Use of soluble TREM-1 levels to identify subjects likely to respond to anti-inflammatory therapy

Abstract

To provide in vitro methods for identifying human subjects suffering from an inflammatory disorder susceptible to respond to a TREM-1 inhibitor, in particular an acute inflammatory disorder such as systemic inflammatory response syndrome (SIRS), sepsis or septic shock, susceptible to respond to a therapy, in particular to the TREM-1 inhibitor.SOLUTION: The method includes: a) measuring a level of soluble Triggering Receptors Expressed on Myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) identifying a human subject suffering from an inflammatory disorder with the level of sTREM-1 measured in step a) higher than the predetermined sTREM-1 value of step b) as susceptible to respond to a therapy, in particular to a TREM-1 inhibitor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the treatment of inflammatory disorders, preferably acute inflammatory disorders, in human subjects, particularly in a subpopulation of human subjects that are likely to respond to therapy, particularly to TREM-1 inhibitors. Accordingly, the present invention relates to a method for identifying human subjects suffering from an inflammatory disorder, preferably an acute inflammatory disorder such as systemic inflammatory response syndrome (SIRS), sepsis or septic shock, and that are likely to respond to therapy, particularly to TREM-1 inhibitors. [Background technology]

[0002] Systemic inflammatory response syndrome (SIRS) is characterized by systemic inflammation and widespread tissue damage. SIRS can occur as a response to nonspecific injury of either infectious or non-infectious origin. Examples of non-infectious injury include, but are not limited to, trauma, burns, pancreatitis, autoimmune disease, and surgery. Examples of infectious injury include bacterial infection, fungal infection, and viral infection.

[0003] Sepsis has been defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al., JAMA. 2016 Feb 23;315(8):801-10). Sepsis, therefore, occurs when the body's response to infection injures its own tissues and organs, ultimately leading to death in 30-50% of cases (Fleischmann et al., Dtsch Arztebl Int. 2016 Mar 11;113(10):159-66). Furthermore, many survivors suffer from post-sepsis syndrome, with reported increases in sensory, intestinal, digestive, respiratory, chest pain, renal, and musculoskeletal problems after sepsis (Huang et al., Int J Qual Health Care. 2018 Jun 19). According to the World Health Organization, sepsis is estimated to affect more than 30 million people worldwide annually, potentially resulting in 6 million deaths.

[0004] Septic shock is defined as a subset of sepsis, in which particularly severe cardiovascular, cellular, and metabolic abnormalities are associated with a higher risk of mortality than sepsis alone (Singer et al., JAMA. 2016 Feb 23;315(8):801-10). Clinically, patients with septic shock can be identified as those with (i) persistent hypotension after adequate fluid resuscitation requiring the use of vasopressors to maintain a mean blood pressure above 65 mmHg, and (ii) serum lactate levels above 2 mmol / L (Shankar-Hari et al., JAMA. 2016 Feb 23;315(8):775-87).

[0005] Currently, there is no specific etiological treatment for sepsis or septic shock. Therefore, patient management relies primarily on early recognition, allowing for prompt initiation of correct therapeutic measures, such as administration of appropriate antibiotics, source control measures if necessary, and resuscitation with intravenous fluids and vasoactive agents if necessary (Cohen et al., Lancet Infect Dis. 2015 May;15(5):581-614). Previous attempts to develop treatments, such as those targeting endotoxin and TLRs, have been unsuccessful (Cuvier et al., Br J Clin Pharmacol. 2018 June 8).

[0006] Recently, the applicant developed a therapeutic approach targeting the TREM-1 (triggering receptor expressed on myeloid cells-1) pathway. TREM-1 is an immunoreceptor expressed by innate immune cells (monocytes / macrophages, neutrophils, platelets, and dendritic cells) and endothelial cells. Activation of TREM-1 leads to rapid neutrophil degranulation and oxidative burst, along with cytokine and chemokine production. The function of TREM-1 is to regulate / amplify, rather than activate / initiate, inflammation to trigger a rich immune response by synergizing with pathogen recognition receptors (PRRs) such as Toll-like receptors (TLRs). In particular, the TREM-1 pathway has been implicated in the pathophysiology of sepsis and septic shock. Therefore, the applicant has shown that TREM-1 inhibitors, i.e., short TLT-1 (TREM-like transcript-1) peptides that inhibit TREM-1 activity, can be used to treat inflammatory disorders, particularly acute inflammatory disorders such as systemic inflammatory response syndrome (SIRS), sepsis, or septic shock (WO2011 / 124685).TLT-1 (Trem-like transcript-1) is a receptor that is a member of the TREM family and is expressed exclusively by megakaryocytes and platelets.

[0007] However, for TREM-1 inhibitors to have the greatest therapeutic effect in treating acute inflammatory disorders such as SIRS, sepsis, or septic shock, there remains a need to identify human subjects suffering from acute inflammatory disorders that are likely to respond to therapies, particularly TREM-1 inhibitors. In particular, there remains a need to identify human subjects suffering from acute inflammatory disorders such as SIRS, sepsis, or septic shock that are likely to respond to therapies, particularly TLT-1 peptides that inhibit TREM-1 activity.

[0008] Applicants now show that by measuring levels of soluble TREM-1 (sTREM-1) in biological samples from human subjects suffering from septic shock and comparing those measured sTREM-1 levels to predetermined sTREM-1 values, it is possible to identify human subjects suffering from septic shock who are likely to respond to a TREM-1 inhibitor. In particular, Applicants show that human subjects suffering from septic shock who have circulating levels of sTREM-1 higher than a predetermined median sTREM-1 level in a reference population of human subjects suffering from septic shock are likely to respond to, and therefore benefit from, administration of a TLT-1 peptide that inhibits TREM-1 activity.

[0009] The present invention therefore relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably an acute inflammatory disorder such as SIRS, sepsis or septic shock, and who is likely to respond to a therapy, in particular a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) identifying a human subject suffering from an inflammatory disorder, preferably an acute inflammatory disorder such as SIRS, sepsis or septic shock, in which the level of sTREM-1 measured in step a) is higher than the predetermined sTREM-1 value in step b), as likely to respond to a therapy, in particular a TREM-1 inhibitor. The present invention also relates to a therapeutic method, preferably a TREM-1 inhibitor, for use in the treatment of an inflammatory disorder, preferably an acute inflammatory disorder such as SIRS, sepsis or septic shock, in a subject in need thereof, wherein a level of sTREM-1 measured in a biological sample from the subject that is higher than a predetermined sTREM-1 value indicates that the subject is likely to respond to the therapeutic method, preferably a TREM-1 inhibitor. Summary of the Invention [Problem to be solved by the invention]

[0010] Accordingly, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder that is susceptible to therapy, preferably a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) identifying a human subject suffering from an inflammatory disorder in which the level of sTREM-1 measured in step a) is higher than the predetermined sTREM-1 value in step b) as likely to respond to a therapy, preferably a TREM-1 inhibitor.

[0011] In one embodiment, the predetermined sTREM-1 value in step b) is obtained from a reference population, hi one embodiment, the reference population is a population of human patients suffering from an inflammatory disorder, preferably systemic inflammatory response syndrome (SIRS), sepsis or septic shock.

[0012] In one embodiment, the predetermined sTREM-1 value in step b) is the median sTREM-1 value in a reference population or the third quartile of sTREM-1 in a reference population.

[0013] In one embodiment, the level of sTREM-1 measured in step a) is a level measured before the start of therapy, preferably before administration of a TREM-1 inhibitor. In one embodiment, the level of sTREM-1 measured in step a) is measured within the first 24 hours after diagnosis or hospitalization of the human subject for an inflammatory disorder.

[0014] In one embodiment, the biological sample is a blood sample, a serum sample, or a plasma sample.

[0015] In one embodiment, the level of sTREM-1 measured in step a) is the protein level, preferably measured by ELISA, electrochemiluminescence immunoassay (ECLIA) or electrochemiluminescence (ECL), also called enzyme-linked fluorescence assay (ELFA).

[0016] In one embodiment, the treatment comprises the administration of a TREM-1 inhibitor, preferably selected from the group consisting of a peptide that inhibits the function, activity, or expression of TREM-1, an antibody directed against TREM-1 and / or sTREM-1, or a TREM-1 and / or sTREM-1 ligand, a small molecule that inhibits the function, activity, or expression of TREM-1, an siRNA directed against TREM-1, an shRNA directed against TREM-1, an antisense oligonucleotide directed against TREM-1, a ribozyme directed against TREM-1, and an aptamer directed against TREM-1. In one embodiment, the treatment comprises the administration of a TREM-1 inhibitor, wherein the TREM-1 inhibitor is a peptide that targets the sTREM-1 ligand, preferably a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12. In one embodiment, the treatment comprises the administration of a TREM-1 inhibitor, wherein the TREM-1 inhibitor is a peptide having the amino acid sequence set forth in SEQ ID NO:9.

[0017] In one embodiment, the therapeutic agent is a TREM-1 inhibitor, preferably selected from the group consisting of a peptide that inhibits the function, activity, or expression of TREM-1, an antibody directed against TREM-1 and / or sTREM-1, or a TREM-1 and / or sTREM-1 ligand, a small molecule that inhibits the function, activity, or expression of TREM-1, an siRNA directed against TREM-1, an shRNA directed against TREM-1, an antisense oligonucleotide directed against TREM-1, a ribozyme directed against TREM-1, and an aptamer directed against TREM-1. In one embodiment, the TREM-1 inhibitor is a peptide that inhibits the function, activity, or expression of TREM-1 by targeting a TREM-1 ligand, preferably a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12. In one embodiment, the TREM-1 inhibitor is a peptide having the amino acid sequence set forth in SEQ ID NO:9.

[0018] In one embodiment, the inflammatory disorder is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis and septic shock, and preferably, the inflammatory disorder is septic shock. In one embodiment, the human subject suffers from organ dysfunction, which is defined as an acute change in Sequential Organ Failure Assessment (SOFA) score of at least 2 points.

[0019] In one embodiment, a human subject suffering from SIRS, sepsis or septic shock who is susceptible to a therapy, preferably a TREM-1 inhibitor, is a human subject who is susceptible to having a reduced Sequential Organ Failure Assessment (SOFA) score after administration of the therapy, preferably after administration of a TREM-1 inhibitor. In one embodiment, a human subject suffering from septic shock who is susceptible to a therapy, preferably a TREM-1 inhibitor, is a human subject suffering from septic shock who is susceptible to reversing hypotensive shock within or after a period of administration of the therapy, preferably a TREM-1 inhibitor, where hypotensive shock reversal is defined as the absence of any vasopressor therapy for a 24-hour period. definition

[0020] In the present invention, the following terms have the following meanings:

[0021] The use of "about" before a number includes the value of that number plus or minus 10% or less. It is to be understood that the value to which the term "about" refers is itself also specifically, preferably disclosed.

[0022] "APACHE II" refers to "Acute Physiology and Chronic Health Evaluation II." APACHE II is a commonly used scoring system to assess the severity of illness and determine prognosis in adult patients admitted to intensive care units. APACHE II provides a general measure of illness severity using a point score ranging from 0 to 71 based on initial values ​​of 12 routine physiological measurements (i.e., variables), age, and previous health status (Knaus et al., Crit Care Med. 1985 Oct;13(10):818-29).

[0023] "APACHE III" stands for "Acute Physiology and Chronic Health Evaluation III." APACHE III is a redefined scoring system from the APACHE II scoring system to more accurately predict the risk of hospital mortality in critically ill hospitalized adults (Knaus et al., Chest. 1991 Dec;100(6):1619-36). The APACHE III scoring system is similar to the APACHE II scoring system, but several variables are added to those used in the APACHE II scoring system, resulting in 17 variables calculated into a point score ranging from 0 to 299.

[0024] "APACHE-IV" stands for "Acute Physiology and Chronic Health Evaluation-IV." APACHE-IV is an improved and updated model for estimating short-term mortality risk and predicting length of intensive care unit (ICU) stay (Zimmerman et al., Crit Care Med. 2006 May;34(5):1297-310). The APACHE-IV scoring system takes into account more variables, particularly the effect of mechanical ventilation, thrombolysis, and sedation on the Glasgow Coma Scale, rescaled Glasgow Coma Scale, PaO2 / FiO2 ratio, and disease-specific subgroups. APACHE-IV uses a point score ranging from 0 to 286.

