASH is also referred to as MASH (metabolic dysfunction- associated steatohepatitis).

[0005] There remains a need to provide new effective pharmaceutical agents to treat liver diseases.Attorney Docket No.: 92EW-395024-WOSUMMARY

[0006] Compositions and methods for treating liver diseases are provided herein. In one embodiment, the disclosure provides a method for treating a liver disease in a subject, comprising administering to the subject an anti-CD36 antibody or antigen-binding fragment thereof.

[0007] In some embodiments, the anti-CD36 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 comprise, respectively, the amino acid sequences of SEQ ID NO: 3-8. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 1 and the VL comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibody comprises a human IgG4 Fc fragment.

[0008] In some embodiments, the subject has an increased fatty acid concentration in the liver as compared to a reference healthy subject. In some embodiments, the liver disease is selected from the group consisting of alcoholic liver disease (ALD), autoimmune liver diseases, genetic liver disease, drug-induced liver injury (DILI), cryptogenic steatotic liver disease (SLD), and nonalcoholic fatty liver disease (NAFLD).

[0009] In some embodiments, the subject has nonalcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH). In some embodiments, the MASH has a stage selected from the group consisting of steatosis, mild MASH, moderate MASH, advanced MASH and cirrhosis.

[0010] In some embodiments, the subject has obese MASH or NAFLD. In some embodiments, the subject has a body mass index (BMI) of 25 kg / m2or higher. In some embodiments, the subject has a BMI of 28 kg / m2or higher, or 30 kg / m2or higher.

[0011] In some embodiments, the subject has non-obese or lean MASH or NAFLD. In some embodiments, the subject has a BMI of 25 kg / m2or lower, or 23 kg / m2or lower.Attorney Docket No.: 92EW-395024-WO

[0012] In some embodiments, the subject has cryptogenic SLD.

[0013] In some embodiments, the subject is administered the antibody or antigen-binding fragment thereof at a dose of 10 mg to 500 mg twice per week, 20 mg to 400 mg twice per week, 30 mg to 300 mg twice per week, 40 mg to 250 mg twice per week, 50 mg to 200 mg twice per week, 60 mg to 180 mg twice per week, 70 mg to 160 mg twice per week, 80 mg to 150 mg twice per week, 90 mg to 140 mg twice per week, or 100 mg to 120 mg twice per week.

[0014] In some embodiments, the subject is administered the antibody or antigen-binding fragment thereof at a dose of 10 mg to 500 mg once per week, 20 mg to 400 mg once per week, 30 mg to 300 mg once per week, 40 mg to 250 mg once per week, 50 mg to 200 mg once per week, 60 mg to 180 mg once per week, 70 mg to 160 mg once per week, 80 mg to 150 mg once per week, 90 mg to 140 mg once per week, or 100 mg to 120 mg once per week.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A-I show that CD36 expression is elevated in liver macrophages during NASH development. (A) CD36 expression in human normal and NASH livers from the GSE484521 dataset (GEO). (B) Cd36 expression comparison from single-cell RNA-seq of myeloid populations in mouse livers fed CHOW or Western diet (Liver Cell Atlas) www.livercellatlas.org (C) Study design comparing MCD-NASH and CHOW diet mice. (D) Representative histogram (left) and quantitative geometric mean fluorescence intensity (MFI) (right) of CD36 in splenic macrophages, liver lipid-associated macrophages (LAM), and Kupffer cells from MCD-diet-fed mice. (E,F) Representative histograms and MFI of CD36 expression in LAM (E) and resident Kupffer cells (F) in CHOW and MCD-NASH mice. (G-I) Representative histograms and MFI of BODIPY 493 / 503 in splenic macrophages, LAM, and Kupffer cells from MCD diet-fed mice (G), stratified by CD36 expression in LAM (H) and Kupffer cells (I).

[0016] FIG.2A-I show that CD36Ab treatment alleviates steatosis and inflammation in NASH. (A) Study design of MCD-diet-induced NASH mice treated with 200 pg anti-CD36Ab or PBS, administered three times weekly. (B) Representative H&E staining images. (C) Quantification of lipid droplet area in PBS and CD36Ab-treated mice. (D) Serum ALT levels in MCD-NASH mice treated with PBS or CD36Ab. (E) MFI comparison of BODIPY 493 / 503 in resident Kupffer cellsAttorney Docket No.: 92EW-395024-WO (resKCs) and splenic macrophages from MCD-NASH mice. (F,G) Quantification of crown-like structures per high-power field (HPF) and representative F4 / 80 staining images (right). (H,I) Percentage (H) and absolute count (I) of transitory macrophages (transMac), LAM, and monocyte-derived Kupffer cells (MonoKC) among CD45+ cells in MCD-NASH mice treated with PBS or CD36Ab.

[0017] FIG.3A-G show that CD36Ab treatment ameliorated fibrosis development in NASH. (A) Study design of CDA-HFD-induced NASH with PBS-control or CD36Ab treatment. (B) Serum ALT levels after 6 weeks of CDA-HFD NASH induction. (C, D) Representative images (C) of Picro-Sirius-Red staining and quantification of Sirius-Red-positive area (D) after 6 weeks of CDA-HFD NASH induction. (E,F) Representative images (E) of Trichrome staining and quantification of collagen area (F) after 6 weeks of CDA-HFD NASH induction in PBS-control and CD36Ab-treated mice. (G) Cell counts of transitory macrophages (transMac), LAM, and resident Kupffer cells (resKC) after 4 and 6 weeks of CDA-HFD NASH induction, comparing PBS-control and CD36Ab-treated mouse livers.

[0018] FIG.4A-H show that PLT001 exhibited enforced NASH amelioration with decreased injection frequency. (A) Experimental design for CDA-HFD-induced NASH with PLT001 or PBS treatment, administered twice weekly for 2 weeks. (C) Quantitative MFI of cell-bound PLT001 in CDA-HFD-induced NASH mice treated with PLT001 or PBS. (B) Serum ALT levels in CDA-HFD-induced NASH mice treated with PLT001 or PBS (D, E) Representative TMB-stained liver images (D) and quantification of lipid area (E) in CDA-HFD-induced NASH mice treated with PLT001 or PBS. (F) Decreased inflammatory cell infiltration in the livers of PLT001 -treated CDA-HFD NASH mice. (G, H) Relative (G) and absolute (H) numbers of bone-marrow-derived macrophages in livers of CDA-HFD NASH mice treated with PLT001 or PBS.

