Lipid binding protein molecular therapy

Abstract

Methods of using a lipid binding protein molecule to treat a subject having one or more conditions or at risk of one or more conditions. The method generally includes measuring ApoA-I levels and / or HDL cholesterol levels in the subject, and administering one or more doses of the lipid binding protein molecule to the subject if the measured ApoA-I levels are below a target ApoA-I level or target ApoA-I range, and / or the measured HDL levels are below a target HDL level.

Description

[0001] 1. Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 594,669, filed October 31, 2023, the contents of which are incorporated herein by reference in their entirety.

[0003] 2. Abstract

[0004] This application contains a sequence list, which has been electronically submitted in XML format and is incorporated herein by reference in its entirety. The XML sequence list was created on October 21, 2024, named CRN-053WO_SL, and has a size of 3223 bytes. 3. Technical Field

[0006] This application relates to personalized methods for treating patients with conditions that are treatable with lipid-binding molecular therapy and those at risk of conditions that are treatable with lipid-binding molecular therapy. 4. Summary of the Invention

[0008] This disclosure provides methods for treating various conditions using lipid-binding protein molecules, such as conditions associated with inflammation, such as sepsis. In some embodiments, the methods of this disclosure can be performed in intensive care settings, for example, in relation to the treatment of subjects in a hospital (e.g., in an intensive care unit) for the conditions described herein.

[0009] In one aspect, this disclosure provides a method for treating a subject who has a condition treatable with lipid-binding protein molecules or who is at risk of a condition treatable with lipid-binding protein molecules, the method comprising measuring the subject’s ApoA-I level or HDL level (e.g., HDL cholesterol (HDL-C) level), and administering one or more doses of lipid-binding protein molecules to the subject if the measured ApoA-I level is below a target ApoA-I level or a target ApoA-I range, or if the measured HDL level is below a target HDL level.

[0010] ApoA-I or HDL measurements may be performed prior to the first administration of the lipid-binding protein molecule to the subject. Pretreatment measurements may be used, for example, for the selection of the starting dose and / or frequency of administration. Alternatively or additionally, the subject's ApoA-I or HDL levels may be measured after the subject has received one or more doses of the lipid-binding protein molecule.

[0011] In some embodiments, the lipid-binding protein molecule is a component of a lipid-binding protein-based complex. The lipid-binding protein-based complex may contain amphiphilic molecules, such as lipids, like sphingomyelin, and / or negatively charged lipids. An exemplary lipid-binding protein-based complex that can be used in the methods of this disclosure is CER-001. CER-001 is a negatively charged lipoprotein complex and contains recombinant human ApoA-I, sphingomyelin (SM), and 1,2-bishexadecanoyl-sn-glycerol-3-phosphoyl-(1'-racemic-glycerol) (dipalmitoylphosphatidyl-glycerol; DPPG).

[0012] In some respects, lipid-binding protein molecules (e.g., ApoA-I) are administered in combination with standard care therapies for the subject's disease or condition. For example, antibiotics may be administered and / or hemodynamic support may be given to a subject with sepsis.

[0013] In some cases, antihistamines (such as dextrochlorpheniramine, hydroxyzine, diphenhydramine, cetirizine, fexofenadine, or loratadine) can be administered before lipid-binding protein molecules (such as ApoA-I). Antihistamines can reduce the probability of allergic reactions.

[0014] Further characteristics of exemplary lipid-binding protein molecules and lipid-binding protein-based complexes that can be used in the methods of this disclosure are described in Section 6.1 below and in specific embodiments 239 to 267.

[0015] Exemplary conditions that can be treated according to the methods of this disclosure and further characteristics of the subject population are described in Section 6.2 below and in specific embodiments 158 to 238 and 405 to 427.

[0016] Exemplary target ApoA-I levels, target ApoA-I ranges, target HDL ranges, and methods for measuring ApoA-I and HDL levels are further described in detail in Section 6.3 and in specific embodiments 54 to 147 below.

[0017] Further features of the exemplary dosing regimens are described in Section 6.4 below and in specific embodiments 1 to 53, 148 to 157, 268 to 388 and 428.

[0018] Further features of the exemplary combination therapy are described below in Section 6.5 and in specific embodiments 389 to 404. 5. Description of the attached drawings

[0020] Figure 1 A schematic diagram of the clinical study of Example 1 is shown.

[0021] Figures 2A-2FThe results show that in the clinical study of Example 1, the changes in lipopolysaccharide (LPS) relative to baseline were observed in the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 2A For each group of AD, the change in LPS relative to baseline ( Figure 2B ); percentage change in LPS relative to peak value in the standard care (SOC) group (Group A) and the three experimental groups (Group BD) Figure 2C The percentage change in LPS relative to peak value in the SOC group (Group A) and the three experimental groups (Group BD) was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 2D ); the change in LPS relative to baseline for each subject in the SOC group and the three experimental groups ( Figure 2E ); and the change in LPS relative to baseline for each subject in the SOC group and each of the three experimental groups ( Figure 2F ).

[0022] Figures 3A-3E The changes in endotoxin activity assay (EAA) shown in the clinical study of Example 1: for the standard care (SOC) group (Group A) and the three experimental groups (Group BD) Figure 3A ), the change relative to the baseline; for each in group AD, the change relative to the baseline ( Figure 3B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 3C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 3D ); and the changes relative to baseline in the SOC group (Group A) and the three experimental groups (Group BD). Figure 3E ).

[0023] Figures 4A-4F This shows the changes in TNF-α in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 4A For each in group AD, the change relative to the baseline ( Figure 4B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 4C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 4D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 4E); and the change in each subject relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 4F ).

[0024] Figures 5A-5F Showing: In the clinical study of Example 1, changes in MCP-1: for the standard care (SOC) group (Group A) and the three experimental groups (Group BD), the changes relative to baseline ( Figure 5A For each in group AD, the change relative to the baseline ( Figure 5B For the standard care (SOC) group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was ( Figure 5C For the standard care (SOC) group (Group A) and the three experimental groups (Groups B and D), the percentage relative to peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 5D For each subject in the standard care (SOC) group (Group A) and the three experimental groups (Group BD), the change relative to baseline was ( Figure 5E ); and for each subject in each of the standard care (SOC) group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 5F ).

[0025] Figures 6A-6F This shows the changes in IL-6 in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 6A For each in group AD, the change relative to the baseline ( Figure 6B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 6C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 6D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 6E ); and the change in each subject relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 6F ).

[0026] Figures 7A-7F This shows the changes in IL-8 in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 7A For each in group AD, the change relative to the baseline ( Figure 7BFor the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 7C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 7D For the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 7E ); and the changes relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 7F ).

[0027] Figures 8A-8D This shows the changes in IL-10 in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 8A For each in group AD, the change relative to the baseline ( Figure 8B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 8C ); and for the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value, categorized by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 8D ).

[0028] Figures 9A-9F This shows the changes in s-TREM-1 in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 9A For each in group AD, the change relative to the baseline ( Figure 9B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 9C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 9D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 9E ); and for each subject in each of the SOC group (Group A) and the three experimental groups (Groups BD), the change relative to baseline ( Figure 9F ).

[0029] Figures 10A-10F This shows the changes in s-VCAM in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 10AFor each in group AD, the change relative to the baseline ( Figure 10B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 10C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 10D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 10E ); and the change in each subject relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 10F ).

[0030] Figure 11A-11F This shows the changes in s-ICAM in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 11A For each in group AD, the change relative to the baseline ( Figure 11B ); For the SOC group (Group A) and the three experimental groups (Group BD), the percentage relative to the peak value (Figure 11 C); For the SOC group (Group A) and the three experimental groups (Group BD), the percentage relative to the peak value, categorized by whether the subjects were enrolled from the intensive care unit or the nephrology department ( Figure 11D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 11E ); and the change in each subject relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 11F ).

[0031] Figure 12A-12D This shows the changes in ferritin in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 12A For each in group AD, the change relative to the baseline ( Figure 12B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 12C ); and for the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value, categorized by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 12D ).

[0032] Figures 13A-13DThis shows the changes in white blood cell counts in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 13A For each in group AD, the change relative to the baseline ( Figure 13B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 13C ); and for the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value, categorized by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 13D ).

[0033] Figure 14A-14F This shows the changes in C-reactive protein (CRP) in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 14A For each in group AD, the change relative to the baseline ( Figure 14B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 14C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 14D For each subject in the SOC group (Group A) and the three experimental groups (Group BD), the change relative to baseline ( Figure 14E ); and the change in each subject relative to baseline in each of the SOC group (Group A) and the three experimental groups (Groups BD). Figure 14F ).

[0034] Figures 15A-15D This shows the changes in KIM-1 in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 15A For each in group AD, the change relative to the baseline ( Figure 15B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 15C ); and for the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value, categorized by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 15D ).

[0035] Figures 16A-16E This shows the changes in serum albumin in the clinical study of Example 1: changes relative to baseline for the standard care (SOC) group (Group A) and the three experimental groups (Groups BD). Figure 16A For each in group AD, the change relative to the baseline ( Figure 16B For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value ( Figure 16C For the SOC group (Group A) and the three experimental groups (Groups BD), the percentage relative to the peak value was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 16D ); and the changes relative to baseline for each subject in the SOC group (Group A) and the three experimental groups (Group BD). Figure 16E ).

[0036] Figure 17A-17F This shows the changes in serum creatinine relative to baseline in the standard care (SOC) group (Group A) and the three experimental groups (Group BD) in the clinical study of Example 1. Figure 17A ); the change in serum creatinine relative to baseline for each individual in group AD ( Figure 17B ); the percentage change in serum creatinine relative to peak value in the SOC group (Group A) and the three experimental groups (Groups BD) Figure 17C The percentage change in serum creatinine relative to peak value in the SOC group (Group A) and the three experimental groups (Groups B and D) was determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 17D ); AUC (mean ± SEM) of serum creatinine in the SOC group (Group A) and the three experimental groups (Group BD) ( Figure 17E ); and the AUC (95% confidence interval) of serum creatinine in the SOC group (Group A) and the three experimental groups (Group BD) ( Figure 17F ).

[0037] Figures 18A-18F This shows the estimated changes in glomerular filtration rate (eGFR) in the clinical study of Example 1: for all subjects in the standard care (SOC) group (Group A) and the three experimental groups (Group BD). Figure 18A ), change relative to baseline; for all subjects in each of the AD groups, change relative to baseline ( Figure 18B ); only for subjects in the SOC group (Group A) with AKI and the three experimental groups (Group BD) who entered the clinical study of Example 2, the change relative to baseline ( Figure 18C ); for and Figure 18C For the same subjects, the change relative to baseline ( Figure 18D ); For all subjects in the SOC group (Group A) and the pooled group BD, the percentage relative to the peak ( Figure 18E ); and only for SOC group (group A) and summary group BD ( Figure 18FThe percentage of subjects with AKI who entered the study relative to the peak value.

[0038] Figure 19 The changes in P / F relative to baseline are shown for all subjects in the standard care (SOC) group (Group A) and the three experimental groups (Group BD) in the clinical study of Example 1.

[0039] Figure 20 This shows the survival rate of all subjects after several days in the ICU in the clinical study of Example 1, for the standard care group (Group A, "SOC") and the pooled group BD ("CER-001").

[0040] Figures 21A-21B The 30-day survival rate of all subjects is shown: for the standard care group (Group A, "SOC") and the pooled group BD ("CER-001") ( Figure 21A ); and the 30-day survival rate of all subjects admitted to the study from the intensive care unit: for the standard care group (Group A, "SOC") and the pooled group BD ("CER-001") Figure 21B ).

[0041] Figures 22A-22B This shows the evolution of AKI staging in the clinical study of Example 1: for the standard care group (Group A, "SOC") ( Figure 22A ); and for the summary group BD(“CER-001”)( Figure 22B ).

[0042] Figure 23 The number of days of mechanical ventilation for all subjects admitted to the study from our intensive care unit in the clinical study of Example 1 is shown: for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0043] Figure 24 The following is shown in the clinical study of Example 1. The number of days that all subjects admitted to the study from our intensive care unit received vasopressor therapy: for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0044] Figures 25A-25B This shows the number of dialysis days for all subjects in the clinical study of Example 1: the number of dialysis days for all subjects admitted to the study from the intensive care unit, for the standard care group (Group A, "SOC") and the pooled group BD ("CER-001") ( Figure 25A ); and the number of dialysis days for all subjects enrolled in the study, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”). Figure 25B).

[0045] Figure 26 The data shows the number of days all subjects admitted to the study from the intensive care unit without organ support in the clinical study of Example 1, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0046] Figures 27A-27B The following daily mean arterial pressure (MAP) changes were shown in the clinical study of Example 1: for all subjects admitted to the study from the intensive care unit, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”) (…). Figure 27A ); and each subject admitted to the study from the intensive care unit, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”) ( Figure 27B ).

[0047] Figure 28 This shows the variation in average daily heart rate (HR) of all subjects admitted to the study from the intensive care unit in the clinical study of Example 1, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0048] Figure 29 The following is a description of the changes in the daily mean P / F ratio for all subjects admitted to the study from the intensive care unit in the clinical study of Example 1, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0049] Figures 30A-30D This shows the mean ApoA-I levels in the control group and the pooled study group in the clinical study of Example 1. Figure 30A ApoA-I levels for each subject, categorized by study group ( ); Figure 30B ); the change in ApoA-I levels relative to baseline for each subject ( Figure 30C ); and the change in ApoA-I levels relative to baseline for each subject divided by study group ( Figure 30D ).

[0050] Figures 31A-31B The clinical study shown in Example 1 illustrates the change in aspartate aminotransferase (AST) levels in each subject relative to baseline. Figure 31A ); and the change in alanine aminotransferase (ALT) levels relative to baseline for each subject ( Figure 31B ).

[0051] Figure 32This shows the number of days experienced by all subjects admitted to the study from the intensive care unit of our center until discharge from the ICU in the clinical study of Example 1, for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0052] Figure 33 This shows the changes in triglycerides relative to baseline between the standard care group (Group A, "SOC") and the experimental group (Group BD, "CER-001") in the clinical study of Example 1.

[0053] Figures 34A-34D Four exemplary administration procedures for lipid-binding protein molecules are illustrated. The doses AE each represent the dosage of the lipid-binding protein molecule; arrows indicate the number of days since administration; asterisks indicate measurements of ApoA-I levels and / or HDL levels; and arrows with dashed outlines indicate administration only when the measured ApoA-I level is below the target ApoA-I level or the ApoA-I range, or when the measured HDL level is below the target level. Figure 34A After administering a three-day induction regimen of doses A, B, and C, ApoA-I or HDL levels are measured on day 4, and if the measured ApoA-I level is below the target level or target range, or if the measured HDL level is below the target level, doses D and E are administered on days 5 and 6. Figure 34B After administering doses A, B, and C on days 1-3, measure ApoA-I or HDL levels on day 5. If the measured ApoA-I level is below the target level or target range, or if the measured HDL level is below the target level, administer doses D and E on days 5 and 6. Figure 34C Measure ApoA-I or HDL levels on day 1. If the measured ApoA-I level is below the target ApoA-I level or target ApoA-I range, or if the measured HDL level is below the target HDL level, administer twice the reference or standard dose on days 2 and 3 (2x A, 2x B, which may correspond to two administrations of the reference or standard dose on the same day, or a single administration of twice the reference or standard dose). Administer dose C on day 4. Measure ApoA-I or HDL levels on day 5. If the measured ApoA-I level on day 5 is below the target ApoA-I level or target range, or if the measured HDL level on day 5 is below the target HDL level, administer doses D and E on days 6 and 7. Figure 34CIn another embodiment of the illustrated scheme, if the measured Apo-AI level is at or above the target ApoA-I level, within the target ApoA-I range, or if the measured HDL level is at or above the target HDL level, a reference or standard dose is administered on days 2 and 3 (alternative embodiments are not shown). Figure 34D After administering doses A, B, C, and D on days 1-4, measure ApoA-I or HDL levels on day 5. If the measured ApoA-I level is below the target level or target range, or if the measured HDL level is below the target level, administer doses E and F on days 6 and 7. 6. Detailed Description of the Invention

[0055] This disclosure provides a method of treating a subject with or at risk of various conditions, such as sepsis (e.g., septic shock), with a lipid-binding protein molecule. In some embodiments, the condition is an acute condition, such as an acute condition related to inflammation. In some embodiments, the subject is treated in an intensive care setting. The method typically includes measuring the subject's ApoA-I level or HDL level, and administering one or more doses of the lipid-binding protein molecule to the subject if the measured ApoA-I level is below a target ApoA-I level or a target ApoA-I range, or if the measured HDL level is below a target HDL level. Measuring the ApoA-I level or HDL level may optionally be performed prior to administering one or more doses of the lipid-binding protein molecule. The target ApoA-I level may be, for example, a normal ApoA-I level in a healthy subject, and / or the target ApoA-I range may be the normal ApoA-I range in a healthy subject. The target HDL level may be, for example, a normal HDL-C level in a healthy subject. ApoA-I or HDL measurement and subsequent administration steps can be repeated once or multiple times, for example, until the subject's ApoA-I level is at or above the target level or within the target range, or until the subject's HDL level is at or above the target level.

[0056] If the measured ApoA-I value is at or above the target level or within the target range, or if the measured HDL value is at or above the target level, administration of the lipid-binding protein molecule may be discontinued (if the subject has previously received the lipid-binding protein molecule) or not initiated (if the subject has not previously received the lipid-binding protein molecule). Alternatively, if the subject has previously received the lipid-binding protein molecule, one or more doses may be administered to the subject at a lower dose and / or frequency than previously administered. The subject's ApoA-I level or HDL level may then be measured again, and if the subject's ApoA-I level fails to fall below the target ApoA-I level or the target ApoA-I range, or if the subject's HDL level fails to fall below the target HDL level, the administration regimen may be restarted or adjusted (as appropriate).

[0057] In several respects, the condition is sepsis (e.g., septic shock, such as post-traumatic (e.g., abdominal trauma) septic shock, or non-traumatic septic shock, such as postoperative sepsis), sepsis with a risk of developing acute kidney injury (e.g., high risk), bacterial infection (e.g., Gram-positive or Gram-negative bacterial infection), optionally antibiotic-resistant bacteria (e.g., MRSA), urinary tract infection, bloodstream infection, postoperative infection, gastrointestinal perforation, duodenal ulcer perforation, intestinal perforation, pneumonia (e.g., hospital-acquired pneumonia), pancreatitis (e.g., necrotizing pancreatitis), viral infection (e.g., SARS-CoV-2). (COVID-19) infection or influenza virus infection), acute myocardial infarction (AMI), cytokine release syndrome (CRS), ischemia-reperfusion induced tissue damage, postoperative inflammation, sepsis-induced acute kidney injury (AKI), hypoalbuminemia (e.g., hypoalbuminemia associated with vitamin deficiency, hypoalbuminemia associated with inflammatory bowel disease (IBD), hypoalbuminemia associated with kidney disease, hypoalbuminemia associated with infection (optionally, where the infection can be Gram-positive bacterial infection, Gram-negative bacterial infection, or viral infection, such as SARS-CoV-2) Hypoalbuminemia may be caused by (COVID-19) infection or influenza virus infection, stress-related hypoalbuminemia, hypoalbuminemia associated with thyroid disease, hypoalbuminemia associated with diabetes, hypoalbuminemia associated with nephrotic syndrome, hypoalbuminemia associated with lupus, hypoalbuminemia associated with cirrhosis, hypoalbuminemia associated with liver disease, hypoalbuminemia associated with heart failure or malnutrition, cytokine release syndrome (CRS; cytokine storm), risk of CRS, or risk of acute kidney injury (AKI) or development of AKI. In some aspects, the subject has undergone recent surgery. For example, recent surgery may be surgery performed within the previous month. As another example, recent surgery may be surgery performed within the previous two weeks. In yet another example, recent surgery may be surgery performed within the previous week. In some aspects, the subject is a candidate for surgery (e.g., surgery performed within one week, two weeks, or one month). In some implementations, the surgery will be performed within one week. In some implementations, the surgery will be performed within two weeks. In some implementations, the surgery will be performed within one month.

[0058] In some embodiments, lipid-binding protein molecules are provided as components of a lipid-binding protein-based complex. In some embodiments, the lipid-binding protein-based complex is an apomer (e.g., as described in WO 2019 / 030575), a cargomer (e.g., as described in WO 2019 / 030574), an HDL-based complex, or an HDL-mimicking complex. In a specific embodiment, the lipid-binding protein-based complex is CER-001.

[0059] Exemplary features of lipid-binding protein molecules and lipid-binding protein-based complexes comprising lipid-binding protein molecules that can be used in the methods and compositions of this disclosure are described in Section 6.1. Section 6.2 describes exemplary populations of subjects that can be treated by the methods and compositions of this disclosure.

[0060] In some embodiments, the method of this disclosure includes administering a lipid-binding protein molecule (e.g., ApoA-I) to a subject in an initial “induction” regimen. In some embodiments, the subject’s ApoA-I level is measured after the induction regimen. In some embodiments, the induction regimen is followed by a “consolidation” regimen, for example, if the subject’s ApoA-I level is below a target value or below a target range, or if the subject’s HDL level is below a target value after the induction regimen. Alternatively, the lipid-binding protein molecule (e.g., ApoA-I) may be administered to the subject in a single phase, for example, according to an administration regimen corresponding to the dose and frequency of administration of the induction or consolidation regimen described herein. For example, the subject’s ApoA-I level may be measured before administration of the lipid-binding protein molecule, and treatment with the lipid-binding protein molecule may be initiated if the measured ApoA-I level is below a target value or below a target range. As another example, the subject’s HDL level may be measured before administration of the lipid-binding protein molecule, and treatment with the lipid-binding protein molecule may be initiated if the measured HDL level is below a target value.

[0061] Induction regimens that can be used in the methods of this disclosure are described in Section 6.4.1, and consolidation regimens that can be used in the methods of this disclosure are described in Section 6.4.2. Dosing regimens of this disclosure include administering a lipid-binding protein molecule (e.g., ApoA-I) as a monotherapy or as part of a combination therapy with one or more drugs, such as in combination with standard care therapy for a disease or condition of the subject. Combination therapies are described in Section 6.5.

[0062] 6.1. Lipid-binding protein molecules and lipid-binding protein-based complexes

[0063] 6.1.1. Lipid-binding protein molecules

[0064] Lipid-binding protein molecules that can be used directly or in the lipid-binding protein-based complexes described herein include apolipoproteins, such as those described in Section 6.1.1.1, and apolipoprotein mimic peptides, such as those described in Section 6.1.1.2. In some embodiments, a mixture of lipid-binding protein molecules may be used, optionally as a member of the complex. In some embodiments, the mixture of lipid-binding protein molecules may contain one or more apolipoproteins. In some embodiments, the mixture of lipid-binding protein molecules may contain one or more apolipoprotein mimic peptides. In some embodiments, the mixture of lipid-binding protein molecules may contain one or more apolipoproteins and one or more apolipoprotein mimic peptides.

[0065] 6.1.1.1. Apolipoproteins

[0066] Suitable apolipoproteins that can be selected from lipid-binding protein molecules and can be included in the lipid-binding protein-based complexes disclosed herein include apolipoproteins ApoA-I, ApoA-II, ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoJ, ApoH, and any combination of two or more of the foregoing. Polymorphic forms, isotypes, variants, mutants, and truncated forms of the aforementioned apolipoproteins can also be used, the most common being apolipoprotein AI. Milano (ApoA-I M ), apolipoprotein AI Paris (ApoA-I P ) and apolipoprotein AI Zaragoza (ApoA-I Z Apolipoprotein mutants containing cysteine ​​residues are also known and can be used (see, for example, U.S. Publication No. 2003 / 0181372). Apolipoproteins can be in monomeric or dimer form, and can be homodimers or heterodimers. For example, ApoA-I (Duverger et al., 1996, Arterioscler. Thromb. Vasc. Biol. 16(12):1424-29) can be used. M (Franceschini et al., 1985, J. Biol. Chem. 260:1632-35), ApoA-I P(Daum et al., 1999, J. Mol. Med. 77:614-22), ApoA-II (Shelness et al., 1985, J. Biol. Chem. 260(14):8637-46; Shelness et al., 1984, J. Biol. Chem. 259(15):9929-35), ApoA-IV (Duverger et al., 1991, Euro. J. Biochem. 201(2):373-83), ApoE (McLean et al., 1983, J. Biol. Chem. 258(14):8993-9000), homodimers and heterodimers of ApoJ and ApoH (where feasible).

[0067] Apolipoproteins can be modified in their primary sequence to make them less sensitive to oxidation, for example, as described in U.S. Publications 2008 / 0234192 and 2013 / 0137628 and U.S. Patents 8,143,224 and 8,541,236. Apolipoproteins may include residues corresponding to elements that facilitate their dissociation, such as a His tag, or other elements designed for other purposes. Preferably, the apolipoprotein or apolipoprotein-containing complex is soluble in biological fluids (e.g., lymph, cerebrospinal fluid, vitreous fluid, aqueous humor, blood) or blood fractions (e.g., serum or plasma).

[0068] In some embodiments, the lipid-binding protein molecule comprises covalently bound lipid-binding protein monomers, such as dimerized apolipoprotein AI. Milano This is a mutant form of ApoA-I containing the cysteine ​​residue. This cysteine ​​residue allows for the formation of disulfide bonds, which can lead to homodimers or heterodimers (e.g., ApoA-I). Milano The formation of -ApoA-II).

[0069] In some embodiments, the apolipoprotein molecule comprises ApoA-I, ApoA-II, ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC-III, ApoD, ApoE, ApoJ, or ApoH molecules or combinations thereof.

[0070] In some embodiments, the apolipoprotein molecule comprises or is composed of ApoA-I molecules. In some embodiments, the ApoA-I molecule is a human ApoA-I molecule. In some embodiments, the ApoA-I molecule is recombinant. In some embodiments, the ApoA-I molecule is not ApoA-I. Milano .

[0071] In some implementations, the ApoA-I molecule is an apolipoprotein AI. Milano (ApoA-I M ), apolipoprotein AI Paris (ApoA-I P ) or apolipoprotein AI Zaragoza (ApoA-I Z )molecular.

[0072] Apolipoproteins can be purified from animal sources (and particularly from human sources) or recombinantly generated as is known in the art, see, for example, Chung et al., 1980, J. Lipid Res. 21(3):284-91; Cheung et al., 1987, J. Lipid Res. 28(8):913-29. See also U.S. Patent Nos. 5,059,528, 5,128,318, 6,617,134; U.S. Publications Nos. 2002 / 0156007, 2004 / 0067873, 2004 / 0077541, and 2004 / 0266660; and PCT Publications Nos. WO2008 / 104890 and WO 2007 / 023476. Other purification methods are also possible, for example as described in PCT Publication No. WO 2012 / 109162, the disclosure of which is incorporated herein by reference in its entirety.

[0073] In a specific implementation, ApoA-I is recombinant ApoA-I produced from mammalian host cells. These host cells can be derived from any mammalian cell line. The polynucleotide encoding ApoA-I can be codon-optimized for expression in the recombinant host cells. In some embodiments, the host cell is a mammalian host cell, including but not limited to Chinese hamster ovary cells (e.g., CHO-K1; ATCC number CCL 61; CHO-S (e.g., GIBCO Life Technologies Inc., Rockville, MD, catalog #11619012)), VERO cells, BHK (ATCC number CRL 1632), BHK 570 (ATCC number CRL 10314), HeLa cells, COS-1 (ATCC number CRL 1650), COS-7 (ATCC number CRL 1651), MDCK cells, 293 cells (ATCC number CRL 1573; Graham et al., J. Gen. Virol. 36:59-72, 1977), 3T3 cells, myeloma cells (particularly mouse), PC12 cells, and W138 cells. In some embodiments, mammalian cells (e.g., CHO-S cells) are suitable for growth in serum-free medium. Other suitable cell lines are known in the art and are available from public repositories such as the American Center for Type Culture Collection, Manassas, Va.

[0074] In some embodiments, recombinant ApoA-I is produced by CHO cells (e.g., CHO-S cells). As will be known to those skilled in the art, recombinant polypeptides (e.g., recombinant ApoA-I) expressed by mammalian host cells such as CHO cells may undergo post-translational processing (e.g., glycosylation, etc.). The resulting recombinant ApoA-I may have one or more structural features (e.g., glycosylation patterns) different from those of ApoA-I purified from human plasma.

[0075] Apolipoproteins can be in a protoproto, protoproto, or mature form. For example, an apolipoprotein may contain ApoA-I (e.g., human ApoA-I), where ApoA-I can be protopro ... In some implementations, ApoA-I has at least 90% sequence identity with SEQ ID NO:1: PPQSPWDRVKDLATVYVDVLKDSGRDYVSQFEGSALGKQLNLKLLDNWDSVTSTFSKLREQLGPVTQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ (SEQ ID NO:1)

[0076] In other embodiments, ApoA-I shares at least 95% sequence identity with SEQ ID NO:1. In other embodiments, ApoA-I shares at least 98% sequence identity with SEQ ID NO:1. In other embodiments, ApoA-I shares at least 99% sequence identity with SEQ ID NO:1. In other embodiments, ApoA-I shares 100% sequence identity with SEQ ID NO:1.

