Methods for treating acute conditions using lipid-binding protein-based complexes

Abstract

The present invention provides compounds used for the treatment of acute conditions including sepsis, sepsis-associated AKI, ischemia / reperfusion AKI, and CSA AKI, as well as CRS, such as CRS associated with immunotherapy and CRS secondary to infections like COVID-19. [Solution] A lipid-binding protein-based complex is provided for use in a method of treating an acute condition, the method comprising the step of administering a high dose of the lipid-binding protein-based complex to a subject in need thereof, the acute condition may include acute inflammation.

Description

[Technical Field]

[0001] 1. Cross-reference of related applications This application is U.S. Provisional Application No. 63 / 011,055, filed on April 16, 2020. Filing No. 63 / 092,070 on October 15, 2020, and December 2020 This claim asserts the benefit of priority from patent no. 63 / 121,640, filed on the 4th of the month, and The contents of each of these are incorporated herein by reference to them as a whole.

[0002] 2. Sequence Listing This application includes sequence listings submitted electronically in ASCII format, and by reference thereof This entirety is incorporated herein. ASCI created April 13, 2021. The copy is titled CRN-039WO_SL.txt and has a size of 2519 bytes. . [Background technology]

[0003] 3.Background Various acute conditions, such as sepsis, acute kidney injury (AKI), and cytokine release syndrome. Conditions that may be associated with acute inflammation, such as CRS (Chronic Red Streptococcus), are commonly observed and potentially life-threatening. Current treatments for such conditions are often inadequate or suboptimal.

[0004] 3.1. Sepsis Sepsis is a potentially life-threatening condition caused by infection that can lead to damage to tissues and organs. It is a systemic immune response that threatens [the body] (Singer et al., 2016, JAMA. 315(8):801-10). Common signs and symptoms of hememia include fever, increased heart rate, increased respiratory rate, and cough. Includes delusion (confusion). A cough associated with pneumonia, or painful urination associated with a kidney infection, etc. Symptoms associated with heterologous infection may also be present (Jui et al., 2011, "Ch. 146: Septic Shock." In Tintinalli JE, et al. (eds.). Tintinalli's Emergency Medicine: A Comprehensive S Study Guide (7th ed.). New York: McGraw-Hill. pp. 1003-14). Severe sepsis is not adequately treated. It may be related to the function of certain organs or blood flow (Dellinger et al., 2013, Critical Care Medici ne. 41(2):580-637). The presence of hypotension, hyperlactate, or hypourinary excretion indicates insufficient blood flow. This may suggest that sepsis can progress to septic shock, which requires fluid replacement. t) Characterized by hypotension that does not improve later (Dellinger et al., 2013, Critical Care Medicine. 41(2):580-637).

[0005] Bacterial infections are the most common cause of sepsis, but fungi, viruses, and protozoa can also cause it. Infection can also lead to sepsis (Jui et al., 2011, "Ch. 146: Septic Shock." In Tintin alli JE, et al. (eds.). Tintinalli's Emergency Medicine: A Comprehensive Study G uide (7th ed.). New York: McGraw-Hill. pp. 1003-14). Common locations for primary infection. This includes the lungs, brain, urinary tract, skin, and abdominal organs (Jui et al., 2011, "Ch. 146: Septic) Shock." In Tintinalli JE, et al. (eds.). Tintinalli's Emergency Medicine: A Com Prehensive Study Guide (7th ed.). New York: McGraw-Hill. pp. 1003-14). Risk factors Children may be very young, elderly, have a weakened immune system due to conditions such as cancer or diabetes, or be large This includes trauma or burns (www.cdc.gov / sepsis / what-is-sepsis.html). Sepsis diagnosis is Also known as the Quick SOFA Score (qSOFA), this is a shortened sequential organ failure assessment. Based on the score (SOFA score), it is determined that there are three things: increased respiratory rate, and level of consciousness. At least two of the following are required: changes in blood pressure and hypotension (Singer et al., 2016, JAM) A. 315(8):801-10).

[0006] Sepsis may require emergency treatment with intravenous fluid resuscitation and antimicrobial agents (Rhodes et al., 2017, Intensive Care Medicine. 43(3):304-377). Ongoing care is provided in the intensive care unit. This often persists. If appropriate attempts at fluid replacement are insufficient to maintain blood pressure, The use of medication to raise blood pressure may be necessary. It may also be necessary to support lung and kidney function. Mechanical ventilation and dialysis may be required. Other useful measures The parameters include cardiac output and superior vena cava oxygen saturation (Dellinger et al., 2013, Critical C are Medicine. 41(2):580-637).

[0007] The risk of death due to sepsis is as high as 30%, while for severe sepsis , it is as high as 50%, and for septic shock it is 80% (Jawad et al., 20 12, J Glob Health. 2(1):010404). Early detection and treatment are essential for survival and to limit disabilities.

[0008] 3.2. Acute kidney injury Acute kidney injury (AKI) frequently occurs in ICU patients and has an estimated incidence of >50% (Hoste et al., 2015, Intensive Care Med; 41:1411-1423). Furthermore , an increase in AKI severity is associated with an increase in mortality. Sepsis is the main cause of AKI, accounting for 45% - 70% of cases, and approximately 25% of sepsis cases are from abdominal viscera (Seymour et al., 2016, JAMA, 315:762-774; Bagshaw et al., 2007, Clin J Am Soc Nephrol, 2:431-439). Ischemia / reperfusion injury (IRI) can cause AKI and is a common complication seen in organ transplant recipients, with an incidence of 50 - 75% after lung and heart transplantation (Gueler et al., 2014, Transplantation 98:337-338). Cardiac surgery-related AKI ( CSA AKI) has been reported to occur in up to 3*% of patients undergoing cardiac surgery (Rosner and Okusa, 2006, Clin J Am Soc Nephrol. 1(1):19-323). Postoperative IL 6 and IL10 levels predict AKI onset and outcome (Zhang et al., 2015, J Am Soc Nephrol. 26(12):3123 - 32), there are no good treatment options other than dialysis (Kullmar et al., 2020, Crit Care Clin. 36(4):691 - 704).

[0009] Early diagnosis of AKI in the context of sepsis is important to provide optimal treatment and avoid further kidney injury (Peerapornratana et al., 2019, Kidney International 2019, 96:1083 - 1099). Treatment options for sepsis - related AKI are limited to symptomatic care. The use of blood filtration devices, including high - volume hemofiltration and polymyxin B hemoperfusion, has not shown significant benefit (Joannes - Boyau et al., 2013, Intensive care medicine, 39:1535 - 1546; Zhang et al., 2012, Nephrology, dialysis, transplantation: official publi cation of the European Dialysis and Transplant Association - European Renal Asso ciation 27:967 - 973; Vincent et al.,​​​​​​​​​​​​​​​With the exception of , and reltesimod (AB103), experimental pharmacological treatments are usually for sepsis. It targets AKI rather than disease-induced AKI. In recent clinical trials, recombinant AP did not reduce endogenous creatinine clearance, the primary clinical endpoint. It improved the secondary endpoint of mortality (Pickkers et al., 2018, JAMA, 320:1998-2020). 09). ATII refers to patients with AKI in the High Output Shock Study (ATHOS-3). Post-analysis showed some benefit, as demonstrated by the ASK-IT trial (NCT00711789). We are currently investigating sepsis-related AKI in [location], however, since 2011, No new research has been conducted. Levocarnitine is used in RACE studies for septic shock. It did not show improvement in organ dysfunction (Jones et al., 2018, JAMA network open, 1:e18) 6076) In the Carnisave trial (NCT02664753), AK It is currently under investigation as an adjunctive treatment for septic shock patients with condition I. D is a Phase 3 placebo-controlled trial (NCT0340) in patients with sepsis-related AKI. The investigation was conducted in 3751), but it was recently terminated due to poor registration rates. (clinicaltrials.gov / ct2 / show / NCT03403751)

[0011] Alterations in lipid and lipoprotein metabolism occur during infection, affecting host defense or tissue repair. It has been reported that this leads to the redistribution of nutrients to important cells (Khovidhunkit et al., 2004, J Lipid Res, 45(7):1169-96). In addition, lipoproteins and lipids They play a major role in host defense against infection, protecting the host from the toxic effects of microorganisms. Protect (Feingold and Grunfeld, 2012, J Lipid Res. 53(12):2487-248). High-density lipo Protein (HDL) is a major component of circulating blood, mainly composed of phospholipids and free cholesterol. Terol, cholesteryl ester, triglyceride, apolipoprotein (ApoA-I) It contains proteins such as ApoA-II and other proteins. It is important for vascular endothelial function and immunity. It is thought to be an anti-inflammatory lipoprotein that regulates disease (Singh et al., 2007, JAMA, 298(7)). :786-798; Navab et al., 2011, Nat Rev Cardiol 8(4):222-32). In fact, HDL is immune This includes suppression of inflammatory signaling and direct inhibition of endothelial activation in epidemic effector cells. Furthermore, it plays a crucial protective role in all steps of endothelial dysfunction. Clinical research has shown that HDL levels drop by 40-70% during systemic inflammation, which is a prognosis in sepsis patients. It has been demonstrated that it is associated with poor outcomes (van Leeuwen et al., 2003, Critical Care Medicine). cine, 31:1359-1366;Chien et al., 2005, Critical care medicine, 33:1688-1693;Ts ai et al., Journal of hepatology, 50:906-915;Eggesbφ et al., 1996, Cytokine, 8 (2):152-160;Morin et al., 2015, Frontiers in Pharmacology, doi.org / 10.3389 / fpha (r.2015.00244). Furthermore, low levels of HDL are associated with acute kidney injury (AK) in the course of sepsis. I) is associated with an increased risk (Roveran et al., 2017, Journal of International l medicine, 281:518-529;Zhang et al., 2009, Am J Physiol Heart Circ Physiol 297 (H866-H873). The kidneys are involved in the recycling of aging HDL particles, and their filtering function is Because of their levels and contents, renal function and plasma HDL are strongly related to each other. (Yang et al., 2016, Current opinion in nephrology and hypertension, 2) 5:174-179).

[0012] Treatment based on HDL has been proposed for septic-induced systemic inflammatory response syndrome. Morin et al., 2015, Frontiers in Pharmacology, doi.org / 10.3389 / fphar.2015.00244 (Tanaka et al., 2020, Crit Care 24:134). Several studies have shown that recombinant HDL(r Correction of abnormal lipoproteinemia caused by HDL is crucial for inhibiting and treating systemic inflammatory responses. This suggests that it may provide a positive transition (Morin et al., 2015, Frontiers in Pharmac). doi.org / 10.3389 / fphar.2015.00244;Roveran et al., 2017, Journal of intern al medicine, 281:518-529;Pajkrt et al., 1996, Journal of Experimental Medicine, 184(5): 1601-1608;Pajkrt et al., 1997, Thrombosis and Haemostasis 77(2):303-7 ;Guo et al., 2013, J. Biol. Chem. 288(25):17947-53;Li et al., 2008, European j McDonald et al., 2003, Shock 20(6):551-7). CSL-11 is an rHDL originally produced for the treatment of atherosclerosis. 1 (Tardif et al., 2007, JAMA, 297(15):1675-82) describes in vitro and rabbit odor (Casas et al., 1995, The Journal of Surgical Research, 59:544-552) and also In the model (Pajkrt et al., 1996, Journal of Experimental Medicine, 184(5): 1601-8; Pajkrt et al., 1997, Thrombosis and Haemostasis, 77(2):303-7), LPS-induced It has shown efficacy in reducing the inflammatory response during induced endotoxemia in a human model. In this context, CSL-111 infusion is used to address the procoagulant state caused by endotoxin exposure. It reduces monocyte activation and cytokine production, thereby improving clinical symptoms. This has been shown (Pajkrt et al., 2016, Journal of Experimental Medicine, 184(5): 160 1-1608;Pajkrt et al., 1997, Thrombosis and Haemostasis, 77(2):303-7). ApoA ApoA1 Milano, a natural variety of A1, was shown in Phase I trials (Casas et al.). (1995, The Journal of Surgical Research, 59:544-552) and other further clinical studies In the context of cardiovascular disease (CVD), it was widely investigated. Recently, Zhang and My colleague also found that ApoA1 is effective against inflammation in a rat model of endotoxemia. This was demonstrated (Zhang et al., 2015, Biological Chemistry, 396(1):53-60). HDL imitation. Among body peptides, L-4F has been adopted in several preclinical models of sepsis. It blocks cytokine production, reverses sepsis-induced hypotension, and prevents organ damage. It has been shown to restore kidney, liver, and cardiac function and increase survival rates. (Zhang et al., 2009, Am J Physiol Heart Circ Physiol 297: H866-H873). serum lipids Changes in levels, particularly cholesterol levels, are associated with human immunodeficiency virus (HIV) and It has also been reported to occur between viral infections, including hepatitis C virus (HCV). (Meher et al., 2019, J. Phys. Chem. B, 123(50):10654-10662). HDL And despite interest in HDL therapies, sepsis-related AKI, ischemia / reperfusion AKI, And regulatory approval for the treatment of sepsis or AKI, including CSA AKI. There is no HDL or HDL mimic available.

[0013] 3.3. Cytokine Release Syndrome Cytokine release syndrome (CRS), also known as cytokine storm syndrome (CSS). ) is a type of infection, or a part of immunotherapy such as monoclonal antibody and adoptive T-cell therapy in Thailand. This is a systemic inflammatory response that can be triggered by various factors, including treatment using p (Shimab). ukuro-Vornhagen, et al., 2018, J. Immunotherapy Cancer, 6:56). The symptoms of CRS are, Symptoms include fever, nausea, headache, rash, tachycardia, hypotension, and difficulty breathing. (This is especially true for those with CRS.) Most patients have a mild reaction, but sometimes CRS can be severe and even life-threatening. (NCI Dictionary of Cancer Terms(www.cancer.gov / publications / dictionaries / can cer-terms / def / cytokine-release-syndrome)).

[0014] Since the latter half of 2019, a new coronavirus called COVID-19 (SARS-CoV-19) has emerged. V-2) is spreading worldwide. The data shows high levels of interleukin-6 (IL-6). In patients with severe illness accompanied by present symptoms, there may be mild or severe cytokine storms. This suggests that CRS may be a contributing factor to the death of these patients (Zhang et al., 2020). , International Journal of Antimicrobial Agents, doi.org / 10.1016 / j.ijantimicag.2 020.105954;Mehta et al., 2020, The Lancet, 395(10229):1033-1034).

[0015] Therefore, it includes sepsis, sepsis-related AKI, ischemia / reperfusion AKI, and CSA AKI. Meta-AKI, as well as CRS, for example, CRS and COVID-19 associated with immunotherapy. There remains a need for new treatments for acute conditions such as CRS that develops as a result of infections like these. [Overview of the project]

[0016] 4. Overview This disclosure describes the use of high-dose lipid-binding protein-based complexes to treat acute conditions, such as acute This provides a method for treating subjects with pathological conditions associated with inflammatory inflammatory disease. High doses are typical. The dose that would be used to treat chronic conditions such as familial hypercholesterolemia. Higher than that. High doses are typically administered over a relatively short period, for example, 3 days to 2 weeks. It is administered over time, typically multiple doses of lipid-binding protein-based complexes, for example This includes 3 to 10 individual doses. Each individual dose is for less than one day (e.g., twice a day). Alternatively, it can be divided into doses over one day or several days (for example, once a day).

[0017] In some embodiments of the methods disclosed herein, the lipid-binding protein-based complex is suf Contains ingomyelin and / or negatively charged lipids, e.g., CER-001. -001 is a negatively charged lipoprotein complex, recombinant human ApoA-I, S Fingomyelin (SM), and 1,2-dihexadecanoyl-sn-glycero-3- Phospho-(1'-rac-glycerol)(dipalmitoylphosphatidyl-glycerol) It contains DPPG (Dihydrogen-Drug Particles). It is the form that HDL particles take before obtaining cholesterol. It mimics naturally occurring, newly formed, disc-shaped pre-beta HDL. Without being constrained by theory, CER-001 therapy may reduce serum levels of inflammatory cytokines such as IL-6, Therefore, it is necessary to identify individuals who have an acute condition or are at risk of developing an acute condition, such as those with acute inflammatory conditions. It is thought to provide clinical benefits to subjects who have or are at risk of having [the condition].

[0018] In some embodiments, this disclosure relates to lipid-binding protein-based complexes (e.g., CER A method for treating a subject with sepsis using -001), and a subject with AKI Alternatively, it provides methods for treating individuals at risk of AKI.

[0019] In one embodiment, the present disclosure relates to a lipid-binding protein-based complex (e.g., CER A method for treating a subject with sepsis is provided, including the step of administering to the subject (-001). do.

[0020] In another embodiment, the present disclosure relates to lipid-binding protein-based complexes (e.g., CER- The step of administering to a person with acute kidney injury (AKI) or AKI (001) is included. Patients at risk (for example, patients with sepsis who have not yet developed AKI, organs) recipients of organ transplants, or those who have undergone cardiac surgery, or those with acute or chronic conditions. This provides a method for treating patients with liver disease who are at risk of hepatorenal syndrome (HRS). ru.

[0021] In some embodiments, this disclosure relates to lipid-binding protein-based complexes (e.g., CER -001) is used to treat cytokine release syndrome (CRS) in subjects that require it. To propose methods for treating and / or reducing one or more inflammatory markers. To provide.

[0022] In one embodiment, the disclosure relates to a therapeutically effective amount of a lipid-binding protein-based compound applied to a target. A procedure comprising the step of administering a body (e.g., CER-001) having CRS or CRS Individuals at risk, such as those with CRS secondary to COVID-19 or those with immune systems. This invention provides a method for treating subjects with CRS caused by therapy.

[0023] In another embodiment, the Disclosure relates to one or more inflammatory media in subjects requiring it. Serum levels of one or more markers associated with CRS, such as IL-6. The method provides a way to reduce it. The target is, for example, a person who has CRS or is at risk of CRS. A subject, for example, a subject infected with a virus such as COVID-19 or a subject receiving immunotherapy. It could be one of those targets.

[0024] In some aspects, this disclosure relates to acute pathological conditions (e.g., those associated with acute inflammation), such as death. Septicemia, AKI (e.g., sepsis, ischemia / reperfusion, cardiac surgery, or hepatorenal syndrome) Having an AKI (or AKI) or having a sepsis that has not yet progressed to an AKI (for example, sepsis that has not yet progressed to an AKI) Lipid-binding therapy for subjects with the disease or subjects at risk of acute conditions such as CRS. Provides drug regimens for protein-based therapies (e.g., CER-001 therapy). .

[0025] The drug regimens described herein typically involve multiple administrations of CER-001 to the subject. For example, administered daily. CER-001 therapy is administered for a predetermined period, for example, one week or one week. It can last for a longer period than a week (for example, two weeks). Alternatively, CER-00 to the target Administration of drug 1 is for the lowering of one or more symptoms of an acute condition (e.g., acute inflammation or CRS). This may continue until diarrhea occurs, or the serum levels of one or more inflammatory markers may decrease. For example, it may decrease to a normal level, or the baseline levels that were measured before the start of CER-001 therapy. Compared to line measurements, this may continue until it decreases. CRS or AKI caused by infection. For patients at risk of developing CRS, or at risk of CRS due to immunotherapy, In some embodiments, this continues until the subject recovers from the infection or discontinues immunotherapy. It can continue.

[0026] The drug regimen described herein involves targeting lipid-binding proteins in accordance with the initial "induction" regimen. The steps include administering the base complex (e.g., CER-001), followed optionally by... Steps to administer a lipid-binding protein-based complex to the subject according to the "enhancement" regimen It may be accompanied by a p.

[0027] Inducement regimens typically involve targeting lipid-binding protein-based complexes (e.g., CE). The step of administering multiple doses of R-001), for example, six doses over three days. include.

[0028] An intensification regimen is typically administered after the final dose of the induction regimen, for example, the final dose of the induction regimen. One day or several days after the final dose, the target is subjected to a lipid-binding protein-based complex (e.g.) The step includes administering one or more doses of CER-001. In this regimen, the first dose of the intensification regimen is administered on the third day after the final dose of the induction regimen. For example, the drug regimen is one in which lipids are administered to a subject according to the induction regimen on days 1, 2, and 3. Administration of a binding protein-based complex (e.g., CER-001), as well as strong treatment on day 6. This may include administering a lipid-binding protein-based complex to a subject according to a chemical regimen. In this embodiment, the reinforcement regimen is a two-dose lipid-binding protein-based complex. Includes.

[0029] In certain embodiments, this disclosure, - A dose twice daily on days 1, 2, and 3 (induction regimen), with the option of adding to that. To be continued, - Two follow-up doses (intensified regimen) on day 4 or thereafter. According to the drug regimen, a lipid-binding protein-based complex (e.g., CER-0) is administered. 01) Using this method, subjects with CRS, sepsis, or AKI, or CRS or How to treat individuals at risk of AKI (e.g., individuals with COVID-19) To provide. In some embodiments, the regimen is - A dose twice daily on days 1, 2, and 3 (induction regimen), followed by, - Two doses on day 6 (intensified regimen) Includes.

[0030] In a particular embodiment, lipid-binding protein-based complexes (e.g., CER-00) 1) Standard care for sepsis, including antibiotic therapy and / or hemodynamic support. It is administered in combination with the other.

[0031] In a particular embodiment, lipid-binding protein-based complexes (e.g., CER-00) 1) Before administering the drug, take an antihistamine (e.g., dexchlorpheniramine, hydroxydi (Diphenhydramine, cetirizine, fexofenadine, or lorantadine) It may be administered. Antihistamines can reduce the likelihood of an allergic reaction. [Brief explanation of the drawing]

[0032] 5. Brief description of the drawing [Figure 1] This graph shows the serum IL-6 levels in a porcine model of sepsis-induced AKI (Example 1). [Figure 2] This graph shows the serum levels of soluble VCAM-1 in a porcine model of sepsis-induced AKI (Example 2). [Figure 3] This graph shows the serum levels of soluble ICAM-1 in a porcine model of sepsis-induced AKI (Example 3). [Figure 4] This graph shows the serum LPS levels in a porcine model of sepsis-induced AKI (Example 1). [Figure 5] This figure shows an overview of the clinical investigation in Example 2. [Figure 6] This is a flowchart for the investigation of Example 3. [Figure 7] This is a flowchart for the investigation of Example 4. [Modes for carrying out the invention]

[0033] 6. Detailed explanation This disclosure describes the use of high-dose lipid-binding protein-based complexes to treat acute conditions, such as acute This invention provides a method for treating subjects with acute conditions, including inflammatory bowel movements.

[0034] In one embodiment, the present disclosure relates to a lipid-binding protein-based complex (e.g., CER A method for treating a subject with sepsis is provided using -001).

[0035] In other embodiments, this disclosure relates to lipid-binding protein-based complexes (e.g., CER- 001) is used (for example, in sepsis, viral infection, ischemia / reperfusion, cardiac surgery, and (This refers to patients who have acute kidney injury (AKI) or are at risk of AKI due to hepatorenal syndrome.) To provide a method for treating elephants.

[0036] In other embodiments, this disclosure may apply to subjects that have or are at risk of having a CRS, for example This is a condition in patients with CRS secondary to COVID-19 or caused by immunotherapy. This invention provides a method for treating subjects with CRS.

[0037] In some embodiments, the lipid-binding protein-based complex is an apomer. (Registered trademark), Cargomer (Registered trademark), HDL-based complex, or HDL It is a mimetic-based complex. In a specific embodiment, it is lipid-binding protein-based. The composite is CER-001.

[0038] Lipid-binding protein-based complexes that may be used in the methods and compositions disclosed herein Exemplary characteristics are described in Section 6.1. By the methods and compositions of the present disclosure Exemplary target populations that can be treated with this method are described in Section 6.2.

[0039] In some embodiments, the method disclosed herein involves targeting lipid-binding proteins in two steps. The procedure includes the step of administering a complex of lipids (e.g., CER-001). First, lipid-binding agents are administered. Protein-based complexes (e.g., CER-001) are used in the initial strong "induction" regimen. It is administered in this manner. A less potent "enhancement" regimen follows the induction regimen. Alternative Specifically, lipid-binding protein-based complexes (e.g., CER-001) are, for example, [details omitted]. Dosage regimens corresponding to the dosage and frequency of induction or intensification regimens described in the detailed document. Accordingly, it can be administered to the target in a single stage.

[0040] The derivative regimes that may be used in the methods of this disclosure are described in Section 6.3, and the methods of this disclosure Enhanced regimens that may be used in law are described in Section 6.3.2. Men can be used as a monotherapy or as part of a combination therapy with one or more medications, for example. In combination with standard care for sepsis, such as antibiotic treatment and / or hemodynamic support. In combination, a lipid-binding protein-based complex (e.g., CER-001) is administered. This includes steps. Combination therapies are described in Section 6.4.

[0041] 6.1. Lipid-binding protein-based complexes 6.1.1. HDL and HDL mimetic-based complexes In one embodiment, the lipid-binding protein-based complex is HDL or HDL mimic. This includes body-based complexes. For example, a complex is one in which each of its contents is referenced to others. The U.S. Patent No. 8,206,750, International Publication, is incorporated herein by reference in its entirety. Pamphlet No. 2012 / 109162, International Publication Pamphlet No. 2015 / 173633 Lett (e.g., CER-001), or U.S. Patent Application Publication No. 2004 / 022979 May include lipoprotein complexes as described in Specification No. 4. "Lipoprotein" and " The term "apolipoprotein" is used interchangeably herein and may vary depending on the context. Unless otherwise required, the term "lipoprotein" encompasses lipoprotein mimes. Includes. The terms "lipid-binding protein" and "lipid-binding polypeptide" also apply to this specification. As used interchangeably in writing, unless otherwise required by context, the term means a specific This does not imply a length of the amino acid sequence.

