Treatment methods using SIRP-alpha FC fusion polypeptides

Abstract

The present disclosure provides methods for administration of a signal-regulatory protein α (SIRPα) Fc fusion polypeptide to a subject to treat atherosclerosis. Dosage regimens for use in the methods are provided herein.

Description

Attorney Docket: BTRT-Oll / OIWO 342313-2192TREATMENT METHODS USING SIRP-ALPHA FC FUSION POLYPEPTIDESCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 742,369, filed January 6, 2025, U.S. Provisional Patent Application No. 63 / 754,440, filed February 5, 2025, and US. Provisional Patent Application No. 63 / 769,669, filed March 10, 2025, all of which are incorporated herein by reference in their entirety.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (BTRT_011_03WO_SeqList_ST26.xml; Size: 21,083 bytes; and Date of Creation: January 5, 2026) are herein incorporated by reference in their entirety.BACKGROUND

[0003] Atherosclerosis is a disease characterized by formation of plaques on the walls of arteries.Typically, atherosclerotic plaques result from accumulation of lipids, inflammatory cells, smooth muscle cells, and necrotic cell debris in the intima of the artery underneath a monolayer of endothelial cells that line the interior vessel wall. Plaques can grow to sufficient size to reduce blood flow in the lumen of the vessel and may cause angina (e.g., chest pain) during exercise or stress. Additionally, such plaques can become unstable and rupture, resulting in formation of a thrombus or blood clot that may completely obstruct blood flow (e.g., causing myocardial infarction) or travel to the brain (e.g., causing stroke).

[0004] Atherosclerosis is the most common form of cardiovascular (CV) disease, which accounts for nearly a third of all deaths worldwide. Atherosclerotic cardiovascular disease (ASCVD) typically manifests clinically as ischemic heart disease, ischemic stroke, or peripheral arterial disease. Existing pharmacologic therapies for ASCVD are primarily directed at traditional risk factors such as hypertension, hypercholesterolemia, diabetes mellitus, and obesity. Atherosclerosis is not limited to cardiovascular tissues, and can develop in other body tissues as well.

[0005] Recent work has established a role for inflammation in the pathogenesis of atherosclerosis. There however remains a need for therapeutic agents that safely and329750705 1Attorney Docket: BTRT-Oll / OIWO 342313-2192effectively treat atherosclerosis, e.g., by regulating inflammatory pathways. Provided herein are the same, including modulators of cardio-immunology for treating subjects having atherosclerosis (e.g., ASCVD).SUMMARY

[0006] In some aspects, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal-regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 75 mg per kg (mg / kg) of body weight of the subject.

[0007] In some aspects, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the SIRPa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 5 mg per kg (mg / kg) of body weight of the subject.

[0008] In some aspects, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of a dose of the SIRPa Fc fusion polypeptide to achieve a target occupancy of at least about 20%.

[0009] In some embodiments of any of the foregoing or related aspects, the dose of the SIRPa Fc fusion polypeptide administered is about 0.1 to about 5 mg / kg of body weight of the subject. In some embodiments, the dose of the SIRPa Fc fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the dose of the SIRPa Fc fusion polypeptide administered is about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject. In some embodiments, the dose is about 0.5 to about 5 mg / kg of body weight of the subject. In some embodiments, the dose is about 1, 3 or 5 mg / kg of body weight of the subject. In some embodiments, the dose of the SIRPa Fc fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the dosing frequency is once every about 1 day to about 14 days329750705 2Attorney Docket: BTRT-Oll / OIWO 342313-2192for at least one month. In some embodiments, the dosing frequency is once every about 7 days to about 30 days for at least two months.

[0010] In some embodiments of any of the foregoing or related aspects, the dosing regimen comprises a starting dosing cycle and a maintenance dosing cycle. In some embodiments, the starting dosing cycle comprises administration of a starting dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days for a duration of time. In some embodiments, the starting dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject. In some embodiments, the maintenance dosing cycle comprises administration of a maintenance dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days. In some embodiments, the maintenance dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject. In some embodiments, the dosing frequency of the starting dosing cycle and the maintenance dosing cycle is the same. In some embodiments, the dosing frequency of the starting dosing cycle and the maintenance dosing cycle are different. In some embodiments, the starting dose and the maintenance dose are the same. In some embodiments, the starting dose and the maintenance dose are different. In some embodiments, the dosing frequency of the starting dosing cycle is once every about 1 to about 7 days for about 1 to about 6 months, and the dosing frequency of the maintenance dosing cycle is once every about 7 to about 30 days for at least 2 months. In some embodiments, the starting dose is administered at a dose of about 0.3 to about 3 mg / kg of body weight of the subject, and the maintenance dose is administered at a dose of about 0.5 to about 1 mg / kg of body weight of the subject. In some embodiments, the starting dose is administered at a dose of about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject, and the maintenance dose is administered at a dose of about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject.

[0011] In some embodiments of any of the foregoing or related aspects, the dosing regimen comprises administration of a starting dose followed by a maintenance dose. In some embodiments, the dosing regimen comprises administration of a single starting dose. In some embodiments, the dosing regimen comprises administration of a maintenance dose once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the dosing regimen comprises administration of the maintenance dose beginning about 1 to about 4 weeks following the starting dose. In some embodiments, the starting dose is about 1 mg / kg to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg to about 1 mg / kg.329750705 3Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0012] In some embodiments of any of the foregoing or related aspects, the subject is at least about 40 years old and up to about 85 years old. In some embodiments, the subject has a body weight of at least about 40 kg and up to about 140 kg.

[0013] In some embodiments of any of the foregoing or related aspects, the subject has atherosclerotic disease or is at risk of developing atherosclerotic disease. In some embodiments, the subject has exhibited at least one atherosclerotic cardiovascular disease (ASCVD) event prior to treatment. In some embodiments, the subject exhibited an ASCVD event not more than about 12 months prior to treatment. In some embodiments, the ASCVD event is selected from the group consisting of a stroke, transient ischemic attack, carotid artery disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, mesenteric ischemia, and a combination thereof. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a history of asymptomatic carotid artery stenosis of at least about 50%. In some embodiments, the subject has at least two of the following: (i) an age greater than about 65 years; (ii) a history of hypertension; (iii) a history of hyperlipidaemia on lipid lowering therapy, or a medical history of intolerance to lipid lowering therapy and an LDL-cholesterol of about 190 mg / dL or higher; (iv) a history of smoking; (v) a history of non-insulin dependent diabetes mellitus; (vi) a level of C-reactive protein of about 2 mg / L or higher as measured by a high sensitivity C-reactive protein blood test; (viii) peripheral artery disease; and (ix) a maximum target-to-background ratio of about 1.6 or higher in a carotid artery as measured by 18F-FDGPET / CT. In some embodiments, the subject has received or is receiving a treatment for ASCVD, optionally wherein the treatment comprises administration of a statin.

[0014] In some embodiments of any of the foregoing or related aspects, the subject has exhibited a risk factor for ASCVD prior to the dosing regimen. In some embodiments, the risk factor is selected from the group consisting of: (i) a genotype comprising a homozygous or heterozygous 9p21 risk allele, optionally wherein the 9p21 risk allele comprises a single polymorphism (SNP) variant at 9p21; (ii) a presence of perivascular inflammation, optionally wherein the presence is measured by a coronary heart scan; (iii) a presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells, optionally wherein CHIP is measured by gene sequencing; (iv) an intermediate or high level of C-reactive protein (CRP); (v) an elevated polygenic risk score; (vi) an increased level of a marker of inflammation, optionally wherein the marker of inflammation is selected from IL-6, IL-8,329750705 4Attorney Docket: BTRT-Oll / OIWO 342313-2192fibrinogen, human serum amyloid A (SAA), haptoglobin, phospholipase A2 (sPLA2), lipoprotein(a), an apolipoprotein B (APOB) to apolipoprotein Al (AP0A1) ratio, a white blood cell count, and a combination thereof; and (vii) a combination of any of (i)-(vi).

[0015] In some embodiments of any of the foregoing or related aspects, the SIRPa Fc fusion polypeptide is administered by intravenous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered by subcutaneous injection.

[0016] In some embodiments of any of the foregoing or related aspects, administration of the SIRPa Fc fusion polypeptide achieves a peak target occupancy of about 20% to about 100%. In some embodiments, the peak target occupancy is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample or an atherosclerotic plaque specimen. In some embodiments, the peak target occupancy is measured on white blood cells (“WBCs”) (e.g., CD45-positive cells in blood) and / or red blood cells (“RBCs”) (e.g., CD45-negative cells in blood). In some embodiments, the peak target occupancy is about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, the peak target occupancy occurs about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide. In some embodiments, administration of the SIRPa Fc fusion polypeptide achieves an average target occupancy of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% for a duration of time of at least about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide. In some embodiments, the average target occupancy is measured on WBCs (e.g., CD45-positive cells in blood) and / or RBCs (e.g., CD45-negative cells in blood).

[0017] In some embodiments of any of the foregoing or related aspects, the treatment results in the stabilization of or a reduction in a plaque lesion size, optionally wherein plaque lesion size is a measure of total vessel area. In some embodiments, the plaque lesion size is reduced by at least about 5%. In some embodiments, plaque lesion size is measured by imaging.

[0018] In some embodiments of any of the foregoing or related aspects, administration of the SIRPa Fc fusion polypeptide does not result in an adverse event requiring discontinuation of treatment. In some embodiments, administration of the SIRPa Fc fusion polypeptide is tolerated in the subject. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not substantially alter plasma levels of hemoglobin and / or platelets. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not substantially alter329750705 5Attorney Docket: BTRT-Oll / OIWO 342313-2192a plasma level of neutrophils. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not result in anemia and / or thrombocytopenia. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not result in a detectable antidrug antibody (ADA) response. In some embodiments, administration of the SIRPa Fc fusion polypeptide achieves an average Cmax of about 50 ng / mL to about IxlO4ng / mL (e.g., about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 500 ng / mL, about IxlO3ng / mL, about 2xl03ng / mL, about 3xl03ng / mL, about 4xl03ng / mL, about 5xl03ng / mL, about 6xl03ng / mL, about 7xl03ng / mL, about 8xl03ng / mL, about 9xl03ng / mL or about lxl04ng / mL). In some embodiments, the average Cmax is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample (e.g., whole blood, serum, or plasma). In some embodiments, administration of the SIRPa Fc fusion polypeptide achieves an average AUC of about IxlO4h per ng / mL (h*ng / mL) to about 5xl06h*ng / mL (e.g., about lxl04h*ng / mL, about 5xl04h*ng / mL, about IxlO5h*ng / mL, about 5xl05h*ng / mL, about lxl06h*ng / mL, or about 5xl06h*ng / mL). In some embodiments, the average AUC is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample (e.g., whole blood, serum, or plasma). In some embodiments, the average AUC is determined to a last quantifiable time point. In some embodiments, the last quantifiable time point is about 500-1500 hours following administration of the SIRPa Fc fusion polypeptide.

[0019] In some embodiments of any of the foregoing or related aspects, the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises one or more of the following mutations relative to SEQ ID NO: 1 : V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue. In some embodiments, the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0020] In some embodiments of any of the foregoing or related aspects, the Fc domain comprises the IgG4 Fc domain amino acid sequence of any of SEQ ID NOs: 7-8 and 16-17 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least329750705 6Attorney Docket: BTRT-Oll / OIWO 342313-219290%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the Fc domain comprises M252Y-S254T-T256E, relative to SEQ ID NO: 7-8 and 16-17, according to the EU numbering scheme. In some embodiments, the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0021] In some embodiments of any of the foregoing or related aspects, the Fc domain comprises any of SEQ ID NOs: 7-9 and 16-18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the high affinity SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0022] In some embodiments of any of the foregoing or related aspects, the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0023] In some embodiments of any of the foregoing or related aspects, the SIRPa Fc fusion polypeptide comprises any of SEQ ID NOs: 10, 13-14, and 19, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0024] In some embodiments of any of the foregoing or related aspects, the method comprises administering a second therapeutic agent to the subject, optionally wherein the second therapeutic agent comprises a TNFa antagonist.

[0025] In some aspects, the disclosure provides a kit comprising a container comprising: a pharmaceutical composition comprising a SIRPa fusion polypeptide and a pharmaceutically acceptable carrier or diluent, and instructions for use in treating atherosclerotic disease in a human subject, wherein the treatment comprises administration of the pharmaceutical composition at a dose of about 0.1 to about 5.0 mg / kg of the SIRPa fusion polypeptide by body weight of the subject, and wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain.329750705 7Attorney Docket: BTRT-Oll / OIWO 342313-2192BRIEF DESCRIPTION OF THE FIGURES

[0026] FIG. 1 is a schematic showing an exemplary mechanism of action for a SIRPa Fc fusion polypeptide of the disclosure. As shown, and without being held to theory or mechanism, the SIRPa Fc fusion polypeptide binds to CD47 on a target cell, thereby blocking the “don’t eat me” SIRPa-CD47 signaling axis and facilitating phagocytosis of the CD47-expressing target cell by the SIRPa-expressing phagocytic cell, e.g., by favoring an “eat me” pathway such as that between LRP1 (low-density lipoprotein receptor-related protein 1) and calreticulin (CALN).

[0027] FIG. 2A is a graph showing luciferase signal (RLU) from a co-culture of effector cells (Jurkat cells expressing a FcyRIIIa-luciferase) and target cells (Raji cells) in the presence of the indicated concentration of an exemplary SIRPa Fc fusion polypeptide of the disclosure (“CV1-G4(YTE)”) as a measure of antibody-dependent cellular cytotoxicity (ADCC). Positive control was ADCC-inducing antibody rituximab. Negative control was an IgG4 isotype antibody (“huIgG4”).

[0028] FIG. 2B is a graph showing percent target cell death from a co-culture of effector cells (primary human NK cells) and target cells (Raji cells) in the presence of the indicated concentration of CV1-G4(YTE) as a measure of ADCC. Positive control was ADCC-inducing antibody rituximab. Negative control was an IgG4 isotype antibody (“huIgG4”).

[0029] FIGs. 2C-2D are graphs showing cell viability of target cells (Raji cells) following exposure to the indicated concentration of CV1-G4(YTE), either in the presence or absence of complement-containing serum (FIG. 2C and FIG. 2D respectively) as a measure of complement dependent cytotoxicity (CDC). Positive control was CDC-inducing antibody rituximab. Negative control was an IgG4 isotype antibody (“huIgG4”).

[0030] FIG. 3 shows a hemagglutination assay in which red blood cells are exposed to a decreasing concentration of CV1-G4(YTE) and evaluated for clumping (punctate dot) or dispersion (a characteristic of hemagglutination). Positive control was anti-CD47 CC2C6 antibody. Negative control was an IgG4 isotype antibody (“huIgG4”).

[0031] FIG. 4 is a graph showing CD47 target occupancy as a percentage of total CD47 on CD45-negative cells (RBCs) in whole blood obtained from mice administered the indicated dose of CV1-G4(YTE). The indicated time point from the first dose of CV1-G4(YTE) is shown on the y-axis. Control mice received an IgG4 isotype antibody (“isotype”).

[0032] FIGs. 5A-5C are graphs showing average concentration (ng / mL) of CV1-G4(YTE) measured in serum of male (M) or female (F) rats following weekly subcutaneous329750705 8Attorney Docket: BTRT-Oll / OIWO 342313-2192administration of a 1 mg / kg, 10 mg / kg, or 50 mg / kg dose of CV1-G4(YTE) on day 1 (FIG.5A), day 22 (FIG. 5B), and day 29 (FIG. 5C) following the first dose.

[0033] FIGs. 6A-6B are graphs showing average concentration (pg / mL) of CV1-G4(YTE) measured in serum of male (M) or female (F) non-human primates (NHPs) following weekly subcutaneous administration of a 2.5 mg / kg, 15 mg / kg, or 75 mg / kg dose of CV1-G4(YTE) on day 1 (FIG. 6A) or day 29 (FIG. 6B) following the first dose.

[0034] FIGs. 7A-7E are graphs showing average hemoglobin concentration (FIG. 7A), platelet count (FIG. 7B), white blood cell count (FIG. 7C), neutrophil count (FIG. 7D), and lymphocyte count (FIG. 7E) measured in the serum of NHPs described in FIGs. 6A-6B.

[0035] FIG. 8 is a schematic showing dosing cohorts in a Phase 1 randomized, double-blind, placebo-controlled single dose study to evaluate subcutaneous doses of CV1-G4(YTE) in healthy male participants.

[0036] FIGs. 9A-9B are graphs showing CD47 target occupancy as a percentage of total CD47 on CD45-positive cells (white blood cells; “WBCs”) (FIG. 9A) or CD45-negative cells (red blood cells; “RBCs”) (FIG. 9B) in whole blood obtained from participants described in FIG. 8 at indicated time points relative to the day on which participants received the subcutaneous dose of CV1-G4(YTE) (i.e., day 1).

[0037] FIG. 10 is a graph showing average concentration (ng / mL) of CV1-G4(YTE) measured in plasma obtained from participants described in FIG. 8 at indicated time points relative to day 1.

[0038] FIGs. 11A-11C are graphs respectively showing hemoglobin, platelet count, and absolute neutrophil count measured in blood obtained from participants described in FIG. 8 at indicated time points relative to day 1.DETAILED DESCRIPTION

[0039] Provided herein are dosing regiments that are useful for treating subjects with atherosclerosis (e.g., ASCVD), some of whom despite receiving prior treatments, remain at significant residual risk for life-threatening cardiovascular events. The inventors have found that particular dosing regimens of a SIRPa Fc fusion polypeptide described herein can potentially decrease this residual risk by modulating the macrophage response within inflamed atherosclerotic plaque.

[0040] Accordingly, the present disclosure is directed to methods of treating atherosclerosis in a human subject by administering an effective amount of a SIRPa Fc fusion polypeptide329750705 9Attorney Docket: BTRT-Oll / OIWO 342313-2192described herein. As described herein, the SIRPa Fc fusion polypeptides for use in the methods of the disclosure interfere with, disrupt, or block binding of SIRPa with CD47. In some embodiments, the methods and compositions of the disclosure decrease and / or resolve inflammation associated with atherosclerosis, thereby reducing the risk of atherosclerotic disease (e.g., ASCVD).

[0041] As appreciated by the skilled artisan, CD47 is a cell surface transmembrane protein expressed on a broad range of cell types (Brown, et al (2001) Trends Cell Biol 11:130).Typically, the interaction between CD47 and SIRPa (signal-regulatory protein alpha) on macrophages acts as an inhibitory ‘don’t eat me’ signal to protect healthy cells from phagocytosis (Kojima, et al (2016) Nature 536:86; Jarr, et al (2022) Axis. Arterioscler Thromb Vase Biol.; 42(6):el45-el54). Conversely, foreign materials or cells are taken up by phagocytes due, at least in part, to the absence of CD47.

[0042] An atherosclerotic plaque in a vessel wall is characterized by the accumulation of diseased and dying apoptotic cell debris. Without being bound by theory or mechanism, the increased expression of CD47 in the atherosclerotic plaque is thought to prevent macrophage clearance of the cellular debris, resulting in increased inflammation and / or expansion of the plaque. As described herein, it is demonstrated that exemplary SIRPa Fc fusion polypeptides of the disclosure, when administered in particular dosage regimens, in an animal model of atherosclerosis, result in a reduction of atherosclerotic plaque burden. Without being bound by theory or mechanism, binding of the SIRPa Fc fusion polypeptide to CD47 present in an atherosclerotic plaque results in increased phagocytosis of CD47-expressing cells by SIRPa-expressing phagocytes (see, e.g., FIG. 1), thereby promoting clearance of diseased and dying apoptotic cells from the atherosclerotic plaque and reducing atherosclerotic plaque size.

[0043] It has been further demonstrated that administration of a range of doses of a SIRPa Fc fusion polypeptide to a human subject, according to the methods and dosing regimens described herein, was tolerated (e.g., without requiring discontinuation of treatment) and achieved a dose-dependent target occupancy (e.g., CD47 occupancy) of 10% or higher (e.g., when measured as a percentage of total target on white blood cells present in a blood sample obtained from the subject). In exemplary embodiments described herein, administration of a dose of SIRPa Fc fusion polypeptide of the disclosure to human subjects was demonstrated to be safe and well-tolerated, e.g., as evidenced by a lack of significant effect on hematologic parameters (e.g., a plasma level or count of hemoglobin, platelets, and / or absolute neutrophils) as compared to placebo, and a lack of serious adverse effects.329750705 10Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0044] Without being bound by theory or mechanism, administration of a SIRPa Fc fusion polypeptide of the disclosure to a human subject, at a particular dose and dosing regimen described herein (e.g., a dosing regimen comprising administering the dose of the SIRPa Fc fusion polypeptide at a dosing frequency, for a duration of time, by a route of administration, each of which are described herein) provides a level of the SIRPa Fc fusion polypeptide (e.g., as measured by target occupancy of the SIRPa Fc fusion polypeptide) sufficient to yield a desired therapeutic effect, such as a beneficial clinical outcome (e.g., a stabilization or reduction in atherosclerotic plaque size and / or a reduced risk of occurrence of an ASCVD event) without adverse effects (e.g., anemia and / or thrombopenia) or a substantial change in hematological parameters (e.g., platelet count, neutrophil count, and / or hemoglobin levels as measured in a blood sample obtained from the human subject).Definitions

[0045] Unless otherwise defined herein, scientific and technical terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art.Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell biology, immunology, pharmacology, and protein chemistry, described herein, are those well-known and commonly used in the art.

[0046] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” refers to one or mixtures of such candidates, and reference to “a method” includes reference to equivalent steps and methods known to those skilled in the art, and so forth.

[0047] As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar in magnitude and / or within a similar range to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0048] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated329750705 11Attorney Docket: BTRT-Oll / OIWO 342313-2192range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0049] As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

[0050] As used herein, the terms “polypeptide” and “protein” are used interchangeably and refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, to include disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component.

[0051] As used herein, the term “nucleic acid sequence” or “nucleotide sequence” refers to a molecule comprising either of a sequence of DNA or RNA nucleotides, presented from 5' to 3'.

[0052] As used herein, "antibody" includes reference to a full-length immunoglobulin molecule immunologically reactive with a particular antigen, including both polyclonal and monoclonal antibodies. The term includes humanized antibodies, chimeric antibodies e.g., murine variable region with a human constant region, and conjugated antibodies.