[0019] FIG. 5A-G show that PLT001 ameliorated hallmarks of Obese MASH. (A) Experimental design for Western Diet-induced NASH with PLT001 or PBS treatment. (B) PLT001 treatment reduced the hepatic lipid accumulation, reducing steatosis, as shown by the H&E histological analysis and quantification of lipid droplet area. (C) Fibrosis progression, quantified by collagen deposition using trichrome (TMB) staining, was decreased in the PLT001 group. The histological improvements were accompanied by lower serum ALT and AST (D),Attorney Docket No.: 92EW-395024-WO reflecting diminished liver injury. (E) Longitudinal ALT measurements assessed after MASH induction before treatment and at the end of the treatment period showed ongoing hepatocellular damage in PBS controls (left) and stabilized levels in PLT001 -treated mice (right). Flow cytometry from the non-parenchymal cell fraction (NPC) within the liver revealed a trend toward decreased overall hepatic leukocyte content, neutrophil, and monocyte infiltration (F), while inflammatory macrophages, including resident Kupffer cells (resKC) and monocyte-derived Kupffer cells (MonoKC) were markedly reduced following PLT001 treatment (G).

[0020] FIG.6A-K show that PLT001 has therapeutic potential in lean MASH and cryptogenic steatotic liver disease. (A) Experimental design for CDA-HFD-induced NASH with PLT001 or PBS treatment. Weight gain did not differ between groups (B), while steatosis was reduced with PLT001 as determined histologically by lipid area quantification (C and D). PLT001 reduced hepatocellular injury as shown by a reduction in Serum ALT (E). Flow cytometry from the NPC fraction revealed an overall reduction of infiltrating leukocytes in PLT001 -treated livers, as well as neutrophils and total monocytes (F). This reduction reflected decreases in bone marrow-derived macrophage subsets, including lipid-associated macrophages (LAM), transitional macrophages (transMac), MonoKC, and resKC (G, H). qPCR from total liver tissue showed lower expression of proinflammatory mediators, such as TNFa, predominantly secreted by macrophages in MASH, and of monocyte chemoattractant protein- 1 (Ccl2) (I). Flow cytometry analysis showed CCR2 (the CCL2 receptor) expression was decreased on bone marrow-derived macrophages (BM-Mac) and MonoKC, but not on resKC (J). Expression of the CSF1 receptor (CSF1R) was particularly reduced in differentiated macrophage populations (MonoKC and resKC) from PLT001 -treated mice, as shown by flow cytometry analysis (K).

[0021] FIG.7A-E show that PLT001 mitigated hepatic fibrosis and inflammation in lean and cryptogenic steatotic liver disease. (A) Experimental design for CDA-HFD-induced NASH with PLT001 or PBS treatment. PLT001 treatment (10 mg / kg) reduced hepatic fibrosis, as quantified by histology analysis of Piero Sirius Red-positive area (B and C). This antifibrotic effect was accompanied by a marked reduction in macrophage subsets, including transMac, LAM, MonoKC, and resKC, as determined by flow cytometry of the liver (D). Expression of the inflammatory mediator TNFa and the macrophage recruitment chemokine Ccl2 was decreased in liver tissue from PLT001 -treated mice in qPCR measurement (E).Attorney Docket No.: 92EW-395024-WO

[0022] FIG. 8A-G show that PLT001 reduced macrophage adhesion and influx in MASH by reducing endothelial activation. PLT001 antibody bound to the surface to endothelial cells (A) and did not affect endothelial cell counts (B). PLT001 effectively decreased endothelial lipid uptake (C). Expression of the adhesion molecule ICAM-1 was reduced in liver tissue of CDA-HFD mice treated for 2 weeks with PLT001- but not IgA-treated mice (D, left), as well as in PLT001 -treated mice after 10 weeks of WD (10 mg / kg, twice weekly for 4 weeks) or PBS as control (D, right). Analysis of CD31+singlets from 2-week CDA-HFD mice treated with PET001 (lOmg / kg) or PBS revealed markedly increased macrophage remnants on endothelial surfaces, indicated by VSIG4 expression (E). Endothelial-immune cell doublets, including hepatic macrophages, were strongly reduced in PLT001 -treated mice (F). Flow cytometric analysis of these endothelial-immune cell interactions, specifically CD31+F4 / 80+CD64+, showed decreased leukocyte adhesion molecules (CD44, CD62L) and reduced CCR2 expression (G).

[0023] FIG.9A-H compares PLT001 and CD36Ab (Anti-CD36 IgA) with respect to treatment efficacy of MASH. (A) Experimental design for CDA-HFD-induced NASH with PLT001 or Anti-CD36 IgA treatment. PLT001 demonstrated superior efficacy in the CDA-HFD mouse model than anti-CD36 IgA at the same concentration, 10 mg / kg, with a more effective reduction of liver injury markers (ALT and AST) (B). At the metabolic level, PLT001 selectively decreased de novo lipogenesis, as indicated by reduced expression of key rate- limiting lipogenic enzymes liver tissue measured by qPCR (C), while P-oxidation and long-chain fatty acid import pathways remained unaltered (D). PLT001 reduced steatosis, as shown by histological analysis of lipid deposition area (E). In addition, PLT001 (but not anti-CD36 IgA) exhibited early antifibrotic potential, evidenced by decreased expression of Col3al and Collal by qPCR of whole liver tissue (F), reflecting reduced stellate cell activation and collagen deposition. Both PLT001 and anti-CD36 IgA lowered pro-inflammatory mediator expression, such as TNFa, assessed by qPCR of whole livers, although the effect was more pronounced with PLT001 (G). Notably, IL-ip was only reduced by PLT001, not anti-CD36 IgA. Flow cytometry analysis showed that only PLT001 reduced early differentiation-state pathogenic bone marrow-derived macrophage subsets (LAM and transMac), whereas MonoKC and resKC were decreased by both PLT001 and anti-CD36 IgA(H).Attorney Docket No.: 92EW-395024-WODETAILED DESCRIPTIONDefinitions

[0024] It is to be noted that the term “a” or “an” entity refers to one or more of that entity; for example, “an antibody,” is understood to represent one or more antibodies. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0025] As used herein, an “antibody” or “antigen-binding polypeptide” refers to a polypeptide or a polypeptide complex that specifically recognizes and binds to an antigen. An antibody can be a whole antibody and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule having biological activity of binding to the antigen. Examples of such include, but are not limited to a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, or at least one portion of a binding protein.