[0025] "Electrochemiluminescence immunoassay (ECLIA)" refers to an immunoassay in which signal detection is based on electrochemiluminescence, a form of chemiluminescence in which an electrochemical reaction occurs before the light-emitting chemiluminescent reaction.

[0026] "Fluid therapy" refers to treatment aimed at restoring and / or maintaining normal body fluid volume and composition, particularly with regard to water and electrolyte balance. Fluid therapy is thus aimed at correcting and / or preventing volume and / or electrolyte deficiencies.

[0027] "Immunodeficiency" refers to a subject whose ability to develop a normal immune response, for example, to fight infection or cancer, is impaired or completely absent. Similarly, "immunocompromised" refers to a subject whose ability to develop a normal immune response, for example, to fight infection or cancer, is impaired. "Immunosuppressed" refers to a subject whose immune system is reduced in activation or effectiveness, particularly due to the administration of immunosuppressive therapy. For example, immunosuppression in a subject can be assessed by measuring PD-1 levels, measuring circulating IL-7 levels, or measuring HLA-DR.

[0028] "Measuring" or "measurement," or "detecting" or "detection," means assessing the presence, absence, quantity, or amount (which may be an effective amount) of a given substance, i.e., sTREM-1, in a biological sample from a human subject. As used herein, "measuring" or "measurement," or "detecting" or "detection" includes deriving a qualitative or quantitative concentration (e.g., blood or plasma concentration) of a substance, i.e., sTREM-1, in a biological sample and in a human subject.

[0029] As used herein, " organ dysfunction score " or " organ dysfunction scoring system " refers to the score used to assess organ dysfunction in human subjects, particularly those suffering from SIRS, sepsis or septic shock, at the time of admission, particularly in ICU or emergency room. Examples of organ dysfunction scores include but are not limited to SOFA score, qSOFA score, MODS (multiple organ dysfunction score), P-MODS (pediatric multiple organ dysfunction score) and LODS (logistic organ dysfunction system).

[0030] "qSOFA score" refers to the quick SOFA score (also known as quickSOFA). The qSOFA scoring system relies on three criteria: respiratory rate ≥ 22 breaths / min, impaired consciousness (Glasgow Coma Scale < 15), and systolic blood pressure ≥ 100 mmHg (Seymour et al., JAMA. 2016 Feb 23;315(8):762-74).

[0031] "Quantile(s)" refers to (a) cutoff value(s) that divide observations / measurements made in a population into groups of equal size, each group comprising an equal proportion (percentage) of the aforementioned observations / measurements. Thus, as used herein, "quantile(s)" refers to cutoff sTREM-1 value(s) that divide the sTREM-1 levels measured in biological samples from each of the human subjects of a reference population into groups of equal size, each containing an equal proportion (percentage) of the sTREM-1 level measurements. In other words, "quantile(s)" refers to a cutoff sTREM-1 value above and below which lie a predetermined percentage of the sTREM-1 levels measured in the reference population. For example, as used herein, "quartile(s)" refers to three cutoff sTREM-1 values ​​that divide the sTREM-1 levels measured in a reference population into four groups, each containing 25% of the sTREM-1 levels measured in the reference population. It should be noted that "quantile" can also refer to groups defined by cutoff values. For example, "quartiles" can refer to four groups defined by three cutoff sTREM-1 values, dividing the sTREM-1 levels measured in a reference population. However, as used herein, unless otherwise specified, the term "quantile" refers to a cutoff value.

[0032] "SAPS" refers to "Simplified Acute Physiology Score." SAPS is a scoring system that reflects the risk of death in ICU patients. SAPS relies on 14 biological and clinical variables (Le Gall et al., Crit Care Med. 1984 Nov;12(11):975-7).

[0033] "SAPSII" refers to the "Simplified Acute Physiology Score II." SAPSII is a scoring system for estimating in-hospital mortality in adult patients admitted to an intensive care unit (ICU). SAPSII includes 17 variables: 12 physiological variables, age, type of admission, and three variables related to underlying disease (Le Gall et al., JAMA. 1993 Dec 22-29;270(24):2957-63). SAPSII uses a point score ranging from 0 to 163.

[0034] "SAPS3" refers to "Simplified Acute Physiology Score III." SAPS3 is a scoring system for predicting hospital mortality in patients admitted to the intensive care unit (ICU) (Metnitz et al., Intensive Care Med. 2005 Oct;31(10):1336-1344 and Moreno et al., Intensive Care Med. 2005 Oct;31(10):1345-55). SAPS3 is based on 20 different variables.

[0035] As used herein, " severity score " or " severity scoring system " refers to the score used to assess the disease severity and / or prognosis of human subjects, particularly those suffering from SIRS, sepsis or septic shock, when admitted to ICU or emergency room. Examples of severity scores include, but are not limited to, APACHE II score, APACHE III score, APACHE IV score, SAPS score, SAPS II score and SAPS 3 score.

[0036] As used herein, "SIRS, sepsis, or septic shock therapy" refers to a therapy administered to a subject in need thereof for the treatment of SIRS, sepsis, or septic shock. In one embodiment, the SIRS, sepsis, or septic shock therapy is an immunomodulatory or anti-inflammatory therapy. Examples of immunomodulatory or anti-inflammatory therapy include, but are not limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA4; TLR (Toll-like receptor) inhibitors; cytokine inhibitors such as anti-cytokine or anti-cytokine receptors (e.g., IL-1RA, an interleukin-1 receptor antagonist); inhibitors of immunostimulants such as G-CSF (granulocyte colony-stimulating factor), IL-7 (interleukin-7), CD28 antagonist peptides and antibodies, particularly monoclonal antibodies against CD28; and cell therapy such as adoptive cell therapy. In one embodiment, the SIRS, sepsis, or septic shock therapy is an angiogenesis inhibitor, particularly an angiopoietin-2 (Ang-2 or Ang2) inhibitor. In one embodiment, the SIRS, sepsis or septic shock therapy is a TREM-1 inhibitor. In one embodiment, the TREM-1 inhibitor is a peptide that targets a TREM-1 ligand, preferably a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12.

[0037] "Shock" or "hypotension shock" or "dysdistribution shock" refers to reduced or inadequate perfusion that impairs organ function and is generally associated with a decrease in arterial blood pressure. Hypotensive shock may not respond to fluid resuscitation and may require vasopressor therapy to increase arterial blood pressure, restore effective tissue perfusion, and normalize cellular metabolism.

[0038] As used herein, "shock reversal" or "hypotensive shock reversal" is defined as the absence of any vasopressor therapy for at least 24 hours (i.e., no need to resume vasopressor therapy 24 hours after the end of vasopressor therapy). In one embodiment, shock reversal can occur within the administration period of SIRS, sepsis, or septic shock therapy. In one embodiment, shock reversal can occur 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, or 72 hours after the start of administration of SIRS, sepsis, or septic shock therapy. In one embodiment, shock reversal can occur after the administration period of SIRS, sepsis, or septic shock therapy. In one embodiment, shock reversal can occur 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, or 72 hours after the end of administration of SIRS, sepsis, or septic shock therapy.

[0039] "SOFA score" refers to the Sequential Organ Failure Assessment (SOFA) score (originally called the Sepsis-Associated Organ Failure Assessment), which is commonly used to assess the presence of organ dysfunction. The SOFA scoring system (Vincent et al., Crit Care Med. 1998 Nov;26(11):1793-800) relies on assessment of the respiratory system (i.e., PaO2 / FiO2 (mmHg)), nervous system (i.e., Glasgow Coma Scale), cardiovascular system (i.e., mean arterial pressure or required vasopressor administration), liver function (i.e., bilirubin (mg / dL or μmol / L)), coagulation (i.e., platelet count), and renal function (i.e., creatinine (mg / dL or μmol / L) or urine output (mL / d)).

[0040] "Standard of care" refers to the care routinely provided to patients suffering from an inflammatory disorder, particularly systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. In one embodiment, the patient suffers from septic shock, and the standard of care includes at least one of antimicrobial therapy, fluid therapy, vasopressor therapy, cardiovascular support, respiratory support, renal support, and sedation.

[0041] "TREM-1" refers to "triggering receptor-1 expressed on myeloid cells." TREM-1 is a membrane-bound glycoprotein receptor belonging to the Ig superfamily, specifically expressed on myeloid cells. TREM-1 activates downstream signaling pathways with the aid of an adaptor protein called DAP12. TREM-1 consists of three distinct domains: an Ig-like structure (primarily involved in ligand binding), a transmembrane portion, and a cytoplasmic tail that binds to DAP12. Unless otherwise noted, the TREM-1 protein has the amino acid sequence set forth in SEQ ID NO: 1, which corresponds to UniProtKB / Swiss-Prot accession numbers Q9NP99-1, last revised on October 1, 2000, and Q38L15-1, last revised on November 22, 2005. Several transcripts of TREM-1 are known. The transcript commonly referred to as TREM1-201 (Transcript ID Ensemble ENST00000244709.8) encodes the amino acid sequence set forth in SEQ ID NO: 1. The transcript commonly referred to as TREM1-202, also known as TREM-1 isoform 2 (Ensemble Transcript ID ENST00000334475.10), encodes the amino acid sequence set forth in SEQ ID NO: 2 (corresponding to UniProtKB / Swiss-Prot accession number Q9NP99-2). The transcript commonly referred to as TREM1-207, also known as TREM-1 isoform 3 (Ensemble Transcript ID ENST00000591620.1), encodes the amino acid sequence set forth in SEQ ID NO: 3 (corresponding to UniProtKB / Swiss-Prot accession number Q9NP99-3). The transcript commonly referred to as TREM1-204 (ensemble transcript ID ENST00000589614.5) encodes the amino acid sequence set forth in SEQ ID NO: 4 (corresponding to UniProtKB / Swiss-Prot accession number K7EKM5-1, last revised on January 9, 2013).

[0042] The term "sTREM-1" in "soluble triggering receptor-1 expressed in myeloid cells" refers to a soluble form of TREM-1 that lacks the transmembrane and intracellular domains of TREM-1. Thus, in one embodiment, sTREM-1 corresponds to a soluble form of the extracellular domain of TREM-1. Soluble TREM-1 can be generated by proteolytic cleavage of the TREM-1 Ig-like ectodomain from membrane-anchored TREM-1 by matrix metalloproteinases (Gomez-Pina et al., J Immunol. 2007 Sep. 15;179(6):4065-73). Thus, in one embodiment, sTREM-1 corresponds to a truncated TREM-1 released from the membrane of myeloid cells, particularly activated myeloid cells. It has also been suggested that sTREM-1 results from alternative splicing of TREM-1 mRNA. A TREM-1 splice variant was characterized by Baruah et al. in 2015 (J Immunol. 2015 Dec 15;195(12):5725-31) and was found to be secreted from primary and secondary human neutrophil granules. Thus, in one embodiment, sTREM-1 corresponds to a TREM-1 splice variant, in particular the TREM-1 transcript commonly referred to as TREM1-202, also known as TREM-1 isoform 2, which encodes the amino acid sequence set forth in SEQ ID NO:2.

[0043] As used herein, "median sTREM-1" refers to a predetermined sTREM-1 value obtained from a reference population that divides the sTREM-1 levels measured in the reference population into two groups, each containing 50% of the sTREM-1 levels measured in the reference population.

[0044] As used herein, "sTREM-1 tertile" refers to a predetermined sTREM-1 value obtained from a reference population that divides the sTREM-1 levels measured in the reference population into three groups, each containing one-third of the sTREM-1 levels measured in the reference population. In one embodiment, the sTREM-1 tertile is the last sTREM-1 tertile (i.e., the second sTREM-1 tertile) and corresponds to the sTREM-1 value below which two-thirds of the sTREM-1 levels measured in the reference population lie and above which one-third of the sTREM-1 levels measured in the reference population lie.