[0053] The term “Fc domain” (also interchangeably referred to herein as “Fc sequence”, “Fc region”, or simply as “Fc”) as used herein refers to a fragment crystallizable region monomer of an antibody domain comprising a constant heavy chain 2 domain (CH2) and a constant heavy chain 3 domain (CH3). In some embodiments the “Fc domain” sequence comprises an IgG region sequence. In some embodiments, Fc domains dimerize or form other multimers. Exemplary human Fc domains include IgGl, IgG2, IgG3, and IgG4 Fc domains.

[0054] Unless otherwise noted, modifications in an Fc domain are presented according to the EU numbering scheme. However, there are multiple numbering schemes which can be easily cross-referenced by one of skill in the art (www.imgt.org / IMGTScientificChart / Numbering / Hu IGHGnb er. html#ref s) .

[0055] As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules and / or RNA329750705 12Attorney Docket: BTRT-Oll / OIWO 342313-2192molecules) and / or between polypeptide molecules. Calculation of the percent identity of two protein sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The amino acid residues at corresponding positions are then compared. When a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two protein sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing:Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference.Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux et al., Nucleic Acids Research, 12(1): 387,1984, BLASTP, BLASTN, and FASTA, Altschul, S. F. et al., J. Molec. Biol., 215, 403, 1990.

[0056] As used herein, the terms "treatment," "treating," and the like, refer to administering an agent, or carrying out a procedure, for the purposes of obtaining an effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of effecting a partial or complete cure for a disease and / or effecting partial or complete reduction of symptoms of the disease. The term includes, but is not limited to, inhibiting the disease, e.g., arresting its initiation, development, and / or progression; and relieving the disease, e.g., causing regression of the disease.329750705 13Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0057] Treating may refer to any indicia of success in the treatment or amelioration or prevention of disease, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disease condition more tolerable to the subject; slowing in the rate of degeneration or decline; or making the final point of degeneration less debilitating. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of an examination by a physician. Generally, treating includes administration of a therapeutic agent (e.g., a SIRPa Fc fusion polypeptide described herein) to prevent or delay, to alleviate, or to arrest or inhibit development of symptoms or conditions associated with atherosclerotic disease (e.g., an ASCVD event).

[0058] As used herein, the term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and / or prophylactic effect and / or elicits a desired biological and / or pharmacological effect.

[0059] As used herein, the term "therapeutic effect" refers to the reduction, elimination, or prevention of the disease, symptoms of the disease, or side effects of the disease in the subject.

[0060] As used herein, the terms “individual,” “subject,” and “subject” are used interchangeably and refer to any subject for whom treatment is desired. The subject may be a mammalian subject. Mammalian subjects include, e. g., humans, non-human primates, rodents, (e.g., rats, mice), lagomorphs (e.g., rabbits), ungulates (e.g., cows, sheep, pigs, horses, goats, and the like), etc. In some embodiments, the subject is a human. In some embodiments, the subject is a non- human primate, for example a cynomolgus monkey. In some embodiments, the subject is a companion animal (e.g., cats, dogs).

[0061] The term “sample” with respect to a subject or subject encompasses blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The definition also includes samples that have been manipulated in any way after their procurement, such as by treatment with reagents; washed; or enrichment for certain cell populations. The definition also includes sample that have been enriched for particular types of molecules, e.g., nucleic acids, polypeptides, etc. In some embodiments, the sample comprises blood or a component thereof (e.g., serum or plasma) obtained from the subject. In some embodiments, the sample comprises an atherosclerotic plaque specimen. Methods for obtaining an atherosclerotic plaque specimen from a subject are known in the art, and include, for example, removing an atherosclerotic plaque or portion thereof during an invasive procedure (e.g., surgery)329750705 14Attorney Docket: BTRT-Oll / OIWO 342313-2192performed on the subject or extracting the atherosclerotic plaque or portion thereof during catheterization.

[0062] As used herein, the term “dosing regimen” refers to a schedule and manner by which a therapeutic agent of the disclosure is administered to a subject (e.g., a human subject). The term encompasses the dose, dosing frequency, route of administration, and duration of dosing. In some embodiments, the dosing regimen comprises administration of more than one dose of the therapeutic agent, wherein the more than one dose is administered in a dosing cycle for a duration of time. In some embodiments, the dosing regimen comprises a first dosing cycle and at least one subsequent dosing cycle.

[0063] As used herein, the term “dose” refers to an amount of a therapeutic agent administered to a subject. In some embodiments, the dose is a flat dose, wherein the amount of the therapeutic agent administered to a subject is independent of the weight of the subject. In some embodiments, the dose is a weight-based dose, wherein the amount of the therapeutic agent administered to a subject depends upon the weight of the subject.

[0064] As used herein, the terms “starting dose” are used interchangeably to refer to the dose of the therapeutic agent administered to a subject administered in a first dosing cycle of a dosing regimen. In some embodiments, the starting dose is selected to deliver an amount of the therapeutic agent to the subject that is tolerated by the subject (e.g., does not result in in adverse effects that require discontinuation of treatment). In some embodiments, the starting dose is selected to achieve a predetermined pharmacokinetic and / or pharmacodynamic property associated with a desired therapeutic effect (e.g., a predetermined target occupancy associated with a desired therapeutic effect).

[0065] As used herein, the term “maintenance dose” refers to a dose of the therapeutic agent administered to as subject in a second or further dosing cycle of a dosing regimen. In some embodiments, the maintenance dose is selected to deliver an amount of the therapeutic agent to the subject that is tolerated by the subject (e.g., does not result in in adverse effects that require discontinuation of treatment) and / or maintains a predetermined pharmacokinetic property and / or pharmacodynamic property associated with a desired therapeutic effect for a duration of time.

[0066] As used herein, the term “dosing cycle” refers to a dose of a therapeutic agent administered to a subject at a regular dosing frequency over a duration of time. For example, in some embodiments, the dosing cycle comprises administration of a dose of a SIRPa Fc fusion polypeptide to a subject at a dosing frequency of once every 1-60 days for a duration of time. In some embodiments, the duration of time is a 2x to 50x multiple of the dosing329750705 15Attorney Docket: BTRT-Oll / OIWO 342313-2192frequency (e.g., a lOx multiple of a dosing frequency of once every 7 days is 70 days, such that 10 doses are administered in the dosing cycle).

[0067] As used herein, the term “dosing frequency” refers to a discrete amount of time, expressed in units of time (e.g., days), that transpires between individual administrations of a dose of a therapeutic agent (e.g., a SIRPa Fc fusion polypeptide). For example, in some embodiments, a dosing frequency starts on the day a first dose is administered (e.g., initial dose), and ends on the day a second dose (e.g., a subsequent dose) is administered.

[0068] As used herein, the terms "in combination with," "combination therapy" and "combination products," each refer to the concurrent administration to a subject of a compositions described herein (e.g., the compositions comprising a SIRPa Fc fusion polypeptide) and a second therapeutic agent (e.g., a statin). When administered in combination, each component can be administered at the same time or sequentially in any order at different points in time. Thus, each component can be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. In some embodiments, a subject treated with a method of the disclosure is receiving a regular (daily) dose of a statin and one or more doses of a SIRPa Fc fusion polypeptide described herein.

[0069] As used herein, the term “effective amount” of a therapeutic agent is that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of administering an agent that treats atherosclerotic disease, an effective amount of an agent is, for example, an amount sufficient to achieve treatment, as defined herein, of atherosclerotic disease, as compared to the response obtained without administration of the agent. In some embodiments, a therapeutically effective amount is an amount of a therapeutic agent to be delivered (e.g., SIRPa Fc fusion polypeptide) that is sufficient, when administered to a subject suffering from or at risk of developing a disease, disorder, and / or condition associated with atherosclerosis, to treat, improve symptoms of, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. In some embodiments, the effective amount is administered in a single dose. In some embodiments, the effective amount is administered in more than one dose.

[0070] As used herein, the term “no observed adverse effect level” or “NOAEL” refers to the highest dose level of a therapeutic agent (e.g., a SIRPa Fc fusion polypeptide described herein) administered to subject that does not produce a significant increase in adverse effects in comparison to a control subject not receiving the therapeutic agent. In some embodiments, the NOAEL is determined in a nonclinical toxicology study, such as one described herein. In329750705 16Attorney Docket: BTRT-Oll / OIWO 342313-2192some embodiments, an adverse effect comprises observation of overt toxicity (e.g., clinical signs of toxicity such as weight loss) and / or an increase in a toxicity biomarker (e.g., serum liver enzyme levels). In some embodiments, the adverse effect comprises an observation selected from the group consisting of: decreased mortality, injection site reaction, dermal irritation, altered (e.g., increased or decreased) food consumption (e.g., quantitative and / or qualitative food consumption), an altered (e.g., increased or decreased) pathology parameter, altered (e.g., increased or decreased) blood pressure, altered (e.g., increased or decreased) respiratory rate, altered ophthalmology, altered electrocardiography, and a combination thereof. In some embodiments, the pathology parameter comprises a hematology, coagulation, urinalysis, and / or blood chemical parameter. For example, in some embodiments, the pathology parameter comprises a myeloid:erythroid (M:E) ratio, immunophenotype, cytokine analysis, numbers of megakaryocytes, absolute reticulocyte counts, lymphocyte counts, neutrophil counts, white blood cell (WBC) counts, eosinophil counts, erythrocyte mass (RBC count, hemoglobin concentration and / or hematocrit), monocyte counts, fibrinogen concentrations, RBC distribution width, incidence of erythrocyte polychromasia, and bilirubin, albumin, and total protein concentrations.

[0071] As used herein, the term “human equivalent dose” or “HED” refers to dose in humans anticipated to provide the same degree of effect as that observed in animals at a given dose.

[0072] As used herein, the term “maximum recommended starting dose” or “MRSD” refers to the highest dose recommended as the initial dose in a clinical trial, e.g., a dose in a clinical trial of adult healthy volunteers that is expected to cause no adverse reactions.

[0073] As used herein, the term “pharmacologically active dose” or “PAD” refers to the lowest dose tested in an animal species having the intended pharmacologic activity.

[0074] The term “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0075] As used herein, the term “atherosclerosis” is used interchangeably with the terms “atherosclerotic disease,” “arteriosclerosis,” “atheromatous vascular disease,” or “arterial occlusive disease,” and refers to a pathology characterized by plaque accumulation on vessel walls and vascular inflammation. Vascular inflammation is a hallmark of active atherosclerotic disease, unstable plaque, or vulnerable plaque. The plaque consists of accumulated intracellular and extracellular lipids, smooth muscle cells, connective tissue,329750705 17Attorney Docket: BTRT-Oll / OIWO 342313-2192inflammatory cells, and glycosaminoglycans. Certain plaques also contain calcium. Unstable or active or vulnerable plaques are enriched with inflammatory cells.

[0076] As used herein, the terms “atherosclerosis cardiovascular disease event” or “ASCVD event” refer to any pathological condition of the CV system associated with atherosclerosis. Exemplary ASCVD events include, but are not limited to, stroke, transient ischemic attack, carotid artery disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, mesenteric ischemia, and any combination thereof.Methods of Use

[0077] The present disclosure provides methods of treating atherosclerosis disease in a human subject comprising administering to the subject a SIRPa Fc fusion polypeptide described herein, or a pharmaceutical composition thereof described herein.

[0078] In some embodiments, the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof is administered according to a dosing regimen described herein.

[0079] In some embodiments, the dosing regimen comprises administering the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof to the subject at a dose and dosing frequency described herein. In some embodiments, the dosing regimen comprises a single dosing cycle. In some embodiments, the dosing regimen comprises more than one dosing cycle. In some embodiments, the dosing regimen comprises (i) a first dosing cycle, wherein the first dosing cycle comprises administering the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof to the subject at a first dose and a first dosing frequency described herein; and (ii) at least one subsequent dosing cycle, wherein the at least one subsequent dosing cycle comprises administering the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof to the subject at a second dose and a second dosing frequency described herein. In some embodiments, the first dose and the second dose are the same; in other embodiments, the first dose and the second dose are different. In some embodiments, the first dosing frequency and the second dosing frequency are the same. In some embodiments, the first dosing frequency and the second dosing frequency are different. In some embodiments, at least one subsequent dosing cycle is initiated immediately upon completion of the first dosing cycle or a previous dosing cycle. In some embodiments, the dosing regimen comprises a duration of time between the first dosing cycle and the second329750705 18Attorney Docket: BTRT-Oll / OIWO 342313-2192dosing cycle, wherein the subject is not administered the SIRPa Fc fusion polypeptide or the pharmaceutical composition for the duration of time.

[0080] In some embodiments, the subject has atherosclerotic disease. In some embodiments, the subject has experienced a prior ASCVD event. In some embodiments, the subject has experienced the prior ASCVD event not more than about 6 to about 18 months prior to onset of treatment (e.g., about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 months prior to onset of treatment). In some embodiments, the ASCVD event is one described herein. In some embodiments, the prior ASCVD event is a myocardial infarction, a transient ischemic attack, or a stroke. In some embodiments, the prior ASCVD event is an asymptomatic carotid artery stenosis of at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. In some embodiments, the subject is at least about 40, 45, 50, 55, 60, or 65 years of age. In some embodiments, the subject is about 45 to about 80 years of age. In some embodiments, the subject is about 45 to about 85 years of age. In some embodiments, the subject exhibits a risk factor for atherosclerotic disease. In some embodiments, the risk factor is one described herein. In some embodiments, the subject exhibits at least two or more risk factors described herein (e.g., 2, 3, 4, or 5 risk factors described herein). In some embodiments, the risk factor is selected from the group consisting of: an age of 65 years or older; a history of hypertension; a history of hyperlipidaemia; current smoking; a history of non-insulin dependent diabetes mellitus; high sensitivity c-reactive protein of about 2 mg / L or higher; peripheral artery disease; an arterial 18 fluorodeoxyglucose F (18F-FDG) uptake characterized by a maximum target-to-background ratio (TBRmax) of at least about 1.6 or higher (e.g., in an aorta, coronary artery, carotid artery, intracranial carotid artery, renal artery, mesenteric artery, iliac artery, and / or arteries of the lower limb) as measured by 18F-FDG PET combined with CT (PET / CT); and a combination thereof. In some embodiments, the subject is at risk of developing atherosclerotic disease, e.g., exhibits a risk factor for atherosclerotic disease, but has not experienced a prior ASCVD event. In some embodiments, the subject exhibits arterial 18F-FDG uptake (e.g., in an aorta, coronary artery, carotid artery, intracranial carotid artery, renal artery, mesenteric artery, iliac artery, and / or arteries of the lower limb) as measured by 18F-FDG PET / CT as further described herein. In some embodiments, the arterial 18F-FDG uptake is characterized by a TBRmax of at least about 1.6 or higher. In some embodiments, the administration of the SIRPa Fc fusion polypeptides or the disclosure in the dosing cycles provided herein, results in a clinical outcome described herein. In some embodiments, clinical outcome is associated with tolerability of the SIRPa Fc fusion polypeptide administered to the subject (e.g., absence of an adverse event requiring329750705 19Attorney Docket: BTRT-Oll / OIWO 342313-2192discontinuation of treatment, e.g., absence of anemia and / or thrombocytopenia). In some embodiments, the clinical outcome is associated with a therapeutic effect (e.g., reducing the size of an atherosclerotic plaque and / or reducing vascular inflammation associated with an atherosclerotic plaque). In some embodiments, the clinical outcome comprises nonoccurrence of an ASCVD event within a duration of time following onset of treatment.

[0081] In some embodiments, the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof is administered as monotherapy.

[0082] In some embodiments, the SIRPa Fc fusion polypeptide or pharmaceutical composition thereof is administered in a combination therapy described herein.Dosing Regimens

[0083] The present disclosure provides dosing regimens comprising administering an effective amount of a SIRPa Fc fusion polypeptide described herein, or a pharmaceutical composition comprising a SIRPa Fc fusion polypeptide described herein, to a subject (e.g., a subject having, or at risk of having, an atherosclerotic disease).

[0084] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject by a selected route (e.g., subcutaneous or intravenous injection), at a particular dose, and with a dosing frequency that results in a level of the SIRPa Fc fusion polypeptide (e.g., a plasma level of the SIRPa Fc fusion polypeptide) that is tolerated by the subject (e.g., does not result in an adverse event sufficient to discontinue treatment and / or result in undesirable adverse toxicity). In some embodiments, the administration (e.g., selected route / dose / dosing frequency) results in a level of the SIRPa Fc fusion polypeptide (e.g., a plasma level of the SIRPa Fc fusion polypeptide) that reduces the risk of an ASCVD event (e.g., by decreasing the size of an atherosclerotic plaque and / or by increasing clearance or phagocytosis of inflammatory debris in an atherosclerotic lesion). In some embodiments, the administration (selected route / dose / dosing frequency) results in a level of the SIRPa Fc fusion polypeptide (e.g., a level of the SIRPa Fc fusion polypeptide as measured in circulation or in the atherosclerotic plaque) that reduces the size an atherosclerotic plaque in the subject.

[0085] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject in a single dose. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject in two or more doses (which may or may not contain the same amount of the SIRPa Fc fusion polypeptide). In some embodiments, the two or more doses are each administered over time, or as a continuous infusion via an implantation device or catheter. In some embodiments, the two or more doses are each administered as a bolus injection. In329750705 20Attorney Docket: BTRT-Oll / OIWO 342313-2192some embodiments, the bolus injection is administered at a single site. In some embodiments, the bolus injection is administered at multiple sites (e.g., intravenous or subcutaneous).Dose

[0086] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose that results in a level of the SIRPa Fc fusion polypeptide that provides a desired clinical outcome (e.g., a level of the SIRPa Fc fusion polypeptide that is tolerated by the subject, effective for reducing the risk of an ASCVD event, and / or effective for reducing the size of an atherosclerotic plaque).

[0087] In some embodiments, the dose used in the dosing regimen is identified according to a method described herein. In some embodiments, the method comprises identifying a starting dose and evaluating the dose in humans in, e.g., a Phase I dose escalation study as described further herein. Methods for determining a starting dose include, but are not limited to, dose by factor, similar drug, pharmacokinetically guided, and comparative approaches (see, e.g., Reigner, et al (2002) Eur J Clin Pharmacol 57:835).

[0088] In some embodiments, the method comprises the dose by factor approach comprising determining the no observed adverse effect level (NOAEL) and converting the NOAEL to an estimated human equivalent dose (HED). In some embodiments, the NOAEL is determined in mice, rats, guinea pigs, rabbits, dogs, non-human primates, pigs, or hamsters. In some embodiments, the NOAEL is determined in rats. In some embodiments, the NOAEL is determined in a non-human primate (e.g., cynomolgus monkey). In some embodiments, the NOAEL is converted to an HED by multiplying the NOAEL by a conversion factor. In some embodiments, the conversion factor depends on the species used in the animal study. Suitable conversion factors are known in the art, see, e.g., USFDA. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Adult Healthy Volunteer. Rockville, MD: US Food and Drug Administration; 2005. In some embodiments, the HED is converted to a maximum recommended starting dose (MRSD) by multiplying the HED by a safety factor. In some embodiments, the safety factor is l.lx to 50x. In some embodiments, the safety factor is 5x to 20x. In some embodiments, the safety factor is 5x, 6x, 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, or 15x.

[0089] In some embodiments, the dose is further selected to provide a level of the SIRPa Fc fusion polypeptide that is tolerated by the subject and / or reduces the risk of an ASCVD event, e.g., as determined based on pharmacokinetic and / or pharmacodynamic property of the SIRPa Fc fusion polypeptide following administration.329750705 21Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0090] In some embodiments, the pharmacokinetic properties comprise a Cmax. As used herein, Cmax refers to the maximum (or peak) concentration of the SIRPa Fc fusion polypeptide as measured in a sample obtained from the subject after the administration and prior to administration of a subsequent dose of the SIRPa Fc fusion polypeptide. In some embodiments, the pharmacokinetic properties comprise a maximum peak of the SIRPa Fc fusion polypeptide, e.g., as measured in plasma, serum, or whole blood sample. As is understood by one skilled in the art, the Cmax may be measured following each dose administered to the subject (e.g., the first, second, third, fourth, etc. dose). The Tmax refers to the time at which the maximum concentration (Cmax) is observed relative to the time of administration. In some embodiments, the pharmacokinetic properties comprise an area under the concentration-time curve (“AUC”). As used herein, AUC refers to the concentration of the SIRPa Fc fusion polypeptide as measured in a sample obtained from the subject integrated over time. In some embodiments, AUC is determined to the last quantifiable time point (AUClast). In some embodiments, the last quantifiable time point is about 500-1500 hours (e.g., about 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 hours) following administration of the SIRPa Fc fusion polypeptide. In some embodiments, AUC is extrapolated to infinity (AUCinf).

[0091] In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide (e.g., a dose of about 0.1 mg / kg to about 5 mg / kg of the SIRPa Fc fusion polypeptide, e.g., a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg of the SIRPa Fc fusion polypeptide) results in an average Cmax of at least about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 500 ng / mL, about IxlO3ng / mL, about 2xl03ng / mL, about 3xl03ng / mL, about 4xl03ng / mL, about 5xl03ng / mL, about 6xl03ng / mL, about 7xl03ng / mL, about 8xl03ng / mL, about 9xl03ng / mL or about lxl04ng / mL, e.g., as measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide (e.g., a dose of about 0.1 mg / kg to about 5 mg / kg of the SIRPa Fc fusion polypeptide, e.g., a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg of the SIRPa Fc fusion polypeptide) results in an average Cmax of about 50-200 ng / mL, about 100-500 ng / mL, about 100-1000 ng / mL, about 500-1000 ng / mL, about 1000-3000 ng / mL, about 1000-5000 ng / mL, about 2000-9000 ng / mL, about 5000-10000 ng / mL, or about 6000-10000 ng / mL e.g., as measured in a sample (e.g., a plasma, serum, or whole329750705 22Attorney Docket: BTRT-Oll / OIWO 342313-2192blood sample) obtained from the subject. In some embodiments, the dose is administered subcutaneously. In some embodiments, the dose is administered intravenously.