[0077] In some embodiments, ApoA-I comprises a sequence having at least 90% sequence identity with amino acids 25 to 267 of SEQ ID NO:2:

[0078] MKAAVLTLAVLFLTGSQARHFWQQDEPPQSPWDRVKDLATVYVDVLKDSGRDYVSQFEGSALGKQLNLKLLDNWDSVTSTFSKLREQLGPVTQEFWDNLEKETEGLRQEMSKDLEEVKAKVQPYLDDFQKKWQ EEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ (SEQ ID NO:2).

[0079] In other embodiments, the complex comprises ApoA-I having at least 95% sequence identity with amino acids 25 to 267 of SEQ ID NO:2. In other embodiments, the complex comprises ApoA-I having at least 98% sequence identity with amino acids 25 to 267 of SEQ ID NO:2. In other embodiments, the complex comprises ApoA-I having at least 99% sequence identity with amino acids 25 to 267 of SEQ ID NO:2. In other embodiments, the complex comprises ApoA-I having 100% sequence identity with amino acids 25 to 267 of SEQ ID NO:2.

[0080] In a specific implementation, ApoA-I is recombinant ApoA-I produced from mammalian host cells. These host cells can be derived from any mammalian cell line. The polynucleotide encoding ApoA-I can be codon-optimized for expression in the recombinant host cells. Preferred host cells are mammalian host cells, including but not limited to Chinese hamster ovary cells (e.g., CHO-K1; ATCC number CCL 61; CHO-S (GIBCO Life Technologies Inc., Rockville, MD, catalog #11619012)), VERO cells, BHK (ATCC number CRL 1632), BHK 570 (ATCC number CRL10314), HeLa cells, COS-1 (ATCC number CRL 1650), COS-7 (ATCC number CRL 1651), MDCK cells, 293 cells (ATCC number CRL 1573; Graham et al., J. Gen. Virol. 36:59-72, 1977), 3T3 cells, myeloma cells (particularly mouse), PC12 cells, and W138 cells. In some embodiments, mammalian cells, such as CHO-S cells (Invitrogen™, Carlsbad CA), are suitable for growth in serum-free medium. Other suitable cell lines are known in the art and are available from public repositories such as the American Type Culture Collection, Manassas, Va.

[0081] In a specific implementation, recombinant ApoA-I is produced by CHO cells. As those skilled in the art will appreciate, expression in mammalian host cells, such as CHO cells, can undergo post-translational processing (e.g., glycosylation, etc.). The resulting population of recombinant ApoA-I may possess one or more characteristics different from ApoA-I purified from human plasma (e.g., homogeneity, glycosylation pattern).

[0082] In some embodiments, the nucleotide sequence encodes the amino acid sequence of the mature ApoA-I protein, preferably operably linked to a signal sequence and / or protopeptide sequence for the secretion of ApoA-I from host cells. In some embodiments, the nucleotide sequence encodes the amino acid sequence of SEQ ID NO:2 (human protopeptide ApoA-I), which comprises a signal sequence (amino acids 1-18) and a propeptide sequence (amino acids 19-24). Other signal sequences suitable for the directed secretion of ApoA-I may be heterologous to ApoA-I, such as human albumin signal peptide or human IL-2 signal peptide, or homologous to ApoA-I.

[0083] In some embodiments, ApoA-I is generated from CHO cells (e.g., CHO-S cells) engineered to express the amino acid sequence of SEQ ID NO:2. The engineered cells may contain a nucleotide sequence encoding SEQ ID NO:2 operatively linked to a promoter, such as a constitutive promoter. In some embodiments, the engineered cells contain a nucleotide sequence encoding SEQ ID NO:2 operatively linked to a simian cytomegalovirus immediate early promoter.

[0084] In some embodiments, recombinant ApoA-I can be produced by culturing any mammalian host cell described herein under conditions in which ApoA-I is expressed and secreted. ApoA-I can be recovered from the supernatant of the cultured mammalian host cells and optionally purified to produce mature, biologically active ApoA-I.

[0085] Further methods for the recombinant expression and purification of ApoA-I are described in detail in WO 2012 / 109162, the contents of which are incorporated herein by reference in their entirety. See, for example, Sections 6.1.2-6.1.4 and Examples 1-2 of PCT Publication WO 2012 / 109162, the contents of which are incorporated herein by reference in their entirety.

[0086] In some embodiments, the lipid-binding protein-based complex comprises 1 to 8 apolipoprotein molecules (e.g., 1 to 6, 1 to 4, 1 to 2, 2 to 8, 2 to 6, 2 to 4, 4 to 8, 4 to 6, or 6 to 8 apolipoprotein molecules). In some embodiments, the complex comprises 1 apolipoprotein molecule. In some embodiments, the complex comprises 2 apolipoprotein molecules. In some embodiments, the complex comprises 3 apolipoprotein molecules. In some embodiments, the complex comprises 4 apolipoprotein molecules. In some embodiments, the complex comprises 5 apolipoprotein molecules. In some embodiments, the complex comprises 6 apolipoprotein molecules. In some embodiments, the complex comprises 7 apolipoprotein molecules. In some embodiments, the complex comprises 8 apolipoprotein molecules.

[0087] Apolipoprotein molecules may comprise chimeric apolipoproteins, which include an apolipoprotein and one or more attached functional moieties, such as one or more CER-001 complexes, one or more targeting moieties, a moieties having desired biological activity, affinity tags to aid purification, and / or reporter molecules for characterization or localization studies. The biologically active attachment moieties may have activities that enhance and / or synergize with the biological activity of compounds incorporated into the complexes of this disclosure. For example, the biologically active moieties may have antimicrobial (e.g., antifungal, antibacterial, antiprotozoal, bacteriostatic, antifungal, or antiviral) activity. In one embodiment, the attached functional moieties of the chimeric apolipoprotein are not in contact with a hydrophobic surface of the complex. In another embodiment, the attached functional moieties are in contact with a hydrophobic surface of the complex. In some embodiments, the functional moieties of the chimeric apolipoprotein may be inherent to a natural protein. In some embodiments, the chimeric apolipoprotein includes ligands or sequences that are recognized by or capable of interacting with cell surface receptors or other cell surface moieties.

[0088] In one embodiment, the chimeric apolipoprotein includes a targeting moiety that is not inherent to the native apolipoprotein, such as *Saccharomyces cerevisiae* α-mating factor peptide, folic acid, transferrin, or lactoferrin. In another embodiment, the chimeric apolipoprotein includes a moiety having a desired biological activity that enhances and / or synergizes with the activity of compounds incorporated into the complex of this disclosure. In one embodiment, the chimeric apolipoprotein may include a functional moiety inherent to the apolipoprotein. One example of an intrinsic functional moiety of an apolipoprotein is an intrinsic targeting moiety formed approximately of amino acids 130-150 of human ApoE, which includes a receptor-binding region recognized by members of the low-density lipoprotein receptor family. Other examples of intrinsic functional moieties of apolipoproteins include the ApoB-100 region, which interacts with the low-density lipoprotein receptor, and the ApoA-I region, which interacts with scavenger receptor type B1. In other embodiments, functional moieties may be added synthetically or recombinantly to produce the chimeric apolipoprotein. Another example is an apolipoprotein having a preproto or proto sequence from another preproto-apolipoprotein (e.g., a preproto sequence from preproto-apoA-II replacing the preproto-apoA-I preproto sequence). Another example is an apolipoprotein in which some of its amphiphilic sequence segments have been replaced by other amphiphilic sequence segments from another apolipoprotein.

[0089] As used herein, "chimerism" refers to two or more molecules that can exist individually and link together to form a single molecule having the desired functionality of all its constituent molecules. The constituent molecules of a chimeric molecule can be synthetically linked by chemical conjugation, or, where the constituent molecules are all polypeptides or their analogues, polynucleotides encoding the polypeptide can be recombined and fused together, resulting in the expression of a single, continuous polypeptide. Such chimeric molecules are called fusion proteins. A "fusion protein" is a chimeric molecule in which the constituent molecules are all polypeptides and are linked (fused) to each other, such that the chimeric molecule forms a continuous single chain. The various components can be directly linked to each other or coupled via one or more linkers. One or more segments of the various components can, for example, be inserted into an apolipoprotein sequence, or, as another example, added to the N-terminus or C-terminus of an apolipoprotein sequence. For example, a fusion protein may contain an antibody light chain, antibody fragment, heavy chain antibody, or single-domain antibody.

[0090] In some embodiments, chimeric apolipoproteins are prepared by chemically conjugating the apolipoprotein and the functional moiety to be linked. Methods for chemically conjugating molecules are well known to those skilled in the art. Such methods will vary depending on the structure of the moiety to be linked, but will be readily determined by those skilled in the art. Peptides typically contain a variety of functional groups, such as carboxylic acid (-COOH), free amino (-NH2), or thiol (-SH) groups, which can be used to react with suitable functional groups on the functional moiety or linker to bind the moiety thereto. The functional groups can be linked to functional groups at the N-terminus, C-terminus, or internal residues (i.e., residues in the intermediate position between the N-terminus and C-terminus) of the apolipoprotein molecule. Alternatively, the apolipoprotein and / or the moiety to be labeled can be derivatized to expose or link additional reactive functional groups.

[0091] In some implementations, the fusion protein containing the functional part of the polypeptide is synthesized using a recombinant expression system. Typically, this involves generating nucleic acid (e.g., DNA) sequences encoding an apolipoprotein and the functional part, such that the two polypeptides are in the same frame when expressed, placing the DNA under the control of a promoter, expressing the protein in a host cell, and isolating the expressed protein.

[0092] Nucleic acids encoding chimeric apolipoproteins can be incorporated into recombinant expression vectors in a form suitable for expression in host cells. As used herein, an "expression vector" is a nucleic acid that, when introduced into a suitable host cell, can be transcribed and translated into a polypeptide. Vectors may also include regulatory sequences, such as promoters, enhancers, or other expression control elements (e.g., polyadenylation signals). These regulatory sequences are known to those skilled in the art (see, for example, Goeddel, 1990, GeneExpression Technology: Meth. Enzymol. 185, Academic Press, San Diego, Calif.; Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology 152 Academic Press, Inc., San Diego, Calif.; Sambrook et al., 1989, Molecular Cloning—A Laboratory Manual (2nd ed.) Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, NY, etc.).

[0093] In some embodiments, the apolipoprotein has been modified such that when the apolipoprotein is incorporated into the complex of this disclosure, the modification will increase the stability of the complex, impart targeting capability, or increase capacity. In one embodiment, the modification includes introducing cysteine ​​residues into the apolipoprotein molecule to allow, for example, the formation of intramolecular or intermolecular disulfide bonds through site-directed mutagenesis. In another embodiment, a chemical cross-linking agent is used to form intermolecular links between apolipoprotein molecules to enhance the stability of the complex. Intermolecular cross-linking prevents or reduces the dissociation of apolipoprotein molecules from the complex and / or prevents their replacement by endogenous apolipoprotein molecules in the individual administering the complex. In other embodiments, the apolipoprotein is modified by chemical derivatization of one or more amino acid residues or by site-directed mutagenesis to impart targeting capability to cell surface receptors or to be recognized by cell surface receptors.

[0094] Lipid-binding protein molecules and complexes containing them can target specific cell surface receptors by engineering receptor recognition properties into apolipoproteins. For example, lipid-binding protein molecules or complexes can target specific cell types known to contain specific types of infectious agents, for instance, by modifying apolipoproteins with other lipid-binding protein molecules to enable them to interact with receptors on the surface of the targeted cell type. For example, lipid-binding protein molecules or complexes can target macrophages by altering apolipoproteins or other lipid-binding protein molecules to confer recognition by macrophage-endocytosed scavenger receptor type A (SR-A). SR-A binding ability can be conferred by site-directed mutagenesis of apolipoproteins or other lipid-binding protein molecules to replace one or more positively charged amino acids with neutral or negatively charged amino acids. SR-A recognition can also be conferred by preparing chimeric apolipoproteins containing N- or C-terminal extensions, the N- or C-terminal extensions having ligands recognized by SR-A or amino acid sequences with a high concentration of negatively charged residues. Lipid-binding protein molecules and complexes containing lipid-binding protein molecules (e.g., apolipoproteins) can also interact with apolipoprotein receptors, such as, but not limited to, ABCA1 receptors, ABCG1 receptors, megalin, cupulin, and HDL receptors such as SR-B1.

[0095] 6.1.1.2. Apolipoprotein mimics

[0096] Peptides, peptide analogs, and agonists that mimic the activity of apolipoproteins (collectively referred to herein as "apolipoprotein peptide mimics") may be used alone, in combination with one or more other lipid-binding proteins, as lipid-binding protein molecules or in the complexes described herein. Peptides and peptide analogs corresponding to apolipoproteins, as well as mimics of ApoA-I and ApoA-I... MAgonists of the activity of ApoA-II, ApoA-IV, and ApoE, which can be used as lipid-binding protein molecules and / or suitable for inclusion in complexes and compositions described herein, are disclosed in U.S. Patent Nos. 6,004,925, 6,037,323, and 6,046,166 (issued to Dasseux et al.), U.S. Patent No. 5,840,688 (issued to Tso), U.S. Patent No. 6,743,778 (issued to Kohno), U.S. Publications 2004 / 0266671, 2004 / 0254120, 2003 / 0171277, and 2003 / 0045460 (issued to Fogelman), U.S. Publication 2006 / 0069030 (issued to Bachovchin), U.S. Publication 2003 / 0087819 (issued to Bielicki), and U.S. Publication 2009 / 0081293. (Issued to Murase et al.) and PCT Publication No. WO / 2010 / 093918 (Issued to Dasseux et al.), the disclosures of which are incorporated herein by reference in their entirety. These peptides and peptide analogs may consist of L-amino acids or D-amino acids or mixtures of L- and D-amino acids. They may also include one or more non-peptide or amide bonds, such as one or more well-known peptide / amide isosteres. Such apolipoprotein peptide mimics can be synthesized or manufactured using any technique known in the art for peptide synthesis, including, for example, those described in U.S. Patent Nos. 6,004,925, 6,037,323, and 6,046,166.

[0097] In some embodiments, the lipid-binding protein molecule comprises an apolipoprotein peptide mimic molecule and optionally one or more apolipoprotein molecules, such as the apolipoprotein molecules described above.

[0098] In some embodiments, the apolipoprotein peptide mimicry includes ApoA-I peptide mimicry, ApoA-II peptide mimicry, ApoA-IV peptide mimicry, or ApoE peptide mimicry, or combinations thereof.

[0099] 6.1.2. Lipid-binding protein-based complexes

[0100] In some respects, lipid-binding proteins are components of lipid-binding protein-based complexes, such as complexes with one or more amphiphilic molecules (e.g., lipids). Usable lipid-binding protein-based complexes include those based on HDL and HDL mimics.

[0101] In some aspects, lipid-binding protein-based complexes may comprise lipoprotein complexes as described in U.S. Patent No. 8,206,750, PCT Publication No. WO 2012 / 109162, PCT Publication No. WO 2015 / 173633 A2 (e.g., CER-001), or US 2004 / 0229794A1, the contents of which are incorporated herein by reference in their entirety. The terms “lipoprotein” and “apolipoprotein” are used interchangeably herein, and unless the context requires otherwise, the term “lipoprotein” encompasses lipoprotein mimics. The terms “lipoprotein-binding protein” and “lipoprotein-binding polypeptide” are also used interchangeably herein, and unless the context requires otherwise, the terms do not imply a specific length of amino acid sequence.

[0102] Lipoprotein complexes may comprise protein fractions (e.g., apolipoprotein fractions) and lipid fractions (e.g., phospholipid fractions). The protein fractions include one or more lipid-binding protein molecules, such as apolipoproteins, peptides, or apolipoprotein peptide analogs or mimics, as described in Section 6.1.1.

[0103] Lipid fractions typically include one or more phospholipids, which may be neutral, negatively charged, positively charged, or a combination thereof. Exemplary phospholipids and other amphiphilic molecules that may be included in lipid fractions are described in Section 6.1.3.

[0104] In some embodiments, the lipid fraction comprises at least one neutral phospholipid (e.g., sphingomyelin (SM)) and optionally one or more negatively charged phospholipids. In a lipoprotein complex comprising both neutral and negatively charged phospholipids, the neutral and negatively charged phospholipids may have fatty acid chains containing the same or different carbon numbers and the same or different degrees of saturation. In some cases, the neutral and negatively charged phospholipids will have the same acyl tail, such as C16:0 or palmitoyl, acyl chain. In specific embodiments, particularly those in which protein SM is used as a neutral lipid, the weight ratio of apolipoprotein fraction to lipid fraction is in the range of about 1:2.7 to about 1:3 (e.g., 1:2.7).

[0105] Any phospholipid carrying at least a partial negative charge at physiological pH can be used as a negatively charged phospholipid. Non-limiting examples include negatively charged forms (e.g., salts) of phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, and phosphatidic acid. In specific embodiments, the negatively charged phospholipid is 1,2-dipalmitoyl-sn-glycerol-3-[phosphatidyl-racemic-(1-glycerol)], or DPPG, phosphatidylglycerol. Preferred salts include potassium and sodium salts.

[0106] In some embodiments, the lipoprotein complexes used in the methods of this disclosure are lipoprotein complexes as described in U.S. Patent No. 8,206,750 or WO 2012 / 109162 (and its U.S. counterpart US 2012 / 0232005), the contents of which are incorporated herein by reference in their entirety. In specific embodiments, the lipid-binding protein molecular components of the lipoprotein complex are as described in Section 6.1, and preferably Section 6.1.1, of WO 2012 / 109162 (and US 2012 / 0232005), and the lipid components are as described in Section 6.2 of WO 2012 / 109162 (and US 2012 / 0232005), which may optionally be combined together in the amounts described in Section 6.3 of WO 2012 / 109162 (and US 2012 / 0232005). The contents of each of these sections are incorporated herein by reference. In some respects, the lipoprotein complexes of this disclosure are at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% homogeneous in the complex population, as described in section 6.4 of WO 2012 / 109162 (and US 2012 / 0232005), the contents of which are incorporated herein by reference.

[0107] In some embodiments, the complex comprises 1 to 8 ApoA-I equivalences (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 8, 2 to 6, 2 to 4, 4 to 6, or 4 to 8 ApoA-I equivalences). Lipid-binding proteins can be represented by ApoA-I equivalences based on the number of amphiphilic helices they contain. For example, ApoA-I typically exists in the form of a disulfide-bridged dimer. M It can be represented as two ApoA-I equivalents, because each ApoA-I M The molecule contains twice as many amphiphilic helices as the ApoA-I molecule. Conversely, a peptide mimic containing a single amphiphilic helix can be represented as 1 / 10 to 1 / 6 of an ApoA-I equivalent, since each molecule contains 1 / 10 to 1 / 6 of the amphiphilic helices of an ApoA-I molecule.

[0108] In a specific implementation, the lipoprotein complex that can be used in the method of this disclosure comprises 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 50-80 molecules of lecithin, and 20-50 molecules of SM.

[0109] In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 50 molecules of lecithin, and 50 molecules of SM.

[0110] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 80 molecules of lecithin, and 20 molecules of SM.

[0111] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 70 molecules of lecithin, and 30 molecules of SM.

[0112] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 60 molecules of lecithin, and 40 molecules of SM.

[0113] In a specific implementation, the lipoprotein complex that can be used in the method of this disclosure is basically composed of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 50-80 molecules of lecithin and 20-50 molecules of SM.

[0114] In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure is essentially composed of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 50 molecules of lecithin, and 50 molecules of SM.

[0115] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure is essentially composed of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 80 molecules of lecithin, and 20 molecules of SM.

[0116] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure is essentially composed of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 70 molecules of lecithin and 30 molecules of SM.

[0117] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure is essentially composed of 2-4 ApoA-I equivalents, 2 molecules of charged phospholipids, 60 molecules of lecithin, and 40 molecules of SM.

[0118] In a specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises a lipid component comprising about 90 to 99.8 wt% SM and about 0.2 to 10 wt% negatively charged phospholipids, for example, about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids. In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises about 90 to 99.8 wt% lecithin and about 0.2 to 10 wt% negatively charged phospholipids, for example, about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids.

[0119] In a specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises a lipid component that is substantially composed of about 90 to 99.8 wt% SM and about 0.2 to 10 wt% negatively charged phospholipids (e.g., about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids). In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure is substantially composed of about 90 to 99.8 wt% lecithin and about 0.2 to 10 wt% negatively charged phospholipids (e.g., about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt%, 0.2-5 wt%, 0.2-6 wt%, 0.2-7 wt%, 0.2-8 wt%, 0.2-9 wt%, or 0.2-10 wt% total negatively charged phospholipids).

[0120] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises a lipid fraction comprising about 9.8 to 90 wt% SM, about 9.8 to 90 wt% lecithin, and about 0.2 to 10 wt% negatively charged phospholipids, for example, about 0.2 to 1 wt%, 0.2 to 2 wt%, 0.2 to 3 wt%, 0.2 to 4 wt%, 0.2 to 5 wt%, 0.2 to 6 wt%, 0.2 to 7 wt%, 0.2 to 8 wt%, 0.2 to 9 wt% to 0.2 to 10 wt% total negatively charged phospholipids.

[0121] In yet another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises a lipid fraction that is substantially composed of about 9.8 to 90 wt% SM, about 9.8 to 90 wt% lecithin, and about 0.2 to 10 wt% negatively charged phospholipids (e.g., about 0.2 to 1 wt%, 0.2 to 2 wt%, 0.2 to 3 wt%, 0.2 to 4 wt%, 0.2 to 5 wt%, 0.2 to 6 wt%, 0.2 to 7 wt%, 0.2 to 8 wt%, 0.2 to 9 wt% to 0.2 to 10 wt% total negatively charged phospholipids).

[0122] In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises ApoA-I apolipoprotein and a lipid fraction, wherein the lipid fraction comprises sphingomyelin and about 3 wt% negatively charged phospholipids, wherein the molar ratio of the lipid fraction to ApoA-I apolipoprotein is about 2:1 to 200:1, and wherein the complex is a small or large disc-shaped particle containing 2-4 ApoA-I equivalents.

[0123] In another specific embodiment, the lipoprotein complex that can be used in the method of this disclosure comprises ApoA-I apolipoprotein and a lipid fraction, wherein the lipid fraction is substantially composed of sphingomyelin and about 3 wt% of negatively charged phospholipids, wherein the molar ratio of the lipid fraction to ApoA-I apolipoprotein is about 2:1 to 200:1, and wherein the complex is a small or large disc-shaped particle containing 2-4 ApoA-I equivalents.

[0124] HDL-based or HDL-mimicry-based complexes may contain a single type of lipid-binding protein, or a mixture of two or more different lipid-binding proteins, which may be derived from the same or different species. Although not essential, the complex will preferably contain a lipid-binding protein derived from or corresponding in amino acid sequence to the animal species being treated, in order to avoid inducing an immune response to the therapy. Therefore, for treating human patients, human-derived lipid-binding proteins are preferred. The use of peptide-mimicking apolipoproteins can also reduce or avoid immune responses.

[0125] In some embodiments, the lipid component comprises two types of phospholipids: sphingomyelin (SM) and negatively charged phospholipids. Exemplary SM and negatively charged lipids are described in Section 6.1.3.1.

[0126] The lipid component of the SM may optionally include small amounts of additional lipids. Almost any type of lipid may be used, including but not limited to lysophospholipids, galactocerebrosides, gangliosides, cerebrosides, glycerides, triglycerides, and cholesterol and its derivatives.

[0127] When included, such optional lipids will typically comprise less than about 15 wt% of the lipid fraction, although in some cases more optional lipids may be included. In some embodiments, the optional lipids comprise less than about 10 wt%, less than about 5 wt%, or less than about 2 wt%. In some embodiments, the lipid fraction does not include optional lipids.

[0128] In specific embodiments, the phospholipid fraction comprises egg SM or palmitoyl SM or phytosphingomyelin and DPPG, with a weight ratio (SM: negatively charged phospholipid) ranging from 90:10 to 99:1, more preferably from 95:5 to 98:2. In some embodiments, the weight ratio is 97:3.

[0129] The molar ratio of the lipid to protein components in the complexes disclosed herein can vary and will depend, among other factors, on the identity of the apolipoprotein containing the protein component, the identity and amount of the lipids containing the lipid component, and the desired size of the complex. Since the biological activity of apolipoproteins (e.g., ApoA-I) is thought to be mediated by the amphiphilic helices containing the apolipoprotein, it is convenient to use ApoA-I protein equivalents to represent the apolipoprotein fraction with a lipid:apolipoprotein molar ratio. ApoA-I is generally considered to contain 6-10 amphiphilic helices, depending on the method used to calculate the helices. Other apolipoproteins can be represented by ApoA-I equivalents based on the number of amphiphilic helices they contain. For example, -ApoA-I, which typically exists as a disulfide-bridged dimer. MIt can be represented as two ApoA-I equivalents, because each ApoA-I M The molecule contains twice the number of amphiphilic helices as an ApoA-I molecule. Conversely, a peptide apolipoprotein containing a single amphiphilic helix can be represented as 1 / 10 to 1 / 6 of an ApoA-I equivalent, since each molecule contains 1 / 10 to 1 / 6 of an ApoA-I molecule's amphiphilic helix. Typically, the lipid:ApoA-I equivalent molar ratio (defined herein as "Ri") of the lipoprotein complex ranges from about 105:1 to 110:1. In some embodiments, Ri is about 108:1. For phospholipids, a weight ratio of about 650-800 MW can be used to obtain the weight ratio.

[0130] In some embodiments, the lipid:ApoA-I equivalent molar ratio (“RSM”) ranges from about 80:1 to about 110:1, for example, from about 80:1 to 100:1. In a specific example, the RSM of the complex may be about 82:1.

[0131] In some embodiments, the lipoprotein complex used in the methods of this disclosure is a negatively charged complex comprising a protein fraction (preferably mature full-length ApoA-I) and a lipid fraction (comprising neutral phospholipids, sphingomyelin (SM) and negatively charged phospholipids).

[0132] In a specific embodiment, the lipid portion contains SM (e.g., egg SM, palmitoyl SM, phytoSM, or a combination thereof) and negatively charged phospholipids (e.g., DPPG), with a weight ratio (SM: negatively charged phospholipid) ranging from 90:10 to 99:1, more preferably from 95:5 to 98:2, for example 97:3.

[0133] In specific embodiments, the ratio of protein to lipid components can range from about 1:2.7 to about 1:3, preferably 1:2.7. This corresponds to a molar ratio of ApoA-I protein to lipids ranging from about 1:90 to 1:140. In some embodiments, the molar ratio of protein to lipids in the complex is about 1:90 to about 1:120, about 1:100 to about 1:140, or about 1:95 to about 1:125.

[0134] In a particular embodiment, the complex comprises CER-001, CSL-111, CSL-112, CER-522, ETC-216, or ETC-642. In a preferred embodiment, the complex is CER-001.

[0135] As used in the literature and in the following examples, CER-001 refers to the complex described in Example 4 of WO 2012 / 109162. WO 2012 / 109162 relates to CER-001 as a complex having a lipoprotein weight to total phospholipid weight ratio of 1:2.7, wherein the SM:DPPG weight:weight ratio is 97:3. Example 4 of WO 2012 / 109162 also describes its preparation method.

[0136] When used in the context of the methods and / or CER-001 dosing regimens of this disclosure, CER-001 refers to a lipoprotein complex whose individual components may vary by up to 20% relative to CER-001 as described in Example 4 of WO 2012 / 109162. In some embodiments, the components of the lipoprotein complex vary by up to 10% relative to CER-001 as described in Example 4 of WO 2012 / 109162. Preferably, the components of the lipoprotein complex are those described in Example 4 of WO 2012 / 109162 (plus / minus acceptable manufacturing tolerance variations). The SM in CER-001 may be natural or synthetic. In some embodiments, the SM is a natural SM, such as the natural SM described in WO 2012 / 109162, such as egg SM or plant SM. In some embodiments, the SM is a synthetic SM, such as the synthetic SM described in WO 2012 / 109162, for example, synthetic palmitoylsphingomyelin, as described in WO 2012 / 109162. Methods for synthesizing palmitoylsphingomyelin are known in the art, for example, as described in WO 2014 / 140787 and WO 2024 / 003612, the contents of which are incorporated herein by reference in their entirety. The lipoprotein, apolipoprotein AI (ApoA-I) in CER-001 preferably has an amino acid sequence corresponding to amino acids 25 to 267 of SEQ ID NO:2. ApoA-I can be purified from animal sources (particularly human sources) or recombinantly produced. In a preferred embodiment, the ApoA-I in CER-001 is recombinant ApoA-I. The CER-001 used in the dosing regimens of this disclosure is preferably highly homogeneous, for example, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% homogeneous, as reflected by a single peak in gel permeation chromatography. See, for example, Section 6.4 of WO 2012 / 109162.

[0137] CSL-111 is a recombinant human ApoA-I purified from plasma and conjugated with soybean phosphatidylcholine (SBPC) (Tardif et al., 2007, JAMA 297:1675-1682).

[0138] CSL-112 is an ApoA-I formulation purified from plasma and recombined to form an HDL suitable for intravenous infusion (Diditchenko et al., 2013, DOI 10.1161 / ATVBAHA.113.301981).