[0026] The terms “antibody fragment” or “antigen-binding fragment,” as used herein, is a portion of an antibody such as F(ab’)2, F(ab)2, Fab’, Fab, Fv, scFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody. The term “antibody fragment” includes aptamers, spiegelmers, and diabodies. The term “antibody fragment” also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.

[0027] The term antibody encompasses various broad classes of polypeptides that can be distinguished biochemically. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon ( y , p, a, 5, s) with some subclasses among them (e.g., yl-y4). It is the nature of this chain that determines the “class” of the antibody as IgG, IgM, IgA IgG, or IgE, respectively.

[0028] The immunoglobulin subclasses (isotypes) e.g., IgGl, IgG2, IgG3, IgG4, IgG5, etc. are well characterized and are known to confer functional specialization. Modified versions ofAttorney Docket No.: 92EW-395024-WO each of these classes and isotypes are readily discernable to the skilled artisan in view of the instant disclosure and, accordingly, are within the scope of the instant disclosure. All immunoglobulin classes are clearly within the scope of the present disclosure, the following discussion will generally be directed to the IgG class of immunoglobulin molecules. With regard to IgG, a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000. The four chains are typically joined by disulfide bonds in a “Y” configuration wherein the light chains bracket the heavy chains starting at the mouth of the “Y” and continuing through the variable region.

[0029] Antibodies, antigen-binding polypeptides, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, human, humanized, primatized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab’ and F(ab’)2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VK or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-id antibodies to the antibodies disclosed herein). Immunoglobulin or antibody molecules of the disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule.

[0030] As used herein, the term “chimeric antibody” will be held to mean any antibody wherein the immunoreactive region or site is obtained or derived from a first species and the constant region (which may be intact, partial or modified in accordance with the instant disclosure) is obtained from a second species. In certain embodiments the target binding region or site will be from a non-human source (e.g. mouse or primate) and the constant region is human.

[0031] Antibodies disclosed herein can be from any animal origin including birds and mammals. Preferably, the antibodies are human, murine, donkey, rabbit, goat, guinea pig, camel, llama, horse, or chicken antibodies. In some embodiments, the variable region may be condricthoid in origin (e.g., from sharks).

[0032] As used herein, the term “recombinant” as it pertains to polypeptides or polynucleotides intends a form of the polypeptide or polynucleotide that does not exist naturally, a non-limitingAttorney Docket No.: 92EW-395024-WO example of which can be created by combining polynucleotides that would not normally occur together.

[0033] Hybridoma technology can be performed under conditions of different “stringency.” In general, a low stringency hybridization reaction is carried out at about 40°C in about 10 x SSC or a solution of equivalent ionic strength / temperature. A moderate stringency hybridization is typically performed at about 50°C in about 6 x SSC, and a high stringency hybridization reaction is generally performed at about 60°C in about 1 x SSC. Hybridization reactions can also be performed under “physiological conditions” which is well known to one of skill in the art. A nonlimiting example of a physiological condition is the temperature, ionic strength, pH and concentration of Mg2+normally found in a cell.Treatment of Liver Diseases

[0034] It has been demonstrated herein that CD36 was highly expressed on resident Kupffer cells (KC) and recruited lipid-associated macrophages (LAM) in two diet-induced (MCD and CDA-HFD) nonalcoholic steatohepatitis (NASH or MASH) and cryptogenic steatotic liver disease (SLD) models. Moreover, CD36hlghLAMs and KCs exhibited higher lipid content compared to KCs and LAMs expressing low levels of CD36.

[0035] Moreover, targeting CD36-mediated lipid uptake with an IgA type anti-CD36 antibody, CD36Ab (or “Anti-CD36 IgA”), reduced NASH progression in diet models. Treatment with CD36 blocking antibody significantly ameliorated liver damage, as assessed by ALT serum levels, and led to a strong decline in BM-derived macrophage populations. Importantly, lipid deposition in hepatic sections as well as crown-like structures were also decreased in response to CD36 blockade. In the long-term NASH induction model, CD36Ab treatment significantly reduced the proportion of alternatively activated tissue-resident CD8 T cells (PD-1hlghand CXCR-6hlgh). This population has been recently linked to liver damage during NASH progression.

[0036] Also interestingly, a new anti-CD36 antibody, PLT001, exhibited higher efficacy in treating MASH in a CDA-HFD mouse model than CD36Ab at the same dose. At 10 mg / kg, as compared to CD36Ab, PLT001 exhibited more effective reduction of liver injury markers (ALTAttorney Docket No.: 92EW-395024-WO and AST). PLT001 selectively decreased de novo lipogenesis, as indicated by reduced expression of key rate-limiting lipogenic enzymes, and reduced steatosis. Also importantly, PLT001, but not CD36Ab, exhibited early antifibrotic potential, evidenced by decreased expression of Col3al and Coll al by qPCR of whole liver tissue, reflecting reduced stellate cell activation and collagen deposition. In addition, PLT001 lowered pro-inflammatory mediator expression, such as TNFa and IL-ip, more than CD36Ab. Moreover, only PLT001 reduced early differentiation-state pathogenic bone marrow-derived macrophage subsets (LAM and transMac). These findings underscore PLTOOl’s unexpected impact on the inflammatory-fibrotic microenvironment, demonstrating PLTOOl’s unique ability in treating MASH.