[0092] In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide (e.g., a dose of about 0.1 mg / kg to about 5 mg / kg of the SIRPa Fc fusion polypeptide, e.g., a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg of the SIRPa Fc fusion polypeptide) results in an average AUC of at least about lxl04h*ng / mL, about 5xl04h*ng / mL, about IxlO5h*ng / mL, about 5xl05h*ng / mL, about lxl06h*ng / mL, or about 5xl06h*ng / mL e.g., as measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject. As used herein, “h*ng / mL” is a measure of time multiplied by concentration, in which “h” refers to hours, refers to a multiplication operator, and “ng / mL” refers to the concentration unit of nanograms per milliliter. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide (e.g., a dose of about 0.1 mg / kg to about 5 mg / kg of the SIRPa Fc fusion polypeptide, e.g., a dose of about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg of the SIRPa Fc fusion polypeptide) results in an average AUC of at least about IxlO3- 5xl04h*ng / mL, about IxlO4- 5xl04h*ng / mL, about 2xl04- 5xl04h*ng / mL, about 5xl04- IxlO5h*ng / mL, about IxlO5- 5xl05h*ng / mL, about 5xl05- IxlO6h*ng / mL, or about IxlO6- 5xl06h*ng / mL, e.g., as measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject. In some embodiments, the dose is administered subcutaneously. In some embodiments, the dose is administered intravenously. In some embodiments, the average AUC is determined to the last quantifiable time point, wherein the last quantifiable time point is about 500-1500 hours following administration of the SIRPa Fc fusion polypeptide.

[0093] In some embodiments, the pharmacodynamic properties comprise a target occupancy (e.g., a CD47 occupancy) of the SIRPa Fc fusion polypeptide, e.g., as measured in a blood sample or in the atherosclerotic plaque itself. As appreciated by the skilled artisan, target occupancy refers to a measure of binding of a therapeutic agent to a target (see, e.g., MABS (2023) 15:e2156317). Methods to measure target occupancy are known by those versed in the art, see, for example, in Liang, et al (2016) Cytometry B Clin Cytom 90:117. The present disclosure further provides exemplary assays for measuring target occupancy (see the Examples). In one example, the assay uses flow cytometry to measure target occupancy of CD47 present on cells (e.g., CD45 negative RBCs and / or CD45 positive WBCs) in a test sample obtained from a subject following administration of a SIRPa Fc fusion protein329750705 23Attorney Docket: BTRT-Oll / OIWO 342313-2192described herein. The assay uses an Fc-targeting detection antibody to detect the SIRPa Fc fusion protein. Signal from the detection antibody is compared between the test sample and a control sample comprising a saturating level of the SIRPa Fc fusion protein. In some embodiments, the control sample is prepared by addition of the SIRPa Fc fusion protein at a saturating level (e.g., a level of about 100 nM or higher) to a sample obtained from the subject (e.g., a sample obtained from the subject prior to the administration or at the same time point as the test blood sample). The percent target occupancy is equal to the ratio of signal between the test sample and the control sample, multiplied by 100.

[0094] In some embodiments, target occupancy is measured in a subject following administration of a dose of a SIRPa Fc fusion protein described herein and prior to administration of a subsequent dose of the SIRPa Fc fusion protein. In some embodiments, target occupancy is measured at multiple time points (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more time points) following administration of a dose of the SIRPa Fc fusion protein and prior to administration of a subsequent dose of the SIRPa Fc fusion protein (e.g., at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and / or 35 days following administration of the dose and prior to administration of the subsequent dose). In some embodiments, target occupancy is measured at an interval of once every 2 to 10 days (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 days) following administration of the dose of a SIRPa Fc fusion protein. In some embodiments, target occupancy is measured at a time point prior to administration of a subsequent dose of the SIRPa Fc fusion protein, e.g., immediately prior to or not more than about 1 hour to about 72 hours prior to the subsequent dose. In some embodiments, the target occupancy is measured on RBCs (e.g., CD45 negative cells in blood) and / or WBCs (e.g., CD45 positive cells in blood).

[0095] Generally, several parameters are evaluated in measuring target occupancy. One parameter is the peak target occupancy, which refers to the highest target occupancy measured following administration of the dose of the SIRPa Fc fusion protein to the subject and prior to administration of the subsequent dose, e.g., as identified on a plot of target occupancy over time following administration of the dose. Another parameter is the trough target occupancy, which refers to the target occupancy measured prior to administration of a subsequent dose of the SIRPa Fc fusion protein to the subject. For example, in some embodiments, the trough target occupancy is the target occupancy measured immediately prior to or not more than about 1-72 hours prior to administration of the subsequent dose. An additional parameter is the average target occupancy, which refers to the target occupancy averaged over a period of time following the administration of the dose of the SIRPa Fc329750705 24Attorney Docket: BTRT-Oll / OIWO 342313-2192fusion protein to the subject and prior to administration of the subsequent dose. Another parameter is the spot target occupancy, which refers to the target occupancy measured at a particular time point following administration of the dose of the SIRPa Fc fusion protein to the subject.

[0096] In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of at least about 10% and up to about 100%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of at least about 20% and up to about 100%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of at least about 30% and up to about 100%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of at least about 30% and up to about 90%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of at least about 30% and up to about 80%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 10%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 20%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 30%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 40%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 50%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 60%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 70%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 80%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 90%. In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in a peak target occupancy of about 100%. In some embodiments, the peak target occupancy is measured on RBCs (e.g., CD45 negative cells in blood) and / or WBCs (e.g., CD45 positive cells in blood).329750705 25Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0097] In some embodiments, the peak target occupancy is achieved at about 3 to about 30 days following administration of the dose of the SIRPa Fc fusion polypeptide. In some embodiments, the peak target occupancy is achieved at about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days following administration of the dose of the SIRPa Fc fusion polypeptide. In some embodiments, the peak target occupancy is achieved at about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days following administration of the dose of the SIRPa Fc fusion polypeptide.

[0098] In some embodiments, the administration results in a target occupancy of the SIRPa Fc fusion polypeptide that is maintained for a duration of time following the administration. In some embodiments, the administration results in a target occupancy of the SIRPa Fc fusion polypeptide of at least about 10% that is maintained for at least about 1 day and up to about 30 days following the administration. In some embodiments, the administration results in a target occupancy of the SIRPa Fc fusion polypeptide of at least about 20% that is maintained for at least about 3 days and up to about 20 days following the administration. In some embodiments, the administration results in a target occupancy of the SIRPa Fc fusion polypeptide of about 20% and up to about 100% that is maintained for about 1, 2, or 3 days to about 15, 16, 17, 18, 19 or 20 days following the administration.

[0099] In some embodiments, administration of the dose of the SIRPa Fc fusion polypeptide results in an average target occupancy of at least about 10% over a duration of time extending from administration of the dose to administration of a subsequent dose. In some embodiments, the average target occupancy is at least about 20% over the duration of time. In some embodiments, the average target occupancy is at least about 30% over the duration of time. In some embodiments, the average target occupancy is at least about 40% over the duration of time. In some embodiments, the average target occupancy is at least about 50% over the duration of time. In some embodiments, the average target occupancy is at least about 60% over the duration of time. In some embodiments, the average target occupancy is at least about 70% over the duration of time. In some embodiments, the average target occupancy is at least about 80% over the duration of time. In some embodiments, the average target occupancy is at least about 90% over the duration of time. In some embodiments, the average target occupancy is measured on RBCs (e.g., CD45 negative cells in blood) and / or WBCs (e.g., CD45 positive cells in blood).

[0100] In some embodiments, the target receptor is CD47. In some embodiments, the peak target occupancy is measured on target cells in a sample obtained from the subject. In some embodiments, the sample is a blood sample. In some embodiments, the target cells comprise329750705 26Attorney Docket: BTRT-Oll / OIWO 342313-2192white blood cells and / or red blood cells. In some embodiments, the target cells are white blood cells. In some embodiments, the target cells are red blood cells. In some embodiments, the sample is of an atherosclerotic plaque. In some embodiments, target occupancy is measured by an assay described herein, e.g., a flow cytometry assay described herein.Dosing Frequency

[0101] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dosing frequency that results in a level of the SIRPa Fc fusion polypeptide that provides a desired clinical outcome (e.g., a level of the SIRPa Fc fusion polypeptide that is tolerated by the subject, effective for reducing the risk of an ASCVD event, and / or effective for reducing the size of an atherosclerotic plaque).

[0102] In some embodiments, the dosing frequency takes into account the pharmacokinetic and / or pharmacodynamic parameters of the SIRPa Fc fusion polypeptide used in the dosing regimen. In some embodiments, a clinician will administer the composition at a frequency to achieve or maintain a desired level of the SIRPa Fc fusion polypeptide that is associated with a desired therapeutic effect (e.g., a level of the SIRPa Fc fusion polypeptide that is tolerated by the subject, effective for reducing the risk of an ASCVD event, and / or effective for reducing the size of an atherosclerotic plaque). In some embodiments, the desired level of the SIRPa Fc fusion polypeptide is associated with a reduced occurrence of ASCVD events (e.g., as measured in a clinical population administered the SIRPa Fc fusion polypeptide according to the dosing regimen compared to a population administered a control or placebo). In some embodiments, the desired level of the SIRPa Fc fusion polypeptide is associated with a reduced size of an atherosclerotic plaque in the subject. In some embodiments, maintenance of a desired level of the SIRPa Fc fusion polypeptide is determined by analyzing one or more biological sample(s) (e.g., blood sample, e.g., sample of an atherosclerotic plaque) obtained from the subject at regular intervals during a dosing regimen.

[0103] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dosing frequency that achieves and / or maintains a desired target occupancy. For example, in some embodiments, a first and at least one subsequent dose of the SIRPa Fc fusion polypeptide is administered to the subject at a dosing frequency, wherein the dosing frequency results in a trough target occupancy of at least about 5%. In some embodiments, the trough target occupancy is about 5% to about 90%. In some embodiments, the trough target occupancy is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.329750705 27Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0104] In some embodiments, the dosing frequency is once every about 1 to about 60 days, wherein the trough target occupancy is at least about 5%. In some embodiments, the dosing frequency is once every about 1 to about 30 days, wherein the trough target occupancy is at least about 5%. In some embodiments, the dosing frequency is once every about 1 to about 30 days, wherein the trough target occupancy is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the dosing frequency is once every about 1 to about 14 days, wherein the trough target occupancy is at least about 5%. In some embodiments, the dosing frequency is once every about 1 to about 14 days, wherein the trough target occupancy is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the dosing frequency is once every about 1 to about 14 days, wherein the trough target occupancy is about 50% to about 80%. In some embodiments, the dosing frequency is once every about 1 to about 14 days, wherein the trough target occupancy is about 60% to about 80%. In some embodiments, the dosing frequency is once every about 1 to about 7 days, wherein the trough target occupancy is at least about 5%. In some embodiments, the dosing frequency is once every about 1 to about 7 days, wherein the trough target occupancy is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the dosing frequency is once every about 1 to about 7 days, wherein the trough target occupancy is about 50% to about 80%. In some embodiments, the dosing frequency is once every about 1 to about 7 days, wherein the trough target occupancy is about 60% to about 80%.Exemplary Dose and Dosing Frequency

[0105] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of at least about 0.1 mg per kg (mg / kg) and up to about 75 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 1.0 mg / kg and up to about 50 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 2.5 mg per kg (mg / kg) and up to about 75 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.1 mg per kg (mg / kg) and up to about 5329750705 28Attorney Docket: BTRT-Oll / OIWO 342313-2192mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 5 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.1 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 2 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 1 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.5 mg per kg (mg / kg) and up to about 2 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.5 mg per kg (mg / kg) and up to about 1 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 1 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject.

[0106] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 0.1, 0.3, 1, or 3 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 1, 10, or 50 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 2.5, 15, or 75 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 0.3 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 0.5 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 1 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is329750705 29Attorney Docket: BTRT-Oll / OIWO 342313-2192administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 1.5 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 2 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 3 mg / kg of body weight of the subject. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 5 mg / kg of body weight of the subject.

[0107] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.1 mg per kg (mg / kg) and up to about 75 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 1.0 mg / kg and up to about 50 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 2.5 mg per kg (mg / kg) and up to about 75 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.1 mg per kg (mg / kg) and up to about 5 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 5 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.1 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 2 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 0.3 mg per kg (mg / kg) and up to about 1 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the329750705 30Attorney Docket: BTRT-Oll / OIWO 342313-2192SIRPa Fc fusion polypeptide of at least about 1 mg per kg (mg / kg) and up to about 3 mg / kg of body weight of the subject.

[0108] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 0.1, 0.3, 1, or 3 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 1, 10, or 50 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 2.5, 15, or 75 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 0.3 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 1 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 2 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 3 mg / kg of body weight of the subject by subcutaneous injection. In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of about 5 mg / kg of body weight of the subject.

[0109] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dose of the SIRPa Fc fusion polypeptide of at least about 5 mg and up to 1g. In some embodiments, the dose is about 5 mg to about 900 mg. In some embodiments, the dose is about 5 mg to about 800 mg. In some embodiments, the dose is about 5 mg to about 700 mg. In some embodiments, the dose is about 5 mg to about 600 mg. In some embodiments, the dose is about 5 mg to about 500 mg. In some embodiments, the dose is about 10 mg to about 500 mg. In some embodiments, the dose is about 50 mg to about 500 mg. In some embodiments, the dose is about 100 mg to about 500 mg. In some embodiments, the dose is about 10 mg to about 300 mg. In some embodiments, the dose is about 10 mg to about 200 mg. In some embodiments, the dose is about 10 mg to about 100 mg. In some embodiments, the dose is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.329750705 31Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0110] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject at a dosing frequency of once every about 1 day to about 60 days for a duration of time. In some embodiments, the dosing frequency is once every about 1 day to about 50 days for a duration of time. In some embodiments, the dosing frequency is once every about 1 day to about 40 days for a duration of time. In some embodiments, the dosing frequency is once every about 1 day to about 30 days for a duration of time. In some embodiments, the dosing frequency is once every about 1 day to about 14 days for a duration of time. In some embodiments, the dosing frequency is once every about 1 day to about 7 days for a duration of time. In some embodiments, the dosing frequency is once every about 7 days to about 60 days for a duration of time. In some embodiments, the dosing frequency is once every 7 days to 50 days for a duration of time. In some embodiments, the dosing frequency is once every 7 days to 40 days for a duration of time. In some embodiments, the dosing frequency is once every 7 days to 30 days for a duration of time.[OHl] In some embodiments, the dosing frequency is once per day for a duration of time. In some embodiments, the dosing frequency is once every 7 days for a duration of time. In some embodiments, the dosing frequency is once every 14 days for a duration of time. In some embodiments, the dosing frequency is once every 28 to 30 days for a duration of time. In some embodiments, the dosing frequency is once every 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 days for a duration of time.

[0112] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject in a starting dose and a maintenance dose, wherein the starting dose is about 0.1 mg / kg and up to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 5 mg / kg. In some embodiments, the starting dose is about 0.5 mg / kg and up to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 3 mg / kg. In some embodiments, the starting dose is about 0.5 mg / kg and up to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 1 mg / kg. In some embodiments, the starting dose is about 1 mg / kg and up to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 1 mg / kg. In some embodiments, the starting dose is about 1 mg / kg and up to about 3 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 1 mg / kg. In some embodiments, the starting dose is about 1 mg / kg and up to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 0.5 mg / kg. In some embodiments, the starting dose is about 1 mg / kg and up to about 3 mg / kg, and the maintenance dose is about 0.1 mg / kg and up to about 0.5 mg / kg.329750705 32Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0113] In some embodiments, the SIRPa Fc fusion polypeptide is administered to the subject in a single starting dose and a maintenance dose given once every about 1 to about 4 weeks, wherein the single starting dose is about 0.1 mg / kg and up to about 5 mg / kg, and each of the maintenance doses is about 0.1 mg / kg and up to about 5 mg / kg. In some embodiments, the single starting dose is about 0.5 mg / kg and up to about 5 mg / kg, and each maintenance dose is about 0.1 mg / kg and up to about 3 mg / kg. In some embodiments, the single starting dose is about 1 mg / kg and up to about 5 mg / kg, and each maintenance dose is about 0.1 mg / kg and up to about 3 mg / kg. In some embodiments, the single starting dose is about 1 mg / kg and up to about 3 mg / kg, and each maintenance dose is about 0.1 mg / kg and up to about 1 mg / kg. In some embodiments, the single starting dose is about 1 mg / kg and up to about 5 mg / kg, and each maintenance dose is about 0.1 mg / kg and up to about 0.5 mg / kg. In some embodiments, administration of the starting dose is subcutaneous. In some embodiments, administration of the starting dose is intravenous. In some embodiments, administration of the maintenance dose is subcutaneous. In some embodiments, administration of the maintenance dose is intravenous.

[0114] In some embodiments, the duration of time is a 2x to lOOx multiple of the dosing frequency. In some embodiments, the duration of time is at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, or 24 months.

[0115] In some embodiments, the duration of time is a period of time sufficient to achieve a therapeutic effect described herein.Dosing Cycles

[0116] In some embodiments, a subject is administered a dose of the SIRPa Fc fusion polypeptide in a dosing cycle. In some embodiments, the dosing cycle comprises at least one dose. In some embodiments, a dosing cycle comprises at least two doses. In some embodiments, a dosing cycle comprises at least three doses. In some embodiments, a dosing cycle comprises at least four doses. In some embodiments, a dosing cycle comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses. In some embodiments, the dosing cycle comprises a dosing frequency described herein (e.g., once per day, once per week, three times per week, once per month, twice per month, three times per month). In some embodiments, a dosing cycle is for a duration of time. In some embodiments, the duration of the dosing cycle is about 7-42 days, about 7-21 days, about 14-28 days, about 21-28 days, about 21-35 days, about 28-35 days, about 21-42 days, or about 28-42 days. In some embodiments, the duration of the329750705 33Attorney Docket: BTRT-Oll / OIWO 342313-2192dosing cycle is 28 days. In some embodiments, the duration of the dosing cycle is 35 days. In some embodiments, the duration of the dosing cycle is 42 days. In some embodiments, the duration of the dosing cycle is 56 days. In some embodiments, the duration of the dosing cycle is about 3 weeks. In some embodiments, the duration of the dosing cycle is about 4 weeks. In some embodiments, the duration of the dosing cycle is about 6 weeks. In some embodiments, the duration of the dosing cycle is about 8 weeks.

[0117] In some embodiments, the subject is administered the SIRPa Fc fusion polypeptide in more than one dosing cycle.

[0118] In some embodiments, the subject is administered the SIRPa Fc fusion polypeptide in a first dosing cycle and at least one subsequent dosing cycle, wherein the first and subsequent dosing cycles each independently comprise administering a dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every 1 day to 60 days for a duration of time. In some embodiments, the first and subsequent dosing cycles each independently comprise administering the SIRPa Fc fusion polypeptide at a dosing frequency for a duration of time, wherein (i) the dose of the first and subsequent dosing cycles is different, (ii) the dosing frequency of the first and subsequent dosing cycles is different, and / or (iii) the duration of time of the first and subsequent dosing cycles is different.

[0119] In some embodiments, the dose of the first dosing cycle serves as a starting dose and the dose(s) of the subsequent dosing cycle are one or more maintenance doses. In some embodiments, the starting dose is 2-fold to 200-fold higher than the maintenance dose. In some embodiments, the dosing frequency of the first dosing cycle is once per every 1 day to 60 days for a duration of time, and the dosing frequency for the subsequent dosing cycle is every 1 day to 60 days for a duration of time. In some embodiments, the duration of time for the first dosing cycle is a 2x to 6x multiple of the dosing frequency, and the duration of time for the subsequent dosing cycle is a 2x to lOOx multiple of the dosing frequency. In some embodiments, the subsequent dosing cycle is indefinite or occurs until a therapeutic effect described herein is achieved.

[0120] In some embodiments, the interval between the first dosing cycle and the subsequent dosing cycle is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, or about 18 months. In some embodiments, the interval between the first dosing cycle and the subsequent dosing cycle is less than 1 month. In some embodiments, the interval is about 1 day to about 30 days.329750705 34Attorney Docket: BTRT-Oll / OIWO 342313-2192In some embodiments, the interval is about 1 day to about 14 days. In some embodiments, the interval is about 1 day to about 7 days.

[0121] In some embodiments, the subject is administered the SIRPa Fc fusion polypeptide for a specified time period. In some embodiments, dosing occurs until a therapeutic effect described herein is achieved.

[0122] In some embodiments, the subject is administered a starting dose of the of the SIRPa Fc fusion polypeptide in a first dosing cycle and a maintenance dose of the of the SIRPa Fc fusion polypeptide in a subsequent dosing cycle. In some embodiments, the starting dose is at least about 0.1 mg / kg and up to about 5 mg / kg of body weight of the subject. In some embodiments, the starting dose is at least about 1 mg / kg and up to about 5 mg / kg of body weight of the subject. In some embodiments, the starting dose is about 0.3, 1, 3, or 5 mg / kg of body weight of the subject. In some embodiments, the starting dose is about 1 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.1 mg / kg and up to about 5 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.1 mg / kg and up to about 3 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.1 mg / kg and up to about 1 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.1, 0.3, or 1 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.3 mg / kg of body weight of the subject. In some embodiments, the first dosing cycle comprises a single starting dose. In some embodiments, the first dosing cycle comprises more than one starting dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) administered at a dosing frequency of once every 1 day to 60 days (e.g., once every 1 to 30 days; e.g., once every 1 day to 14 days; e.g., once every 1 day to 7 days). In some embodiments, the subsequent dosing cycle comprises a single maintenance dose. In some embodiments, the subsequent dosing cycle comprises more than one maintenance dose (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) administered at a dosing frequency of once every 1 day to 60 days (e.g., once every 1 day to 14 days; e.g., once every 1 day to 7 days). In some embodiments, the first dosing cycle comprises a single starting dose and the subsequent dosing cycle comprises more than one maintenance dose.Combinations

[0123] In some embodiments, the method comprises administering the SIRPa Fc fusion polypeptide to a subject in combination with a second therapeutic agent. In some embodiments, the second therapeutic agent comprises a lipid modifying therapy. Exemplary329750705 35Attorney Docket: BTRT-Oll / OIWO 342313-2192lipid modifying therapies include, but are not limited to, a statin, ACL inhibitor (e.g., bempedoic acid), fibrate, niacin, bile acid sequestrant, ezetimibe, lomitapide, phytosterol, and / or orlistat.

[0124] In some embodiments, the subject has received a statin prior to administration of the SIRPa Fc fusion polypeptide. In some embodiments, the subject is receiving a statin at the time of administration of the SIRPa Fc fusion polypeptide. Statins are inhibitors of HMG-CoA reductase enzyme. These agents are well known in the art. For example, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140; rosuvastatin and related compounds as disclosed in U.S. Pat. No. 6,589,959; lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938; pravastatin and related compounds as disclosed in U.S. Pat. No. 4,346,227; simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171; fluvastatin and related compounds as disclosed in U.S. Pat. No. 5,354,772; atorvastatin and related compounds as disclosed in U.S. Pat Nos.4,681,893, 5,273,995 and 5,969,156; and cerivastatin and related compounds as disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080. Additional agents and compounds are disclosed in U.S. Pat. Nos. 5,208,258; 5,130,306; 5,116,870; 5,049,696; RE 36,481; and RE 36,520. Statins include the salts and / or ester thereof.