[0139] ETC-216 (also known as MDCO-216) contains recombinant ApoA-I Milano The lipid-depleted form of HDL (Nicholls et al., 2011, Expert Opin Biol Ther. 11(3):387-94. doi: 10.1517 / 14712598.2011.557061).

[0140] ETC-642 is a complex of a 22-amino acid amphiphilic peptide (ESP-2418) with sphingomyelin and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (dipalmitoylphosphatidylcholine, DPPC) (Di Bartolo et al., 2011, Atherosclerosis 217:395-400).

[0141] In another embodiment, the complex that can be used in the method of this disclosure is CER-522. CER-522 is a lipoprotein complex comprising a combination of three phospholipids and a 22-amino acid peptide, CT80522:

[0142]

[0143] The phospholipid component of CER-522 consists of sphingomyelin, 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (dipalmitoylphosphatidylcholine, DPPC), and 1,2-dipalmitoyl-sn-glycerol-3-[phospho-racemic-(1-glycerol)] (dipalmitoylphosphatidylglycerol, DPPG) in a weight ratio of 48.5:48.5:3. The ratio of peptides to total phospholipids in the CER-522 complex is 1:2.5 (w / w).

[0144] In some embodiments, the lipoprotein complex is defatted HDL. Most HDL in plasma is cholesterol-rich. Lipids in HDL can be depleted, for example, partially depleted and / or selectively depleted, for example, to reduce its cholesterol content. In some embodiments, defatted HDL can resemble small α, preβ-1, and other preβ forms of HDL. A method for selectively depleting HDL is described in Sacks et al., 2009, J Lipid Res. 50(5): 894–907.

[0145] In some embodiments, the lipoprotein complex comprises bioactive agent delivery particles as described in US 2004 / 0229794.

[0146] Bioactive agent delivery particles may comprise a lipid-binding polypeptide (e.g., an apolipoprotein as described earlier in this section or in Section 6.1.1), a lipid bilayer (e.g., comprising one or more phospholipids as described earlier in this section or in Section 6.1.3.1), and a bioactive agent (e.g., an anticancer agent), wherein the interior of the lipid bilayer contains hydrophobic regions, and wherein the bioactive agent associates with the hydrophobic regions of the lipid bilayer. In some embodiments, the bioactive agent delivery particles are as described in US2004 / 0229794.

[0147] In some implementations, the bioactive agent delivery particles do not contain a hydrophilic core.

[0148] In some implementations, the bioactive agent delivery particles are disc-shaped (e.g., with a diameter of about 7 to about 29 nm).

[0149] The bioactive agent delivery particles comprise bilayer-forming lipids, such as phospholipids (e.g., as described earlier in this section or in Section 6.1.3.1). In some embodiments, the bioactive agent delivery particles comprise both bilayer-forming and non-bilayer-forming lipids. In some embodiments, the lipid bilayer of the bioactive agent delivery particles comprises phospholipids. In one embodiment, the phospholipids incorporated into the delivery particles include dimyristicophosphatidylcholine (DMPC) and dimyristicophosphatidylglycerol (DMPG). In some embodiments, the lipid bilayer comprises DMPC and DMPG in a 7:3 molar ratio.

[0150] In some embodiments, the lipid-binding peptide is an apolipoprotein (e.g., as described earlier in this section or in Section 6.1.1). The primary interaction between the lipid-binding peptide (e.g., an apolipoprotein molecule) and the lipid bilayer is typically a hydrophobic interaction between residues on the hydrophobic facet of the amphiphilic structure (e.g., the α-helix of the lipid-binding peptide) and the lipid fatty acyl chains on the peripheral outer surface of the particle. Bioactive agent delivery particles may contain exchangeable and / or non-exchangeable apolipoproteins. In one embodiment, the lipid-binding peptide is ApoA-I.

[0151] In some embodiments, the bioactive agent delivery particles contain lipid-binding polypeptide molecules, such as apolipoprotein molecules, which have been modified to increase particle stability. In one embodiment, the modification includes introducing cysteine ​​residues to form intramolecular and / or intermolecular disulfide bonds.

[0152] In another embodiment, the bioactive agent delivery particle includes a chimeric lipid-binding polypeptide molecule, such as a chimeric apolipoprotein molecule, having one or more bound functional portions, such as one or more targeting portions and / or one or more portions having desired biological activity, such as antimicrobial activity, which can enhance the activity of the bioactive agent incorporated into the delivery particle or synergize with the activity of the bioactive agent incorporated into the delivery particle.

[0153] In some embodiments of the methods described herein, a lipid-binding protein-based complex (e.g., CER-001) can be used as a carrier to deliver one or more active agents to a subject's body or a portion thereof. In some embodiments, the one or more active ingredients can be considered as cargo portions and can be non-covalently compounded to the lipid-binding protein-based complex (e.g., CER-001) or covalently compounded to a component of the complex (e.g., via anchors or linkers). In some embodiments, the one or more active agents are not covalently linked to the complex. One or more active agents can be added to a pre-formed complex (e.g., pre-formed CER-001) to form a complex further comprising the one or more active agents. Methods for producing lipid-binding protein-based complexes having active agents are described in WO 2012 / 109162, WO 2019 / 030574, and WO 2022 / 069942.

[0154] 6.1.3. Amphiphilic molecules

[0155] Amphiphilic molecules are molecules that have both hydrophobic (nonpolar) and hydrophilic (polar) elements. Amphiphilic molecules that can be used in the complexes described herein include lipids (e.g., as described in Section 6.1.3.1), detergents (e.g., as described in Section 6.1.3.2), fatty acids (e.g., as described in Section 6.1.3.3), and nonpolar molecules and sterols (e.g., as described in Section 6.1.3.4) covalently linked to polar molecules (e.g., but not limited to sugars or nucleic acids).

[0156] The complex may comprise a single class of amphiphilic molecules (e.g., a single type of phospholipid or a mixture of phospholipids) or may contain a combination of amphiphilic molecule classes (e.g., phospholipids and detergents). The complex may contain one type of amphiphilic molecule or a combination of amphiphilic molecules configured to promote the dissolution of the lipid-binding protein molecules.

[0157] In some embodiments, the amphiphilic molecules included include phospholipids, detergents, fatty acids, nonpolar moieties covalently linked to sugars, or sterols, or combinations thereof (e.g., selected from the types of amphiphilic molecules discussed above).

[0158] In some embodiments, the amphiphilic molecule comprises or is composed of phospholipid molecules. In some embodiments, the phospholipid molecules comprise negatively charged phospholipids, neutral phospholipids, positively charged phospholipids, or combinations thereof. In some embodiments, the phospholipid molecules contribute 1-3 net charges to each apolipoprotein molecule in the complex. In some embodiments, the net charge is negative. In some embodiments, the net charge is positive. In some embodiments, the phospholipid molecules consist of a combination of negatively charged phospholipids and neutral phospholipids. In some embodiments, the molar ratio of negatively charged phospholipids to neutral phospholipids ranges from 1:1 to 1:3. In some embodiments, the molar ratio of negatively charged phospholipids to neutral phospholipids is about 1:1 or 1:2.

[0159] In some implementations, the amphiphilic molecule comprises neutral phospholipids and negatively charged phospholipids in a weight ratio of 95:5 to 99:1.

[0160] 6.1.3.1. Lipids

[0161] The lipid-binding protein-based complex may comprise one or more lipids. In various embodiments, the one or more lipids may be saturated and / or unsaturated, natural and / or synthetic, charged or uncharged, zwitterionic or non-zwitterionic. In some embodiments, lipid molecules (e.g., phospholipid molecules) may collectively contribute 1-3 (e.g., 1-3, 1-2, 2-3, 1, 2, or 3) of the net charge of each lipid-binding protein molecule in the complex. In some embodiments, the net charge is negative. In other embodiments, the net charge is positive.

[0162] In some embodiments, the lipid comprises a phospholipid. The phospholipid may have two identical or different acyl chains (e.g., chains with different numbers of carbon atoms, different degrees of saturation between the acyl chains, different branches of the acyl chains, or combinations thereof). The lipid may also be modified to contain a fluorescent probe (e.g., as described at avantilipids.com / product-category / products / fluorescent-lipids / ). Preferably, the lipid comprises at least one phospholipid.

[0163] Phospholipids may have unsaturated or saturated acyl chains ranging from about 6 to about 24 carbon atoms (e.g., 6-20, 6-16, 6-12, 12-24, 12-20, 12-16, 16-24, 16-20, or 20-24). In some embodiments, the phospholipids used in the complexes disclosed herein have one or two acyl chains of 12, 14, 16, 18, 20, 22, or 24 carbons (e.g., two acyl chains of the same length or two acyl chains of different lengths).

[0164] Non-limiting examples of acyl chains that may be present in common fatty acids and can be included in phospholipids are provided in Table 1 below:

[0165]

[0166] Lipids that may be present in the complexes disclosed herein include, but are not limited to: small alkyl chain phospholipids, lecithin choline, soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearyl phosphatidylcholine, 1-myristoyl-2-palmitoyl phosphatidylcholine, 1-palmitoyl-2-myristoyl phosphatidylcholine, 1-palmitoyl-2-stearoyl phosphatidylcholine, 1-stearoyl-2-palmitoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dioleoyl phosphatidylethanolamine, dilauroyl phosphatidylglycerol phosphatidylcholine, phosphatidylserine, and phosphatidylethanolamine. Phosphatidylinositol, phosphatidylglycerol, diphosphatidylglycerol (e.g., dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, distearyl phosphatidylglycerol, dioleoyl phosphatidylglycerol), dimyristoyl phosphatidyl acid, dipalmitoyl phosphatidyl acid, dimyristoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, dimyristoyl phosphatidylserine, dipalmitoyl phosphatidylserine, cerebrophosphatidylserine, cerebrosphingomyelin, palmitic acid Acylsphingomyelin, dipalmitoylsphingomyelin, sphingomyelin, lactosphingomyelin, phytosphingomyelin, distearate sphingomyelin, dipalmitoylphosphatidylglycerol, phosphatidic acid, galactocerebroside, ganglioside, cerebroside, dilauroylphosphatidylcholine, (1,3)-D-mannosyl-(1,3)glycerol diester, aminophenyl glycoside, 3-cholesterolyl-6'-(glycosylthio)hexyl ether glycolipid, and cholesterol and its derivatives. Synthetic lipids, such as synthetic palmitoylsphingomyelin or N-palmitoyl-4-hydroxysphingosine-1-phosphocholine (a form of phytosphingomyelin), can be used to minimize lipid oxidation.

[0167] In some embodiments, the lipid-binding protein-based complex comprises two types of phospholipids: neutral lipids, such as lecithin and / or sphingomyelin (abbreviated as SM), and charged phospholipids (e.g., negatively charged phospholipids). The “neutral” phospholipids have a net charge of approximately zero at physiological pH. In many embodiments, the neutral phospholipids are zwitterions, although other types of net neutral phospholipids are known and can be used. In some embodiments, the molar ratio of charged phospholipids (e.g., negatively charged phospholipids) to neutral phospholipids ranges from 1:1 to 1:3, for example, about 1:1, about 1:2, or about 1:3.

[0168] Neutral phospholipids may contain one or both of, for example, lecithin and / or SM, and may optionally contain other neutral phospholipids. In some embodiments, the neutral phospholipid contains lecithin but not SM. In other embodiments, the neutral phospholipid contains SM but not lecithin. In still other embodiments, the neutral phospholipid contains both lecithin and SM. All these specific exemplary embodiments may contain neutral phospholipids in addition to lecithin and / or SM, but in many embodiments, such additional neutral phospholipids are not included.

[0169] As used herein, the term "SM" includes sphingomyelin derived from or obtained from natural sources, as well as analogues and derivatives of naturally occurring SM that are unaffected by LCAT hydrolysis, just like naturally occurring SM. SM is a phospholipid structurally very similar to lecithin, but unlike lecithin, it does not have a glycerol backbone and therefore does not have ester bonds linking acyl chains. Instead, SM has a ceramide backbone in which amide bonds link acyl chains. SM can be obtained, for example, from eggs, yolks, or brains. SM analogues or derivatives may also be used. Non-limiting examples of useful SM analogues and derivatives include, but are not limited to, palmitoylsphingomyelin, N-palmitoyl-4-hydroxysphingosine-1-phosphocholine (a form of plant sphingomyelin), palmitoylsphingomyelin, stearoylsphingomyelin, D-erythro-N-16:O-sphingomyelin and its dihydroisomer D-erythro-N-16:O-dihydrosphingomyelin. Synthetic sphingomyelin, such as synthetic palmitoylsphingomyelin or N-palmitoyl-4-hydroxysphingosine-1-phosphocholine (plant sphingomyelin), can be used to produce a more homogeneous complex and with fewer contaminants and / or oxidation products than animal-derived sphingomyelin. Methods for synthesizing sphingomyelin are described in U.S. Publication No. 2016 / 0075634.

[0170] Sphingomyelins isolated from natural sources can be artificially enriched within a specific saturated or unsaturated acyl chain. For example, lactose sphingomyelin (Avanti Phospholipid, Alabaster, Ala.) is characterized by long saturated acyl chains (i.e., acyl chains with 20 or more carbon atoms). In contrast, sphingomyelin is characterized by short saturated acyl chains (i.e., acyl chains with fewer than 20 carbon atoms). For instance, while only about 20% of lactose sphingomyelin contains C16:0 (16 carbon, saturated) acyl chains, about 80% of sphingomyelin contains C16:0 acyl chains. Using solvent extraction, the composition of lactose sphingomyelin can be enriched to have an acyl chain composition comparable to that of sphingomyelin, or vice versa.

[0171] SMs can be semi-synthetic, resulting in a specific acyl chain. For example, sphingomyelins can be purified from milk, and then a specific acyl chain, such as a C16:0 acyl chain, can be cleaved and replaced with another acyl chain. SMs can also be fully synthetic, for example, through large-scale synthesis. See, for example, Dong et al., US Pat. No. 5,220,043, entitled Synthesis of D-erythro-sphingomyelins, issued Jun. 15, 1993; Weis, 1999, Chem. Phys. Lipids 102 (1-2):3-12. SMs can also be fully synthetic, as described in, for example, US Publication No. 2014 / 0275590.

[0172] The length and saturation level of the acyl chains comprising the semi-synthetic or synthetic SM can be selectively varied. The acyl chains can be saturated or unsaturated and can contain about 6 to about 24 carbon atoms. Each chain can contain the same number of carbon atoms, or each chain can contain different numbers of carbon atoms. In some embodiments, the semi-synthetic or synthetic SM comprises mixed acyl chains such that one chain is saturated and one chain is unsaturated. In such mixed acyl chain SMs, the chain lengths can be the same or different. In other embodiments, the acyl chains of the semi-synthetic or synthetic SM are both saturated or both are unsaturated. Furthermore, the chains can contain the same or different numbers of carbon atoms. In some embodiments, the two acyl chains comprising the semi-synthetic or synthetic SM are identical. In a specific embodiment, the chains correspond to the acyl chains of naturally occurring fatty acids, such as oleic acid, palmitic acid, or stearic acid. In another embodiment, an SM with saturated or unsaturated functionalized chains is used. In yet another specific embodiment, both acyl chains are saturated and contain 6 to 24 carbon atoms. Non-limiting examples of acyl chains that may be present in common fatty acids that can be included in semi-synthetic and synthetic SMs are provided in Table 1 above.

[0173] In some embodiments, SM is palmitoyl SM, such as synthetic palmitoyl SM (which has a C16:0 acyl chain), or SM is egg SM (which contains palmitoyl SM as a major component).

[0174] In specific implementation schemes, functionalized sphingomyelins, such as plant sphingomyelins, are used.

[0175] Lecithin may be derived from or isolated from natural sources, or it may be synthesized. Examples of suitable lecithin isolated from natural sources include, but are not limited to, lecithin acylcholine and soybean phosphatidylcholine. Other non-limiting examples of suitable lecithin include dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearyl phosphatidylcholine, 1-myristoyl-1,2-palmitoyl phosphatidylcholine, 1-palmitoyl-1,2-myristoyl phosphatidylcholine, 1-palmitoyl-1,2-stearoyl phosphatidylcholine, 1-stearoyl-1,2-palmitoyl phosphatidylcholine, 1-palmitoyl-1,2-oleoyl phosphatidylcholine, 1-oleoyl-1,2-palmitoyl phosphatidylcholine, dioleoyl phosphatidylcholine, and their ether derivatives or analogues.

[0176] Lecithin derived from or isolated from natural sources can be enriched to include specific acyl chains. In embodiments using semi-synthetic or synthetic lecithin, the identity of the acyl chains can be selectively varied, as discussed above with respect to SM. In some embodiments of the complex described herein, the two acyl chains on the lecithin are identical. In some embodiments of the complex comprising SM and lecithin, the acyl chains of SM and lecithin are entirely identical. In specific embodiments, the acyl chains correspond to the acyl chains of myristic acid, palmitic acid, oleic acid, or stearic acid.

[0177] The complexes disclosed herein may comprise one or more negatively charged phospholipids (e.g., alone or in combination with one or more neutral phospholipids). As used herein, a “negatively charged phospholipid” is a phospholipid having a net negative charge at physiological pH. The negatively charged phospholipid may comprise a single type of negatively charged phospholipid or a mixture of two or more different negatively charged phospholipids. In some embodiments, the charged phospholipid is a negatively charged glycerophospholipid. Specific examples of suitable negatively charged phospholipids include, but are not limited to: 1,2-dipalmitoyl-sn-glycerol-3-[phosphatidyl-racemic-(1-glycerol)], phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidic acid, and their salts (e.g., sodium or potassium salts). In some embodiments, the negatively charged phospholipid comprises one or more phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, and / or phosphatidic acid. In a specific embodiment, the negatively charged phospholipid comprises a salt of phosphatidylglycerol or a salt of phosphatidylinositol, or is composed of a salt of phosphatidylglycerol or a salt of phosphatidylinositol. In another specific embodiment, the negatively charged phospholipid comprises 1,2-dipalmitoyl-sn-glycerol-3-[phosphatidyl-racemic-(1-glycerol)] or DPPG or a salt thereof, or is composed of 1,2-dipalmitoyl-sn-glycerol-3-[phosphatidyl-racemic-(1-glycerol)] or DPPG or a salt thereof.

[0178] Negatively charged phospholipids can be obtained from natural sources or prepared by chemical synthesis. In embodiments employing synthetic negatively charged phospholipids, the identity of the acyl chains can be selectively varied, as discussed above with respect to SM. In some embodiments of the complex disclosed herein, the two acyl chains on the negatively charged phospholipid are identical. In some embodiments, the acyl chains of all types of phospholipids contained in the complex disclosed herein are identical. In a specific embodiment, the complex comprises negatively charged phospholipids and / or SM, each having a C16:0 or C16:1 acyl chain. In a specific embodiment, the fatty acid moiety of SM is primarily C16:1 palmitoyl. In one specific embodiment, the acyl chains of the charged phospholipid, lecithin, and / or SM correspond to the acyl chains of palmitic acid. In yet another specific embodiment, the acyl chains of the charged phospholipid, lecithin, and / or SM correspond to the acyl chains of oleic acid.

[0179] Examples of positively charged phospholipids that may be included in the complexes disclosed herein include N1-[2-((1S)-1-[(3-aminopropyl)amino]-4-[di(3-aminopropyl)amino]butylcarbamoyl)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2-di-O-octadecenyl-3-trimethylammonium propane, 1,2-dimyristoyl-sn-glycerol-3-ethylphosphocholine, 1-palmitoyl-2- Oleoyl-sn-glycerol-3-ethylphosphocholine, 1,2-dioleoyl-sn-glycerol-3-ethylphosphocholine, 1,2-distearatel-sn-glycerol-3-ethylphosphocholine, 1,2-dipalmitoyl-sn-glycerol-3-ethylphosphocholine, 1,2-dimyristoyl-sn-glycerol-3-ethylphosphocholine, 1,2-dilauroyl-sn-glycerol-3-ethylphosphocholine, 1,2-dilauroyl-sn-glycerol -3-Ethylphosphocholine, 1,2-dioleoyl-3-dimethylammonium-propane, 1,2-dimyristoyl-3-dimethylammonium-propane, 1,2-dipalmitoyl-3-dimethylammonium-propane, N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)prop-1-ammonium, 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-stearoyl-3-trimethylammonium-propane Methylammonium-propane, 1,2-dipalmitoyl-3-trimethylammonium-propane, 1,2-dimyristoyl-3-trimethylammonium-propane, N-[1-(2,3-dimyristoyloxy)propyl]-N,N-dimethyl-N-(2-hydroxyethyl)ammonium bromide, N,N,N-trimethyl-2-bis[(1-oxo-9-octadecenyl)oxy]-(Z,Z)-1-propylaminomethyl sulfate, and their salts (e.g., chloride or bromide salts).

[0180] The lipids used are preferably at least 95% pure and / or contain oxidants (e.g., but not limited to peroxides) that reduce oxidation levels. Lipids obtained from natural sources preferably have a smaller polyunsaturated fatty acid fraction and / or a fatty acid fraction less susceptible to oxidation. The oxidation level in the sample can be determined using iodometric titration, which provides a peroxide value expressed as milliequivalents of iodine separated per kg of sample, abbreviated as meq O / kg. See, for example, Gray, 1978, Journal of the American Oil Chemists Society 55:539-545; Heaton et al., 1958, Journal of the Science of Food and Agriculture 9:781-786. Preferably, the oxidation level or peroxide level is low, for example, less than 5 meq O / kg, less than 4 meq O / kg, less than 3 meq O / kg, or less than 2 meq O / kg.

[0181] In some embodiments, the complex may contain a small amount of additional lipids. Almost any type of lipid can be used, including but not limited to lysophosphatidylcholine, galactocerebroside, ganglioside, cerebroside, glycerides, triglycerides, and sterols and sterol derivatives (e.g., phytosterols, animal sterols, such as cholesterol, or sterol derivatives, such as cholesterol derivatives). For example, the complexes of this disclosure may contain cholesterol or cholesterol derivatives, such as cholesterol esters. Cholesterol derivatives may also be substituted cholesterol or substituted cholesterol esters. The complexes of this disclosure may also contain oxidized sterols, such as, but not limited to, oxidized cholesterol or oxidized sterol derivatives (e.g., but not limited to, oxidized cholesterol esters). In some embodiments, the complex does not contain cholesterol and / or its derivatives (e.g., cholesterol esters or oxidized cholesterol esters).

[0182] 6.1.3.2. Detergent

[0183] The complex may contain one or more detergents. The detergents may be zwitterionic, nonionic, cationic, anionic, or a combination thereof. Exemplary zwitterionic detergents include 3-[(3-cholamidopropyl)dimethylammonium]-1-propanesulfonate (CHAPS), 3-[(3-cholamidopropyl)dimethylammonium]-2-hydroxy-1-propanesulfonate (CHAPSO), and N,N-dimethyldodecylamine N-oxide (LDAO). Exemplary nonionic detergents include D-(+)-trehalose 6-monooleate, N-octanoyl-N-methylglucosamine, N-nonanoyl-N-methylglucosamine, N-decanoyl-N-methylglucosamine, 1-(7Z-hexadecenoyl)-racemic-glycerol, 1-(8Z-hexadecenoyl)-racemic-glycerol, 1-(8Z-heptadecenoyl)-racemic-glycerol, 1-(9Z-hexadecenoyl)-racemic-glycerol, and 1-decanoyl-racemic-glycerol. Exemplary cationic detergents include (S)-O-methyl-serine dodecylamide hydrochloride, dodecyl ammonium chloride, decyltrimethylammonium bromide, and hexadecyltrimethylammonium sulfate. Exemplary anionic detergents include cholesterol hemisuccinate, cholates, alkyl sulfates, and alkyl sulfonates.

[0184] 6.1.3.3. Fatty acids

[0185] The complex may contain one or more fatty acids. These fatty acids may include short-chain fatty acids with an aliphatic tail of five or fewer carbons (e.g., butyric acid, isobutyric acid, valeric acid, or isovaleric acid), medium-chain fatty acids with an aliphatic tail of 6 to 12 carbons (e.g., hexanoic acid, caprylic acid, capric acid, or lauric acid), long-chain fatty acids with an aliphatic tail of 13 to 21 carbons (e.g., myristic acid, palmitic acid, stearic acid, or arachidic acid), ultra-long-chain fatty acids with an aliphatic tail of 22 or more carbons (e.g., behenic acid, tetracosanoic acid, or hexacosanoic acid), or combinations thereof. The one or more fatty acids may be saturated (e.g., caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, docosanoic acid, tetracosanoic acid, or hexacosanoic acid), unsaturated (e.g., myristone acid, palmitic acid, sapienic acid, oleic acid, trans oleic acid, isoleic acid, linoleic acid, trans linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, or docosahexaenoic acid), or combinations thereof. The unsaturated fatty acids may be cis or trans fatty acids. In some embodiments, the unsaturated fatty acids used in the complexes of this disclosure are cis fatty acids.

[0186] 6.1.3.4. Nonpolar molecules linked to sugars and sterols

[0187] The complex may contain one or more amphiphilic molecules, which comprise a nonpolar molecule or portion (e.g., a hydrocarbon chain, acyl group, or diacyl chain) or sterol (e.g., cholesterol) linked to a sugar (e.g., a monosaccharide such as glucose or galactose, or a disaccharide such as maltose or trehalose). The sugar may be a modified sugar or a substituted sugar. Exemplary amphiphilic molecules containing a nonpolar molecule linked to a sugar include dodecyl-2-yloxy-β-D-maltose, tridecyl-3-yloxy-β-D-maltose, tridecyl-2-yloxy-β-D-maltose, n-dodecyl-β-D-maltose (DDM), n-octyl-β-D-glucoside, n-nonyl-β-D-glucoside, n-decyl-β-D-maltose, n-dodecyl-β-D-maltopyranoside, 4-n-dodecyl-α,α-trehalose, 6-n-dodecyl-α,α-trehalose, and 3-n-dodecyl-α,α-trehalose.

[0188] In some implementations, the nonpolar portion is an acyl chain or a diacyl chain.

[0189] In some implementations, the sugar is a modified sugar or a substituted sugar.

[0190] 6.1.4. Formulation

[0191] Lipid-binding protein molecules and lipid-binding protein-based complexes containing lipid-binding protein molecules can be formulated, for example, according to techniques known in the art for the intended route of administration (e.g., as described in Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22nd Edition, PharmaceuticalPress, London, UK).

[0192] CER-001, intended for infusion administration, can be formulated in phosphate buffer containing sucrose and mannitol excipients, for example as described in WO 2012 / 109162.

[0193] 6.2. Subject Population

[0194] Subjects who can be treated according to the methods described herein are preferably mammals, with humans being the most preferred.

[0195] In some respects, the subject has or is at risk of: sepsis (e.g., septic shock, such as post-traumatic (e.g., abdominal trauma) septic shock, or non-traumatic septic shock, such as postoperative sepsis), sepsis-induced cognitive deficits, sepsis with a risk of developing acute kidney injury (e.g., high risk), bacterial infection (e.g., Gram-positive or Gram-negative bacterial infection), optionally antibiotic-resistant bacteria (e.g., MRSA), urinary tract infection, bloodstream infection, postoperative infection, gastrointestinal perforation, duodenal ulcer perforation, intestinal perforation, pneumonia (e.g., hospital-acquired pneumonia), pancreatitis (e.g., necrotizing pancreatitis), viral infection (e.g., SARS-CoV-2). (COVID-19) infection or influenza virus infection), acute myocardial infarction (AMI), cytokine release syndrome (CRS), ischemia-reperfusion induced tissue damage, postoperative inflammation, sepsis-induced acute kidney injury (AKI), hypoalbuminemia (e.g., vitamin deficiency-related hypoalbuminemia, inflammatory bowel disease (IBD)-related hypoalbuminemia, nephropathy-related hypoalbuminemia, infection-related hypoalbuminemia, optionally wherein said infection is a Gram-positive bacterial infection, a Gram-negative bacterial infection, or a viral infection, such as SARS-CoV-2). (COVID-19) infection or influenza infection, stress-related hypoalbuminemia, hypoalbuminemia related to thyroid disease, hypoalbuminemia related to diabetes, hypoalbuminemia related to nephrotic syndrome, hypoalbuminemia related to lupus, hypoalbuminemia related to cirrhosis, hypoalbuminemia related to liver disease, hypoalbuminemia related to heart failure or malnutrition, cytokine release syndrome (CRS; cytokine storm), risk of CRS, acute kidney injury (AKI), risk of developing AKI, acute respiratory distress syndrome (ARDS) or risk of developing ARDS.

[0196] In some respects, the participants have graft-versus-host disease (GVHD) or are at risk of developing GVHD. Participants with GVHD or at risk of developing GVHD may have already received stem cell transplants, bone marrow transplants, or organ transplants.

[0197] In some respects, the subjects had asthma, such as acute severe asthma.

[0198] In some respects, subjects had bacterial infections or were at risk of bacterial infections. Examples of bacteria that commonly cause infections and sepsis (e.g., septic shock) include Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa (GBD 2019 Antimicrobial Resistance Collaborators, 2023, Lancet 400(10369):2221-2248), Acinetobacter baumannii, Bacteroides fragilis, and Proteus mirabilis.

[0199] In some implementations, the subject has cytokine release syndrome (CRS, cytokine storm) or is at risk of developing it. In some implementations, CRS is secondary to an infection, such as a bacterial or viral infection.