[0042] Lipoprotein complexes include protein fractions (e.g., apolipoprotein fractions) and It may contain lipid fractions (e.g., phospholipid fractions). The protein fraction may contain apolipoproteins. , peptides, or apolipoprotein peptide analogs or mimics, one or more of these. A number of lipid-binding protein molecules, for example, one or more lipids as described in Section 6.1.2. Contains binding protein molecules.

[0043] Lipid fractions are typically neutral, negatively charged, positively charged, or a combination thereof. It contains one or more phospholipids that may be present in the lipid fraction. Other amphiphilic molecules are described in Section 6.1.3.

[0044] In a particular embodiment, the lipid fraction comprises at least one neutral phospholipid (for example, Sphingomyelin (SM), and optionally one or more negatively charged phospholipids. It contains both neutral and negatively charged phospholipids in a lipoprotein complex. In this context, neutral and negatively charged phospholipids have the same or different number of carbon atoms, and the same Alternatively, they may have fatty acid chains with different degrees of saturation. In some cases, they may be neutral and negatively charged. The electrolyzed phospholipid has the same acyl tail, for example, C16:0, or portitoyl, acyl chain. It will have. In specific embodiments, particularly those in which egg SM is used as a neutral lipid, The weight ratio of apolipoprotein fraction to lipid fraction is approximately 1:2.7 to approximately 1:3 (for example, This is within the range of 1:2.7).

[0045] Any phospholipid that has at least a partial negative charge at physiological pH is negatively charged It can be used as a lipid. Non-exclusive examples include phosphatidylinositol, phosphatidylinositol. Negatively charged forms of dyrserine, phosphatidylglycerol, and phosphatidic acid , for example, salt. In a specific embodiment, the negatively charged phospholipid is phosphatidyl 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac] is a glycerol. -(1-glycerol)], i.e., DPPG. Preferred salts are potassium and sodium. Contains thorium salts.

[0046] In some embodiments, the lipoprotein complex used in the methods of this disclosure is The contents of each of these are incorporated herein by reference as a whole, U.S. 8 Specification No. 206,750 or International Publication No. 2012 / 109162 ( (and its U.S. counterpart, U.S. Patent Application Publication No. 2012 / 0232005) The lipoprotein complex is described. In a particular embodiment, the lipoprotein complex The protein components are described in International Publication No. 2012 / 109162 (and in the US). Section 6.1 and preferably Section 6.1 of the National Patent Application Publication No. 2012 / 0232005. As described in Section 6.1.1, the lipid components are as stated in International Publication No. 2012 / 109 Brochure No. 162 (and U.S. Patent Application Publication No. 2012 / 0232005) As described in Section 6.2, these are optional and are included in International Publication No. 2012 / 1 Brochure No. 09162 (and U.S. Patent Application Publication No. 2012 / 0232005 specification) They can be combined together in the quantities described in Section 6.3 of the book. These are incorporated by reference in this specification. In certain embodiments, the references in this disclosure The polyprotein complex is an international publicly available Brochure No. 2012 / 109162 (and U.S. Patent Application Publication No. 2012 / 02) As described in Section 6.4 of Specification No. 32005, at least 85%, at least A composite that is 90%, at least 95%, at least 97%, or at least 99% homogeneous. The body is in a collective state.

[0047] In specific embodiments, lipoprotein complexes that may be used in the methods of this disclosure It consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 50-80 resinase molecules. Contains tin and 20-50 SM molecules.

[0048] In another specific embodiment, lipoprotein complex that may be used in the method of the present disclosure The compound consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 50 lecithin molecules. It contains , and 50 molecules of SM.

[0049] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 80 molecules of Contains lecithin and 20 molecules of SM.

[0050] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 70 molecules of Contains lecithin and 30 molecules of SM.

[0051] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 60 molecules of Contains lecithin and 40 molecules of SM.

[0052] In specific embodiments, lipoprotein complexes that may be used in the methods of this disclosure It consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 50-80 resinase molecules. It essentially consists of tin and 20-50 SM molecules.

[0053] In another specific embodiment, lipoprotein complex that may be used in the method of the present disclosure The compound consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 50 lecithin molecules. It essentially consists of 50 molecules of SM.

[0054] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 80 molecules of It essentially consists of lecithin and 20 molecules of SM.

[0055] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 70 molecules of It essentially consists of lecithin and 30 molecules of SM.

[0056] In yet another specific embodiment, lipotams that may be used in the method of the present disclosure The complex consists of 2-4 ApoA-I equivalents, 2 charged phospholipid molecules, and 60 molecules of It essentially consists of lecithin and 40 molecules of SM.

[0057] In specific embodiments, lipoprotein complexes that may be used in the methods of this disclosure It contains approximately 90-99.8 wt% SM and approximately 0.2-10 wt% negatively charged phospholipids. Quality, for example, approximately 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt %, 0.2~5wt%, 0.2~6wt%, 0.2~7wt%, 0.2~8wt%, 0. Lipid components containing 2-9 wt% or 0.2-10 wt% negatively charged total phospholipids. Includes. In another specific embodiment, lipoproteins that may be used in the methods of the present disclosure The lecithin complex contains approximately 90-99.8 wt% lecithin and approximately 0.2-10 wt% negative lecithin. Charged phospholipids, for example, about 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2~4wt%, 0.2~5wt%, 0.2~6wt%, 0.2~7wt%, 0.2~ Contains 8 wt%, 0.2-9 wt%, or 0.2-10 wt% negatively charged total phospholipids. nothing.

[0058] In specific embodiments, lipoprotein complexes that may be used in the methods of this disclosure It contains approximately 90-99.8 wt% SM and approximately 0.2-10 wt% negatively charged phospholipids. Quality, for example, approximately 0.2-1 wt%, 0.2-2 wt%, 0.2-3 wt%, 0.2-4 wt %, 0.2~5wt%, 0.2~6wt%, 0.2~7wt%, 0.2~8wt%, 0. Lipids essentially consisting of 2-9 wt% or 0.2-10 wt% negatively charged total phospholipids. Includes qualitative components. In another specific embodiment, it may be used in the method of the present disclosure. The lipoprotein complex consists of approximately 90-99.8 wt% lecithin and approximately 0.2-10 wt% lecithin. t% of negatively charged phospholipids, for example, about 0.2-1 wt%, 0.2-2 wt%, 0.2- 3wt%, 0.2~4wt%, 0.2~5wt%, 0.2~6wt%, 0.2~7wt% , 0.2~8 wt%, 0.2~9 wt%, or 0.2~10 wt% negatively charged total ri It is essentially made up of lipids.

[0059] In yet another specific embodiment, a repotential that may be used in the method of this disclosure The protein complex contains approximately 9.8-90 wt% SM, approximately 9.8-90 wt% lecithin, and and approximately 0.2-10 wt% negatively charged phospholipids, for example, from approximately 0.2-1 wt%, 0 .2~2wt%, 0.2~3wt%, 0.2~4wt%, 0.2~5wt%, 0.2~6 wt%, 0.2~7wt%, 0.2~8wt%, 0.2~9wt%, 0.2~10wt% It contains a lipid fraction including negatively charged total phospholipids up to a certain point.

[0060] In yet another specific embodiment, a repotential that may be used in the method of this disclosure The protein complex contains approximately 9.8-90 wt% SM, approximately 9.8-90 wt% lecithin, and and approximately 0.2-10 wt% negatively charged phospholipids, for example, from approximately 0.2-1 wt%, 0 .2~2wt%, 0.2~3wt%, 0.2~4wt%, 0.2~5wt%, 0.2~6 wt%, 0.2~7wt%, 0.2~8wt%, 0.2~9wt%, 0.2~10wt% It contains a lipid fraction essentially consisting of negatively charged total phospholipids up to a certain point.

[0061] In another specific embodiment, lipoprotein complex that may be used in the method of the present disclosure The compound contains the ApoA-I apolipoprotein and a lipid fraction, the lipid fraction being sphingol. It contains gomyophyllin and approximately 3 wt% negatively charged phospholipids, and the lipid fraction is ApoA-I The molar ratio of the polypoproteins is approximately 2:1 to 200:1, and the complex consists of 2 to 4 A These are small or large disc-shaped particles containing poA-I equivalents.

[0062] In another specific embodiment, lipoprotein complex that may be used in the method of the present disclosure The compound contains the ApoA-I apolipoprotein and a lipid fraction, the lipid fraction being sphingol. Essentially composed of gomyophyllin and approximately 3 wt% negatively charged phospholipids, lipid fraction vs. Ap The molar ratio of oA-I apolipoprotein is approximately 2:1 to 200:1, and the complex is 2 These are small or large disc-shaped particles containing approximately 4 ApoA-I equivalents.

[0063] HDL-based or HDL mimetic-based complexes are single-type lipid-binding proteins. Quality, or a mixture of two or more different lipid-binding proteins that may originate from the same or different species. It may contain a compound. Although not required, the compound preferably provides immunity to the therapy. To avoid inducing an epidemic response, use ingredients derived from the animal species being treated or amino acids. The acid sequence will likely contain the corresponding lipid-binding protein. Therefore, in the treatment of human patients In this regard, human-derived lipid-binding proteins are preferably used. The use of lipoproteins may also reduce or avoid the immune response.

[0064] In some embodiments, the lipid components are two types of phospholipids: sphingomyelia Contains phosphorus (SM) and negatively charged phospholipids. Exemplary SM and negatively charged lipids. This is described in Section 6.1.3.1.

[0065] Lipid components including SM may optionally contain small amounts of additional lipids. Lipids, galactocerebroside, ganglioside, cerebroside, glycerides, triglycerides This includes, but is not limited to, lids, cholesterol, and its derivatives, and is virtually limited to those found therein. Any type of lipid can be used.

[0066] If present, such optional lipids typically make up less than 15 wt% of the lipid fraction. This would constitute the composition, however, in some cases, it may contain more optional lipids. In some embodiments, the optional lipid is less than about 10 wt%, less than about 5 wt%, Or it constitutes less than approximately 2 wt%. In some embodiments, the lipid fraction is an optional lipid. It does not include.

[0067] In a specific embodiment, the phospholipid fraction is in the range of 90:10 to 99:1, more preferably Or, a weight ratio in the range of 95:5 to 98:2 (SM: negatively charged phospholipids), egg SM Or palmitoyl SM or phytosphingomyelin and D It contains PPG. In one embodiment, the weight ratio is 97:3.

[0068] The molar ratio of lipid components to protein components of the complex of this disclosure may vary, depending on other factors. In particular, the uniqueness of apolipoproteins that make up protein components, and the composition of lipid components This will depend on the specificity and quantity of the lipids that make up the complex, as well as the desired size of the complex. The biological activity of apolipoproteins such as poA-I is determined by the two components that make up the apolipoprotein. Since it is thought to be mediated by a affinity helix, the ApoA-I protein equivalent Using this method, we express an apolipoprotein fraction with a lipid:apolipoprotein molar ratio. This is advantageous. Depending on the method used to calculate the helix, ApoA-I It is generally recognized that it contains 6 to 10 amphiphilic helices. Polypoproteins are classified into ApoA-I, etc., based on the number of amphiphilic helices they contain. This can manifest from the perspective of valence. For example, A, which typically exists as a disulfide-bridged dimer. poA-I M It can be expressed as two ApoA-I equivalents because ApoA-I M This is because each molecule contains twice as many amphiphilic helices as the ApoA-I molecule. Conversely, peptide apolipoproteins containing a single amphipathic helix are 1 / It can be expressed as 10 to 1 / 6 ApoA-I equivalents because each molecule is ApoA This is because it contains 1 / 10 to 1 / 6 of the amphiphilic helices in the -I molecule. Generally speaking, Lipid:ApoA-I equivalent molar ratio of lipoprotein complex (referred to as "Ri" in this specification) The ratio (as defined) will be in the range of approximately 105:1 to 110:1. The ratio of Ri to phospholipids is approximately 108:1. It can be obtained using MW.

[0069] In some embodiments, the lipid:ApoA-I equivalent molar ratio ("RSM") is approximately 8 The range is from 0:1 to approximately 110:1, for example, from approximately 80:1 to approximately 100:1. In this context, the ratio of RSM to the complex can be approximately 82:1.

[0070] In some embodiments, the lipoprotein complex used in the methods of this disclosure is Preferably, a protein fraction consisting of mature, full-length ApoA-I, neutral phospholipids, and sphing. A lipid fraction comprising gomielin (SM) and negatively charged phospholipids, It is a complex.

[0071] In specific embodiments, the lipid components are in the range of 90:10 to 99:1, more preferably Or a weight ratio in the range of 95:5 to 98:2, for example, 97:3 (SM: negatively charged phosphorus) Lipids) and SM (for example, egg SM, palmitoyl SM, phyto SM, or a combination thereof) It contains (a) and negatively charged phospholipids (e.g., DPPG).

[0072] In a specific embodiment, the ratio of protein components to lipid components is approximately 1:2.7. It can be in the range of approximately 1:3, with 1:2.7 being preferred. This is approximately 1:90 to 1:140. This corresponds to the molar ratio of ApoA-I protein to lipid in the range of [value]. In some embodiments, The molar ratio of protein to lipid in the complex is approximately 1:90 to 1:120, and approximately 1:100. It is approximately 1:140, or approximately 1:95 to 1:125.

[0073] In a particular embodiment, the composite is CER-001, CSL-111, CSL-11 2. Includes CER-522 or ETC-216. In a preferred embodiment, composite This is CER-001.

[0074] CER-001 as used in this document and in the following examples refers to the International Publication. This refers to the composite described in Example 4 of Brochure No. 2012 / 109162. Brochure No. 2012 / 109162 shows a SM:DPPG weight:weight ratio of 97:3. Along with this, C as a complex having a lipoprotein weight:total phospholipid weight ratio of 1:2.7 Refer to ER-001. Example 4 of International Publication No. 2012 / 109162. The manufacturing method will also be described.

[0075] The methods and / or the context in which the CER-001 medication regimen is used in this disclosure. In summary, CER-001 refers to the individual components of the bread described in International Publication No. 2012 / 109162. The lipoprotein CER-001 described in Example 4 of the fret may differ by up to 20%. This refers to a protein complex. In a particular embodiment, the components of a lipoprotein complex are national CER-001 as described in Example 4 of the International Publication Brochure No. 2012 / 109162 This differs by up to 10%. Preferably, the components of the lipoprotein complex are as described in International Publication No. 2 This is described in Example 4 of pamphlet No. 012 / 109162 (plus / minus). (Acceptable manufacturing tolerance variation of eggplant). SM in CER-001 refers to natural or synthetic eggplant. It may be formed. In some embodiments, SM is natural SM, for example, International Publication No. 2012 Natural SM, as described in pamphlet No. 109162, is, for example, chicken egg SM. In one embodiment of the part, SM is a synthetic SM, e.g., International Publication No. 2012 / 109162 Synthetic SMs listed in the pamphlet, for example, pamphlet International Publication No. 2012 / 109162 This is a synthetic palmitoylsphingomyelin as described by Lett. Methods for synthesizing gomielin can be found, for example, in the international publication no. 2014 / 140787. As described in the lett, it is publicly known in the art. The apolipoprotein AI (ApoA-I), which is a polyprotein, is preferably internationally publicly available. Corresponds to amino acids 25-267 of Sequence ID No. 1 in Pamphlet No. 2012 / 109162. It has the following amino acid sequence. ApoA-I is derived from animal sources (especially from human sources). (a) It can be purified or produced by recombinant DNA. In a preferred embodiment, C The ApoA-I in ER-001 is recombinant ApoA-I. The drug regimen of this disclosure The CER-001 used in the process is preferably extremely homogeneous, and is suitable for gel permeation chromatography. For example, at least 80%, so that it is reflected by a single peak in the tography. , at least 85%, at least 90%, at least 95%, at least 97%, less Both are 98% or at least 99% homogeneous. For example, International Publication No. 2012 / 109 Please refer to Section 6.4 of Pamphlet No. 162.

[0076] CSL-111 is purified from plasma and is compounded with soy phosphatidylcholine (SBPC). This is a reconstituted human ApoA-I (Tardif et al., 2007, JAMA 297:1675-1682).

[0077] CSL-112 is purified from plasma and rehydrated to form HDL suitable for intravenous infusion. This is a formulation of the ApoA-I compound (Diditchenko et al., 2013, DOI 10.1161 / ATVBAH). A.113.301981).

[0078] ETC-216 (also known as MDCO-216) is a recombinant ApoA-I ミラ ノ This is a lipid-depleted form of HDL containing [specific component]. Nicholls et al., 2011, Expert Opin Biol See Ther. 11(3):387-94. doi: 10.1517 / 14712598.2011.557061.

[0079] In another embodiment, the composite that may be used in the method of the present disclosure is CER-522. Yes, CER-522 is a combination of three phospholipids and a 22-amino acid peptide CT. It is a lipoprotein complex containing 80522.

[0080] [ka]

[0081] The phospholipid components of CER-522 are egg sphingin in a weight ratio of 48.5:48.5:3. Gomielin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (dipalmito Ilphosphatidylcholine (DPPC), and 1,2-dipalmitoyl-sn-glycerides Ro-3-[phospho-rac-(1-glycerol)](dipalmitoylphosphatidyl- It consists of glycerol and DPPG. Peptides versus total phospholipid in the CER-522 complex. The quality ratio is 1:2.5 (w / w).

[0082] In some embodiments, the lipoprotein complex is defatted HDL in plasma. Most HDL is rich in cholesterol. By depleting the lipids in HDL, For example, partially and / or selectively depleting, for example, its cholesterol content It can be reduced. In some embodiments, degreased HDL has a small α, pre It may resemble β-1 and other pre-β forms. The process for selective depletion of HDL is Sack This is described in s et al., 2009, J Lipid Res. 50(5): 894-907.

[0083] In a particular embodiment, the lipoprotein complex is described in U.S. Patent Application Publication No. 2004. Includes bioactive agent delivery particles as described in Specification No. / 0229794.

[0084] Bioactive agent delivery particles are lipid-binding polypeptides (for example, in this section or in 6.1) In Section 2, apolipoproteins (as previously described), lipid bilayers (for example, in this section) (or one or more phospholipids as previously described in Section 6.1.3.1) It may also contain a bioactive agent (e.g., an anticancer agent), and the interior of the lipid bilayer contains a hydrophobic region. The bioactive agent binds to the hydrophobic region of the lipid bilayer. In some embodiments, the US Patent Bioactive agent delivery particles as described in the specification of the patent application publication No. 2004 / 0229794.

[0085] In some embodiments, the bioactive agent delivery particles do not contain a hydrophilic core.

[0086] In some embodiments, the bioactive agent delivery particles are disc-shaped (e.g., about 7 to about 2 (Having a diameter of 9 nm).

[0087] The bioactive agent delivery particles are composed of lipids that form a bilayer, such as phospholipids (for example, the odor in this section). (or as previously described in Section 6.1.3.1). In some embodiments, this includes: The bioactive agent delivery particles contain both lipids that form a bilayer and lipids that do not form a bilayer. In some embodiments, the lipid bilayer of the bioactive agent delivery particle contains phospholipids. In terms of morphology, the phospholipid incorporated into the delivery particle is dimyristoylphosphatidylcholine. Contains DMPC and dimyristoylphosphatidylglycerol (DMPG). In one embodiment, the lipid bilayer contains DMPC and DMPG in a molar ratio of 7:3.

[0088] In some embodiments, the lipid-binding polypeptide is an apolipoprotein (see, for example, this section) (as previously described in Section 6.1.2 or elsewhere). Lipid-binding polypeptides. For example, the main interaction between apolipoprotein molecules and lipid bilayers is generally between the two. The hydrophobic residues of a hydrophilic structure, such as the α-helix of a lipid-binding polypeptide, and the particle This is a hydrophobic interaction between the lipid acyl chains of the surrounding outer surface lipids. The particles may contain replaceable and / or non-replaceable apolipoproteins. In the application form, the lipid-binding polypeptide is ApoA-I.

[0089] In some embodiments, the bioactive agent delivery particles are modified to increase particle stability. This includes modified lipid-binding polypeptide molecules, such as apolipoprotein molecules. In terms of form, the modification involves the formation of intramolecular and / or intermolecular disulfide bonds. This includes the introduction of an in residue.

[0090] In another embodiment, the bioactive agent delivery particle contains a bioactive agent incorporated within the delivery particle. One or more bound mechanisms that can enhance the activity of or act in a synergistic effect with that activity. Active portion, e.g., one or more targeting portions and / or desired biological activity, e.g. For example, a chimeric lipid-binding polypeptide with one or more moieties that have antimicrobial activity. It includes offspring, such as chimeric apolipoprotein molecules.

[0091] 6.1.2. Lipid-binding protein molecules The lipid-binding protein molecules that may be used in the complexes described herein are those specified in section 6. Apolipoproteins such as those described in Section 1.2.1, and those described in Section 6.1.2.2 It contains apolipoprotein mimetic peptides such as those listed. In some embodiments, The complex contains a mixture of lipid-binding protein molecules. In some embodiments, the complex is , one or more lipid-binding protein molecules, and one or more apolipoproteins Contains a mixture of phosphate mimetic peptides.

[0092] In some embodiments, the complex comprises 1 to 8 ApoA-I equivalents (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 2-8 It contains 2-6, 2-4, 4-6, or 4-8 ApoA-I equivalents. Lipid-bound Proteins are evaluated based on the number of amphiphilic helices they contain, and are equivalent to ApoA-I proteins. It can be expressed at points. For example, ApoA-, which typically exists as a disulfide-bridged dimer. I M It can be expressed as two ApoA-I equivalents because ApoA-I M Each of the minutes This is because the offspring contains twice as many amphipathic helices as the ApoA-I molecule. In addition, peptide mimetic molecules containing a single amphipathic helix have 1 / 10 to 1 / 6 Ap It can be expressed as an oA-I equivalent because each molecule is 1 / 10th the size of an ApoA-I molecule. This is because it contains approximately 1 / 6 amphiphilic helices.

[0093] 6.1.2.1. Apolipoproteins Suitable apolipoproteins that can be included in lipid-binding protein-based complexes are apolipoproteins. Polyproteins 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 aforementioned. Protein polymorphisms, isoforms, varieties, and mutants, as well as excised forms, Among them, the most commonly observed apolipoprotein AI Milano (ApoA-IM), apolipoprotein Apolipoprotein AI paris (ApoA-IP) and apolipoprotein AI zaragoza (ApoA-IZ) may also be used. Apolipoprotein mutations containing cysteine ​​residues. The body is also publicly known and can be used (for example, U.S. Patent Application Publication No. 2003 / 0181372) (See Specification No. 1). Apolipoproteins exist as monomers, homodimers, or It can exist as a dimer that is a heterodimer. For example, ApoA-I (Duverger et al.) al., 1996, Arterioscler. Thromb. Vasc. Biol. 16(12):1424-29), ApoA-IM(F ranceschini et al., 1985, J. Biol. Chem. 260:1632-35), ApoA-IP (Daum et al. al., 1999, J. Mol. Med. 77:614-22), ApoA-II (Shelness et al., 1985, J. B iol. Chem. 260(14):8637-46;Shelness et al., 1984, J. Biol. Chem. 259(15):9929-3 5), 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), ApoJ, Homodimers and heterodimers of ApoH (if feasible) may be used.

[0094] For example, U.S. Patent Application Publication No. 2008 / 0234192 and No. 2013 / 01 U.S. Patent No. 37628, and U.S. Patent Nos. 8,143,224 and No. 8,54 As described in Specification No. 1,236, apolipoproteins are used in their primary sequences. They can be modified to make them less susceptible to oxidation. Apolipoproteins are Hista Residues equivalent to elements that facilitate their isolation, such as those used in the genuity of the genuity, or residues designed for other purposes. It may include other elements that have been measured. Preferably, the apolipoprotein in the complex is , biological fluids (e.g., lymph, cerebrospinal fluid, vitreous fluid, aqueous humor, blood, or blood fractions) It is soluble in (for example, serum or plasma).

[0095] In some embodiments, the complex is a covalently bound lipid-binding protein monomer, for example Dimeric apolipoprotein AI-I is a variant form of ApoA-I that contains cysteine. Contains lano. Cysteine ​​exists as a homodimer or heterodimer (e.g., ApoA-I mira This enables the formation of disulfide bridges that can lead to the formation of (no-ApoA-II).

[0096] In some embodiments, the apolipoprotein molecule is ApoA-I, ApoA-II , ApoA-IV, ApoA-V, ApoB, ApoC-I, ApoC-II, ApoC -III, ApoD, ApoE, ApoJ, or ApoH molecules, or combinations thereof Includes se.

[0097] In some embodiments, the apolipoprotein molecule includes the ApoA-I molecule or It consists of the above. In some embodiments, the ApoA-I molecule is a human ApoA-I molecule. In some embodiments, the ApoA-I molecule is recombinant. Morphologically, the ApoA-I molecule is not ApoA-I Milano.

[0098] In some embodiments, the ApoA-I molecule is an apolipoprotein AI Milano (A poA-IM), apolipoprotein AI pari (ApoA-IP), or apolipota It is an amino acid AI (ApoA-IZ) molecule.

[0099] Apolipoproteins are, as is well known in the art, derived from animal sources (especially It can be purified (from human sources) or produced by recombinant organisms, e.g., Chung et al. al., 1980, J. Lipid Res. 21(3):284-91;Cheung et al., 1987, J. Lipid Res. 28(8) See 913-29. U.S. Patent No. 5,059,528, Sections 5,128,31 Specification No. 8, No. 6,617,134; U.S. Patent Application Publication No. 2002 / 01560 Specification No. 07, Specification No. 2004 / 0067873, Specification No. 2004 / 0077541 Detailed description, and Specification No. 2004 / 0266660; and International Publication No. 2008 / 10 See also Pamphlet No. 4890 and International Publication No. 2007 / 023476. It is desired that such disclosure be incorporated herein in whole by reference, for example, international public disclosure. Other purification methods are also possible, as described in pamphlet No. 2012 / 109162. .