[0045] As used herein, "sTREM-1 quartile" refers to a predetermined sTREM-1 value obtained from a reference population that divides the sTREM-1 levels measured in the reference population into four groups, each containing 25% of the sTREM-1 levels measured in the reference population. In one embodiment, the sTREM-1 quartile is the last sTREM-1 quartile (i.e., the third sTREM-1 quartile, also referred to as Q3) and corresponds to the sTREM-1 value below which 75% of the sTREM-1 levels measured in the reference population lie and above which 25% of the sTREM-1 levels measured in the reference population lie.

[0046] As used herein, "sTREM-1 quintile" refers to a predetermined sTREM-1 value obtained from a reference population that divides the sTREM-1 levels measured in the reference population into five groups, each containing 20% ​​of the sTREM-1 levels measured in the reference population. In one embodiment, the sTREM-1 quintile is the last sTREM-1 quintile (i.e., the fourth sTREM-1 quintile) and corresponds to the sTREM-1 value below which 80% of the sTREM-1 levels measured in the reference population lie and above which 20% of the sTREM-1 levels measured in the reference population lie.

[0047] As used herein, "sTREM-1 decile" refers to a predetermined sTREM-1 value obtained from a reference population that divides the sTREM-1 levels measured in the reference population into 10 groups, each containing 10% of the sTREM-1 levels measured in the reference population. In one embodiment, the sTREM-1 decile is the last sTREM-1 decile (i.e., the 9th sTREM-1 decile) and corresponds to the sTREM-1 value below which 90% of the sTREM-1 levels measured in the reference population lie and above which 10% of the sTREM-1 levels measured in the reference population lie.

[0048] As used herein, " sTREM-1 percentile " refers to a predetermined sTREM-1 value obtained from a reference population, which divides the sTREM-1 levels measured in the reference population into groups corresponding to a predetermined percentage of the sTREM-1 levels measured in the reference population.Therefore, as used herein, sTREM-1 percentile is a predetermined sTREM-1 value obtained from a reference population, below which a predetermined percentage of the sTREM-1 levels measured in the reference population exist.For example, the 40th percentile is the sTREM-1 value obtained from a reference population, below which 40% of the sTREM-1 levels measured in the reference population exist.

[0049] A "therapeutically effective amount" or "therapeutically effective dose" refers to an amount or dosage of a therapy (preferably a TREM-1 inhibitor) intended to (1) delay or prevent the onset of an inflammatory disorder (preferably SIRS, sepsis, or septic shock) in a human subject, (2) reduce the severity or incidence of an inflammatory disorder (preferably SIRS, sepsis, or septic shock), (3) slow or stop the progression, progression, or worsening of one or more symptoms of an inflammatory disorder (preferably SIRS, sepsis, or septic shock) affecting a human subject, (4) result in amelioration of the symptoms of an inflammatory disorder (preferably SIRS, sepsis, or septic shock) affecting a human subject, or (5) cure an inflammatory disorder (preferably SIRS, sepsis, or septic shock) affecting a human subject, without causing significant negative or harmful side effects to the human subject. In one embodiment, the administration of a therapeutically effective dose (or amount) of a therapy, preferably a TREM-1 inhibitor, to a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, is aimed at inducing at least one of the following in the subject: - preferably reversal of hypotensive shock during or after the administration period of the therapy (preferably a TREM-1 inhibitor), e.g., over 6 hours, 12 hours, 18 hours or 24 hours after the end of administration, where reversal of hypotensive shock is defined as the absence of any vasopressor therapy for at least 24 hours (i.e., no need to restart vasopressor therapy within 24 hours of the end of vasopressor therapy), - A reduction in severity scores (such as APACHE II score, APACHE III score, APACHE IV score, SAPS score, SAPS II score, or SAPS 3 score) used to assess the severity and / or prognosis of a subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock, upon admission to the ICU or emergency room, - A decrease in organ dysfunction score (such as SOFA score, qSOFA score, MODS (Multiple Organ Dysfunction Score), P-MODS (Pediatric Multiple Organ Dysfunction Score), or LODS (Logistic Organ Dysfunction System)) used to assess the presence of organ dysfunction in human subjects suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, upon admission to an ICU or emergency room, - a decrease in the SOFA score and / or qSOFA score, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after initiation of administration of the therapy (preferably a TREM-1 inhibitor), and in one embodiment the decrease in the SOFA score is a decrease of at least 1 point (also referred to as delta-1 point or ΔSOFA-1 point), preferably at least 1.5 points, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular on the 3rd or 5th day after initiation of administration of the therapy, - a reduction in the need for cardiovascular support, e.g., a reduction in the use of vasopressor therapy over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to the need for cardiovascular support upon admission to the ICU or emergency room or before initiation of therapy, - a reduction in the need for respiratory support, e.g. a reduction in the use of invasive mechanical ventilation (IMV), preferably with reference to the need for respiratory support at the time of admission to the ICU or emergency room or before the start of the administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after the start of the therapy, preferably the administration of a TREM-1 inhibitor, - a reduced need for renal support, e.g., a reduced use of continuous or non-continuous renal replacement therapy, also called RRT (such as dialysis), preferably over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), with reference to the need for renal support at the time of admission to the ICU or emergency room or before initiation of therapy, - a reduced risk of reinfection, in particular 28, 90 or 365 days after the initial inflammatory disorder, in particular the initial infection causing the inflammatory disorder, - absence of reinfection, especially 28, 90 or 365 days after the initial inflammatory disorder, especially the initial infection causing the inflammatory disorder; - A reduced risk of readmission, particularly at 28, 90 or 365 days after the initial inflammatory disorder, particularly the initial infection causing the inflammatory disorder; - No readmission, especially no readmission 28, 90 or 365 days after the initial admission; - an increased chance of survival, in particular surviving 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years after initiation of administration of a therapy (preferably a TREM-1 inhibitor), in one embodiment survival chance, particularly in subjects with multiple comorbidities, is assessed by the Charlson Comorbidity Index (CCI), and an increased 10-year chance of survival preferably corresponds to a decrease in the Charlson Comorbidity Index, with reference to the CCI assessed at the time of admission to the ICU or emergency room or before initiation of administration of the therapy, - a reduced risk of sepsis-related death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - A reduction in the risk of all-cause death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - a reduced risk of post-septic or post-shock morbidity, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); -Improved quality of life (particularly post-sepsis or shock quality of life), which can be assessed, for example, by assessing survival and quality-adjusted life years (QALYs), as estimated from the EuroQoL Quality of Life Scale, commonly known as EQ5D. For example, a health-related quality of life (HRQoL) score of the EQ 5D 5L (a 5-level EQ-5D version) can be calculated and converted into a utility score, particularly at 3, 6, 9, 12, 18, 24 or 36 months after the start of treatment. - a decrease in the levels of inflammatory markers such as CRP or IL6, IL-8, IL-10, MCP-1 and TNF-α, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to levels assessed upon admission to the ICU or emergency room or before initiation of therapy, or - A decrease in levels of markers of endothelial damage such as, for example, Ang-2, VCAM-1, VGEFR-1 and E-selectin, preferably relative to levels assessed at the time of admission to the ICU or emergency room or before initiation of therapy, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor).

[0050] A therapeutically effective amount of a therapy, preferably a TREM-1 inhibitor, may be administered for prophylactic or preventative purposes prior to the onset of an inflammatory disorder, preferably SIRS, sepsis or septic shock, prior to diagnosis of an inflammatory disorder, preferably SIRS, sepsis or septic shock, prior to admission to an ICU or emergency room, or prior to the initiation of vasopressor therapy. Alternatively or additionally, a therapeutically effective amount of a therapy, preferably a TREM-1 inhibitor, may be administered for therapeutic purposes after the onset of an inflammatory disorder, preferably SIRS, sepsis or septic shock, after diagnosis of an inflammatory disorder, preferably SIRS, sepsis or septic shock, after admission to an ICU or emergency room, or after the initiation of vasopressor therapy.

[0051] "TLT-1" refers to TREM-like transcript-1. TLT-1 is a member of the TREM family of receptors and is expressed exclusively by megakaryocytes and platelets. TLT-1 contains a v-set Ig-type extracellular domain, a transmembrane region, and a cytoplasmic tail containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and a polyproline-rich domain.

[0052] "Treating" or "treatment" refers to therapeutic treatment, prophylactic or preventative measures, or both, the purpose of which is to prevent, slow (alleviate), or cure the targeted pathological condition or disorder, i.e., an inflammatory disorder, preferably SIRS, sepsis, or septic shock. In one embodiment of the present invention, "treating" or "treatment" refers to therapeutic treatment. In another embodiment of the present invention, "treating" or "treatment" refers to prophylactic or preventative treatment. In yet another embodiment of the present invention, "treating" or "treatment" refers to both prophylactic (or preventative) treatment and therapeutic treatment. Treatment is necessary when a patient already suffers from an inflammatory disorder, preferably SIRS, sepsis, or septic shock, as well as when a patient is susceptible to developing an inflammatory disorder, preferably SIRS, sepsis, or septic shock, or when an inflammatory disorder, preferably SIRS, sepsis, or septic shock, should be prevented. A human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, is successfully "treated" if, after being administered a therapeutically effective amount of a therapy, preferably a TREM-1 inhibitor, the human subject exhibits at least one of the following: - reversal of hypotensive shock, preferably during or after the administration period of therapy (preferably a TREM-1 inhibitor), e.g., for 6, 12, 18 or 24 hours after the end of administration, defined as the absence of any vasopressor therapy for at least 24 hours (i.e., no need to restart vasopressor therapy within 24 hours of the end of vasopressor therapy), - A reduction in severity scores (such as APACHE II score, APACHE III score, APACHE IV score, SAPS II score, or SAPS 3 score) used to assess the severity and / or prognosis of a subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock, upon admission to the ICU or emergency room, - A decrease in organ dysfunction score (such as SOFA score, qSOFA score, MODS (Multiple Organ Dysfunction Score), P-MODS (Pediatric Multiple Organ Dysfunction Score), or LODS (Logistic Organ Dysfunction System)) used to assess the presence of organ dysfunction in human subjects suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, upon admission to an ICU or emergency room, - a decrease in the SOFA score and / or qSOFA score, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after initiation of administration of the therapy (preferably a TREM-1 inhibitor), and in one embodiment the decrease in the SOFA score is a decrease of at least 1 point (also referred to as delta-1 point or ΔSOFA-1 point), preferably at least 1.5 points, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular on the 3rd or 5th day after initiation of administration of the therapy, - a reduction in the need for cardiovascular support, e.g., a reduction in the use of vasopressor therapy over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to the need for cardiovascular support upon admission to the ICU or emergency room or before initiation of therapy, - a reduction in the need for respiratory support, e.g. a reduction in the use of invasive mechanical ventilation (IMV), preferably with reference to the need for respiratory support at the time of admission to the ICU or emergency room or before the start of the administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after the start of the therapy, preferably the administration of a TREM-1 inhibitor, - a reduced need for renal support, e.g., a reduced use of continuous or non-continuous renal replacement therapy, also called RRT (such as dialysis), preferably over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), with reference to the need for renal support at the time of admission to the ICU or emergency room or before initiation of therapy, - a reduced risk of reinfection, in particular 28, 90 or 365 days after the initial inflammatory disorder, in particular the initial infection causing the inflammatory disorder, - absence of reinfection, especially 28, 90 or 365 days after the initial inflammatory disorder, especially the initial infection causing the inflammatory disorder; - A reduced risk of re-hospitalization, particularly a reduced risk of re-infection 28, 90 or 365 days after the initial inflammatory disorder, particularly the initial infection causing the inflammatory disorder; - No readmission, especially no readmission 28, 90 or 365 days after the initial admission; - an increased chance of survival, in particular surviving 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years after initiation of administration of a therapy (preferably a TREM-1 inhibitor), in one embodiment survival chance, particularly in subjects with multiple comorbidities, is assessed by the Charlson Comorbidity Index (CCI), and an increased 10-year chance of survival preferably corresponds to a decrease in the Charlson Comorbidity Index, with reference to the CCI assessed at the time of admission to the ICU or emergency room or before initiation of administration of the therapy, - a reduced risk of sepsis-related death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - A reduction in the risk of all-cause death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - a reduced risk of post-septic or post-shock morbidity, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - Improved quality of life, particularly post-sepsis or post-shock quality of life, which can be assessed, for example, by assessing survival and quality-adjusted life years (QALYs) estimated from the EQ5D. For example, the EQ5D5L Health-Related Quality of Life (HRQoL) score can be calculated and converted to a utility score, particularly at 3, 6, 9, 12, 18, 24 or 36 months after the start of treatment. - a decrease in the levels of inflammatory markers such as CRP or IL6, IL-8, IL-10, MCP-1 and TNF-α, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to levels assessed upon admission to the ICU or emergency room or before initiation of therapy, or - A decrease in levels of markers of endothelial damage such as, for example, Ang-2, VCAM-1, VGEFR-1 and E-selectin, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to levels assessed upon admission to the ICU or emergency room or before initiation of therapy.