[0200] In some implementations, the subject's SOFA score before treatment with the lipid-binding protein molecule was 1 to 24, for example, scores of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 (see Vincent et al., 1996, Intensive Care Med, 22:707–710).

[0201] In some implementations, prior to treatment with lipid-binding protein molecules (e.g., ApoA-I), the subject's SOFA score was 2 to 24, for example 2 to 16, such as SOFA scores of 2 to 3, 2 to 4, 3 to 4, 2 to 5, 3 to 5, 4 to 5, 2 to 6, 3 to 6, 4 to 6, 5 to 6, 2 to 7, 3 to 7, 4 to 7, 5 to 7, 6 to 7, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8. 7 to 8, 2 to 9, 3 to 9, 4 to 9, 5 to 9, 6 to 9, 7 to 9, 8 to 9, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, 9 to 10, 2 to 11, 3 to 11, 4 to 11, 5 to 11, 6 to 11, 7 to 11, 8 to 11, 9 to 11, 10 to 11, 2 to 12, 3 to 12, 4 to 12, 5 to 12, 6 to 12, 7 to 1 2, 8 to 12, 9 to 12, 10 to 12, 11 to 12, 2 to 13, 3 to 13, 4 to 13, 5 to 13, 6 to 13, 7 to 13, 8 to 13, 9 to 13, 10 to 13, 11 to 13, 12 to 13, 2 to 14, 3 to 14, 4 to 14, 5 to 14, 6 to 14, 7 to 14, 8 to 14, 9 to 14, 10 to 14, 11 to 14, 12 to 14, 13 to 14 2 to 15, 3 to 15, 4 to 15, 5 to 15, 6 to 15, 7 to 15, 8 to 15, 9 to 15, 10 to 15, 11 to 15, 12 to 15, 13 to 15, 14 to 15, 2 to 16, 3 to 16, 4 to 16, 5 to 16, 6 to 16, 7 to 16, 8 to 16, 9 to 16, 10 to 16, 11 to 16, 12 to 16, 13 to 16, 14 to 16 or 15 to 16.

[0202] In one aspect, this disclosure provides a method for increasing the survival probability of subjects with SOFA scores of 2 to 24 (e.g., 2 to 16 or any of the subranges described in the preceding paragraphs), the method comprising administering a lipid-binding protein molecule (e.g., ApoA-I) to the subject, the increased survival probability being relative to subjects of the same or similar age, underlying medical condition, and SOFA score who received standard care and were not administered the lipid-binding protein molecule (e.g., ApoA-I). The increased survival may be determined over a period from 30 days to 1 year (e.g., 30 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months) from the date of first administration of the lipid-binding protein molecule (e.g., ApoA-I). In some embodiments, the increased survival is determined within 30 days (i.e., 30-day survival).

[0203] 6.3. Measurement and Target Level

[0204] 6.3.1. ApoA-I Measurement

[0205] ApoA-I levels can be measured in serum, plasma, or other blood samples from a subject. In some embodiments, the blood sample is a serum sample. For example, ApoA-I levels can be measured using an enzyme-linked immunosorbent assay (ELISA), immunoturbidimetry, or immunonephelometry utilizing anti-ApoA-I antibodies. Exemplary ELISA kits for measuring ApoA-I levels in blood samples are available from R&D Systems, Minneapolis MN, USA (catalog number DAPA10). Commercial blood testing laboratories routinely perform immunoturbidimetric and immunonephelometry detection of ApoA-I (e.g., Quest Diagnostics test code 5223; Labcorp test code 016873) and can use such assays. The blood sample used for testing can be a serum sample, a plasma sample, or a whole blood sample. In some embodiments, a serum sample is used.

[0206] The target ApoA-I level or range can be defined with reference to healthy subjects. Normal ApoA-I levels or ranges in healthy subjects can vary between men and women. Typically, the lower limit of normal ApoA-I levels or normal ApoA-I ranges in women is approximately 0.1 g / L higher than in men. In some embodiments, the target ApoA-I level or range is the serum ApoA-I level or range, such as the normal ApoA-I level or range in healthy subjects.

[0207] In some embodiments, a level of 0.8 g / L is used as the normal cutoff (making levels >0.8 g / L considered normal). In other embodiments, a level of 0.9 g / L is used as the normal cutoff. In other embodiments, a cutoff of 1.0 g / L is used as the normal cutoff. In other embodiments, a cutoff of 1.1 g / L is used as the normal cutoff. In other embodiments, a cutoff of 1.2 g / L is used as the normal cutoff. In other embodiments, a cutoff of 1.3 g / L is used as the normal cutoff. In some embodiments, 1.8 g / L is used as the upper limit cutoff for normal levels. In other embodiments, 1.9 g / L is used as the upper limit cutoff for normal levels. In some embodiments, 2.0 g / L is used as the upper limit cutoff for normal levels. In some embodiments, 2.1 g / L is used as the upper limit cutoff for normal levels.

[0208] In some implementations, the target ApoA-I level is an ApoA-I level of 1.0 g / L or 1.1 g / L (e.g., serum level).

[0209] In some implementations, the target ApoA-I level (e.g., serum level) is between 1.0 g / L and 2.0 g / L, for example, 1.0 g / L to 1.1 g / L, 1.0 g / L to 1.2 g / L, 1.1 g / L to 1.2 g / L, 1.0 g / L to 1.3 g / L, 1.1 g / L to 1.3 g / L, 1.2 g / L to 1.3 g / L, 1.0 g / L to 1.4 g / L, 1.1 g / L to 1.4 g / L, 1.2 g / L to 1.4 g / L, 1.3 g / L to 1.4 g / L, 1.0 g / L to 1.5 g / L, 1.1 g / L to 1.5 g / L, 1.2 g / L to 1.5 g / L, 1.3 g / L to 1.5 g / L, and 1.4 g / L to 1.5 g / L. g / L, 1.0 g / L to 1.6 g / L, 1.1 g / L to 1.6 g / L, 1.2 g / L to 1.6 g / L, 1.3 g / L to 1.6 g / L, 1.4 g / L to 1.6 g / L, 1.5 g / L to 1.6 g / L, 1.0 g / L to 1.7 g / L, 1.1 g / L to 1.7 g / L, 1.2 g / L to 1.7 g / L, 1.3 g / L to 1.7 g / L, 1.4 g / L to 1.7 g / L, 1.5 g / L to 1.7 g / L, 1.6 g / L to 1.7 g / L, 1.0 g / L to 1.8 g / L, 1.1 g / L to 1.8 g / L, 1.2 g / L to 1.8 g / L, 1.3 g / L to 1.8 g / L, 1.4 g / L g / L to 1.8 g / L, 1.5 g / L to 1.8 g / L, 1.6 g / L to 1.8 g / L, 1.7 g / L to 1.8 g / L, 1.0 g / L to 1.9 g / L, 1.1 g / L to 1.9 g / L, 1.2 g / L to 1.9 g / L, 1.3 g / L to 1.9 g / L, 1.4 g / L to 1.9 g / L, 1.5 g / L to 1.9 g / L, 1.6 g / L to 1.9 g / L, 1.7 g / L to 1.9 g / L, 1.8 g / L to 1.9 g / L, 1.0 g / L to 2.0 g / L, 1.1 g / L to 2.0 g / L, 1.2 g / L to 2.0 g / L, 1.3 g / L to 2.0 g / L, 1.4 g / L to 2.0 g / L. g / L, 1.5 g / L to 2.0 g / L, 1.6 g / L to 2.0 g / L, 1.7 g / L to 2.0 g / L, 1.8 g / L to 2.0 g / L, 1.9 g / L to 2.0 g / L, 1.1 g / L to 2.1 g / L, 1.2 g / L to 2.1 g / L, 1.3 g / L to 2.1 g / L, 1.4 g / L to 2.1 g / L, 1.5 g / L to 2.1 g / L, 1.6 g / L to 2.1 g / L, 1.7 g / L to 2.1 g / L, 1.8 g / L to 2.1 g / L, 1.9 g / L to 2.1 g / L, or 2.0 g / L to 2.1 g / L. Each of the foregoing ranges can be used as a target ApoA-I range (e.g., target serum ApoA-I).

[0210] In some implementations, the target ApoA-I range is a serum ApoA-I level of 1.0 g / L to 2.0 g / L, 1.1 g / L to 1.7 g / L, 1.2 g / L to 1.8 g / L, 1.0 g / L to 1.8 g / L, 1.1 g / L to 1.8 g / L, or 1.1 g / L to 2.1 g / L.

[0211] 6.3.2. HDL Measurement

[0212] HDL levels can be measured in serum, plasma, or other blood samples from a subject. In some implementations, the blood sample is a serum sample. HDL levels can be measured as HDL cholesterol (HDL-C) or HDL particle number (HDL-P), with HDL-C being more commonly used. HDL-C levels can be measured, for example, by enzymatic assays, such as enzymatic colorimetric assays. Common HDL-C (HDL cholesterol) tests involve reacting HDL-C with cholesterol oxidase (CHOD) and cholesterol esterase (CHER) after non-HDL lipoproteins such as LDL, VLDL, and chylomicrons (CM) have been made inaccessible to enzymes using polyanionic acid and detergents (e.g., polyvinyl sulfonate (PVS) and polyethylene glycol methyl ether (PEGME)). HDL-C reacts with the enzymes to form hydrogen peroxide, which can be detected and quantified photometrically by a Trinder reaction. Commercially available laboratory tests can be used to determine HDL-C levels (e.g., Quest Diagnostics test code 608; Labcorp test code 001925). HDL-C testers that require minimal blood volume and provide rapid results are commercially available and usable. HDL-C testers typically feature a test strip and provide results based on a reading of the light reflected from the strip, which changes color upon application of blood. Exemplary HDL-C testers include the CardioChek® PA Testing System (PTS Diagnostics) and the Cholestech LDX. TM Analyzer (Abbott). HDL-P can be determined by nuclear magnetic resonance (NMR). Commercially available laboratory tests can be used to determine HDL-P levels (e.g., Labcorp test code 818542).

[0213] According to guidelines published by the National Library of Medicine, National Institutes of Health (medlineplus.gov / cholesterollevelswhatyouneedtoknow.html), HDL-C levels below 40 mg / dL (men) or below 50 mg / dL (women) are considered low. In some implementations, target HDL-C levels are 50 mg / dL, 45 mg / dL, 40 mg / dL, or 35 mg / dL. The target HDL-C level can be set the same for both men and women, or it can be different for men and women, for example, 40 mg / dL for men and 50 mg / dL for women.

[0214] 6.4. Dosing regimen

[0215] In some aspects, the methods disclosed herein relate to personalized medicine approaches in which ApoA-I levels in a subject are measured (e.g., before and / or during a treatment process) and lipid-binding protein molecules such as ApoA-I (including ApoA-I-based complexes such as CER-001) are administered to increase and / or maintain ApoA-I levels at or above a target value (e.g., a target corresponding to normal ApoA-I levels in healthy subjects as described in Section 6.3.1) and / or within a target range (e.g., a target corresponding to the normal ApoA-I range in healthy subjects as described in Section 6.3.1).

[0216] As an alternative to (or in addition to) measuring a subject's ApoA-I level, the subject's high-density lipoprotein (HDL) level (e.g., HDL-C) (e.g., as described in Section 6.3.2) can be measured. Low HDL levels generally indicate low ApoA-I levels in a subject. Therefore, measuring a subject's HDL level may be useful, for example, if an ApoA-I test is unavailable, or if an HDL test can provide faster results compared to an ApoA-I test. When an HDL level is measured and found to be below a target HDL level (e.g., a target HDL level corresponding to a normal HDL level), one or more doses of the lipid-binding protein molecule can be administered to the subject. Normal or high HDL levels are not necessarily indicative of normal or high ApoA-I levels in a subject, as it is believed that subjects may have HDL with poor ApoA-I levels in some cases. Therefore, if the measured HDL level is at or above the target HDL level, a subsequent ApoA-I test may optionally be performed to determine whether the subject's ApoA-I level is actually low. In some implementations, treatment is administered based on the results of HDL testing without waiting for the results of subsequent ApoA-I testing. Once the results of the ApoA-I test are obtained, treatment can be continued or modified based on those results. For example, if the subject's ApoA-I level measured in a subsequent test is below or within the target ApoA-I level, treatment can continue, and if the ApoA-I level measured in a subsequent test is at or above the target ApoA-I level, treatment can be stopped or otherwise modified.

[0217] Subjects may be tested as described in Section 6.2. ApoA-I or HDL levels may be measured and compared to target levels or ranges as described in Section 6.3.

[0218] ApoA-I or HDL levels in subjects can be measured prior to treatment. This information can be used to assess appropriate dosing regimens, such as induction regimens as described in Section 6.4.1.

[0219] Alternatively or additionally, the subject's ApoA-I or HDL levels may be measured during treatment. This can provide information about how the subject is responding to treatment, such as whether the subject is clearing HDL cholesterol and / or ApoA-I at a higher rate than normal subjects (e.g., in subjects with acute indications such as sepsis, a higher rate of ApoA-I clearance is considered to reflect increased toxin clearance), and can be used to assess whether to continue administration of lipid-binding protein molecules and / or adjust the frequency and / or dosage of administration.

[0220] For example, a subject's ApoA-I level (e.g., serum level) or HDL level may be measured before the first administration of a lipid-binding protein (e.g., ApoA-I, such as in an ApoA-I-based complex like CER-001), and if the measured value is below a target value or range, one or more doses of the lipid-binding protein molecule may be administered to the subject. As another example, after administration of a lipid-binding protein (e.g., ApoA-I, such as in an ApoA-I-based complex like CER-001), a subject's ApoA-I level or HDL level may be measured, and if the subject's serum ApoA-I level is below a target level or below a target range, and / or the subject's HDL level is below a target level, an additional dose of the lipid-binding protein molecule may be administered to the subject to increase the subject's ApoA-I level or HDL level. When ApoA-I or HDL levels are measured during treatment and low levels are observed, the treatment regimen can be adjusted to increase the subject's ApoA-I or HDL levels, for example, by increasing the dose and / or dose frequency and / or treatment duration (e.g., extending the initial three-day treatment regimen beyond three days). As another example, if a subject has already completed an initial treatment regimen with a lipid-binding protein molecule such as ApoA-I (e.g., CER-001), ApoA-I or HDL levels can be measured in the subject after the initial treatment regimen (e.g., at the end of treatment or after a period of time, such as one week), and if the measured ApoA-I or HDL levels are below the target level or below the target range, the subject can be retreated with a lipid-binding protein molecule. Unbound by theory, such personalized medicine approaches are considered particularly useful in treating acute conditions such as sepsis with lipid-binding proteins (e.g., ApoA-I, for example, in ApoA-I-based complexes such as CER-001), because the clearance rate of lipid-binding proteins is thought to vary more significantly among subjects with sepsis than among subjects with other non-acute conditions. In some embodiments, the methods of this disclosure are performed in intensive care settings, such as in a hospital intensive care unit.

[0221] In some aspects, the method of this disclosure includes administering a lipid-binding protein molecule such as ApoA-I (e.g., in an ApoA-I-based complex such as CER-001) to a subject according to an initial treatment regimen, and then measuring the ApoA-I level at the end of the initial treatment regimen. For example, the initial regimen may last for three days or longer (e.g., four or five days). If the measured ApoA-I level is below a target level or below a target range, treatment with the lipid-binding protein molecule may be continued by administering one or more additional doses (e.g., over one, two, or more days). If the measured ApoA-I level is above a target value or within a target range, treatment with ApoA-I may be discontinued. Alternatively, if the measured ApoA-I level is above a target value or within a target range, the lipid-binding protein molecule may be administered to the subject at a lower dose and / or frequency than the initial treatment regimen. Figures 34A-34D Further exemplary treatment procedures are shown.

[0222] In some aspects, the methods of this disclosure may include administering ApoA-I to a subject in an amount sufficient to raise the subject's ApoA-I level to a normal level (e.g., serum level greater than 1.1 g / L) or within a normal range (e.g., 1.1 g / L to 1.7 g / L, 1.2 g / L to 1.8 g / L, 1.0 g / L to 1.8 g / L, or 1.1 g / L to 1.8 g / L). In some embodiments, the amount of ApoA-I administered is sufficient to increase the subject's ApoA-I level to and / or maintain a normal ApoA-I level or range until the subject's condition improves and / or continues for a predetermined period of time (e.g., 3 days, 4 days, 5 days, or more than 5 days). Preferably, the amount and / or frequency of ApoA-I administration is sufficient to maintain a normal ApoA-I level or range during treatment.

[0223] In the methods disclosed herein, a single dose of the lipid-binding protein molecule is typically administered daily or more frequently than once daily (e.g., twice daily). Alternatively, in intensive care settings (e.g., for patients in a hospital intensive care unit), the lipid-binding protein molecule may be administered via continuous infusion rather than a single dose.

[0224] In some aspects, the method of this disclosure requires optionally administering one or more doses of a lipid-binding protein molecule to a subject; measuring the subject's ApoA-I level (typically serum ApoA-I level, although other blood samples, such as whole blood or plasma, may also be used); and administering one or more doses of a lipid-binding protein molecule (e.g., ApoA-I) if the measured ApoA-I level is below a target ApoA-I level or a target ApoA-I range. Alternatively (or in addition to measuring the subject's ApoA-I level), the subject's HDL level (e.g., serum, plasma, or whole blood HDL level) may also be measured; and if the measured HDL level is below a target HDL level, one or more doses of a lipid-binding protein molecule (e.g., ApoA-I) may be administered.

[0225] When a subject is administered one or more doses of a lipid-binding protein molecule before measuring their ApoA-I or HDL levels, the subject's ApoA-I or HDL levels can be measured, for example, 0.5 days to 1 week after the most recent administration of the lipid-binding protein molecule. In some embodiments, the subject's ApoA-I or HDL levels are measured 0.5 days to 1 day after the most recent administration of the lipid-binding protein molecule, one day after the most recent administration of the lipid-binding protein molecule, two days after the most recent administration of the lipid-binding protein molecule, three days after the most recent administration of the lipid-binding protein molecule, or more than three days after the most recent administration of the lipid-binding protein molecule (e.g., four days, five days, six days, or one week). In some embodiments, the subject's ApoA-I or HDL levels are measured after the final administration of the lipid-binding protein molecule during the induction regimen.

[0226] In some implementations, the subject has already completed a course of treatment with lipid-binding protein molecules (e.g., for sepsis) and will undergo a subsequent surgical procedure. The subject's ApoA-I or HDL levels can be measured before or after surgery, and if the subject's ApoA-I level is below a target value or range (e.g., below normal or range) or if the subject's HDL level is below a target value, the subject can be retreated with lipid-binding protein molecules (using the same or a different lipid-binding protein molecule regimen).

[0227] In some implementations, one or more doses of the lipid-binding protein molecule are administered (e.g., after an HDL test result is below the HDL target value) while awaiting the results of the ApoA-I test. For example, one or more doses of the lipid-binding protein may be administered before the results of the ApoA-I test are known, such as in cases where the ApoA-I test will take a significant amount of time or be otherwise delayed.

[0228] ApoA-I or HDL levels can be measured at any desired frequency, such as twice daily, once daily, every other day, or every three days. In some implementations, the time interval between measurements can be constant or substantially constant (e.g., it can vary by minutes or hours depending on standard procedures in a hospital or other clinical setting). In some implementations, the time interval between measurements can be chosen to vary according to the clinician's judgment (e.g., consistent with the timing of other clinical measurements as part of the subject's treatment).

[0229] In some implementations, if a subject's ApoA-I or HDL level is already above a target (e.g., normal) level for one, two, or three consecutive measurements, the time interval between measurements may be increased, among other possibilities obvious to those skilled in the art who benefit from this disclosure. Alternatively or additionally, if a subject's ApoA-I or HDL level increases within one interval between measurements, two consecutive intervals between measurements, or three consecutive measurements, or other possibilities, the time interval between measurements may be increased.

[0230] In some implementations, the time interval between measurements may be reduced if a subject's ApoA-I or HDL level is already below the target level for one, two, or three consecutive measurements, or other possibilities. Alternatively, if a subject's ApoA-I or HDL level decreases within one, two, or three consecutive intervals between measurements, the time interval between measurements may be reduced, except for other possibilities that would be obvious to those skilled in the art who benefit from this disclosure.

[0231] When the measured ApoA-I level is below the target level or below the target range, a certain amount of lipid-binding protein can be administered to the subject to increase the subject's ApoA-I level to or above the target value or within the target range.

[0232] When the measured HDL level is below the target level, a certain amount of lipid-binding protein can be administered to the subject to effectively increase the subject's HDL level to or above the target value.

[0233] Measuring ApoA-I or HDL levels in subjects may be performed, for example, before the first administration of the lipid-binding protein molecule to the subject; simultaneously, one day after the first administration, two days after the first administration, three days after the first administration, or after the final administration of the induction regimen, and other possibilities.

[0234] In some implementations, if a subject's ApoA-I level is above normal for one, two, or three consecutive measurements, the time interval between administrations of a lipid-binding protein molecule (e.g., ApoA-I) may be increased, among other possibilities obvious to those skilled in the art who benefit from this disclosure. Alternatively or additionally, if a subject's ApoA-I level increases within one interval between measurements, two consecutive intervals between measurements, or three consecutive measurements, or other possibilities, the time interval between administrations of a lipid-binding protein molecule (e.g., ApoA-I) may be increased. A similar adjustment to the time interval between administrations may be made when using HDL levels instead of ApoA-I levels.

[0235] In some implementations, if a subject's ApoA-I level has been below normal levels or range for one, two, or three consecutive measurements, and other possibilities, the time interval between administrations of a lipid-binding protein molecule (e.g., ApoA-I) may be reduced. Alternatively, if a subject's ApoA-I level decreases within one, two, or three consecutive intervals between measurements, the time interval between administrations of a lipid-binding protein molecule (e.g., ApoA-I) may be reduced, among other possibilities obvious to those skilled in the art who benefit from this disclosure. A similar adjustment to the time interval between administrations may be made when using HDL instead of ApoA-I levels.

[0236] The administration of lipid-binding protein molecules can be performed at the dosage, frequency, and route of administration as described herein. In some embodiments, if measurements indicate that a subject's ApoA-I level is below a target (e.g., normal) level or range, or that a subject's HDL level is below a target level, the subject receives a first dose of lipid-binding protein molecules; if measurements indicate that a subject's ApoA-I level is at or above a target level or within a target range, or that a subject's HDL level is at or above a target level, the subject receives a second dose of lipid-binding protein molecules, which is less than the first dose.

[0237] In some implementations, the first dose is 5 mg / kg, 10 mg / kg, or 20 mg / kg (based on the molecular weight of the lipid-binding protein and body weight), and the second dose is 5 mg / kg or 10 mg / kg, provided that the second dose is less than the first dose.

[0238] In some implementations, if a measurement indicates that a subject's ApoA-I level is below a target level or range, the subject receives a first dose of lipid-binding protein molecules; if a measurement indicates that a subject's ApoA-I level is at or above a target level or within a target range, the subject receives a second dose of lipid-binding protein molecules, which is less than the first dose.

[0239] In some implementations, if a measurement indicates that a subject's ApoA-I level is below a target level or range, the subject receives one or more doses of lipid-binding protein molecules at a first frequency; if a measurement indicates that a subject's ApoA-I level is at or above a target level or within a target range, the subject receives one or more doses of lipid-binding protein molecules at a second frequency lower than the first frequency.

[0240] The subject's ApoA-I level can be repeatedly measured, and then one or more doses of the lipid-binding protein molecule can be administered, for example, until the subject's condition has improved (e.g., a subject in the ICU has improved enough to be discharged from the ICU), or until the subject's ApoA-I level is above the target value or within the target range.

[0241] In one implementation, the lipid-binding protein molecule is administered to the subject at least once daily (e.g., once or twice daily) on days 1, 2, and 3 of the treatment regimen, and ApoA-I levels are measured on day 4.

[0242] In one implementation, the lipid-binding protein molecule is administered to the subject at least once daily (e.g., once or twice daily) on days 1, 2, 3, and 4 of the treatment regimen, and ApoA-I levels are measured on day 5.

[0243] In one implementation, the lipid-binding protein molecule is administered to the subject at least once daily (e.g., once or twice daily) on days 1, 2, 3, 4, and 5 of the treatment regimen, and ApoA-I levels are measured on day 6.

[0244] In one implementation, the lipid-binding protein molecule is administered to the subject at least once daily (e.g., once or twice daily) on days 1, 2, 3, 4, 5, and 6 of the treatment regimen, and ApoA-I levels are measured on day 7.

[0245] The lipid-binding protein molecule was administered to the subjects at least once a day (e.g., once or twice a day) on days 1, 2, 3, 4, 5, 6 and 7 of the treatment regimen, and ApoA-I levels were measured on day 8.

[0246] In some implementations, the lipid-binding protein molecule is administered to the subject at least once daily (e.g., once or twice daily) on days 1, 2, 3, and 6 of the treatment regimen, and ApoA-I levels are measured on day 4 and / or day 7.

[0247] In some implementations, a subject may be identified as having a high ApoA-I clearance rate. This identification may include assessing the subject's ApoA-I level after administration of a given amount of ApoA-I (e.g., as a single dose or multiple doses) and comparing the measured ApoA-I level to a standard value (e.g., derived from a population with the same condition as the subject). If the measured value is below the standard value, the subject may be identified as having a high ApoA-I clearance rate.

[0248] Identifying subjects with high ApoA-I clearance can provide useful information to clinicians. In some implementations, the dose and / or frequency of administration of the lipid-binding protein molecule is selected in response to subjects identified as having high ApoA-I clearance. For example, if a subject is identified as having high ApoA-I clearance, a higher dose and / or frequency of administration can be selected compared to subjects not identified as having high ApoA-I clearance.

[0249] In some embodiments, the amount of lipid-binding protein molecules delivered by each dose (e.g., administered before and / or after ApoA-I measurement) may be from 5 mg / kg to 40 mg / kg (based on protein weight). In some embodiments, the amount of lipid-binding protein molecules delivered by each dose may be from 5 mg / kg to 10 mg / kg (based on protein weight). In some embodiments, the amount of lipid-binding protein molecules delivered by each dose may be from 5 mg / kg to 20 mg / kg (based on protein weight). In some embodiments, the amount of lipid-binding protein molecules delivered by each dose may be from 10 mg / kg to 30 mg / kg (based on protein weight). In some embodiments, the amount of lipid-binding protein molecules delivered by each dose may be from 10 mg / kg to 20 mg / kg (based on protein weight). In some embodiments, the dose is 5 mg / kg (based on protein weight). In some embodiments, the dose is 6 mg / kg (based on protein weight). In some embodiments, the dose is 7 mg / kg (based on protein weight). In some embodiments, the dose is 8 mg / kg (based on protein weight). In some embodiments, the dose is 9 mg / kg (based on protein weight). In some embodiments, the dose is 10 mg / kg (based on protein weight). In some embodiments, the dose is 11 mg / kg (based on protein weight). In some embodiments, the dose is 12 mg / kg (based on protein weight). In some embodiments, the dose is 13 mg / kg (based on protein weight). In some embodiments, the dose is 14 mg / kg (based on protein weight). In some embodiments, the dose is 15 mg / kg (based on protein weight). In some embodiments, the dose is 16 mg / kg (based on protein weight). In some embodiments, the dose is 17 mg / kg (based on protein weight). In some embodiments, the dose is 18 mg / kg (based on protein weight). In some embodiments, the dose is 19 mg / kg (based on protein weight). In some embodiments, the dose is 20 mg / kg (based on protein weight). In some embodiments, the dose is 21 mg / kg (based on protein weight). In some embodiments, the dose is 22 mg / kg (based on protein weight). In some embodiments, the dose is 23 mg / kg (based on protein weight). In some embodiments, the dose is 24 mg / kg (based on protein weight). In some embodiments, the dose is 25 mg / kg (based on protein weight). In some embodiments, the dose is 26 mg / kg (based on protein weight). In some embodiments, the dose is 27 mg / kg (based on protein weight). In some embodiments, the dose is 28 mg / kg (based on protein weight).In some embodiments, the dose is 29 mg / kg (based on protein weight). In some embodiments, the dose is 30 mg / kg (based on protein weight). In some embodiments, the dose is 31 mg / kg (based on protein weight). In some embodiments, the dose is 32 mg / kg (based on protein weight). In some embodiments, the dose is 33 mg / kg (based on protein weight). In some embodiments, the dose is 34 mg / kg (based on protein weight). In some embodiments, the dose is 35 mg / kg (based on protein weight). In some embodiments, the dose is 36 mg / kg (based on protein weight). In some embodiments, the dose is 37 mg / kg (based on protein weight). In some embodiments, the dose is 38 mg / kg (based on protein weight). In some embodiments, the dose is 39 mg / kg (based on protein weight). In some embodiments, the dose is 40 mg / kg (based on protein weight).

[0250] In some implementations, the lipid-binding protein molecules are administered according to the induction protocol and optionally the consolidation protocol as described in Sections 6.4.1 and 6.4.2, respectively. For example, ApoA-I levels may be measured after the induction protocol, and the consolidation protocol may be administered to the subject if the measured ApoA-I level is below the target level or below the target range.

[0251] In some implementations, the lipid-binding protein molecule can be administered in a single stage, such as after an ApoA-I measurement prior to any administration of the lipid-binding protein molecule.