[0100] Apolipoproteins can exist in prepro, pro, or mature forms. For example, The complex consists of ApoA-I, pre-proApoA-I, proApoA-I, or mature A This may include ApoA-I (e.g., human ApoA-I), which is a poA-I. Some implementations In this state, the complex has at least 90% sequence identity with SEQ ID NO: 1. Includes I.

[0101] [Chemical]

[0102] In other embodiments, the complex comprises ApoA-I having at least 95% sequence identity with SEQ ID NO: 1. In other embodiments, the complex comprises ApoA-I having at least 98 % sequence identity with SEQ ID NO: 1. In other embodiments, the complex comprises ApoA-I having at least 99 % sequence identity with SEQ ID NO: 1. In other embodiments, the complex comprises ApoA-I having 100% sequence identity with SEQ ID NO: 1.

[0103] In some embodiments, the 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 apo lipoprotein molecules. In some embodiments, the complex comprises 8 apolipoprotein molecules.

[0104] The apolipoprotein molecule is an apolipoprotein and, for example, one or more CRNs -001 One or more attached functional parts of a complex, etc., one or more targeted areas A portion, a portion having the desired biological activity, an affinity tag to aid in purification, and / or Chimeric apolipoproteins containing reporter molecules for characterization or localization investigation It may contain a substance. The attached portion having biological activity is incorporated into the complex of this disclosure. It may enhance the biological activity of the compound and / or have an activity that may produce a synergistic effect with that activity. It is possible. For example, the part that has biological activity may be antimicrobial (e.g., antifungal, antibacterial, antimicrobial). It may have protozoan, bacteriostatic, fungal, or antiviral activity. In one embodiment, The functional portion to which the chimeric apolipoprotein is attached is not in contact with the hydrophobic surface of the complex. In another embodiment, the attached functional portion is in contact with the hydrophobic surface of the composite. In some embodiments, the functional portion of a chimeric apolipoprotein is a native protein. It may be specific to the cell surface receptor. In some embodiments, the chimeric apolipoprotein is a cell surface receptor. Ligands that are recognized by or can interact with the contents or other cell surface parts. This includes arrays.

[0105] In one embodiment, the chimeric apolipoprotein is, for example, S. cerevisiae (S. cerev isiae) α-conjugation factor peptide, folic acid, transferrin, or lactoferrin, etc. It contains a targeting region that is not specific to the natural apolipoprotein. In another embodiment, it is a chimeric. Apolipoproteins enhance the activity of compounds incorporated into the complex of this disclosure, and / or includes a portion having a desired biological activity that produces a synergistic effect with that activity. One embodiment In this context, chimeric apolipoproteins contain functional parts unique to apolipoproteins. Obtain. One example of apolipoprotein-specific functional parts is the approximately amino acid of human ApoE. It is a unique targeting region formed by acid 130-150, which is low-density lipotan It contains a receptor-binding region recognized by members of the protein receptor family. Another example of a protein-specific functional part is A, which interacts with low-density lipoprotein receptors. The poB-100 region and ApoA interact with scavenger receptor type B1. -Includes region I. In other embodiments, functional parts are added by synthesis or rearrangement. In addition, it can produce chimeric apolipoproteins. Another example is another preproapolipoprotein Protein-derived prepro or pro sequences (for example, the prepro sequence of prepro apoA-I) Apolipotan having a prepro sequence derived from prepro apoA-II that is substituted in place. It is a protein. Another example is when a portion of an amphipathic sequence segment is derived from another apolipoprotein. It is an apolipoprotein that is substituted by other amphipathic sequence segments.

[0106] As used herein, "chimera" refers to a component that may exist separately and is a component of The molecules are joined together to form a single molecule that has all the desired functionalities of the molecule. It refers to two or more molecules. The constituent molecules of a chimeric molecule are chemically conjugated. It can be synthetically linked by, or all of its constituent molecules are polypeptides or If they are analogs, the polypeptide is coded so that a single continuous polypeptide is expressed. Polynucleotides can fuse with each other through recombination. Such chimeric molecules are It is called a fusion protein. A "fusion protein" is a protein in which all of its constituent molecules are polypeptides. They are chimeric molecules that are attached (fused) to each other so as to form a continuous single chain. They are chimeric molecules. The various components can be directly attached to each other or conjugated through one or more linkers. One or more segments of the various components can be inserted into, for example, the sequence of an apolipoprotein, or alternatively, added to the sequence of an apolipoprotein at the N-terminus or C-terminus. For example, the fusion protein can include an antibody light chain, an anti- body fragment, a heavy chain antibody, or a single domain antibody.

[0107] In some embodiments, the chimeric apolipoprotein is prepared by chemically conjugating an apolipoprotein with a target functional moiety to be attached. The means for chemically conjugating molecules are well known to those skilled in the art. Such means will vary depending on the structure of the moiety to be attached, but will be readily elucidated by those skilled in the art. The polypeptide typically has available for reaction with suitable functional groups on or in a linker that binds the moiety, various functional groups such as carboxylic acid (--COOH), free amino (--NH2), or sulfhydryl (--SH) groups and is contained therein. The functional moiety can be attached to a functional group on the N-terminus, C-terminus, or internal residue (i.e., a residue at an intermediate position between the N and C termini) of the apolipoprotein molecule. Alternatively, the apolipoprotein and / or the moiety to be tagged can be derivatized to expose or attach additional reactive functional groups.

[0108] In some embodiments, the fusion protein comprising a polypeptide functional moiety is recombinant It is synthesized using an expression system. Typically, this involves the expression of two polypeptides. Co Steps to create a nucleic acid (e.g., DNA) sequence, and DNA under the control of a promoter. The steps of arranging, expressing the protein in host cells, and expression This involves a step to isolate the resulting protein.

[0109] Nucleic acids encoding chimeric apolipoproteins are in a form appropriate for expression in host cells. It can be incorporated into recombinant expression vectors. When used herein, "expression vector" "-" means that when introduced into a suitable host cell, it can be transcribed and translated into polypeptides. The nucleic acid obtained is the vector, which contains promoters, enhancers, or other expression regulatory elements. This may also include regulatory sequences such as signals (e.g., polyadenylation signals). This is publicly known to those skilled in the art (e.g., Goeddel, 1990, Gene Expression Technology: Meth). Enzymol. 185, Academic Press, San Diego, Calif.; Berger and Kimmel, Guide to Mo. lecular Cloning Techniques, Methods in Enzymology 152 Academic Press, Inc., San Diego, Calif.;Sambrook et al., 1989, Molecular Cloning--A Laboratory Manual (2n d ed.) Vol. 1-3, Cold Spring Harbor Laboratory, Cold Spring Harbor Press, NY, etc. (See reference).

[0110] In some embodiments, the apolipoprotein is a compound of the apolipoprotein of the present disclosure. When incorporated into the body, the modification increases the stability of the complex, confers targeting ability, Or it has been modified so as to increase the capacity. In one embodiment, the modification is For example, site-directed mutations can be used to enable the formation of intramolecular or intermolecular disulfide bonds. This includes introducing cysteine ​​residues into the apolipoprotein molecule to achieve this. Another embodiment In this process, a chemical crosslinking agent is used to form intermolecular links between apolipoprotein molecules. This enhances the stability of the complex. Intermolecular crosslinking allows apolipoprotein molecules to separate from the complex. To inhibit or reduce dissociation and / or endogenous a in individuals to whom the complex is administered It prevents replacement by polypoprotein molecules. In other embodiments, apolipotan The protein is obtained by chemical derivatization of one or more amino acid residues or by site-directed derivatization. By introducing mutations, the ability to target or recognize cell surface receptors is conferred. ru.

[0111] The complex manipulates receptor recognition properties within apolipoproteins to achieve specific targeting. It can target cell surface receptors. For example, the complex can target apolipoproteins, for instance. Modify the cell type to have a surface receptor that can interact with it. By doing so, it targets specific cell types known to carry a particular type of infectious agent. It can be transformed. For example, the complex is macrophage endocytosis class A scavenging Modifying apolipoproteins to confer recognition by the SR-A receptor. This can be targeted to macrophages. One or more positively charged amino acids Site-directed mutagenesis, which involves replacing amino acids with neutral or negatively charged amino acids, can be performed to remove apolipotas. By modifying the protein, SR-A binding ability can be conferred to the complex. N- or C-terminal extensions having ligands that are recognized as such, or high concentrations of negatively charged residues By preparing chimeric apolipoproteins containing amino acid sequences with a group, SR -A recognition may also be conferred. The complex containing the apolipoprotein is the ABCA1 receptor, ABC HDL receptors such as G1 receptors, megalin, cubilin, and SR-B1. However, it is not limited to those receptors; it can also interact with apolipoprotein receptors.

[0112] 6.1.2.2. Apolipoprotein mimetic Peptides, peptide analogs, and agonists that mimic the activity of apolipoproteins. In this specification, "apolipoprotein peptide mimes" (collectively referred to as such) are also single In Germany, in combination with one or more other lipid-binding proteins, as described herein. It can be used in complexes. Suitable for encapsulation in complexes and compositions described herein. The peptides and peptide analogues corresponding to apolipoproteins, as well as Ap oA-I, ApoA-I M The activity of ApoA-II, ApoA-IV, and ApoE Non-exclusive examples of imitation agonists are disclosed by reference to this specification as a whole. Incorporated in this document are U.S. Patent No. 6,004,925 and No. 6,037,323. Detailed statement, and Specification No. 6,046,166 (issued to Dasseux et al.), U.S. Patent No. 5,840,688 (issued to Tso), U.S. Patent No. 6, Specifications No. 743,778 (issued to Kohno), U.S. Patent Application Publication No. 200 Specification No. 4 / 0266671, Specification No. 2004 / 0254120, No. 2003 / 01 Specification No. 71277 and Specification No. 2003 / 0045460 (Fogelman) (In contrast), U.S. Patent Application Publication No. 2006 / 0069030 (Bachovchi (for n), U.S. Patent Application Publication No. 2003 / 0087819 (Bielick) (for i), U.S. Patent Application Publication No. 2009 / 0081293 (Murase et al.) (for), and International Publication No. 2010 / 093918 (Dasseu These peptides and peptide analogs are disclosed in (to x et al.). Alternatively, it may consist of D-amino acids, or a mixture of L- and D-amino acids. These include one or more well-known peptide / amide isosteres, one or more non-peptides. This may also include ptide or amide linkages. Such apolipoprotein peptide mimes are For example, U.S. Patent No. 6,004,925, No. 6,037,323, and Techniques known in the art, including the techniques described in Patent No. 6,046,166 Petit can be synthesized or manufactured using any technique for petit synthesis.

[0113] In some embodiments, the lipid-binding protein molecule is an apolipoprotein peptide. Modular molecules, and optionally, one or more apolipoproteins such as those described above. Contains mineral molecules.

[0114] In some embodiments, the apolipoprotein peptide mimetic molecule is ApoA-I Peptide mimetic, ApoA-II peptide mimetic, ApoA-IV peptide mimetic, or This includes ApoE peptide mimetic compounds or combinations thereof.

[0115] 6.1.3. Amphiphilic Molecules Amphiphilic molecules possess both hydrophobic (nonpolar) and hydrophilic (polar) elements. These are molecules. The amphiphilic molecules that may be used in the complexes described herein are lipids. (For example, as described in Section 6.1.3.1), surfactants (for example, as described in Section 6.1.3.2 (as described in the section), fatty acids (for example, as described in section 6.1.3.3), and sugars Or nonpolar molecules covalently attached to polar molecules such as nucleic acids, etc. This includes sterols (for example, as described in Section 6.1.3.4).

[0116] The complex is composed of a single class of amphiphilic molecules (e.g., a single type of phospholipid or a mixture of phospholipids). amphiphilic molecules of a class that may include or combine (e.g., phospholipids and It may contain surfactants. The complex facilitates the solubilization of lipid-binding protein molecules. It may contain a single species of amphiphilic molecule or a combination of amphiphilic molecules composed of such a structure. .

[0117] In some embodiments, the amphiphilic molecules included are phospholipids, surfactants, fatty acids, A nonpolar moiety or sterol attached to a sugar by a covalent bond, or a combination thereof (for example) This includes (selected from the types of amphiphilic molecules discussed above).

[0118] In some embodiments, the amphiphilic molecule includes or consists solely of phospholipid molecules. It consists of. In some embodiments, the phospholipid molecules are negatively charged phospholipids, neutral phosphorus This includes lipids, positively charged phospholipids, or combinations thereof. In some embodiments, Phospholipid molecules contribute 1-3 net charge points per apolipoprotein molecule in the complex. In some embodiments, the net charge is a negative net charge. And the net charge is a positive net charge. In some embodiments, the phospholipid molecule is negative It consists of a combination of negatively charged and neutral phospholipids. In some embodiments, negative The molar ratio of charged phospholipids to neutral phospholipids is in the range of 1:1 to 1:3. Morphologically, the molar ratio of negatively charged phospholipids to neutral phospholipids is approximately 1:1 or approximately 1: The answer is 2.

[0119] In some embodiments, the amphiphilic molecules are neutral phosphorus in a weight ratio of 95:5 to 99:1. It contains lipids and negatively charged phospholipids.

[0120] 6.1.3.1. Lipids Lipid-binding protein-based complexes may contain one or more lipids. Various implementations In terms of form, one or more lipids are saturated and / or unsaturated, natural and / or It may be synthetic, charged or uncharged, zwitterionic or anzwitterionic. In one embodiment, when lipid molecules (e.g., phospholipid molecules) are combined, they form a complex. And each lipid-binding protein molecule contains 1-3 molecules (for example, 1-3, 1-2, 2-3, 1, 2, Alternatively, it may contribute to the net charge in 3). In some embodiments, the net charge is negative. In this embodiment, the net charge is positive.

[0121] In some embodiments, the lipids include phospholipids. Phospholipids are the same or different. Two acyl chains (for example, with different numbers of carbon atoms, different degrees of saturation between acyl chains, acyl chains) Lipids may have chains with different branching patterns or combinations thereof. It may also be modified to include it (for example, avantilipids.com / product-category / products (as described in / fluorescent-lipids / ). Preferably, the lipid is at least one phospholipid. Includes.

[0122] Phospholipids have approximately 6 to 24 carbon atoms (for example, 6 to 20, 6 to 16, 6 to 12, 1 (2-24, 12-20, 12-16, 16-24, 16-20, or 20-24 pieces) The complex may have a range of unsaturated or saturated acyl chains. In some embodiments, the complex of the present disclosure The phospholipids used in this process are 12, 14, 16, 18, 20, 22, or 24. One or two acyl chains of carbon (for example, two acyl chains of the same length or different lengths) It has two acyl chains.

[0123] A non-exclusive example of acyl chains found in common fatty acids that can be contained in phospholipids is shown below. Provided in Table 1.

[0124] [Table 1]

[0125] Lipids that may be present in the complex of this disclosure include small alkyl chain phospholipids, egg phosphatidyl phospholipids. Phosphorus, soy phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, 1-myristoyl-2 -Palmitoylphosphatidylcholine, 1-Palmitoyl-2-Myristoylphosphatidylcholine Zilcholine, 1-palmitoyl-2-stearoylphosphatidylcholine, 1-stearo Il-2-palmitoylphosphatidylcholine, dioleoylphosphatidylcholine, di Dioleophosphatidylethanolamine, Gila Uroyl phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, Phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerin Roll, diphosphatidylglycerol, for example dimyristoylphosphatidylglycerol Dipalmitoyl phosphatidylglycerol, distearoyl phosphatidylglycerol Cerol, dioleoylphosphatidylglycerol, dimyristoylphosphatidic acid , dipalmitoylphosphatidic acid, dimyristoylphosphatidylethanolamine, Dipalmitoylphosphatidylethanolamine, dimyristoylphosphatidylserine Dipalmitoyl phosphatidylserine, cerebral phosphatidylserine, cerebral sphingomyelia N, palmitoyl sphingomyelin, dipalmitoyl sphingomyelin, egg sphingomyelin Gomphaena, Milk sphingomphaena, Phytosphingomphaena, Distealoyrus Fingomyelin, dipalmitoylphosphatidylglycerol salt, phosphatidic acid, Galactocerebroside, ganglioside, cerebroside, dilaurylphosphatidylcholine (1,3)-D-mannosyl-(1,3) diglyceride, aminophenyl glycoside , 3-cholesteryl-6'-(glycosylthio)hexyl ether glycolipid, and cholesteryl This includes, but is not limited to, sterols and their derivatives. Synthetic palmit Ilsphingomyelin or N-palmitoyl-4-hydroxysphinganin-1- Using synthetic lipids such as phosphocholine (a form of phytosphingomyelin), lipid oxidation Minimize the risk.

[0126] In some embodiments, the lipid-binding protein-based complex is composed of two types of phosphorus Lipids: Neutral lipids, such as lecithin and / or sphingomyelin (abbreviated as SM) , and also include charged phospholipids (e.g., negatively charged phospholipids). "Neutral" phospholipids The quality has a net charge of approximately zero at physiological pH. In many embodiments, neutral phospholipids are used. Although its properties are zwitterionic, other types of net neutral phospholipids are known and used. In some embodiments, charged phospholipids (for example, negatively charged phospholipids) The molar ratio of neutral phospholipids is in the range of 1:1 to 1:3, for example, approximately 1:1, approximately 1:2, or It's approximately 1:3.

[0127] Neutral phospholipids may include, for example, lecithin and / or SM, or both, optional. Other neutral phospholipids may be included by choice. In some embodiments, the neutral phospholipid is lecithin. It contains but does not contain SM. In other embodiments, the neutral phospholipid contains SM, but does not contain It does not contain thin. In yet another embodiment, the neutral phospholipid is lecithin and S This includes both M. All of these specific exemplary embodiments include lecithin and / or In addition to SM, it may contain neutral phospholipids, but in many embodiments, such additional medium It does not contain phospholipids.

[0128] As used herein, the term "SM" means derived from natural sources or The sphingomyelin obtained therefrom, as well as naturally occurring SM, LCAT Includes naturally occurring analogs and derivatives of SM that are not affected by hydrolysis. SM is It is a phospholipid that is structurally very similar to lecithin, but unlike lecithin, it is glyc It lacks a cerol skeleton and therefore does not have ester links attached to acyl chains. Rather, SM has a ceramide skeleton in which amide links connect acyl chains. SM is, for example, a mill It can be obtained from eggs or brains. SM analogs or derivatives may also be used. Useful Non-limiting examples of SM analogs and derivatives include palmitoyl sphingomyelin, N-P Lumitoyl-4-hydroxysphinganin-1-phosphocholine (phytosphingomyelia A form of phosphorus), palmitoyl sphingomyelin, stearoyl sphingomyelin, D-erythro-N-16:0-sphingomyelin and its dihydro isomer D-erythro It includes, but is not limited to, thro-N-16:0-dihydro-sphingomyelin. No. Synthetic palmitoyl sphingomyelin or N-palmitoyl-4-hydrox Synthetic SMs such as cisphinganin-1-phosphocholine (phytosphingomyelin) are used. And it has fewer impurities and / or oxidation products than animal-derived sphingolipids. A homogeneous complex can be produced. A method for synthesizing SM is described in U.S. Patent Application Publication No. 201. It will be listed in the statement of item 6 / 0075634.

[0129] Sphingomyelin isolated from natural sources is a specific saturated or unsaturated ash tree. It can be artificially enriched in the milk chain. For example, milk sphingomyelin (Avanti Ph Ospholipid (albaster, Ala.) is a long saturated acyl chain. Characterized by acyl chains having 20 or more carbon atoms. In contrast, egg sphingomyelin has short saturated acyl chains (i.e., fewer than 20). Characterized by acyl chains having carbon atoms. For example, milk sphingomye Only about 20% of phosphorus contains a C16:0 (16 carbon atoms, saturated) acyl chain, whereas Approximately 80% of egg sphingomyelin contains a C16:0 acyl chain. Solvent extraction is used. The composition of milk sphingomyelin is comparable to that of egg sphingomyelin, with acyl chains. It can be enriched to have a certain composition, or vice versa.

[0130] SM can be semi-synthetic such that it has a specific acyl chain. For example, milk sulf Ingomylene can first be purified from milk, and then a specific acyl chain, for example, C1 A 6:0 acyl chain can be cleaved and replaced by another acyl chain. SM is, for example, It can be completely synthesized by large-scale synthesis. For example, issued on June 15, 1993 The title is "Synthesis of D-erythro-sphingomyelins". U.S. Patent No. 5,220,043 by Dong et al.; Weis, 1999, Chem. Phys. Li See pids 102 (1-2):3-12. SM is, for example, U.S. Patent Application Publication No. 2014 / 0 As described in Specification No. 275590, it may be entirely a composite.

[0131] The length and saturation level of acyl chains, including semi-synthetic or synthetic SMs, can be selectively varied. The acyl chain can be saturated or unsaturated and may contain about 6 to about 24 carbon atoms. Each chain may contain the same number of carbon atoms, or alternatively, each chain may contain a different number of carbon atoms. It may contain. In some embodiments, the semi-synthetic or synthetic SM is one chain saturated. , including mixed acyl chains such that one chain is unsaturated. In this embodiment, the chain lengths may be the same or different. In other embodiments, semi-synthetic or The acyl chains of synthetic SM are either both saturated or both unsaturated. It may contain the same or different number of carbon atoms. In some embodiments, it is semi-synthetic or The two acyl chains containing the synthetic SM are identical. In a specific embodiment, the chain is, for example, O The acyl chain of naturally occurring fatty acids such as leic acid, palmitic acid, or stearic acid has a phase in it. In another embodiment, SM having saturated or unsaturated functionalized chains is used. In another specific embodiment, both acyl chains are saturated, and 6 to 24 carbon atoms It contains citric acid, which is present in common fatty acids that can be found in semi-synthetic and synthetic SM. Non-restrictive examples of chains are provided in Table 1 above.

[0132] In some embodiments, SM is a synthetic palmitoyl SM having a C16:0 acyl chain. Eggs containing palmitoyl SM as a main component, such as palmitoyl SM. be.

[0133] In specific embodiments, functionalized SMs such as phytosphingomyelin are used.

[0134] Lecithin may be derived from natural sources or isolated therefrom, or it may be compounded It can be obtained in its natural state. An example of suitable lecithin isolated from natural sources is egg phosphatidyl. It contains, but is not limited to, zylcholine and soy phosphatidylcholine. Appropriate additional non-limiting examples of lecithin include dipalmitoylphosphatidylcholine, di Myristoylphosphatidylcholine, distearoylphosphatidylcholine, 1-myris Toyl (myristoy1)-2-palmitoylphosphatidylcholine, 1-palmitoyl (pal mitoy1)-2-myristoylphosphatidylcholine, 1-palmitoyl-2-stearoy 1-stearoyl(stearoy1)-2-palmitoylphosphatidylcholine, 1-stearoyl(stearoy1)-2-palmitoylphosphatidylcholine Zilcholine, 1-palmitoyl-2-oleylphosphatidylcholine, 1-oleyl(ol eoy1)-2-palmitoylphosphatidylcholine, dioleoylphosphatidylcholine, This includes ether derivatives or analogs thereof.

[0135] Lecithin derived from or isolated from natural sources contains the specified acyl chain. It can be enriched. In embodiments employing semi-synthetic or synthetic lecithin, the acyl chain The uniqueness can vary selectively, as discussed above in relation to SM. In some embodiments of the complex, both acyl chains on lecithin are identical. In some embodiments of the complex containing both SM and lecithin, the ascithin of SM and lecithin All acyl chains are identical. In a specific embodiment, the acyl chain is myristic acid (my (Ristitic), corresponds to the acyl chain of palmitic acid, oleic acid, or stearic acid.

[0136] The complex of this disclosure comprises one or more negatively charged phospholipids (e.g., one or more, or May contain (one or more neutral phospholipids in combination). In this context, "negatively charged phospholipids" refer to phosphorus that has a net negative charge at physiological pH. They are lipids. Negatively charged phospholipids can be single-type negatively charged phospholipids or two-type negatively charged phospholipids. The above may include a mixture of different negatively charged phospholipids. In some embodiments, the charged The phospholipids are negatively charged glycerophospholipids. A specific example is 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1 -Glycerol), phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol Phatidylserine, phosphatidic acid, and their salts (e.g., sodium salt or potassium salt) It includes, but is not limited to, um salts. In some embodiments, it is negatively charged. The phospholipids that were electrolyzed are phosphatidylinositol, phosphatidylserine, and phosphatidi Containing one or more of glycerol and / or phosphatidic acid. In a typical embodiment, the negatively charged phospholipid is a salt of phosphatidylglycerol or This includes or consists of a salt of phosphatidylinositol. In another specific embodiment, In this case, negatively charged phospholipids are 1,2-dipalmitoyl-sn-glycero-3-[H Sufo-rac-(1-glycerol), i.e., DPPG, or a salt thereof. It consists of that.

[0137] Negatively charged phospholipids can be obtained from natural sources or synthesized chemically. It can be manufactured. In embodiments employing synthetically negatively charged phospholipids, the acyl chain is Identity may vary selectively, as discussed above in relation to SM. In some embodiments of the complex, both acyl chains on the negatively charged phospholipid are identical. In some embodiments, all types of phospholipids included in the complex of the present disclosure The chains are all identical. In a specific embodiment, the complex is negatively charged phospholipid. Quality, and / or all containing SMs having C16:0 or C16:1 acyl chains In a specific embodiment, the fatty acid portion of SM is mostly C16:1 palmitoyl Yes. In one specific embodiment, charged phospholipids, lecithin, and / or The acyl chain of SM corresponds to the acyl chain of palmitic acid. In yet another specific embodiment... In this case, the charged phospholipid, lecithin, and / or SM acyl chains are of oleic acid This corresponds to an acyl chain.