[0125] In some embodiments, the second therapeutic agent comprises a TNFa antagonist. In some embodiments, the TNFa antagonist is one described in WO2016138306, which is hereby incorporated by reference. In some embodiments, the TNFa antagonist comprises a monoclonal anti-TNFa antibody, an anti-TNF receptor antibody, or a soluble TNF receptors. In some embodiments, the TNFa antagonist is an antibody (e.g., a monoclonal antibody), or an antigen binding fragment thereof, targeting TNFa. In some embodiments, the TNFa antagonist comprises golimumab or an antigen binding fragment thereof. In some embodiments, the TNFa antagonist comprises certolizumab or an antigen binding fragment thereof. In some embodiments, the TNFa antagonist comprises adalimumab or an antigen binding fragment thereof. In some embodiments, the TNFa antagonist comprises infliximab or an antigen binding fragment thereof. In some embodiments, the TNFa antagonist is an antibody (e.g., a monoclonal antibody) targeting the TNFa receptor. In some embodiments, the TNFa antagonist comprises etanercept or an antigen binding fragment thereofAdministration

[0126] In some embodiments, a SIRPa Fc fusion polypeptide is delivered to a subject subcutaneously, intravenously, intravitreally, orally, intranasally, transdermally,329750705 36Attorney Docket: BTRT-Oll / OIWO 342313-2192intraperitoneally, intramuscularly, intrathecally, intrapulmonary, vaginally, or rectally. In some embodiments, the SIRPa Fc fusion polypeptide is administered subcutaneously. In some embodiments, the SIRPa Fc fusion polypeptide is administered subcutaneously using an auto-injector. In some embodiments, the SIRPa Fc fusion polypeptide is administered intravenously.Disease Indications

[0127] The present disclosure provides methods for treating a subject (e.g., a human subject) having atherosclerosis. In some embodiments, the subject is selected for treatment by a method of the disclosure on the basis of having atherosclerosis or a risk factor for atherosclerotic disease.

[0128] Atherosclerosis is a pathology associated with numerous conditions of the cardiovascular system, such as, but not limited to, coronary artery disease, peripheral artery disease, cerebrovascular disease, chronic venous disease, arterial dissection, and vasculitides. Coronary artery disease (also known as ischemic heart disease or coronary heart disease) results from atherosclerotic disease of arteries supplying the heart and other parts of the body that partially or completely block the flow of blood. Cerebrovascular disease results from atherosclerotic disease of arteries supplying the brain.

[0129] Subjects with clinical ASCVD encompass subjects with acute coronary syndrome (ACS), those with history of myocardial infarction, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease including aortic aneurysm. ACS encompasses all forms of unstable coronary artery disease. Myocardial infarction (both ST and non-ST elevation) represents an unstable form of atherosclerotic cardiovascular disease. Myocardial infarction is an ischemic myocardial necrosis usually resulting from abrupt reduction in coronary blood flow to a segment of myocardium. In the great majority of subjects with acute MI, an acute thrombus, often associated with plaque rupture, occludes the artery that supplies the damaged area. Plaque rupture occurs generally in vessels previously partially obstructed by an atherosclerotic plaque enriched in inflammatory cells. Altered platelet function induced by endothelial dysfunction and vascular inflammation in the atherosclerotic plaque presumably contributes to thrombogenesis. Myocardial infarction can be classified into ST- elevation and non-ST elevation MI (also referred to as unstable angina). In both forms of myocardial infarction, there is myocardial necrosis. In ST-elevation myocardial infraction there is transmural myocardial injury which leads to ST-elevations on electrocardiogram. In non-ST329750705 37Attorney Docket: BTRT-Oll / OIWO 342313-2192elevation myocardial infarction, the injury is sub-endocardial and is not associated with ST segment elevation on electrocardiogram. Heart failure can occur as a result of myocardial dysfunction caused by myocardial infraction.

[0130] In some embodiments, the subject has atherosclerosis characterized by plaque accumulation on vessel walls and vascular inflammation. In some embodiments, the plaque accumulation is detected using a method described herein (e.g., CT, MRI, intravascular angiography or the coronary vessels or other vessels, and / or intravascular ultrasonography). In some embodiments, evidence of atherosclerosis is detected using stress (e.g., exercise) induced provocative testing, nuclear imaging, direct or computational methods of arterial flow dynamics, or perivascular signals of inflammation (e.g., perivascular fat attenuation signals). In some embodiments, the plaque comprises accumulated intracellular and extracellular lipids, smooth muscle cells, connective tissue, inflammatory cells, and / or glycosaminoglycans. Vascular inflammation occurs in combination with lipid accumulation in the vessel wall, and vascular inflammation is a hallmark of the atherosclerosis disease process.

[0131] In some embodiments, the subject has experienced an ASCVD event prior to treatment. Subjects with recent ASCVD are at high risk of experiencing recurrent ASCVD events in the near term. In some embodiments, the subject is treated according to a method described herein to reduce the risk of a recurring ASCVD event.

[0132] In some embodiments, the subject has experienced a non-fatal ASCVD event within 1 month to 18 months prior to treatment. In some embodiments, the subject was hospitalized as a result of the ASCVD event.

[0133] In some embodiments, the subject has experienced a non-fatal ASCVD event prior to treatment. In some embodiments, the non-fatal ASCVD event comprises stroke, transient ischemic attack, carotid artery disease, heart attack, angina (e.g., unstable angina requiring hospitalization), heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, and / or mesenteric ischemia. In some embodiments, the non-fatal ASCVD event comprises myocardial infarction. In some embodiments, the non-fatal ASCVD event comprises myocardial infarction, transient ischemic attack, or stroke, wherein the non-fatal ASCVD event has occurred not more than about 6 months to about 18 months prior to onset of treatment according to a method described herein. In some embodiments, the non-fatal ASCVD event has occurred not more than about 12 months prior to onset of treatment.329750705 38Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0134] In some embodiments, the subject has experienced a single non-fatal ASCVD event prior to treatment. In some embodiments, the subject has experienced 2, 3, 4, or more non-fatal ASCVD events prior to treatment.

[0135] In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0136] In some embodiments, the risk factor comprises a genotype comprising a homozygous or heterozygous 9p21 risk allele. In some embodiments, the 9p21 risk allele comprises a single polymorphism (SNP) variant at 9p21. Subjects with one or more 9p21 risk allele(s) have been shown to have an increased risk of: early onset myocardial infarction, abdominal aortic aneurysm, stroke, peripheral artery disease, and myocardial infarction / coronary heart disease. This risk is independent of traditional risk factors, including diabetes, hypertension, cholesterol, and obesity. See, for example, Helgadottir et al. Science. 2007; 316(5830): 1491 -1493; Helgadottir et al. Nat Genet. 2008; 40(2):217-224; Palomaki et al. JAMA. 2010; 303(7) :648-656; and Roberts et al. Curr Opin Cardiol. 2008; 23:629-633, each herein specifically incorporated by reference. The 9p21 locus is in tight LD (linkage disequilibrium), and a number of single nucleotide polymorphisms (SNP) markers have been shown to be useful in diagnosis. Representative SNPs include without limitation rsl0757278; rs3217992; rs4977574; rsl333049; rsl0757274; rs2383206; rs2383207; Rs3217989; rsl333040; rs2383207; rsl0116277; rs7044859; rsl292136; rs7865618; rsl333045; rs9632884; rsl0757272; rs4977574; rs2891168; rs6475606; rsl333048; rsl333049; Rsl333045; etc.

[0137] In some embodiments, the risk factor comprises presence of perivascular inflammation. In some embodiments, the perivascular inflammation is measured by coronary heart scan.

[0138] In some embodiments, the risk factor comprises presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells. In some embodiments, the CHIP is measured by gene sequencing.

[0139] In some embodiments, the risk factor comprises an intermediate or high level of C-reactive protein (CRP). In some embodiments, the level of CRP is higher than about 2 mg / L, about 2.5 mg / L, or about 3 mg / L, e.g., as measured in a blood sample.

[0140] In some embodiments, the risk factor comprises an elevated polygenic risk score.

[0141] In some embodiments, the risk factor comprises an elevated level of a marker of inflammation. In some embodiments, the marker of inflammation is selected from CRP, IL-6, IL-8, fibrinogen, human serum amyloid A (SAA), haptoglobin, phospholipase A2 (sPLA2),329750705 39Attorney Docket: BTRT-Oll / OIWO 342313-2192lipoprotein(a), an apolipoprotein B (APOB) to apolipoprotein Al (AP0A1) ratio, a white blood cell count, and a combination thereof.

[0142] In some embodiments, the risk factor comprises heterozygous familial hypercholesterolemia. In some embodiments, the risk factor comprises a history of coronary artery bypass surgery. In some embodiments, the risk factor comprises a history of percutaneous coronary intervention. In some embodiments, the risk factor comprises a history of diabetes mellitus. In some embodiments, the risk factor comprises a history of non-insulin dependent diabetes mellitus. In some embodiments, the risk factor comprises a history of hypertension (e.g., elevated blood pressure despite standard of care treatment). In some embodiments, the risk factor comprises an elevated level of LDL-C (e.g., a level of LDL-C greater than about 100 mg / dL as measured in a blood sample). In some embodiments, the elevated level of LDL-C is maintained for a duration of time despite the subject receiving standard of care (e.g., a statin therapy). In some embodiments, the elevated level of LDL-C is maintained for a duration of time despite the subject receiving standard of care, wherein the elevated level is greater than about 100, 110, 120, 130, 140, 150, 160, 170, 180, or 190 mg / dL. In some embodiments, the elevated level of LDL-C is maintained for a duration of time despite the subject receiving standard of care, wherein the elevated level is greater than about 190 mg / dL. In some embodiments, the risk factor comprises a history of congestive heart failure. In some embodiments, the risk factor comprises a history of smoking. In some embodiments, the risk factor comprises obesity.

[0143] In some embodiments, the risk factor comprises a history of peripheral arterial disease. In some embodiments, the history of peripheral arterial disease comprises intermittent claudication. In some embodiments, the history of peripheral arterial disease comprises lower extremity stenosis greater than about 50% (e.g., as measured by an imaging technique such as ultrasound, computed tomography angiography, or magnetic resonance angiography).

[0144] In some embodiments, the risk factor comprises age (e.g., older than about 40, 45, 50, 55, 60, 65, 70, 75, or 80 years), race, national origin, gender (male or female), lifestyle habits (e.g., diet and exercise), preexisting medical conditions (e.g., diabetes, high blood pressure), and medication status. In some embodiments, the risk factor is an age older than about 60 years. In some embodiments, the risk factor is an age older than about 65 years. In some embodiments, the risk factor is an age older than about 70 years. In some embodiments, the risk factor is a history of hypertension. In some embodiments, the risk factor is a history of non-insulin dependent diabetes mellitus.329750705 40Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0145] In some embodiments, the subject has an indicator of vascular inflammation, e.g., as measured by a method described herein, e.g., 18F-FDG PET / CT. In some embodiments, the indicator of vascular inflammation is a target-to-background ratio (TBR) of at least about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 as measured in an artery (e.g., an aorta, coronary artery, extracranial carotid artery, intracranial carotid artery, renal artery, mesenteric artery, iliac artery, and / or arteries of the lower limb) by 18F-FDG PET / CT. Methods to measure TBR are known in the art and further described herein.

[0146] In some embodiments, the subject has at least two of the following: (i) an age greater than about 65 years; (ii) a history of hypertension; (iii) a history of hyperlipidaemia on lipid lowering therapy, or a medical history of intolerance to lipid lowering therapy and an LDL-cholesterol of about 190 mg / dL or higher; (iv) a history of smoking; (v) a history of noninsulin dependent diabetes mellitus; (vi) a level of C-reactive protein of about 2 mg / L or higher as measured by a high sensitivity C-reactive protein blood test; (viii) peripheral artery disease; and (ix) a maximum target-to-background ratio of about 1.6 or higher in a carotid artery as measured by 18F-FDG PET / CT.

[0147] In some embodiments, the subject does not have a hemoglobin level below the lower limit of normal (e.g., below about 13 g / dL for an adult male human subject and below about 12 g / dL for an adult female human subject). In some embodiments, the subject does not have a platelet count below the lower limit of normal (e.g., below about 150k platelets per microliter). In some embodiments, the subject does not have a neutrophil count below the lower limit of normal (e.g., below about 1.5k cells per microliter). In some embodiments, the subject does not have a lymphocyte count below the lower limit of normal (e.g., below about Ik cells per microliter). In some embodiments, the subject has not experienced blood loss of more than about 400 mL within about 8 weeks prior to treatment. In some embodiments, the subject does not have uncontrolled hypertension characterized by systolic blood pressure of 160 mmHg or diastolic blood pressure of 100 mmHg. In some embodiments, the subject does not have a history of acute coronary syndrome, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, transient ischemic attack, stroke, or sudden cardiac arrest within 12 months prior to treatment. In some embodiments, the subject has diabetes, wherein the subject is not receiving injectable insulin or has an HbAlc greater than about 8%. In some embodiments, the subject does not have permanent atrial fibrillation. In some embodiments, the subject does not have a history of heart failure, characterized by a left ventricular ejection fraction less than about 30% or New York Heart Association class III or IV. In some embodiments, the subject does not have renal impairment characterized by329750705 41Attorney Docket: BTRT-Oll / OIWO 342313-2192creatinine clearance of less than about 40 ml / min (calculated using the Cockcroft-Gault equation). In some embodiments, the subject does not have a history of kidney transplant. In some embodiments, the subject does not have a history of contrast nephropathy. In some embodiments, the subject is not pregnant or lactating.Clinical Outcomes

[0148] Certain aspects of the disclosure are directed to methods that provide a desired therapeutic effect in a subject having, or at risk of having, atherosclerosis, wherein the method comprises administering a SIRPa Fc fusion polypeptide described herein, or a pharmaceutical composition comprising a SIRPa Fc fusion polypeptide, to the subject.

[0149] In some embodiments, the method provides a desired therapeutic effect related to the risk of an ASCVD event. In some embodiments, the subject has experienced an ASCVD event prior to initiating treatment with the method. In some embodiments, the subject has not experienced an ASCVD event prior to initiating treatment with the method. In some embodiments, the subject experiences no ASCVD event within a duration of time following onset of treatment. In some embodiments, the duration of time is at least about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months following onset of treatment. In some embodiments, the subject experiences no ASCVD event during the course of treatment.

[0150] In some embodiments, the ASCVD event is a condition associated with atherosclerosis disease. Exemplary ASCVD events include, but are not limited to, stroke, transient ischemic attack, carotid artery disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, and mesenteric ischemia.

[0151] In some embodiments, the method results in an increased time to first occurrence of a non-fatal ASCVD event.

[0152] In some embodiments, the method provides a therapeutic effect related to the occurrence or size of an atherosclerotic plaque. In some embodiments, the atherosclerotic plaque is present in an aorta, coronary artery, extracranial carotid artery, intracranial carotid artery, renal artery, mesenteric artery, iliac artery, and / or arteries of the lower limb (e.g., superficial femoral artery, deep femoral artery, or tibial artery). Methods to detect and measure atherosclerotic plaque are known in the art, and include, for example, echocardiography, angiography, computed tomography (CT), magnetic resonance imaging (MRI), vascular angiography, and intravascular ultrasonography.329750705 42Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0153] In some embodiments, the method results in a reduction in atherosclerotic plaque size. In some embodiments, atherosclerotic plaque size is determined as a measure of total vessel area (e.g., as a percentage of total vessel area). In some embodiments, the method results in a reduction in atherosclerotic plaque size by at least about 1.1-fold, about 1.5-fold, about 2-fold, about 10-fold, about 50-fold, or about 100-fold as compared to prior to onset of treatment. In some embodiments, the atherosclerotic plaque is in the carotid artery. In some embodiments, the atherosclerotic plaque is in the coronary artery. Methods to measure carotid or coronary artery plaque burden include carotid CT and coronary CT angiography respectively.

[0154] In some embodiments, the method results in stabilization of atherosclerotic plaque size. In some embodiments, the method results in atherosclerotic plaque size remaining substantially the same as compared to prior to the treatment.

[0155] In some embodiments, the method provides a therapeutic effect related to atherosclerotic plaque inflammation. In some embodiments, the method reduces atherosclerotic plaque inflammation. Methods to measure and detect inflammation in atherosclerotic plaque are known in the art, and include, for example, positron emission tomography (PET) performed with fluorine 18 fluorodeoxyglucose (FDG) (18F-FDGPET) and 18F-FDGPET combined with CT (PET / CT) (see, e.g., WO2022 / 093628, herein incorporated by reference). Arterial 18F-FDG uptake is expressed as the Target-to-Background Ratio (TBR), that is a measure of the blood-normalized standardized uptake value (SUV). 18F-FDG is taken up mostly by macrophages within the atherosclerotic plaques, although other cells (i.e., endothelial cells, vascular smooth muscle cells, neutrophils, lymphocytes) may participate in tracer uptake. TBR, as a measure of SUV, has been demonstrated to be a reproducible index for quantification of 18F-FDG uptake in the inflamed arterial wall. While many atherosclerotic plaques are not metabolically active at FDG PET, focal intense activity within atherosclerotic plaques may be a marker of lesions that are vulnerable to disruption and have more inflammatory cellular components.

[0156] In some embodiments, the method results in reduced atherosclerotic plaque inflammation as monitored by18F-FDG PET / CT, including specifically the determination of TBR as a function of SUV, wherein decreased uptake (e.g. up to about 5% decrease, up to about 10% decrease, up to about 25% decrease, up to about 50% decrease, or more) is indicative of reduced atherosclerotic plaque inflammation. In some embodiments, 18F-FDG uptake is reduced as measured by SUV and / or TBR. In some embodiments, the change in vascular 18F-FDG uptake is monitored by combined Positron Emission Tomography (PET)329750705 43Attorney Docket: BTRT-Oll / OIWO 342313-2192and computed tomography (CT). In some embodiments, 18F-FDG is reduced as measured by TBR in the carotid artery, aorta, femoral artery, and / or an arterial bed.

[0157] In some embodiments, the method provides a therapeutic effect related to the level of a marker of inflammation. In some embodiments, the marker of inflammation is one described in WO2022 / 093628. In some embodiments, the marker of inflammation is selected from18F-FDG uptake as measured by 18-FDG measured by PET / CT, high sensitivity C-reactive protein (hsCRP), C-reactive protein (CRP), IL-6, IL-8, fibrinogen, Human serum amyloid A (SAA), Haptoglobin (Hp), secretory phospholipase A2 (sPLA2), Lipoprotein(a), apolipoprotein B (APOB) to apolipoprotein Al (APOA1 ) ratio, and white blood cell count (WBC). In some embodiments, the effectiveness of the method is determined by measuring the marker of inflammation prior to treatment compared to a particular time point following initiation of treatment. In some embodiments, the particular time point following initiation of treatment is about 1 month to about 18 months. In some embodiments, the effectiveness of the method is determined by measuring the marker of inflammation in a plurality of subjects receiving the treatment as compared to subjects treated with a control or placebo formulation.

[0158] In some embodiments, the method results in an increased level of the marker. In some embodiments, the method results in a level of the marker that is increased by at least about 1.5-fold, about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 50-fold, about 100-fold at a particular time point following initiation of treatment as compared to prior to the treatment. In some embodiments, the method results in a level of the marker that is increased by at least about 1.5-fold, about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 50-fold, about 100-fold in a plurality of subjects receiving the treatment as compared to subjects treated with a control or placebo formulation.

[0159] In some embodiments, the method results in substantially no change in the level of the marker. In some embodiments, the method results in a level of the marker at a particular time point following initiation of treatment that is ±1% to ±10% of the level prior to the treatment. In some embodiments, the method results in a level of the marker in a plurality of subjects receiving the treatment that is ±1% to ±10% of the level measured in subjects treated with a control or placebo formulation.

[0160] In some embodiments, the method results in a decreased level of the marker. In some embodiments, the method results in a level of the marker that is decreased by at least about 1.5-fold, about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 50-fold, about 100-fold at a particular time point following initiation of treatment as compared to prior to the treatment. In some embodiments, the method results in a level of the marker that329750705 44Attorney Docket: BTRT-Oll / OIWO 342313-2192is decreased by about 1.5-fold, about 2-fold, about 5-fold, about 10-fold, about 15-fold, about 20-fold, about 50-fold, about 100-fold in a plurality of subjects receiving the treatment as compared to subjects treated with a control or placebo formulation.

[0161] In some embodiments, the method provides the desired clinical outcome without resulting in an adverse event requiring discontinuation of treatment. In some embodiments, the method provides the desired clinical outcome in a manner that is tolerated by the subject.

[0162] In some embodiments, the method provides the desired clinical outcome without resulting in anemia and / or thrombocytopenia.

[0163] In some embodiments, the method provides the desired clinical outcome without substantially altering the plasma level of hemoglobin. In some embodiments, the level of hemoglobin as measured in plasma at a particular time point following initiation of treatment (e.g., 1 day to 30 days following initiation of treatment) is no more than about ±1% to ±10% of the level prior to the treatment. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not substantially alter a hemoglobin level as compared to prior to the administration. In some embodiments, a hemoglobin level of at least about 13 grams per deciliter and up to about 18 grams per deciliter is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0164] In some embodiments, the method provides the desired clinical outcome without substantially altering the plasma level of platelets. In some embodiments, the level of platelets as measured in plasma at a particular time point following initiation of treatment (e.g., 1 day to 30 days following initiation of treatment) is no more than about ±1% to ±10% of the level prior to the treatment. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not substantially alter a platelet count as compared to prior to the administration. In some embodiments, a platelet count of at least about 150,000 platelets per microliter and up to about 450,000 platelets per microliter is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0165] In some embodiments, the method provides the desired clinical outcome without substantially altering the plasma level of neutrophils. In some embodiments, an absolute count of neutrophils as measured in plasma at a particular time point following initiation of treatment (e.g., 1 day to 30 days following initiation of treatment) is no more than about ±1% to ±10% of the absolute count prior to the treatment. In some embodiments, administration of the SIRPa Fc fusion polypeptide does not substantially alter an absolute neutrophil count as compared to prior to the administration. In some embodiments, an absolute neutrophil count of at least about 2,500 neutrophils per microliter and up to about 8,000 neutrophils per329750705 45Attorney Docket: BTRT-Oll / OIWO 342313-2192microliter is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0166] In some embodiments, the method provides the desired clinical outcome without resulting in a detectable anti drug antibody (ADA) response.Signal-regulatory protein a (SIRPa) Fc fusion polypeptides

[0167] Provided herein are fusion polypeptides comprising a SIRPa domain and a Fc domain, useful for disrupting and / or blocking the binding of endogenous SIRPa to a CD47 protein. In some embodiments, the fusion polypeptide comprises a modified Fc domain.SIRPa Fc Fusion Polypeptide Sequences

[0168] A SIRPa Fc fusion polypeptide as provided herein comprises a SIRPa domain and an Fc domain. In this section, the SIRPa domain aspect of the fusion protein is described in greater detail.