[0252] In some implementations, subjects are not treated with lipid-binding protein molecules, depending on the maintenance regimen, such as a regimen that includes long-term (e.g., one month or longer) administration of the lipid-binding protein molecule.

[0253] The lipid-binding protein molecule (e.g., ApoA-I) administration regimen disclosed herein can last up to one week, one week, or more than one week (e.g., two or three weeks).

[0254] In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) administered to the subject may be in the range of 4 to 40 mg / kg (e.g., 10 to 40 mg / kg) based on protein weight (e.g., 5, 10, 15, 20, 25, 30, 35, or 40 mg / kg or any range defined by any two of the foregoing values, e.g., 10 to 20 mg / kg, 15 to 25 mg / kg, 20 to 40 mg / kg, 25 to 35 mg / kg, or 30 to 40 mg / kg). As used herein, the expression "based on protein weight" means that the dose of the lipid-binding protein molecule (e.g., ApoA-I) to be administered to the subject is calculated based on the amount of the lipid-binding protein molecule (e.g., ApoA-I) to be administered and the weight of the subject. For example, a subject weighing 70 kg who will receive a dose of CER-001 of 20 mg / kg will receive a dose of CER-001 of 1400 mg ApoA-I (70 kg x 20 mg / kg).

[0255] For each individual dose, the same amount of lipid-binding protein may be administered. Alternatively, the amount of lipid-binding protein may vary between the doses. For example, one or more individual doses may be administered at a first dose amount, and subsequently, one or more individual doses may be administered at different second dose amounts. For example, the first dose amount may be 5 mg / kg (based on protein weight), and the second dose amount may be a higher amount, such as 10 mg / kg (based on protein weight). As another example, the first dose amount may be 10 mg / kg (based on protein weight), and the second dose amount may be a higher amount, such as 15 mg / kg (based on protein weight). As another example, the first dose amount may be 10 mg / kg (based on protein weight), and the second dose amount may be a higher amount, such as 20 mg / kg (based on protein weight). As another example, the first dose amount may be 15 mg / kg (based on protein weight), and the second dose amount may be a higher amount, such as 20 mg / kg (based on protein weight). As another example, the first dose may be 20 mg / kg (based on protein weight), and the second dose may be a lower amount, such as 10 mg / kg (based on protein weight). As another example, the first dose may be 20 mg / kg (based on protein weight), and the second dose may be a lower amount, such as 5 mg / kg (based on protein weight). As another example, the first dose may be 10 mg / kg (based on protein weight), and the second dose may be a lower amount, such as 5 mg / kg (based on protein weight). For example, different doses can be selected after measuring the subject's ApoA-I level. If the ApoA-I level measured after administering the first dose is below the target level or below the target range, a second, higher dose can be selected for subsequent administration. Conversely, if the ApoA-I level measured after administering the first dose is above the target level or above the target range, a second, lower dose can be selected for subsequent administration.

[0256] In some aspects, lipid-binding protein molecules (e.g., ApoA-I) can be administered on a unit dose basis. The unit dose used in the methods of this disclosure can vary between 300 mg and 4000 mg (e.g., 600 mg to 4000 mg) per administration (by protein weight) in some embodiments.

[0257] In certain embodiments, the dosage of the lipid-binding protein molecule (e.g., ApoA-I) is 300 mg to 400 mg, 300 mg to 500 mg, 300 mg to 600 mg, 300 mg to 800 mg, 300 mg to 1000 mg, 300 mg to 1200 mg, 300 mg to 1500 mg, 300 mg to 2000 mg, 300 mg to 2400 mg, 300 mg to 3000 mg, 400 mg to 500 mg, 400 mg to 600 mg, 400 mg to 800 mg, 400 mg to 1000 mg, 400 mg to 1200 mg, 400 mg to 1500 mg, 400 mg to 2000 mg, 400 mg to 2400 mg, 400 mg to 3000 mg, 400 mg to 4000 mg, 500 mg to 600 mg. mg, 500 mg to 800 mg, 500 mg to 1000 mg, 500 mg to 1200 mg, 500 mg to 1500 mg, 500 mg to 2000 mg, 500 mg to 2400 mg, 500 mg to 3000 mg, 500 mg to 4000 mg, 600 mg to 800 mg, 600 mg to 1000 mg, 600 mg to 1200 mg, 600 mg to 1500 mg, 600 mg to 2000 mg, 600 mg to 2400 mg, 600 mg to 3000 mg, 600 mg to 4000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 2400 mg, 800 mg to 3000 mg, 800 mg to 3000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 24 ... mg to 4000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1000 mg to 2000 mg, 1000 mg to 2400 mg, 1000 mg to 3000 mg, 1000 mg to 4000 mg, 1200 mg to 1500 mg, 1200 mg to 2000 mg, 1200 mg to 2400 mg, 1200 mg to 3000 mg, 1200 mg to 4000 mg, 1500 mg to 2000 mg, 1500 mg to 2400 mg, 1500 mg to 3000 mg, 1500 mg to 4000 mg, 2000 mg to 2400 mg, 2000 mg to 3000 mg, 2000 mg to 4000 mg, 2400 mg to 3000 mg, 2400 mg to 4000 mgmg or 3000 mg to 4000 mg (based on protein weight).

[0258] Lipid-binding protein molecules (e.g., ApoA-I) are preferably administered via intravenous infusion. For example, a stock solution of CER-001 can be diluted in physiological saline (e.g., physiological saline (0.9% NaCl)) to a total volume between 125 ml and 1 L, such as between 125 ml and 250 ml, 250 ml and 500 ml, or 500 ml and 1 L. In some embodiments, the total volume is 125 ml, 250 ml, 500 ml, or 1000 ml. The total volume can be readily selected based on the total dose of the lipid-binding protein molecule to be administered. In some embodiments, subjects weighing less than 80 kg will have a total volume of 125 ml, while subjects weighing at least 80 kg will have a total volume of 250 ml. In some embodiments, the dose of CER-001 is administered at a total volume of 250 ml. Lipid-binding protein molecules (e.g., ApoA-I) can be administered over a period ranging from one hour to 24 hours. Depending on the subject's needs, administration can be performed via slow infusion lasting longer than one hour (e.g., up to two hours or up to 24 hours), rapid infusion over a period of one hour or less (e.g., over a period of one and a half to one hour), or by a single bolus injection. In one embodiment, the lipid-binding protein molecule (e.g., ApoA-I) is administered over a one-hour period, for example, using an infusion pump at a fixed rate of 125 ml / hr or 250 ml / hr. In one embodiment, the dose of the lipid-binding protein molecule (e.g., ApoA-I) is administered as an infusion over a 24-hour period.

[0259] 6.4.1. Induction Scheme

[0260] Induction regimens suitable for use with the methods of this disclosure typically require the administration of multiple doses of a lipid-binding protein molecule (e.g., ApoA-I) over several consecutive days, such as three, four, five, six, or seven consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for three consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for four consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for five consecutive days.

[0261] In some embodiments, the induction regimen suitable for the methods of this disclosure requires the administration of multiple doses of a lipid-binding protein molecule (e.g., ApoA-I) over more than six consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for seven consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for eight consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for nine consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for ten consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for eleven consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for twelve consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for thirteen consecutive days. In some embodiments, the lipid-binding protein molecule (e.g., ApoA-I) is administered for fourteen consecutive days.

[0262] In some implementations, the subject's ApoA-I or HDL levels are measured after the induction regimen (e.g., 0.5 days to 1 week after the last dose of the induction regimen).

[0263] In some embodiments, an induction regimen suitable for use with the methods of this disclosure requires administration of a lipid-binding protein molecule (e.g., ApoA-I) twice daily, for example, for several consecutive days. Twice-daily administration may include, for example, two doses spaced approximately 12 hours apart, or a morning dose and an evening dose (the interval may be more or less than 12 hours).

[0264] In one embodiment, the induction regimen comprises two doses of a lipid-binding protein molecule (e.g., ApoA-I) daily for three consecutive days. In one embodiment, the induction regimen comprises two doses of a lipid-binding protein molecule (e.g., ApoA-I) daily for four consecutive days. In one embodiment, the induction regimen comprises two doses of a lipid-binding protein molecule (e.g., ApoA-I) daily for five consecutive days. In one embodiment, the induction regimen comprises two doses of a lipid-binding protein molecule (e.g., ApoA-I) daily for six consecutive days.

[0265] In some embodiments, the induction regimen includes administering two doses of a lipid-binding protein molecule (e.g., ApoA-I) daily for more than six consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for seven consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for eight consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for nine consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for ten consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for eleven consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for twelve consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for thirteen consecutive days. In some embodiments, two doses of a lipid-binding protein molecule (e.g., ApoA-I) are administered daily for fourteen consecutive days.

[0266] The therapeutic dose of a lipid-binding protein molecule (e.g., ApoA-I) administered by infusion in the induction regimen may be in the range of 4 to 40 mg / kg (e.g., 4 to 30 mg / kg) by protein weight (e.g., 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, or 40 mg / kg, or any range defined by any two of the foregoing values, e.g., 5 to 15 mg / kg, 10 to 20 mg / kg, or 15 to 25 mg / kg). In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the induction regimen is 5 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the induction regimen is 10 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the induction regimen is 15 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the induction regimen is 20 mg / kg. In some embodiments, the induction regimen includes administering six doses of a lipid-binding protein molecule (e.g., ApoA-I) at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg over three days. In some embodiments, the induction regimen includes administering eight doses of a lipid-binding protein molecule (e.g., ApoA-I) at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg over four days. In some embodiments, the induction regimen includes administering ten doses of a lipid-binding protein molecule (e.g., ApoA-I) at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg over five days. In some embodiments, the induction regimen includes administering twelve doses of a lipid-binding protein molecule (e.g., ApoA-I) at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg over six days.

[0267] In other respects, lipid-binding protein molecules (e.g., ApoA-I) can be administered on a unit dose basis. The unit dose used during the induction phase can vary between 300 mg and 4000 mg (e.g., 300 mg to 3000 mg) per infusion (based on protein weight).

[0268] In a particular embodiment, the dosage of the lipid-binding protein molecule (e.g., ApoA-I) used during the induction phase is 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg (by protein weight) administered by infusion per administration. In certain embodiments, the dosage of the lipid-binding protein molecule (e.g., ApoA-I) is 300 mg to 400 mg, 300 mg to 500 mg, 300 mg to 600 mg, 300 mg to 800 mg, 300 mg to 1000 mg, 300 mg to 1200 mg, 300 mg to 1500 mg, 300 mg to 2000 mg, 300 mg to 2400 mg, 300 mg to 3000 mg, 400 mg to 500 mg, 400 mg to 600 mg, 400 mg to 800 mg, 400 mg to 1000 mg, 400 mg to 1200 mg, 400 mg to 1500 mg, 400 mg to 2000 mg, 400 mg to 2400 mg, 400 mg to 3000 mg, 400 mg to 4000 mg, 500 mg to 600 mg. mg, 500 mg to 800 mg, 500 mg to 1000 mg, 500 mg to 1200 mg, 500 mg to 1500 mg, 500 mg to 2000 mg, 500 mg to 2400 mg, 500 mg to 3000 mg, 500 mg to 4000 mg, 600 mg to 800 mg, 600 mg to 1000 mg, 600 mg to 1200 mg, 600 mg to 1500 mg, 600 mg to 2000 mg, 600 mg to 2400 mg, 600 mg to 3000 mg, 600 mg to 4000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 2400 mg, 800 mg to 3000 mg, 800 mg to 3000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 24 ... mg to 4000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1000 mg to 2000 mg, 1000 mg to 2400 mg, 1000 mg to 3000 mg, 1000 mg to 4000 mg, 1200 mg to 1500 mg, 1200 mg to 2000 mg, 1200 mg to 2400 mg, 1200 mg to 3000 mg, 1200 mg to 4000 mg, 1500 mg to 2000 mg, 1500 mg to 2000 mg, 1500 mg to 4 ...mg to 2400 mg, 1500 mg to 3000 mg, 1500 mg to 4000 mg, 2000 mg to 2400 mg, 2000 mg to 3000 mg, 2000 mg to 4000 mg, 2400 mg to 3000 mg, 2400 mg to 4000 mg or 3000 mg to 4000 mg (based on protein weight).

[0269] 6.4.2. Consolidation Plan

[0270] Consolidation regimens suitable for use with the methods of this disclosure typically require the administration of one or more doses of a lipid-binding protein molecule (e.g., ApoA-I) after the induction regimen. ApoA-I level measurements can be performed prior to the consolidation regimen. For example, a consolidation regimen can be administered if the subject's ApoA-I level is below the target ApoA-I level or below the target ApoA-I range, or if the subject's HDL level is below the target HDL level. ApoA-I measurements prior to the consolidation regimen can also be used, for example, to guide parameters of the consolidation regimen. For example, if the ApoA-I or HDL measurement is relatively low, a relatively higher dose and / or administration frequency can be selected, while if the ApoA-I or HDL measurement is relatively high, a relatively lower dose and / or administration frequency can be selected.

[0271] In some implementations, the consolidation regimen includes administering two doses of a lipid-binding protein molecule (e.g., ApoA-I). For example, the two doses may be administered approximately 12 hours apart, or as a morning dose and an evening dose (which may be administered more or less than 12 hours apart).

[0272] In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 6 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 4 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 5 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 7 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 8 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 9 of a dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 10 of the dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 11 of the dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 12 of the dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 13 of the dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 14 of the dosing regimen that begins with the induction regimen on day 1. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen may be administered on day 15 of the dosing regimen that begins with the induction regimen on day 1.

[0273] In some embodiments, the consolidation regimen includes administering a lipid-binding protein molecule (e.g., ApoA-I) once daily following the induction regimen, which includes administering the lipid-binding protein molecule (e.g., ApoA-I) twice daily following the induction regimen. Each individual dose of the consolidation regimen may be the same as, higher than, or lower than each individual dose of the induction regimen.

[0274] In a consolidation regimen, the therapeutic dose of a lipid-binding protein molecule (e.g., ApoA-I) administered by infusion may be from 4 mg / kg to 40 mg / kg (e.g., 4 to 30 mg / kg) based on protein weight (e.g., 4, 5, 6, 7, 8, 9, 10, 12, 15, 20, 25, 30, or 40 mg / kg, or any range defined by any two of the foregoing values, e.g., 5 to 15 mg / kg, 10 to 20 mg / kg, or 15 to 25 mg / kg). In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the consolidation regimen is 5 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the consolidation regimen is 10 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) in the consolidation regimen is 15 mg / kg. In some embodiments, the dose of the lipid-binding protein molecule (e.g., ApoA-I) used in the consolidation regimen is 20 mg / kg. In some implementations, the consolidation regimen includes administering two doses of a lipid-binding protein molecule (e.g., ApoA-I) per day at doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg.

[0275] In other respects, lipid-binding protein molecules (e.g., ApoA-I) may be administered on a unit dose basis. The unit dose used in the consolidation phase may vary between 300 mg and 4000 mg (e.g., 300 mg to 3000 mg by protein weight) per administration via infusion.

[0276] In a particular embodiment, the dosage of the lipid-binding protein molecule (e.g., ApoA-I) used during the consolidation phase is 300 mg to 1500 mg, 400 mg to 1500 mg, 500 mg to 1200 mg, or 500 mg to 1000 mg (by protein weight) administered by infusion per administration. In certain embodiments, the dosage of the lipid-binding protein molecule (e.g., ApoA-I) is 300 mg to 400 mg, 300 mg to 500 mg, 300 mg to 600 mg, 300 mg to 800 mg, 300 mg to 1000 mg, 300 mg to 1200 mg, 300 mg to 1500 mg, 300 mg to 2000 mg, 300 mg to 2400 mg, 300 mg to 3000 mg, 400 mg to 500 mg, 400 mg to 600 mg, 400 mg to 800 mg, 400 mg to 1000 mg, 400 mg to 1200 mg, 400 mg to 1500 mg, 400 mg to 2000 mg, 400 mg to 2400 mg, 400 mg to 3000 mg, 400 mg to 4000 mg, 500 mg to 600 mg. mg, 500 mg to 800 mg, 500 mg to 1000 mg, 500 mg to 1200 mg, 500 mg to 1500 mg, 500 mg to 2000 mg, 500 mg to 2400 mg, 500 mg to 3000 mg, 500 mg to 4000 mg, 600 mg to 800 mg, 600 mg to 1000 mg, 600 mg to 1200 mg, 600 mg to 1500 mg, 600 mg to 2000 mg, 600 mg to 2400 mg, 600 mg to 3000 mg, 600 mg to 4000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 2400 mg, 800 mg to 3000 mg, 800 mg to 3000 mg, 800 mg to 1000 mg, 800 mg to 1200 mg, 800 mg to 1500 mg, 800 mg to 2000 mg, 800 mg to 24 ... mg to 4000 mg, 1000 mg to 1200 mg, 1000 mg to 1500 mg, 1000 mg to 2000 mg, 1000 mg to 2400 mg, 1000 mg to 3000 mg, 1000 mg to 4000 mg, 1200 mg to 1500 mg, 1200 mg to 2000 mg, 1200 mg to 2400 mg, 1200 mg to 3000 mg, 1200 mg to 4000 mg, 1500 mg to 2000 mg, 1500 mg to 2000 mg, 1500 mg to 4 ...mg to 2400 mg, 1500 mg to 3000 mg, 1500 mg to 4000 mg, 2000 mg to 2400 mg, 2000 mg to 3000 mg, 2000 mg to 4000 mg, 2400 mg to 3000 mg, 2400 mg to 4000 mg or 3000 mg to 4000 mg (based on protein weight).

[0277] Lipid-binding protein molecules (such as ApoA-I) can be administered during the consolidation phase in the same manner as described in Section 6.4, for example, via IV infusion over a one-hour period.

[0278] 6.5. Combination Therapy

[0279] Lipid-binding protein molecules (e.g., ApoA-I) may be administered to subjects as part of a monotherapy or combination therapy regimen, as described herein. For example, a combination therapy may comprise a lipid-binding protein molecule (e.g., ApoA-I) combined with standard care for a condition in a subject who has, for example, sepsis (e.g., septic shock) and / or AKI, or is at risk of having, for example, sepsis (e.g., septic shock) and / or AKI. See, for example, Rhodes et al., 2017, Intensive Care Med 43:304–377; Dugar et al., 2020, Cleveland Clinic Journal of Medicine 87(1):53-64.

[0280] In some implementations, for example, for subjects with sepsis (e.g., septic shock), the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and fluid replacement therapy. In some implementations, for example, for subjects with sepsis, the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and an antimicrobial agent. In some implementations, for example, for subjects with sepsis, the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and an antibiotic (e.g., ceftriaxone, meropenem, ceftazidime, cefotaxime, cefepime, piperacillin and tazobactam, ampicillin and sulbactam, imipenem and cilastatin, levofloxacin, or clindamycin).

[0281] In some implementations, mechanical ventilation is performed on the subject when the lipid-binding protein molecule is first administered.

[0282] In some implementations, subjects are not mechanically ventilated when the lipid-binding protein molecule is first administered.

[0283] In some implementations, subjects are receiving vasopressor therapy when the lipid-binding protein molecule is first administered.

[0284] In some implementations, subjects were not receiving vasopressor treatment when the lipid-binding protein molecule was first administered.

[0285] In some implementations, when the lipid-binding protein molecule is first administered, the subject's blood lactate level is 0.4 mmol / L to 12 mmol / L (e.g., 0.4 mmol / L to 5 mmol / L, 1 mmol / L to 5 mmol / L, or 1 mmol / L to 4 mmol / L).

[0286] In some implementations, when the lipid-binding protein molecule is first administered, the subject’s P / F ratio (the ratio of PaO2 (partial pressure of arterial oxygen obtained from arterial blood gases) to FiO2 (fraction of inhaled oxygen)) is 90 to 550 (e.g., 90 to 250, 150 to 400, or 300 to 510).

[0287] In some implementations, when the lipid-binding protein molecule is first administered, the subject's serum creatinine level is 0.5 mg / dL to 6 mg / dL (e.g., 0.5 mg / dL to 3 mg / dL or 3 mg / dL to 6 mg / dL).

[0288] In some implementations, subjects were in the intensive care unit (ICU) when the lipid-binding protein molecule was first administered. Administration of the lipid-binding protein molecule reduced the number of days subjects spent in the ICU compared to standard care.

[0289] In some implementations, the subject is not in the intensive care unit (ICU) when the lipid-binding protein molecule is first administered.

[0290] In some implementations, the subjects had sepsis, and the method increased survival by 30 days compared to standard care.

[0291] In some implementations, for example, for subjects with a viral infection, the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and an antiviral agent. In some implementations, the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and a blood pressure-raising drug (e.g., norepinephrine or epinephrine). In some implementations, the subject is treated with a combination of a lipid-binding protein molecule (e.g., ApoA-I) and an immunosuppressant such as tacrolimus or everolimus.

[0292] Combination therapy regimens may, in some embodiments, include one or more anti-IL-6 agents and / or one or more other agents used to treat CRS, such as corticosteroids (e.g., methylprednisolone and / or dexamethasone). Exemplary anti-IL-6 agents include tocilizumab, sutuximab, olokizumab, Islimo, BMS-945429, sirukumab, levilimab, and CPSI-2364. In some embodiments, a lipid-binding protein molecule (e.g., ApoA-I) is used in combination with tocilizumab.

[0293] In some implementations, an antihistamine (e.g., diphenhydramine, cetirizine, fexofenadine, or loratadine) may be administered prior to the administration of a lipid-binding protein molecule (e.g., ApoA-I). Antihistamines can reduce the likelihood of allergic reactions.

[0294] 7. Specific Implementation Plan

[0295] This disclosure is illustrated by the numbered implementation scheme described below.

[0296] Throughout the following implementation and the entire specification, unless otherwise stated, the conjunction "or" is intended to be used in its proper sense as a Boolean logic operator, encompassing both the selection of features in the alternatives (A or B, where the selection of A is mutually exclusive with B) and the selection of combined features (A or B, where both A and B are selected). In some places in the text, the term "and / or" is used for the same purpose and should not be construed as implying that "or" refers to the use of mutually exclusive alternatives.

[0297] 1. A method for treating a subject suffering from or at risk of a condition treatable with lipid-binding protein molecules, wherein the condition is optionally sepsis (e.g., septic shock), the method comprising:

[0298] (a) Optionally, administer one or more doses of the lipid-binding protein molecule to the subject;

[0299] (b) Measure the subject's ApoA-I or HDL levels; and

[0300] (c) If the measured ApoA-I level is below the target ApoA-I level or the target ApoA-I range, or if the measured HDL level is below the target HDL level, administer one or more doses of the lipid-binding protein molecule to the subject.

[0301] 2. The method of Implementation Scheme 1, comprising administering one or more doses of the lipid-binding protein molecule to the subject prior to step (b).

[0302] 3. The method of implementation scheme 2, wherein step (b) includes measuring ApoA-I or HDL levels 0.5 days to one week after the most recent administration of the lipid-binding protein molecule.

[0303] 4. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I level or HDL level the day after the most recent administration of the lipid-binding protein molecule.

[0304] 5. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I or HDL levels 0.5 to 1 day after the most recent administration of the lipid-binding protein molecule.

[0305] 6. The method of any one of Implementation Scheme 2 or Implementation Scheme 3, wherein step (b) includes measuring ApoA-I level or HDL level 0.5 days after the most recent administration of the lipid-binding protein molecule.

[0306] 7. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I level or HDL level 1 day after the most recent administration of the lipid-binding protein molecule.

[0307] 8. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I level or HDL level one day after the most recent administration of the lipid-binding protein molecule.

[0308] 9. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I levels or HDL levels two days after the most recent administration of the lipid-binding protein molecule.

[0309] 10. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I levels or HDL levels three days after the most recent administration of the lipid-binding protein molecule.

[0310] 11. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I levels or HDL levels four days after the most recent administration of the lipid-binding protein molecule.

[0311] 12. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I or HDL levels five days after the most recent administration of the lipid-binding protein molecule.

[0312] 13. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I levels or HDL levels six days after the most recent administration of the lipid-binding protein molecule.

[0313] 14. The method of embodiment 2 or embodiment 3, wherein step (b) includes measuring ApoA-I levels or HDL levels seven days after the most recent administration of the lipid-binding protein molecule.

[0314] 15. The method of any one of embodiments 2 to 14, wherein step (a) comprises administering the lipid-binding protein molecule according to an induction protocol.

[0315] 16. The method of embodiment 15, wherein the induction regimen comprises administering one or more doses of the lipid-binding protein molecule over three days.

[0316] 17. The method of embodiment 15, wherein the induction regimen comprises administering one or more doses of the lipid-binding protein molecule over four days.

[0317] 18. The method of embodiment 15, wherein the induction regimen comprises administering one or more doses of the lipid-binding protein molecule over five days.

[0318] 19. The method of embodiment 15, wherein the induction regimen comprises administering one or more doses of the lipid-binding protein molecule over six days.

[0319] 20. The method of embodiment 15, wherein the induction regimen comprises administering one or more doses of the lipid-binding protein molecule over seven days.

[0320] 21. The method of any one of embodiments 15 to 20, wherein the induction regimen comprises administering the lipid-binding protein molecule once daily.

[0321] 22. The method of any one of embodiments 15 to 20, wherein the induction regimen comprises administering the lipid-binding protein molecule twice daily.

[0322] 23. The method described in Implementation Scheme 1, wherein the lipid-binding protein molecule is administered to the subject at least once daily on days 1, 2 and 3 of the treatment regimen, and ApoA-I levels or HDL levels are measured on day 4.

[0323] 24. The method of implementation scheme 23, wherein the lipid-binding protein molecule is administered to the subject twice daily on days 1, 2 and 3.

[0324] 25. The method described in Implementation Scheme 1, wherein the lipid-binding protein molecule is administered to the subject at least once daily on days 1, 2, 3 and 4 of the treatment regimen, and ApoA-I or HDL levels are measured on day 5.

[0325] 26. The method of implementation scheme 25, wherein the lipid-binding protein molecule is administered to the subject twice daily on days 1, 2, 3 and 4.

[0326] 27. The method described in Implementation Scheme 1, wherein the lipid-binding protein molecule is administered to the subject at least once daily on days 1, 2, 3, 4 and 5 of the treatment regimen, and ApoA-I levels or HDL levels are measured on day 6.

[0327] 28. The method of implementation scheme 27, wherein the lipid-binding protein molecule is administered to the subject twice daily on days 1, 2, 3, 4 and 5.

[0328] 29. The method described in Implementation Scheme 1, wherein the lipid-binding protein molecule is administered to the subject at least once daily on days 1, 2, 3, 4, 5 and 6 of the treatment regimen, and apoA-I levels or HDL levels are measured on day 7.

[0329] 30. The method of implementation scheme 29, wherein the lipid-binding protein molecule is administered to the subject twice daily on days 1, 2, 3, 4, 5 and 6.

[0330] 31. The method of implementation scheme 1, wherein the lipid-binding protein molecule is administered to the subject at least once daily on days 1, 2, 3, 4, 5, 6 and 7 of the treatment regimen, and ApoA-I level or HDL level is measured on day 8.

[0331] 32. The method of implementation scheme 31, wherein the lipid-binding protein molecule is administered to the subject twice daily on days 1, 2, 3, 4, 5, 6 and 7.

[0332] 33. The method according to any one of embodiments 1 to 32, comprising administering multiple doses of the lipid-binding protein molecule to the subject prior to step (b).

[0333] 34. The method of embodiment 33, wherein step (c) comprises administering multiple doses of lipid-binding protein molecules at a higher frequency than the multiple doses of lipid-binding protein molecules administered in step (a).

[0334] 35. The method of embodiment 33, wherein step (c) comprises administering multiple doses of lipid-binding protein molecules at a lower frequency than the multiple doses of lipid-binding protein molecules administered in step (a).

[0335] 36. The method according to any one of embodiments 1 to 35, comprising step (a), wherein the dose of the lipid-binding protein molecule applied in step (c) is the same as the dose applied in step (a).

[0336] 37. The method according to any one of embodiments 1 to 35, comprising step (a), wherein the dose of the lipid-binding protein molecule applied in step (c) is greater than the dose applied in step (a).

[0337] 38. The method according to any one of embodiments 1 to 37, further comprising repeating steps (b) and (c) once or more.

[0338] 39. The method described in implementation scheme 38, wherein the ApoA-I level or HDL level is measured daily.

[0339] 40. The method of implementation scheme 38, wherein the ApoA-I level or HDL level is measured twice daily.

[0340] 41. The method of implementation scheme 38, wherein the ApoA-I level or HDL level is measured every other day.

[0341] 42. The method of implementation scheme 38, wherein the ApoA-I level or HDL level is measured every three days.

[0342] 43. The method of embodiment 38, wherein if the most recently measured ApoA-I level or HDL level is higher than the previously measured ApoA-I level or HDL level, the time period between ApoA-I or HDL measurements is increased.

[0343] 44. The method of embodiment 38, wherein if the most recently measured ApoA-I level or HDL level is lower than the previously measured ApoA-I level or HDL level, the time period between ApoA-I or HDL measurements is reduced.

[0344] 45. The method of any one of embodiments 38 to 44, wherein steps (b) and (c) are repeated until the measured ApoA-I level is at or above the target ApoA-I level or within the target ApoA-I range or until the measured HDL level is at or above the target HDL level.