[0138] An example of a positively charged phospholipid that may be included in the complex of this disclosure is N1-[2-((1S)- 1-[(3-aminopropyl)amino]-4-[di(3-amino-propyl)amino] [Cylcarboxamide)ethyl]-3,4-di[oleyloxy]-benzamide, 1,2 -di-O-octadecenyl-3-trimethylammoniumpropane, 1,2-dimylist Dimyristoleoyl-sn-glycero-3-ethylphosphocholine, 1-palmit Il-2-oleoyl-sn-glycero-3-ethylphosphocholine, 1,2-dioleoyl L-sn-glycero-3-ethylphosphocholine, 1,2-distearoyl-sn-glycerol Ro-3-ethylphosphocholine, 1,2-dipalmitoyl-sn-glycero-3-ethylphosphocholine Suphocholine, 1,2-dimiristoyl-sn-glycero-3-ethylphosphocholine, 1, 2-Dilauroyl-sn-glycero-3-ethylphosphocholine, 1,2-Dilauroyl- sn-glycero-3-ethylphosphocholine, 1,2-dioleoyl-3-dimethylammonium Nium-propane, 1,2-dimyristoyl-3-dimethylammonium-propane, 1 ,2-Dipalmitoyl-3-dimethylammonium-propane, N-(4-carboxybe N,N-dimethyl-2,3-bis(oleoyloxy)propane-1-aminonitrile Um, 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-dioleoyl Oil-3-trimethylammonium-propane, 1,2-stearoyl-3-trimethicone Diammonium-propane, 1,2-dipalmitoyl-3-trimethylammonium-p Ropan, 1,2-dimyristoyl-3-trimethylammonium-propane, N-[1- [(2,3-Dimyristyloxy)propyl]-N,N-dimethyl-N-(2-hydroxy) Ethyl)ammonium bromide, N,N,N-trimethyl-2-bis[(1-oxo-9 -Octadecenyl)oxy]-(Z,Z)-1propaneaminium methyl sulfate ( It includes sulfates, and salts thereof (e.g., chloride or bromide salts).

[0139] The lipids used are preferably at least 95% pure and / or reduced It contains a level of oxidizing agent (such as peroxides, but not limited to them). It is obtained from natural sources. The lipids are preferably less polyunsaturated fatty acid and / or affected by oxidation. It has a fatty acid portion that is less susceptible to oxidation. The oxidation level in the sample is meq O / kg The peroxide value is expressed as the number of milliequivalents of isolated iodine per kg sample, abbreviated as [a specific abbreviation]. This can be determined using the iodine titration method provided. For example, Gray, 1978, Measurement of Lip id Oxidation: A Review, Journal of the American Oil Chemists Society 55:539-545 ;Heaton, FW and Ur, Improved Iodometric Methods for the Determination of Lipi See Peroxides, 1958, Journal of the Science of Food and Agriculture 9:781-786. Please illuminate. Preferably, the oxidation level, i.e., the peroxide level, should be low, for example, 5 me. Less than q O / kg, less than 4 meq O / kg, less than 3 meq O / kg, or 2 meq It is less than 0 / kg.

[0140] In some embodiments, the complex may contain small amounts of additional lipids, such as lysophospholipids. Galactocerebroside, ganglioside, cerebroside, glyceride, triglyceride , as well as sterols and sterol derivatives (e.g., plant sterols, cholesterol It contains animal sterols such as serole, or sterol derivatives such as cholesterol derivatives, but Virtually any type of lipid can be used, not limited to those mentioned above. For example, the composites of the present disclosure The body contains cholesterol or cholesterol derivatives, such as cholesterol esters. It may have. Cholesterol derivatives are substituted cholesterol or substituted cholesterol s It may also be tel. The complex of the present disclosure is oxidized cholesterol or oxidized sterol derivative. (This includes, but is not limited to, oxidized cholesterol esters, etc.) It may also contain sterol oxides that are not oxidized. In some embodiments, the complex contains cholesterol Cholesterol and / or its derivatives (cholesterol esters or oxidized cholesterol esters) Does not include (such as tel).

[0141] 6.1.3.2. Surfactants The complex may contain one or more surfactants. The surfactants are zwitterionic. It can be nonionic, cationic, anionic, or a combination thereof. Exemplary zwitter The ionic surfactant is 3-[(3-coramidopropyl)dimethylammonio]-1-pro Pansulfonate (CHAPS), 3-[(3-coramidopropyl )dimethylammonio-2-hydroxy-1-propanesulfonate (propanesulfonate) te)(CHAPSO), and N,N-dimethyldodecylamine N-oxide (LDAO ) contains. An example of a nonionic surfactant is D-(+)-trehalose 6-monoleate monooleate, N-octanoyl-N-methylglucamine, N-nonanoyl-N- Methylglucamine, N-decanoyl-N-methylglucamine, 1-(7Z-hexadeceno 1-(8Z-hexadecenoyl)-rac-glycerol 1-(8Z-heptadecenoyl)-rac-glycerol, 1-(9Z-hexadece Includes noyl-rac-glycerol and 1-decanoyl-rac-glycerol. Typical cationic surfactants include (S)-O-methyl-serine dodecylamide hydrochloride, chloride Dodecylammonium, decyltrimethylammonium bromide, and cetyltrimethylammonium sulfate Contains ammonium. An example of anionic surfactant is cholesteryl hemysuccinate. It contains cholates, alkyl sulfates, and alkyl sulfonates.

[0142] 6.1.3.3.Fatty acids The complex may contain one or more fatty acids. One or more fatty acids may contain as many as five. Or short-chain fatty acids with an aliphatic tail of fewer carbon atoms (e.g., butyric acid, isobutyric acid) (Valeric acid, or isovaleric acid), medium-chain fatty acids having a fatty acid tail of 6 to 12 carbon atoms (e.g.) For example, caproic acid, caprylic acid, capric acid, or lauric acid, with 13 to 21 carbon atoms. Long-chain fatty acids having a fatty acid tail (e.g., myristic acid, palmitic acid, stearic acid) (or arachidic acid), an extra-long fatty acid tail having 22 or more carbon atoms. Chain fatty acids (e.g., behenic acid, lignoceric acid, or serotinic acid), or combinations thereof May contain a mixture. One or more fatty acids may be saturated (e.g., caprylic acid, capric acid, Lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, li Gnoceric acid (or cerotic acid), unsaturated (e.g., myristoleic acid, palmitate) nic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoleic acid Linolenic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, e It may be lucaic acid (or docosahexaenoic acid), or a combination thereof. Unsaturated fatty acids These may be cis or trans fatty acids. In some embodiments, the complex of the present disclosure The unsaturated fatty acids used in this context are cis fatty acids.

[0143] 6.1.3.4. Nonpolar molecules and sterols attached to sugars The complex consists of sugars (for example, monosaccharides such as glucose or galactose, or maltose) Nonpolar molecules or parts (for example, carbon) attached to disaccharides such as trehalose or other disaccharides. Contains hydrogenated chains, acyl or diacyl chains, or sterols (e.g., cholesterol). It may contain one or more amphiphilic molecules. The sugars are modified sugars or substituted sugars. It is possible. Exemplary amphiphilic molecules, including nonpolar molecules attached to sugars, include dodecane-2-yl. Oxy-β-D-maltoside, tridecane-3-yloxy-β-D-maltoside, tri Decane-2-yloxy-β-D-maltoside, n-dodecyl-β-D-maltoside (D DM), n-octyl-β-D-glucoside, n-nonyl-β-D-glucoside, n-de cyl-β-D-maltoside, n-dodecyl-β-D-maltopyranoside, 4-n-dodecyl Lu-α,α-trehalose, 6-n-dodecyl-α,α-trehalose, and 3-n- Contains dodecyl-α,α-trehalose.

[0144] In some embodiments, the nonpolar portion is an acyl or diacyl chain.

[0145] In some embodiments, the sugars are modified sugars or substituted sugars.

[0146] 6.1.4. Formulations Lipid-binding protein-based complexes can be constructed using techniques known in the art, for example (e.g., , Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22n In accordance with the information provided in d Edition, Pharmaceutical Press, London, UK, the intent of administration It can be formulated for use via the route of administration.

[0147] CER-001 intended for administration by infusion is, for example, International Publication No. 2012 / 1091 As described in pamphlet No. 62, it contains sucrose and mannitol excipients. It can be formulated in phosphate buffer.

[0148] 6.2. Target population The subjects that can be treated according to the methods described herein are preferably mammals, most preferably Or rather, it is a human.

[0149] In some aspects, the subjects have acute conditions, including acute inflammation.

[0150] In some embodiments, the subjects require therapy for sepsis and / or AKI. It could be a target.

[0151] In some embodiments, the subject is sepsis (e.g., associated with Gram-negative bacterial infection) It has. Sepsis can be caused in some embodiments by an intra-abdominal infection. Alternatively, it could be urinary tract sepsis. Sepsis is a risk factor for AKI. Therefore, some actual In terms of administration methods, the subjects may be at risk of AKI, for example, due to sepsis. In one embodiment, the subject has sepsis associated with a Gram-negative bacterial infection. Other embodiments In this case, the subject has sepsis associated with a Gram-positive bacterial infection.

[0152] In some embodiments, the subject is a therapeutic treatment using a lipid-binding protein-based complex. Previously, having a SOFA score of 1-4, for example, a score of 1, 2, 3, or 4 (Vincen See t et al. 1996, Intensive Care Med, 22:707-710.

[0153] In some embodiments, the subject is subjected to the administration of a lipid-binding protein-based complex before the administration of the complex. >0.6, Endotoxin Activity Assay (EEA(trademark)) (Spectral Medi (cal) has endotoxin activity levels measured by (Marshall et al., 2004, J Inf See ect Dis. 190(3):527-34.

[0154] In some embodiments, the subject has AKI or is at risk of AKI. For example AKI can be categorized as sepsis-associated AKI, ischemia / reperfusion AKI, CSA-AKI, or hepatonephropathy. It may be a syndrome (HSA) AKI. In some embodiments, AKI is sepsis-related AKI. In other embodiments, AKI is ischemia / reperfusion AKI. In other embodiments, AKI is CSA AKI. Those at risk for HRS are individuals with liver disease (e.g., chronic liver disease or acute liver disease). Includes subjects with a disease. In some embodiments, the subject has a chronic liver disease. In some embodiments, the subject has acute liver disease. In some embodiments, the subject is He has alcoholic liver disease. Historically, HRS has been associated with renal dysfunction lasting several days to several weeks. Type 1 HRS is characterized by a rapid deterioration, while type 2 HRS is characterized by a deterioration that lasts for several months. They are similar. Therefore, in some embodiments, treatment according to the drug regimen of this disclosure The patient being treated has type 1 HRS. In other embodiments, the medication regimen of this disclosure Therefore, the subjects to be treated are those with type 2 HRS. Newer diagnostic and classification of HRS For example, the ICA diagnostic criteria for acute kidney injury (AKI) using HRS have been developed. See in et al., 2019, Seminars in Nephrology 39(1):17-30. Therefore, In some embodiments, subjects with HRS meet the ICA diagnostic criteria for HRS AKI. Help.

[0155] In some embodiments, the subject is any entity that has CRS or is at risk of having CRS. Elephants and / or decreased serum levels of one or more inflammatory markers such as IL-6 It can be any object as required. In some embodiments, the object has a CRS. In one embodiment, the subject is an infection, such as COVID-19 or influenza. It has CRS that is secondary to viral infections such as infection by [unclear]. In some embodiments, the target is , has CRS secondary to COVID-19 infection. In other embodiments, the subject is immunocompromised. Epidemiological therapies, such as antibody or chimeric antigen receptor (CAR) T-cell therapy, can be caused by It has CRS. In another embodiment, the subject is, for example, COVID-19 or This carries a risk of CRS due to infections such as influenza. In other embodiments, The target group is those at risk of CRS due to immunotherapy.

[0156] In another embodiment, the subject requires a reduction in the serum levels of one or more inflammatory markers. For example, subjects with elevated levels of one or more inflammatory markers compared to normal levels. This is a subject with a certain level. An example of an inflammatory cytokine is interleukin-6 (IL). -6) C-reactive protein, D-dimer, ferritin, interleukin 8 (IL-8) ), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein (Monocyte chemoattractant protein)(MCP)1 and tumor necrosis factor α (TNFα) ) includes. In some embodiments, one or more cytokines include IL-6. In some embodiments, one or more cytokines are used in combination of the aforementioned, For example, interleukin-6 (IL-6), C-reactive protein, D-dimer, ferritin Interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM- CSF), monocyte chemotactic protein (MCP) 1, and tumor necrosis factor α (TNFα) sac This includes all 2, 3, 4, 5, 6, 7, or 8 types of chi.

[0157] 6.3. Medication regimen The methods disclosed herein typically involve lipid-binding protein-based complexes (e.g., CER-0). 01) involves multiple administrations, for example, 3 to 10 individual doses. In some embodiments, The administration regimen is a four-part lipid-binding protein-based complex (e.g., CER-001). More than one dose, for example, 5, 6, 7, 8, 9, 10, 11, 12 times, or more than 12 times It may contain a dose.

[0158] In some embodiments, the lipid-binding protein-based complexes are as described in section 6.3. In accordance with the induction and optional reinforcement regimens described in Section 1 and Section 6.3.2, In some embodiments, the lipid-binding protein-based complex is provided, for example, in this section. It may be administered in a single step according to the administration regimen described. In some embodiments, The target is maintenance regimens, for example, long-term (e.g.,) lipid-binding protein-based complexes. According to a regimen that includes administration for one month or longer, lipid-binding protein-based It is not treated with a complex.

[0159] The lipid-binding protein-based conjugate (e.g., CER-001) administration regimen of the present disclosure It can last for a maximum of one week, one week, or longer (for example, two weeks).

[0160] For example, a lipid-binding protein-based complex (e.g., CER-001) administration regimen teeth, - Five doses of CER-001 over one week; - Six doses of CER-001 over one week; - Seven doses of CER-001 over one week; - Ten doses of CER-001 over a two-week period; - 12 doses of CER-001 over a two-week period; - 14 doses of CER-001 over a two-week period The procedure may include the step of administering [a substance].

[0161] In one embodiment, the method of the present disclosure (for example, CRS, or a countermeasure with the risk of CRS) The method for treating the elephant involves, for example, 1, 2, 3, 4, 5, 6, and over a week. The procedure includes the step of administering seven doses of CER-001 on the seventh day.

[0162] In some embodiments of the methods disclosed herein, a lipid-binding protein-based complex (e.g.) (CER-001) is taken daily, for example, for at least 5 days, at least 6 days, at least Daily for 7 days or longer (for example, daily for up to 1 week, or every 2 weeks) It is administered in a day. In other embodiments, a lipid-binding protein-based complex (e.g., CER-001) is administered less frequently, for example, every other day, twice a week, per week It is administered three times, or once a week.

[0163] In reality, for example, there may be slight variations in the medication schedule for multiple doses per week. To accommodate this, an administration window may be provided. For example, ±2 days before, after, or after the day of administration. A window of ±1 day may be used.

[0164] Lipid-binding protein-based complexes (e.g., CER-001) are used for a predetermined period of time, for example For example, it may be administered for one week using the method of this disclosure. Alternatively, a lipid-binding protein-based Administration of the complex (e.g., CER-001) is indicated by the presence of one or more acute symptoms (e.g., CRS) This may continue until multiple symptoms subside, or one or more inflammatory markers A decrease in serum levels, for example, a decrease to normal levels, or a decrease to baseline levels for the subject. Values, for example, before initiating lipid-binding protein-based complex therapy (e.g., CER-001). This can continue until the levels decrease compared to the baseline values ​​measured. Reference or “normal” levels are publicly known in the art. For example, Mayo Cl inic Laboratories test catalog (www.mayocliniclabs .com / test-catalog) provides the following reference value: IL-6: ≤ 1.8 pg / ml;C Reactive protein: ≤8.0 mg / ml; D-dimer: ≤500 ng / mL fibrino Fibrinogen Equivalent Units (FEU); Ferritin: 24-336 mg cg / L (male), 11~307mcg / L (female); IL-8<57.8pg / mL; TNF-α < 5.6 pg / mL.

[0165] Patients who have CRS due to immunotherapy or are at risk of developing CRS due to immunotherapy When administering a lipid-binding protein-based complex (e.g., CER-001) to an elephant, Lipid-binding protein-based complexes (e.g., CER-001) are used before immunotherapy begins. It can be administered simultaneously with immunotherapy, after immunotherapy has been completed, or in combination with other therapies. For example, lipid-binding protein-based complexes (e.g., CER-001) are used in immunotherapy. Before and concurrently with immunotherapy, concurrently with and after immunotherapy, or with immunotherapy It can be administered before, concurrently with, and after immunotherapy. Concurrent administration should occur at exactly the same time. The administration of lipid-binding protein-based conjugates (e.g., CER-001) and immunotherapy. It is not limited to this, but rather refers to the action of one agent while the course of therapy using the other is underway. It includes the administration of quality.

[0166] The methods disclosed herein (for example, the methods for treating acute conditions described herein) are representative of the original text. Typically, high doses of lipid-binding protein-based conjugates (e.g., CER-001) are administered. This includes the step of taking the medication. High doses are taken over multiple days, for example (e.g., 3 days, 4 days, 5 days, 6 days). Between 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, Multiple individual doses (e.g., 2, 3, 4) are administered over a period of 15 days. It may be a set of 5, 6, 7, 8, 9, or 10 individual doses. In some embodiments, the dosage is administered daily, twice daily, or with intervals of 2-3 days between doses. .

[0167] In some embodiments, high doses are administered to the target HDL and / or ApoA-I blood. Increase the level and / or, for example, circulating vascular cell adhesion molecule 1 (VCAM-1) The blood of the subject is measured by the level of intercellular adhesion molecule 1 (ICAM-1) and / or by the level of intercellular adhesion molecule 1 (ICAM-1). This is an effective amount for improving endothelial function. In some embodiments, high doses or individual doses The dosage is such that 2-4 hours after administration, the target HDL and / or ApoA-I levels decrease. This is an amount that would increase it by at least 25%, at least 30%, and at least 35%.

[0168] In some embodiments, high doses include one or more inflammatory markers, such as IL-6. , C-reactive protein, D-dimer, ferritin, IL-8, GM-CSF, and MC This is an effective amount to lower one or more serum levels of P1 and TNF-α. In some embodiments, serum levels of one or more inflammatory markers are elevated in certain regions. It decreases from the normal range and / or decreases by at least 20%, at least 40%, or less Even without it, it will decrease by 60%.

[0169] The use of lipid-binding protein-based complexes (e.g., CER-001) administered to the target Quantity (for example, one or more individual doses that, when combined with other individual doses, form a higher dose) The dosage is, in some embodiments, 4-40 mg / kg on a protein weight basis (e.g. For example, it could be in the range of 10-40 mg / kg (e.g., 5, 10, 15, 20, 25 The threshold is determined by 30, 35, or 40 mg / kg, or any two of the aforementioned values. Any range, for example, 10-20 mg / kg, 15-25 mg / kg, 20-40 mg / (kg, 25-35 mg / kg, or 30-40 mg / kg). Used as specified herein. When using the term "protein weight basis," the expression refers to the lipid-bound protein that should be administered to the subject. The dose of the protein-based complex (e.g., CER-001) is the lipid-binding dose to be administered. The amount and type of ApoA-I in protein-based complexes (e.g., CER-001) This means it is calculated based on the weight of the elephant. For example, if it weighs 70 kg and 20 Those who should receive CER-001 at a dose of mg / kg are those who should receive 1400 mg of ApoA- The patient will receive the amount of CER-001 that provides I (70 kg × 20 mg / kg).

[0170] In yet another embodiment, a lipid-binding protein-based complex (e.g., CER-00) 1) may be administered on a unit dose basis. Unit dose used in the method of this disclosure In some embodiments, the dose is 300 mg to 4000 mg per administration (for example, 600 mg). It varies from g to 4000 mg (based on protein weight).

[0171] In certain embodiments, lipid-binding protein-based complexes (e.g., CER-00) 1) The dosage is 600mg-3000mg, 800mg-3000mg, 1 000mg to 2400mg, or 1000mg to 2000mg (based on protein weight) (and so on).

[0172] In some embodiments, a lipid-binding protein-based complex (e.g., CER-001) High doses, for example, in groups of multiple individual doses, range from 600 mg to 40 g (protein weight). (In this embodiment) In certain embodiments, the high dose is 3g to 35g or 5g to 30g (Based on protein weight)

[0173] Lipid-binding protein-based complexes (e.g., CER-001) are preferably administered via IV injection. It is administered as an infusion. For example, the stock solution of CER-001 is physiological saline (0. Dilute in 125-250 ml of normal saline (such as 9% NaCl) to a total volume. It is possible. In some embodiments, for subjects weighing less than 80 kg, 125 ml total While it would have a certain volume, an object weighing at least 80 kg would require a total of 250 ml. It will have a capacity. In some embodiments, the dose of CER-001 is 250 ml It is administered in total volume. Lipid-binding protein-based complex (e.g., CER-001) It can be administered over a period ranging from 1 to 24 hours. Depending on the needs of the patient, The dose was given with a duration longer than one hour (for example, up to two hours or up to 24 hours). By slow injection, by rapid injection over one hour or less, or by single bolus injection. This may be due to: In one embodiment, a lipid-binding protein-based complex (e.g. For example, CER-001) uses a fixed rate of 125 ml / hour or 250 ml / hour, It is administered over a period of one hour using an infusion pump. In one embodiment, lipid The dose of a protein-binding protein-based complex (e.g., CER-001) over a 24-hour period. It is administered as an infusion solution over time.

[0174] 6.3.1. Induction regimens In one embodiment, a suitable induction regimen for use in the method of this disclosure is a continuous multiple day For example, over three consecutive days, a lipid-binding protein-based complex (e.g., CER-0) The procedure involves administering multiple doses of 01).

[0175] In some embodiments, the appropriate induction regimen for use in the methods of this disclosure is a sequential multiplication Lipid-binding protein-based complexes (e.g., CER-001) are administered twice a day for several days. This involves administering the drug twice a day. The twice-daily doses are, for example, two doses spaced approximately 12 hours apart. , or including a morning dose and an evening dose (which may be separated by more than 12 hours) It is visible.

[0176] In one embodiment, the derived regimen involves administering lipid-binding protein daily for three consecutive days. Includes two doses of the complex (e.g., CER-001).

[0177] Lipid-binding protein-based complexes administered by injection in induction regimens (e.g.) For example, the therapeutic dose of CER-001 is 4-40 mg / kg on a protein weight basis (example). For example, it could be in the range of 4-30 mg / kg (e.g., 4, 5, 6, 7, 8, 9, 10 12, 15, 20, 25, 30, or 40 mg / kg, or any of the values ​​mentioned above. Any range bounded by two factors, for example, 5-15 mg / kg, 10-20 mg / kg, (or 15-25 mg / kg). In some embodiments, used in derivative regimens. The dose of the lipid-binding protein-based complex (e.g., CER-001) is 5 mg / It is in kg. In some embodiments, the lipid-binding protein used in the derivative regimen The dosage of the chlorine-based complex (e.g., CER-001) is 10 mg / kg. In the embodiment, a lipid-binding protein-based complex used in the derived regimen The dose of (for example, CER-001) is 15 mg / kg. In some embodiments, Lipid-binding protein-based complexes used in derivative regimens (e.g., CER- The dose of 001) is 20 mg / kg. In some embodiments, the derivative regimen is 3 Administered over several days, 5 mg / kg, 10 mg / kg, 15 mg / kg, or 2 Lipid-binding protein-based complexes (e.g., CER-001) at a dose of 0 mg / kg Includes 6 doses.

[0178] In yet another embodiment, a lipid-binding protein-based complex (e.g., CER-00) 1) can be administered on a unit dose basis. The unit dose used in the induction phase is as follows: 300mg to 4000mg per dose (for example, 300mg to 3000mg) It can vary (based on protein weight).

[0179] In certain embodiments, a lipid-binding protein-based complex is used during the induction phase. The dosage of (for example, CER-001) is 300 mg to 1500 mg per infusion. g, 400mg~1500mg, 500mg~1200mg, or 500mg~100 It is 0 mg (based on protein weight).

[0180] 6.3.2. Enhanced Regiments A suitable enhancement regimen for use in the method disclosed herein is a lipid-binding regimen that is applied after the derivation regimen. A single dose or multiple doses of protein-based complexes (e.g., CER-001) The procedure involves an administration step.

[0181] In one embodiment, the reinforcement regimen is a lipid-binding protein-based complex (for example, The procedure includes the step of administering two doses of CER-001). For example, the two doses may be approximately They may be administered 12 hours apart, or morning dose and evening dose (more or less 12 hours apart). It can be administered as (possibly at a distance greater than the interval)

[0182] Lipid-binding protein-based complexes in reinforcement regimens (e.g., CER-001) The dosage, in some embodiments, is 6 of the drug regimen starting with the induction regimen on day 1. It may be administered on day 1. Lipid-binding protein-based complexes in strengthening regimens (e.g.) The dosage of CER-001) starts with the induction regimen on day 1 in some embodiments. It may be administered on the 4th day of the drug regimen. Lipid-binding protein base in the strengthening regimen The dosage of the complex (e.g., CER-001) is, in some embodiments, the induction dose on day 1. It may be administered on the 5th day of a drug regimen starting with the introductory regimen. Lipids in the reinforcement regimen The dosage of the binding protein-based complex (e.g., CER-001) varies depending on the embodiment. It can be administered on day 7 of a drug regimen that begins with an induction regimen on day 1.

[0183] Lipid-binding protein-based complexes administered by injection in strengthening regimens (e.g.) For example, the therapeutic dose of CER-001 is 4 mg / kg to 40 mg based on protein weight. It can be in the range of / kg (for example, 4-30 mg / kg) (for example, 4, 5, 6, 7, 8 9, 10, 12, 15, 20, 25, 30, or 40 mg / kg, or the values ​​mentioned above. Any range bounded by any two of the following, for example, 5-15 mg / kg, 10-20 mg g / kg, or 15-25 mg / kg). In some embodiments, the enhanced regimen is Dosage of lipid-binding protein-based complex (e.g., CER-001) used in The concentration is 5 mg / kg. In some embodiments, lipids used in the reinforcement regimen The dose of the binding protein-based complex (e.g., CER-001) is 10 mg / kg. In some embodiments, lipid-binding protein-based complexes in the reinforcement regimen. The dose of (for example, CER-001) is 15 mg / kg. In some embodiments, Lipid-binding protein-based complexes used in strengthening regimens (e.g., CER- The dose of 001) is 20 mg / kg. In some embodiments, the strengthening regimen is 1 Administered daily in doses of 5 mg / kg, 10 mg / kg, 15 mg / kg, or 20 mg / kg Two doses of a lipid-binding protein-based complex (e.g., CER-001) at a dose of g Includes quantity.