[0037] In addition to efficacy for obesity-associated liver pathologies, PLT001 has also exhibited superior efficacy in treating lean MASH and cryptogenic steatotic liver disease (SLD). A MASH patient is considered to have lean MASH (or non-obese MASH) when the BMI is below 25 kg / m2(or below25 kg / m2for Asian patients). Compared to obese MASH, lean MASH is associated with increased mortality. SLD refers to a condition where excess fat builds up, inflammation, fibrosis, and progressive liver injury, in the liver. Cryptogenic SLD means the SLD has no known origin where, after causes are ruled out, no specific reason for the fat accumulation can be identified.

[0038] In accordance with one embodiment of the present disclosure, provided is a method for treating a liver disease in a subject, comprising administering to the subject an anti-CD36 antibody or antigen-binding fragment of the present disclosure. A representative example of the present disclosure is PLT001 which binds to both Domain 1 (residues 153 to 160) and Domain 2 (residues 191 to AA197) of the CD36 protein. These domains, structural analysis shows, are important for oxidized low-density lipoprotein (OxLDL) uptake. Accordingly, it is contemplated that PLT001 can effectively block fatty acid uptake by the target cells.

[0039] In some embodiments, an anti-CD36 antibody or antigen-binding fragment of the present disclosure includes a heavy chain variable region (VH) that includes a VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) that includes a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 include, respectively, the amino acid sequences of SEQ ID NO: 3-8. In someAttorney Docket No.: 92EW-395024-WO embodiments, the VH includes the amino acid sequence of SEQ ID NO: 1 and the VL includes the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody is humanized. In some embodiments, the antibody is of IgG4 type with a human IgG4 Fc fragment.

[0040] These antibodies and antigen-binding fragments can be suitably used to treat or prevent liver diseases. Liver diseases represent a broad category of conditions affecting the liver, which plays a vital role in many body functions, including metabolizing nutrients, detoxifying harmful substances, making blood clotting proteins, and producing bile to aid in digestion. These conditions can vary significantly in their causes, mechanisms, severity, and treatments.

[0041] In one embodiments, the liver disease being treated or prevented is alcoholic liver disease (ALD). ALD results from excessive alcohol consumption, and can progress from fatty liver to alcoholic hepatitis to cirrhosis.

[0042] In one embodiment, the liver disease being treated or prevented is autoimmune liver diseases. These include autoimmune hepatitis, primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), where the body’s immune system attacks liver cells.

[0043] In one embodiment, the liver disease being treated or prevented is genetic liver diseases. Conditions like hemochromatosis and Wilson’s disease are caused by genetic mutations and can lead to liver damage through the accumulation of iron or copper in the liver, respectively.

[0044] In one embodiment, the liver disease being treated or prevented is drug-induced liver injury (DILI). Medications, supplements, and even herbal products can cause liver damage, ranging from mild to severe.

[0045] In one embodiment, the liver disease being treated or prevented is cryptogenic steatotic liver disease (SLD). Cryptogenic SLD, in some embodiments, refers to excess fat builds up, inflammation, fibrosis, and progressive liver injury in the liver where, after causes are ruled out, no specific reason for the fat accumulation can be identified.

[0046] In yet one embodiment, the liver disease being treated or prevented is non-alcoholic fatty liver disease (NAFLD) or and NASH. NAFLD is a spectrum of liver conditions not caused by alcohol abuse, characterized by the accumulation of fat in liver cells. It is the most commonAttorney Docket No.: 92EW-395024-WO liver disorder in Western countries. NAFLD can progress to a more severe form known as Non-Alcoholic Steatohepatitis (NASH), also referred to as metabolic dysfunction-associated steatohepatitis (MASH), which involves inflammation and liver cell damage, in addition to fat in the liver.

[0047] In some embodiments, the NASH or MASH being treated or prevented is one of the following subtypes or stages. In one embodiment, it is simple steatosis, which is characterized by fat accumulation in liver cells without inflammation or damage. This stage is considered relatively benign and has a better prognosis. In another embodiment, the NASH or MASH is at a later stage that involves steatosis, liver inflammation, and hepatocyte injury. In some embodiments, the NASH or MASH has progressed to fibrosis, cirrhosis, and eventually, or liver cancer. The various stages are briefly summarized in the table below.Stages of NASH (MASH)

[0048] In one embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is used to treat or prevent steatosis. In one embodiments, an antibody or antigenbinding fragment thereof of the present disclosure is used to treat or prevent mild NASH or MASH. In one embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is used to treat or prevent moderate NASH or MASH. In one embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is used to treat or prevent advanced NASH or MASH. In one embodiments, an antibody or antigen-binding fragment thereof of the present disclosure is used to treat or prevent cirrhosis.Attorney Docket No.: 92EW-395024-WO

[0049] In one aspect of any one of the above embodiments, the subject is obese. In some embodiments, the subject has obese MASH or NAFLD. In some embodiment, the obese subject has a BMI that is 25 kg / m2, 26 kg / m2, 27 kg / m2, 28 kg / m2, 29 kg / m2, 30 kg / m2, 31 kg / m2, 32 kg / m2, 33 kg / m2, 34 kg / m2, 35 kg / m2, or 40 kg / m2or higher.

[0050] In one aspect of any one of the above embodiments, the subject is non-obese or is lean. In some embodiments, the subject has non-obese or lean MASH or NAFLD. In some embodiment, the non-obese or lean subject has a BMI that is 25 kg / m2, 24 kg / m2, 23 kg / m2, 22 kg / m2, 21 kg / m2, 20 kg / m2, 19 kg / m2, 18 kg / m2, 17 kg / m2, 16 kg / m2, 15 kg / m2or lower.

[0051] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the particular antibodies, variant or derivative thereof used, the patient’s age, body weight, general health, sex, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. Judgment of such factors by medical caregivers is within the ordinary skill in the art. The amount will also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the antibody used, the severity of the disease, and the desired effect. The amount used can be determined by pharmacological and pharmacokinetic principles well known in the art.