[0345] 46. ​​The method of any one of embodiments 38 to 45, wherein when step (b) includes measuring the ApoA-I level, steps (b) and (c) are repeated until the measured ApoA-I level is at or above the target ApoA-I level.

[0346] 47. The method of any one of embodiments 38 to 45, wherein when step (b) includes measuring the ApoA-I level, steps (b) and (c) are repeated until the measured ApoA-I level is within the target ApoA-I range.

[0347] 48. The method of any one of embodiments 38 to 45, wherein when step (b) includes measuring HDL levels, steps (b) and (c) are repeated until the measured HDL level is at or above the target HDL level.

[0348] 49. The method according to any one of embodiments 1 to 48, comprising step (a), and further comprising:

[0349] (d) If the measured ApoA-I level or HDL level is at or above the target ApoA-I level, within the target ApoA-I range, or at or above the target HDL level, administer one or more doses of the lipid-binding protein molecule to the subject at a lower dose and / or frequency than in step (a).

[0350] 50. The method of embodiment 49, further comprising repeating step (i) and (ii) step (c) or step (d).

[0351] 51. The method of embodiment 49 or embodiment 50, wherein step (d) comprises administering one or more doses of the lipid-binding protein molecule to the subject at a lower dose than in step (a).

[0352] 52. The method of embodiment 49 or embodiment 50, wherein step (d) includes administering one or more doses of the lipid-binding protein molecule to the subject at a lower frequency than in step (a).

[0353] 53. The method of embodiment 49 or embodiment 50, wherein step (d) includes administering one or more doses of the lipid-binding protein molecule to the subject at a lower dose and at a lower frequency than in step (a).

[0354] 54. The method according to any one of embodiments 1 to 53, wherein the ApoA-I level is a serum ApoA-I level.

[0355] 55. The method according to any one of embodiments 1 to 53, wherein the ApoA-I level is the plasma ApoA-I level.

[0356] 56. The method according to any one of embodiments 1 to 53, wherein the ApoA-I level is the whole blood ApoA-I level.

[0357] 57. The method according to any one of embodiments 1 to 56, wherein the target ApoA-I level is the normal ApoA-I level in a healthy subject.

[0358] 58. The method according to any one of embodiments 1 to 56, wherein the target ApoA-I level is an ApoA-I level of 1.0 g / L.

[0359] 59. The method according to any one of embodiments 1 to 56, wherein the target ApoA-I level is an ApoA-I level of 1.1 g / L.

[0360] 60. The method of any one of embodiments 1 to 59, wherein the target ApoA-I range is the normal ApoA-I range in healthy subjects.

[0361] 61. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.1 g / L.

[0362] 62. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.2 g / L.

[0363] 63. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.3 g / L.

[0364] 64. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.4 g / L.

[0365] 65. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.5 g / L.

[0366] 66. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.6 g / L.

[0367] 67. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.7 g / L.

[0368] 68. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.8 g / L.

[0369] 69. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 1.9 g / L.

[0370] 70. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 2.0 g / L.

[0371] 71. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.0 g / L to 2.1 g / L.

[0372] 72. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.2 g / L.

[0373] 73. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.3 g / L.

[0374] 74. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.4 g / L.

[0375] 75. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.5 g / L.

[0376] 76. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.6 g / L.

[0377] 77. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.7 g / L.

[0378] 78. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.8 g / L.

[0379] 79. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 1.9 g / L.

[0380] 80. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 2.0 g / L.

[0381] 81. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.1 g / L to 2.1 g / L.

[0382] 82. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.3 g / L.

[0383] 83. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.4 g / L.

[0384] 84. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.5 g / L.

[0385] 85. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.6 g / L.

[0386] 86. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.7 g / L.

[0387] 87. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.8 g / L.

[0388] 88. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 1.9 g / L.

[0389] 89. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 2.0 g / L.

[0390] 90. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.2 g / L to 2.1 g / L.

[0391] 91. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.4 g / L.

[0392] 92. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.5 g / L.

[0393] 93. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.6 g / L.

[0394] 94. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.7 g / L.

[0395] 95. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.8 g / L.

[0396] 96. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 1.9 g / L.

[0397] 97. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 2.0 g / L.

[0398] 98. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.3 g / L to 2.1 g / L.

[0399] 99. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 1.5 g / L.

[0400] 100. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 1.6 g / L.

[0401] 101. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 1.7 g / L.

[0402] 102. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 1.8 g / L.

[0403] 103. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 1.9 g / L.

[0404] 104. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 2.0 g / L.

[0405] 105. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.4 g / L to 2.1 g / L.

[0406] 106. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 1.6 g / L.

[0407] 107. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 1.7 g / L.

[0408] 108. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 1.8 g / L.

[0409] 109. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 1.9 g / L.

[0410] 110. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 2.0 g / L.

[0411] 111. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.5 g / L to 2.1 g / L.

[0412] 112. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.6 g / L to 1.7 g / L.

[0413] 113. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.6 g / L to 1.8 g / L.

[0414] 114. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.6 g / L to 1.9 g / L.

[0415] 115. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.6 g / L to 2.0 g / L.

[0416] 116. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.6 g / L to 2.1 g / L.

[0417] 117. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.7 g / L to 1.8 g / L.

[0418] 118. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.7 g / L to 1.9 g / L.

[0419] 119. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.7 g / L to 2.0 g / L.

[0420] 120. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.7 g / L to 2.1 g / L.

[0421] 121. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.8 g / L to 1.9 g / L.

[0422] 122. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.8 g / L to 2.0 g / L.

[0423] 123. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.8 g / L to 2.1 g / L.

[0424] 124. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.9 g / L to 2.0 g / L.

[0425] 125. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 1.9 g / L to 2.1 g / L.

[0426] 126. The method according to any one of embodiments 1 to 60, wherein the target ApoA-I ranges from 2.0 g / L to 2.1 g / L.

[0427] 127. The method according to any one of embodiments 1 to 126, wherein the HDL level is a serum HDL level.

[0428] 128. The method according to any one of embodiments 1 to 126, wherein the HDL level is a plasma HDL level.

[0429] 129. The method according to any one of embodiments 1 to 126, wherein the HDL level is the whole blood HDL level.

[0430] 130. The method according to any one of embodiments 1 to 129, wherein the HDL level is the HDL-cholesterol (HDL-C) level.

[0431] 131. The method of any one of embodiments 1 to 129, wherein the target HDL level is the normal HDL level in a healthy subject.

[0432] 132. The method according to any one of embodiments 1 to 129, wherein the target HDL level is an HDL-C level of 50 mg / dL.

[0433] 133. The method according to any one of embodiments 1 to 129, wherein the target HDL level is an HDL-C level of 45 mg / dL.

[0434] 134. The method of any one of embodiments 1 to 129, wherein the target HDL level is an HDL-C level of 40 mg / dL.

[0435] 135. The method according to any one of embodiments 1 to 129, wherein the target HDL level is an HDL-C level of 35 mg / dL.

[0436] 136. The method of any one of embodiments 1 to 129, wherein for female subjects, the target HDL level is an HDL-C level of 50 mg / dL.

[0437] 137. The method of any one of embodiments 1 to 129, wherein for female subjects, the target HDL level is an HDL-C level of 45 mg / dL.

[0438] 138. The method of any one of embodiments 1 to 129, wherein for female subjects, the target HDL level is an HDL-C level of 40 mg / dL.

[0439] 139. The method according to any one of embodiments 1 to 129, wherein for female subjects, the target HDL level is an HDL-C level of 35 mg / dL.

[0440] 140. The method of any one of embodiments 1 to 129, wherein for male subjects, the target HDL level is an HDL-C level of 50 mg / dL.

[0441] 141. The method of any one of embodiments 1 to 129, wherein for male subjects, the target HDL level is an HDL-C level of 45 mg / dL.

[0442] 142. The method of any one of embodiments 1 to 129, wherein for male subjects, the target HDL level is an HDL-C level of 40 mg / dL.

[0443] 143. The method of any one of embodiments 1 to 129, wherein for male subjects, the target HDL level is an HDL-C level of 35 mg / dL.

[0444] 144. The method of any one of embodiments 1 to 143, wherein the ApoA-I level is the ApoA-I level as measured by enzyme-linked immunosorbent assay (ELISA).

[0445] 145. The method of any one of embodiments 1 to 143, wherein the ApoA-I level is the ApoA-I level as measured by immunoturbidimetry.

[0446] 146. The method of any one of embodiments 1 to 143, wherein the ApoA-I level is the ApoA-I level as measured by immunoturbidimetry.

[0447] 147. The method of any one of embodiments 1 to 146, wherein the HDL level is the HDL-C level as measured by enzymatic assay of cholesterol oxidase (CHOD) and cholesterol esterase (CHER).

[0448] 148. The method according to any one of embodiments 1 to 147, wherein the amount of the lipid-binding protein molecule administered to the subject in step (c) effectively increases the subject's ApoA-I level to or above the target ApoA-I level.

[0449] 149. The method according to any one of embodiments 1 to 148, wherein the amount of the lipid-binding protein molecule administered to the subject in step (c) effectively increases the subject's ApoA-I level to a level within the target ApoA-I range.

[0450] 150. The method according to any one of embodiments 1 to 149, wherein the amount of the lipid-binding protein molecule administered to the subject in step (c) effectively increases the subject's HDL level to a level at or above the target HDL level.

[0451] 151. The method of any one of embodiments 1 to 150, wherein step (b) includes measuring the ApoA-I level.

[0452] 152. The method of implementation scheme 151, wherein step (c) includes administering one or more doses of a lipid-binding protein molecule to the subject if the measured ApoA-I level is below the target ApoA-I level.

[0453] 153. The method of implementation scheme 151, wherein step (c) includes administering one or more doses of a lipid-binding protein molecule to the subject if the measured ApoA-I level is below the target ApoA-I range.

[0454] 154. The method of any one of embodiments 1 to 153, wherein step (b) includes measuring HDL levels.

[0455] 155. The method of embodiment 154, wherein step (c) includes administering one or more doses of the lipid-binding protein molecule to the subject if the measured HDL level is below a target HDL level.

[0456] 156. The method of implementation scheme 154, further comprising measuring the ApoA-I level if the measured HDL level is at or above the target HDL level.

[0457] 157. The method of embodiment 156, further comprising administering one or more doses of the lipid-binding protein molecule to the subject if the measured ApoA-I level is below a target ApoA-I level or a target ApoA-I range.

[0458] 158. The method of any one of embodiments 1 to 157, wherein the condition is related to inflammation.

[0459] 159. The method according to any one of embodiments 1 to 158, wherein the condition is an acute condition.

[0460] 160. The method of any one of embodiments 1 to 159, wherein the disease is sepsis.

[0461] 161. The method of any one of embodiments 1 to 159, wherein the condition is a cognitive deficit induced by sepsis.

[0462] 162. The method of embodiment 160 or embodiment 161, wherein the subject is at risk of sepsis (e.g., at risk of sepsis due to surgery).

[0463] 163. The method of embodiment 160 or embodiment 161, wherein the subject suffers from sepsis.

[0464] 164. The method of implementation scheme 163, wherein the subject suffers from septic shock.

[0465] 165. The method of implementation scheme 164, wherein the subject suffers from septic shock following trauma (e.g., abdominal injury).

[0466] 166. The method of implementation scheme 164, wherein the subject suffers from non-traumatic septic shock.

[0467] 167. The method of any one of embodiments 163 to 166, wherein the subject is at risk (e.g., high risk) of developing acute kidney injury.

[0468] 168. The method of any one of embodiments 1 to 167, wherein the subject suffers from a bacterial infection, optionally an antibiotic-resistant bacterial infection (e.g., MRSA).

[0469] 169. The method of any one of embodiments 1 to 168, wherein the subject has a Staphylococcus aureus infection.

[0470] 170. The method of any one of embodiments 1 to 168, wherein the subject has an Escherichia coli infection.

[0471] 171. The method of any one of embodiments 1 to 168, wherein the subject has a Streptococcus pneumoniae infection.

[0472] 172. The method of any one of embodiments 1 to 168, wherein the subject has Klebsiella pneumoniae infection.

[0473] 173. The method of any one of embodiments 1 to 168, wherein the subject has a Pseudomonas aeruginosa infection.

[0474] 174. The method of any one of embodiments 1 to 168, wherein the subject has Acinetobacter baumannii infection.

[0475] 175. The method of any one of embodiments 1 to 168, wherein the subject suffers from Bacteroides fragilis infection.

[0476] 176. The method of any one of embodiments 1 to 168, wherein the subject has a Proteus mirabilis infection.

[0477] 177. The method of any one of embodiments 1 to 168, wherein the subject has a Gram-positive bacterial infection.

[0478] 178. The method of any one of embodiments 1 to 168, wherein the subject has a Gram-negative bacterial infection.

[0479] 179. The method of any one of embodiments 1 to 178, wherein the subject suffers from a urinary tract infection.

[0480] 180. The method of any one of embodiments 1 to 178, wherein the subject suffers from an intraperitoneal infection.

[0481] 181. The method of any one of embodiments 1 to 178, wherein the subject suffers from a blood infection.

[0482] 182. The method of any one of embodiments 1 to 178, wherein the subject suffers from a postoperative infection.

[0483] 183. The method of any one of embodiments 1 to 178, wherein the subject suffers from gastrointestinal perforation.

[0484] 184. The method of any one of embodiments 1 to 178, wherein the subject suffers from duodenal ulcer perforation.

[0485] 185. The method of any one of embodiments 1 to 178, wherein the subject suffers from intestinal perforation.

[0486] 186. The method of any one of embodiments 1 to 178, wherein the subject suffers from pneumonia, such as hospital-acquired pneumonia.

[0487] 187. The method of any one of embodiments 1 to 178, wherein the subject suffers from pancreatitis, such as necrotizing pancreatitis.

[0488] 188. The method of any one of embodiments 1 to 167, wherein the subject has a viral infection.

[0489] 189. The method of implementation scheme 188, wherein the viral infection is SARS-CoV-2 (COVID-19) infection.

[0490] 190. The method of implementation scheme 188, wherein the viral infection is an influenza virus infection.

[0491] 191. The method according to any one of embodiments 1 to 159, wherein the condition is acute myocardial infarction (AMI).

[0492] 192. The method of any one of embodiments 1 to 159, wherein the condition is cytokine release syndrome (CRS).

[0493] 193. The method of any one of embodiments 1 to 159, wherein the condition is ischemia-reperfusion induced tissue damage.

[0494] 194. The method of any one of embodiments 1 to 159, wherein the condition is postoperative inflammation.

[0495] 195. The method of any one of embodiments 1 to 159, wherein the condition is sepsis-induced acute kidney injury (AKI).

[0496] 196. The method of any one of embodiments 1 to 159, wherein the condition is hypoalbuminemia.

[0497] 197. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with vitamin deficiency.

[0498] 198. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with inflammatory bowel disease (IBD).

[0499] 199. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with kidney disease.

[0500] 200. The method of embodiment 196, wherein the condition is infection-related hypoalbuminemia, optionally wherein the infection is a Gram-positive bacterial infection, a Gram-negative bacterial infection, or a viral infection, such as SARS-CoV-2 (COVID-19) infection or influenza virus infection.

[0501] 201. The method of implementation scheme 196, wherein the condition is stress-related hypoalbuminemia.

[0502] 202. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with thyroid disease.

[0503] 203. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with diabetes.

[0504] 204. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with nephrotic syndrome.

[0505] 205. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with lupus.

[0506] 206. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with cirrhosis.

[0507] 207. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with liver disease.

[0508] 208. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with heart failure.

[0509] 209. The method of implementation scheme 196, wherein the condition is hypoalbuminemia associated with malnutrition.

[0510] 210. The method of any one of embodiments 1 to 159, wherein the condition is asthma, such as acute severe asthma.

[0511] 211. The method of any one of embodiments 1 to 159, wherein the condition is graft-versus-host disease (GVHD), optionally wherein the subject has received stem cell transplantation, bone marrow transplantation or organ transplantation.

[0512] 212. The method of any one of embodiments 1 to 211, wherein the subject has CRS or is at risk of CRS.

[0513] 213. The method of implementation scheme 212, wherein the subject suffers from CRS.

[0514] 214. The method of implementation scheme 212, wherein the subject is at risk of CRS.

[0515] 215. The method of any one of embodiments 1 to 214, wherein the subject has acute kidney injury (AKI) or is at risk of developing acute kidney injury (AKI).

[0516] 216. The method of implementation scheme 215, wherein the subject suffers from AKI.

[0517] 217. The method of implementation scheme 215, wherein the subject is at risk of AKI.

[0518] 218. The method of any one of embodiments 1 to 217, wherein the subject suffers from acute respiratory distress syndrome (ARDS).

[0519] 219. The method of any one of embodiments 1 to 217, wherein the subject is at risk of ARDS.

[0520] 220. The method of any one of embodiments 1 to 219, wherein the subject has recently undergone surgery or is a candidate for surgery.

[0521] 221. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 1 to 24 prior to the first administration of the lipid-binding protein molecule.

[0522] 222. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 5 to 24 prior to the first administration of the lipid-binding protein molecule.

[0523] 223. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 10 to 24 prior to the first administration of the lipid-binding protein molecule.

[0524] 224. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 15 to 24 prior to the first administration of the lipid-binding protein molecule.

[0525] 225. The method of any one of embodiments 1 to 220, wherein the subject has an SOFA score of 1 to 20 prior to the first administration of the lipid-binding protein molecule.

[0526] 226. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 5 to 20 prior to the first administration of the lipid-binding protein molecule.

[0527] 227. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 10 to 20 prior to the first administration of the lipid-binding protein molecule.

[0528] 228. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 10 to 15 prior to the first administration of the lipid-binding protein molecule.

[0529] 229. The method of any one of embodiments 1 to 220, wherein the subject has an SOFA score of 1 to 10 prior to the first administration of the lipid-binding protein molecule.

[0530] 230. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 2 to 10 prior to the first administration of the lipid-binding protein molecule.

[0531] 231. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 2 to 5 prior to the first administration of the lipid-binding protein molecule.

[0532] 232. The method of any one of embodiments 1 to 220, wherein the subject has a SOFA score of 5 to 10 prior to the first administration of the lipid-binding protein molecule.

[0533] 233. The method of any one of embodiments 1 to 232, wherein the subject is hospitalized and the subject's SOFA score increases by at least 2 points during the hospitalization and before the first administration of the lipid-binding protein molecule.

[0534] 234. The method according to any one of embodiments 1 to 233, wherein the subject has two or more of the following prior to the first administration of the lipid-binding protein molecule:

[0535] (d) Body temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F);

[0536] (e) A respiratory rate of more than 20 breaths per minute;

[0537] (f) Heart rate greater than 90 beats per minute;

[0538] (g) White blood cell count greater than 12,000 cells / µl or less than 4,000 cells / µl; or

[0539] (h)pCO2 value is less than 32 mm Hg (4.27 kPa).

[0540] 235. The method of any one of embodiments 1 to 234, wherein the subject has a mean arterial pressure of less than 65 mm Hg and / or a serum lactate level of more than 2 mmol / L (18 mg / dL) prior to the first administration of the lipid-binding protein molecule.

[0541] 236. The method of any one of embodiments 1 to 235, wherein the subject has an endotoxin activity assay level greater than 0.6 prior to the first administration of the lipid-binding protein molecule.

[0542] 237. The method of any one of embodiments 1 to 236, wherein the subject is receiving treatment in a hospital.

[0543] 238. The method of implementation scheme 237, wherein the subject is being treated in an intensive care unit (ICU).

[0544] 239. The method according to any one of embodiments 1 to 238, wherein the lipid-binding protein molecule is an apolipoprotein.

[0545] 240. The method of embodiment 239, wherein the apolipoprotein is ApoA-I.

[0546] 241. The method of embodiment 240, wherein the ApoA-I has the amino acid sequence of amino acids 25-267 of SEQ ID NO:2.

[0547] 242. The method of embodiment 240 or embodiment 241, wherein the ApoA-I is recombinant ApoA-I.

[0548] 243. The method of embodiment 242, wherein the ApoA-I is produced by mammalian host cells.

[0549] 244. The method of implementation scheme 243, wherein the mammalian host cell is a Chinese hamster ovary (CHO) cell.

[0550] 245. The method of embodiment 244, wherein the CHO cells are CHO-S cells.

[0551] 246. The method of any one of embodiments 242 to 245, wherein the ApoA-I has undergone post-translational processing (e.g., glycosylation) such that the ApoA-I has one or more structural features (e.g., glycosylation patterns) different from those of human ApoA-I purified from human plasma.

[0552] 247. The method of any one of embodiments 1 to 238, wherein the lipid-binding protein molecule is an apolipoprotein mimic.

[0553] 248. The method of any one of embodiments 1 to 247, wherein the lipid-binding protein molecule is a component of a lipid-binding protein-based complex, optionally wherein the lipid-binding protein-based complex is a reconstructed HDL or an HDL mimic.

[0554] 249. The method of any one of embodiments 1 to 248, wherein the lipid-binding protein molecule is a component of a lipid-binding protein-based complex, and the lipid-binding protein-based complex is an Apomer or a Cargomer.

[0555] 250. The method of any one of embodiments 1 to 249, wherein the lipid-binding protein molecule is a component of a lipid-binding protein-based complex, and the lipid-binding protein-based complex comprises sphingomyelin.

[0556] 251. The method of embodiment 250, wherein the lipid-binding protein-based complex comprises ApoA-I and phospholipids in a weight-to-total-phospholipid ratio of 1:2.7 + / - 20%, and the phospholipids are sphingomyelin and DPPG in a weight-to-total-phospholipid ratio of 97:3 + / - 20%.

[0557] 252. The method of embodiment 251, wherein the lipid-binding protein-based complex comprises ApoA-I and phospholipids in a weight-to-total-phospholipid ratio of 1:2.7+ / -10%, and the phospholipids are sphingomyelin and DPPG in a weight-to-total-phospholipid ratio of 97:3+ / -10%.

[0558] 253. The method of embodiment 252, wherein the lipid-binding protein-based complex comprises ApoA-I and phospholipids in an ApoA-I weight:to total phospholipid weight ratio of 1:2.7, and the phospholipids are sphingomyelin:DPPG weight:to total phospholipids in a sphingomyelin and DPPG weight ratio of 97:3.

[0559] 254. The method of any one of embodiments 250 to 253, wherein the lipid-binding protein-based complex comprises natural sphingomyelin.

[0560] 255. The method of embodiment 254, wherein the natural sphingomyelin is egg sphingomyelin.

[0561] 256. The method of embodiment 254, wherein the natural sphingomyelin is a lactose sphingomyelin.

[0562] 257. The method of any one of embodiments 250 to 253, wherein the lipid-binding protein-based complex comprises synthetic sphingomyelin.

[0563] 258. The method of embodiment 257, wherein the sphingomyelin comprises palmitoylsphingomyelin.

[0564] 259. The method of any one of embodiments 1 to 258, wherein the lipid-binding protein molecule is a component of a lipid-binding protein-based complex, and the lipid-binding protein-based complex comprises negatively charged lipids.

[0565] 260. The method of embodiment 259, wherein the negatively charged lipid is 1,2-dipalmitoyl-sn-glycerol-3-[phosphate-racemic-(1-glycerol)(DPPG)] or a salt thereof.

[0566] 261. The method of embodiment 248, wherein the lipid-binding protein-based complex is CER-001, CSL-111, CSL-112, CER-522, ETC-216, or ETC-642.

[0567] 262. The method of embodiment 261, wherein the lipid-binding protein-based complex is CER-001.

[0568] 263. The method of embodiment 262, wherein CER-001 is administered in the form of a formulation, wherein CER-001 is at least 95% homogeneous.

[0569] 264. The method of embodiment 263, wherein CER-001 is administered in the form of a formulation, wherein CER-001 is at least 97% homogeneous.

[0570] 265. The method of embodiment 264, wherein CER-001 is administered in the form of a formulation, wherein CER-001 is at least 98% homogeneous.

[0571] 266. The method of embodiment 265, wherein CER-001 is administered in the form of a formulation, wherein CER-001 is at least 99% homogeneous.

[0572] 267. The method of any one of embodiments 248 to 266, wherein the lipid-binding protein-based complex is a carrier of the active agent.

[0573] 268. The method of any one of embodiments 1 to 267, wherein the lipid-binding protein molecule is administered systemically, optionally by infusion.

[0574] 269. The method of any one of embodiments 1 to 268, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is from 4 mg / kg to 40 mg / kg (by protein weight).

[0575] 270. The method of embodiment 269, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 mg / kg, 10 mg / kg, or 20 mg / kg (by protein weight).

[0576] 271. The method of embodiment 269, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 mg / kg (based on protein weight).

[0577] 272. The method of embodiment 269, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 mg / kg (based on protein weight).

[0578] 273. The method of embodiment 269, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 20 mg / kg (based on protein weight).

[0579] 274. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 30 mg / kg (based on protein weight).

[0580] 275. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 to 25 mg / kg (based on protein weight).

[0581] 276. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 30 mg / kg (based on protein weight).

[0582] 277. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 20 mg / kg (based on protein weight).

[0583] 278. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 mg / kg (based on protein weight).

[0584] 279. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 15 mg / kg (based on protein weight).

[0585] 280. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 5 mg / kg (based on protein weight).

[0586] 281. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 10 mg / kg (based on protein weight).

[0587] 282. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 15 mg / kg (based on protein weight).

[0588] 283. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 20 mg / kg (based on protein weight).

[0589] 284. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 25 mg / kg (by protein weight).

[0590] 285. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 4 to 35 mg / kg (based on protein weight).

[0591] 286. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 10 mg / kg (based on protein weight).

[0592] 287. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 20 mg / kg (based on protein weight).

[0593] 288. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 25 mg / kg (based on protein weight).

[0594] 289. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 30 mg / kg (based on protein weight).

[0595] 290. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 35 mg / kg (based on protein weight).

[0596] 291. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 5 to 40 mg / kg (based on protein weight).

[0597] 292. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 15 mg / kg (based on protein weight).

[0598] 293. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 25 mg / kg (based on protein weight).

[0599] 294. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 35 mg / kg (based on protein weight).

[0600] 295. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 10 to 40 mg / kg (based on protein weight).

[0601] 296. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 to 20 mg / kg (based on protein weight).

[0602] 297. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 to 30 mg / kg (based on protein weight).

[0603] 298. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 to 35 mg / kg (based on protein weight).

[0604] 299. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 15 to 40 mg / kg (based on protein weight).

[0605] 300. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 20 to 25 mg / kg (based on protein weight).

[0606] 301. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 20 to 30 mg / kg (based on protein weight).

[0607] 302. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 20 to 35 mg / kg (based on protein weight).

[0608] 303. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 20 to 40 mg / kg (based on protein weight).

[0609] 304. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 25 to 30 mg / kg (based on protein weight).

[0610] 305. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 25 to 35 mg / kg (based on protein weight).

[0611] 306. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 25 to 40 mg / kg (based on protein weight).

[0612] 307. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 30 to 35 mg / kg (based on protein weight).

[0613] 308. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 30 to 40 mg / kg (based on protein weight).

[0614] 309. The method of any one of embodiments 1 to 273, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is 35 to 40 mg / kg (based on protein weight).

[0615] 310. The method of any one of embodiments 1 to 273, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 4000 mg (by protein weight).

[0616] 311. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 300 mg to 400 mg (by protein weight).

[0617] 312. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 300 mg to 500 mg (by protein weight).

[0618] 313. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 300 mg to 600 mg (by protein weight).

[0619] 314. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 300 mg to 800 mg (by protein weight).

[0620] 315. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 1000 mg (by protein weight).

[0621] 316. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 1200 mg (by protein weight).

[0622] 317. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 1500 mg (by protein weight).

[0623] 318. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 2000 mg (by protein weight).

[0624] 319. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 2400 mg (by protein weight).

[0625] 320. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 3000 mg (by protein weight).

[0626] 321. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 400 mg to 500 mg (by protein weight).

[0627] 322. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 400 mg to 600 mg (by protein weight).

[0628] 323. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 400 mg to 800 mg (by protein weight).

[0629] 324. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 1000 mg (by protein weight).

[0630] 325. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 1200 mg (by protein weight).

[0631] 326. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 1500 mg (by protein weight).

[0632] 327. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 2000 mg (by protein weight).

[0633] 328. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 2400 mg (by protein weight).

[0634] 329. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 3000 mg (by protein weight).

[0635] 330. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 400 mg to 4000 mg (by protein weight).

[0636] 331. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 500 mg to 600 mg (by protein weight).

[0637] 332. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 500 mg to 800 mg (by protein weight).

[0638] 333. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 500 mg to 1000 mg (by protein weight).

[0639] 334. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 500 mg to 1200 mg (by protein weight).

[0640] 335. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 500 mg to 1500 mg (by protein weight).

[0641] 336. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 500 mg to 2000 mg (by protein weight).

[0642] 337. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 500 mg to 2400 mg (by protein weight).

[0643] 338. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 500 mg to 3000 mg (by protein weight).

[0644] 339. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 500 mg to 4000 mg (by protein weight).

[0645] 340. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 600 mg to 800 mg (by protein weight).

[0646] 341. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 600 mg to 1000 mg (by protein weight).

[0647] 342. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 600 mg to 1200 mg (by protein weight).