[0184] In yet another embodiment, a lipid-binding protein-based complex (e.g., CER-00) 1) can be administered on a unit dose basis. The unit dose used in the intensification phase is as follows: 300mg to 4000mg per dose (for example, 300mg to 3000mg) It can vary (based on protein weight).

[0185] In certain embodiments, lipid-binding protein-based complexes are used during the reinforcement phase. The dosage of (for example, CER-001) is 300 mg to 1500 mg per infusion. g, 400mg~1500mg, 500mg~1200mg, or 500mg~100 It is 0 mg (based on protein weight).

[0186] Lipid-binding protein-based complexes (e.g., CER-001) can be used for, for example, a period of 1 hour. As an intermittent IV infusion, administered during the enhancement phase in the same manner as described in Section 6.3. It is possible.

[0187] 6.4. Combination Therapy Lipid-binding protein-based complexes (e.g., CER-001) can be used as monotherapy. Alternatively, it may be administered to the subjects described herein as part of a combination therapy regimen. For example. In addition, combination therapy is used in combination with standard care treatment for sepsis and / or AKI. It may contain lipid-binding protein-based complexes (e.g., CER-001). For example, Rh odes et al., 2017, Intensive Care Med 43:304-377;Dugar et al., 2020, Cleveland Please refer to Clinic Journal of Medicine 87(1):53-64.

[0188] In some embodiments, the subject is lipid-binding protein ve Treatment is performed using a complex of the serotype (e.g., CER-001). In some embodiments, The target is lipid-binding protein-based conjugates in combination with antimicrobial agents (for example, Treatment is performed using CER-001). In some embodiments, the subject is treated with an antibiotic (e.g., For example, ceftriaxone, meropenem, ceftazidime, cefotaxime, cefepime, pi Peracillin and tazobactam, ampicillin and sulbactam, imipenem and ci In combination with rastatin, levofloxacin, or clindamycin, lipid binding Treatment is carried out using protein-based complexes (e.g., CER-001). Morphologically, the target is a lipid-binding protein-based compound used in combination with antiviral drugs. Treatment is performed using a composite (e.g., CER-001). In some embodiments, the subject is ...in combination with blood pressure-raising medications (e.g., norepinephrine or epinephrine) Therapy is performed using lipid-binding protein-based complexes (e.g., CER-001).

[0189] In some embodiments, the combination therapy regimen includes one or more anti-IL-6 agents, and / or corticosteroids (e.g., methylprednisolone and / or dexamethoxazole) It may contain one or more other active ingredients for treating CRS, such as methazone. The exemplary anti-IL6 agents are tocilizumab, siltuximab, olokizumab, and Lucilimomab, BMS-945429, silukumab, levilimab, and Contains CPSI-2364. In some embodiments, a lipid-binding protein-based complex. The drug (e.g., CER-001) is administered in combination with tocilizumab. Subjects who have or have had D-19 infection are from recovered COVID-19 patients Antibodies against the original COVID-19 spike protein, one or more antibodies Antiviral agents (e.g., lopinavir, remdesivir, danoprevir, galidesivir, daruna) Viru, ritonavir, chloroquine, hydroxychloroquine, azithromycin, inter Feron (for example, interferon alpha or interferon beta, that (These may be pegylated), or one or more additional therapies such as a combination thereof. In combination, using a lipid-binding protein-based complex (e.g., CER-001) It can be treated.

[0190] In certain embodiments, lipid-binding protein-based complexes (e.g., CER- Before administering 001), take an antihistamine (e.g., diphenhydramine, cetirizine, f Fexofenadine or lorantadine may be administered. Antihistamines are used for allergies. - This may reduce the likelihood of a reaction. [Examples]

[0191] 7. Examples 7.1. Example 1: CER-001 therapy in a porcine model of LPS-induced AKI The ability of CER-001 to alleviate sepsis-related AKI is related to lipopolysaccharide (LPS) induction in AKI. The evaluation was performed using a guided pig model.

[0192] 7.1.1. Materials and Methods Pigs were randomly divided into three groups: LPS (endotoxemia pigs, n=3), single dose CE R-001 treated pigs (endotoxin blood treated with a single dose of CER-001 at 20 mg / kg) Sick pigs (n=3), and multi-dose CER-001 treated pigs (20 mg / kg CER Endotoxemia pigs treated with two doses of -001; n=3).

[0193] In T0, intravenous infusion of a physiological saline solution containing 300 μg / kg of LPS was performed. Sepsis was induced in the pigs treated with a single dose of CER-001 and in pigs treated with multiple doses of CER-001. Multiple dose-treated pigs received a 20 mg / kg dose of CER-001 at T0. 01. Multiple-dose treated pigs received a second 20 mg / kg dose at 3 hours (T3) during CER. -001 was administered. Serum IL-6, LPS, MCP-1, sVCAM-1, and sIC were detected. AM-1 levels were monitored over time. Renal tissue damage and fibrosis were assessed at the end of the study period. I evaluated it as such.

[0194] 7.1.2.Results Compared to the LPS group, an increase in survival rate was observed in both CER-001 treatment groups. (Data not shown). LPS injection was compared to the baseline condition (T0) in endotoxemia animals. This led to a time-dependent increase in IL-6 (Figure 1). The CER-001 process was IL- As shown by the decrease of 6 levels, the LPS effect could be reversed (Figure 1, "20MG"). (and "40MG"). Second dose of CER-001 3 hours (T3) after the first dose. The infusion was intended to strongly reduce IL-6 serum levels to baseline levels by the end of the study (T completion). This was done (Figure 1, "40MG"). Similarly, compared to the baseline conditions, high levels were observed in endotoxemia pigs. A level of MCP-1 was observed, while the MCP-1 level was treated with CER-001. The levels were lower in pigs (data not shown).

[0195] Endothelial dysfunction can be diagnosed by measuring serum levels of sVCAM-1 and sICAM-1. All were evaluated. Time-dependent evaluation of sVCAM-1 and sICAM-1 in endotoxemia animals. A significant increase was observed, while the CER-001 treatment was more effective than sVCAM-1 in both treatment groups. It significantly reduced sICAM-1 levels (Figures 2 and 3, respectively). IL-6 results In line with this, two doses of CER-001 (Figure 2, "40MG") were administered via sVCAM. It was more efficient to reduce -1 to the baseline level. The LPS level was CER-0 In 01 treated animals, the levels were strongly reduced (Figure 4, "20MG" and "40MG"), and the effect was This was more evident after the second injection of CER-001 (Figure 4, "40MG").

[0196] Endotoxemia renal biopsy reveals tubular vacuolation, epithelial flattening, and some apoptosis of the tubular cells. The patient presented with cysts. CER-001 treatment significantly reduced the inflammatory process and tubular damage. In toxin-stimulating animals, Masson's trichrome staining reveals extensive collagen at the interstitial level. Deposition was revealed. In both CER-001 treatment groups, compared to the LPS group, the renal parenchyma was There was significantly less collagen deposition in this case.

[0197] These preclinical data show that CER-001 treatment reduces systemic inflammation and endothelial dysfunction. This demonstrates that it limits renal injury in an LPS-induced pig model of AKI. .

[0198] 7.2. Example 2: Different doses of short-term CER to prevent sepsis-induced acute kidney injury -001 Randomized pilot study comparing injections Currently, there are no approved treatments for sepsis-related AKI. Inflammatory response to endotoxemia. However, it is a major cause of hemodynamic instability and progression to AKI in sepsis patients. The main purpose of this study is to consider and investigate various doses of CE in combination with standard care (SOC) treatment. The use of R-001 is safe and effective, and represents a new strategy for treating sepsis patients. We will investigate whether providing G-cell glycerin reduces the inflammatory response and prevents progression to AKI. That is the case. Without being constrained by theory, there are two possible mechanisms of action. Yes, CER-001 binds to endotoxins and CER-001 has a direct anti-inflammatory effect. It includes both.

[0199] 7.2.1. Survey Protocol Study group: This group consisted of patients admitted to the intensive care unit (ICU) of participating facilities who had an intra-abdominal infection. A single-center, randomized, dose-range study including patients with sepsis or urinary tract sepsis caused by [unspecified cause]. This is a Phase II study. The principal investigator will select all patients who meet the following inclusion and exclusion criteria. Ensure that patients are offered the opportunity to register for the survey.

[0200] Inclusion criteria: - At the time of registration, adult males or non-pregnant women aged 18 or older; - Compared to the SOFA score at the time of containment, at least 2 points in the SOFA score Meeting the criteria for sepsis 3, which is defined as an acute increase; -> Endotoxin level of 0.6 (Endotoxin activity assay (EEA(trademark); Spectral (Measured by Medical) (Marshall et al., 2004, J Infect Dis. 190(3) ): See pages 527-34. - An info signed and dated by the patient themselves or their legal representative. Mudoconcent.

[0201] Exclusion criteria: - Patients weighing over 100 kg; - Alanine transaminase / aspartate transaminase >5 times the upper limit of normal -ZE (ALT / AST); - Stage 4 severe chronic kidney disease or requiring dialysis (i.e., <30 ml / min / 1.73m 2 Estimated glomerular filtration rate (eGFR); - <2.0 × 10^9 white blood cells; - Pregnancy or breastfeeding; - I received an organ transplant within the last year. - Expected travel to a different hospital, not the investigation site, within 72 hours; - Having an average life expectancy of less than 30 days (as assessed by the attending physician) or "not being resuscitated" This refers to terminal stage cancer, including metastatic or hematological malignancies, classified as "i"; - A prior medical history of chronic organ failure in the terminal stage; - Diagnosed with HIV; - Uncontrolled bleeding within the last 24 hours; - Patients who used the investigational drug or device within 30 days of the first dose of CER-001.

[0202] Number of subjects: 20 subjects were registered and randomly divided into 4 experimental groups (1:1:1 1) Group A patients continue to receive conventional therapy, Group B patients receive conventional therapy plus 3 days of CE R-001 5mg / kg BID was added, followed by 5mg / kg BID on day 6. Group C: Patients receive 3 days of CER-001 10 mg / kg BID in addition to their conventional therapy. Then, on the 6th day, 10 mg / kg BID is administered; patients in group D receive conventional therapy for 3 days. Add CER-001 20mg / kg BID, and then on day 6, 20mg / kg BID continues (Figure 5).

[0203] Survey duration: This survey will be completed in 24 weeks (6 months). The registration period is for the initial target group. It has been approximately 20 weeks (5 months) since registration. The survey will end when the last subject has passed away. It is a hospital.

[0204] Primary endpoint: The primary endpoint of the study is the presence of patients with persistent sepsis caused by Gram-negative bacteria. In patients, the safety and optimal dose of CER-001 in combination with standard care. It is about defining something.

[0205] Secondary outcome measures: The secondary outcome measures are, - Endotoxin and IL-6 levels from baseline to days 3, 6, and 9 Change - Baseline is defined as the last measurement taken before medication administration on day 1. - Change in SOFA score from baseline to day 3, day 6, and day 9 (Vinc et al. 1996, Intensive Care Med, 22:707-710) - Major inflammatory markers (CRP) from baseline to days 3, 6, and 9. (D-dimer, ferritin, IL-8, GM-CSF, MCP1, and TNF-α) Changes - KDIGO Standards (Kidney Disease Improving Global Outcomes. KDIGO Clinical Pra ctice Guideline for Acute Kidney Injury. Kidney International Supplements 2012; Changes in AKI biomarkers and the development of AKI, according to 2: 1-138) - Mortality rate on day 30 - Outcome data from independent medical expert review during the trial. That is the case.

[0206] Intervention / Exposure: Informed consent form approved by the Ethics Committee (EC) Twenty patients who meet the eligibility criteria and sign and date the form will be classified into two groups: conventional therapy (Group A) and low-dose therapy. Dose CER-001 (Group B), or intermediate dose CER-001 (Group C), or high dose C Patients were randomized and assigned to ER-001 (Group D) in a ratio of (1:1:1:1). Conventional therapy This will be adjusted according to the clinical condition. All non-experimental treatments will be administered during the patient's participation in this study. Permission is granted for administration in conjunction with: other than the investigational drug specified by the protocol. Any medications taken by the patient are considered incidental medications and are recorded in the investigation record.

[0207] Each patient is identified by a patient number during screening. Once assigned to a patient... Once created, the patient number will not be reused. A randomized list and allocation sequence will be created. The principal investigator who registers the trial will not have any participation in this process. The randomized list will be kept properly confidential to prevent any attempts to disrupt randomization. .

[0208] Treatment group: All patients receive conventional therapy. The treatment group receives additional therapy along with the investigational drug. To receive. In particular, - Group A: Conventional therapy (i.e., antibiotic treatment and hemodynamic support according to the patient's condition) support) - Group B: Conventional therapy + CER-001 5 mg / kg BID for 3 consecutive days, followed by On day 6, 5 mg / kg BID - Group C: Conventional therapy + CER-001 10 mg / kg BID for 3 consecutive days, and On the following day, day 6, 10 mg / kg BID - Group D: Conventional therapy + CER-001 20 mg / kg BID for 3 consecutive days, and On the following day, day 6, 20 mg / kg BID

[0209] To avoid any potential infusion reactions, patients should be given antihypertensive medication before each CER-001 dose. Stamina drugs (e.g., dexchlorpheniramine 5 mg or hydroxyzine 100 mg) Pre-treatment should be performed. If any of the following occurs, the patient should discontinue the investigational medication. It may be possible or it may be discontinued.

[0210] Any drug-related adverse event, or the opinion of the principal investigator, may result in the patient's withdrawal from the study or Other reasons that jeopardize the interpretation of the test data (e.g., requiring additional care measures or further Severe comorbidities that hinder medication; significant tolerability issues.

[0211] At the time of discontinuation of the drug under investigation, the investigation site will document the reason for discontinuation. The patient will be clinically... If continued monitoring is performed and no other contraindications are observed, the investigation drug can be restarted within 2 days of discontinuation. Every attempt will be made to open it.

[0212] The reasons for discontinuing the drug in the study are as follows: - Requests from the principal investigator for safety reasons, such as severe adverse reactions; - Requests from the principal investigator for reasons such as patient non-compliance; - Patient requests due to tolerability; - Patient requests for other reasons, such as withdrawal from informed consent. This may include, but is not limited to, those listed above.

[0213] Discontinuing the investigational drug alone does not constitute discontinuation or withdrawal from the investigation. Patients may think they are not taking the drug. They continue to be tracked as if they have completed the treatment phase. The investigation drug is administered early (e.g., the third dose). Patients who discontinue treatment (before completion of the dosage) should undergo a completion of the study and evaluation at any time if possible.

[0214] Statistical analysis: Comparisons between groups are performed using appropriate statistical tests: dichotomous variables (base Line characteristics, mortality rate, and AKI incidence are analyzed, and chi-squared or Fisher's scale is used as needed. Use of exact tests, ANOVA or Kruskall-Wallis test, t-Stu Compare using continuous baseline features as determined by the Dent or Mann-Whitney U test. Changes in inflammatory markers are compared between groups using ANOVA and represented graphically. The proportion of individuals and the mortality rate are calculated for each group. All analyses are performed on Windows. The analysis was performed using SPSS 12.0; p<0.05 was considered statistically significant.

[0215] Procedure: The following procedures will be performed during the screening visit. After randomization, the subjects will be divided into two groups. Treatment will begin within business days. - Informed consent - Medical history - records of past and present illnesses, as well as demographic data of the subject (date of birth, This includes collecting information on gender and race. - Includes examination of body type, height and weight, BMI, and waist circumference. Medical checkup - Vital signs (pulse, blood pressure, and oral, ear, axillary, or core body temperature) - Review of inclusion / exclusion criteria - Record adverse events starting from the time informed consent is obtained. - Collect prior medications starting 4 weeks before the first dose of the test product. All current medications Record it. - Complete blood count (CBC) - White blood cell count (WBC) and platelet count with differential classification. Includes red blood cell count (RBC), hemoglobin (Hb), and hematocrit (Hct). - Fasting chemistry panel / electrolytes: sodium, potassium, chloride, blood urea nitrogen (BUN) ; or urine), serum creatinine, calculated clearance creatinine (CKD-EP) I) Glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, γGT, ALP, total and direct bilirubin, albumin, total cholesterol, HDL, LDL, Contains ligcerides, LDH, and CPK. - ABG (for evaluating respiratory and / or metabolic disorders) - ApoA-I (for pharmacokinetic and pharmacodynamic evaluation) - Coagulation test - Prothrombin time (PT) (expressed as International Normalized Ratio [INR]) ) and partial thromboplastin time (PTT) are included. - Urinalysis - Evaluation of specific gravity, pH, protein / albumin, glucose, ketones, and hemoglobin Contains moglobin / blood. - Microalbumunuria and proteinuria g / 24 hours - Serum or urine pregnancy test within 7 days prior to randomization (for women of childbearing potential) - Pharmacokinetic and pharmacodynamic evaluations are performed on apoA-I and total cholesterol levels. include. - Endotoxin levels are measured using the EAA(trademark) kit. AKI Biomarker (TIMP-2 and IGFBP-7) are Nephrocheck® kits. It is measured using a marker. Inflammatory markers include CRP, D-dimer, ferritin, and IL-6. This includes IL-8, GM-CSF, MCP1, and TNF-α.

[0216] In addition to biological samples collected for daily laboratory evaluations performed in the central laboratory, hand, - 5 ml of serum in two tubes - 3 ml of plasma in one tube - Urine 30ml Collect biological samples for research purposes, including [specific samples].

[0217] These samples were used to obtain a more comprehensive characterization of registered patients in relation to treatment. To better evaluate the response, and to provide more information in follow-up studies More importantly, new potential bacteria that may be useful in the early diagnosis of sepsis-induced AKI Evaluation of additional inflammatory cytokines and urinary biomolecules to discover iomarkers. The analysis is performed using ELISA and protein arrays.

[0218] Therapy visits (treatment period): The treatment period is defined as starting from the beginning of treatment. Visits are 3 Plan appointments on day 1, day 6, and day 9. Plan the final visit on day 30. The following procedures will be performed. , to be performed between therapy visits: - Records of adverse events and associated medications - Review of appropriate laboratory test results - Medical examination - Measure vital signs (pulse, blood pressure, and oral, ear, axillary, or core body temperature). . - Continuously record adverse events and associated medications. - Complete blood count (CBC) - white blood cell count (WBC), platelet count, red blood cell count (RBC) with classification ), including hemoglobin (Hb) and hematocrit (Hct). - Fasting chemistry panel / electrolytes: sodium, potassium, chloride, blood urea nitrogen (BUN) ; or urine), serum creatinine, calculated clearance creatinine (CKD-EP) I) Glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, γGT, ALP, total and direct bilirubin, albumin, total cholesterol, HDL, LDL, Contains ligcerides, LDH, and CPK. - ABG (for evaluating respiratory and / or metabolic disorders) - ApoA-I (for pharmacokinetic and pharmacodynamic evaluation) - Coagulation test - Prothrombin time (PT) (expressed as International Normalized Ratio [INR]) ) and partial thromboplastin time (PTT) are included. - Urinalysis - Evaluation of specific gravity, pH, protein / albumin, glucose, ketones, and hemoglobin Contains moglobin / blood. - Microalbuminuria and proteinuria g / 24 hours - Serum or urine pregnancy test within 7 days prior to randomization (for women of childbearing potential) - Pharmacokinetic and pharmacodynamic evaluations are performed on apoA-I and total cholesterol levels. It will include. - Endotoxin levels are measured using the EAA(trademark) kit. AKI Biomarker (TIMP-2 and IGFBP-7) are Nephrocheck® kits. It is measured using a marker. Inflammatory markers include CRP, D-dimer, ferritin, and IL-6. This includes IL-8, GM-CSF, MCP1, and TNF-α.

[0219] In addition to biological samples collected for daily laboratory evaluations performed in the central laboratory, hand, - 5 ml of serum in two tubes - 3 ml of plasma in one tube - Urine 30ml Collect biological samples for research purposes, including [specific samples].

[0220] Clinical scores include the SOFA score (Table 2), as well as scores for AKI assessment and staging. Includes the KDIGO criteria (Table 3). Each individual component of the score is documented.

[0221] [Table 2]

[0222] [Table 3]

[0223] Table 4 provides an overview of the investigation protocol for this embodiment.

[0224] [Table 4]

[0225] Safety assessment: The safety assessment includes the following evaluations: physical examination (including weight), vital signs (blood pressure). (Pulse, body temperature), CBC with classification, platelet count, blood chemistry, and fasting lipid profile Il [HDL-cholesterol, LDL-cholesterol, and lipoprotein (a)] [Includes] urine, glucose, 24-hour urine protein determination, serum creatinine and calculated Creativity-induced creatinine clearance (CKD-EPI), as well as adverse event monitoring, The information collected will be used to carry out the survey. All women of childbearing potential will be screened before the survey. During the leaning / baseline assessment, and thereafter if clinically necessary, quantitative serum A pregnancy test is performed. Patients are monitored through investigations for the occurrence of adverse events. It will be recorded. By the principal investigator or as a result of general questions during a medical examination, depending on the subject. Record any adverse events that were voluntarily reported or discovered. Duration (start date and time) (and end date), severity, cause and relationship with the investigated drug, patient outcome, actions taken, and For each reported adverse event, an assessment of whether the event was serious or not should be recorded. ru.

[0226] Adverse events: Definition

[0227] The term "adverse event" is synonymous with the term "adverse experience" used by the FDA. Adverse events (AEs) are those that occur in people participating in a clinical study, regardless of whether there is a causal relationship. The signs, symptoms, diseases, or laboratory or physiological findings that result from These are troublesome, undesirable, and unexpected clinical events. These include: - Any clinically significant exacerbation of a pre-existing condition - Any recurrence of a pre-existing condition - Accidental or intentional overdose of the investigational item by the principal investigator (i.e., clinical AEs caused by a higher dose than prescribed by a healthcare professional for medical reasons. - A result of misuse of the investigational product by the principal investigator (i.e., use without clinical reason). E - AEs associated with the principal investigator discontinuing the use of the investigational product

[0228] The procedure itself is not an AE, but the reason for the procedure may be an AE.

[0229] "Pre-existing medical condition" refers to a condition diagnosed before the subject signed the informed consent form. The clinical condition (the condition being treated) is documented as part of the medical history of the subject. (including) whether the condition existed before the start of the investigation's activity phase, and what its severity was. Questions about whether the event is increasing in frequency and / or under treatment are used to determine if the event is occurring under treatment. Whether or not a treatment-emergent adverse event (TEAE) occurred. Determine. An AE is (1) one that does not exist when the investigation activity phase began and is not related to the medical care of the subject. (2) If it is not a chronic condition that is part of the history, or if it is also at the start of the active phase of the investigation Alternatively, it may have been present as part of the subject's medical history, but the severity or frequency increased during the activity phase. If this occurs, it is considered to have occurred under treatment. The investigation's active phase begins from the time of the first dose of the drug. It begins.

[0230] A "serious adverse event" is defined by the following criteria: - Causes death - Life-threatening (see below) - The hospitalization in question, or an extension of an existing hospitalization, is required (see below). - Causes permanent or significant physical disability or incapacity (see below) - Causes new malignant tumors - Causes congenital abnormalities or birth defects. Any AE that occurs at any dose and satisfies one or more of the following conditions.

[0231] In addition, it may not cause death, may not threaten life, or may not be fatal. Important medical events that may not require hospitalization should be treated based on appropriate medical judgment. It could endanger the elephant and require medical or surgical intervention to prevent one of the outcomes listed above. If intervention may be required, it may be considered a SAE. Examples of such events may occur in the emergency room or This includes allergic bronchospasm requiring intensive care at home, and blood cachexia or other conditions that do not require hospitalization. This includes seizures, or the onset of drug dependence or abuse.

[0232] A "life-threatening adverse event" is defined as an event that poses an imminent risk of death. Any AE that exposes an elephant. A life-threatening event is one that occurs in a more severe form. It could have caused death, but in reality, it did not pose an imminent risk of death. It does not include elephants. For example, drug-induced hepatitis that resolves without evidence of liver failure, even if more severe Even if drug-induced hepatitis of a certain nature can be fatal, it is not considered life-threatening. Ro.

[0233] Hospitalization or prolonged hospitalization is a criterion for considering an adverse event (AE) to be serious. In addition, the principal investigator should not report hospitalization or extension of hospitalization on the form. This applies in the following situations: hospitalization or treatment required by protocol. An extension of hospitalization is necessary. Daytime or nighttime visits for examinations required by protocol are necessary. It is not considered serious.

[0234] Timing for reporting serious adverse events: Any SAE, regardless of causality, should be reported upon completion. By faxing a serious adverse event form, you can immediately inform a medical monitor. (Reported no later than 24 hours after the principal investigator notices the SAE.) Follow-up information regarding E will be provided by faxing the completed serious adverse event form. Therefore, within 24 hours of receiving the information from the principal investigator, the medical monitor (or designated person) It will be reported. The patient will remain in contact with the patient until the condition resolves or stabilizes, or until the cause is identified. Carefully observe and monitor the situation. In case of any emergency, contact the medical monitor. Therefore, it will be reported immediately (within 24 hours) to the medical monitor (or designated person).

[0235] Events / information that must be reported: Regardless of the relationship with the test item or protocol, if the subject is From the time of signing the informed consent form until 15 days after the last dose in question. Therefore, AEs or SAEs may occur during the screening and placebo induction periods. This includes events that occur in the original document and in the CRF. All AEs and SAEs are recorded in the original document and in the CRF. All AEs and SAEs that occur after the screening period are recorded in the CRF. It can be done.