[0052] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once per day, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per day. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once per day, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per day. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the presentAttorney Docket No.: 92EW-395024-WO disclosure is 10 mg to 500 mg once per day, 20 mg to 400 mg once per day, 30 mg to 300 mg once per day, 40 mg to 250 mg once per day, 50 mg to 200 mg once per day, 60 mg to 180 mg once per day, 70 mg to 160 mg once per day, 80 mg to 150 mg once per day, 90 mg to 140 mg once per day, or 100 mg to 120 mg once per day.

[0053] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every two days, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every two days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every two days, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every two days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every two days, 20 mg to 400 mg once every two days, 30 mg to 300 mg once every two days, 40 mg to 250 mg once every two days, 50 mg to 200 mg once every two days, 60 mg to 180 mg once every two days, 70 mg to 160 mg once every two days, 80 mg to 150 mg once every two days, 90 mg to 140 mg once every two days, or 100 mg to 120 mg once every two days.

[0054] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every three days, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every three days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every three days, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg,Attorney Docket No.: 92EW-395024-WO 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every three days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every three days, 20 mg to 400 mg once every three days, 30 mg to 300 mg once every three days, 40 mg to 250 mg once every three days, 50 mg to 200 mg once every three days, 60 mg to 180 mg once every three days, 70 mg to 160 mg once every three days, 80 mg to 150 mg once every three days, 90 mg to 140 mg once every three days, or 100 mg to 120 mg once every three days.

[0055] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every four days, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every four days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every four days, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every four days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every four days, 20 mg to 400 mg once every four days, 30 mg to 300 mg once every four days, 40 mg to 250 mg once every four days, 50 mg to 200 mg once every four days, 60 mg to 180 mg once every four days, 70 mg to 160 mg once every four days, 80 mg to 150 mg once every four days, 90 mg to 140 mg once every four days, or 100 mg to 120 mg once every four days.

[0056] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every five days, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg,Attorney Docket No.: 92EW-395024-WO 700 mg, 750 mg, 800 mg or 900 mg once every five days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every five days, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every five days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every five days, 20 mg to 400 mg once every five days, 30 mg to 300 mg once every five days, 40 mg to 250 mg once every five days, 50 mg to 200 mg once every five days, 60 mg to 180 mg once every five days, 70 mg to 160 mg once every five days, 80 mg to 150 mg once every five days, 90 mg to 140 mg once every five days, or 100 mg to 120 mg once every five days.

[0057] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every six days, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every six days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every six days, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every six days. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every six days, 20 mg to 400 mg once every six days, 30 mg to 300 mg once every six days, 40 mg to 250 mg once every six days, 50 mg to 200 mg once every six days, 60 mg to 180 mg once every six days, 70 mg to 160 mg once every six days, 80 mg to 150 mg once every six days, 90 mg to 140 mg once every six days, or 100 mg to 120 mg once every six days.Attorney Docket No.: 92EW-395024-WO

[0058] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg twice per week, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg twice per week. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg twice per week, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg twice per week. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg twice per week, 20 mg to 400 mg twice per week, 30 mg to 300 mg twice per week, 40 mg to 250 mg twice per week, 50 mg to 200 mg twice per week, 60 mg to 180 mg twice per week, 70 mg to 160 mg twice per week, 80 mg to 150 mg twice per week, 90 mg to 140 mg twice per week, or 100 mg to 120 mg twice per week.

[0059] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once per week, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per week. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once per week, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per week. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once per week, 20 mg to 400 mg once per week, 30 mg to 300 mg once per week, 40 mg to 250 mg once per week, 50 mg to 200 mg once per week, 60 mg to 180Attorney Docket No.: 92EW-395024-WO mg once per week, 70 mg to 160 mg once per week, 80 mg to 150 mg once per week, 90 mg to 140 mg once per week, or 100 mg to 120 mg once per week.

[0060] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every two weeks, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every two weeks. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every two weeks, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every two weeks. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once every two weeks, 20 mg to 400 mg once every two weeks, 30 mg to 300 mg once every two weeks, 40 mg to 250 mg once every two weeks, 50 mg to 200 mg once every two weeks, 60 mg to 180 mg once every two weeks, 70 mg to 160 mg once every two weeks, 80 mg to 150 mg once every two weeks, 90 mg to 140 mg once every two weeks, or 100 mg to 120 mg once every two weeks.

[0061] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every three weeks, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every three weeks. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every three weeks, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg orAttorney Docket No.: 92EW-395024-WO 900 mg once every three weeks. In some embodiments, a suitable dose of an antibody or antigenbinding fragment of the present disclosure is 10 mg to 500 mg once every three weeks, 20 mg to 400 mg once every three weeks, 30 mg to 300 mg once every three weeks, 40 mg to 250 mg once every three weeks, 50 mg to 200 mg once every three weeks, 60 mg to 180 mg once every three weeks, 70 mg to 160 mg once every three weeks, 80 mg to 150 mg once every three weeks, 90 mg to 140 mg once every three weeks, or 100 mg to 120 mg once every three weeks.

[0062] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once every four weeks, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every four weeks. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once every four weeks, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once every four weeks. In some embodiments, a suitable dose of an antibody or antigenbinding fragment of the present disclosure is 10 mg to 500 mg once every four weeks, 20 mg to 400 mg once every four weeks, 30 mg to 300 mg once every four weeks, 40 mg to 250 mg once every four weeks, 50 mg to 200 mg once every four weeks, 60 mg to 180 mg once every four weeks, 70 mg to 160 mg once every four weeks, 80 mg to 150 mg once every four weeks, 90 mg to 140 mg once every four weeks, or 100 mg to 120 mg once every four weeks.

[0063] In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is at least 10 mg once per month, or at least 20 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per month. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is no more than 50 mg once perAttorney Docket No.: 92EW-395024-WO month, or no more than 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg or 900 mg once per month. In some embodiments, a suitable dose of an antibody or antigen-binding fragment of the present disclosure is 10 mg to 500 mg once per month, 20 mg to 400 mg once per month, 30 mg to 300 mg once per month, 40 mg to 250 mg once per month, 50 mg to 200 mg once per month, 60 mg to 180 mg once per month, 70 mg to 160 mg once per month, 80 mg to 150 mg once per month, 90 mg to 140 mg once per month, or 100 mg to 120 mg once per month.