[0648] 343. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 600 mg to 1500 mg (by protein weight).

[0649] 344. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 600 mg to 2000 mg (by protein weight).

[0650] 345. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 600 mg to 2400 mg (by protein weight).

[0651] 346. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 600 mg to 3000 mg (by protein weight).

[0652] 347. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 600 mg to 4000 mg (by protein weight).

[0653] 348. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 800 mg to 1000 mg (by protein weight).

[0654] 349. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 800 mg to 1200 mg (by protein weight).

[0655] 350. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 800 mg to 1500 mg (by protein weight).

[0656] 351. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 800 mg to 2000 mg (by protein weight).

[0657] 352. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 800 mg to 2400 mg (by protein weight).

[0658] 353. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 800 mg to 3000 mg (by protein weight).

[0659] 354. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 800 mg to 4000 mg (by protein weight).

[0660] 355. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1000 mg to 1200 mg (by protein weight).

[0661] 356. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1000 mg to 1500 mg (by protein weight).

[0662] 357. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1000 mg to 2000 mg (by protein weight).

[0663] 358. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1000 mg to 2400 mg (by protein weight).

[0664] 359. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1000 mg to 3000 mg (by protein weight).

[0665] 360. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1,000 mg to 4,000 mg (by protein weight).

[0666] 361. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1200 mg to 1500 mg (by protein weight).

[0667] 362. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1200 mg to 2000 mg (by protein weight).

[0668] 363. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1200 mg to 2400 mg (by protein weight).

[0669] 364. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1200 mg to 3000 mg (by protein weight).

[0670] 365. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1200 mg to 4000 mg (by protein weight).

[0671] 366. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 1500 mg to 2000 mg (by protein weight).

[0672] 367. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1500 mg to 2400 mg (by protein weight).

[0673] 368. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1,500 mg to 3,000 mg (by protein weight).

[0674] 369. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 1,500 mg to 4,000 mg (by protein weight).

[0675] 370. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 2000 mg to 2400 mg (by protein weight).

[0676] 371. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 2000 mg to 3000 mg (by protein weight).

[0677] 372. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 2000 mg to 4000 mg (by protein weight).

[0678] 373. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 2400 mg to 3000 mg (by protein weight).

[0679] 374. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 2400 mg to 4000 mg (by protein weight).

[0680] 375. The method of embodiment 310, wherein each dose of the lipid-binding protein molecule applied in step (c) is 3000 mg to 4000 mg (by protein weight).

[0681] 376. The method of any one of embodiments 1 to 375, wherein the lipid-binding protein molecule is administered by infusion in step (a) (when performed) and / or step (c).

[0682] 377. The method of embodiment 376, wherein each individual dose of the lipid-binding protein molecule is administered by continuous infusion, for example, for a predetermined period of time.

[0683] 378. The method of implementation scheme 377, wherein the continuous infusion exceeds 1 day.

[0684] 379. The method of implementation scheme 377, wherein the continuous infusion lasts for more than 2 days.

[0685] 380. The method of embodiment 377, wherein the continuous infusion lasts for more than 3 days.

[0686] 381. The method of implementation scheme 377, wherein the continuous infusion lasts for more than 4 days.

[0687] 382. The method of implementation scheme 377, wherein the continuous infusion lasts for more than 5 days.

[0688] 383. The method of implementation scheme 377, wherein the continuous infusion lasts for more than 6 days.

[0689] 384. The method of implementation scheme 377, wherein the continuous infusion lasts for more than 7 days.

[0690] 385. The method of implementation scheme 376, wherein each individual dose is administered over a period of 1 to 24 hours.

[0691] 386. The method of implementation scheme 377, wherein each individual dose is administered over a 24-hour period.

[0692] 387. The method of embodiment 376, wherein each individual dose is administered over a period of one hour or less.

[0693] 388. The method of embodiment 376, wherein each individual dose is administered over a period of one and a half hours to one hour.

[0694] 389. The method of any one of embodiments 1 to 388, further comprising administering an antihistamine to the subject prior to each dose of the lipid-binding protein molecule.

[0695] 390. The method of embodiment 389, wherein the antihistamine includes dextrochlorpheniramine, hydroxyzine, diphenhydramine, cetirizine, fexofenadine, or loratadine.

[0696] 391. The method of embodiment 390, wherein the antihistamine includes dextrochlorpheniramine.

[0697] 392. The method of embodiment 390, wherein the antihistamine includes hydroxyzine.

[0698] 393. The method of embodiment 390, wherein the antihistamine includes diphenhydramine.

[0699] 394. The method of embodiment 390, wherein the antihistamine comprises cetirizine.

[0700] 395. The method of embodiment 390, wherein the antihistamine includes fexofenadine.

[0701] 396. The method of embodiment 390, wherein the antihistamine includes loratadine.

[0702] 397. The method according to any one of embodiments 1 to 396, wherein the subject is receiving or has received one or more additional therapies and / or further includes administering one or more additional therapies to the subject.

[0703] 398. The method of embodiment 397, wherein the one or more additional therapies comprise one or more anti-IL-6 agents.

[0704] 399. The method of embodiment 398, wherein the one or more anti-IL-6 agents include tocilizumab, stactusumab, olloccimab, islimo, BMS-945429, cilulumab, lenvillimab, CPSI-2364, or combinations thereof.

[0705] 400. The method of embodiment 399, wherein one or more anti-IL-6 agents include tocilizumab.

[0706] 401. The method of any one of embodiments 397 to 400, wherein the one or more additional therapies comprise one or more corticosteroids.

[0707] 402. The method of embodiment 401, wherein the one or more corticosteroids include methylprednisolone, dexamethasone, or a combination thereof.

[0708] 403. The method of any one of embodiments 397 to 402, wherein the one or more additional therapies comprise one or more standard care therapies for the condition.

[0709] 404. The method of implementation scheme 403, wherein one or more standard care therapies for a subject suffering from sepsis include antibiotic therapy and / or hemodynamic support.

[0710] 405. The method of any one of embodiments 1 to 404, wherein the subject is a human being.

[0711] 406. The method of any one of embodiments 1 to 405, wherein the subject is not mechanically ventilated when the lipid-binding protein molecule is first administered.

[0712] 407. The method of any one of embodiments 1 to 405, wherein the subject is mechanically ventilated when the lipid-binding protein molecule is first administered.

[0713] 408. The method of any one of embodiments 1 to 407, wherein the subject is receiving vasopressor therapy when the lipid-binding protein molecule is first administered.

[0714] 409. The method of any one of embodiments 1 to 407, wherein the subject did not receive vasopressor therapy when the lipid-binding protein molecule was first administered.

[0715] 410. The method of any one of embodiments 1 to 409, wherein when the lipid-binding protein molecule is first administered, the subject's blood lactate level is from 0.4 mmol / L to 12 mmol / L.

[0716] 411. The method of any one of embodiments 1 to 409, wherein when the lipid-binding protein molecule is first administered, the subject's blood lactate level is 0.4 mmol / L to 5 mmol / L.

[0717] 412. The method of any one of embodiments 1 to 409, wherein when the lipid-binding protein molecule is first administered, the subject's blood lactate level is 1 mmol / L to 5 mmol / L.

[0718] 413. The method of any one of embodiments 1 to 409, wherein when the lipid-binding protein molecule is first administered, the subject's blood lactate level is between 1 mmol / L and 4 mmol / L.

[0719] 414. The method of any one of embodiments 1 to 413, wherein when the lipid-binding protein molecule is first administered, the subject's P / F ratio (the ratio of PaO2 (partial pressure of arterial oxygen obtained from arterial blood gas) to FiO2 (fraction of inhaled oxygen)) is 90 to 550.

[0720] 415. The method of any one of embodiments 1 to 413, wherein the P / F ratio of the subject is 90 to 250 when the lipid-binding protein molecule is first administered.

[0721] 416. The method of any one of embodiments 1 to 413, wherein when the lipid-binding protein molecule is first administered, the subject's P / F ratio is 150 to 400.

[0722] 417. The method of any one of embodiments 1 to 413, wherein the P / F ratio of the subject is 300 to 510 when the lipid-binding protein molecule is first administered.

[0723] 418. The method of any one of embodiments 1 to 417, wherein when the lipid-binding protein molecule is first administered, the subject's serum creatinine level is from 0.5 mg / dL to 6 mg / dL.

[0724] 419. The method of any one of embodiments 1 to 417, wherein when the lipid-binding protein molecule is first administered, the subject's serum creatinine level is from 0.5 mg / dL to 3 mg / dL.

[0725] 420. The method of any one of embodiments 1 to 417, wherein when the lipid-binding protein molecule is first administered, the subject's serum creatinine level is 3 mg / dL to 6 mg / dL.

[0726] 421. The method of any one of embodiments 1 to 420, wherein the subject is in an intensive care unit (ICU) when the lipid-binding protein molecule is first administered.

[0727] 422. The method of implementation 421 reduces the number of days subjects spend in the ICU compared to standard care.

[0728] 423. The method of any one of embodiments 1 to 420, wherein the subject is not in the intensive care unit (ICU) when the subject is first administered the lipid-binding protein molecule.

[0729] 424. The method of any one of embodiments 1 to 423, wherein the subject suffers from sepsis, and wherein the method increases survival by 30 days compared to the standard care.

[0730] 425. The method of any one of the foregoing embodiments, wherein step (a) comprises the induction scheme as described in 6.4.1.

[0731] 426. A method of treating a subject with asthma (e.g., acute severe asthma), comprising administering one or more doses of a lipid-binding protein molecule to the subject.

[0732] 427. A method for treating a subject with graft-versus-host disease (GVHD) or at risk of GVHD (e.g., a subject who has received a stem cell transplant, bone marrow transplant, or organ transplant), comprising administering one or more doses of a lipid-binding protein molecule to said subject.

[0733] 428. The method of embodiment 425 or embodiment 427, wherein the lipid-binding protein molecule is the lipid-binding protein molecule of any one of the preceding embodiments.

[0734] 8. Examples

[0735] 8.1. Example 1: A randomized pilot study comparing different doses of short-term CER-001 infusion for the prevention of sepsis-induced acute kidney injury.

[0736] Currently, there are no approved treatments for sepsis-related acute kidney injury (AKI). Given that the inflammatory response of endotoxemia is a major cause of hemodynamic instability and progression to AKI in sepsis patients, the primary objective of this study was to investigate the safety and efficacy of combining different doses of CER-001 with standard of care (SOC) therapy, providing a new strategy for treating sepsis patients, reducing inflammation, and preventing progression to AKI. Unbound by conventional wisdom, the expected mechanism of action is dual, involving both the binding of CER-001 to endotoxin and its direct anti-inflammatory effect.

[0737] The study reported in this embodiment included 20 patients with Gram-negative sepsis who were at high risk of acute kidney injury due to high levels of endotoxin activity and decreased function of one or more organ systems. Patients received standard care alone, or standard care in combination with one of three dosage regimens of CER-001 (5 patients per group), to investigate the safety and efficacy of different doses of CER-001 in combination with standard care (SOC), to provide a potential new strategy for treating sepsis patients, reducing inflammatory responses to endotoxins and preventing progression to AKI (according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria), and the safety and tolerability of the dosage regimens in order to select the optimal dose of CER-001.

[0738] One of the metabolic hallmarks of bacterial infections (such as sepsis) or viral infections (such as SARS-CoV-2) is a sharp decrease in circulating lipoproteins, particularly high-density lipoprotein (HDL) and its main constituent protein, apolipoprotein A1 (ApoA-I). For example, ApoA-I levels have recently been described as a biomarker for predicting long-term mortality after surgical sepsis.

[0739] One of the goals of this study was to use CER-001 to restore ApoA-I levels in order to reconstruct all the functions of this personalized biomarker, leading to benefits in sepsis pathology.

[0740] 8.1.1. Research Plan

[0741] Study population: This is a single-center, randomized, dose-range (phase II) study that included patients with sepsis due to intra-abdominal infection or urosepsis admitted to the intensive care unit (ICU) of participating centers. Investigators ensured that all patients meeting the following inclusion and exclusion criteria were enrolled in the study.

[0742] Inclusion criteria:

[0743] -Male or non-pregnant female adults aged ≥18 years at enrollment;

[0744] - Meets the sepsis 3 criteria, defined as an acute increase of at least 2 points in SOFA score relative to the SOFA score at admission;

[0745] - Endotoxin level (measured by endotoxin activity assay (EAA™); Spectral Medical) > 0.6 (see Marshall et al., 2004, J Infect Dis. 190(3):527-34);

[0746] - An informed consent form signed and dated by the patient or their legal representative.

[0747] Exclusion criteria:

[0748] - Patients weighing over 100 kg;

[0749] - Alanine aminotransferase / aspartate aminotransferase (ALT / AST) > 5 times the upper limit of normal;

[0750] Stage 4 severe chronic kidney disease or requiring dialysis (i.e., estimated glomerular filtration rate (eGFR) <30 ml / min / 1.73 m³ / min). 2 );

[0751] - White blood cell count <2.0×10^9;

[0752] - Women who are pregnant or breastfeeding;

[0753] - Received an organ transplant in the past year;

[0754] - Expected to be transferred to another hospital within 72 hours, which is not the research site;

[0755] - Advanced disease, including metastatic tumors or hematologic malignancies, with a life expectancy of less than 30 days (assessed by the attending physician) or cases classified as "refusal of cardiopulmonary resuscitation";

[0756] - History of end-stage chronic organ failure;

[0757] - Diagnosed with HIV;

[0758] - Uncontrolled bleeding within the last 24 hours;

[0759] - Patients who have used the investigational drug or device within 30 days of the first dose of CER-001.

[0760] Number of participants: Twenty participants were recruited and randomized (1:1:1:1) to four experimental groups, defined as AD groups as follows. Baseline characteristics of the participants are summarized in the table below:

[0761]

[0762]

[0763] The study population had the following baseline clinical and demographic characteristics.

[0764]

[0765] Study duration This study was completed over 24 weeks (6 months). The enrollment period was approximately 20 weeks (5 months) from the first participant's enrollment. The study ended with the last visit of the last participant.

[0766] Primary endpoint The common primary endpoints of this study were (1) to determine the safety and optimal dosage of CER-001 in combination with standard care for patients with sepsis caused by Gram-negative bacteria, (2) to determine the occurrence of AKI according to the KDIGO criteria, and (3) to determine the severity of AKI according to the KDIGO criteria.

[0767] Secondary endpoint: Secondary endpoints are:

[0768] - Changes in endotoxin and IL-6 levels from baseline to days 3, 6, and 9.

[0769] - The baseline is defined as the last measurement taken before administration on day 1.

[0770] - Changes in SOFA score (Vincent et al., 1996, Intensive Care Med, 22:707–710) from baseline to day 3, day 6, and day 9.

[0771] - Changes in key inflammatory markers (CRP, D-dimer, ferritin, IL-8, GM-CSF, MCP1, and TNF-α) from baseline to days 3, 6, and 9.

[0772] - According to the KDIGO criteria (Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney International Supplements 2012; 2: 1–138), changes in AKI biomarkers and the onset of AKI

[0773] - Mortality rate on day 30

[0774] Intervention / Exposure Twenty eligible patients, who had signed and dated informed consent forms approved by the Ethics Committee (EC), were randomly assigned in a 1:1:1:1 ratio to receive standard therapy (Group A), low-dose CER-001 (Group B), medium-dose CER-001 (Group C), or high-dose CER-001 (Group D). Standard therapy was adjusted based on clinical circumstances. All non-experimental treatments were permitted to be administered concurrently with the patients during the study: any medications taken by the patients, except for the study drug as specified in the protocol, were considered concomitant medications and recorded in the study record.

[0775] Each patient is identified by their patient number during screening. Once assigned to a patient, the patient number is not reused. Investigators enrolling patients are not involved in randomization or assignment. The randomization list for dividing patients into blocks is fully hidden to prevent attempts to compromise randomization.

[0776] Treatment group: All patients received standard therapy. The treatment group received additional therapy using the investigational drug. Specifically:

[0777] Group A: Standard therapy (i.e., antibiotic treatment and hemodynamic support based on the patient's condition).

[0778] Group B: Standard therapy + CER-001 5 mg / kg BID for 3 consecutive days, followed by 5 mg / kg BID on day 6.

[0779] Group C: Standard therapy + CER-001 10 mg / kg BID for 3 consecutive days, followed by 10 mg / kg BID on day 6.

[0780] Group D: Standard therapy + CER-001 20 mg / kg BID for 3 consecutive days, followed by 20 mg / kg BID on day 6.

[0781] Figure 1 The research plan was summarized.

[0782] Pre-treat patients with an antihistamine before each CER-001 dose (e.g., dextrochlorpheniramine 5 mg or hydroxyzine 100 mg) to avoid any potential infusion reactions.

[0783] Statistical analysis: Intergroup comparisons were performed using appropriate statistical tests: dichotomous variables (baseline characteristics, mortality, and progression to AKI) were compared using chi-square or Fisher's exact test; continuous baseline characteristics were compared using ANOVA or Kruskall-Wallis test; and t-Student or Mann-Whitney U test, as appropriate. Changes in inflammatory markers between groups were compared using ANOVA and presented graphically. The proportion of AKI patients and mortality rates were calculated for each group. All data analyses were performed using SPSS 12.0 (Windows version); p < 0.05 was considered statistically significant.

[0784] program: The following procedures were performed during the screening visits. After randomization, participants began treatment within 2 business days.

[0785] -Informed Consent Form

[0786] -Medical history—including: recording past and present illnesses and collecting demographic data of the subjects (date of birth, sex, and race).

[0787] - Physical examination, including checking systemic factors, height and weight, BMI, and waist circumference.

[0788] - Vital signs (pulse, blood pressure, and oral, ear, armpit, or core temperature).

[0789] - Review inclusion / exclusion criteria.

[0790] - Begin recording adverse events from the moment informed consent is obtained.

[0791] Collect previous medications 4 weeks before the first dose of the test product. Record all current medications.

[0792] - Complete blood count (CBC) – includes white blood cell count (WBC) and differential, platelet count, red blood cell count (RBC), hemoglobin (Hb), and hematocrit (Het).

[0793] - Fasting biochemical and electrolyte tests: including sodium, potassium, chloride, blood urea nitrogen (BUN; or urea), serum creatinine, calculated creatinine clearance (CKD-EPI), glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, GT, ALP, total bilirubin and direct bilirubin, albumin, total cholesterol, HDL, LDL, triglycerides, LDH, CPK,

[0794] -ABG (used to assess respiratory and / or metabolic disorders)

[0795] -ApoA-I (used for pharmacokinetic and pharmacodynamic evaluation)

[0796] - Coagulation tests include prothrombin time (PT) (expressed as International Normalized Ratio [INR]) and partial thromboplastin time (PTT).

[0797] - Urine analysis—including specific gravity, pH, assessment of protein / albumin, glucose, ketones, and hemoglobin / blood.

[0798] - Microalbuminuria and proteinuria g / 24 h

[0799] - Perform a serum or urine pregnancy test within 7 days prior to randomization (for women of childbearing age).

[0800] - Pharmacokinetic and pharmacodynamic assessments include ApoA-I and total cholesterol levels.

[0801] Endotoxin levels were measured using the EAA™ kit. AKI biomarkers (TIMP-2 and IGFBP-7) were measured using the Nephrocheck® kit. Inflammatory biomarkers included: CRP, D-dimer, ferritin, IL-6, IL-8, GM-CSF, MCP-1, and TNF-α.

[0802] In addition to collecting biological samples for routine laboratory assessments conducted in the central laboratory, biological samples are also collected for research purposes, including:

[0803] -2 tubes of 5 ml serum

[0804] -1 tube of 3 ml plasma

[0805] - 30 ml of urine

[0806] These samples were used to evaluate additional inflammatory cytokines and urinary biomolecules to obtain a more comprehensive characterization of enrolled patients, to better assess treatment response, to provide more information during follow-up, and, more importantly, to discover new potential biomarkers for the early diagnosis of sepsis-induced AKI. Analysis was performed using ELISA assays and protein arrays.

[0807] Treatment visit (during treatment) The treatment period is defined as the start of treatment. Visits are scheduled for days 3, 6, and 9. The final visit is scheduled for day 30. The following procedures will be performed during treatment visits:

[0808] - Adverse events and concomitant medication records

[0809] - Check appropriate laboratory information

[0810] - Physical examination

[0811] - Assess vital signs (pulse, blood pressure, and oral, ear, axillary, or core temperature).

[0812] -Continuously record adverse events and concomitant medications.

[0813] - Complete blood count (CBC) – includes white blood cell count (WBC) and differential, platelet count, red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Het).

[0814] - Fasting biochemical and electrolyte tests: including sodium, potassium, chloride, blood urea nitrogen (BUN; or urea), serum creatinine, calculated creatinine clearance (CKD-EPI), glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, γGT, ALP, total bilirubin and direct bilirubin, albumin, total cholesterol, HDL, LDL, triglycerides, LDH, and CPK.

[0815] -ABG (used to assess respiratory and / or metabolic disorders)

[0816] -ApoA-I (used for pharmacokinetic and pharmacodynamic evaluation).

[0817] Specifically, serum ApoA-I levels were assessed on days 1, 3, 6, and 9. For subjects in the treatment group, serum ApoA-I levels were assessed prior to CER-001 administration. Specifically, values ​​were determined on day 1 before any administration, on day 3 approximately 12 hours after the fourth dose, on day 6 60 hours after the sixth dose, and on day 9 60 hours after the last dose.

[0818] - Coagulation tests include prothrombin time (PT) (expressed as International Normalized Ratio [INR]) and partial thromboplastin time (PTT).

[0819] -Urine analysis includes specific gravity, pH, assessment of protein / albumin, glucose, ketone bodies, and hemoglobin / blood.

[0820] - Microalbuminuria and proteinuria g / 24 h

[0821] - Perform a serum or urine pregnancy test within 7 days prior to randomization (for women of childbearing age).

[0822] - Pharmacokinetic and pharmacodynamic assessments include ApoA-I and total cholesterol levels.

[0823] Endotoxin levels were measured using the EAA™ kit. AKI biomarkers (TIMP-2 and IGFBP-7) were measured using the Nephrocheck® kit. Inflammatory biomarkers included: CRP, D-dimer, ferritin, IL-6, IL-8, GM-CSF, MCP-1, and TNF-α.

[0824] In addition to collecting biological samples for routine laboratory assessments conducted in the central laboratory, biological samples are also collected for research purposes, including:

[0825] -2 tubes of 5 ml serum

[0826] -1 tube of 3 ml plasma

[0827] - 30 ml of urine

[0828] Clinical scores include the SOFA score (Table 2) and the KDIGO criteria for AKI assessment and staging (Table 3). Each component of the score is recorded.

[0829]

[0830]

[0831] Table 4 provides a summary of the research scheme in this embodiment.

[0832]

[0833] Safety assessment: Safety assessment was conducted using information gathered from the following evaluations: physical examination (including weight), vital signs (blood pressure, pulse, temperature), CBC and differential, platelet count, blood chemistry and fasting lipid profile, including HDL-cholesterol, LDL-cholesterol and lipoprotein(a), urea, glucose, 24-hour urine protein measurement, serum creatinine and calculated creatinine clearance (CKD-EPI), and adverse event monitoring. All women of childbearing potential underwent a qualitative serum pregnancy test during pre-study screening / baseline assessment and if clinically indicated. Adverse events were monitored and recorded throughout the study. Adverse events reported by subjects, as a result of general investigator questioning, or discovered through physical examination were recorded. For each reported adverse event, the duration (start and end dates), severity, etiology and relationship to the study drug, patient outcome, actions taken, and assessment of the severity of the event were recorded.

[0834] In all subjects, the changes in liver enzymes after 9 days ranged from approximately 0.2 to approximately 4 times the baseline level. Figures 31A-31B The changes in liver enzyme levels in subjects receiving CER-001 were comparable to those in the group receiving standard care only.

[0835] Adverse events: Of the 20 subjects, 9 experienced adverse events, of which 7 were definitely unrelated to the test product (i.e., the adverse events could be fully explained by the subject's clinical status or other drugs / therapies) and 2 were possibly unrelated to the test product (i.e., the adverse events were most likely explained by the subject's clinical status or other drugs / therapies, rather than the test product).

[0836] 8.1.2. Results

[0837] In Sections 8.1.2.1 through 8.1.2.25, the following abbreviations are used: nd, undetermined; NS, not significant; NT, untested.

[0838] 8.1.2.1. Serum ApoA-I

[0839] Figures 30A-30D The mean ApoA-I levels in the control group and the pooled study group were shown. Figure 30A The study showed the mean ApoA-I levels in the control and pooled study groups. Figure 30B The mean ApoA-I levels were shown in the control group and each study group. Figure 30C The changes in ApoA-I for each subject in the standard care group (SOC) and the experimental group (CER-001) were shown, and Figure 30DThe changes in ApoA-I levels relative to baseline for each subject divided by study group, as measured by ELISA, are shown. In patients receiving CER-001, serum ApoA-I levels increased rapidly during the first 3 days of treatment, while the increase was delayed in the SOC group. Statistically significant differences were assessed using a mixed-model ANOVA (ns: p>0.05).

[0840] The table below reports the serum ApoA-I levels assessed on days 1, 3, 6, and 9 in subjects in the CER-001 treatment group.

[0841]

[0842] The results showed that subjects in the treatment group had a wide range of ApoA-I levels (0.32 g / L to 1.55 g / L) on day 1 prior to CER-001 treatment. The results also indicated that some, but not all (2 / 8) subjects with ApoA-I levels below 1.0 g / L on day 1 had ApoA-I levels of 1.0 g / L or higher on day 9. Furthermore, most, but not all (5 / 6) subjects with ApoA-I levels above 1.0 g / L on day 1 had ApoA-I levels of 1.0 g / L or higher on day 9.

[0843] 8.1.2.2. Lipopolysaccharide (LPS)

[0844] Figures 2A-2F The changes in lipopolysaccharide (LPS) were shown in the standard care group (Group A) and the experimental group (Group BD). Figure 2A Changes in LPS relative to baseline for Group A and Summary Group BD. Figure 2B Changes in LPS relative to baseline for groups A, B, C, and D. Figure 2C Changes in LPS in group A and pooled group BD are reported as a percentage of peak LPS level (peak = 100%). The treatment-to-study-day effect relative to peak is p < 0.0005. Figure 2D The changes in LPS in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 2E Changes in LPS relative to baseline for each subject in Group A and the pooled group BD. Figure 2F The change in LPS relative to baseline for each subject in each AD group. LPS levels were measured by ELISA. Statistically significant differences were assessed using a pooled model ANOVA (ns: p > 0.05).

[0845] Typically, treatment regimens of CER-001 at 5 mg / kg, 10 mg / kg, or 20 mg / kg in addition to SOC reduce LPS more significantly than SOC alone. The table below summarizes significant or near-significant results:

[0846]

[0847] Consistent with animal data and observed increases in ApoA-I, treatment with CER-001 significantly reduced LPS blood flow concentrations compared to SOC subjects. Figure 2E This observation reinforces the hypothesis that reducing LPS has a positive impact on clinical outcomes. However, other studies have emphasized the need to extend this hypothesis beyond simple LPS removal (Monard et al., 2023, Critical Care 27(1):36; Cavaillon et al., 2020, EMBO Molecular Medicine 12(4)). Indeed, pleiotropic effects, including LPS reduction / inactivation and inhibition of cytokine storm cascades and / or endothelial dysfunction, may have strong biochemical and clinical implications. Unbound by theory, CER-001 is believed to not only reduce LPS levels in animals and humans but also interact directly with the immune system via ApoA-I and provide endothelial protection.

[0848] 8.1.2.3. Endotoxin Activity Assay (EAA)

[0849] Figures 3A-3E The changes in endotoxin activity assay (EAA) were shown in the standard care group (Group A) and the experimental group (Group BD). Figure 3A Changes in EAA relative to baseline for Group A and Summary Group BD. Figure 3B Changes in EAA relative to baseline for groups A, B, C, and D. Figure 3C Changes in EAA in group A and pooled group BD are reported as a percentage of peak EAA level (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.1769. Figure 3D The changes in EAA in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 3E Changes in EAA relative to baseline for group A and pooled group BD. EAA was performed at each time point using a commercial kit (Spectral Medical, Toronto, Canada). Statistically significant differences were assessed using a pooled model ANOVA (ns: p > 0.05).

[0850] Typically, treatment regimens providing 10 mg / kg CER-001 in addition to SOC reduce EAA more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0851]

[0852] 8.1.2.4. TNF-α

[0853] Figures 4A-4F The changes in TNF-α in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 4A Changes in TNF-α relative to baseline in group A and pooled group BD. Figure 4B Changes in TNF-α relative to baseline in groups A, B, C, and D. Figure 4C TNF-α changes in group A and pooled group BD are reported as a percentage of peak TNF-α levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.0004. Figure 4D Changes in TNF-α in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 4E Changes in TNF-α relative to baseline for each subject in Group A and the pooled group BD. Figure 4F Changes in TNF-α relative to baseline for each subject in each AD group.

[0854] Typically, treatment regimens that provide 10 mg / kg CER-001 in addition to SOC reduce TNF-α more effectively than SOC alone.