[0236] Regarding SEA: The principal investigator will document all aspects of the event (e.g., additional tests). Provide medical monitors with timely information (e.g., laboratory tests, medical reports, discharge summaries, autopsy reports, etc.). Reports relating to the subsequent progress of the subject should be made until the event resolves or until permanent functional impairment occurs. In some cases, the patient will be submitted to the principal investigator until the patient's condition stabilizes.

[0237] The following events were recorded and reported within the same timeframe and after the same process as the SAE. To be done:

[0238] Abuse and overdose of the test product, with or without adverse events (i.e., non-clinical reasons). (Use in clinical settings). Overdose can result in higher doses than those prescribed by a healthcare professional for clinical reasons. It's about the quantity. It's up to the principal investigator to determine whether the dose is excessive.

[0239] Accidental or inattentive exposure to the test item, with or without adverse events.

[0240] SAEs related to the test items after the investigation.

[0241] SAEs resulting from fraudulent or accidental use by persons who did not participate in the study.

[0242] Abnormal biological values ​​or biometrics deemed clinically relevant by the participating principal investigator Talcine values. These are measured within the same timeframe and after the same process as AE or SAE. It will be reported to [the relevant authority].

[0243] Records and reports: At each required investigative visit, all information regarding events since the previous visit should be recorded. The adverse event (AE) is recorded in the adverse event record of the relevant CRF. The information recorded is from the relevant screening. and based on signs or symptoms detected during clinical evaluation. Obtained from such sources. In addition to the information, participants will be asked the following non-specific question: "Since your last visit, have you been..." How are you feeling? (Using standard medical terminology) It is recorded. Health outcome assessment tests conducted to investigate subjects are related to their quality of life. The intention is to investigate the subject's own feelings. However, the principal investigator may be latent in The test examines for the presence of existing AEs or SAEs and determines the occurrence of AEs or SAEs. When doing so, the subject's perception should be taken into consideration. The subject's evaluation is influenced by the principal investigator. This is not intended. Every effort will be made to maintain an unbiased evaluation. This includes AE information (if applicable): specific conditions or events, and changes. Whether the condition was pre-existing (i.e., whether the acute condition was present at the start of the investigation, or (History of a chronic condition), if so, it is worsening (in terms of severity and / or frequency) Whether or not; date and time of occurrence; severity; causal relationship with the test item; actions taken; The outcome was as follows: Any clinically significant abnormal laboratory values, in the opinion of the principal investigator, were treated as adverse events (AEs). It will be reported.

[0244] The causal relationship between the AE and the test product is determined based on his or her clinical judgment and the following provisions. And this is determined by the principal investigator: - Definitely related: The event can be adequately explained by the administration of the test item. - Probably related: The event is more related to the clinical condition or other active ingredients / therapies than to the clinical condition of the subject. This is most likely to be explained by the administration of the test substance. - Possibly related: The event may be caused by the administration of the test item, or by the subject's clinical condition or other This can be explained by the active substance / therapy. - Probably unrelated: The event is more related to the subject's clinical condition or other factors than to the test item. It is most likely to be explained by the substance / therapy used. - Definitely unrelated: The event is not related to the clinical condition of the subject or to other active substances / therapies. It can be fully explained.

[0245] When evaluating the relationship between administration of the test substance and adverse events (AEs), the following should be considered: - The temporal relationship between administration of the test item and adverse events (AEs). - Biological validity of the relationship - The underlying clinical condition or associated active substances and / or therapies of the subject

[0246] If applicable, would discontinuing the test item reduce the adverse event (AE)?

[0247] If applicable, it depends on whether repeated exposure to the test item causes the adverse event (AE) to reappear. Nevertheless, SAEs unrelated to the investigational item are not subject to the jurisdiction of the participating principal investigator or The act of clinical research, i.e., the subject of the research, is carried out by a medical monitor (or designated person). It can be considered related to participation. For example, protocol-related SAEs are washable. Events that occur during the out-of-bounds period or are related to procedures required by the protocol. The severity of AEs is determined by the National Cancer Institute (NCI) Common Toxicity. Criteria for Adverse Events (CTCAE) version Evaluated according to 5.0. The following provisions apply to poisons not specified in the NCI CTCAE. Used for sexual purposes: - Mild (Grade 1): AE is noticeable to the individual but does not interfere with daily activities. AE This does not require discontinuing or reducing the dose of the test product. - Moderate (Grade 2): AE interferes with daily activities but responds to symptomatic treatment or rest. AEs may require reducing the dose of the test product rather than discontinuing its administration. - Severe (Grade 3): AEs are those who, despite symptomatic treatment, are unable to perform daily activities. It severely limits the ability. In addition, AEs may cause discontinuation of administration of the test product or a reduction in the dose. This will lead to a decrease in blood pressure. - Life-threatening (Grade 4): AEs require discontinuation of the test product. The elephant is at imminent risk of death.

[0248] 7.2.2.Results Treatment with CER-001 delays the onset of AKI in patients with sepsis. Alternatively, it may be found that it can be prevented.

[0249] 7.3. Example 3: CER-0 for treating CRS secondary to Covid-19 infection 01 Therapy COVID-19 is a cell surface receptor that affects angiotensin-converting enzyme 2 (ACE2). It infects host cells through the binding of the virus spike protein (SARS-2-S), and HD L-scavenger receptor B type 1 (SR-B1) enables ACE2-dependent entry of the virus. To encourage. (Wei et al., Nature Metabolism doi.org / 10.1038 / s42255-020-00324-0). Theory Without being constrained by, lipid-binding protein-based complexes such as CER-001 Competitive binding to SR-B1 provides therapeutic effects in subjects with COVID-19 infection. It may provide benefits (e.g., a reduction in the severity and / or duration of CRS), and therefore This is thought to limit the virus's ability to infect further cells.

[0250] A pilot study was conducted in patients with CRS secondary to COVID-19 infection. The safety and efficacy of seven CER-001 injections will be examined. The study will be conducted from nine visits. ru: - Pre-medication (baseline) visit: Evaluation of baseline inflammatory markers and safety laboratory values. - Medication visit: Seven doses (dose 1-7) will be administered once a day over a period of seven days. It is administered as follows. IL-6 levels are measured daily from pre-injection samples. - Follow-up visit: Patients will have their final evaluation on day 8. Inflammatory markers and safety Measure the sex test values.

[0251] A flowchart for the investigation is shown in Figure 6.

[0252] 7.3.1. Selection of Survey Subjects 7.3.1.1. Inclusion Criteria Eligible patients who meet the following criteria will be enrolled in the study: 1. At the time of registration, adult males or non-pregnant women who are 18 years of age or older. 2. Within 72 hours prior to hospitalization, polymerase chain reaction () was performed on an oral, pharyngeal, or anal specimen. Determined by PCR or other commercial or public health status assays in a laboratory. This person has been confirmed to have COVID-19. 3. A disease of any duration, and at least one of the following: a. Radiographic infiltrates detected by imaging (chest X-ray, CT scan, etc.), b. Clinical evaluation (evidence of rales / crackling sounds during health checkups) and SpO2 ≤ 93% in room air. ,or c. Requires mechanical ventilation and / or oxygen supplementation, d. Persistent fever within the last 24 hours and unresponsiveness to NSAIDs or steroids. 4. Serum IL-6 levels ≥ 3 times the upper limit of normal 5. Agree to and abide by the use of acceptable forms of contraception throughout the study, and be able to give birth. Sexually active women. The acceptable form of contraception for this study is barrier method + hormone therapy (implantation). It is defined as (injections, oral contraceptives, and IUDs) or abstinence.

[0253] 7.3.1.1. Exclusion criteria Patients who meet the following criteria will be excluded from the study: Patients weighing more than 1,100 kg 2. Alanine transaminase / aspartate transaminase levels >5 times the upper limit of normal. -Ze (ALT / AST) 3. Severe chronic kidney disease of stage 4 or requiring dialysis (i.e., <30 ml / min / Estimated glomerular filtration rate (eGFR) for 1.73 m² 4. Hemoglobin <80g / L 5. <2.0 × 10^9 white blood cells 6. <50 × 10^9 platelets 7. Pregnancy or breastfeeding 8.72 hours or less, expected to be moved to a different hospital, not the investigation site. 9. The expected lifespan does not exceed 7 days. 10. Patients who used the investigational drug within 30 days of the first dose of CER-001.

[0254] 7.3.1.2. Restrictions during the investigation There are no patient restrictions other than those outlined in the inclusion / exclusion criteria above.

[0255] 7.3.1.3. Withdrawal Criteria The reasons for patient withdrawal from the investigational drug are as follows: • Requests from the principal investigator for safety reasons, such as severe adverse reactions; • Requests from the principal investigator for reasons such as patient non-compliance; • Patient requests based on tolerability; • Patient requests for reasons other than informed consent, such as withdrawal from informed consent. This may include, but is not limited to, those listed above.

[0256] Discontinuing the investigational drug alone does not constitute discontinuation or withdrawal from the investigation. Patients may think they are not taking the drug. They continue to be tracked as if they have completed the treatment phase. The investigation drug is administered early (e.g., 7th dose). Patients who discontinue treatment (before completion of the dosage) should undergo a completion of the study and evaluation at any time if possible.

[0257] 7.3.2. Patient Treatment 7.3.2.1. Investigational Products CER-001 is produced in approximately 18 mL at a concentration of 8 mg / mL (ApoA-I content). The product is provided frozen in a 20 mL vial. CER-001 is administered by weight. Thaw the entire volume, then dilute it with physiological saline to a volume of 250 mL.

[0258] Medication will be administered at each of the seven medication visits. At each of these visits, the patient will receive an injection. Use an injection pump to administer a single IV infusion of CER001 (20 mg) over a 24-hour period. To avoid any potential infusion reactions, administer each CER-00 to the patient. 1. Take an antihistamine (e.g., dexchlorpheniramine 5 mg or hydrox) before the dose. Pre-treatment is performed with cidin 100mg.

[0259] 7.3.2.2. Interruption or discontinuation of the investigation drug If any of the following occurs, the patient may discontinue or stop taking the investigational medication. To be done: • Any drug-related adverse event, or in the opinion of the principal investigator, may result in the patient's withdrawal from the study or Other reasons that jeopardize the interpretation of the test data (e.g., requiring additional care measures or further (Severe co-occurring illnesses that hinder medication) • Serious tolerability issues

[0260] At the time of discontinuation of the drug under investigation, the investigation site will document the reason for discontinuation. The patient will be clinically... If continued monitoring is performed and no other contraindications are observed, the investigation drug can be restarted within 2 days of discontinuation. Every attempt will be made to open it.

[0261] 7.3.3. Ancillary Treatments All non-experimental treatments are permitted to be administered incidentally during patients' participation in this study. It is permitted. Any medication taken by the patient other than the investigation drug specified by the protocol is permitted. It will be considered an incidental medication and recorded in the investigation records.

[0262] 7.3.4. Prohibited Medicines No medications are excluded.

[0263] 7.3.5. Monitoring of patient compliance CER-001 is administered in a hospital setting under direct supervision.

[0264] 7.3.6. Evaluation of efficacy 7.3.6.1. Effectiveness Assessment Inflammatory markers include CRP, D-dimer, ferritin, IL-6, IL-8, and GM-CS. Includes F, MCP1, and TNF-α.

[0265] 7.3.6.2. Efficacy Parameters (a) Primary efficacy parameter The primary efficacy parameter is the change in IL-6 from baseline to day 8. The baseline is defined as the average of measurements taken at baseline visit and before medication on day 1. It will be done.

[0266] (b) Secondary efficacy parameter Secondary efficacy parameters include the inflammatory markers CRP and D from baseline to day 8. For dimer, ferritin, IL-8, GM-CSF, MCP1, and TNF-α Includes changes.

[0267] 7.3.7. Safety Evaluation 7.3.7.1. Safety Parameters (a) Pregnancy test (if applicable) Women of childbearing potential have received documented treatment at any point during hospitalization and before medication administration. She has a negative pregnancy test result.

[0268] (b) Safety test value testing Two time points: baseline and day 8, for chemical and hematological analysis, blood Collect a sample. The following tests will be performed by a local hospital laboratory:

[0269] [Table 5]

[0270] 7.3.8.Results IL-6 levels decrease from baseline to day 8. Secondary efficacy parameters also decrease from baseline. The sline decreased on day 8, and CRS could be treated with CER-001 therapy, and inflammation was also reduced. This indicates that it may lower serum levels of the marker.

[0271] 7.4. Example 4: CER-0 for treating CRS secondary to Covid-19 infection 01 Therapy - Additional Treatment Protocols This example involves a COVID-19 patient with severe cytokine release syndrome and renal impairment. This is a study on CER-001 therapy in patients.

[0272] 7.4.1. Selection of Target 7.4.1.1. Inclusion Criteria Eligible patients must meet the following criteria before registering for the study: 1. At the time of registration, the applicant must be an adult male or a non-pregnant female aged 18. 2. Within 72 hours prior to hospitalization, polymerase chain reaction () was performed on an oral, pharyngeal, or anal specimen. Determined by PCR or other commercial or public health status assays in a laboratory. He has been confirmed to have a COVID-19 infection. 3. A disease of any duration, and at least one of the following: Radiographic infiltrates detected by imaging (chest X-ray, CT scan, etc.), or Clinical evaluation (evidence of rales / crackling sounds during health checkups) and SpO2 < 93% in indoor air, Taha Requires mechanical ventilation and / or oxygen supplementation, Within the last 24 hours, persistent fever and unresponsiveness to NSAIDs or steroids have occurred. 4. Serum IL-6 >3 times the upper limit of normal 5. Agree to and abide by the use of acceptable forms of contraception throughout the study, and be able to give birth. Sexually active women. The acceptable form of contraception for this study is barrier method + hormone therapy (implantation). It is defined as (injections, oral contraceptives, and IUDs) or abstinence.

[0273] 7.4.1.2. Exclusion criteria Patients who meet any of the following criteria will be excluded from this study. 1. Clinical history suggestive of allergy to CER-001 2. Pregnancy or breastfeeding 3. Expected transfer to another hospital within 3.72 hours. 4. The expected lifespan does not exceed 7 days. 5. Patients who used the investigational drug within 30 days of the first dose of CER-001.

[0274] 7.4.2. Treatment 7.4.2.1. Treatments administered To avoid any potential infusion reactions, patients should be given antihypertensive medication before each CER-001 dose. Stamina drugs (e.g., dexchlorpheniramine 5 mg or hydroxyzine 100 mg) Pre-treatment is performed using ).

[0275] The patient received intravenous infusions of CER-001 at a dose of 15 mg / kg BID for three consecutive days. Receive. At the discretion of the principal investigator, patients may receive up to two additional doses.

[0276] If any of the following occurs, the patient may discontinue or interrupt the investigational medication. It can be stopped: 1. Any drug-related adverse event, or the opinion of the principal investigator, may lead to the patient's inability to participate in the study. Other reasons that jeopardize the interpretation of the test data (e.g., requiring additional care measures or Severe co-occurring illnesses that hinder the administration of other medications; 2. Serious tolerability issues

[0277] At the time of discontinuation of the drug under investigation, the investigation site will document the reason for discontinuation. The patient will be clinically... If continued monitoring is performed and no other contraindications are observed, the investigation drug can be restarted within 2 days of discontinuation. Every attempt will be made to open it.

[0278] The reasons for discontinuing the drug in the study are as follows: 1. Requests from the principal investigator for safety reasons, such as severe adverse reactions. 2. Requests from the principal investigator for other reasons, such as patient non-compliance. 3. Patient requests based on tolerability. 4. Patient requests for reasons other than informed consent, such as withdrawal from informed consent. This may include, but is not limited to, those listed above.

[0279] Discontinuing the investigational drug alone does not constitute discontinuation or withdrawal from the investigation. Patients may think they are not taking the drug. They continue to be tracked as if they have completed the treatment phase. The investigation drug is administered early (e.g., the third dose). Patients who discontinue treatment (before completion of the dosage) should undergo a completion of the study and evaluation at any time if possible.

[0280] 7.4.2.2. Dose changes In cases of clinical necessity as defined by the principal investigator, the drug dose may be reduced. It can be obtained or increased.

[0281] 7.4.2.3. Related Medications / Therapies All non-experimental treatments are permitted to be administered incidentally during patients' participation in this study. It is permitted. Any medication taken by the patient other than the investigation drug specified by the protocol is permitted. It will be considered an incidental medication and recorded in the investigation records.

[0282] 7.4.3. Survey and Evaluation The following procedures will be performed during the baseline visit. The following tests will be performed at the local hospital laboratory. It will be implemented by [method / method]. 1. Informed consent 2. Medical history includes records of past and present illnesses, as well as demographic data of the subject (date of birth). This includes collecting information on gender and race. 3. A medical examination that includes assessment of body type, height and weight, BMI, and waist circumference. 4. Vital signs (pulse, blood pressure, and oral, ear, axillary, or core body temperature) 5. Review of inclusion / exclusion criteria 6. Start recording adverse events from the time informed consent is obtained. 7. Collect prior medications starting 4 weeks before the first dose of the test product. All current medications Record it. 8. Complete blood count (CBC) - white blood cell count (WBC), platelet count, red blood cell count (RBC) with classification ), including hemoglobin (Hb) and hematocrit (Hct). 9. Fasting Chemistry Panel / Electrolytes: Sodium, Potassium, Chloride, Blood Urea Nitrogen (BUN) ; or urine), serum creatinine, calculated clearance creatinine (CKD-EP) I) Glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, GT, A LP, total and direct bilirubin, albumin, total cholesterol, HDL, LDL, triglycerides Contains glycerides, LDH, and CPK. 10. ABG (for evaluating respiratory and / or metabolic disorders) 11. ApoA-I (for pharmacokinetic and pharmacodynamic evaluation) 12. Coagulation Test - Prothrombin Time (PT) (expressed as International Normalized Ratio [INR]) This includes (and partial thromboplastin time (PTT)). 13. Urinalysis - Evaluation of specific gravity, pH, protein / albumin, glucose, ketones, and Contains hemoglobin / blood. 14. Microalbuminuria and proteinuria g / 24 hours 15. Serum or urine pregnancy test within 7 days prior to randomization (for women of childbearing potential) ) 16. Pharmacokinetic and pharmacodynamic evaluations include apoA-I and total cholesterol levels. Includes. 17. Inflammatory markers include CRP, PCT, D-dimer, ferritin, IL-6, and IL-8. It includes GM-CSF, MCP1, and TNF-α.

[0283] Clinical and laboratory parameters were reported in Figure 7, from baseline to 8 days later. We will monitor your eyes until your final visit, including the following procedures: 1. Recording of adverse events and associated medications. 2. Review of appropriate test result information 3. Medical examination 4. Assess vital signs (pulse, blood pressure, and oral, ear, axillary, or core body temperature). . 5. Continuously record adverse events and associated medications. 6. Complete blood count (CBC) - white blood cell count (WBC), platelet count, red blood cell count (RBC) with classification ), including hemoglobin (Hb) and hematocrit (Hct). 7. Fasting Chemotherapy Panel / Electrolytes: Sodium, Potassium, Chloride, Blood Urea Nitrogen (BUN) ; or urine), serum creatinine, calculated clearance creatinine (CKD-EP) I) Glucose, calcium, phosphorus, total protein, uric acid, AST, ALT, GT, A LP, total and direct bilirubin, albumin, total cholesterol, HDL, LDL, triglycerides Contains glycerides, LDH, and CPK. 8. ABG (for evaluating respiratory and / or metabolic disorders) 9. ApoA-I (for pharmacokinetic and pharmacodynamic evaluation) 10. Coagulation Test - Prothrombin Time (PT) (expressed as International Normalized Ratio [INR]) This includes (and partial thromboplastin time (PTT)). 11. Urinalysis - Evaluation of specific gravity, pH, protein / albumin, glucose, ketones, and Contains hemoglobin / blood. 12. Microalbuminuria and proteinuria g / 24 hours 13. Inflammatory markers include CRP, PCT, D-dimer, ferritin, IL-6, and IL-8. It includes GM-CSF, MCP1, and TNF-α.

[0284] 7.4.4. Reporting Adverse Events (AEs) An AE is a therapeutic reaction in clinical research patients that does not necessarily have a causal relationship with the product. Any troubles associated with the use of the test product (active drug or placebo, biologic, or device) It is a minor medical event. Therefore, whether or not an AE is considered to be related to the investigational product... Regardless of any undesirable and unintended actions related in time to the use of the investigational product It may be a sign (e.g., an abnormal test result), a symptom, or a disease.

[0285] Adverse events are, • Symptoms described by the patient • Clinically significant changes in the patient's examination, or to the principal investigator or medical staff. Other signs thus observed · Test abnormalities (laboratory tests) that reflect changes from baseline and / or changes in the administration of the investigational product or changes in medical care (diagnostic or therapeutic) that may result · Conditions present at baseline that are worsening or recurring after resolution may be included.

[0286] At each study visit, the patient is evaluated for new AEs and the status of existing AEs.

[0287] 7.4.5. Results IL-6 levels and other inflammatory markers decrease on day 8 from baseline.

[0288] 7.5. Example 5: CER-001 Therapy for Treating Ischemia / Reperfusion AKI This example is an investigation of CER-001 therapy for treating ischemia / reperfusion AKI.

[0289] 7.5.1. Materials and Methods Pigs weighing 45 - 60 kg are fasted for 24 hours before the investigation. To reduce pharyngeal and tracheal secretions and prevent bradycardia after intubation, all animals are pre-administered an intramuscular mixture of azaperone (8 mg / kg g kg -1 ) and atropine (0.03 mg / kg -1 ). After anesthesia, a midline laparotomy is performed to access both kidneys. Next the renal arteries and veins are isolated, and a vascular loop is placed around the renal artery using right-angle forceps. By pulling on the vascular loop, warm ischemia is induced for 60 minutes. After ischemia, 3 hours of reperfusion follows, and one-half of the animals receive CER-001 administered directly through the renal artery 5 minutes before the start of reperfusion. After 24 hours, the animals are given pentobarbital at 1 mL / kg BW​​​​ The animals are euthanized by intravenous administration of [a substance]. Then, their kidneys are removed for analysis.

[0290] 7.5.2.Results CER-001 alleviates ischemia / reperfusion acute kidney injury (AKI).