[0064] Methods of administration of the antibody, fragment, or antibody-drug conjugate include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The antigen-binding polypeptides or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Thus, pharmaceutical compositions containing the antigen-binding polypeptides of the disclosure may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, drops or transdermal patch), buccally, or as an oral or nasal spray.

[0065] The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion.

[0066] Administration can be systemic or local. In addition, it may be desirable to introduce the antibodies of the disclosure into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.Attorney Docket No.: 92EW-395024-WO

[0067] It may be desirable to administer the antigen-binding polypeptides or compositions of the disclosure locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction, with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the disclosure, care must be taken to use materials to which the protein does not absorb.

[0068] The amount of the antibodies, fragments, or antibody-drug conjugates of the disclosure which will be effective in the treatment, inhibition and prevention of an inflammatory, immune or malignant disease, disorder or condition can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease, disorder or condition, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose- response curves derived from in vitro or animal model test systems.

[0069] In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. Further, a “pharmaceutically acceptable carrier” will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0070] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride,Attorney Docket No.: 92EW-395024-WO dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin, incorporated herein by reference. Such compositions will contain a therapeutically effective amount of the antigen-binding polypeptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0071] In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachets indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.Attorney Docket No.: 92EW-395024-WOEXAMPLESExample 1: Identification of PLTOOl’s Binding Domains

[0072] This example examined the binding domains on the target CD36 protein for the anti-CD36 antibody PLT001, which has the VH and VL sequences as provided in Table 1.

[0073] The Fab domain of PLT001 (PLTOOl-Fab) was incubated with the extracellular domain of CD36 (CD36-ECD) in vitro, followed by structural analysis. Two binding domains on CD36, AA153-AA160 (Domain 1) and AA191-AA197 (Domain 2), were identified through CryoEM examination. The interaction between PLTOOl-Fab and CD36-ECD was further confirmed by FACS-based binding assays. Point mutations in Domain 1 (M156F, S160F, numbering according to the whole CD36 protein which further includes a signal peptide (SEQ ID NO:9) before the ECD (SEQ ID NO: 10)) reduced the interaction between PLTOOl-Fab and CD36-ECD by nearly 50%, whereas mutations in Domain 2 (Y192R, P193R, F194R) only slightly affected the interaction at lower concentrations of PLT001. Importantly, the interaction was completely abolished when mutations were introduced in both Domains 1 and 2, thereby confirming the findings from structural analyses. Domains 1 and 2 are responsible for fatty acid / oxLDL uptake through CD36.Table 1. Antibody and Target SequencesAttorney Docket No.: 92EW-395024-WOExample 2. NASH Treatment with CD36 Antibodies

[0074] This example identified that CD36, a lipid transporter known to cause foam cell formation, was highly expressed on resident Kupffer cells (KC) and recruited lipid-associated macrophages (LAM) in two diet-induced (MCD and CDA-HFD) nonalcoholic steatohepatitis (NASH / MASH) models (FIG. 1). Moreover, CD36hlghLAMs and KCs exhibited higher lipid content compared to KCs and LAMs expressing low levels of CD36.

[0075] This example next investigated whether targeting CD36-mediated lipid uptake could reduce NASH progression in two different diet models. In both models, treatment with a commercial CD36 blocking antibody (“CD36Ab”) significantly ameliorated liver damage, as assessed by ALT serum levels, and led to a strong decline in BM-derived macrophage populations (LAM and transitional macrophages) (FIG.2).

[0076] Importantly, lipid deposition in hepatic sections as well as crown-like structures (aggregates of macrophages surrounding dying hepatocytes) were also decreased in response to CD36 blockade (FIG. 3). In the long-term NASH induction model, CD36Ab treatment significantly reduced the proportion of alternatively activated tissue-resident CD8 T cells (PD-1hlghand CXCR-6hlgh). This population has been recently linked to liver damage during NASH progression. Altogether, these results highlight that the expression of CD36 in myeloid cells within the liver may contribute to NASH, and CD36 blockade appears to be an attractive target for preventing NASH progression.Attorney Docket No.: 92EW-395024-WO

[0077] The treatment effect of PLT001 was also tested. PLT001 or PBS was administered twice weekly for 2 weeks to mice with CDA-HFD-induced NASH (FIG. 4). Quantitative MFI of cellbound PLT001 in CDA-HFD-induced NASH mice was measured in the animals. Decreased inflammatory cell infiltration was observed in the livers of PLT001 -treated CDA-HFD NASH mice, as compared to control. Likewise, PLT001 treatment has reduced relative and absolute numbers of bone-marrow-derived macrophages in the liver.

[0078] The findings also highlight the advantage of PLT001 for which a twice-weekly injection was more effective than the three-time per week regiment of CD36Ab.Example 3. PLT001 Ameliorated hallmarks of Obese Metabolic Dysfunction-Associated Steatohepatitis (MASH)

[0079] This example tested the effect of PLT001 in treating metabolic dysfunction-associated steatohepatitis (MASH).

[0080] A Western diet-induced MASH mouse model was established using a diet containing 40% fat, 20% fructose, and 2% cholesterol for 10 weeks, followed by randomization into PBS control and PLT001 treatment groups. PLT001 (10 mg / kg, equivalent to 200 pg / mouse) treatment was administered twice weekly for an additional 4 weeks in parallel with WD feeding (FIG. 5A). This model reliably reproduced obesity-associated metabolic dysfunction, resulting in hepatic steatosis, hepatocellular injury, inflammation, and progression to fibrosis, providing a translational model of metabolic syndrome-induced MASH.