[0169] The SIRPa domains provided herein comprise a membrane distal (DI) domain of SIRPa, which binds to the CD47 protein (either wild type of modified versions thereof). In some embodiments, a SIRPa fusion polypeptide of the disclosure comprises a wild type human SIRPa DI sequence comprising SEQ ID NO: 1 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0170] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprise a SIRPa DI domain with one or more amino acid modifications relative to a wild type sequence of the DI domain, for example the DI domain of SEQ ID NO: 1. A modification includes an amino acid substitution, an amino acid deletion, and an amino acid addition. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least one amino acid modification relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least two amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least three amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least four amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least five amino acid modifications relative to the wild-type sequence of the DI domain. In329750705 46Attorney Docket: BTRT-Oll / OIWO 342313-2192some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least six amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least seven amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least eight amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least nine amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least ten amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least eleven amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twelve amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least thirteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least fourteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least fifteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least sixteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least seventeen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least eighteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least nineteen amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty-one amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty -two amino acid329750705 47Attorney Docket: BTRT-Oll / OIWO 342313-2192modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty -three amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty-four amino acid modifications relative to the wild-type sequence of the DI domain. In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI domain, with at least twenty-five amino acid modifications relative to the wild-type sequence of the DI domain.

[0171] In some embodiments, a SIRPa Fc fusion polypeptide comprises a SIRPa DI polypeptide that exhibits a higher binding affinity ( / .<?., lower KD value) to CD47 by at least 5-fold, 10-fold, at least 20-fold, at least 50- fold, at least 100-fold, at least 500-fold, at least 1000-fold or more relative to a wild type SIRPa DI domain.

[0172] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a modification relative to the wild type SIRPa DI domain sequence of SEQ ID NO: 1 at one or more of the following residues V6, S14, S20, 122, H24, V27, 131, A45, E47, K53, E54, H56, S66, E70, S77, V92, and / or a duplication of the DI 00 residue.

[0173] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a modification relative to the wild type SIRPa DI domain sequence of SEQ ID NO: 1 of one or more of the following: V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue.

[0174] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a modification relative to the wild type SIRPa DI domain sequence of SEQ ID NO: 1, wherein the modification comprises: V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue.

[0175] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a SIRPa DI sequence of SEQ ID NO: 2 (referred to herein as CV1, an exemplary SIRPa DI domain which exhibits higher binding affinity to CD47), or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0176] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a SIRPa DI sequence of SEQ ID NO: 3 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.329750705 48Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0177] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a SIRPa DI sequence of SEQ ID NO: 4 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0178] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a SIRPa DI sequence of SEQ ID NO: 5 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0179] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises one or more of the following substitutions relative to the SIRPa DI sequences of SEQ ID NOs: 1-5: E3G, L4V, L4I, V6I, V6L, S12F, S14L, S20T, A21V, I22T, H24L, H24R, V27A, V27I, V27L, 13 IF, 13 IS, I31T,Q37H, A45G, E47V, E47L, K53R, E54Q, E54P, H56P, H56R, V63I, E65D, S66T, S66G, S66L, K68R, E70N, M72R, S75P, R77S, S79G, N80A, N80X, 18 IN, T82N, P83N, P83X, V92I, F94L, F94V, duplication of D100, E102V, E102T, E102F, F103E, F103V, K104F, K104V, A115G, K116A, and K116G, wherein X= any amino acid.

[0180] In some embodiments, a SIRPa Fc fusion polypeptide sequence of the disclosure may comprise any of the SIRPa DI sequences described in WO2013109752, WO2014094122A1, WO2017027422, W02016023040, WO2016024021 Al, WO2023183892A1, each of which is incorporated herein in its entirety.Fc Domains

[0181] In some embodiments, the SIRPa Fc fusion polypeptide comprises a wild-type Fc domain. In some embodiments, the SIRPa Fc fusion polypeptide comprises a modified Fc domain. As provided herein, one or more modifications (e.g., substitutions) may be introduced into a wild type IgG Fc domain sequence, e.g., a human IgGl, IgG2, IgG3, or IgG4 domain to improve a functional property of the SIRPa Fc fusion polypeptide, e.g., to improve a pharmacokinetic property, efficacy and / or safety of the fusion polypeptide.

[0182] The Fc domains provided herein can be modified domains of any species, e.g., human or mouse, or may be an engineered non-naturally occurring Fc domain, e.g. a human or mouse IgG domain comprising one or more modifications. In some embodiments, the Fc domain is a modified human IgGl or IgG4 Fc domain. Canonical wild type sequences for these are presented herein.

[0183] In some embodiments the Fc domain is a modified human IgG2 or IgG3 domain, or a mouse IgGl, IgG2a, IgG2b, or IgG3 domain.329750705 49Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0184] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises the human IgGl Fc amino sequence of SEQ ID NO: 6 or 15 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0185] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises the human IgG4 Fc amino sequence of SEQ ID NO: 7 or 16 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0186] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises an Fc domain of an IgG4 human Fc domain and the polypeptide is prone to the dynamic process of Fab-arm exchange. Accordingly, in some embodiments the IgG4 Fc domain may comprise a S228P substitution relative to SEQ ID NO: 7 or 16 according to EU numbering scheme, resulting in the reduction of this process. In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises the IgG4 Fc amino sequence of SEQ ID NO: 8 or 17 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0187] In some embodiments, the IgG4Fc amino acid sequence comprises the substitution L445P relative to SEQ ID NO: 8 or 17, according to the EU numbering scheme.

[0188] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises the human IgGl Fc sequence of SEQ ID NO: 6 or 15 comprising one or more modifications (e.g., substitutions) to increase effector function. In some embodiments, the substitutions are selected from the group consisting of V215A, G236A, S239D, I332E, T250Q, M252Y, S254T, T256E, S267E, N325S, L328F, N343S, M428L, H433K, andN434F relative to SEQ ID NO: 6 or 15 according to the EU numbering scheme. Exemplary combinations include: G236A-S239D, G236A-I332E, S239D-I332E, V215A-G236A-S239D-I332E, G236A-S239D-I332E, K326W-E333S, S267E-H268F-S324T, and E345R-E430G-S440Y, F243L-R292P-Y300L-V305I-P396L, S239D-I332E, S298A-E333A-K334A, L234Y-L235Q-G236W-S239M-H268D-D270E-S298A, and D270E-K326D-A330M-K334E, relative to SEQ ID NO: 6 or 15 according to the EU numbering scheme.

[0189] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a human IgGlFc sequence of SEQ ID NO: 6 or 15 comprising one or more modifications (e.g., substitutions) to decrease effector function. In some embodiments, the substitutions are329750705 50Attorney Docket: BTRT-Oll / OIWO 342313-2192selected from the group consisting of: N297A, N297Q, N297G, L235E, L234A, L235A, K214R, P329G, D356E, and L358M.

[0190] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a human IgG4 Fc sequence of any one of SEQ ID NOs: 7-8 and 16-17 comprising one or more modifications (e.g., substitutions) to decrease effector function. In some embodiments, the substitutions are selected from the group consisting of: L235A, L235E, S228P, and F234A. Exemplary combinations include L235E-S228P, S228P-F234A, and S228P-F234A-L235A.

[0191] In other embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises an IgGl Fc or an IgG4 Fc domain in which a modification is present to increase serum half-life. In some embodiments the mutations are selected from the group consisting of T250Q, M252Y, S254T, T256E, S267E, N325S, L328F, N343S, M428L, N434F, and H443K relative to IgGl Fc domain sequence SEQ ID NO: 6 or 15 or IgG4 Fc domain sequence any one of SEQ ID NOs: 7-8 and 16-17 according to the EU numbering scheme. In some embodiments the mutations are selected from the group consisting of T250Q-M428L, M252Y-S254T-T256E, M428L-N434S, S267E-L328F, N325S-L328F, and H433K-N434F, relative to IgGl Fc domain sequence SEQ ID NO: 6 or 15 or IgG4 Fc domain sequence any one of SEQ ID NOs: 7-8 and 16-17 according to the EU numbering scheme.

[0192] In some embodiments, an exemplary SIRPa Fc fusion polypeptide of the disclosure comprises an IgG4 human Fc domain of SEQ ID NO: 8 or 17 comprising substitutions M252Y, S254T, and T256E, relative to SEQ ID NO: 8 or 17.

[0193] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises the human IgG4 Fc amino sequence of SEQ ID NO: 9 or 18 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0194] In some embodiments, a SIRPa Fc fusion polypeptide of the disclosure comprises a peptide linker joining the SIRPa domain and the Fc domain. In some embodiments, the SIRPa Fc fusion polypeptide comprises a peptide linker of about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, or about 16 amino acids in length. In some embodiments, the peptide linker comprises Alanine (A), Glycine (G) and / or Serine (S) amino acids. In some embodiments, the peptide linker is 8 amino acids of G and S amino acids. In some embodiments, the linker is AAA. In some embodiments, the linker is GGGSGGGS (SEQ ID NO: 11). In some embodiments, the linker comprises a human IgG sequence, e.g., ASTKGPSVFPLAP (SEQ ID NO: 12).329750705 51Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0195] In exemplary embodiments, a SIRPa Fc fusion polypeptide as provided herein comprises a SIRPa domain sequence of any of SEQ ID NOS: 1-5 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and a modified Fc domain sequence of any of SEQ ID NOS: 6-9 and 15-18 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0196] In exemplary embodiments, a SIRPa Fc fusion polypeptide as provided herein comprises the Fc domain sequence of SEQ ID NO: 9 or 18 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the SIRPa domain sequence of SEQ ID NO: 2 or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0197] Exemplary SIRPa Fc fusion polypeptides comprising a SIRPa domain and a modified Fc domain comprise the sequence of any of SEQ ID NOs: 10, 13-14, and 19, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.Exemplary Methods

[0198] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 75 mg per kg of body weight of the subject, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the dose is administered by intravenous injection. In some embodiments, the dose is administered by329750705 52Attorney Docket: BTRT-Oll / OIWO 342313-2192subcutaneous injection. In some embodiments, the dose is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0199] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 5 mg per kg of body weight of the subject, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the dose is administered by intravenous injection. In some embodiments, the dose is administered by subcutaneous injection. In some embodiments, the dose is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0200] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the dosing regimen comprises administration of a dose of the SIRPa fusion polypeptide to achieve a target occupancy of at least about 10%, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at329750705 53Attorney Docket: BTRT-Oll / OIWO 342313-2192least 99% sequence identity thereto. In some embodiments, administration of the dose of the SIRPa fusion polypeptide achieves a peak target occupancy of at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, the dose is about 0.1 to about 5 mg per kg of body weight of the subject. In some embodiments, the dose is administered by intravenous injection. In some embodiments, the dose is administered by subcutaneous injection. In some embodiments, the dose is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0201] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 75 mg per kg of body weight of the subject, wherein the dose of the SIRPa fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the dosing frequency is once every about 3, 7, 14, 21, 28, 35, 48, 56, or 60 days. In some embodiments, the dose is administered by intravenous injection. In some embodiments, the dose is administered by subcutaneous injection. In some embodiments, the dose is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0202] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion329750705 54Attorney Docket: BTRT-Oll / OIWO 342313-2192polypeptide in a dosing regimen, wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 5 mg per kg of body weight of the subject, wherein the dose of the SIRPa fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the dosing frequency is once every about 3, 7, 14, 21, 28, 35, 48, 56, or 60 days. In some embodiments, the dose is administered by intravenous injection. In some embodiments, the dose is administered by subcutaneous injection. In some embodiments, the dose is administered at a dosing frequency of once every about 1 to about 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0203] In some embodiments, a peak target occupancy measured on cells (e.g., RBCs and / or WBCs) in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide is about 10% to about 100% (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%). In some embodiments, the peak target occupancy is about 80% to about 100% (e.g., about 80%, 90%, or 100%), wherein the dose of the SIRPa Fc fusion polypeptide is at least about 3 mg / kg (e.g., at least about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject. In some embodiments, the peak target occupancy is about 20% to about 100% (e.g., about 20%, about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), wherein the dose of the SIRPa Fc fusion polypeptide is at least about 0.5 mg / kg (e.g., at least about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject. In some embodiments, the peak target occupancy is about 10% to about 100% (e.g., about 20%, about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), wherein the dose of the SIRPa Fc fusion polypeptide is at least about 0.1 mg / kg (e.g., at least about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject.329750705 55Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0204] In some embodiments, an average target occupancy measured on cells (e.g., RBCs and / or WBCs) in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject over a duration of time following administration of the dose of the SIRPa Fc fusion polypeptide is about 10% to about 100% (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), wherein the duration of time is about 3 to about 30 days following administration of the dose of the SIRPa Fc fusion polypeptide. In some embodiments, the average target occupancy is about 30% to about 100% (e.g., about 60%, 70%, 80%, 90%, or 100%), wherein the dose of the SIRPa Fc fusion polypeptide is at least about 1 mg / kg (e.g., at least about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject. In some embodiments, the average target occupancy is about 10% to about 100% (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%), wherein the dose of the SIRPa Fc fusion polypeptide is at least about 0.1 mg / kg (e.g., at least about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject.

[0205] In some embodiments, a Cmax measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide is at least about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 500 ng / mL, about IxlO3ng / mL, about 2xl03ng / mL, about 3xl03ng / mL, about 4xl03ng / mL, about 5xl03ng / mL, about 6xl03ng / mL, about 7xl03ng / mL, about 8xl03ng / mL, about 9xl03ng / mL, or about lxl04ng / mL. In some embodiments, the Cmax measured in the sample is at least about 50-100 ng / mL, about 60-150 ng / mL, about 70-300 ng / mL, about 50-400 ng / mL, or about 50-500 ng / mL, wherein the dose is about 0.1-2 mg / kg (e.g., about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, or about 2 mg / kg) of body weight of the subject. In some embodiments, the Cmax measured in the sample is at least about 500-1000 ng / mL, about 1000-3000 ng / mL, about 1000-5000 ng / mL, about 2000-9000 ng / mL, or about 5000-10000 ng / mL, wherein the dose is about 2-4 mg / kg (e.g., about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg) of body weight of the subject. In some embodiments, the Cmax measured in the sample is at least about 2000-9000 ng / mL, about 5000-10000 ng / mL, or about 6000-10000 ng / mL, wherein the dose is about 3-5 mg / kg (e.g., about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject.

[0206] In some embodiments, an average AUC measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide is about lxl04h*ng / mL, about 5xl04h*ng / mL, about IxlO5329750705 56Attorney Docket: BTRT-Oll / OIWO 342313-2192h*ng / mL, about 5xl05h*ng / mL, about lxl06h*ng / mL, or about 5xl06h*ng / mL. In some embodiments, the average AUC measured in the sample is about IxlO3- 5xl04h*ng / mL, about IxlO4- 5xl04h*ng / mL, about 2xl04- 5xl04h*ng / mL, wherein the dose is about 0.1-2 mg / kg (e.g., about 0.1 mg / kg, about 0.3 mg / kg, about 0.5 mg / kg, about 0.8 mg / kg, about 1 mg / kg, or about 2 mg / kg) of body weight of the subject. In some embodiments, the average AUC measured in the sample is about 5xl04- lxl05h*ng / mL, about IxlO5- 5xl05h*ng / mL, about 2xl05- IxlO6h*ng / mL, wherein the dose is about 2-4 mg / kg (e.g., about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg) of body weight of the subject. In some embodiments, the average AUC measured in the sample is about IxlO5- 2xl06h*ng / mL, about 5xl05- 3xl06h*ng / mL, or about IxlO6- 5xl06h*ng / mL, wherein the dose is about 3-5 mg / kg (e.g., about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg) of body weight of the subject. In some embodiments, the average AUC is determined to the last quantifiable time point, wherein the last quantifiable time point is about 500-1500 hours following administration of the SIRPa Fc fusion polypeptide.

[0207] In some embodiments, a hemoglobin level measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide no more than about ±1% to ±10% of the level prior to the administration. In some embodiments, the hemoglobin level is about 13 grams per deciliter to about 18 grams per deciliter following the administration, e.g., as measured in plasma. In some embodiments, the hemoglobin level is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0208] In some embodiments, a platelet count measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide no more than about ±1% to ±10% of the level prior to the administration. In some embodiments, the platelet count is about 150,000 platelets per microliter to about 450,000 platelets per microliter following the administration, e.g., as measured in plasma. In some embodiments, the platelet count is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0209] In some embodiments, a neutrophil count measured in a sample (e.g., a plasma, serum, or whole blood sample) obtained from the subject following administration of the dose of the SIRPa Fc fusion polypeptide no more than about ±1% to ±10% of the level prior to the administration. In some embodiments, the neutrophil count is about 2,500 neutrophils per microliter to about 8,000 neutrophils per microliter following the administration, e.g., as329750705 57Attorney Docket: BTRT-Oll / OIWO 342313-2192measured in plasma. In some embodiments, the neutrophil count is maintained for a duration of time (e.g., a duration of 1-50 days) following the administration.

[0210] In some embodiments, the disclosure provides a method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen comprising a starting dose cycle and a maintenance dosing cycle, wherein the starting dosing cycle comprises administration of a starting dose of the SIRPa fusion polypeptide at a dosing frequency of once every about 1 to about 60 days for a duration of time, wherein the maintenance dosing cycle comprises administration of a maintenance dose of the SIRPa fusion polypeptide at a dosing frequency of once every about 1 to about 60 days, wherein the SIPRa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto, and wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto. In some embodiments, the starting dose is about 0.1 to about 5 mg / kg of body weight of the subject. In some embodiments, the maintenance dose is about 0.1 to about 5 mg / kg of body weight of the subject. In some embodiments, the dosing frequency of the starting dosing cycle is once every about 3, 7, 14, 21, 28, 35, 48, 56, or 60 days. In some embodiments, the dosing frequency of the maintenance dosing cycle is once every about 3, 7, 14, 21, 28, 35, 48, 56, or 60 days. In some embodiments, the subject has experienced an ASCVD event prior to treatment. In some embodiments, the ASCVD event comprises carotid artery disease. In some embodiments, the subject has a risk factor for atherosclerotic disease prior to treatment.

[0211] In some embodiments, the subject has (A) an age of at least about 45 years (e.g., about 45, 50, 55, 60, 65, 70, 75, or 80 years); and (B)(i) experienced an ASCVD event prior to treatment, wherein the ASCVD event is selected from a myocardial infarction, a transient ischemic attack, or a stroke, and wherein the ASCVD event occurs not more than about 6 to about 18 months prior to onset of treatment (e.g., not more than about 12 months prior to onset of treatment); or (ii) at least two risk factors for atherosclerotic disease prior to treatment, wherein the risk factors are selected from (a) an age of at least about 65 years old, (b) hypertension, (c) hyperlipidemia on a lipid lowering therapy (e.g., a statin), or a history of intolerance to lipid lowering therapy and an LDL-cholesterol of at least 190 mg / dL, (d) an329750705 58Attorney Docket: BTRT-Oll / OIWO 342313-2192ongoing smoking habit, (e) non-insulin dependent diabetes mellitus, (f) high sensitivity C-reactive protein of at least about 2 mg / L, and (g) peripheral arterial disease (e.g., documented history of intermittent claudication or lower extremity stenosis of at least 50% as measured by an imaging test). In some embodiments, the subject has a weight of at least about 50 kg (e.g., about 50 kg to about 200 kg). In some embodiments, the subject has an arterial TBRmax measured by 18F-FDGPET / CT of at least about 1.6 or higher (e.g., in an aorta, coronary artery, extracranial carotid artery, intracranial carotid artery, renal artery, mesenteric artery, iliac artery, and / or arteries of the lower limb).Pharmaceutical Compositions

[0212] In some embodiments, a SIRPa Fc fusion polypeptide is present in a pharmaceutical composition. In particular embodiments, the pharmaceutical compositions may be in a water-soluble form, such as in pharmaceutically acceptable salts, which is meant to include both acid and base addition salts. The compositions for administration will commonly include the polypeptide dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline. The composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions. The concentration of active agents in the formulations can vary and are selected based on fluid volumes, viscosities, and body weight in accordance with the particular mode of administration selected and the subject's needs (e.g., Remington's Pharmaceutical Science (15th ed., 1980) and Goodman & Gillman, The Pharmacological Basis of Therapeutics (Hardman et al., eds., 1996)).Kits

[0213] The present disclosure provides kits comprising a SIRPa Fc fusion polypeptide described herein for administration by a medical professional or the subject in need thereof. The kit may comprise, for example, a container, a dose of the SIRPa Fc fusion polypeptide, a syringe and / or a vial, and instructions for use thereof. In some embodiments the kit comprises a SIRPa fusion polypeptide and instructions for administering the polypeptide to treat atherosclerosis.

[0214] In some embodiments, the kit comprises a SIRPa Fc fusion polypeptide described herein, and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administering the SIRPa Fc fusion polypeptide to a human subject to treat329750705 59Attorney Docket: BTRT-Oll / OIWO 342313-2192atherosclerosis disease, wherein the treatment comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to 75 mg / kg (e.g., 0.1 to 5 mg / kg) of body weight of the subject.

[0215] In some embodiments, the kit comprises a SIRPa Fc fusion polypeptide described herein, and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administering the SIRPa Fc fusion polypeptide to a human subject to treat atherosclerosis disease, wherein the treatment comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to 75 mg / kg (e.g., 0.1 to 5 mg / kg) of body weight of the subject and a dosing frequency of once per every about 1 to about 60 days.

[0216] In some embodiments, the kit comprises a SIRPa Fc fusion polypeptide described herein, and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administering the SIRPa Fc fusion polypeptide to a human subject to treat atherosclerosis disease, wherein the treatment comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to 75 mg / kg (e.g., 0.1 to 5 mg / kg) of body weight of the subject, wherein the subject is receiving, has received, or subsequently receives a second therapeutic agent described herein (e.g., a lipid modifying agent, e.g., a statin).ENUMERATED EMBODIMENTS

[0217] The present disclosure provides the following exemplary embodiments.