[0291] 8. Specific Implementations 8.1. Specific Embodiments: Group 1 Various aspects of this disclosure are described in the embodiments specified in the following numbered paragraphs: References to previously numbered embodiments refer to the previously numbered embodiments in this Section 8.1. It refers to the form of application. 1. Administer a high dose of a lipid-binding protein-based complex to the target that needs it. A method for treating subjects with acute conditions, including apnea, wherein the acute condition is optionally acute. Methods involving inflammation. 2. High doses are administered over a period of 3 days to approximately 2 weeks, and high doses are optional. 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days Embodiment 1 is administered over a period of 13, 14, or 15 days. Method of description. 3. High doses are a set of 2 to 10 individual doses, and optional high doses are 3, 4, and 5. Embodiment 1 or Embodiment 1 is a collection of 6, 7, 8, 9, or 10 individual doses. The method described in 2. 4. The method according to Embodiment 3, wherein multiple individual doses are administered daily or twice daily. 5. Multiple individual doses are administered 2-3 days apart, as in Embodiment 3 or Embodiment 4. Method of description. 6. Each individual dose is effective in increasing the target HDL level, according to the embodiment. The method described in any one of 3 to 5. 7. Each individual dose should reduce the target HDL level by at least 2 hours after administration. Embodiments that are effective in increasing by 5%, at least 30%, or at least 35% The method described in 6. 8. Each individual dose should reduce the target HDL level by at least 25% two hours after administration. Embodiment 7 is effective in increasing by at least 30%, or at least 35%. Method of description. 9. Each individual dose should reduce the target HDL level by at least 25% three hours after administration. Embodiment 7 is effective in increasing by at least 30%, or at least 35%. Method of description. 10. Each individual dose should raise the target HDL level by at least 25% four hours after administration. Embodiment 7 is effective in increasing by %, at least 30%, or at least 35%. Methods used. 11. Each individual dose is effective in increasing the target ApoA-I level. The method according to any one of embodiments 3 to 10. 12. Each individual dose is intended to reduce the target ApoA-I level 2-4 hours after administration. It is effective in increasing it by at least 25%, at least 30%, or at least 35%. The method according to Embodiment 11. 13. Each individual dose should reduce the target ApoA-I level 2 hours after administration. It is also effective in increasing by 25%, at least 30%, or at least 35%, by implementing The method described in Form 12. 14. Each individual dose should reduce the target ApoA-I level 3 hours after administration. It is also effective in increasing by 25%, at least 30%, or at least 35%, by implementing The method described in Form 12. 15. Each individual dose is intended to reduce the target ApoA-I level 4 hours after administration. It is also effective in increasing by 25%, at least 30%, or at least 35%, by implementing The method described in Form 12. 16. High doses are effective in improving the vascular endothelial function of the target vascular endothelial function, and optional vascular endothelial function The performance is measured by circulating VCAM-1 and / or ICAM-1, according to Embodiment 1. The method described in any one of the 15 above. 17. High doses reduce serum levels of one or more inflammatory markers in the subjects. A method according to any one of embodiments 1 to 16, which is effective for this purpose. 18. High doses are effective in lowering serum levels of interleukin-6 ("IL-6"). The method according to embodiment 17 is effective. 19. High doses are effective in lowering serum levels of C-reactive protein, in practice. The method described in Embodiment 17 or Embodiment 18. 20. High doses are effective in lowering serum levels of D-dimer, as in Embodiment 17. The method described in any one of the 19 above. 21. High doses are effective in lowering serum ferritin levels, as in Embodiment 17. The method described in any one of the 20 above. 22. High doses are effective in lowering serum levels of interleukin-8 (IL-8). A method according to any one of embodiments 17 to 21. 23. High doses affect serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF). A method according to any one of embodiments 17 to 22, which is effective in reducing the value. 24. High doses are effective in lowering serum levels of monocyte chemotactic protein (MCP) 1. The method according to any one of embodiments 17 to 23. 25. High doses are effective in lowering serum levels of tumor necrosis factor α (TNF-α). The method according to any one of embodiments 17 to 24. 26. High doses may cause serum levels of one or more inflammatory markers to move from elevated to normal levels. A method according to any one of embodiments 17 to 25, which is effective in reducing. 27. High doses can increase serum levels of one or more inflammatory markers by at least 20%, or less. Embodiments 17 to 2 are effective in reducing by at least 40%, or at least 60%. The method described in any one of the six. 28. The subject is any of Embodiments 1 to 27, which has CRS or is at risk of CRS. One method. 29. The method according to Embodiment 28, wherein the subject is CRS. 30. The method according to Embodiment 29, relating to a patient having CRS secondary to infection. 31. The method according to embodiment 30, wherein the infection is a viral infection. 32. The method according to embodiment 31, wherein the viral infection is a coronavirus infection. 33. The method according to embodiment 32, wherein the coronavirus is COVID-19. 34. The method according to embodiment 31, wherein the viral infection is an influenza infection. 35. The subject is a patient having CRS caused by immunotherapy, as described in Embodiment 29. method. 36. The method according to embodiment 35, wherein the immunotherapy includes antibody therapy. 37. Immunotherapy includes chimeric antigen receptor (CAR) T cell therapy as described in Embodiment 35. method. 38. Lipid-binding protein-based complexes are administered before immunotherapy begins, in practice. The method described in any one of states 35 to 37. 39. The lipid-binding protein-based complex is administered concurrently with immunotherapy, Embodiment 35 The method described in any one of 38. 40. Lipid-binding protein-based complexes are administered after immunotherapy is completed. The method according to any one of forms 35 to 39. 41. The method described in Embodiment 28, which carries a risk of CRS. 42. The method according to Embodiment 41 applies to cases where there is a risk of CRS due to infection. 43. The method according to embodiment 42, wherein the infection is a viral infection. 44. The method according to embodiment 43, wherein the viral infection is a coronavirus infection. 45. The method according to Embodiment 44, wherein the coronavirus is COVID-19. 46. ​​The method according to embodiment 43, wherein the viral infection is an influenza infection. 47. The method according to Embodiment 41 is applicable to patients who are at risk of CRS due to immunotherapy. 48. The method according to Embodiment 47, wherein the immunotherapy includes antibody therapy. 49. Immunotherapy includes chimeric antigen receptor (CAR) T cell therapy as described in Embodiment 47. method. 50. Lipid-binding protein-based complexes are administered before immunotherapy begins, in practice. The method described in any one of states 47 to 49. 51. The lipid-binding protein-based conjugate is administered concurrently with immunotherapy, Embodiment 47 The method described in any one of the 50 methods. 52. Lipid-binding protein-based complexes are administered after immunotherapy is completed. The method according to any one of forms 47 to 51. 53. The subjects are those who have sepsis or are at risk of developing sepsis, as described in Embodiments 1 to 27. The method described in one of the following options. 54. Sepsis is associated with Gram-negative bacterial infection, according to the method of embodiment 53. 55. Sepsis is associated with Gram-positive bacterial infection, according to the method of embodiment 53. 56. The method according to any one of embodiments 53 to 55, relating to a subject having an intra-abdominal infection. . 57. The method according to any one of embodiments 53 to 55, relating to a subject with urinary tract sepsis. . 58. High doses are effective in reducing the severity of sepsis, as shown in embodiments 53 to 57. Any one of the following methods. 59. High doses reduce the likelihood that the subject will develop acute kidney injury (AKI). The method according to any one of embodiments 1 to 58, which is effective for [the purpose of the invention]. 60. High doses are effective in delaying the onset of AKI, as described in Embodiments 1 to 59. The method described in one of the following options. 61. A high dose is effective in preventing AKI, as shown in any one of Embodiments 1 to 59. Methods used. 62. The subjects are those who have or are at risk of developing acute kidney injury (AKI), as in Embodiment 1. The method described in any one of 58. 63. The method according to embodiment 62, wherein the AKI is sepsis-related AKI. 64. The method according to embodiment 62, wherein AKI is ischemia / reperfusion AKI. 65. The method according to embodiment 62, wherein AKI is cardiac surgery-related AKI. 66. The method according to embodiment 62, wherein AKI is hepatorenal syndrome (HRS) AKI. 67. The method according to embodiment 66, wherein HRS is type 1 HRS. 68. The method according to embodiment 66, wherein HRS is type 2 HRS. 69. The method according to any one of embodiments 62 to 68, wherein the subject has AKI. 70. AKI is secondary to viral infection, and the viral infection is selected as COVID-19. The method according to embodiment 69. 71. High doses are effective in reducing the severity of AKI, as in Embodiment 69 or Implementation The method described in form 70. 72. The method of any one of embodiments 62 to 66 that has an AKI risk. . 73. The method according to embodiment 72, relating to a subject with sepsis. 74. Sepsis is associated with Gram-negative bacterial infection, according to the method of embodiment 73. 75. Sepsis is associated with Gram-positive bacterial infection, according to the method of embodiment 73. 76. The method according to any one of embodiments 73 to 75, for subjects having an intra-abdominal infection. . 77. The method according to any one of embodiments 73 to 75, relating to a subject with urinary tract sepsis. . 78. The subjects have a viral infection, and the viral infection is randomly selected to be COVID-19. The method according to Embodiment 72. 79. The method of embodiment 72 applies to subjects who have undergone heart surgery. 80. The method according to Embodiment 72, for subjects with acute liver disease. 81. The method according to Embodiment 72, for subjects with chronic liver disease. 82. High doses are effective in reducing the likelihood that the subject will develop AKI. The method according to any one of embodiments 72 to 81. 83. High doses are effective in delaying the onset of AKI, as described in embodiments 72 to 82. Either one of the methods. 84. High doses are effective in preventing AKI, any one of embodiments 72 to 82. The method used. 85. If the patient develops AKI, high doses are effective in reducing the severity of AKI. A method according to any one of embodiments 72 to 83. 86. Prior to administration of the lipid-binding protein-based complex, subjects had an SOFA score of 1-4. The method according to any one of embodiments 53 to 85, having the following characteristics. 87. Prior to administration of the lipid-binding protein-based complex, subjects had SOFA scores of 2-4. The method according to embodiment 86, wherein the method is characterized by having the following features. 88. Prior to administration of the lipid-binding protein-based complex, subjects had an SOFA score of 1. The method according to embodiment 86. 89. Prior to administration of the lipid-binding protein-based complex, subjects had a SOFA score of 2. The method according to embodiment 86. 90. Prior to administration of the lipid-binding protein-based complex, subjects had an SOFA score of 3. The method according to embodiment 86. 91. Prior to administration of the lipid-binding protein-based complex, subjects had a SOFA score of 4. The method according to embodiment 86. 92. Prior to administration of the lipid-binding protein-based complex, subjects had an endotoxin activity level >0.6. The method according to any one of embodiments 1 to 91, comprising a bell. 93. High doses are effective in reducing the endotoxin activity level of the target, from Embodiment 1. The method described in any one of the 92 methods. 94. Lipid-binding protein-based complexes are reconstituted HDL or HDL mimics. The method described in any one of the application forms 1 to 93. 95. Lipid-binding protein-based complexes are apomers (registered trademark) or cargomers (registered trademark). The method according to any one of Embodiments 1 to 93, which is a registered trademark. 96. The lipid-binding protein-based complex contains sphingomyelin, from Embodiment 1 The method described in any one of the 95 methods. 97. Lipid-binding protein-based complexes contain negatively charged lipids, Embodiments 1 to 9 The method described in any one of the six. 98. Negatively charged lipids are 1,2-dipalmitoyl-sn-glycero-3-[phospho-r The method described in Embodiment 97, which is ac-(1-glycerol)(DPPG) or a salt thereof. Law. 99. Lipid-binding protein-based complexes include CER-001, CSL-111, and CSL The method according to embodiment 94, wherein the CER-112, CER-522, or ETC-216. 100. The lipid-binding protein-based complex is CER-001, as described in Embodiment 99. Method of loading. 101. Lipid-binding protein-based complexes are administered systemically, optionally by injection. The method according to any one of Embodiments 1 to 100. 102. Lipid-binding protein-based complexes are serum receptors for one or more inflammatory markers. The method according to any one of embodiments 1 to 101, wherein the administration is carried out until the Bell level decreases. 103. Lipid-binding protein-based complexes are serum receptors for one or more inflammatory markers. The method according to embodiment 102, wherein the drug is administered until the bell level drops to the normal range. 104. Lipid-binding protein-based complexes are serum receptors for one or more inflammatory markers. Bell measured one or more types of inflammation before administration of a lipid-binding protein-based complex. Embodiment 10: Administered until the marker level drops below baseline. The method described in 2. 105. The individual doses of each lipid-binding protein-based complex administered are 4-40 The value is mg / kg (based on protein weight), in any one of Embodiments 1 to 104. Method of description. 106. The individual doses of each lipid-binding protein-based complex are 4-30 mg / kg. The method according to Embodiment 105, which is (on a protein weight basis). 107. The individual doses of each lipid-binding protein-based complex are 15-25 mg / kJ. The method according to Embodiment 105, wherein the amount is g (based on protein weight). 108. The individual doses of each lipid-binding protein-based complex are 10-30 mg / kJ. The method according to Embodiment 105, wherein the amount is g (based on protein weight). 109. The individual doses of each lipid-binding protein-based complex are 10-20 mg / kJ. The method according to Embodiment 105, wherein the amount is g (based on protein weight). 110. The individual doses of each lipid-binding protein-based complex are 5 mg / kg (tan). The method according to Embodiment 105, which is based on protein weight. 111. The individual dose of each lipid-binding protein-based complex is 10 mg / kg ( The method according to Embodiment 105, which is based on protein weight. 112. The individual dose of each lipid-binding protein-based complex is 15 mg / kg ( The method according to Embodiment 105, which is based on protein weight. 113. The individual dose of each lipid-binding protein-based complex is 20 mg / kg ( The method according to Embodiment 105, which is based on protein weight. 114. The individual doses of each lipid-binding protein-based complex are 5-15 mg / kg. The method according to Embodiment 105, which is (on a protein weight basis). 115. The individual doses of each lipid-binding protein-based complex are 10-20 mg / kJ. The method according to Embodiment 105, wherein the amount is g (based on protein weight). 116. The individual doses of each lipid-binding protein-based complex are 15-25 mg / kJ. The method according to Embodiment 105, wherein the amount is g (based on protein weight). 117. High doses are administered according to the induction regimen, followed optionally by an intensification regimen. The method according to any one of embodiments 1 to 116. 118. The derivative regimen involves administering a lipid-binding protein-based complex once or twice daily. The method according to Embodiment 117, comprising the step of administering. 119. The intensified regimen involves administering a lipid-binding protein-based complex once daily or every other day. The method according to Embodiment 117 or Embodiment 118, comprising the step of administering a single dose. 120. The subject is not treated with a maintenance regimen, any one of embodiments 1 to 119. The method used. 121. The intensification regimen is administered one or more days after the final dose of the induction regimen. The step involves administering one or more doses of a lipid-binding protein-based complex to the subject. The method according to any one of embodiments 117 to 120, including the method described in any one of embodiments 117 to 120. 122. Initial dose of lipid-binding protein-based complex administered during an intensification regimen. This is administered at least two days after the final dose of the induction regimen, as described in Embodiment 121. method. 123. Initial dose of lipid-binding protein-based complex administered during an intensification regimen. This is administered at least three days after the final dose of the induction regimen, as described in Embodiment 121. method. 124. Initial dose of lipid-binding protein-based complex administered during an intensification regimen The method according to Embodiment 123, which is administered 3 days after the final dose of the induction regimen. . 125. Administer a lipid-binding protein-based complex twice daily on days 1, 2, and 3. The induction regimen includes two doses of a lipid-binding protein-based complex on day 6. The method according to any one of embodiments 117 to 124, including an intensified regimen. 126. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual doses are 4-40 mg / kg (on a protein weight basis), as in Embodiment 117. The method described in any one of the 125. 127. Each of the lipid-binding protein-based complexes administered in the induction regimen Individual doses range from 4 to 30 mg / kg (on a protein weight basis), as in Embodiment 117. The method described in any one of the 126s. 128. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual dose is 15-25 mg / kg (on a protein weight basis), Embodiment 117 The method described in any one of 126. 129. Each of the lipid-binding protein-based complexes administered in the induction regimen Individual doses are 10-30 mg / kg (on a protein weight basis), Embodiment 117 The method described in any one of 126. 130. Each of the lipid-binding protein-based complexes administered in the induction regimen Individual doses are 10-20 mg / kg (on a protein weight basis), Embodiment 117 The method described in any one of 126. 131. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual dose is 5 mg / kg (on a protein weight basis), Embodiments 117 to 12 The method described in any one of the six. 132. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual dose is 10 mg / kg (on a protein weight basis), Embodiments 117 to 1 The method described in any one of the 26 methods. 133. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual dose is 15 mg / kg (on a protein weight basis), Embodiments 117 to 1 The method described in any one of the 26 methods. 134. Each of the lipid-binding protein-based complexes administered in the induction regimen The individual dose is 20 mg / kg (on a protein weight basis), Embodiments 117 to 1 The method described in any one of the 26 methods. 135. The dose of lipid-binding protein-based complex administered in the intensified regimen is 5 The values ​​are ~15 mg / kg (on a protein weight basis), according to embodiments 117 to 134. The method described in one of the following options. 136. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 1 The values ​​are 0-20 mg / kg (on a protein weight basis), according to embodiments 117 to 134. Either one of the methods. 137. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 1 The values ​​are 5-25 mg / kg (on a protein weight basis), according to embodiments 117 to 134. Either one of the methods. 138. The dose of lipid-binding protein-based complex administered in the intensified regimen is 5 mg / kg (based on protein weight), any one of embodiments 117 to 134 The method used. 139. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 1 Any of Embodiments 117 to 134, which is 0 mg / kg (on a protein weight basis). One method. 140. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 1 5 mg / kg (on a protein weight basis), any of embodiments 117 to 134 One method. 141. The individual dose of each lipid-binding protein-based complex administered is 300 ml. g to 4000 mg (on a protein weight basis), any of Embodiments 1 to 140. One method. 142. The individual dose of each lipid-binding protein-based complex administered is 300 ml. The method according to Embodiment 141, wherein the amount is g to 3000 mg (on a protein weight basis). 143. The individual dose of each lipid-binding protein-based complex administered is 300 ml. The method according to Embodiment 141, wherein the amount is g to 1500 mg (on a protein weight basis). 144. The individual dose of each lipid-binding protein-based complex administered is 400 ml. The method according to Embodiment 141, wherein the amount is g to 4000 mg (on a protein weight basis). 145. The individual dose of each lipid-binding protein-based complex administered is 400 ml. The method according to Embodiment 141, wherein the amount is g to 1500 mg (on a protein weight basis). 146. The individual dose of each lipid-binding protein-based complex administered is 500 ml. The method according to Embodiment 141, wherein the amount is g to 1200 mg (on a protein weight basis). 147. The individual dose of each lipid-binding protein-based complex administered is 500 ml. The method according to Embodiment 141, wherein the amount is g to 1000 mg (on a protein weight basis). 148. The individual dose of each lipid-binding protein-based complex administered is 600 ml. The method according to Embodiment 141, wherein the amount is g to 3000 mg (on a protein weight basis). 149. The individual dose of each lipid-binding protein-based complex administered is 800 ml. The method according to Embodiment 141, wherein the amount is g to 3000 mg (on a protein weight basis). 150. The individual dose of each lipid-binding protein-based complex administered is 1000 The method according to Embodiment 141, wherein the amount is between mg and 2400 mg (on a protein weight basis). 151. The individual dose of each lipid-binding protein-based complex administered is 1000 The method according to Embodiment 141, wherein the amount is between mg and 2000 mg (on a protein weight basis). 152. High doses of lipid-binding protein-based complexes are 600 mg to 40 g (protein The method according to any one of embodiments 1 to 151, wherein the weight is (on a weight basis). 153. High doses of lipid-binding protein-based complexes are 3g to 35g (protein weight basis) The method according to any one of Embodiments 1 to 151, wherein the method is as follows: 154. High doses of lipid-binding protein-based complexes are 5g to 30g (protein weight basis) The method according to any one of Embodiments 1 to 151, wherein the method is as follows: 155. The lipid-binding protein-based complex is administered by injection, from Embodiment 1 The method described in any one of the 154 methods. 156. Each individual dose is administered over a period of 1 to 24 hours, Embodiment 15 The method described in 5. 157. Each individual dose is administered over a 24-hour period, as in Embodiment 156. Method of description. 158. The step of administering an antihistamine to the subject before each individual dose is further The method according to any one of Embodiments 1 to 157, including the method described in each of Embodiments 1 to 157. 159. Antihistamines include dexchlorpheniramine or hydroxyzine, The method described in Form 158. 160. The subject is receiving or has received one or more additional therapies. This has been done, and / or the method involves administering one or more additional therapies. The method according to any one of embodiments 1 to 159, further comprising the step of [doing something]. 161.1 Additional therapies include one or more anti-IL-6 agents, in practice The method described in form 160. 162.1 or more anti-IL-6 agents include tocilizumab, siltuximab, and orokizumab. B, Elsirimomab, BMS-945429, Silkumab, Levilimab, CPSI-23 The method according to embodiment 161, including 64, or a combination thereof. 163. The embodiment 162 describes one or more anti-IL-6 agents, including tocilizumab. method. 164.1 or more additional therapies include one or more corticosteroids. The method according to any one of embodiments 160 to 163. 165.1 or more corticosteroids, methylprednisolone, dexamethasone The method according to embodiment 164, including n, or a combination thereof. 166. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. Additional therapies include antibodies derived from recovered COVID-19 patients, as described in Embodiment 160. The method described in any one of the 165 methods. 167. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. Additional therapies include, in embodiments, antibodies against the COVID-19 spike protein. The method described in any one of 160 to 166. 168. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. The additional therapy includes one or more antiviral agents, as in any of embodiments 160 to 167. The method described in one of the following options. 169.1 The antiviral agent is lopinavir, as described in Embodiment 168. Law. 170.1 One or more antiviral agents include remdesivir, as in Embodiment 168 or The method described in the application method 169. 171.1 One or more antiviral agents include danoprevir, embodiments 168 to 17 A method that is one of 0. 172.1 One or more antiviral agents include galidesivir, Embodiments 168 to 17 The method described in any one of the above. 173.1 One or more antiviral agents include darunavir, as in Embodiments 168 to 172 The method described in any one of the following ways. 174.1 One or more antiviral agents include ritonavir, as in Embodiments 168 to 173 The method described in any one of the following ways. 175. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. Additional therapies include chloroquine or hydroxychloroquine, as shown in embodiments 160 to 17. The method described in any one of the four methods. 176. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. Additional therapies include azithromycin, as described in any one of embodiments 160 to 175. Method of loading. 177. The subject has or has had a COVID-19 infection, and has one or more of the following conditions. Additional therapies include interferon, as described in any one of embodiments 160 to 176. Method of loading. 178. The interferon is interferon alpha, as described in Embodiment 177. method. 179. The interferon is interferon beta, as described in Embodiment 177. Law. 180. Interferon is pegylated, any one of embodiments 177 to 179 The method used. 181. The lipid-binding protein-based complex is CER-001, Embodiments 1 to 1 The method described in any one of the 80. 182.CER-001 has an ApoA-I weight:to total phospholipid weight ratio of 1:2.7±20%. ApoA-I and phospholipids, and 97:3±20% sphingomyelin:DPPG weight Quantity: A lipoprotein complex containing phospholipids sphingomyelin and DPPG in weight ratio. The method according to Embodiment 181. 183.CER-001 has an ApoA-I weight:to total phospholipid weight ratio of 1:2.7±10%. ApoA-I and phospholipids, and 97:3±10% sphingomyelin:DPPG weight Quantity: A lipoprotein complex containing phospholipids sphingomyelin and DPPG in weight ratio. The method according to Embodiment 181. 184.CER-001 is an ApoA-I weight:total phospholipid weight ratio of 1:2.7. AI and phospholipids, and phosphorus in a sphingomyelin:DPPG weight:weight ratio of 97:3 Embodiments include a lipoprotein complex comprising the lipid sphingomyelin and DPPG. The method described in 181. 185. ApoA-I is sequence number of the international publication brochure No. 2012 / 109162. One of embodiments 182 to 184 having an amino acid sequence of 25 to 267 amino acids. One method. 186. ApoA-I is expressed by recombinant DNA, as in any of embodiments 182 to 185. One method. 187.CER-001 contains natural sphingomyelin, as described in embodiments 182 to 186. Any one of the following methods. 188. Natural sphingomyelin is chicken egg sphingomyelin, Embodiment 18 The method described in 7. 189.CER-001 contains synthetic sphingomyelin, as described in Embodiments 182 to 186. Any one of the following methods. 190. Synthetic sphingomyelin is palmitoyl sphingomyelin, Embodiment 1 The method described in 89. 191. CER-001 is available in the form of a formulation in which CER-001 is at least 95% homogeneous. The method according to any one of embodiments 181 to 190, which is administered. 192. CER-001 is available in the form of a formulation in which CER-001 is at least 97% homogeneous. The method according to Embodiment 191, which is administered. 193. CER-001 is available in the form of a formulation in which CER-001 is at least 98% homogeneous. The method according to Embodiment 191, which is administered. 194. CER-001 is available in the form of a formulation in which CER-001 is at least 99% homogeneous. The method according to Embodiment 191, which is administered.