[0053] The above parameters for assessing successful treatment and disease improvement are readily measurable by routine procedures familiar to physicians.

[0054] A "TREM-1 inhibitor" refers to an active agent capable of inhibiting the function, activity or expression of TREM-1. Examples of TREM-1 inhibitors include, but are not limited to, peptides that inhibit the function, activity or expression of TREM-1, antibodies directed against TREM-1 and / or sTREM-1 or TREM-1 and / or sTREM-1 ligands, small molecules that inhibit the function, activity or expression of TREM-1, siRNAs directed against TREM-1, shRNAs directed against TREM-1, antisense oligonucleotides directed against TREM-1, ribozymes directed against TREM-1, and aptamers directed against TREM-1.

[0055] "Vasopressor therapy" refers to therapies used to treat shock, i.e., hypotensive shock, which impairs organ function and is generally defined as reduced or inadequate perfusion associated with a fall in arterial blood pressure. Vasopressor therapy is indicated, particularly when hypotension does not respond to fluid resuscitation. Vasopressor therapy aims to increase arterial blood pressure, maintain adequate blood pressure, restore effective tissue perfusion, and normalize cellular metabolism. Examples of vasopressor therapy include, but are not limited to, administering vasoactive catecholamine hormones such as norepinephrine, dopamine, epinephrine, vasopressin, and / or phenylephrine. DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder that is likely to respond to a therapy, the method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) identifying a human subject suffering from an inflammatory disorder in which the level of sTREM-1 measured in step a) is higher than the predetermined sTREM-1 value in step b) as likely to respond to the therapy.

[0057] In other words, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder that is likely to respond to a therapy, wherein a level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) measured in a biological sample from the human subject that is higher than a predetermined sTREM-1 value indicates that the human subject is likely to respond to the therapy.

[0058] The present invention also relates to an in vitro method for selecting a human subject suffering from an inflammatory disorder for therapy, preferably treatment with a TREM-1 inhibitor, the method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) selecting a human subject suffering from an inflammatory disorder in which the level of sTREM-1 measured in step a) is higher than the predetermined sTREM-1 value in step b) for treatment with a therapy, preferably a TREM-1 inhibitor.

[0059] Another object of the present invention is a therapeutic agent, preferably a TREM-1 inhibitor, for use in treating an inflammatory disorder in a subject in need thereof, wherein a level of sTREM-1 measured in a biological sample from the subject that is higher than a predetermined sTREM-1 value indicates that the subject is likely to respond to the therapeutic agent, preferably a TREM-1 inhibitor.

[0060] Accordingly, the present invention also relates to a method for treating an inflammatory disorder in a human subject identified as susceptible to therapy, preferably a TREM-1 inhibitor, the method comprising: A human subject suffering from an inflammatory disorder amenable to therapy, preferably a TREM-1 inhibitor, a) obtaining a biological sample from a human subject and measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the biological sample; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value; c) identifying human subjects suffering from an inflammatory disorder in which the level of sTREM-1 measured in step a) is higher than the predetermined sTREM-1 value of step b) by identifying them as likely to respond to a therapy, preferably a TREM-1 inhibitor; administering a therapy, preferably a TREM-1 inhibitor, to a subject suffering from an inflammatory disorder identified as being susceptible to therapy, preferably a TREM-1 inhibitor, thereby treating the inflammatory disorder in the human subject identified as being susceptible to therapy, preferably a TREM-1 inhibitor.

[0061] TREM-1 (triggering receptor-1 expressed on myeloid cells) is a glycoprotein receptor belonging to the Ig superfamily that is specifically expressed in myeloid cells. sTREM-1 is a soluble form of TREM-1 that does not contain the transmembrane and intracellular domains of TREM-1. Without wishing to be bound by theory, the applicant suggests that engagement of PRRs (pathogen recognition receptors), such as Nod-like receptors (NLRs) and Toll-like receptors (TLRs), induces upregulation of TREM-1 expression and / or its recruitment and clustering at the plasma membrane, leading to its dimerization and multimerization. Activation of the above-mentioned NLRs and TLRs can occur through the ligation of DAMPs (danger-associated molecular patterns) or PAMPs (pathogen-associated molecular patterns). In particular, activation of NLRs and TLRs can occur under sterile inflammatory conditions by ligating DAMPs (danger-associated molecular patterns) and / or alarmins, or under infectious conditions by ligating PAMPs (pathogen-associated molecular patterns). This activation of NLRs and TLRs induces the upregulation of proteases, particularly metalloproteinases, which, among other targets, induce the proteolytic cleavage of membrane-anchored TREM-1, liberating soluble TREM-1 (Gomez-Pina et al., J Immunol. 2007 Sept. 15;179(6):4065-73). Proteolytic cleavage is dependent on TREM-1 receptor dimerization. Thus, sTREM-1 is released from the membrane of myeloid cells, particularly activated myeloid cells, and sTREM-1 release is a marker of TREM-1 activation. In one embodiment, sTREM-1 corresponds to a soluble form of the extracellular domain of TREM-1. In one embodiment, sTREM-1 corresponds to truncated TREM-1 released from the membrane of myeloid cells, particularly activated myeloid cells.

[0062] sTREM-1 can also result from alternative splicing of TREM-1 mRNA. TREM-1 splice variants were characterized by Baruah et al. in 2015 (J Immunol. 2015 Dec 15;195(12):5725-31) and found to be secreted from primary and secondary human neutrophil granules. In one embodiment, sTREM-1 corresponds to a TREM-1 splice variant. In one embodiment, sTREM-1 corresponds to the TREM-1 transcript commonly referred to as TREM1-202, also known as TREM-1 isoform 2, which encodes the amino acid sequence set forth in SEQ ID NO:2. Thus, in one embodiment, sTREM-1 has the amino acid sequence set forth in SEQ ID NO: 2 (MRKTRLWGLLWMLFVSELRAATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFRCSTLSFSWLVDS).

[0063] In one embodiment, sTREM-1 has the amino acid sequence set forth in SEQ ID NO: 5 (ATKLTEEKYELKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRVPVFN), which corresponds to amino acids 21 to 205 of SEQ ID NO: 1.

[0064] In another embodiment, sTREM-1 has the amino acid sequence set forth in SEQ ID NO: 6 (LKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGFSGTPGSNENSTQNVYKIPPTTTKALCPLYTSPRTVTQAPPKSTADVSTPDSEINLTNVTDIIRVPVFN), which corresponds to amino acids 31 to 205 of SEQ ID NO: 1.

[0065] In another embodiment, sTREM-1 comprises the amino acid sequence set forth in SEQ ID NO: 19 (LKEGQTLDVKCDYTLEKFASSQKAWQIIRDGEMPKTLACTERPSKNSHPVQVGRIILEDYHDHGLLRVRMVNLQVEDSGLYQCVIYQPPKEPHMLFDRIRLVVTKGF), which corresponds to amino acids 31 to 137 of SEQ ID NO: 1, and has a length of 200 or less amino acids, preferably 185 or less amino acids.

[0066] In another embodiment, sTREM-1 has the amino acid sequence set forth in SEQ ID NO: 2, SEQ ID NO: 5, or SEQ ID NO: 6. In another embodiment, sTREM-1 has the amino acid sequence set forth in SEQ ID NO: 5 or SEQ ID NO: 6.

[0067] In one embodiment, sTREM-1 is a variant of SEQ ID NO: 2, a variant of SEQ ID NO: 5, or a variant of SEQ ID NO: 6. In one embodiment, sTREM-1 is a variant of SEQ ID NO: 5 or a variant of SEQ ID NO: 6.

[0068] In one embodiment, a variant of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is an amino acid sequence comprising at least 25 consecutive amino acids, preferably at least 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 165, 170, 175, 180 or 185 consecutive amino acids of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6, respectively.

[0069] In another embodiment, the variant of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is an amino acid sequence comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6, respectively, and additional amino acids at the C-terminus or N-terminus of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6, wherein the number of additional amino acids ranges from 1 to 50, preferably 1 to 20, more preferably 1 to 10 amino acids, for example 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids at the C-terminus and / or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids at the N-terminus.

[0070] In another embodiment, a variant of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is an amino acid sequence that typically differs from the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 by one or more amino acid substitutions, deletions, additions and / or insertions. In one embodiment, the substitution(s), deletion(s), addition(s) and / or insertion(s) may affect 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids.

[0071] In another embodiment, a variant of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is an amino acid sequence of at least 25 amino acids, preferably at least 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 165, 170, 175, 180 or 185 amino acids, which has at least 60%, 65%, 70%, 75%, 80%, 90%, 95%, or at least 96%, 97%, 98%, 99% or more identity to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6, respectively.

[0072] The terms "identical" or "identity," when used in relation to the sequences of two or more polypeptides, refer to the degree of sequence relatedness between the polypeptides, as determined by the number of matches between two or more strings of amino acid residues. "Identity" measures the percentage of identical matches between two or more smaller sequences with gapped alignments (if any) processed by a particular mathematical model or computer program (i.e., "algorithm"). The identity of related polypeptides can be readily calculated by known methods. Such methods are described, but are not limited to, in Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, New York, 1991; and Carillo et al., SIAM J. Applied Math. 48, 1073 (1988). Preferred methods to determine identity are designed to give the largest match between the sequences tested. Methods to determine identity are described in publicly available computer programs.Preferred computer program methods for determining identity between two sequences include those in the GCG program package, such as GAP (Devereux et al., Nucl. Acid. Res. 2,387 (1984); Genetics Computer Group, University of Wisconsin, Madison, Wis.), BLASTP, BLASTN, and FASTA (Altschul et al., J. MoI. Biol. 215, 403-410 (1990)). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al., NCB / NLM / NIH Bethesda, Md. 20894; Altschul et al., supra). Identity can also be determined using the well-known Smith Waterman algorithm.

[0073] In one embodiment, the variant of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is not SEQ ID NO:1.

[0074] In one embodiment, sTREM-1 is a fragment of SEQ ID NO: 2, a fragment of SEQ ID NO: 5, or a fragment of SEQ ID NO: 6. In one embodiment, sTREM-1 is a fragment of SEQ ID NO: 5 or a fragment of SEQ ID NO: 6.

[0075] In one embodiment, a fragment of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6 is an amino acid sequence comprising at least 25 consecutive amino acids, preferably at least 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 165, 170, 175, 180 or 185 consecutive amino acids of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:5 or SEQ ID NO:6, respectively.

[0076] In one embodiment, sTREM-1 corresponds to an extracellular fragment generated by cleavage of membrane-bound TREM-1 having the amino acid sequence set forth in SEQ ID NO: 1 by a protease, preferably a matrix metallopeptidase, more preferably matrix metalloproteinase 9 (MMP9).

[0077] As used herein, "biological sample" refers to a biological sample isolated from a human subject, and may include, by way of example and without limitation, a body fluid, a cell sample, and / or a tissue extract, such as a homogenate or solubilized tissue, obtained from a human subject.

[0078] In one embodiment, the method of the present invention does not involve obtaining a biological sample from a subject. In one embodiment, the biological sample from a human subject is a biological sample previously obtained from a human subject. The biological sample can be stored under appropriate conditions before being used in the method of the present invention.