[0081] PLT001 treatment reduced the hepatic lipid accumulation, reducing steatosis, as shown by the H&E histological analysis and quantification of lipid droplet area (FIG.5B). Fibrosis progression, quantified by collagen deposition using trichrome (TMB) staining, was decreased in the PLT001 group (FIG. 5C). The histological improvements were accompanied by lower serum ALT and AST (FIG. 5D), reflecting diminished liver injury. (FIG. 5E) Longitudinal ALT measurements assessed after MASH induction before treatment and at the end of the treatment period showed ongoing hepatocellular damage in PBS controls (left) and stabilized levels in PLT001 -treated mice (right). Flow cytometry from the non-parenchymal cell fraction (NPC) within the liver revealed a trend toward decreased overall hepatic leukocyte content, neutrophil,Attorney Docket No.: 92EW-395024-WO and monocyte infiltration (FIG.5F), while inflammatory macrophages, including resident Kupffer cells (resKC) and monocyte-derived Kupffer cells (MonoKC) were markedly reduced following PLT001 treatment (FIG. 5G). Collectively, these findings demonstrate that PLT001 effectively mitigates the metabolic, inflammatory, and fibrotic hallmarks of obesity-induced MASH in this preclinical model.Example 4. PLT001 Exhibited Promising Therapeutic Potential in Lean MASH and Cryptogenic Steatotic Liver Disease

[0082] To evaluate the potential of PLT001 beyond obesity-associated liver pathologies, a lean MASH model was established using a choline-deficient, amino acid-defined (0.1% Methionine) high-fat diet (CDA-HFD). A 2-week feeding period recapitulates the inflammation and steatosis characteristic of lean and cryptogenic steatotic liver disease in the absence of metabolic syndrome. PLT001 treatment (10 mg / kg) was initiated at the same time as diet induction and lasted for 2 weeks (FIG. 6A)

[0083] In this lean MASH model, weight gain did not differ between treatment groups (FIG.6B), while steatosis was reduced with PLT001 as determined histologically by lipid area quantification (FIG. 6C and 6D). PLT001 reduced hepatocellular injury as shown by a reduction in Serum ALT (FIG.6E). Flow cytometry from the NPC fraction revealed an overall reduction of infiltrating leukocytes in PLT001 -treated livers, as well as neutrophils and total monocytes (FIG. 6F) This reduction reflected decreases in bone marrow-derived macrophage subsets, including lipid-associated macrophages (LAM), transitional macrophages (transMac), MonoKC, and resKC (FIG. 6G-H).

[0084] Consistently, qPCR from total liver tissue showed lower expression of TNFa, predominantly secreted by macrophages in MASH, and of monocyte chemoattractant protein- 1 (Ccl2), a key chemokine mediating monocyte and macrophage recruitment (FIG.61).Correspondingly, flow cytometry analysis showed CCR2 (the CCL2 receptor) expression was decreased on bone marrow-derived macrophages (BM-Mac) and MonoKC, but not on resKC, which are independent from recruitment signals (FIG.6 J). Moreover, expression of the CSF1 receptor (CSF1R), essential for macrophage differentiation, was particularly reduced inAttorney Docket No.: 92EW-395024-WO differentiated macrophage populations (MonoKC and resKC) from PLT001 -treated mice, as shown by flow cytometry analysis (FIG. 6K).

[0085] Collectively, these findings indicate that PLT001 attenuates hepatocellular injury and steatosis while selectively depleting inflammatory macrophage subsets and reprogramming the hepatic macrophage niche, supporting its potential in treating lean MASH and cryptogenic steatotic liver disease.Example 5. PLT001 Mitigated Hepatic Fibrosis and Inflammation

[0086] To evaluate the efficacy of PLT001 in advanced stages of lean and cryptogenic steatotic liver disease, mice were fed a CDA-HFD for 6 weeks, a model that develops pronounced fibrosis and inflammation in the absence of obesity (FIG. 7A).

[0087] PLT001 treatment (10 mg / kg) reduced hepatic fibrosis, as quantified by histology analysis of Piero Sirius Red-positive area (FIG.7B-C). This antifibrotic effect was accompanied by a marked reduction in macrophage subsets, including transMac, LAM, MonoKC, and resKC, as determined by flow cytometry of the liver (FIG.7D). Consistently, expression of the inflammatory mediator TNFa and the macrophage recruitment chemokine Ccl2 was decreased in liver tissue from PLT001 -treated mice in qPCR measurement (FIG.7E). These findings indicate that PLT001 attenuates both the inflammatory and fibrotic components of lean MASH pathology, suggesting that modulation of CD36-dependent macrophage activation and persistence contributes to its therapeutic benefit in non-obese and cryptogenic forms of steatotic liver disease.

[0088] Lifestyle modification remains the first-line approach in MASH, with weight-reduction targets of 7-10% in obese patients and 3-5% in lean patients. However, many lean or non-obese patients cannot safely lose additional weight, particularly those with low baseline BMI, sarcopenia, frailty, or cirrhosis, where further weight loss may worsen outcomes. This creates a therapeutic gap, as lean MASH patients face serious disease yet remain underrepresented in clinical trials; for example, they comprised only -2.6% of treated patients in the pivotal semaglutide ESSENCE study. By reducing inflammatory and fibrotic drivers independently of weight loss, PLT001 may help address this unmet need in lean MASH patients.Attorney Docket No.: 92EW-395024-WO

[0089] Despite their diverse origins, MASH, cryptogenic Steatotic Liver Disease (SLD), Alcohol- Associated Liver Disease (ALD), Metabolic Dysfunction with Alcohol- Associated Liver Disease (Met ALD), and some forms of Drug-Induced Liver Injury (DILI) share overlapping pathogenic mechanisms, including hepatocellular lipid accumulation, oxidative stress, chronic inflammation, and fibrogenesis. By directly targeting CD36, PLT001 was able to reduce each of these hallmarks in preclinical models, suggesting that CD36 inhibition could hold therapeutic value not only for MASH, whether obese or lean, but also for related alcohol- and drug-associated liver diseases where effective treatment options remain limited.Example 6. PLT001 Reduced Macrophage Adhesion and Influx In MASH

[0090] To assess whether PLT001 reduces macrophage infiltration and activation by limiting endothelial activation and endothelial-macrophage interaction, this example analyzed PLT001 binding using flow cytometry on endothelial cells after 2 weeks of CDA-HFD and PLT001 treatment (lOmg / kg) or PBS as control.