[0292] 8.2. Specific Embodiments: Group 2 Further aspects of this disclosure are described in the embodiments specified in the following numbered paragraphs. References to previously numbered embodiments in this Section 8.2 are the same as those in the previous numbered embodiments. This refers to an embodiment. 1. Cytokine release disease, including the step of administering a therapeutically effective dose of CER-001 to the target. A method of treating individuals who have CRS (Conditioner Syndrome of Critical Condition) or are at risk of developing CRS. 2. C is effective in lowering the serum levels of one or more inflammatory markers in the subjects. The method according to Embodiment 1, comprising the step of administering an amount of ER-001. 3.1 CER-001 is effective in lowering serum levels of one or more inflammatory markers. A step of administering one or more types of drugs to a target that requires it, including the step of administering a target amount. Methods to lower serum levels of inflammatory markers. 4. The method according to Embodiment 3 applies to cases that have CRS or are at risk of CRS. 5. The method according to any one of Embodiments 1 to 4, wherein the subject has a CRS. 6. The method according to Embodiment 5 applies to patients with CRS secondary to infection. 7. The method according to embodiment 6, wherein the infection is a viral infection. 8. The method according to Embodiment 7, wherein the viral infection is a coronavirus infection. 9. The method according to Embodiment 8, wherein the coronavirus is COVID-19. 10. The method according to Embodiment 7, wherein the viral infection is an influenza infection. 11. The subjects are those described in Embodiment 5 who have CRS caused by immunotherapy. Law. 12. The method according to Embodiment 11, wherein the immunotherapy includes antibody therapy. 13. Immunotherapy includes chimeric antigen receptor (CAR) T cell therapy as described in Embodiment 11. method. 14. CER-001 is administered before immunotherapy begins, according to embodiments 11 to 13. Either one of the methods. 15. CER-001 is administered concurrently with immunotherapy, in any of embodiments 11 to 14. One method. 16. CER-001 is administered after the completion of immunotherapy, as described in Embodiments 11 to 15. Any one of the following methods. 17. The method according to any one of Embodiments 1 to 4, which is subject to CRS risk. 18. The method described in Embodiment 17 applies to cases where there is a risk of CRS due to infection. 19. The method according to embodiment 18, wherein the infection is a viral infection. 20. The method according to embodiment 19, wherein the viral infection is a coronavirus infection. 21. The method according to Embodiment 20, wherein the coronavirus is COVID-19. 22. The method according to Embodiment 19, wherein the viral infection is an influenza infection. 23. The method according to Embodiment 17 applies to patients who are at risk of CRS due to immunotherapy. 24. The method according to Embodiment 23, wherein the immunotherapy includes antibody therapy. 25. Immunotherapy includes chimeric antigen receptor (CAR) T cell therapy as described in Embodiment 23. method. 26. CER-001 is administered before immunotherapy begins, according to embodiments 23 to 25. Either one of the methods. 27. CER-001 is administered concurrently with immunotherapy, in any of embodiments 23 to 26. One method. 28. CER-001 is administered after the completion of immunotherapy, as described in Embodiments 23 to 27. Any one of the following methods. 29. One of Embodiments 1 to 28, which includes once-daily administration of CER-001. Method of loading. 30. CER-001 is administered for at least 5 days, according to any one of Embodiments 1 to 29. The method used. 31. CER-001 is administered for at least 6 days, according to any one of Embodiments 1 to 29. The method used. 32. CER-001 is administered for at least 7 days, according to any one of Embodiments 1 to 29. The method used. 33. The method according to Embodiment 32, wherein CER-001 is administered for 7 days. 34. CER-001 is administered for up to one week, as described in any one of Embodiments 1 to 32. Method of loading. 35. CER-001 is administered for up to two weeks, as described in any one of Embodiments 1 to 32. Method of loading. 36. CER-001 is a condition in which one or more symptoms of CRS are reduced, and / or 1 From Embodiment 1, administered until serum levels of one or more inflammatory markers decrease. The method described in any one of the 32. 37. CER-001 is a condition in which serum levels of one or more inflammatory markers decrease to the normal range. The method according to embodiment 36, which is administered until [a certain condition is met]. 38. CER-001 is a condition where the serum levels of one or more inflammatory markers are CER-00 Based on baseline levels of one or more inflammatory markers measured before one dose The method according to embodiment 36, which is administered until the dose drops below the normal level. 39. The dose of CER-001 administered is 10-40 mg / kg (based on protein weight). The method according to any one of Embodiments 1 to 38, wherein the method is as follows: 40. The dose of CER-001 administered in the induction regimen is 10-30 mg / kg ( The method according to Embodiment 39, which is (on a protein weight basis). 41. The dose of CER-001 administered in the induction regimen is 15-25 mg / kg ( The method according to Embodiment 39, which is (on a protein weight basis). 42. The dose of CER-001 administered in the induction regimen is 20 mg / kg (Tampo The method according to Embodiment 39, which is (on a weight basis). 43. The dose of CER-001 administered in each treatment is 600 mg to 4000 mg. The method according to any one of the application forms 1 to 42. 44. The dose of CER-001 administered in each treatment is 600 mg to 3000 mg. The method described in the application method 43. 45. The dose of CER-001 administered in each treatment is 800 mg to 3000 mg. The method described in the application method 43. 46. ​​The dose of CER-001 in each administration is 1000 mg to 2400 mg. The method described in form 43. 47. The dose of CER-001 administered in each treatment is 1000 mg to 2000 mg. The method according to Embodiment 43. 48. CER-001 is administered by infusion, in any one of Embodiments 1 to 47. Method of description. 49. The method according to Embodiment 48, wherein each dose is administered over a period of 1 to 24 hours. 50. The method according to Embodiment 49, wherein each dose is administered over a period of 24 hours. 51.1 or more inflammatory markers, including interleukin-6 (IL-6), The method described in any one of states 2 to 50. 52.1 or more inflammatory markers include C-reactive proteins, Embodiments 2 to 51 The method described in any one of the following ways. 53.1 One or more inflammatory markers include D-dimers, as in any of Embodiments 2 to 52. One method. 54.1 One or more inflammatory markers include ferritin, as in any of Embodiments 2 to 53. One method. 55.1 or more inflammatory markers, including interleukin-8 (IL-8), in practice The method described in any one of states 2 to 54. 56.1 or more inflammatory markers include granulocyte-macrophage colony-stimulating factor (GM) A method according to any one of embodiments 2 to 55, including -CSF. 57.1 or more inflammatory markers include monocyte chemotactic protein (MCP) 1, The method according to any one of forms 2 to 56. 58.1 Types or more inflammatory markers include tumor necrosis factor α (TNF-α), Embodiments The method described in any one of 2 to 57. 59. The step of administering an antihistamine to the subject before each CER-001 dose is further The method according to any one of Embodiments 1 to 58, including the method described in any one of Embodiments 1 to 58. 60. Antihistamines include dexchlorpheniramine or hydroxyzine, in practice. The method described in form 59. 61. The subjects are currently receiving or have received one or more additional therapies. This may occur, and / or the method may involve administering one or more additional therapies. A method according to any one of embodiments 1 to 60, further comprising the steps. 62.1 The embodiment includes one or more additional therapies, one or more anti-IL-6 agents. The method described in 61. 63.1 or more anti-IL-6 agents include tocilizumab, siltuximab, and olokizumab. Elsirimomab, BMS-945429, Silkumab, Levilimab, CPSI-236 4, or the method according to embodiment 62, including a combination thereof. 64. The method according to Embodiment 63, wherein one or more anti-IL-6 agents include tocilizumab. . 65.1 Additional therapies include one or more corticosteroids. The method according to any one of the application forms 61 to 64. 66.1 or more corticosteroids, including methylprednisolone and dexamethasone. The method according to embodiment 65, including a combination thereof. 67. The subject has or has had COVID-19 infection and one or more associated conditions. The additive therapy includes antibodies derived from recovered COVID-19 patients, as described in Embodiments 61 to 66. The method described in any one of the following ways. 68. The subject has or has had COVID-19 infection and one or more associated conditions. The additive therapy includes an antibody against the COVID-19 spike protein, as in Embodiment 6. The method described in any one of 1 to 67. 69. The subject has or has had COVID-19 infection and one or more associated conditions. The additive therapy comprises one or more antiviral agents, any one of embodiments 61 to 68. The method used. 70.1 The method according to Embodiment 69, wherein the antiviral agent comprises lopinavir. 71.1 One or more antiviral agents, including remdesivir, as in Embodiment 69 or the Evidence The method described in condition 70. 72.1 One or more antiviral agents include danoprevir, as in Embodiments 69 to 71. Either one of the methods. 73.1 One or more antiviral agents include galidesivir, as in Embodiments 69 to 72. Either one of the methods. 74.1 One or more antiviral agents, including darunavir, as of Embodiments 69 to 73 The method described in one of the following options. 75.1 One or more antiviral agents, including ritonavir, as of Embodiments 69 to 74 The method described in one of the following options. 76. The subject has or has had COVID-19 infection and one or more associated conditions. The additional therapy includes chloroquine or hydroxychloroquine, as described in Embodiments 61 to 75. Either one of the methods. 77. The subject has or has had COVID-19 infection and one or more associated conditions. The additional therapy is one of the embodiments described in any one of embodiments 61 to 76, comprising azithromycin. Law. 78. The subject has or has had COVID-19 infection and has one or more associated conditions. The additional therapy includes interferon, as described in any one of embodiments 61 to 77. Law. 79. The method according to embodiment 78, wherein the interferon is interferon alpha. . 80. The method according to embodiment 78, wherein the interferon is interferon beta. 81. The interferon is pegylated, as described in any one of embodiments 78 to 80. Method of loading.

[0293] 8.3. Specific Embodiments: Group 3 Further aspects of this disclosure are described in the embodiments specified in the following numbered paragraphs. References to previously numbered embodiments in this Section 8.3 are the same as those in the previous numbered embodiments. This refers to an embodiment. 1. Sepsis, comprising the step of administering a certain amount of a lipid-binding protein-based complex to the target. A method of treating a patient suffering from a disease. 2. Sepsis is associated with Gram-negative bacterial infection, according to the method of Embodiment 1. 3. The method according to Embodiment 1 or Embodiment 2 applies to patients with intra-abdominal infection. 4. The method according to Embodiment 1 or Embodiment 2 applies to patients with urinary tract sepsis. 5. The amount of lipid-binding protein-based complexes is effective in reducing the severity of sepsis. A method according to any one of embodiments 1 to 4. 6. The amount of lipid-binding protein-based complexes is such that the subject develops acute kidney injury (AKI). The method described in any one of Embodiments 1 to 5 is effective in reducing the likelihood of this happening. method. 7. The amount of lipid-binding protein-based complexes is effective in delaying the onset of AKI. The method according to any one of Embodiments 1 to 6. 8. The amount of lipid-binding protein-based complex is effective in blocking AKI, implement The method described in any one of Forms 1 to 6. 9. An acute A method of treating patients with or at risk of kidney injury (AKI). 10. The method according to Embodiment 9, wherein the AKI is sepsis-related AKI. 11. The method according to Embodiment 9 or Embodiment 10, wherein the subject is AKI. 12. The amount of lipid-binding protein complexes is effective in reducing the severity of AKI. The method according to Embodiment 11. 13. The method described in Embodiment 9 or Embodiment 10, which carries an AKI risk. 14. The method according to Embodiment 13, for subjects with sepsis. 15. Sepsis is associated with Gram-negative bacterial infection, according to the method of Embodiment 14. 16. The method according to Embodiment 14 or Embodiment 15, relating to a patient with an intra-abdominal infection. 17. The method according to Embodiment 14 or Embodiment 15, relating to a patient with urinary tract sepsis. 18. The amount of lipid-binding protein-based complexes is the likelihood that the subject will develop AKI. A method according to any one of embodiments 13 to 17, which is effective in reducing the quality. 19. The amount of lipid-binding protein-based complexes is effective in delaying the development of AKI. A method according to any one of embodiments 13 to 18. 20. The amount of lipid-binding protein-based complex is effective in blocking AKI. The method described in any one of the application forms 13 to 18. 21. When the subject develops AKI, the amount of lipid-binding protein-based complexes is AKI The method described in any one of embodiments 13 to 19 is effective in reducing the severity of the condition. Law. 22. Prior to administration of the lipid-binding protein-based complex, subjects had an SOFA score of 1-4. A method according to any one of embodiments 1 to 21, comprising: 23. Prior to administration of the lipid-binding protein-based complex, subjects had SOFA scores of 2-4. The method according to embodiment 22, wherein the method is further comprising [the method described in embodiment 22]. 24. Prior to administration of the lipid-binding protein-based complex, subjects had an SOFA score of 1. The method according to Embodiment 22. 25. Prior to administration of the lipid-binding protein-based complex, subjects had a SOFA score of 2. The method according to Embodiment 22. 26. Prior to administration of the lipid-binding protein-based complex, subjects had a SOFA score of 3. The method according to Embodiment 22. 27. Prior to administration of the lipid-binding protein-based complex, subjects had a SOFA score of 4. The method according to Embodiment 22. 28. Prior to administration of the lipid-binding protein-based complex, subjects had an endotoxin activity level >0.6. The method according to any one of embodiments 1 to 27, comprising a bell. 29. The amount of lipid-binding protein-based complexes reduces the endotoxin activity levels of the target. The method according to any one of embodiments 1 to 28, which is effective for the purpose of 30. The amount of lipid-binding protein-based complexes reduces the serum levels of the target IL-6. A method according to any one of Embodiments 1 to 29, which is effective for [doing something]. 31. Lipid-binding protein-based complexes are reconstituted HDL or HDL mimics. The method according to any one of the application forms 1 to 30. 32. Lipid-binding protein-based complexes are apomers (registered trademark) or cargomers (registered trademark). A method according to any one of Embodiments 1 to 30, which is a registered trademark. 33. The lipid-binding protein-based complex contains sphingomyelin, from Embodiment 1 The method described in any one of the 32. 34. The lipid-binding protein-based complex contains negatively charged lipids, Embodiments 1 to 3 The method described in either of the two methods. 35. Negatively charged lipids are 1,2-dipalmitoyl-sn-glycero-3-[phospho-r The method described in Embodiment 34, which is ac-(1-glycerol)(DPPG) or a salt thereof. Law. 36. Lipid-binding protein-based complexes include CER-001, CSL-111, and CSL The method according to Embodiment 31, wherein the CER-112, CER-522, or ETC-216. 37. The lipid-binding protein-based complex is CER-001, as described in Embodiment 36. The method. 38. Lipid-binding protein-based complexes are administered systemically, optionally by injection. The method according to any one of embodiments 1 to 37. 39. Lipid-binding protein-based complexes are (a) Induction regimens; and optionally, (b) Enhanced regimen The drug is administered according to a drug regimen that includes the lipid-binding protein-based complex, which is optional. The method according to Embodiment 38, including CER-001. 40. The inducing regimen involves administering a lipid-binding protein-based complex over several consecutive days. The method according to embodiment 39, including a top. 41. The induction regimen involves administering a lipid-binding protein-based complex for at least three consecutive days. The method according to embodiment 40, which includes the step of doing so. 42. The inducing regimen involves administering a lipid-binding protein-based complex twice daily. The method according to any one of the application forms 39 to 41. 43. The inducing regimen involves administering a lipid-binding protein-based complex twice daily for three consecutive days. The method according to any one of embodiments 39 to 42, including the provision. 44. The dose of the lipid-binding protein-based complex administered in the induction regimen is 4~ 30 mg / kg (on a protein weight basis), any one of embodiments 39 to 43 The method used. 45. The dose of the lipid-binding protein-based complex administered in the induction regimen is 5- 15 mg / kg (on a protein weight basis), any one of embodiments 39 to 43 The method used. 46. ​​The dose of the lipid-binding protein-based complex administered in the induction regimen is 10 Any of embodiments 39 to 43, which is approximately 20 mg / kg (on a protein weight basis). One method. 47. The dose of the lipid-binding protein-based complex administered in the induction regimen is 15 Any of embodiments 39 to 43, which is approximately 25 mg / kg (on a protein weight basis). One method. 48. The dose of the lipid-binding protein-based complex administered in the induction regimen is 5m The value is g / kg (based on protein weight), as described in any one of embodiments 39 to 43. Method of loading. 49. The dose of the lipid-binding protein-based complex administered in the induction regimen is 10 The value is mg / kg (based on protein weight), in any one of embodiments 39 to 43. Method of description. 50. The dose of the lipid-binding protein-based complex administered in the induction regimen is 20 The value is mg / kg (based on protein weight), in any one of embodiments 39 to 43. Method of description. 51. The dose of CER-001 administered in the induction regimen is 300 mg to 3000 mg. The method according to any one of embodiments 39 to 43, wherein g is the method described in g. 52. The dose of CER-001 administered in the induction regimen is 300 mg to 1500 mg. The method according to any one of embodiments 39 to 43, wherein g is the method described in g. 53. The dose of CER-001 administered in the induction regimen is 400 mg to 1500 mg. The method according to any one of embodiments 39 to 43, wherein g is the method described in g. 54. The dose of CER-001 administered in the induction regimen is 500 mg to 1200 mg. The method according to any one of embodiments 39 to 43, wherein g is the method described in g. 55. The dose of CER-001 administered in the induction regimen is 500 mg to 1000 mg. The method according to any one of embodiments 39 to 43, wherein g is the method described in g. 56. The method according to any one of embodiments 39 to 55, including a reinforcement regimen. 57. The intensification regimen is administered one or more days after the final dose of the induction regimen. The step includes administering one or more doses of a lipid-binding protein-based complex to an elephant. The method described in Embodiment 56. 58. The initial dose of the lipid-binding protein-based complex administered during the intensification regimen is The method according to Embodiment 57, administered at least two days after the final dose of the induction regimen. . 59. The initial dose of the lipid-binding protein-based complex administered during the intensification regimen is The method according to Embodiment 57, administered at least 3 days after the final dose of the induction regimen. . 60. The initial dose of the lipid-binding protein-based complex administered during the intensification regimen is The method according to Embodiment 59, administered three days after the final dose of the induction regimen. 61. The enhanced regimen involves administering a lipid-binding protein-based complex twice daily. A method according to any one of embodiments 56 to 60, including a quantity. 62. Includes twice-daily administration of a lipid-binding protein-based complex on days 1, 2, and 3. The induction regimen includes two doses of a lipid-binding protein-based complex on day 6. The method according to any one of embodiments 39 to 61, including a reinforcement regimen. 63. The dose of lipid-binding protein-based complex administered in the intensified regimen is 4- 30 mg / kg (on a protein weight basis), any one of embodiments 39 to 62 The method used. 64. The dose of lipid-binding protein-based complex administered in the intensified regimen is 5- 15 mg / kg (on a protein weight basis), any one of embodiments 39 to 62 The method used. 65. The dose of the lipid-binding protein-based complex administered in the enhanced regimen is 10 Any of embodiments 39 to 62, which is approximately 20 mg / kg (on a protein weight basis). One method. 66. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 15 Any of embodiments 39 to 62, which is approximately 25 mg / kg (on a protein weight basis). One method. 67. The dose of the lipid-binding protein-based complex administered in the intensified regimen is 5m The value is g / kg (based on protein weight), as described in any one of embodiments 39 to 62. Method of loading. 68. The dose of the lipid-binding protein-based complex administered in the enhanced regimen is 10 The value is mg / kg (on a protein weight basis), in any one of embodiments 39 to 62. Method of description. 69. The dose of lipid-binding protein-based complex administered in the enhanced regimen is 20 The value is mg / kg (on a protein weight basis), in any one of embodiments 39 to 62. Method of description. 70. The dose of CER-001 administered in the induction regimen is 300 mg to 3000 mg. The method according to any one of embodiments 39 to 62, wherein g. 71. The dose of CER-001 administered in the induction regimen is 300 mg to 1500 mg. The method according to any one of embodiments 39 to 62, wherein g. 72. The dose of CER-001 administered in the induction regimen is 400 mg to 1500 mg. The method according to any one of embodiments 39 to 62, wherein g. 73. The dose of CER-001 administered in the induction regimen is 500 mg to 1200 mg. The method according to any one embodiment v, wherein g is g. 74. The dose of CER-001 administered in the induction regimen is 500 mg to 1000 mg. The method according to any one of embodiments 39 to 62, wherein g. 75. Dosage of lipid-binding protein-based complex administered in the induction regimen, and The dose of the lipid-binding protein-based complex administered in the enhanced regimen is the same. The method according to any one of embodiments 56 to 74. 76. Before administering one or more doses of a lipid-binding protein-based complex, use an antihistamine. The method according to any one of Embodiments 1 to 75, wherein a mining drug is administered. 77. An antihistamine is administered before each lipid-binding protein-based complex dose. The method according to embodiment 76. 78. The subjects are those described in Embodiments 1 to 77, who are treated using standard care therapy for sepsis. Any one of the following methods. 79. The subjects are those described in Embodiments 9 to 77, who are treated using standard care therapy for AKI. Any one of the following methods. 80. The method according to Embodiment 78 or Embodiment 79, wherein the standard care therapy includes an antibiotic. 81. Standard care therapy includes hemodynamic support as described in any one of Embodiments 78 to 80. Method of loading. 82. Any embodiment 78 to 81, further comprising the step of administering standard care therapy. One method.

[0294] Although various specific embodiments are illustrated and described, the spirit and scope of this disclosure It will be understood that various changes can be made without deviating from the established framework.

[0295] 9. Incorporation by reference All publications, patents, patent applications, and other documents cited herein are subject to the terms of this application. Each individual publication, patent, patent application, or other document may not be intended for all purposes. To the same extent that they are individually indicated to be incorporated by reference, they are referenced for all purposes. These are incorporated as a whole by this specification.

[0296] Any descriptions of documents, actions, materials, apparatus, items, etc. contained herein are merely exempt from this disclosure. It is intended to provide context for any of these matters. All of these form part of the prior art standards, or it is somewhere before the priority date of this application. Because it existed, it was well known as general knowledge in the field related to this disclosure. This should not be taken as approval.

Claims

1. A lipid-binding protein-based complex used in methods for treating acute conditions, The method involves administering a high dose of the lipid-binding protein-based complex to the target that requires it. A complex comprising the step of giving, wherein the acute pathological condition may include acute inflammation.

2. In the above method, the high dose is administered over a period of 3 days to approximately 2 weeks. The aforementioned high dose is administered for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, and 10 days. It is administered over a period of 11, 12, 13, 14, or 15 days. A lipid-binding protein-based complex according to claim 1 is also preferable.

3. The aforementioned high dose is a collection of 2 to 10 individual doses, and the aforementioned high dose is 3, 4, 5, 6 , or a collection of 7, 8, 9, or 10 individual doses, claim 1 or claim A lipid-binding protein-based complex as described in 2.

4. In the method described above, each of the multiple individual doses is administered daily or twice daily, as per claim 3. A lipid-binding protein-based complex as described.

5. In the above method, the individual doses are administered with a gap of 2 to 3 days between each dose, claim 3 or The lipid-binding protein-based complex described in claim 4.

6. Each individual dose is effective in increasing the HDL level of the subject, claim. A lipid-binding protein-based complex as described in any one of items 3 to 5.

7. Each individual dose is effective in increasing the ApoA-I level of the subject. A lipid-binding protein-based complex according to any one of claims 3 to 6.

8. The aforementioned high dose is effective in improving the vascular endothelial function of the subject, and the vascular endothelial function is The measurements of claims 1 to 7, measured by circulating VCAM-1 and / or ICAM-1. A lipid-binding protein-based complex as described in either item.

9. The aforementioned high dose lowers the serum levels of one or more inflammatory markers in the subject. A lipid-binding protein base according to any one of claims 1 to 8, which is effective for [doing something]. A composite of.

10. The subject has CRS or is at risk of CRS, any one of claims 1 to 9 A lipid-binding protein-based complex as described in the section.

11. The subject is at risk of CRS, the lipid-binding protein-based compound according to claim 10. Combine.

12. The subject is a lipid-bound tannin according to claim 11, which is at risk of CRS due to infection. A protein-based complex.

13. The infection is a viral infection, according to the lipid-binding protein-based complex of claim 12. body.

14. The aforementioned viral infection is a coronavirus infection, according to claim 13. A quality-based complex.

15. The aforementioned coronavirus is COVID-19, the lipid-binding protein according to claim 14. A quality-based complex.

16. The subject is any one of claims 1 to 9, who has or is at risk of developing sepsis. A lipid-binding protein-based complex as described in item 1.

17. The high dose is effective in reducing the severity of the sepsis, as described in claim 16. A lipid-binding protein-based complex.

18. The aforementioned high dose reduces the likelihood that the subject will develop acute kidney injury (AKI). A lipid-binding protein base according to any one of claims 1 to 17, which is effective for A composite of.

19. The aforementioned high dose is effective in delaying the onset of AKI, any one of claims 1 to 18. A lipid-binding protein-based complex as described in item 1.

20. The aforementioned high dose is effective in blocking AKI, according to any one of claims 1 to 18. A lipid-binding protein-based complex as described.

21. The subject is one who has or is at risk of developing acute kidney injury (AKI), as per claim 1. A lipid-binding protein-based complex as described in any one of items 17.

22. The lipid-binding protein base according to claim 21, wherein the AKI is sepsis-related AKI. A composite of.

23. The AKI is ischemia / reperfusion AKI as described in claim 21, which is a lipid-binding protein base A composite of S.

24. The AKI is cardiac surgery-related (CSA) AKI as described in claim 21, which is a lipid-bound tangent. A protein-based complex.

25. The AKI is hepatorenal syndrome (HRS) AKI, according to claim 21. A mineral-based complex.

26. The aforementioned object has AKI, and is a lipid-bound tangent according to any one of claims 21 to 25. A protein-based complex.

27. The high dose is effective in reducing the severity of AKI, as described in claim 26. A complex based on lipid-binding proteins.

28. The subject is at risk of AKI, according to any one of claims 21 to 25. A complex based on combined proteins.

29. The aforementioned high dose is effective in reducing the likelihood that the subject will develop AKI. The lipid-binding protein-based complex according to claim 28.

30. The aforementioned high dose is effective in delaying the onset of AKI, claim 28 or claim 2 A lipid-binding protein-based complex as described in 9.

31. The high dose is effective in blocking AKI, as described in claim 28 or claim 29. A lipid-binding protein-based complex.

32. If the subject develops AKI, the high dose reduces the severity of the AKI. A lipid-binding protein-based according to any one of claims 28 to 30, which is effective for A complex.

33. The aforementioned lipid-binding protein-based complex is reconstituted HDL or an HDL mimetic. A lipid-binding protein-based complex as described in any one of the requirements 1 to 32.

34. The aforementioned lipid-binding protein-based complex is an apomer (registered trademark) or cargomer (registered trademark). A registered trademark) The lipid-binding protein-based according to any one of claims 1 to 32 A complex.

35. Claims 1 to 3, the lipid-binding protein-based complex comprises sphingomyelin. A lipid-binding protein-based complex as described in any one of item 4.

36. Claims 1 to 35, the lipid-binding protein-based complex comprises a negatively charged lipid. A lipid-binding protein-based complex as described in any one of the items.

37. The negatively charged lipid is 1,2-dipalmitoyl-sn-glycero-3-[phospho-r The lipid according to claim 36, which is ac-(1-glycerol)(DPPG) or a salt thereof. A complex based on binding proteins.

38. The lipid-binding protein-based complex is CER-001, CSL-111, CSL Lipid binding according to claim 33, which is -112, CER-522, or ETC-216. A protein-based complex.

39. The lipid-binding protein-based complex is CER-001, as described in claim 38. A complex based on lipid-binding proteins.

40. In the above method, the lipid-binding protein-based complex is systemically, optionally Lipid-bound tannins according to any one of claims 1 to 39, which may be administered by injection. A protein-based complex.

41. The individual doses of the lipid-binding protein-based complex administered are 4 to 40 mg. g / kg (on a protein weight basis), as described in any one of claims 1 to 40 A complex based on lipid-binding proteins.

42. In the above method, the high dose is administered according to the induction regimen, followed by the reinforcement regimen. The lipid-binding protein base according to any one of claims 1 to 41, which may be followed by n. A composite of.

43. The aforementioned derivation regimen involves administering the lipid-binding protein-based complex once or twice daily. The lipid-binding protein-based complex according to claim 42, comprising the step of administering a single dose.

44. The aforementioned enhancement regimen involves administering the lipid-binding protein-based complex once or every two days. The lipid-binding protein according to claim 42 or claim 43, comprising the step of administering it once. A mineral-based complex.

45. The subject is not treated using a maintenance regimen in the method described above, claims 1 to 44. A lipid-binding protein-based complex as described in any one of the items.

46. The intensification regimen is administered one or more days after the final dose of the induction regimen. The subject is administered one or more doses of the lipid-binding protein-based complex. A lipid-binding protein base according to any one of claims 42 to 45, comprising the step A composite of.

47. The above method involves the lipid-binding protein-based complex being used twice a day on days 1, 2, and 3. An induction regimen including one dose, and the lipid-binding protein-based complex on day 6. The lipid according to any one of claims 42 to 46, comprising an enhanced regimen including two doses of the lipid. A protein-binding complex.

48. Each of the lipid-binding protein-based complexes administered in the aforementioned induction regimen Each individual dose is 4 to 40 mg / kg (on a protein weight basis), according to claim 42. A lipid-binding protein-based complex as described in any one of item 47.

49. The use of the lipid-binding protein-based complex administered in the aforementioned enhancement regimen The amount is 5 to 15 mg / kg (on a protein weight basis), according to any of claims 42 to 48 A lipid-binding protein-based complex as described in item one.

50. The use of the lipid-binding protein-based complex administered in the aforementioned enhancement regimen The amount is 15 to 25 mg / kg (on a protein weight basis), according to claims 42 to 48. A lipid-binding protein-based complex as described in either item.

51. The above method involves administering an antihistamine to the subject before each individual dose. Lipid-binding protein-based according to any one of claims 1 to 50, further comprising , A complex.

52. The aforementioned subjects are currently receiving or have received one or more additional therapies. This may occur, and / or the method may involve one or more additional therapies for the subject. Lipid-bound tannin according to any one of claims 1 to 51, further comprising the step of administering A protein-based complex.

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