[0218] Embodiment 1-1. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal-regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 75 mg per kg (mg / kg) of body weight of the subject.

[0219] Embodiment 1-2. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal-regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of a dose of the SIRPa Fc fusion polypeptide to achieve a target occupancy of at least about 20%.

[0220] Embodiment 1-3. The method of embodiment 1-2, wherein the dose of the SIRPa Fc fusion polypeptide administered is about 0.1 to about 5 mg / kg of body weight of the subject.329750705 60Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0221] Embodiment 1-4. The method of any one of embodiments 1-1 to 1-3, wherein the dose of the SIRPa Fc fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days.

[0222] Embodiment 1-5. The method of any one of embodiments 1-1 to 1-4, wherein the dose of the SIRPa Fc fusion polypeptide administered is about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject.

[0223] Embodiment 1-6. The method of any one of embodiments 1-1 to 1-4, wherein the dose is about 0.5 to about 5 mg / kg of body weight of the subject.

[0224] Embodiment 1-7. The method of any one of embodiments 1-1 to 1-4, wherein the dose is about 1, 3, or 5 mg / kg of body weight of the subject.

[0225] Embodiment 1-8. The method of any one of embodiments 1-2 to 1-7, wherein the dosing frequency is once every about 1 day to about 14 days for at least one month.

[0226] Embodiment 1-9. The method of any one of embodiments 1-2 to 1-7, wherein the dosing frequency is once every about 7 days to about 30 days for at least two months.

[0227] Embodiment 1-10. The method of embodiment 1-1 or 1-2, wherein the dosing regimen comprises a starting dosing cycle and a maintenance dosing cycle.

[0228] Embodiment 1-11. The method of embodiment I- 10, wherein the starting dosing cycle comprises administration of a starting dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days for a duration of time.

[0229] Embodiment 1-12. The method of embodiment 1-11, wherein the starting dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject.

[0230] Embodiment 1-13. The method of embodiment 1-11 or 1-12, wherein the maintenance dosing cycle comprises administration of a maintenance dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days.

[0231] Embodiment 1-14. The method of embodiment 1-13, wherein the maintenance dose is about 0.1 to about 5 mg / kg of body weight of the subject.

[0232] Embodiment 1-15. The method of embodiment 1-13 or 1-14, wherein the dosing frequency for the administration of the starting dosing cycle and the maintenance dosing cycle is the same.

[0233] Embodiment 1-16. The method of embodiment 1-13 or 1-14, wherein the dosing frequency for the administration of the starting dosing cycle and the maintenance dosing cycle are different.

[0234] Embodiment 1-17. The method of any one of embodiments 1-13 to 1-16, wherein the starting dose and the maintenance dose are the same.329750705 61Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0235] Embodiment 1-18. The method of any one of embodiments 1-13 to 1-16, wherein the starting dose and the maintenance dose are different.

[0236] Embodiment 1-19. The method of any one of embodiments 1-13 to 1-18, wherein the dosing frequency of the starting dosing cycle is once every about 1 to about 7 days for about 1 to about 6 months, and the dosing frequency of the maintenance dosing cycle is once every about 7 to about 30 days for at least 2 months.

[0237] Embodiment 1-20. The method of embodiment 1-19, wherein the starting dose is administered at about 0.3 to about 3 mg / kg of body weight of the subject, and the maintenance dose is administered at about 0.5 to about 1 mg / kg of body weight of the subject.

[0238] Embodiment 1-21. The method of any one of embodiments 1-1 to 1-20, wherein the subject has atherosclerotic disease or is at risk of developing atherosclerotic disease.

[0239] Embodiment 1-22. The method of any one of embodiments 1-1 to 1-21, wherein the subject has exhibited at least one atherosclerotic cardiovascular disease (ASCVD) event prior to treatment.

[0240] Embodiment 1-23. The method of embodiment 1-22, wherein the ASCVD event is selected from the group consisting of a stroke, transient ischemic attack, carotid artery disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, mesenteric ischemia, and a combination thereof.

[0241] Embodiment 1-24. The method of any one of embodiments 1-1 to 1-23, wherein the subject has received or is receiving a treatment for ASCVD, optionally wherein the treatment comprises administration of a statin.

[0242] Embodiment 1-25. The method of any one of embodiments 1-1 to 1-24, wherein the subject has exhibited a risk factor for ASCVD prior to the dosing regimen.

[0243] Embodiment 1-26. The method of embodiment 1-25, wherein the risk factor is selected from the group consisting of: (i) a genotype comprising a homozygous or heterozygous 9p21 risk allele, optionally wherein the 9p21 risk allele comprises a single polymorphism (SNP) variant at 9p21; (ii) a presence of perivascular inflammation, optionally wherein the presence is measured by a coronary heart scan; (iii) a presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells, optionally wherein CHIP is measured by gene sequencing; (iv) an intermediate or high level of C-reactive protein (CRP); (v) an elevated polygenic risk score; (vi) an increased level of a marker of inflammation, optionally wherein the marker of inflammation is selected from IL-6, IL-8,329750705 62Attorney Docket: BTRT-Oll / OIWO 342313-2192fibrinogen, human serum amyloid A (SAA), haptoglobin, phospholipase A2 (sPLA2), lipoprotein(a), an apolipoprotein B (APOB) to apolipoprotein Al (AP0A1) ratio, a white blood cell count, and a combination thereof; and (vii) a combination of any one of (i)-(vi).

[0244] Embodiment 1-27. The method of any one of embodiments 1-1 to 1-26, wherein the SIRPa Fc fusion polypeptide is administered by intravenous injection.

[0245] Embodiment 1-28. The method of any one of embodiments 1-1 to 1-26, wherein the SIRPa Fc fusion polypeptide is administered by subcutaneous injection.

[0246] Embodiment 1-29. The method of any one of embodiments 1-1 to 1-28, wherein administration of the SIRPa Fc fusion polypeptide achieves a peak target occupancy of about 20% to about 100%.

[0247] Embodiment 1-30. The method of embodiment 1-29, wherein the peak target occupancy is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample or an atherosclerotic plaque specimen.

[0248] Embodiment 1-31. The method of embodiment 1-29 or 1-30, wherein the peak target occupancy is about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0249] Embodiment 1-32. The method of any one of embodiments 1-29 to 1-31, wherein the peak target occupancy occurs about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

[0250] Embodiment 1-33. The method of any one of embodiments 1-1 to 1-32, wherein administration of the SIRPa Fc fusion polypeptide achieves an average target occupancy of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% for a duration of time of at least about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

[0251] Embodiment 1-34. The method of any one of embodiments 1-1 to 1-33, wherein the treatment results in the stabilization of or a reduction in a plaque lesion size, optionally wherein plaque lesion size is a measure of total vessel area.

[0252] Embodiment 1-35. The method of embodiment 1-34, wherein the plaque lesion size is reduced by at least about 5%.

[0253] Embodiment 1-36. The method of embodiment 1-35, wherein plaque lesion size is measured by imaging.329750705 63Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0254] Embodiment 1-37. The method of any one of embodiments 1-1 to 1-36, wherein administration of the SIRPa Fc fusion polypeptide does not result in an adverse event requiring discontinuation of treatment.

[0255] Embodiment 1-38. The method of any one of embodiments 1-1 to 1-37, wherein administration of the SIRPa Fc fusion polypeptide is tolerated in the subject.

[0256] Embodiment 1-39. The method of any one of embodiments 1-1 to 1-38, wherein administration of the SIRPa Fc fusion polypeptide does not substantially alter plasma levels of hemoglobin and / or platelets.

[0257] Embodiment 1-40. The method of any one of embodiments 1-1 to 1-39, wherein administration of the SIRPa Fc fusion polypeptide does not result in anemia and / or thrombocytopenia.

[0258] Embodiment 1-41. The method of any one of embodiments 1-1 to 1-40, wherein administration of the SIRPa Fc fusion polypeptide does not result in a detectable antidrug antibody (ADA) response.

[0259] Embodiment 1-42. The method of any one of embodiments 1-1 to 1-41, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto .

[0260] Embodiment 1-43. The method of embodiment 1-42, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises one or more of the following mutations relative to SEQ ID NO: 1: V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue.

[0261] Embodiment 1-44. The method of any one of embodiments 1-1 to 1-43, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0262] Embodiment 1-45. The method of any one of embodiments 1-1 to 1-44, wherein the Fc domain comprises the IgG4 Fc domain amino acid sequence of any of SEQ ID NOs: 7-8 and 16-17, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.329750705 64Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0263] Embodiment 1-46. The method of embodiment 1-45, wherein the Fc domain comprises M252Y-S254T-T256E, relative to SEQ ID NO: 7-8 and 16-17, according to the EU numbering scheme.

[0264] Embodiment 1-47. The method of any one of embodiments 1-1 to 1-46, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0265] Embodiment 1-48. The method of any one of embodiments 1-1 to 1-41, wherein the Fc domain comprises any of SEQ ID NOs: 7-9 and 16-18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the high affinity SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0266] Embodiment 1-49. The method of any one of embodiments 1-1 to 1-41, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0267] Embodiment 1-50. The method of any of embodiment 1-1 to 1-41, wherein the SIRPa Fc fusion polypeptide comprises any of SEQ ID NOs: 10, 13-14, and 19, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0268] Embodiment 1-51. The method of any one of embodiments 1-1 to 1-50, comprising administering a second therapeutic agent to the subject, optionally wherein the second therapeutic agent comprises a TNFa antagonist.

[0269] Embodiment 1-52. A kit comprising a container comprising: a pharmaceutical composition comprising a SIRPa fusion polypeptide and a pharmaceutically acceptable carrier or diluent, and instructions for use in treating atherosclerotic disease in a human subject, wherein the treatment comprises administration of the pharmaceutical composition at a dose of about 0.1 to about 5.0 mg / kg of the SIRPa fusion polypeptide by body weight of329750705 65Attorney Docket: BTRT-Oll / OIWO 342313-2192the subject, and wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain.

[0270] Embodiment II- 1. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal-regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 75 mg per kg (mg / kg) of body weight of the subject.

[0271] Embodiment II-2. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal-regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of a dose of the SIRPa Fc fusion polypeptide to achieve a target occupancy of at least about 20%.

[0272] Embodiment II-3. The method of embodiment II-2, wherein the dose of the SIRPa Fc fusion polypeptide administered is about 0.1 to about 5 mg / kg of body weight of the subject.

[0273] Embodiment II-4. The method of any one of embodiments II- 1 to II-3, wherein the dose of the SIRPa Fc fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days.

[0274] Embodiment II-5. The method of any one of embodiments II- 1 to II-4, wherein the dose of the SIRPa Fc fusion polypeptide administered is about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject.

[0275] Embodiment II-6. The method of any one of embodiments II- 1 to II-4, wherein the dose is about 0.5 to about 5 mg / kg of body weight of the subject.

[0276] Embodiment II-7. The method of any one of embodiments II- 1 to II-4, wherein the dose is about 1, 3, or 5 mg / kg of body weight of the subject.

[0277] Embodiment II-8. The method of any one of embodiments II-2 to II-7, wherein the dosing frequency is once every about 1 day to about 14 days for at least one month.

[0278] Embodiment II-9. The method of any one of embodiments II-2 to II-7, wherein the dosing frequency is once every about 7 days to about 30 days for at least two months.

[0279] Embodiment II- 10. The method of embodiment II- 1 or II-2, wherein the dosing regimen comprises a starting dosing cycle and a maintenance dosing cycle.329750705 66Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0280] Embodiment II- 11. The method of embodiment II- 10, wherein the starting dosing cycle comprises administration of a starting dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days for a duration of time.

[0281] Embodiment 11-12. The method of embodiment 11-11, wherein the starting dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject.

[0282] Embodiment 11-13. The method of embodiment II- 11 or 11-12, wherein the maintenance dosing cycle comprises administration of a maintenance dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days.

[0283] Embodiment 11-14. The method of embodiment 11-13, wherein the maintenance dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject.

[0284] Embodiment 11-15. The method of embodiment 11-13 or 11-14, wherein the dosing frequency for the administration of the starting dosing cycle and the maintenance dosing cycle is the same.

[0285] Embodiment 11-16. The method of embodiment 11-13 or 11-14, wherein the dosing frequency of the starting dosing cycle and the maintenance dosing cycle are different.

[0286] Embodiment 11-17. The method of any one of embodiments 11-13 to 11-16, wherein the starting dose and the maintenance dose are the same.

[0287] Embodiment 11-18. The method of any one of embodiments 11-13 to 11-16, wherein the starting dose and the maintenance dose are different.

[0288] Embodiment 11-19. The method of any one of embodiments 11-13 to 11-18, wherein the dosing frequency of the starting dosing cycle is once every about 1 to about 7 days for about 1 to about 6 months, and the dosing frequency of the maintenance dosing cycle is once every about 7 to about 30 days for at least 2 months.

[0289] Embodiment 11-20. The method of embodiment 11-19, wherein the starting dose is administered at about 0.3 to about 3 mg / kg of body weight of the subject, and the maintenance dose is administered at about 0.5 to about 1 mg / kg of body weight of the subject.

[0290] Embodiment 11-21. The method of any one of embodiments II- 1 to 11-20, wherein the subject has atherosclerotic disease or is at risk of developing atherosclerotic disease.

[0291] Embodiment 11-22. The method of any one of embodiments II- 1 to 11-21, wherein the subject has exhibited at least one atherosclerotic cardiovascular disease (ASCVD) event prior to treatment.

[0292] Embodiment 11-23. The method of embodiment 11-22, wherein the ASCVD event is selected from the group consisting of a stroke, transient ischemic attack, carotid artery329750705 67Attorney Docket: BTRT-Oll / OIWO 342313-2192disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, mesenteric ischemia, and a combination thereof.

[0293] Embodiment 11-24. The method of any one of embodiments II- 1 to 11-23, wherein the subject has received or is receiving a treatment for ASCVD, optionally wherein the treatment comprises administration of a statin.

[0294] Embodiment 11-25. The method of any one of embodiments II- 1 to 11-24, wherein the subject has exhibited a risk factor for ASCVD prior to the dosing regimen.

[0295] Embodiment 11-26. The method of embodiment 11-25, wherein the risk factor is selected from the group consisting of: (i) a genotype comprising a homozygous or heterozygous 9p21 risk allele, optionally wherein the 9p21 risk allele comprises a single polymorphism (SNP) variant at 9p21; (ii) a presence of perivascular inflammation, optionally wherein the presence is measured by a coronary heart scan; (iii) a presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells, optionally wherein CHIP is measured by gene sequencing; (iv) an intermediate or high level of C-reactive protein (CRP); (v) an elevated polygenic risk score; (vi) an increased level of a marker of inflammation, optionally wherein the marker of inflammation is selected from IL-6, IL-8, fibrinogen, human serum amyloid A (SAA), haptoglobin, phospholipase A2 (sPLA2), lipoprotein(a), an apolipoprotein B (APOB) to apolipoprotein Al (APOA1) ratio, a white blood cell count, and a combination thereof; and (vii) a combination of any one of (i)-(vi).

[0296] Embodiment 11-27. The method of any one of embodiments 11-1 to 11-26, wherein the SIRPa Fc fusion polypeptide is administered by intravenous injection.

[0297] Embodiment 11-28. The method of any one of embodiments 11-1 to 11-26, wherein the SIRPa Fc fusion polypeptide is administered by subcutaneous injection.

[0298] Embodiment 11-29. The method of any one of embodiments 11-1 to 11-28, wherein administration of the SIRPa Fc fusion polypeptide achieves a peak target occupancy of about 20% to about 100%.

[0299] Embodiment 11-30. The method of embodiment 11-29, wherein the peak target occupancy is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample or an atherosclerotic plaque specimen.

[0300] Embodiment II- 31. The method of embodiment 11-29 or 11-30, wherein the peak target occupancy is about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.329750705 68Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0301] Embodiment 11-32. The method of any one of embodiments 11-29 to 11-31, wherein the peak target occupancy occurs about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

[0302] Embodiment 11-33. The method of any one of embodiments II- 1 to 11-32, wherein administration of the SIRPa Fc fusion polypeptide achieves an average target occupancy of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% for a duration of time of at least about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

[0303] Embodiment 11-34. The method of any one of embodiments II- 1 to 11-33, wherein the treatment results in the stabilization of or a reduction in a plaque lesion size, optionally wherein plaque lesion size is a measure of total vessel area.

[0304] Embodiment 11-35. The method of embodiment 11-34, wherein the plaque lesion size is reduced by at least about 5%.

[0305] Embodiment 11-36. The method of embodiment 11-35, wherein plaque lesion size is measured by imaging.

[0306] Embodiment 11-37. The method of any one of embodiments II- 1 to 11-36, wherein administration of the SIRPa Fc fusion polypeptide does not result in an adverse event requiring discontinuation of treatment.

[0307] Embodiment 11-38. The method of any one of embodiments II- 1 to 11-37, wherein administration of the SIRPa Fc fusion polypeptide is tolerated in the subject.

[0308] Embodiment 11-39. The method of any one of embodiments II- 1 to 11-38, wherein administration of the SIRPa Fc fusion polypeptide does not substantially alter plasma levels of hemoglobin and / or platelets.

[0309] Embodiment 11-40. The method of any one of embodiments II- 1 to 11-39, wherein administration of the SIRPa Fc fusion polypeptide does not result in anemia and / or thrombocytopenia.

[0310] Embodiment 11-41. The method of any one of embodiments II- 1 to 11-40, wherein administration of the SIRPa Fc fusion polypeptide does not result in a detectable antidrug antibody (ADA) response.

[0311] Embodiment 11-42. The method of any one of embodiments II- 1 to 11-41, wherein administration of the SIRPa Fc fusion polypeptide achieves an average Cmax of about 50 ng / mL to about IxlO4ng / mL.329750705 69Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0312] Embodiment 11-43. The method of any one of embodiments II- 1 to 11-42, wherein administration of the SIRPa Fc fusion polypeptide achieves an average AUC of about IxlO4h per ng / mL (h*ng / mL) to about 5xl06h*ng / mL.

[0313] Embodiment 11-44. The method of any one of embodiments II- 1 to 11-43, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto .

[0314] Embodiment 11-45. The method of embodiment 11-44, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises one or more of the following mutations relative to SEQ ID NO: 1: V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue.

[0315] Embodiment 11-46. The method of any one of embodiments II- 1 to 11-45, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0316] Embodiment 11-47. The method of any one of embodiments II- 1 to 11-46, wherein the Fc domain comprises the IgG4 Fc domain amino acid sequence of any of SEQ ID NOs: 7-8 and 16-17, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0317] Embodiment 11-48. The method of embodiment 11-47, wherein the Fc domain comprises M252Y-S254T-T256E, relative to SEQ ID NO: 7-8 and 16-17, according to the EU numbering scheme.

[0318] Embodiment 11-49. The method of any one of embodiments II- 1 to 11-48, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0319] Embodiment 11-50. The method of any one of embodiments II- 1 to 11-43, wherein the Fc domain comprises any of SEQ ID NOs: 7-9 and 16-18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the high affinity SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%,329750705 70Attorney Docket: BTRT-Oll / OIWO 342313-2192at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0320] Embodiment 11-51. The method of any one of embodiments II- 1 to 11-43, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0321] Embodiment 11-52. The method of any of embodiment II- 1 -43, wherein the SIRPa Fc fusion polypeptide comprises any of SEQ ID NOs: 10, 13-14, and 19, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

[0322] Embodiment 11-53. The method of any one of embodiments II- 1 to 11-52, comprising administering a second therapeutic agent to the subject, optionally wherein the second therapeutic agent comprises a TNFa antagonist.

[0323] Embodiment 11-54. A kit comprising a container comprising: a pharmaceutical composition comprising a SIRPa fusion polypeptide and a pharmaceutically acceptable carrier or diluent, and instructions for use in treating atherosclerotic disease in a human subject, wherein the treatment comprises administration of the pharmaceutical composition at a dose of about 0.1 to about 5.0 mg / kg of the SIRPa fusion polypeptide by body weight of the subject, and wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain.EXAMPLES

[0324] In the following Examples, “CV1-G4(YTE)” refers to a SIRPa Fc-fusion polypeptide having the sequence of SEQ ID NO: 13, which comprises the SIRPa domain of SEQ ID NO: 2 and an IgG4 Fc domain with a YTE modification (CV1-G4 (YTE)) of SEQ ID NO: 18. Exemplary SIRPa Fc-fusion polypeptides comprising the SIRPa domain of SEQ ID NO: 2 and an IgG4 Fc domain with a YTE modification are further described in US Publication No.2023 / 0365648, which is herein incorporated by reference (see, e.g., “Construct 67”).Example 1: Evaluation of Fc effector function and neonatal Fc receptor binding properties of a SIRPa Fc-fusion polypeptide329750705 71Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0325] CV1-G4(YTE) was evaluated for Fc-dependent effector functions, such as antibodydependent cell-mediated cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC), and binding to the neonatal Fc receptor. Comparison was made to the positive control rituximab, which is a monoclonal antibody containing an IgGl Fc domain that targets CD20.

[0326] The binding of CV1-G4(YTE) to Fc receptors was assessed using bio-layer interferometry to determine the affinity of CV1-G4(YTE) to human FcyRI, FcyRIIa, FcyRIIb / c, FcyRIIIa, and FcRn. Using the Octet platform, His-tagged human Fc-receptor proteins were immobilized onto a capture biosensor using a biotinylated anti-His antibody; then, the CV1-G4(YTE) or rituximab was associated at a range of concentrations and binding kinetics measured. Data were processed and curve fitted using a 1 : 1 binding model.Compared to rituximab that contains an IgGl Fc domain, CV1-G4(YTE) demonstrated significantly reduced binding to all Fc receptors tested besides FcyRI and FcRn (Table 1).Table 1: Comparison of Binding Affinities (KD) Between Rituximab and CV1-G4(YTE) to Human Fc Receptors

[0327] Reduced binding to Fcy-receptors is expected to decrease ADCC activity. FcyRIIIa engagement is considered a key contributor to triggering ADCC. To measure the potential for ADCC, a cell-based reporter assay using CD47-expressing Raji cells as the target cell line and Jurkat as effector cells that carry an FcyRIIIa luciferase reporter gene was utilized. CV1-G4(YTE) binding to Raji target cells did not induce luciferase expression, in contrast with rituximab which exhibited robust activity (FIG. 2A).