[0091] PLT001 antibody bound to the surface of endothelial cells (FIG.8A) and did not affect endothelial cell counts (FIG.8B). In addition, PLT001 effectively decreased endothelial lipid uptake (FIG.8C). Expression of the adhesion molecule ICAM-1, which is highly responsive to IL-ip and TNFa, was reduced in liver tissue of CDA-HFD mice treated for 2 weeks with PLT001- but not IgA-treated mice (FIG. 8D, left), as well as in PLT001 -treated mice after 10 weeks of WD (10 mg / kg, twice weekly for 4 weeks) or PBS as control (FIG.8D, right). Analysis of CD31+singlets from 2-week CDA-HFD mice treated with PLT001 (lOmg / kg) or PBS revealed markedly increased macrophage remnants on endothelial surfaces, indicated by VSIG4 expression (FIG. 8E). Conversely, endothelial-immune cell doublets, including hepatic macrophages, were strongly reduced in PLT001 -treated mice (FIG.8F). Flow cytometric analysis of these endothelial-immune cell interactions, specifically CD31+F4 / 80+CD64+, showed decreased leukocyte adhesion molecules (CD44, CD62L) and reduced CCR2 expression (FIG.8G).

[0092] Together, these findings demonstrate that PLT001 attenuates endothelial activation in MASH, leading to lower adhesion molecule expression and diminished macrophage interaction and differentiation.Attorney Docket No.: 92EW-395024-WOExample 7. Comparison of PLT001 to CD36Ab

[0093] This example compared PLT001 with CD36Ab (also referred to as “Anti-CD36 IgA”), a commercially available IgA anti-CD36 antibody, and showed that PLT001 demonstrated superior efficacy in the CDA-HFD mouse model over CD36Ab at the same concentration.

[0094] At 10 mg / kg (FIG. 9A), PLT001 exhibited more effective reduction of liver injury markers (ALT and AST) than CD36Ab (FIG. 9B). At the metabolic level, PLT001 selectively decreased de novo lipogenesis, as indicated by reduced expression of key rate-limiting lipogenic enzymes liver tissue measured by qPCR (FIG.9C), while P-oxidation and long-chain fatty acid import pathways remained unaltered (FIG.9D). This suggests a targeted reprogramming of hepatocyte lipid metabolism that preserves oxidative function.

[0095] Consistent with these molecular changes, PLT001 reduced steatosis, as shown by histological analysis of lipid deposition area (FIG.9E). In addition, PLT001 (but not CD36Ab) exhibited early antifibrotic potential, evidenced by decreased expression of Col3al and Col lai by qPCR of whole liver tissue (FIG.9F), reflecting reduced stellate cell activation and collagen deposition. Both PLT001 and CD36Ab lowered pro-inflammatory mediator expression, such as TNFa, assessed by qPCR of whole livers, although the effect was more pronounced with PLT001 (FIG. 9G). Notably, IL-ip was only reduced by PLT001, not anti-CD36 IgA (FIG.9G).Importantly, flow cytometry analysis showed that only PLT001 reduced early differentiationstate pathogenic bone marrow-derived macrophage subsets (LAM and transMac), whereas MonoKC and resKC were decreased by both PLT001 and CD36Ab (FIG. 9H).

[0096] These findings highlight PLTOOl’s broader impact on the inflammatory-fibrotic microenvironment, underscoring PLTOOl’s unique position for the treatment of MASH.* * *

[0097] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variationsAttorney Docket No.: 92EW-395024-WO can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0098] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

Attorney Docket No.: 92EW-395024-WO CLAIMSWhat is claimed is:

1. A method for treating a liver disease in a subject, comprising administering to the subject an anti-CD36 antibody or antigen-binding fragment thereof.

2. The method of claim 1, wherein the anti-CD36 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 comprise, respectively, the amino acid sequences of SEQ ID NO:3-8.

3. The method of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO:1 and the VL comprises the amino acid sequence of SEQ ID NO:2.

4. The method of claim 2 or 3, wherein the antibody comprises a human IgG4 Fc fragment.

5. The method of any preceding claim, wherein the subject has an increased fatty acid concentration in the liver as compared to a reference healthy subject.

5. The method of any preceding claim, wherein the liver disease is selected from the group consisting of alcoholic liver disease (ALD), autoimmune liver diseases, genetic liver disease, drug-induced liver injury (DILI), cryptogenic steatotic liver disease (SLD), and nonalcoholic fatty liver disease (NAFLD).

6. The method of claim 5, wherein the subject has metabolic dysfunction-associated steatohepatitis (MASH).Attorney Docket No.: 92EW-395024-WO7. The method claim 6, wherein the MASH has a stage selected from the group consisting of steatosis, mild MASH, moderate MASH, advanced MASH and cirrhosis.

8. The method of any preceding claim, wherein the subject has a body mass index (BMI) of 25 kg / m2or higher.

9. The method of claim 8, wherein the subject has a BMI of 28 kg / m2or higher, or 30 kg / m2or higher.

10. The method of claim 8, wherein the subject has a BMI of 25 kg / m2or lower, or 23 kg / m2or lower.

11. The method of claim 5, wherein the liver disease is cryptogenic SLD.

12. The method of any preceding claim, wherein the subject is administered the antibody or antigen-binding fragment thereof at a dose of 10 mg to 500 mg twice per week, 20 mg to 400 mg twice per week, 30 mg to 300 mg twice per week, 40 mg to 250 mg twice per week, 50 mg to 200 mg twice per week, 60 mg to 180 mg twice per week, 70 mg to 160 mg twice per week, 80 mg to 150 mg twice per week, 90 mg to 140 mg twice per week, or 100 mg to 120 mg twice per week.

13. The method of any one of claims 1-11, wherein the subject is administered the antibody or antigen-binding fragment thereof at a dose of 10 mg to 500 mg once per week, 20 mg to 400 mg once per week, 30 mg to 300 mg once per week, 40 mg to 250 mg once per week, 50 mg toAttorney Docket No.: 92EW-395024-WO200 mg once per week, 60 mg to 180 mg once per week, 70 mg to 160 mg once per week, 80 mg to 150 mg once per week, 90 mg to 140 mg once per week, or 100 mg to 120 mg once per week.

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