[0079] In one embodiment, the biological sample from the human subject is a bodily fluid sample, examples of which include, but are not limited to, blood, plasma, serum, lymph, urine, bronchoalveolar lavage fluid, cerebrospinal fluid, sweat, or any other bodily fluid or derivative thereof.

[0080] As used herein, "blood" includes whole blood, plasma, serum, circulating epithelial cells, components, or any other derivative of blood.

[0081] In one embodiment, the biological sample from the human subject is a blood sample. In one embodiment, the biological sample from the human subject is a whole blood sample or a plasma sample. Methods for obtaining plasma samples are routinely used in clinical laboratories. In one embodiment, the whole blood sample or plasma sample from the human subject is processed to obtain a serum sample. Methods for obtaining serum samples from whole blood or plasma samples are routinely used in clinical laboratories.

[0082] In another embodiment, the biological sample from the human subject is a tissue extract. Tissue extracts are routinely obtained from tissue biopsy and autopsy material.

[0083] According to the present invention, the term "level" as used herein refers to the expression level of sTREM-1. Alternatively, it can refer to the transcription level of sTREM-1 or the translation level of sTREM-1. The expression level can be detected intracellularly or extracellularly.

[0084] TREM-1 levels can be measured by point-of-care testing (POCT) or bedside testing, near-patient testing, or by a central laboratory assay.

[0085] Methods for measuring expression levels, such as transcriptional or translational levels, are well known to those skilled in the art and include, but are not limited to, RT-PCR, RT-qPCR, Northern blot, hybridization techniques such as, for example, the use of microarrays, and combinations thereof, such as, for example, hybridization of amplicons obtained by RT-PCR, sequencing such as, for example, next generation DNA sequencing (NGS) or RNA-seq (also known as "whole transcriptome shotgun sequencing"), immunohistochemistry, multiplex methods (such as Luminex), Western blot, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, multiplex ELISA, electrochemiluminescence (ECL), also called electrochemiluminescence immunoassay (ECLIA) (such as Elecsys®, Roche). Diagnostics), enzyme-linked fluorescence assay (ELFA) (such as VIDAS®, Biomerieux), fluorescence-linked immunosorbent assay (FLISA), enzyme-linked immunosorbent assay (EIA), radioimmunoassay (RIA), flow cytometry (FACS), surface plasmon resonance (SPR), biolayer interferometry (BLI), immunochromatography assay (ICA) (such as NEXUS IB10, Sphingotech) and mass spectrometry-based approaches.

[0086] According to one embodiment, the term "level" as used herein refers to the quantity, amount, or concentration of sTREM-1. Thus, the level of sTREM-1 measured in a biological sample from a human subject refers to the quantity, amount, or concentration of sTREM-1 in the biological sample.

[0087] According to one embodiment, the level of sTREM-1 refers to the protein level, protein quantity, protein amount, or protein concentration.

[0088] In one embodiment, the level of sTREM-1 refers to the level of the amino acid sequence set forth in SEQ ID NO: 2, SEQ ID NO: 5 and / or SEQ ID NO: 6, and / or the fragments and / or variants thereof as described above. In one embodiment, the level of sTREM-1 refers to the level of the amino acid sequence set forth in SEQ ID NO: 5 and / or SEQ ID NO: 6, and / or the fragments and / or variants thereof as described above.

[0089] In one embodiment, the biological sample from the human subject is a blood sample, and the level of sTREM-1 measured in the biological sample corresponds to the blood concentration of sTREM-1 in the human subject.

[0090] In one embodiment, the biological sample from the human subject is a plasma sample, and the level of sTREM-1 measured in the biological sample corresponds to the plasma concentration of sTREM-1 in the human subject.

[0091] In one embodiment, the biological sample from the human subject is a serum sample, and the level of sTREM-1 measured in the biological sample corresponds to the serum concentration of sTREM-1 in the human subject.

[0092] According to the present invention, the level of sTREM-1 can be measured by any method known in the art.

[0093] Methods for measuring sTREM-1 levels, particularly sTREM-1 protein levels, in biological samples such as those described above are well known to those skilled in the art and include, but are not limited to, immunohistochemistry, multiplex methods (such as Luminex), Western blot, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, multiplex ELISA, electrochemiluminescence immunoassay (ECLIA) (such as Elecsys®, Roche Diagnostics), enzyme-linked fluorescence assay (ELFA) (such as VIDAS®, Biomerieux), fluorescence-linked immunosorbent assay (FLISA), enzyme-linked immunosorbent assay (EIA), radioimmunoassay (RIA), flow cytometry (FACS), surface plasmon resonance (SPR), biolayer interferometry (BLI), immunochromatography assay (ICA) (such as NEXUS IB10, Sphingotech), and mass spectrometry-based approaches.

[0094] Typically, measuring the level of sTREM-1 in a biological sample as described above can include contacting the biological sample with a binding partner that can selectively interact with sTREM-1 in the biological sample. In one embodiment, the binding partner is an antibody, such as a monoclonal antibody or an aptamer.

[0095] In one embodiment, measuring the level of sTREM-1 in a biological sample as described above involves the use of an antibody, such as a polyclonal or monoclonal antibody.

[0096] Examples of antibodies that allow the detection of sTREM-1 include, but are not limited to, a polyclonal antibody raised against the Met1-Arg200 amino acids of human TREM-1 (reference AF1278, R&D Systems), a monoclonal antibody raised against the Ala21-Asn205 amino acids of human TREM-1 (reference MAB1278, R&D Systems), a purified anti-human CD354 (TREM-1) antibody (clone TREM-26, reference 314902, BioLegend), a purified anti-human CD354 (TREM-1) antibody (clone TREM-37, reference 316102, BioLegend), a monoclonal mouse anti-human sTREM1 (clone 15G7, reference 298099, USBio), and a mouse anti-human TREM1 (clone 2E2, reference 134704, USBio). Other non-limiting examples of antibodies that allow for the detection of sTREM-1 include sTREM-1 and / or TREM-1 antibodies described in the following patents or patent applications: U.S. Patent No. 2013 / 150559, U.S. Patent No. 2013 / 211050, U.S. Patent No. 2013 / 309239, WO 2013 / 120553 and U.S. Patent No. 8,106,165.

[0097] Some of the aforementioned assays for measuring sTREM-1 levels in biological samples (e.g., Western blot, ELISA, or sandwich ELISA) generally involve binding of a partner (i.e., antibody or aptamer) to a solid support. Solid supports that can be used in practicing the methods of the present invention include, but are not limited to, supports such as nitrocellulose (e.g., nitrocellulose membrane or nitrocellulose microtiter plate), polyvinyl chloride (e.g., polyvinyl chloride sheet, polyvinyl chloride membrane, or polyvinyl chloride microtiter plate), polystyrene latex (e.g., polystyrene latex beads or polystyrene latex microtiter plate), polyvinylidene difluoride or PVDF (e.g., PVDF membrane), diazotized paper, nylon membrane, activated beads, and magnetically responsive beads.

[0098] The level of sTREM-1 may be measured using standard immunodiagnostic techniques, such as immunoassays, such as competitive, direct reaction, or sandwich-type assays. Such assays include, but are not limited to, agglutination tests, enzyme-labeled and mediated immunoassays such as ELISA, biotin / avidin-type assays, radioimmunoassays, immunoelectrophoresis, and immunoprecipitation. Thus, immunoassays include, but are not limited to, enzyme-labeled and mediated immunoassays such as ELISA or enzyme-linked fluorescence assay (ELFA), biotin / avidin-type assays, radioimmunoassays, immunoelectrophoresis, immunoprecipitation, and electrochemiluminescence immunoassays (ECLIA).

[0099] An exemplary biochemical test for identifying a specific protein uses a standardized test format such as an ELISA test, although the information provided herein can be applied to the development of other biochemical tests, including but not limited to the development of ELISA tests (see, for example, Molecular Immunology: A Textbook, edited by Atassi et al., Marcel Dekker Inc., New York and Basel 1984, for a description of ELISA tests). It is understood that commercially available enzyme-linked immunosorbent assay (ELISA) kits for various plasma components are available.

[0100] Thus, an ELISA method can be used to measure the level of sTREM-1 in a biological sample, in which the wells of a microtiter plate are coated with at least one antibody that recognizes sTREM-1. A biological sample containing or suspected of containing sTREM-1 is then added to the coated wells. After an incubation period sufficient to allow the formation of antibody-sTREM-1 complexes, the plate(s) can be washed to remove unbound moieties, and a detectably labeled secondary binding molecule can be added. The secondary binding molecule can react with any captured antibody-sTREM-1 complexes, the plate can be washed, and the presence of the secondary binding molecule can be detected using methods well known in the art.

[0101] In one embodiment, measuring the level of sTREM-1 in a biological sample as described above comprises using an enzyme-linked immunosorbent assay (ELISA), an electrochemiluminescence immunoassay (ECLIA) (such as Elecsys® Roche Diagnostics) or an enzyme-linked fluorescence assay (ELFA).

[0102] Examples of ELISA assays include, but are not limited to, the TREM-1 Quantikine ELISA kit (reference DTRM10C, R&D Systems), human TREM-1 DuoSet (reference DY1278B and DY1278BE, R&D Systems), and sTREM-1 ELISA (reference sTREM-1 ELISA, iQProducts).

[0103] An example of an electrochemiluminescence immunoassay (ECLIA) is Elecsys® (Roche Diagnostics).

[0104] An example of an enzyme-linked fluorescence assay (ELFA) is VIDAS® (Biomerieux).

[0105] Typically, the level of sTREM-1 in a biological sample can be measured by an immunometric assay based on double-antibody "sandwich" technology using a monoclonal antibody specific for sTREM-1. Thus, in one embodiment, measuring the level of sTREM-1 in a biological sample as described above comprises using a sandwich ELISA.

[0106] According to one embodiment, measuring the level of sTREM-1 (with or without immunoassay-based methods) may also include separation of compounds present in a biological sample (i.e., separation of sTREM-1), centrifugation based on the molecular weight of the compound, electrophoresis based on mass and charge, HPLC based on hydrophobicity, size exclusion chromatography based on size, and solid phase affinity based on the affinity of the compound for the particular solid phase used.

[0107] Once separated, the compound (i.e., sTREM-1) can be identified based on the compound's known "separation profile," e.g., retention time, and measured using standard techniques. Alternatively, the separated compound (i.e., sTREM-1) can be detected and measured, for example, by mass spectrometry.

[0108] According to one embodiment, the level of sTREM-1 refers to the nucleic acid level, nucleic acid quantity, nucleic acid amount or nucleic acid concentration. In one embodiment, the nucleic acid is RNA, preferably mRNA, or cDNA.

[0109] Methods for measuring expression levels, particularly sTREM-1 nucleic acid levels, in biological samples as described above are well known to those skilled in the art and include, but are not limited to, PCR, qPCR, RT-PCR, RT-qPCR, Northern blots, hybridization techniques such as the use of microarrays, and combinations thereof, including, but not limited to, hybridization of amplicons obtained by RT-PCR, sequencing such as next generation DNA sequencing (NGS), or RNA-seq (also known as "whole transcriptome shotgun sequencing").

[0110] In one embodiment, sTREM-1 nucleic acid levels are measured using forward and reverse primers having the nucleotide sequences set forth in SEQ ID NO: 13 (GTGGTGACCAAGGGGTTC) and SEQ ID NO: 14 (AGATGGATGTGGCTGGAAGT), respectively.

[0111] In one embodiment, sTREM-1 nucleic acid levels are measured using forward and reverse primers having the nucleotide sequences set forth in SEQ ID NO: 15 (GTGACCAAGGGTTTTTCAGG) and SEQ ID NO: 16 (ACACCGGAACCCTGATGATA), respectively.

[0112] In one embodiment, sTREM-1 nucleic acid levels are measured using forward and reverse primers having the nucleotide sequences set forth in SEQ ID NO: 17 (AAAGGCAAGAACGCCTGAC) and SEQ ID NO: 18 (GGGACTTTACCAAGAGGGAC), respectively.