[0328] Furthermore, ADCC activity was directly measured using an NK killing assay where primary human NK cells were co-cultured with Far Red stained Raji cells in the presence of increasing doses of rituximab or CV1-G4(YTE). After a 4-hour incubation at 37°C, cells were stained with cell viability dye, and Raji cell death was assessed by flow cytometry. There was a dose dependent increase in Raji cell death by rituximab that was not seen with CV1-G4(YTE) (FIG. 2B).

[0329] To evaluate whether CV1-G4(YTE) causes complement-dependent cytotoxicity, Raji cells were incubated with increasing concentrations of CV1-G4(YTE), rituximab, or huIgG4 isotype control protein in the presence or absence of human whole blood derived serum that329750705 72Attorney Docket: BTRT-Oll / OIWO 342313-2192contains complement (FIGs.2C-2D respectively). After incubation, cell viability was determined using CellTiter-Glo and the percentage cytotoxicity calculated. Only rituximab demonstrated significant cytotoxicity (88% at 200 nM treated) in the presence of complement, indicating the presence of CDC. In contrast, CV1-G4(YTE) showed no significant increase in cytotoxicity.Example 2: Evaluation of in vitro hemagglutination of a SIRPa Fc-fusion polypeptide

[0330] A variety of anti-CD47 antibodies, including the common CC2C6 clone, have been shown to cause hemagglutination through homotypic interactions (Kauder, et al (2018) PLoS One 13(8):e0201832). To evaluate the potential for CV1-G4(YTE) to induce hemagglutination, human donor derived red blood cells were plated onto a 96-well conical plate in the presence of increasing doses of either anti-CD47 CC2C6 antibody, CV1-G4(YTE), phosphate buffered saline, or human IgG4 isotype control. Following incubation for 4 hours, cells were visualized for the presence of red blood cell clumping that is characteristic of hemagglutination. While the anti-CD47 CC2C6 demonstrated hemagglutination, red blood cells incubated with CV1-G4(YTE) appear identical to negative control treated cells (FIG.3).

[0331] In the presence of phosphate buffered saline (PBS) or human IgG4 control, red blood cells settle and form a distinct, red-colored dot at the bottom of the plate (arrow shows one well). In the presence of increasing concentrations of anti-CD47 CC2C6 antibody, which binds to red blood cells, the cells form a lattice network causing dispersion consistent with hemagglutination (box). CV1-G4(YTE) does not appear to induce hemagglutination at any of the concentrations tested.Example 3: Subcutaneous injection of SIRPa Fc-fusion polypeptide reduces atherosclerotic plaque burden in ApoE-deficient mice

[0332] An atherosclerosis progression model in mice was used to evaluate effects of CV1-G4(YTE). Negative control was an IgG4 Fc isotype control antibody.

[0333] Male ApoE-deficient mice (B6.129P2-ApoetmlUnc / J) were placed on a high fat diet at 4 weeks of age and randomized to receive subcutaneous administration of 1, 2.5, 10, or 30 mg / kg CV1-G4(YTE) or 30 mg / kg human IgG4 placebo control three times per week for 12 weeks (9 mice / group). For 3 animals per group, blood was collected at 24 and 48 hours after the first dose and after drug administration on weeks 2, 3, 8 and 12 to measure serum329750705 73Attorney Docket: BTRT-Oll / OIWO 342313-2192pharmacokinetics and CD47-target occupancy. Percent target occupancy was calculated based on geometric mean fluorescence intensity (GMFI) signal in the AF647 channel for CD45-h!gG4+ (h!gG4+ RBCs) from samples aliquoted and processed in two tubes, one with receptors unsaturated and the other with receptors saturated. Blood was also collected at termination for complete blood count (CBC) and serum biomarker analysis.Tolerability and Efficacy Evaluation

[0334] Aortic atherosclerotic plaque burden was assessed by systemic administration of a fluorescent cathepsin B activity-based probe (IVISense™ Cat B Fast; Perkin Elmer).Cathepsin B activity-based probes have been shown to correlate with atherosclerotic plaque burden and used to quantify atherosclerotic lesions (Chen, et al (2002) Circulation. ll;105(23):2766-71). The entire aorta from the ascending aorta to the iliac bifurcation was harvested and imaged for average fluorescent radiant efficiency.

[0335] CV1-G4(YTE) was well tolerated in all animals, and body weights of CV1-G4(YTE) treated animals were similar to those of IgG4 isotype control -treated animals over the course of the study. Atherosclerotic plaque burden in the aortas was significantly decreased in all mice treated with CV1-G4 YTE compared to mice treated with the IgG4 isotype control including the lowest dose tested in the study, 1 mg / kg. Compared to treatment with IgG4, plaque burden measured by fluorescence was reduced by 20%, 24%, 31% and 35% in the 1, 2.5, 10 and 30 mg / kg CV1-G4(YTE) groups, respectively.

[0336] Target occupancy on circulating CD45-negative cells (RBCs) was <1% in the IgG4 control group at all time points (FIG. 4). RO in the CV1-G4(YTE) groups was dosedependent, reaching 13.0%, 36.3%, 91.4% and 100% 24 hours after the first dose of 1 mg / kg, 2.5 mg / kg, 10 mg / kg and 30 mg / kg CV1-G4(YTE), respectively. Target occupancy after the first dose of CV1-G4(YTE) was lower at 48 hours than at 24 hours in all groups. Target occupancy declined during week 2 and week 3 of dosing compared to the first dose.Serum Pharmacokinetics

[0337] The serum pharmacokinetics of CV1-G4(YTE) were investigated during the repeat dose pharmacology study in mice. The study was performed as described above. PK samples were analyzed using a qualified Mesoscale Discovery (MSD) based sandwich method with the lower limit of quantitation (LLOQ) as 0.514 ng / mL.

[0338] Pharmacokinetic exposure (as measured by AUC or Cmax) after repeat-dose SC administrations of CV1-G4(YTE) in ApoE- / - mice was confirmed in all CV1-G4(YTE)329750705 74Attorney Docket: BTRT-Oll / OIWO 342313-2192treated animals. CV1-G4(YTE) exposure increased in a greater than dose proportional manner when going from 1 to 30 mg / kg dose levels. The mean observed serum concentration at 24 hours after the 1st dose at week 12 was 57.4-fold and 4.60-fold higher compared with week 1 for doses of 10 mg / kg and 30 mg / kg, respectively.Example 4: Pharmacokinetics of SIRPa Fc-fusion polypeptide following subcutaneous injection in rats

[0339] Pharmacokinetics (PK) or toxicokinetic (TK) studies of CV1-G4(YTE) was evaluated in Wistar Han rats following a weekly subcutaneous injection. In a 29-day study, male and female Wistar Han rats (in recovery study, 10 / sex / group in main study, 6 / sex / group; in the TK cohort, 6 / sex / group in the vehicle group and 12 / sex / group in the CVl-G4(YTE)-treated groups) received five once weekly doses of CV1-G4(YTE) at 0, 1, 10, or 50 mg / kg / dose for 4 weeks (Days 1, 8, 15, 22, and 29), followed by a 4-week recovery period. Serum samples were collected from each animal at predefined time intervals on Days 1, 22, and 29 (3 / sex / group were bled at alternating time points).Material & Methods(i) Electrochemiluminescent Immunoassay for the Quantification of CV1-G4(YTE) in Rat Serum

[0340] Serum CV1-G4(YTE) concentrations in rat were measured using an electrochemiluminescent immunoassay developed and validated at Bioagilytix Laboratories (Durham, NC, USA). The assay uses biotinylated CD47 (Biot-CD47), which is immobilized onto a 96-well streptavidin coated plate, analyte is bound to the capture protein, and a ruthenylated conjugated detection antibody (Ru-Goat Anti-Human IgG) is used to generate a luminescent response that is directly proportional to the amount of analyte detected in the well. Back-calculated concentrations (BCC) of analyte are generated using a 4PL fit model with 1 / Y2 weighting.Pharmacokinetic Evaluation

[0341] CV1-G4(YTE) serum exposures were confirmed in all treated animals following repeat-dose SC injections. The time to reach maximum concentration (Tmax) was 24 to 48 hours across the dose levels (Table 2). CV1-G4(YTE) maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) values exhibited greater than dose proportional increases from 1 mg / kg to 50 mg / kg (Table 2) and exhibited329750705 75Attorney Docket: BTRT-Oll / OIWO 342313-2192accumulation after four to five weekly SC doses for 1 and 10 mg / kg. Overall, CV1-G4(YTE) systemic exposure was similar in both sexes for 1 and 10 mg / kg. CV1-G4(YTE) systemic exposure at 50 mg / kg was numerically higher in female rats compared with male rats. Data corresponding to that in Table 2 is shown in FIGs. 5A-5C.Table 2 Summary TK Parameters by Sex Following Weekly SC Administration in RatsAUCo-ies: area under the curve from 0 to 168 hr post the most recent dosing ; AUCo-ies / D: dose-normalized area under the curve from 0 to 168 hr post the most recent dosing; AUCiast: area under the curve from 0 to time of the last quantifiable concentration; AUCiast / D: dose-normalized area under the curve from 0 to time of the last quantifiable concentration; RAUC: accumulation ratio based on AUC; Cmax / D: dose-normalized maximum observed concentration.Toxicity Evaluation

[0342] Mortality, clinical signs, dermal irritation observations, body weights, body weight gains, food consumption, clinical pathology parameters (hematology, coagulation, clinical chemistry), RBC and WBC RO evaluation, neurob ehavi oral assessment, TK parameters and macroscopic and microscopic examinations were evaluated in the TK study. There were no CVl-G4(YTE)-related effects on clinical observations, body weights, body weight gains, food consumption, neurob ehavi oral observations, or urinalysis parameters.

[0343] Clinical pathology parameters evaluated included myeloid:erythroid (M:E) ratio, myeloid cell lineage, numbers of megakaryocytes, absolute reticulocyte counts, lymphocyte329750705 76Attorney Docket: BTRT-Oll / OIWO 342313-2192counts, neutrophil counts, WBC counts, eosinophil counts, erythrocyte mass (RBC count, hemoglobin concentration and / or hematocrit), monocyte counts, fibrinogen concentrations, RBC distribution width, incidence of erythrocyte polychromasia, and bilirubin, albumin, and total protein concentrations.

[0344] The no observed adverse effect level (NOAEL) was determined to be the 10 mg / kg / dose, with a sex combined mean Cmax and AUCiast of 1590 ng / mL and 227500 hr*ng / mL, respectively, on Day 29.Example 5: Pharmacokinetics of SIRPa Fc-fusion polypeptide following subcutaneous injection in cynomolgus monkeys

[0345] Pharmacokinetics of CV1-G4(YTE) was evaluated in cynomolgus monkeys following a single subcutaneous injection. Male and female cynomolgus monkeys (3 / sex / group in main study and 2 / sex / group in vehicle (formulation buffer) and high dose groups for recovery study) received 5 weekly doses of 0, 2.5, 15, or 75 mg / kg / dose of CV1-G4(YTE) on Days 1, 8, 15, 22 and 29 and a subset of animals in the vehicle and high dose groups remained on study for 4 additional weeks to assess recovery.Materials & Methods(i) Electrochemiluminescent Immunoassay for the Quantification of CV1-G4(YTE) in Cynomolgus Monkey Serum

[0346] Serum CV1-G4(YTE) concentrations in cynomolgus monkey was measured using an electrochemiluminescent immunoassay developed and qualified at Bioagilytix Laboratories, Durham, North Carolina, USA. The immunoassay uses a biotinylated CD47 (Biot-CD47) that is immobilized in a 96-well streptavidin coated plate, analyte is bound to the capture protein, and a ruthenylated conjugated detection antibody (Ru- Goat Anti-Human IgG) is used to generate a luminescent response that is directly proportional to the amount of analyte detected in the well. Back-calculated concentrations (BCC) of analyte are generated using a4PL fit model with 1 / Y2 weighting.(ii) Flow Cytometry Method for the Determination of CV1-G4(YTE) Target occupancy in Red Blood Cells and White Blood Cells

[0347] A flow cytometry validated method for the determination of CD47 target occupancy in red blood cells (RBC) and white blood cells (WBC) in cynomolgus monkey peripheral whole blood was developed and validated at Altasciences Preclinical Seattle LLC. This329750705 77Attorney Docket: BTRT-Oll / OIWO 342313-2192procedure measures CD47 occupied by CV1-G4(YTE) in cynomolgus monkey whole blood using FACS, in which a detection antibody (AF647-conjugated anti-human IgG4) bound to CV1-G4(YTE) is used to generate a fluorescence response in RBCs and WBCs.

[0348] Briefly, whole blood samples were aliquoted into equal samples for unsaturated and saturated samples and maintained and processed at 4°C prior to acquisition on a BD FACS Canto II Flow Cytometer. The cytometer was configured to collect 5,000 events in the WBC gate or until the sample had run for 300 seconds, whichever occurred first. Percent target occupancy calculated based on mean fluorescence intensity (MFI) signal in the AF647 channel for both PI-CD45-hIgG4+ (hIgG4+ RBCs) and PI-CD45+hIgG4+ (hIgG4+ WBCs) from samples aliquoted and processed in two tubes, one with receptors unsaturated and the other with receptors saturated, is reported.Pharmacokinetic Evaluation

[0349] Serum samples were collected from each animal at predefined time intervals on Day 1 and Day 29.

[0350] CV1-G4(YTE) serum exposures were confirmed on Day 1 and Day 29 in all treated animals following 15 and 75 mg / kg repeat-dose SC injections. CV1-G4(YTE) serum exposures were confirmed on Day 1 in all treated animals and were only measurable in one animal on Day 29 following 2.5 mg / kg repeated-dose SC injections. Overall, CV1-G4(YTE) systemic exposure was similar in both sexes for all tested dose levels. On Day 1, the mean time to reach maximum concentration (Tmax) ranged from 29 to 32 hours across the dose levels (Table 3). CV1-G4(YTE) maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) values exhibited greater than dose proportional increases from 2.5 mg / kg to 75 mg / kg (FIGs. 6A-6B and Table 3) and exhibited mild accumulation after five weekly SC doses for 15 and 75 mg / kg.Table 3 Sex Combined Mean ±SD Serum TK Parameters Following Weekly SC Administration in NHP329750705 78Attorney Docket: BTRT-Oll / OIWO 342313-2192AUCO-24: area under the curve from 0 to 24 hr post the most recent dosing; AUC0-24 / D: dose-normalized area under the curve from 0 to 24 hr post the most recent dosing; AUCiast: area under the curve from 0 to time of the last quantifiable concentration; AUCiast / D: dose-normalized area under the curve from 0 to time of the last quantifiable concentration; RAUC: accumulation ratio based on AUC; Cmax / D: dose-normalized maximum observed concentration.Toxicity Evaluation

[0351] The following parameters were evaluated: mortality, clinical observations including injection site observations, qualitative food consumption, body weights, ophthalmology, electrocardiography, blood pressure, respiratory rate, and clinical pathology parameters (hematology, coagulation, serum chemistry, and urinalysis). Blood was collected at multiple time points to characterize CV1-G4(YTE) serum concentrations over time, cytokine analysis, and for flow cytometry to determine RO in RBCs and WBCs. Cell immunophenotyping of peripheral blood was also performed.

[0352] No unscheduled deaths occurred in the study. There were no CVl-G4(YTE)-related clinical observations or indications of local injection site intolerance, and no CV1-G4(YTE)-related effects on food consumption, body weight, ophthalmology, electrocardiography, blood pressure, respiratory rate, and urinalysis parameters.

[0353] RBCs and WBCs collected from CVl-G4(YTE)-treated animals exhibited high RO compared with baseline in a dose-dependent manner during the dosing period. RO remained elevated in the high dose group (75 mg / kg / dose) during the recovery period.

[0354] Based on the absence of adverse findings following SC injection of CV1-G4(YTE) up to 75 mg / kg / dose to cynomolgus monkeys, the NOAEL was considered to be 75 mg / kg / dose, the highest dose tested.Example 6: Evaluation of tolerability and pharmacokinetics of SIRPa Fc fusion polypeptide in healthy male human adults

[0355] A Phase 1 randomized, double-blind, placebo-controlled single dose study was performed to assess the safety, tolerability, PK and PD of single subcutaneous doses of CV1-G4(YTE) in healthy male participants.Clinical Objectives and Endpoints

[0356] The primary objective of the study was to assess the safety and tolerability following single and multiple dose subcutaneous administration of CV1-G4(YTE) in healthy participants. The endpoints to evaluate this objective were Treatment Emergent Adverse329750705 79Attorney Docket: BTRT-Oll / OIWO 342313-2192Events (TEAEs) up until the end of study (EoS) visit, Adverse Events (including serious adverse events) up until the EoS visit, and other safety endpoints including physical exam, vital signs, electrocardiogram (ECG), safety laboratories up until the EoS visit.

[0357] The secondary objective of the study was to assess the PK of single and multiple doses of subcutaneous CV1-G4(YTE) in healthy participants. The endpoints to evaluate this objective were to measure Cmax, Tmax, AUClast, AUCinf, AUCtau and Tl / 2 of CV1-G4(YTE).

[0358] The study further included several exploratory objectives, including assessing the effects of CV1-G4(YTE) on target engagement and target-related PD parameters, the incidence of hypersensitivity reactions and injection site reactions in participants treated with CV1-G4(YTE), and the prevalence and incidence of immunogenicity in participants treated with CV1-G4(YTE). The endpoints to evaluate these objectives included measures of CD47 target occupancy, markers of vascular inflammation (e.g., C-reactive protein, IL-6, etc.), incidence of adverse events indicative of hypersensitivity reactions and incidence of injection site reactions, and development of anti-CVl-G4(YTE) antibodies.Study Design

[0359] 5 cohorts with 6 or 8 participants each (4 or 6 CV1-G4(YTE) and 2 Placebo per cohort) were enrolled for a total of 36 participants (FIG. 8). Cohort 1 consisted of 4 participants receiving CV1-G4(YTE) at a dose of 0.1 mg / kg; cohort 2 consisted of 6 participants receiving CV1-G4(YTE) at a dose of 0.3 mg / kg; cohort 3 consisted of 6 participants receiving CV1-G4(YTE) at a dose of 1 mg / kg; cohort 4 consisted of 6 participants receiving CV1-G4(YTE) at a dose of 3 mg / kg; and cohort 5 consisted of 4 participants receiving CV1-G4(YTE) at a dose of 5 mg / kg. Each cohort included 2 participants that received a single subcutaneous injection of a matching placebo.

[0360] For each single dose cohort, participants underwent an up to a 29-day Screening Period, a Baseline observation period (1 day), a 7-day post dose in-unit observation period (Day 1 to Day 7), followed by an outpatient observation period (Day 8 to Day 49) consisting of 3 outpatient visits and 1 phone safety assessment to evaluate safety, tolerability, PK, PD, and immunogenicity (IG) with Day 49 also being the End of Study (EoS) visit.Study Eligibility

[0361] Participants were male aged 18 to 50 years of age (inclusive), determined to be overtly healthy (based on medical evaluation including medical history, physical329750705 80Attorney Docket: BTRT-Oll / OIWO 342313-2192examination, laboratory tests and cardiac evaluation), and had a body mass index (BMI)between 18.0 kg / m2 and 32.0 kg / m2, inclusive, with minimum and maximum body weights of 50.0 and 120.0 kg, inclusive. Baseline characteristics for participants in each dosingcohort, as well as for the placebo subjects, is detailed in Table 4.Table 4: baseline characteristics of study participantsDose Selection329750705 81Attorney Docket: BTRT-Oll / OIWO 342313-2192

[0362] The starting dose of 0.1 mg / kg for CV1-G4(YTE) was selected based on integrated PK / PD data from pharmacology studies and the toxicity studies conducted in rats and cynomolgus monkeys as described in Examples 4 & 5. The NOAEL and observed PK / PD data form the basis for selection of maximum recommended starting dose (MRSD). The NOAEL in the GLP-compliant toxicity study in rats was 10 mg / kg / week. A conservative approach consisting of adjustment on body surface area (BSA) for therapeutic proteins administered SC was used to estimate the human equivalent dose (HED). The corresponding HED equal to the NOAEL in rats was 1.62 mg / kg. Therefore, the HED of the NOAEL in rat provided a safety factor of approximately 16-fold relative to the 0.1 mg / kg starting dose (e.g., 6 mg SC dose assuming a body weight of 60 kg). Similarly, the corresponding HED of the NOAEL in cynomolgus monkeys was 24.2 mg / kg which represents approximately a 242-fold safety factor relative to the planned starting dose of 0.1 mg / kg. Thus, 0.1 mg / kg was considered to be an appropriate starting dose for the first in human trial.

[0363] Subject peripheral whole blood was evaluated for CD47 target occupancy on WBC (CD45 positive) and RBC (CD45 negative) using a flow cytometry validated method similar to that described in Example 5. As shown in FIGs. 9A-9B, CD47 target occupancy increased in a dose-dependent manner on WBC and RBC respectively, ranging up to 100% target occupancy at the highest doses tested. CD47 target occupancy was sustained for greater than 2 weeks post dosing. In preclinical models of atherosclerosis, CD47 target occupancy of 6-26% correlated with meaningful reductions in aortic plaque burden relative to controls.Pharmacokinetic Evaluation

[0364] Concentration of CV1-G4(YTE) in plasma samples obtained from the study participants at predetermined time points following administration was measured using a validated LC MS / MS method. The LC / MS / MS assay has a calibration range from 10 to 1000 ng / mL. Briefly, the assay involved the extraction of CV1-G4(YTE) and the internal standard (H-(Cam) using an immunocapture with human CD47 followed by tryptic digestion procedure and then analyzed using Sciex LC-MS / MS instrument. A calibration curve was obtained by fitting the peak response ratios of analyte / IS against the nominal concentrations using a linear fit model with 1 / X2weighting, and the resulting equation were used to convert readings of the unknown samples into concentrations.