[0855] 8.1.2.5. MCP-1

[0856] Figures 5A-5F The changes in MCP-1 in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 5A Changes in MCP-1 relative to baseline for group A and summary group BD. Figure 5B Changes in MCP-1 relative to baseline in groups A, B, C, and D. Figure 5C Changes in MCP-1 in groups A and pooled group BD are reported as a percentage of peak MCP-1 levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.0090. Figure 5DThe changes in MCP-1 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 5E Changes in MCP-1 relative to baseline for group A and summary group BD. Figure 5F Changes in MCP-1 relative to baseline for each subject in each AD group.

[0857] 8.1.2.6. Interleukin-6 (IL-6)

[0858] Figures 6A-6F The changes in IL-6 in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 6A Changes in IL-6 relative to baseline in group A and summary group BD. Figure 6B Changes in IL-6 relative to baseline in groups A, B, C, and D. Figure 6C IL-6 changes in group A and pooled group BD are reported as a percentage of peak IL-6 levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.0037. Figure 6D Changes in IL-6 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 6E Changes in IL-6 relative to baseline for each subject in group A and pooled group BD. Figure 6F Changes in IL-6 relative to baseline in each subject in each AD group.

[0859] Typically, CER-001 is provided in addition to SOC, especially the 10 mg / kg CER-001 regimen, which reduces IL-6 more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0860]

[0861] 8.1.2.7. Interleukin-8 (IL-8)

[0862] Figures 7A-7F The changes in IL-8 were shown in the standard care group (Group A) and the experimental group (Group BD). Figure 7A The change in IL-8 relative to baseline in group A and pooled group BD, measured by ELISA. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 7B Changes in IL-8 relative to baseline in groups A, B, C, and D. Figure 7CIL-8 changes in group A and pooled group BD are reported as a percentage of peak IL-8 levels (peak = 100%). Treatment-day effect relative to peak is p < 0.0001. Figure 7D Changes in IL-8 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 7E Changes in IL-8 relative to baseline for each subject in Group A and the pooled group BD. Figure 7F Changes in IL-8 relative to baseline in each subject in each AD group.

[0863] Typically, treatment regimens that provide CER-001 in addition to SOC reduce IL-8 more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0864]

[0865] 8.1.2.8. Interleukin-10 (IL-10)

[0866] Figures 8A-8D The changes in IL-10 in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 8A Changes in IL-10 relative to baseline for Group A and Summary Group BD. Figure 8B Changes in IL-10 relative to baseline in groups A, B, C, and D. Figure 8C IL-10 changes in group A and pooled group BD are reported as a percentage of peak IL-10 levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.3780. Figure 8D Changes in IL-10 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department.

[0867] 8.1.2.9. s-TREM-1

[0868] Figures 9A-9F The changes in s-TREM-1 in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 9A Changes in s-TREM-1 relative to baseline for group A and summary group BD. Figure 9B Changes in s-TREM-1 relative to baseline in groups A, B, C, and D. Figure 9CChanges in s-TREM-1 in groups A and pooled group BD are reported as a percentage of peak s-TREM-1 levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.0003. Figure 9D Changes in s-TREM-1 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 9E Changes in s-TREM-1 relative to baseline for each subject in group A and pooled group BD. Figure 9F : Changes in s-TREM-1 relative to baseline for each subject in each AD group.

[0869] Typically, treatment regimens that provide CER-001 in addition to SOC reduce s-TREM-1 more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0870]

[0871] 8.1.2.10. s-VCAM and s-ICAM

[0872] Figures 10A-10F The changes in s-VCAM in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 10A Changes in s-VCAM relative to baseline for Group A and Summary Group BD. Figure 10B The changes in s-VCAM relative to the baseline for groups A, B, C, and D. Figure 10C Changes in s-VCAM in group A and pooled group BD are reported as a percentage of peak s-VCAM levels (peak = 100%). Treatment-day effect relative to peak is p < 0.0001. Figure 10D The changes in s-VCAM in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 10E Changes in s-VCAM relative to baseline for each subject in Group A and the pooled group BD. Figure 10F The change in S-VCAM relative to baseline for each subject in each AD group.

[0873] Typically, treatment regimens that include CER-001 in addition to SOC reduce s-VCAM more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0874]

[0875] Figure 11A-11FThe changes in s-ICAM in the standard care group (Group A) and the experimental group (Group BD) as measured by ELISA are shown. Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 11a: Changes in s-ICAM relative to baseline in Group A and the pooled group BD. Figure 11B The changes of s-ICAM relative to baseline in groups A, B, C and D. Figure 11C Changes in s-ICAM in group A and pooled group BD are reported as a percentage of peak s-ICAM levels (peak = 100%). The treatment-to-study-day effect relative to peak is p < 0.0001. Figure 11D The changes in s-ICAM in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 11E Changes in s-ICAM relative to baseline for each subject in Group A and the pooled group BD. Figure 11F : Change of s-ICAM relative to baseline for each subject in each AD group.

[0876] Typically, treatment regimens that provide CER-001 in addition to SOC reduce s-ICAM more effectively than SOC alone. The table below summarizes significant or near-significant results:

[0877]

[0878] 8.1.2.11. Ferritin

[0879] Figure 12A-12D The changes in ferritin were shown in the standard care group (Group A) and the experimental group (Groups B and D). Figure 12A Changes in ferritin relative to baseline in group A and pooled group BD. Figure 12B Changes in ferritin levels relative to baseline in groups A, B, C, and D. Figure 12C Ferritin changes in groups A and pooled groups B and D are reported as a percentage of peak ferritin levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.0962. Figure 12D The changes in ferritin in group A and the pooled group B and D were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department.

[0880] 8.1.2.12. White blood cells

[0881] Figures 13A-13D The changes in white blood cell counts were shown in the standard care group (Group A) and the experimental group (Groups B and D). Figure 13A Changes in white blood cell counts relative to baseline in group A and pooled group BD. Figure 13BChanges in white blood cell counts relative to baseline in groups A, B, C, and D. Figure 13C Changes in white blood cell counts in groups A and pooled groups B and D are reported as a percentage of peak white blood cell count (peak = 100%). The treatment-to-study-day effect relative to peak was p = 0.5492. Figure 13D Changes in white blood cell counts in group A and the pooled group BD were determined based on whether the subjects were enrolled from the intensive care unit or the nephrology department.

[0882] 8.1.2.13. C-reactive protein

[0883] Figure 14A-14F The changes in CRP were shown in the standard care group (Group A) and the experimental group (Group BD). Statistically significant differences were assessed using a mixed model ANOVA (ns: p>0.05). Figure 14A Changes in CRP relative to baseline for Group A and Summary Group BD. Figure 14B Changes in CRP relative to baseline in groups A, B, C, and D. Figure 14C Changes in CRP in group A and pooled group BD are reported as a percentage of peak CRP levels (peak = 100%). The treatment-to-study-day effect relative to peak was p < 0.6446. Figure 14D Changes in CRP in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 14E Changes in CRP relative to baseline for each subject in group A and pooled group BD. Figure 14F Changes in CRP relative to baseline for each subject in each AD group.

[0884] 8.1.2.14. KIM-1

[0885] Figures 15A-15D The changes in KIM-1 were shown in the standard care group (Group A) and the experimental group (Group BD). Figure 15A Changes in KIM-1 relative to baseline for Group A and Summary Group BD. Figure 15B Changes in KIM-1 relative to baseline in groups A, B, C, and D. Figure 15C KIM-1 changes in group A and pooled group BD are reported as a percentage of peak KIM-1 levels (peak = 100%). Treatment-day effect relative to peak is p < 0.0001. Figure 15D The changes in KIM-1 in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department.

[0886] 8.1.2.15. Serum albumin

[0887] Figures 16A-16E The changes in serum albumin were shown in the standard care group (Group A) and the experimental group (Group BD). Figure 16A Changes in serum albumin relative to baseline in group A and pooled group BD. Figure 16B Changes in serum albumin levels relative to baseline in groups A, B, C, and D. Figure 16C Changes in serum albumin in groups A and pooled groups B and D are reported as a percentage of peak serum albumin levels (peak = 100%). The treatment-to-study-day effect relative to peak was p = 0.1595. Figure 16D The changes in serum albumin in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 16E Changes in serum albumin relative to baseline for each subject in Group A and the pooled group BD.

[0888] Typically, treatment regimens that provide CER-001 in addition to SOC raise serum albumin levels more than SOC alone.

[0889] The significant or near-significant results are summarized in the table below:

[0890]

[0891] 8.1.2.16. Triglycerides

[0892] Figure 33 The changes in triglycerides relative to baseline were shown between the standard care group (Group A) and the experimental group (Group BD). Generally, treatment regimens that provided CER-001 in addition to SOC had slightly higher triglyceride levels than SOC alone.

[0893] 8.1.2.17. Serum creatinine

[0894] Figure 17A-17F The changes in serum creatinine in the standard care group (Group A) and the experimental group (Group BD) are shown. Figure 17A Changes in serum creatinine relative to baseline in group A and pooled group BD. Figure 17B Changes in serum creatinine relative to baseline in groups A, B, C, and D. Figure 17C Changes in serum creatinine in groups A and pooled groups B and D are reported as a percentage of peak serum creatinine levels (peak = 100%). The treatment-to-study-day effect relative to peak was p = 0.1630. Figure 17D The changes in serum creatinine in group A and the pooled group BD were determined by whether the subjects were enrolled from the intensive care unit or the nephrology department. Figure 17EArea under the curve (AUC) of serum creatinine for all subjects and for the subject population included through the ICU and nephrology pathways (mean ± SEM). Figure 17F AUC (95% confidence interval) of serum creatinine for all subjects, as well as for the subject populations from the ICU and nephrology departments included in group A and pooled group BD.

[0895] 8.1.2.18. Estimating glomerular filtration rate (eGFR)

[0896] Figure 18A , 18B Figures 18E and 18E show the changes in eGFR in all subjects in the standard care group (Group A) and the experimental group (Group BD). Estimated GFR was determined by CKD-EPI. Figure 18A Changes in eGFR relative to baseline for Group A and Summary Group BD. Figure 18B Changes in eGFR relative to baseline in groups A, B, C, and D. Figure 18E Changes in eGFR for all subjects in group A and pooled group BD are shown as a percentage relative to peak level (peak = 100%). The treatment-to-study-day effect relative to peak was p = 0.5666.

[0897] Figure 18C , 18D 18F showed changes in eGFR in subjects with AKI who entered the study. Figure 18C Changes in eGFR relative to baseline for Group A and Summary Group BD. Figure 18D Changes in eGFR in groups A, B, C and D. Figure 18F The changes in eGFR in group A and pooled group BD of subjects with AKI who entered the study are shown as a percentage relative to peak level (peak = 100%). The treatment-to-study-day effect relative to peak was p = 0.2406.

[0898] The significant or near-significant results from - are summarized in the table below:

[0899]

[0900] 8.1.2.19. P / F ratio

[0901] Figure 19 The changes in the P / F ratio for all subjects in the standard care group (Group A) and the pooled group BD are shown.

[0902] 8.1.2.20. Number of days spent in the ICU

[0903] Figure 20The study shows the survival rates of all subjects in the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”) after several days in the ICU.

[0904] 8.1.2.21. Survival time: 30 days

[0905] Figure 21A The 30-day survival rates of all subjects in the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”) are shown.

[0906] Figure 21B The study shows the 30-day survival rate for all subjects admitted from the intensive care unit for the standard care group (Group A, “SOC”) and the pooled group BD (“CER-001”).

[0907] 8.1.2.22. AKI Installment Payment

[0908] Figure 22A The evolution of AKI as assessed by the KDIGO staging criteria is shown for all subjects in the standard care group (Group A, “SOC”). AKI staging: 0, serum creatinine <1.5x baseline or an increase of less than 0.3 mg / dl within 48 hours, urine output >0.5 ml / kg / h for 6–12 hours; 1, serum creatinine from 1.5 to 1.9x baseline or an increase of more than 0.3 mg / dl, or urine output <0.5 ml / kg / h for 6–12 hours; 2, serum creatinine from 2.0 to 2.9x baseline or urine output <0.5 ml / kg / h for more than 12 hours; 3, serum creatinine 3.0x baseline or more or 4.0 mg / dl or more, or urine output <0.3 ml / kg / h for more than 24 hours or ≈0 for more than 12 hours. From day 1 to day 6, approximately 40% of the SOC participants were in AKI 0 (least severe), while the remainder were in AKI 2-3 (more severe to most severe).

[0909] Figure 22B The evolution of AKI as assessed by the KDIGO staging criteria is shown for all subjects in the pooled group BD (“CER-001”). Approximately 60% of CER-001 subjects were in AKI 0 on day 6, and 20% were in AKI 3.

[0910] 8.1.2.23. Number of days of mechanical ventilation and vasopressors

[0911] Figure 23The study showed the number of days of mechanical ventilation for all subjects admitted to the study while in the intensive care unit (ICU) for both the standard care group (Group A, SOC) and the pooled group BD (CER-001). For 5 / 7 subjects, CER-001 reduced the number of days of mechanical ventilation relative to SOC.

[0912] Figure 24 The number of days of vasopressor use was shown for all subjects entering the study while in the intensive care unit for both the standard care group (Group A, SOC) and the pooled group BD (CER-001).

[0913] 8.1.2.24. Number of dialysis days

[0914] Figure 25A The number of days of dialysis for all subjects admitted to the study while in the intensive care unit is shown for the standard care group (Group A) and the pooled group BD. Figure 25B This result is shown for all subjects. Intermittent and continuous dialysis patterns were considered. The reduction in the number of dialysis days indicates improved renal function.

[0915] 8.1.2.25. Days of survival without organ support, days spent in the ICU until discharge, and hemodynamic changes.

[0916] Figure 26 This shows the number of days of survival without organ support for all subjects admitted to the study while in the intensive care unit, for both the standard care group (SOC) and the pooled group BD (CER-001). Any use of vasopressors, mechanical ventilation, and / or renal support was considered organ support.

[0917] Figure 32 This shows the number of days experienced by all subjects from admission to ICU discharge for the Standard Care Group (SOC) and the pooled group BD (CER-001).

[0918] Figures 27A-27B This study shows the changes in daily mean arterial pressure (MAP) for all subjects admitted to the study while in the intensive care unit (ICU) for both the standard care group (SOC) and the pooled group (CER-001). A decrease in MAP is generally expected for ICU subjects.

[0919] Figure 28 This shows the changes in daily mean heart rate (HR) for all subjects entering the study while in the intensive care unit (ICU) for both the standard care group (SOC) and the pooled group BD (CER-001). A decrease in MAP is generally expected for ICU subjects.

[0920] Figure 29This shows the changes in the daily mean P / F ratio for all subjects entering the study while in the intensive care unit for both the standard care group (SOC) and the pooled group BD (CER-001). An increase in the P / F ratio is generally expected for ICU subjects.

[0921] 8.1.3. Conclusion

[0922] Typically, co-administration of CER-001 with standard care leads to improved endotoxin clearance (as shown in LPS and EAA data), CRS modulation (most notably IL-6, IL-8, and s-TREM-1), and vascular endothelial protection (as shown in s-VCAM and s-ICAM data) without increasing inflammation or negatively impacting AKI biomarkers or hemodynamics.

[0923] Notably, the trends of endothelial dysfunction markers s-VCAM and s-ICAM showed a different trend in study participants than those of ApoA-I, as their values ​​increased in patients in the SOC group, while they significantly decreased under CER-001 treatment. Figures 10A-10F , Figure 11A-11F This indicates increased vascular protection, as these mediators help enhance renal tubular cell apoptosis and irreversible mechanisms of kidney injury.

[0924] Recently, the anti-inflammatory effects of CER-001 have been prominent in severe COVID-19 patients in the ICU, with assessments of serum amyloid A-1, inflammatory markers, and cytokines showing significant reductions primarily during CER-001 infusion (Begue et al., 2021, Sci Rep 11, 2291). Similarly, data from this study show that, compared to the SOC group, CER-001 treatment induced significantly lower serum levels of MCP-1, TNF-α, IL-6, and IL-8 in treated patients. Figure 5E , Figure 4E , Figure 6E and Figure 7E This demonstrates the immunomodulatory and anti-inflammatory effects of CER-001 treatment and its ability to regulate cytokine storms. Consistent with the regulation of cytokine storms, the treatment group showed a more significant reduction in C-reactive protein (CRP) within the first 9 days compared to the SOC group. Figure 14E ).

[0925] Soluble triggering receptors expressed on myeloid-1 (s-TREM-1) have been suggested as strong predictors of poor prognosis and poor survival in sepsis patients. Persistently high s-TREM-1 levels during the initial days after ICU admission are associated with mortality in human septic shock (Jolly et al., 2021, Cell Mol Immunol 18, 2054-2056). The results of this example indicate that s-TREM-1 rapidly decreases with CER-001 treatment within the first 3 days and remains low and stable until at least 30 days. Figure 9E More importantly, this reduction was accompanied by improvement in clinical signs and symptoms. In summary, these observations confirm the potential anti-inflammatory effect of the ApoA-I complex, independent of LPS removal. HDL and ApoA-I are known to interact directly with monocytes / macrophages via receptor interactions such as SR-BI or transporters such as ABCA-1 and / or ABCG-1, or by blocking T lymphocyte contact-mediated activation of monocytes / macrophages, as demonstrated by TNF-α reduction. Figure 4E One might hypothesize that the direct cellular effects of HDL and therefore CER-001 on such cells lead to an overall reduction in cytokine production through an unclear mechanism.

[0926] Given the observed strong effects of CER-001, the potential impact of cytokine cascade and endothelial dysfunction on clinical outcomes was assessed.

[0927] The impact on organ dysfunction was analyzed under the hypothesis that the immunomodulatory effects of CER-001 treatment might limit renal dysfunction. For this purpose, renal function was analyzed in study participants, and AKI onset and severity were classified according to KDIGO criteria based on creatinine and urine output. Overall, compared to the SOC group, a lower risk of developing and / or progressing to moderate to severe AKI (AKI stage 2-3) by day 6 was observed in patients treated with CER-001 (26.6%), of whom approximately 60% presented with this condition. Figures 22A-22B These results are consistent with laboratory and histological data reported in animal models and confirm the protective effect of the treatment.

[0928] In addition, the effects of the research drugs on liver function were analyzed. For example... Figures 31A-31B As shown, no significant changes in liver enzymes (AST, ALT) were observed in CER-001 subjects; only two patients in the treatment group showed mild and non-clinically significant increases in AST and ALT. Conversely, an increase in albumin levels was observed in the CER-001 treatment group compared to the SOC group. Figure 16EOverall, these results support the safety of CER-001 and suggest that its early and sustained effects on the inflammatory state may improve liver function and increase albumin production.

[0929] We focused on a subset of critically ill patients enrolled in the ICU to analyze the primary clinical outcomes. Although the small sample size (7 treated patients; 2 SOC participants) limited the statistical assessment, a shorter ICU stay was observed in the treatment group (mean ICU stay 23.2 vs 29 days). Figure 32 Furthermore, compared with SOC subjects who had a lower overall number of days receiving vasopressors, the daily mean arterial pressure (MAP) improved after the second day of treatment during the study period (mean days in the SOC group were 6.5 vs 8). Figures 27A-27B , Figure 24 Similarly, among patients treated with CER-001, the number of days of mechanical ventilation (mean 16.7 vs 26.5 days) was lower. Figure 23 During the study period, both SOC participants required dialysis, while only 3 out of 7 CER-001-treated patients required dialysis. Figures 25A-25B ).

[0930] Finally, the need for any form of organ support (including the composite endpoint of mechanical ventilation, dialysis, and / or use of vasopressors) was lower in treated subjects (mean days of survival versus no organ support: 5.8 vs 2). Figure 26 Overall, these results indicate that patients receiving CER-001 treatment experienced more rapid improvement in clinical condition.

[0931] Specifically, the results show that:

[0932] • CER-001 has a direct and significant effect on endotoxin removal and the resulting reduction of the inflammatory cascade or "cytokine storm".

[0933] •CER-001's significant protective effect on endothelial function

[0934] • Patients treated showed a trend of shorter ICU days, lower organ support requirements, and improved 30-day survival.

[0935] • Enhance the recognized safety features of CER-001

[0936] 8.2. Example 2. CER-001 was administered considering the measured ApoA-I levels in each subject.

[0937] Subjects with sepsis had their serum ApoA-I levels determined by ELISA. Subjects with ApoA-I levels below normal (“low ApoA-I levels”) received CER-001 twice daily until the next determination. In each case prior to CER-001 administration, serum ApoA-I levels were assessed on days 1, 3, 6, and 9. Specifically, the day 1 value was determined before any dosing; the day 3 value was determined approximately 12 hours after administering the fourth dose to any subject with low Apo-I levels on day 1; the day 6 value was determined 60 hours after administering the sixth dose to any subject with low Apo-I levels on day 3; and the day 9 value was determined 60 hours after administering the last dose to any subject with low Apo-I levels on day 6.

[0938] Subjects with sepsis had a range of ApoA-I levels on day 1 prior to CER-001 treatment. Subjects whose ApoA-I levels returned to normal had better clinical outcomes compared to subjects whose ApoA-I levels did not return to normal.

[0939] 8.3. Discussion of Examples

[0940] Current treatment guidelines for sepsis patients are based on hemodynamic resuscitation, supportive therapy, and adequate antibiotic therapy. However, in most critically ill patients, these measures are insufficient to prevent sepsis-related organ dysfunction and the onset of acute kidney injury (AKI). The findings described in the examples demonstrate that, in a pilot clinical study testing the safety and efficacy of CER-001 in a heterogeneous cohort of sepsis patients, CER-001 treatment has been shown to enhance LPS removal, modulate the inflammatory response secondary to sepsis, and prevent endothelial and organ dysfunction.

[0941] In the clinical study of Example 1, CER-001 was administered twice daily for three days, followed by two doses on day 6. A trend toward increased serum ApoA-I levels relative to standard care was observed in subjects receiving CER-001 on day 3, but subnormal ApoA-I levels were observed in some subjects on day 6 (see example...). Figures 30A-30BThis was also observed in some subjects who received relatively high doses of exogenous ApoA-I (as part of CER-001). Without being bound by theory, it is believed that this observation is due to increased ApoA-I clearance in some subjects, which may be exacerbated by impaired ApoA-I production in some subjects in intensive care settings. Furthermore, it is believed that ApoA-I levels are associated with clinical benefit, and that improved treatment benefits in subjects with sepsis and other conditions (e.g., the acute conditions described herein) can be achieved by administering lipid-binding protein molecules such as ApoA-I with a dosing regimen that increases subnormal ApoA-I levels to at least normal levels and / or maintains at least normal levels (e.g., >1.1 g / L).

[0942] In summary, this disclosure provides novel treatment methods for conditions (e.g., acute conditions such as sepsis) using lipid-binding protein molecules, such as ApoA-I, included in lipid-binding protein molecule-based complexes such as CER-001.

[0943] Although various specific implementations have been shown and described, it will be appreciated that various changes can be made without departing from the spirit and scope of this disclosure.

[0944] 9. Merging by reference

[0945] All publications, patents, patent applications and other documents cited in this application are incorporated herein by reference in their entirety for all purposes, as if each individual publication, patent and patent application or other document were individually indicated for all purposes and incorporated herein by reference.

[0946] Any discussion of documents, actions, materials, devices, articles, etc., included in this specification is for the purpose of providing context for this disclosure only. It should not be construed as an admission that any or all of these matters constitute part of the prior art or are common general knowledge in the field relating to this disclosure, as they existed anywhere prior to the priority date of this application.

Claims

1. A method of treating a subject suffering from or at risk of a condition treatable with lipid-binding protein molecules, wherein the condition is optionally sepsis (e.g., septic shock), the method comprising: (a) Optionally, administer one or more doses of lipid-binding protein molecules to the subject; (b) Measure the subject's ApoA-I or HDL levels; and (c) If the measured ApoA-I level is below the target ApoA-I level or the target ApoA-I range, or if the measured HDL level is below the target HDL level, then administer one or more doses of the lipid-binding protein molecule to the subject.

2. The method of claim 1, comprising administering one or more doses of the lipid-binding protein molecule to the subject prior to step (b).

3. The method of claim 2, wherein step (b) comprises measuring the ApoA-I level or HDL level 0.5 days to 1 week after the most recent administration of the lipid-binding protein molecule.

4. The method of claim 2 or 3, wherein step (b) comprises measuring the ApoA-I level or HDL level the day after the most recent administration of the lipid-binding protein molecule.

5. The method of any one of claims 1 to 4, further comprising repeating steps (b) and (c) once or more.

6. The method of claim 5, wherein steps (b) and (c) are repeated until the measured ApoA-I level is at or above the target ApoA-I level or within the target ApoA-I range, or until the measured HDL level is at or above the target HDL level.

7. The method of any one of claims 1 to 6, comprising step (a), and further comprising: (d) If the measured ApoA-I level or HDL level is at or above the target ApoA-I level, within the target ApoA-I range, or at or above the target HDL level, then one or more doses of the lipid-binding protein molecule are administered to the subject at a lower dose and / or frequency than in step (a).

8. The method of any one of claims 1 to 7, wherein the ApoA-I level is a serum, plasma, or whole blood ApoA-I level.

9. The method of any one of claims 1 to 8, wherein the target ApoA-I level is the normal ApoA-I level of a healthy subject.

10. The method of any one of claims 1 to 9, wherein the target ApoA-I range is the normal ApoA-I range of a healthy subject.

11. The method of any one of claims 1 to 10, wherein the HDL level is a serum, plasma, or whole blood HDL level.

12. The method of any one of claims 1 to 11, wherein the HDL level is the HDL cholesterol (HDL-C) level.

13. The method of any one of claims 1 to 12, wherein the target HDL level is the normal HDL level of a healthy subject.

14. The method of any one of claims 1 to 13, wherein the ApoA-I level is an ApoA-I level as measured by enzyme-linked immunosorbent assay (ELISA), immunoturbidimetry, or immunoturbidimetry.

15. The method of any one of claims 1 to 14, wherein the HDL level is the HDL-C level as measured by an enzymatic assay of cholesterol oxidase (CHOD) and cholesterol esterase (CHER).

16. The method of any one of claims 1 to 15, wherein the condition is an acute condition.

17. The method of any one of claims 1 to 16, wherein the disease is sepsis.

18. The method of any one of claims 1 to 16, wherein the condition is sepsis-induced cognitive deficit.

19. The method of claim 17 or claim 18, wherein the subject suffers from sepsis.

20. The method of claim 19, wherein the subject suffers from septic shock.

21. The method of claim 19 or claim 20, wherein the subject is at risk (e.g., high risk) of developing acute kidney injury.

22. The method of any one of claims 1 to 21, wherein the subject suffers from a bacterial infection, optionally an antibiotic-resistant bacterial infection (e.g., MRSA).

23. The method of any one of claims 1 to 21, wherein the subject has a viral infection.

24. The method of any one of claims 1 to 16, wherein the condition is acute myocardial infarction (AMI), cytokine release syndrome (CRS), ischemia-reperfusion induced tissue damage, postoperative inflammation, sepsis-induced acute kidney injury (AKI), or hypoalbuminemia.

25. The method of any one of claims 1 to 16, wherein the condition is asthma, such as acute severe asthma.

26. The method of any one of claims 1 to 16, wherein the condition is graft-versus-host disease (GVHD), optionally wherein the subject has received stem cell transplantation, bone marrow transplantation, or organ transplantation.

27. The method of any one of claims 1 to 26, wherein the subject has CRS or is at risk of CRS.

28. The method of any one of claims 1 to 27, wherein the subject has acute kidney injury (AKI) or is at risk of developing acute kidney injury (AKI).

29. The method of any one of claims 1 to 28, wherein the subject has acute respiratory distress syndrome (ARDS) or is at risk of acute respiratory distress syndrome (ARDS).

30. The method of any one of claims 1 to 29, wherein the lipid-binding protein molecule is an apolipoprotein.

31. The method of claim 30, wherein the apolipoprotein is ApoA-I.

32. The method of claim 31, wherein the ApoA-I has the amino acid sequence of amino acids 25-267 of SEQ ID NO:

2.

33. The method of claim 31 or claim 32, wherein the ApoA-I is recombinant ApoA-I.

34. The method of claim 33, wherein the ApoA-I is produced by mammalian host cells.

35. The method of claim 34, wherein the mammalian host cell is a Chinese hamster ovary (CHO) cell.

36. The method of claim 35, wherein the CHO cells are CHO-S cells.

37. The method of any one of claims 1 to 36, wherein the lipid-binding protein molecule is a component of a lipid-binding protein-based complex, optionally wherein the lipid-binding protein-based complex is a reconstructed HDL or an HDL mimic.

38. The method of claim 37, wherein the lipid-binding protein-based complex is CER-001.

39. The method of any one of claims 1 to 38, wherein the lipid-binding protein molecule is administered systemically, optionally by infusion.

40. The method of any one of claims 1 to 39, wherein each individual dose of the lipid-binding protein molecule applied in step (c) is from 4 mg / kg to 40 mg / kg (based on protein weight).

41. The method of any one of claims 1 to 39, wherein each dose of the lipid-binding protein molecule applied in step (c) is from 300 mg to 4000 mg (by protein weight).

42. The method of any one of claims 1 to 41, wherein the subject is receiving or has received one or more additional therapies, and / or the method further comprises administering one or more additional therapies to the subject.

43. The method of claim 42, wherein the one or more additional therapies comprise one or more standard care therapies for the condition.

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