[0113] In one embodiment, the level of sTREM-1 measured in the biological sample as described above is a baseline level, i.e., the level of sTREM-1 is measured in such a biological sample obtained from a human subject suffering from an inflammatory disorder before the start of therapy, preferably administration of a TREM-1 inhibitor.

[0114] In one embodiment, the level of sTREM-1 is measured in the above-mentioned biological sample obtained from the human subject between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after the onset of an inflammatory disorder, preferably SIRS, sepsis or septic shock, after diagnosis of the human subject with an inflammatory disorder, preferably SIRS, sepsis or septic shock, after hospitalization of the human subject for an inflammatory disorder, preferably SIRS, sepsis or septic shock, in particular admission to an ICU or emergency room, or after initiation of vasopressor therapy.

[0115] In one embodiment, the level of sTREM-1 is measured in the above-mentioned biological sample obtained from the human subject within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, or 48 hours after the onset of an inflammatory disorder, preferably SIRS, sepsis, or septic shock, after diagnosis of the human subject with an inflammatory disorder, preferably SIRS, sepsis, or septic shock, after hospitalization of the human subject, particularly admission to an ICU or emergency room, for an inflammatory disorder, preferably SIRS, sepsis, or septic shock, or after the initiation of vasopressor therapy.

[0116] In one embodiment, the level of sTREM-1 is measured in the biological sample between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after the onset of an inflammatory disorder, preferably SIRS, sepsis or septic shock, after diagnosis of a human subject with an inflammatory disorder, preferably SIRS, sepsis or septic shock, after hospitalization of a human subject for an inflammatory disorder, preferably SIRS, sepsis or septic shock, in particular admission to an ICU or emergency room, or after initiation of vasopressor therapy.

[0117] In one embodiment, the level of sTREM-1 is measured in the above biological sample within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, or 48 hours after the onset of an inflammatory disorder, preferably SIRS, sepsis, or septic shock, after diagnosis of a human subject with an inflammatory disorder, preferably SIRS, sepsis, or septic shock, after hospitalization of a human subject, particularly admission to an ICU or emergency room, for an inflammatory disorder, preferably SIRS, sepsis, or septic shock, or after initiation of vasopressor therapy.

[0118] In one embodiment, the level of sTREM-1 is measured in the above biological sample obtained from a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after re-infection of the human subject.

[0119] In one embodiment, the level of sTREM-1 is measured in the above biological sample obtained from a human subject within the first 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours after reinfection of the human subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock.

[0120] In one embodiment, the level of sTREM-1 is measured in the above biological sample between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after re-infection of a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0121] In one embodiment, the level of sTREM-1 is measured in the above biological sample within the first 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, 24 hours, 30 hours, 36 hours, 42 hours, or 48 hours after reinfection of a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock.

[0122] In one embodiment, the level of sTREM-1 is measured in the above-mentioned biological sample obtained from a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after readmission, in particular to an ICU or emergency room, of the human subject.

[0123] In one embodiment, the level of sTREM-1 is measured in the above biological sample obtained from a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 or 48 hours after readmission of the human subject, in particular to an ICU or emergency room.

[0124] In one embodiment, the level of sTREM-1 is measured in the biological sample between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after readmission, in particular to an ICU or emergency room, of a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0125] In one embodiment, the level of sTREM-1 is measured in the above biological sample within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, or 48 hours after readmission of a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock, in particular after readmission to an ICU or emergency room.

[0126] In one embodiment, the level of sTREM-1 is measured in the above-mentioned biological sample obtained from the human subject between the first 2 hours and the first 48 hours, preferably between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after the onset of septic shock, after the diagnosis of the human subject with septic shock, after the hospitalization of the human subject for septic shock, in particular after admission to an ICU or emergency room, or after the initiation of vasopressor therapy.

[0127] In one embodiment, the level of sTREM-1 is measured in the above biological sample obtained from a human subject within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, or 48 hours after the onset of septic shock, after the diagnosis of the human subject with septic shock, after the hospitalization of the human subject for septic shock, particularly after admission to an ICU or emergency room, or after the initiation of vasopressor therapy.

[0128] In one embodiment, the level of sTREM-1 is measured in the above biological sample between the first 2 hours and the first 12 hours, between the first 12 hours and the first 24 hours, or between the first 24 hours and the first 48 hours after the onset of septic shock, after the diagnosis of the human subject with septic shock, after the hospitalization of the human subject for septic shock, particularly after admission to an ICU or emergency room, or after the initiation of vasopressor therapy.

[0129] In one embodiment, the level of sTREM-1 is measured in the above biological sample within the first 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, or 48 hours after the onset of septic shock, after the diagnosis of a human subject with septic shock, after the hospitalization of a human subject for septic shock, particularly after admission to an ICU or emergency room, or after the initiation of vasopressor therapy.

[0130] In one embodiment, the predetermined sTREM-1 value is a personalized reference value, ie, the predetermined sTREM-1 value is obtained using a biological sample obtained from a human subject.

[0131] In one embodiment, the predetermined value of sTREM-1 is an index value or is derived from one or more risk prediction algorithms or calculated indices of an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0132] In one embodiment, the predetermined value of sTREM-1 is obtained from a reference population.

[0133] According to the present invention, a predetermined sTREM-1 value may be derived from a population study, such as, for example, subjects having a similar age range, subjects within the same or similar ethnic group, subjects with a chronic medical condition associated with an increased risk of inflammatory disorders, preferably SIRS, sepsis or septic shock (atrial fibrillation, cancer, chronic kidney disease, chronic lung disease, cirrhosis, coronary artery disease, deep vein thrombosis, diabetes, dyslipidemia, endocarditis, hypertension, influenza, malaria, etc. or other protozoan parasitic diseases, myocardial infarction, neurological diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), peripheral arterial disease, pulmonary fibrosis, severe obesity and stroke) or a history of an inflammatory disorder such as SIRS, sepsis or septic shock.

[0134] According to one embodiment, the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more substantially healthy human subjects. As used herein, a "substantially healthy subject" is a human subject who has not been previously diagnosed or identified as having or suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock. Thus, according to one embodiment, the predetermined sTREM-1 value is obtained from a reference population of substantially healthy human subjects.

[0135] In one embodiment, a "substantially healthy subject" is a human subject who is not suffering from an infectious disease.

[0136] According to one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is a sTREM-1 level, preferably a blood, plasma or serum level, ranging from about 50 pg / mL to about 250 pg / mL.

[0137] In one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is an sTREM-1 level, preferably a blood, plasma or serum level, of about 50 pg / mL, 75 pg / mL, 100 pg / mL, 125 pg / mL, 150 pg / mL, 175 pg / mL, 200 pg / mL, 225 pg / mL, or 250 pg / mL.

[0138] In one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is a sTREM-1 level, preferably a blood, plasma or serum level, ranging from about 50 pg / mL to about 150 pg / mL, particularly as determined using an enzyme-linked immunosorbent assay (ELISA).

[0139] In one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is a sTREM-1 level, preferably a blood, plasma or serum level, of about 50 pg / mL, 75 pg / mL, 100 pg / mL, 125 pg / mL or 150 pg / mL, particularly as determined using an enzyme-linked immunosorbent assay (ELISA).

[0140] In one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is a sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 150 pg / mL to about 250 pg / mL, particularly as determined using an electrochemiluminescence immunoassay (ECLIA).

[0141] In one embodiment, the predetermined value for sTREM-1 obtained from a reference population of substantially healthy human subjects is a sTREM-1 level, preferably a blood, plasma or serum level, of about 150 pg / mL, 175 pg / mL, 200 pg / mL, 225 pg / mL, or 250 pg / mL, particularly as determined using an electrochemiluminescence immunoassay (ECLIA).

[0142] According to another embodiment, the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects suffering from, or diagnosed or identified as suffering from, an inflammatory disorder, preferably SIRS, sepsis, or septic shock. Thus, according to one embodiment, the predetermined sTREM-1 value is obtained from a reference population of human subjects suffering from, or diagnosed or identified as suffering from, an inflammatory disorder, preferably SIRS, sepsis, or septic shock.

[0143] In one embodiment, the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects diagnosed or identified as having sepsis. Thus, in one embodiment, the predetermined sTREM-1 value is obtained from a reference population of human subjects diagnosed or identified as having sepsis.

[0144] In one embodiment, the in vitro method of the invention is for identifying human subjects suffering from sepsis who are likely to respond to a therapy, particularly the administration of a TREM-1 inhibitor, and the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects diagnosed or identified as suffering from sepsis. In other words, in one embodiment, the in vitro method of the invention is for identifying human subjects suffering from sepsis who are likely to respond to a therapy, particularly the administration of a TREM-1 inhibitor, and the predetermined sTREM-1 value is obtained from a reference population of human subjects diagnosed or identified as suffering from sepsis.

[0145] In one embodiment, the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects diagnosed or identified as suffering from septic shock. Thus, in one embodiment, the predetermined sTREM-1 value is obtained from a reference population of human subjects diagnosed or identified as suffering from septic shock.

[0146] In one embodiment, the in vitro method of the invention is for identifying human subjects suffering from septic shock who are likely to respond to a therapy, particularly the administration of a TREM-1 inhibitor, and the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects diagnosed or identified as suffering from septic shock. In other words, in one embodiment, the in vitro method of the invention is for identifying human subjects suffering from septic shock who are likely to respond to a therapy, particularly the administration of a TREM-1 inhibitor, and the predetermined sTREM-1 value is obtained from a reference population of human subjects diagnosed or identified as suffering from septic shock.

[0147] In one embodiment, the predetermined value for sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects previously diagnosed or identified as suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0148] In one embodiment, the predetermined value of sTREM-1 is derived from measurements of sTREM-1 levels in biological samples from one or more human subjects suffering from an infection that is at high risk of developing an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0149] According to the present invention, the predetermined sTREM-1 value can be derived from statistical analysis and / or risk prediction data of the above-mentioned reference populations obtained from mathematical algorithms and calculated indices of inflammatory disorders, preferably SIRS, sepsis or septic shock.

[0150] According to one embodiment, the predetermined value of sTREM-1 is obtained from a reference population as described above using statistical and / or structural classification methods.

[0151] According to one embodiment, the predetermined sTREM-1 value, preferably obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level.

[0152] In one embodiment, a human subject suffering from an inflammatory disorder that is amenable to treatment is a human subject having an sTREM-1 level measured as described above that is at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, or 10-fold higher than a predetermined sTREM-1, preferably a predetermined sTREM-1 obtained from a reference population of substantially healthy human subjects as described above.

[0153] In one embodiment, a human subject suffering from an inflammatory disorder that is amenable to treatment is a human subject having an sTREM-1 level measured as described above that is at least 1.6-fold, 1.8-fold, 2-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3-fold, 3.2-fold, 3.4-fold, 3.6-fold, 3.8-fold, 4-fold, 4.2-fold, 4.4-fold, 4.6-fold, 4.8-fold, 5-fold, 5.2-fold, 5.4-fold, 5.6-fold, 5.8-fold, or 6-fold higher than a predetermined sTREM-1, preferably a predetermined sTREM-1 obtained from a reference population of substantially healthy human subjects as described above.

[0154] In one embodiment, a human subject suffering from an inflammatory disorder that is amenable to treatment is a human subject having an sTREM-1 level measured as described above that is at least 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold, 2.5-fold, 2.6-fold, 2.7-fold, 2.8-fold, 2.9-fold, 3-fold, 3.1-fold, 3.2-fold, 3.3-fold, 3.4-fold, 3.5-fold, 3.6-fold, 3.7-fold, 3.8-fold, 3.9-fold, or 4-fold higher than a predetermined sTREM-1, preferably a predetermined sTREM-1 obtained from a reference population of substantially healthy human subjects as described above.

[0155] In another embodiment, a human subject suffering from an inflammatory disorder that is amenable to therapy is a human subject having a level of a predetermined sTREM-1, preferably sTREM-1, measured as described above, that is at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold or 2.5-fold higher than a predetermined sTREM-1 obtained from a reference population of human subjects suffering from, or diagnosed or identified as suffering from, an inflammatory disorder, preferably SIRS, sepsis or septic shock.