[0365] As shown in FIG. 10, a dose-dependent rise in CV1-G4(YTE) PK exposure was measurable starting at the 1 mg / kg dose. The average concentration measured in plasma for participants that received CV1-G4(YTE) in the 0.1 mg / kg and 0.3 mg / kg dosing cohorts was329750705 82Attorney Docket: BTRT-Oll / OIWO 342313-2192below the level of detection for the assay. PK parameters calculated from the plasma concentration-time curve are shown in Table 5. At the 3 mg / kg and 5 mg / kg dose, greater-than-proportional increase in exposure (AUC) and Cmax on increasing dose was observed. A 1.7-fold increase in dose (3 mg / kg to 5 mg / kg) resulted in an approximate 3-fold increase in Cmax (from 2710.71 ± 1448.302 ng / mL to 8092.32 ± 5002.029 ng / mL) and 4-fold increase in AUCiast(from 265988.99 ±137975.562 h*ng / mLto 1059404.22 ± 774215.522 h*ng / mL). In Cohort 4 (3 mg / kg) and Cohort 5 (5 mg / kg) Tmax ranged between 72 hour and 316 hour and 72 hour and 144 hour, respectively, which reflected the gradual absorption of the drug following SC administration. The geometric %CV for AUCiast was 108.0 and 71.6 for 3 mg / kg and 5 mg / kg doses, respectively.Table 5: Summary of Plasma Pharmacokinetic Parameters329750705 83Attorney Docket: BTRT-Oll / OIWO 342313-2192N / A = Not applicable;NC = Not calculable;NE = Not estimable;SD = standard deviation;CV = coefficient of variation;Cmax maximum (peak) plasma concentration of CV1-G4(YTE);Tmax = time to reach the maximum (peak) plasma concentration following CV1-G4(YTE) administration;Tiast = time to reach the last quantifiable concentration;AUCiast = area under curve from zero to the time of the last quantifiable concentration;AUCinf = area under plasma concentration-time cure from zero to infinity;AUC% extrap percent of AUCinf obtained by extrapolation;Az = terminal rate constant;Ti / 2 = terminal half-life;Vz / F = apparent volume of distribution during the terminal phase after non-intravenous administrationSafety Evaluation

[0366] The safety and tolerability of participants receiving a subcutaneous injection of CV1-G4(YTE) was assessed by evaluation of adverse events (AEs), vital signs, and laboratory evaluations. Safety assessments were performed at regular, predetermined time points prior to and following administration of CV1-G4(YTE).

[0367] AEs were collected from the start of CV1-G4(YTE) administration on Day 1 through the last visit of the study follow-up period. AEs were characterized as any untoward medical occurrence (e.g., any unfavorable and unintended sign including abnormal laboratory findings, symptoms, or disease) in a participant after the start of dosing until the end of study visit. Serious AEs were characterized as AEs that met the following criteria: fatal or lifethreatening; resulted in persistent or significant disability / incapacity; required inpatient hospitalization or prolongation of existing hospitalization; constituted a congenital329750705 84Attorney Docket: BTRT-Oll / OIWO 342313-2192anomaly / birth defect; and / or was medically significant (e.g., jeopardized the participant or required medical or surgical intervention). A treatment emergent AE (TEAE) was characterized as an AE that occurred during or after administration of CV1-G4(YTE).

[0368] TEAEs were evaluated using injection site inspection (i.e., inspection of injection site following administration of CV1-G4(YTE) for excessive pain, swelling, rash, bleeding, itching, or redness) and measurement of vital signs, body weight / BMI, and laboratory examinations at predetermined time points. The laboratory examinations included hematology, clinical chemistry, urinalysis, and electrocardiogram measurements. The severity grade for a TEAE was determined by the study investigator using the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, grading system.

[0369] A summary of TEAEs and serious TEAEs observed for participants receiving CV1-G4(YTE) or placebo in the dosing cohorts is shown in Table 6. CV1-G4(YTE) was safe at all doses tested with no serious adverse events. Rates of TEAEs were similar between active and placebo-treated participants, and with the most common adverse events being headaches and injection site reactions. Similar rates of injection site reactions were observed between participants receiving CV1-G4(YTE) and placebo.

[0370] Notably, there was no clinically significant impact on hematologic parameters and no observed anemia, thrombocytopenia or febrile neutropenia. FIGs. 11A-11C respectively show hemoglobin, platelet, and neutrophil counts as measured in blood samples obtained from study participants at predetermined time points relative to day 1 (i.e., the day on which participants received an injection of CV1-G4(YTE) or placebo). There was no significant effect on these parameters for study participants that received the CV1-G4(YTE) injection compared to participants that received placebo.Table 6: Summary of safety parameters for study participants329750705 85Attorney Docket: BTRT-Oll / OIWO 342313-2192Example 7: Evaluation of subcutaneous CV1-G4(YTE) in patients with established atherosclerosis

[0371] This example describes a phase 2 randomized, double-blind, placebo-controlled, multiple dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous CV1-G4(YTE) administration in human participants with established atherosclerosis.Clinical Objectives and Endpoints

[0372] The primary objective of the study is to assess the safety and tolerability of multiple dose subcutaneous administration of CV1-G4(YTE) in participants with established atherosclerosis. The primary endpoint is determining the incidence and frequency of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation of treatment, treatment-related grade 3 or higher TEAEs, injection site reactions, and serious adverse events (SAEs) over time through end of study (EOS). TEAEs are assessed from the start of CV1-G4(YTE) administration on Day 1 through to the end of study (Day 120). Adverse Events (AEs) and SAEs are collected from the time of informed consent signing through to end of study (Day 120).

[0373] The secondary objective is to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous administration of CV1-G4(YTE) in participants with established atherosclerosis. Assessment is performed by measuring the change from baseline over time through EOS in collected blood and plasma samples. Samples are obtained at baseline and various hourly timepoints across 24 clinic visits.

[0374] The study includes several exploratory objectives. First, assessing the effect of CV1-G4(YTE) on arterial wall inflammation by measuring change from baseline in the target-to-background ratio in the carotid artery, aorta, femoral arteries, and other arterial beds by18F-FDG-PET / CT. Second, to assess the effect of CV1-G4(YTE) on carotid and coronary artery plaque by measuring change from baseline in the indices of carotid and / or coronary artery plaque burden by carotid CT or coronary CT angiography. Third, to assess the effect of CV1-329750705 86Attorney Docket: BTRT-Oll / OIWO 342313-2192G4(YTE) on target engagement by measuring change from baseline over time in CD47 RO in CD45-negative cells. Fourth, to assess the effect of CV1-G4(YTE) on target-related PD parameters by measuring change from baseline in the plasma levels of biomarkers of vascular inflammation. Fifth, to assess the prevalence and incidence of immunogenicity by measuring incidence and titer of anti-drug antibodies over time.Study Design

[0375] The study includes a multiple dosing phase (Part A) and a cohort expansion phase (Part B). Up to approximately 52 participants with established atherosclerosis are enrolled in the study (up to approximately 32 participants in Phase A in at least a first and second dosing cohort; and approximately 20 participants in a single cohort in Phase B). All participants undergo a screening period of up to 45 days, a treatment period of approximately 13 weeks and a follow-up period of approximately 5 weeks.

[0376] During the screening assessment, participants are evaluated for medical history, safety labs, by18F-FDGPET / CT, and by coronary computed tomography angiography (CCTA). During the treatment period, participants receive subcutaneous administration of CV1-G4(YTE) or matching placebo, based on randomization assignment. In addition, participants are assessed for safety, PK, PD, and immunogenicity. Following the last dose, participants enter a follow-up period.

[0377] All participants in the same cohort receive the same dosing regimen of CV1-G4(YTE) or matching placebo administration.

[0378] Multiple doses of CV1-G4(YTE) or matching placebo are administered to study participants via subcutaneous (SC) injection by site staff. There are up to four cohorts in Part A of the study, with each cohort comprising 6 participants receiving CV1-G4(YTE) and 2 participants receiving placebo (total of 8 participants per cohort).

[0379] The first Part A cohort commences with a dose level based on modelling that was shown to be safe and well-tolerated in the Phase 1 study described in Example 6. A Safety Review Committee (SRC) reviews available data and decides on the dosing regimen for the next cohort. An adaptive design is used that allows for modification of study dose levels based on previous cohort safety, tolerability and PK data.

[0380] Part B is a dose expansion cohort with approximately a further 20 participants dosed at the optimal dose and frequency from Part A.

[0381] All participants are monitored for 13 weeks during the treatment phase and a further 5 weeks during a follow-up phase.329750705 87Attorney Docket: BTRT-Oll / OIWO 342313-2192Dose Selection

[0382] It was determined that cohort 1 starts at a first dose of Img / kg followed by subsequent 12 weekly doses of 0.3 mg / kg. This dose was selected given the 1 mg / kg and 0.3 mg / kg doses were well-tolerated in the Phase 1 study and were 5-fold and 16.6-fold lower than the top dose of 5 mg / kg SC evaluated in the Phase 1 study. Additionally, based on an empirical model of the CD47 RO data from the Phase 1 study, the dosing regimen selected for cohort 1 is expected to achieve a median CD47 RO of 60%-80% during the treatment period.

[0383] Based upon emerging PK and PD data, the dose frequency in subsequent cohorts is reduced to biweekly.Study Eligibility

[0384] Participants are eligible for the study based on meeting certain inclusion criteria. These criteria include (i) age 45 to 80 years (inclusive) at the time of providing informed consent; (ii) minimum and maximum body weights of 50.0 and 120.0 kg (inclusive); (iii) history of myocardial infarction or transient ischemic attack or stroke at least 12 months before screening OR documented asymptomatic carotid artery stenosis > 50% OR known coronary artery disease (CAD) documented by invasive angiography, coronary computed tomography angiography (CCTA), or cardiac perfusion imaging OR at least 2 of the following: (a) age > 65 years; (b) hypertension; (c) hyperlipidaemia on lipid lowering therapy or if history of intolerance to lipid lowering therapy, an LDL-cholesterol > 190 mg / dL; (d) current smoking (including use of e-cigarettes); (e) non-insulin dependent diabetes mellitus; (f) high sensitivity c-reactive protein > 2mg / L at screening; and (g) peripheral arterial disease; and (iv) maximum target-to-background ratio (TBRmax) >1.6 (either right or left carotid artery) on18F-FDG-PET / CT, signifying active vascular inflammation.

[0385] Participants are not included in the study if they meet an exclusion criteria. Exclusion criteria include: a hemoglobin level below the lower limit of normal; a platelet count below the lower limit of normal; an absolute neutrophil count or lymphocyte count below the lower limit of normal; donation or loss of 400 ml or more of blood within 8 weeks prior to administering a first dose; history of acute coronary syndrome, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, transient ischemic attack, stroke (any aetiology), or sudden cardiac arrest within 12 months prior to screening; inadequately controlled hypertension (systolic blood pressure =160 mm Hg or diastolic blood pressure=100 mm Hg) at screening; diabetics taking injectable insulin or an HbAlc > 8% at329750705 88Attorney Docket: BTRT-Oll / OIWO 342313-2192screening; participants with permanent atrial fibrillation; history of heart failure defined as most recent left ventricular ejection fraction <30% or New York Heart Association class III or IV at screening; renal impairment with creatinine clearance < 40 ml / min (using Cockcroft- Gault equation), or history of kidney transplant, or history of contrast nephropathy; and pregnant or lactating.SEQUENCES<<<<329750705 89Attorney Docket: BTRT-Oll / OIWO 342313-2192<<<<329750705 90Attorney Docket: BTRT-Oll / OIWO 342313-2192329750705 91

Claims

Attorney Docket: BTRT-Oll / OIWO 342313-2192CLAIMS1. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a signal -regulatory protein a (SIRPa) Fc fusion polypeptide in a dosing regimen, wherein the SIRPa Fc fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of the SIRPa Fc fusion polypeptide at a dose of about 0.1 to about 5 mg per kg (mg / kg) of body weight of the subject.

2. A method of treating atherosclerosis disease in a human subject, comprising administering to the subject a SIRPa Fc fusion polypeptide in a dosing regimen, wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain, and wherein the dosing regimen comprises administration of a dose of the SIRPa Fc fusion polypeptide to achieve a target occupancy of at least about 20%.

3. The method of claim 1 or 2, wherein the dose of the SIRPa Fc fusion polypeptide administered is about 0.1, 0.3, 1, 3, or 5 mg / kg of body weight of the subject.

4. The method of claim 1 or 2, wherein the dose is about 0.5 to about 5 mg / kg of body weight of the subject.

5. The method of claim 1 or 2, wherein the dose is about 1, 3, or 5 mg / kg of body weight of the subject.

6. The method of any one of claims 1-5, wherein the dose of the SIRPa Fc fusion polypeptide is administered at a dosing frequency of once every about 1 to about 60 days.

7. The method of claim 5, wherein the dosing frequency is once every about 1 day to about 14 days for at least one month.

8. The method of claim 5, wherein the dosing frequency is once every about 7 days to about 30 days for at least two months.329750705 92Attorney Docket: BTRT-Oll / OIWO 342313-21929. The method of claim 1 or 2, wherein the dosing regimen comprises a starting dosing cycle and a maintenance dosing cycle.

10. The method of claim 9, wherein the starting dosing cycle comprises administration of a starting dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days for a duration of time.

11. The method of claim 10, wherein the starting dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject.

12. The method of claim 10 or 11, wherein the maintenance dosing cycle comprises administration of a maintenance dose of the SIRPa Fc fusion polypeptide at a dosing frequency of once every about 1 day to about 60 days.

13. The method of claim 12, wherein the maintenance dose is administered at a dose of about 0.1 to about 5 mg / kg of body weight of the subject.

14. The method of claim 12 or 13, wherein the dosing frequency for the administration of the starting dosing cycle and the maintenance dosing cycle is the same.

15. The method of claim 12 or 13, wherein the dosing frequency of the starting dosing cycle and the maintenance dosing cycle are different.

16. The method of any one of claims 12-15, wherein the starting dose and the maintenance dose are the same.

17. The method of any one of claims 12-15, wherein the starting dose and the maintenance dose are different.

18. The method of any one of claims 12-17, wherein the dosing frequency of the starting dosing cycle is once every about 1 to about 7 days for about 1 to about 6 months, and the dosing frequency of the maintenance dosing cycle is once every about 7 to about 30 days for at least 2 months.329750705 93Attorney Docket: BTRT-Oll / OIWO 342313-219219. The method of claim 18, wherein the starting dose is administered at about 0.3 to about 3 mg / kg of body weight of the subject, and the maintenance dose is administered at about 0.5 to about 1 mg / kg of body weight of the subject.

20. The method of any of claims 1 or 2, wherein the dosing regimen comprises administration of a starting dose followed by a maintenance dose.

21. The method of claim 20, wherein the dosing regimen comprises administration of a single starting dose.

22. The method of claims 20 or 21, wherein the dosing regimen comprises administration of a maintenance dose once every week, once every two weeks, once every three weeks, or once every four weeks.

23. The method of any of claims 20-22, wherein the dosing regimen comprises administration of the maintenance dose beginning about 1 to about 4 weeks following the starting dose.

24. The method of any of claims 20-23, wherein the starting dose is about 1 mg / kg to about 5 mg / kg, and the maintenance dose is about 0.1 mg / kg to about 1 mg / kg.

25. The method of any one of claims 1-24, wherein the subject is at least about 40 years old and up to about 85 years old.

26. The method of any one of claims 1-25, wherein the subject has a body weight of at least about 40 kg and up to about 140 kg.

27. The method of any one of claims 1-26, wherein the subject has atherosclerotic disease or is at risk of developing atherosclerotic disease.

28. The method of any one of claims 1-27, wherein the subject has exhibited at least one atherosclerotic cardiovascular disease (ASCVD) event prior to treatment.329750705 94Attorney Docket: BTRT-Oll / OIWO 342313-219229. The method of claim 28, wherein the subject exhibited an ASCVD event not more than about 12 months prior to treatment.

30. The method of claim 28 or 29, wherein the ASCVD event is selected from the group consisting of a stroke, transient ischemic attack, carotid artery disease, heart attack, angina, heart failure, peripheral arterial disease, renal artery stenosis, atherosclerotic aortic disease, abdominal aortic aneurysm, descending thoracic aneurysm, coronary artery disease, mesenteric ischemia, and a combination thereof.

31. The method of any of claims 1-30, wherein the subject has a history of asymptomatic carotid artery stenosis of at least about 50%.

32. The method of any of claims 1-31, wherein the subject has at least two of the following:(i) an age greater than about 65 years;(ii) a history of hypertension;(iii) a history of hyperlipidaemia on lipid lowering therapy, or a medical history of intolerance to lipid lowering therapy and an LDL-cholesterol of about 190 mg / dL or higher;(iv) a history of smoking;(v) a history of non-insulin dependent diabetes mellitus;(vi) a level of C-reactive protein of about 2 mg / L or higher as measured by a high sensitivity C-reactive protein blood test;(viii) peripheral artery disease; and(ix) a maximum target-to-background ratio of about 1.6 or higher in a carotid artery as measured by 18F-FDG PET / CT.

33. The method of any one of claims 1-32, wherein the subject has received or is receiving a treatment for ASCVD, optionally wherein the treatment comprises administration of a statin.

34. The method of any one of claims 1-33, wherein the subject has exhibited a risk factor for ASCVD prior to the dosing regimen.329750705 95Attorney Docket: BTRT-Oll / OIWO 342313-219235. The method of claim 34, wherein the risk factor is selected from the group consisting of:(i) a genotype comprising a homozygous or heterozygous 9p21 risk allele, optionally wherein the 9p21 risk allele comprises a single polymorphism (SNP) variant at 9p21;(ii) a presence of perivascular inflammation, optionally wherein the presence is measured by a coronary heart scan;(iii) a presence of clonal hematopoiesis of indeterminate potential (CHIP) in peripheral blood cells, optionally wherein CHIP is measured by gene sequencing;(iv) an intermediate or high level of C-reactive protein (CRP);(v) an elevated polygenic risk score;(vi) an increased level of a marker of inflammation, optionally wherein the marker of inflammation is selected from IL-6, IL-8, fibrinogen, human serum amyloid A (SAA), haptoglobin, phospholipase A2 (sPLA2), lipoprotein(a), an apolipoprotein B (APOB) to apolipoprotein Al (AP0A1) ratio, a white blood cell count, and a combination thereof; and (vii) a combination of any one of (i)-(vi).

36. The method of any one of claims 1-35, wherein the SIRPa Fc fusion polypeptide is administered by intravenous injection.

37. The method of any one of claims 1-35, wherein the SIRPa Fc fusion polypeptide is administered by subcutaneous injection.

38. The method of any one of claims 1-37, wherein administration of the SIRPa Fc fusion polypeptide achieves a peak target occupancy of about 20% to about 100%.

39. The method of claim 38, wherein the peak target occupancy is measured in a sample obtained from the subject, optionally wherein the sample is a blood sample or an atherosclerotic plaque specimen.

40. The method of claim 38 or 39, wherein the peak target occupancy is about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.329750705 96Attorney Docket: BTRT-Oll / OIWO 342313-219241. The method of any one of claims 38-40, wherein the peak target occupancy occurs about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

42. The method of any one of claims 1-41, wherein administration of the SIRPa Fc fusion polypeptide achieves an average target occupancy of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% for a duration of time of at least about 2 days to about 30 days following the administration of the SIRPa Fc fusion polypeptide.

43. The method of any one of claims 1-42, wherein the treatment results in the stabilization of or a reduction in a plaque lesion size, optionally wherein plaque lesion size is a measure of total vessel area.

44. The method of claim 43, wherein the plaque lesion size is reduced by at least about 5%.

45. The method of claim 43 or 44, wherein plaque lesion size is measured by imaging.

46. The method of any one of claims 1-45, wherein administration of the SIRPa Fc fusion polypeptide does not result in an adverse event requiring discontinuation of treatment.

47. The method of any one of claims 1-46, wherein administration of the SIRPa Fc fusion polypeptide is tolerated in the subject.

48. The method of any one of claims 1-47, wherein administration of the SIRPa Fc fusion polypeptide does not substantially alter plasma levels of hemoglobin and / or platelets.

49. The method of any one of claims 1-48, wherein administration of the SIRPa Fc fusion polypeptide does not result in anemia and / or thrombocytopenia.329750705 97Attorney Docket: BTRT-Oll / OIWO 342313-219250. The method of any one of claims 1-49, wherein administration of the SIRPa Fc fusion polypeptide does not result in a detectable antidrug antibody (ADA) response.

51. The method of any one of claims 1-50, wherein administration of the SIRPa Fc fusion polypeptide achieves an average Cmax of about 50 ng / mL to about IxlO4ng / mL.

52. The method of any one of claims 1-51, wherein administration of the SIRPa Fc fusion polypeptide achieves an average AUC of about IxlO4h per ng / mL (h*ng / mL) to about 5xl06h*ng / mL.

53. The method of any one of claims 1-52, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto .

54. The method of claim 53, wherein the high affinity SIRPa domain of the SIRPa fusion polypeptide comprises one or more of the following mutations relative to SEQ ID NO: 1 : V6I, S14L, S20T, I22T, H24R, V271, 13 IF, A45G, E47V, K53R, E54Q, H56P, S66T, E70N, S77R, V92I, and / or a duplication of the DI 00 residue.

55. The method of any one of claims 1-54, wherein the high affinity SIRPa domain of the SIRPa Fc fusion polypeptide comprises the amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

56. The method of any one of claims 1-55, wherein the Fc domain comprises the IgG4 Fc domain amino acid sequence of any of SEQ ID NOs: 7-8 and 16-17, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

57. The method of claim 56, wherein the Fc domain comprises M252Y-S254T-T256E, relative to SEQ ID NO: 7-8 and 16-17, according to the EU numbering scheme.329750705 98Attorney Docket: BTRT-Oll / OIWO 342313-219258. The method of any one of claims 1-57, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

59. The method of any one of claims 1-52, wherein the Fc domain comprises any of SEQ ID NOs: 7-9 and 16-18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the high affinity SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

60. The method of any one of claims 1-52, wherein the Fc domain comprises SEQ ID NO: 9 or 18, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto; and the SIRPa domain comprises SEQ ID NO: 2, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

61. The method of any of claim 1-52, wherein the SIRPa Fc fusion polypeptide comprises any of SEQ ID NOs: 10, 13-14, and 19, or an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity thereto.

62. The method of any one of claims 1-61, comprising administering a second therapeutic agent to the subject, optionally wherein the second therapeutic agent comprises a TNFa antagonist.

63. A kit comprising a container comprising:a pharmaceutical composition comprising a SIRPa fusion polypeptide and a pharmaceutically acceptable carrier or diluent, andinstructions for use in treating atherosclerotic disease in a human subject,329750705 99Attorney Docket: BTRT-Oll / OIWO 342313-2192wherein the treatment comprises administration of the pharmaceutical composition at a dose of about 0.1 to about 5.0 mg / kg of the SIRPa fusion polypeptide by body weight of the subject, and wherein the SIRPa fusion polypeptide comprises a high affinity SIRPa domain and an Fc domain.329750705 100

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