[0156] In one embodiment, the predetermined sTREM-1 value obtained from the reference population is the mean sTREM-1 level of the reference population, preferably the mean blood, plasma or serum level. In another embodiment, the predetermined sTREM-1 value obtained from the reference population is the median sTREM-1 level of the reference population, preferably the mean blood, plasma or serum level.

[0157] According to one embodiment, a predetermined sTREM-1 value is obtained from the above-mentioned reference population, and the sTREM-1 levels measured in each biological sample of human subjects in the reference population (i.e., the sTREM-1 levels measured in the reference population) are divided into groups of equal size by cutoff values ​​called "quantiles," each group corresponding to a predetermined proportion (percentage) of the sTREM-1 levels measured in the reference population. Examples of quantiles include, but are not limited to, median (defining two groups, each containing 50% of the sTREM-1 levels measured in a reference population), tercile or tertile (defining three groups, each containing one-third of the sTREM-1 levels measured in a reference population), quartile (defining four groups, each containing 25% of the sTREM-1 levels measured in a reference population), quintile (defining five groups, each containing 20% ​​of the sTREM-1 levels measured in a reference population), and deciles (defining ten groups, each containing 10% of the sTREM-1 levels measured in a reference population).

[0158] According to the present invention, a "quantile" refers to a cutoff sTREM-1 value, above and below which lie a predetermined percentage of sTREM-1 levels measured in a reference population. Thus, a human subject having a measured sTREM-1 level below the first quantile is a human subject having the lowest sTREM-1 level, and a human subject having a measured sTREM-1 level higher than the last quantile is a human subject having the highest sTREM-1 level. For example, the first decile is the sTREM-1 value below which 10% of the sTREM-1 levels measured in the reference population are and above which 90% of the sTREM-1 levels measured in the reference population are.

[0159] Furthermore, the term "quantile" can also refer to a group defined by a cutoff value. Thus, as applied to the present invention, the term "quantile" can also refer to a group of sTREM-1 levels measured in a reference population defined by a cutoff sTREM-1 value. For example, the first decile can refer to a group of sTREM-1 levels measured in a reference population that correspond to the lowest 10% of sTREM-1 levels measured in the reference population. Thus, the tenth decile refers to a group of sTREM-1 levels measured in a reference population that correspond to the highest 10% of sTREM-1 levels measured in the reference population. Thus, sTREM-1 values ​​in the first decile are sTREM-1 values ​​that fall within the lowest 10% of sTREM-1 levels measured in the reference population, and sTREM-1 values ​​in the tenth decile are sTREM-1 values ​​that fall within the highest 10% of sTREM-1 levels measured in the reference population.

[0160] In one embodiment, the predetermined sTREM-1 values ​​are obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into two equal-sized groups, each corresponding to 50% of the sTREM-1 levels measured in the reference population.

[0161] According to this embodiment of the invention, the median sTREM-1 value corresponds to the sTREM-1 value below which 50% of the sTREM-1 levels measured in the reference population fall and above which 50% of the sTREM-1 levels measured in the reference population fall.

[0162] Thus, in one embodiment, the predetermined sTREM-1 value is the median sTREM-1 value for a reference population, as set forth above.

[0163] Thus, in one embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value obtained from a reference population, wherein the predetermined sTREM-1 value is the median value of the reference population; c) identifying human subjects suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having sTREM-1 levels measured in step a) higher than the median value in step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0164] In one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into three equally sized groups, each corresponding to one-third of the sTREM-1 levels measured in the reference population. As described above, the cutoff values ​​("quantiles") are called "terciles" (or "tertiles") because they divide the sTREM-1 levels measured in the reference population. Thus, in one embodiment, the predetermined sTREM-1 value is the sTREM-1 tercile (or tertile) of the reference population, as described above.

[0165] According to this embodiment of the invention: - the first tercile (or tertile) of sTREM-1 corresponds to an sTREM-1 value below which one-third of the sTREM-1 levels measured in a reference population lie and above which two-thirds of the sTREM-1 levels measured in a reference population lie, and The second tercile (or tertile) of sTREM-1 corresponds to the sTREM-1 value below which two-thirds of the sTREM-1 levels measured in the reference population lie and above which one-third of the sTREM-1 levels measured in the reference population lie.

[0166] In one embodiment, the predetermined sTREM-1 value is the second sTREM-1 tertile (ie, the last sTREM-1 tertile) of the reference population, as described above.

[0167] In one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into four equal-sized groups, each corresponding to 25% of the sTREM-1 levels measured in the reference population. As described above, the cutoff values ​​("quantiles") are called "quartiles" because they divide the sTREM-1 levels measured in the reference population. Thus, in one embodiment, the predetermined sTREM-1 value is the sTREM-1 quartile of the reference population, as described above.

[0168] According to this embodiment of the invention: - the first quartile (or Q1) of sTREM-1 corresponds to the sTREM-1 value below which 25% of the sTREM-1 levels measured in the reference population lie and above which 75% of the sTREM-1 levels measured in the reference population lie, the second quartile of sTREM-1 corresponds to the sTREM-1 value below which 50% of the sTREM-1 levels measured in the reference population lie and above which 50% of the sTREM-1 levels measured in the reference population lie (the second quartile is therefore equivalent to the median); - The third quartile (or Q3) of sTREM-1 corresponds to the sTREM-1 value below which 75% of the sTREM-1 levels measured in the reference population lie and above which 25% of the sTREM-1 levels measured in the reference population lie.

[0169] In one embodiment, the predetermined sTREM-1 value is the first sTREM-1 quartile, also referred to as sTREM-1 Q1, of the reference population as described above.

[0170] In one embodiment, the predetermined sTREM-1 value is the third sTREM-1 quartile, also referred to as sTREM-1 Q3 (ie, last sTREM-1 quartile), of the reference population, as described above.

[0171] Thus, in one embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value obtained from a reference population sTREM-1, wherein the predetermined sTREM-1 value is the third quartile of the reference population; c) identifying human subjects suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having sTREM-1 levels measured in step a) higher than the third quartile of step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0172] In one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into five equally sized groups, each corresponding to 20% of the sTREM-1 levels measured in the reference population. As described above, the cutoff values ​​("quantiles") are called "quintiles" because they divide the sTREM-1 levels measured in the reference population. Thus, in one embodiment, the predetermined sTREM-1 value is the sTREM-1 quintile of the reference population, as described above.

[0173] According to this embodiment of the invention: - the first quintile of sTREM-1 corresponds to the sTREM-1 value below which 20% of the sTREM-1 levels measured in the reference population lie and above which 80% of the sTREM-1 levels measured in the reference population lie, - the second sTREM-1 quintile corresponds to the sTREM-1 value below which 40% of the sTREM-1 levels measured in the reference population lie and above which 60% of the sTREM-1 levels measured in the reference population lie, the third quintile of sTREM-1 corresponds to an sTREM-1 value below which 60% of the sTREM-1 levels measured in the reference population lie and above which 40% of the sTREM-1 levels measured in the reference population lie, and - The fourth quintile of sTREM-1 corresponds to the sTREM-1 value below which 80% of the sTREM-1 levels measured in the reference population lie and above which 20% of the sTREM-1 levels measured in the reference population lie.

[0174] In one embodiment, the predetermined sTREM-1 value is a second sTREM-1 quintile of a reference population, as described above.

[0175] In one embodiment, the predetermined sTREM-1 value is the third sTREM-1 quintile (ie, the penultimate sTREM-1 quintile) of the reference population, as described above.

[0176] In one embodiment, the predetermined sTREM-1 value is the fourth sTREM-1 quintile (ie, the last sTREM-1 quintile) of the reference population, as described above.

[0177] In one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into 10 equally sized groups, each corresponding to 10% of the sTREM-1 levels measured in the reference population. As described above, the cutoff values ​​("quantiles") are called "deciles" because they divide the sTREM-1 levels measured in the reference population. Thus, in one embodiment, the predetermined sTREM-1 value is the sTREM-1 decile of the reference population, as described above.

[0178] According to this embodiment of the invention: - the first decile of sTREM-1 corresponds to the sTREM-1 value below which 10% of the sTREM-1 levels measured in the reference population lie and above which 90% of the sTREM-1 levels measured in the reference population lie, - a second decile of sTREM-1 corresponds to the sTREM-1 value below which 20% of the sTREM-1 levels measured in the reference population lie and above which 80% of the sTREM-1 levels measured in the reference population lie, - the third decile of sTREM-1 corresponds to the sTREM-1 value below which 30% of the sTREM-1 levels measured in the reference population lie and above which 70% of the sTREM-1 levels measured in the reference population lie, - the fourth decile of sTREM-1 corresponds to the sTREM-1 value below which 40% of the sTREM-1 levels measured in the reference population lie and above which 60% of the sTREM-1 levels measured in the reference population lie, - the fifth decile of sTREM-1 corresponds to the sTREM-1 value below which 50% of the sTREM-1 levels measured in the reference population lie and above which 50% of the sTREM-1 levels measured in the reference population lie, - the 6th decile of sTREM-1 corresponds to the sTREM-1 value below which 60% of the sTREM-1 levels measured in the reference population lie and above which 40% of the sTREM-1 levels measured in the reference population lie, the seventh decile of sTREM-1 corresponds to the sTREM-1 value below which 70% of the sTREM-1 levels measured in the reference population lie and above which 30% of the sTREM-1 levels measured in the reference population lie, - the 8th decile of sTREM-1 corresponds to the sTREM-1 value below which 80% of the sTREM-1 levels measured in the reference population lie and above which 20% of the sTREM-1 levels measured in the reference population lie, - The 9th decile of sTREM-1 corresponds to the sTREM-1 value below which 90% of the sTREM-1 levels measured in the reference population lie and above which 10% of the sTREM-1 levels measured in the reference population lie.

[0179] In one embodiment, the predetermined sTREM-1 value is the sixth sTREM-1 decile of the reference population, as described above. In one embodiment, the predetermined sTREM-1 value is the seventh sTREM-1 decile of the reference population, as described above. In one embodiment, the predetermined sTREM-1 value is the eighth sTREM-1 decile (i.e., the penultimate sTREM-1 decile) of the reference population, as described above.

[0180] In one embodiment, the predetermined sTREM-1 value is the 9th sTREM-1 decile (ie, the last sTREM-1 decile) of the reference population, as described above.

[0181] In one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the sTREM-1 levels measured in the reference population are divided into groups corresponding to specific percentages of the sTREM-1 levels measured in the reference population. As described above, the cutoff values ​​("quantiles") are called "percentiles" because they divide the sTREM-1 levels measured in the reference population. Thus, in one embodiment, the predetermined sTREM-1 value is the sTREM-1 percentile of the reference population, as described above.

[0182] According to one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above, and the value is associated with a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% predicted mortality rate in the reference population.

[0183] For example, a given sTREM-1 value associated with a 50% expected mortality rate in a reference population means that for subjects in the reference population having sTREM-1 levels higher than this value, the mortality rate is 50%.

[0184] According to one embodiment, the predetermined sTREM-1 value is obtained from a reference population as described above and including patients affected by SIRS, sepsis, or septic shock, wherein more than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of subjects in the reference population who die 28, 90, or 365 days after initial infection or initial hospitalization exhibit a value higher than the predetermined sTREM-1 value.

[0185] According to one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 20 pg / mL to about 6000 pg / mL.

[0186] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is about 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4100, 4200, 4300, 4400, 4500, 5000, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1450, 1500, 1650, 170 0, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, ​​3000, 30 50, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, 3600, 3650, 3700, 3750, 3800, 3850, 3900, 3950, 4000, 4050, 4100, 4150, 4200, 4250, 4300, 4350, 4400, 4450, 4500, 4550, 4600, 4650, 4700, 4 sTREM-1 levels of 750, 4800, 4850, 4900, 4950, 5000, 5050, 5100, 5150, 5200, 5250, 5300, 5350, 5400, 5450, 5500, 5550, 5600, 5650, 5700, 5750, 5800, 5850, 5900, 5950 or 6000 pg / mL, preferably blood, plasma or serum levels.

[0187] According to one embodiment, the predetermined sTREM-1 value, preferably obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 30 pg / mL to about 2000 pg / mL.

[0188] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 30, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 pg / mL.

[0189] According to one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 50 pg / mL to about 1000 pg / mL.

[0190] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is about 50, 75, 100, 125, 150, 175, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, , 440, 450, 460, 470, 480, 490, 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, 800, 820, 840, 860, 880, 900, 920, 940, 960, 980 or 1000 pg / mL of sTREM-1, preferably blood, plasma or serum levels.

[0191] According to another embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 250 pg / mL to about 400 pg / mL.

[0192] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 pg / mL.

[0193] According to another embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 300 pg / mL to about 800 pg / mL.

[0194] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is about 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 7 and sTREM-1 levels, preferably blood, plasma or serum levels, of 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795 or 800 pg / mL.

[0195] According to another embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 350 pg / mL to about 600 pg / mL.

[0196] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, is about 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, sTREM-1 levels of 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 or 600 pg / mL, preferably blood, plasma or serum levels.

[0197] According to another embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 400 pg / mL to about 500 pg / mL.

[0198] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 or 500 pg / mL.

[0199] According to another embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 600 pg / mL.

[0200] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 or 600 pg / mL.

[0201] According to one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, determined by enzyme-linked immunosorbent assay (ELISA).

[0202] As indicated above, examples of ELISA assays include, but are not limited to, the TREM-1 Quantikine ELISA kit (reference DTRM10C, R&D Systems), human TREM-1 DuoSet (reference DY1278B and DY1278BE, R&D Systems), and sTREM-1 ELISA (reference sTREM-1 ELISA, iQProducts).

[0203] In one embodiment, the enzyme-linked immunosorbent assay (ELISA) is the TREM-1 Quantikine ELISA kit (reference DTRM10C, R&D Systems).

[0204] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 50 pg / mL to about 1000 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an electrochemiluminescence immunoassay (ECLIA) or an enzyme-linked fluorescence assay (ELFA).

[0205] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the reference population described above, is about 50, 75, 100, 125, 150, 175, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 520, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090 sTREM-1 levels, preferably blood, plasma or serum levels, of 0, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, 800, 820, 840, 860, 880, 900, 920, 940, 960, 980 or 1000 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ECLIA or ELFA.

[0206] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 300 pg / mL to about 800 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0207] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, when determined using ELISA, is about 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 450, 455, 450, 455, 460, 465, 470, 475, 480, 485, 490, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 5, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 58 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795 or 800 pg / mL, or the corresponding sTREM-1 level, preferably blood, plasma or serum level, when determined using another immunoassay such as ECLIA or ELFA.

[0208] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 350 pg / mL to about 600 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0209] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is about 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 745, 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 8 , 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 or 600 pg / mL sTREM-1 levels, preferably blood, plasma or serum levels, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ECLIA or ELFA.

[0210] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 400 pg / mL to about 500 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0211] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495 or 500 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0212] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 600 pg / mL when determined using an ELISA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0213] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, of about 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595 or 600 pg / mL when determined using an enzyme-linked immunosorbent assay (ELISA), or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ECLIA or ELFA.

[0214] According to one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, determined by electrochemiluminescence immunoassay (ECLIA).

[0215] As indicated above, an example of an electrochemiluminescence immunoassay (ECLIA) is Elecsys® (Roche Diagnostics).

[0216] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 20 pg / mL to about 6000 pg / mL when determined using an electrochemiluminescence immunoassay (ECLIA), or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an enzyme-linked immunosorbent assay (ELISA) or an enzyme-linked fluorescent assay (ELFA).

[0217] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, when determined using ECLIA, is about 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5100, 5200, 5300, 5400, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 1000, 1050, 11 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, ​​3000, 3050, 3100, 3150, 3200, 3250, 3300, 335 0, 3400, 3450, 3500, 3550, 3600, 3650, 3700, 3750, 3800, 3850, 3900, 3950, 4000, 4050, 4100, 4150, 4200, 4250, 4300, 4350, 4400, 4450, 4500, 4550, 4600, 4650, 4700, 4750, 4800, 4850, 4900, 4950, 5000, 5050, 5100, 5150, 5200, 5250, 5 sTREM-1 levels, preferably blood, plasma or serum levels, of 300, 5350, 5400, 5450, 5500, 5550, 5600, 5650, 5700, 5750, 5800, 5850, 5900, 5950 or 6000 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ELFA.

[0218] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 30 pg / mL to about 3000 pg / mL when determined using an ECLIA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ELISA or ELFA.

[0219] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from a reference population as described above, is about 30, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, sTREM-1 levels, preferably blood, plasma or serum levels, of 0, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950 or 3000 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ELFA.

[0220] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 1500 pg / mL, preferably about 800 pg / mL to about 1200 pg / mL when determined using an ECLIA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ELISA or ELFA.

[0221] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 600 pg / mL, about 600 pg / mL to about 700 pg / mL, about 700 pg / mL to about 800 pg / mL, about 800 pg / mL to about 900 pg / mL, or about 900 pg / mL to about 1000 pg / mL when determined using an ECLIA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ELISA or ELFA.

[0222] In one embodiment, the predetermined sTREM-1 value, preferably obtained from a reference population as described above, when determined using an ECLIA, is about 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, 800, 820, 840, 860, 880, 900, 920, 940, 960, 980, 1000, 1020, 1040, 1060, 1080, 1100, 1120, 1140, 1160, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 167 1400, 1420, 1440, 1460, 1480 or 1500 pg / mL sTREM-1 levels, preferably blood, plasma or serum levels, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ELFA.

[0223] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 1000 pg / mL to about 2000 pg / mL, preferably about 1200 pg / mL to about 1600 pg / mL when determined using an ECLIA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ELISA or ELFA.

[0224] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the reference population described above, when determined using an ECLIA, is between about 1000 pg / mL and about 1100 pg / mL, between about 1100 pg / mL and about 1200 pg / mL, between about 1200 pg / mL and about 1300 pg / mL, between about 1300 pg / mL and about 1400 pg / mL, between about 1400 pg / mL and about 1500 pg / mL, between about 1500 pg / mL and about 1600 pg / mL, between about 1 An sTREM-1 level, preferably a blood, plasma or serum level, in the range of 600 pg / mL to about 1700 pg / mL, about 1700 pg / mL to about 1800 pg / mL, about 1800 pg / mL to about 1900 pg / mL, or about 1900 pg / mL to about 2000 pg / mL, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as ELISA or ELFA.

[0225] In one embodiment, the predetermined sTREM-1 value, preferably obtained from the reference population described above, when determined using an ECLIA, is about 1000, 1020, 1040, 1060, 1080, 1100, 1120, 1140, 1160, 1180, 1200, 1220, 1240, 1260, 1280, 1300, 1320, 1340, 1360, 1380, 1400, 1420, 1440, 1460, 1480, 1500, 1520, 1540, 1560, 1580, 1600, 1620, 1640, 1660, 1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830, 1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070, 2080, 2090, 2100, 2110, 2120, 213 1600, 1620, 1640, 1660, 1680, 1700, 1720, 1740, 1760, 1780, 1800, 1820, 1840, 1860, 1880, 1900, 1920, 1940, 1960, 1980 or 2000 pg / mL, or the corresponding sTREM-1 level, preferably blood, plasma or serum level, when determined using another immunoassay such as ELISA or ELFA.

[0226] According to one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above-mentioned reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, determined by enzyme-linked fluorescence assay (ELFA).

[0227] As indicated above, examples of enzyme-linked fluorescence assays (ELFA) include VIDAS® (Biomerieux).

[0228] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 30 pg / mL to about 3000 pg / mL, preferably about 300 pg / mL to about 2000 pg / mL, when determined using an ELFA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay, such as an enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence immunoassay (ECLIA).

[0229] In one embodiment, the predetermined sTREM-1 value, preferably obtained from a reference population as described above, when determined using ELFA, is about 30, 50, 100, 150, 200, 250, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 70 0, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025, 1050, 1075, 1100, 1125, 1150, 1175, 1200, 1225, 1250, 1275, 1300, 1325, 1350, 1375, 1400, 1425, 1450, 1475, 1500, 1525, 1 550, 1575, 1600, 1625, 1650, 1675, 1700, 1725, 1750, 1775, 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 265 sTREM-1 levels, preferably blood, plasma or serum levels, of 0, 2700, 2750, 2800, 2850, 2900, 2950 or 3000 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ECLIA.

[0230] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 1500 pg / mL, preferably about 800 pg / mL to about 1200 pg / mL when determined using ELFA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as an ELISA or ECLIA.

[0231] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the reference population described above, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 500 pg / mL to about 600 pg / mL, about 600 pg / mL to about 700 pg / mL, about 700 pg / mL to about 800 pg / mL, about 800 pg / mL to about 900 pg / mL, or about 900 pg / mL to about 1000 pg / mL when determined using ELFA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as ELISA or ECLIA.

[0232] In one embodiment, a predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from a reference population as described above, when determined using an ELFA, is about 500, 520, 540, 560, 580, 600, 620, 640, 660, 680, 700, 720, 740, 760, 780, 800, 820, 840, 860, 880, 900, 920, 940, 960, 980, 1000, 1020, 1040, 1060, 1080, 1100, 1120, 1140, 1160, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1400, 1420, 1440, 1460, 1480 or 1500 pg / mL sTREM-1 levels, preferably blood, plasma or serum levels, of 160, 1180, 1200, 1220, 1240, 1260, 1280, 1300, 1320, 1340, 1360, 1380, 1400, 1420, 1440, 1460, 1480 or 1500 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ECLIA.

[0233] In one embodiment, the predetermined sTREM-1 value, preferably the predetermined sTREM-1 value obtained from the above reference population, is an sTREM-1 level, preferably a blood, plasma or serum level, in the range of about 1000 pg / mL to about 2000 pg / mL, preferably about 1200 pg / mL to about 1600 pg / mL when determined using ELFA, or a corresponding sTREM-1 level, preferably a blood, plasma or serum level, when determined using another immunoassay such as ELISA or ECLIA.

[0234] In one embodiment, the predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from the reference population described above, when determined using ELFA, is between about 1000 pg / mL and about 1100 pg / mL, between about 1100 pg / mL and about 1200 pg / mL, between about 1200 pg / mL and about 1300 pg / mL, between about 1300 pg / mL and about 1400 pg / mL, between about 1400 pg / mL and about 1500 pg / mL, between about 1500 pg / mL and about 1600 pg / mL, between about 1600 pg / mL and about 1700 pg / mL, between about 1700 pg / mL and about 1800 pg / mL, between about 1800 pg / mL and about 1900 pg / mL, between about 1900 pg / mL and about 2000 pg / mL, between about 2000 pg / mL and about 2100 pg / mL, between about 2100 pg / mL and about 2200 pg / mL, between about 2200 pg / mL and about 2300 pg / mL, between about 2300 pg / mL and about 2400 pg / mL, between about 2400 pg / mL and about 2500 pg / mL, between about 2500 pg / mL and about 2600 pg / mL, between about 2600 pg / mL and about 2700 pg / mL, between about 2700 pg / mL and about 2800 pg / mL, between about 2800 pg / mL and about 2900 pg / mL, between about 2900 pg / mL and about 3000 pg / mL, between about 3000 pg / mL The sTREM-1 level, preferably blood, plasma or serum levels, is in the range of about 100 pg / mL to about 1700 pg / mL, about 1700 pg / mL to about 1800 pg / mL, about 1800 pg / mL to about 1900 pg / mL, or about 1900 pg / mL to about 2000 pg / mL, or the corresponding sTREM-1 level, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ECLIA.

[0235] In one embodiment, a predetermined sTREM-1 value, preferably a predetermined sTREM-1 value obtained from a reference population as described above, when determined using ELFA, is about 1000, 1020, 1040, 1060, 1080, 1100, 1120, 1140, 1160, 1180, 1200, 1220, 1240, 1260, 1280, 1300, 1320, 1340, 1360, 1380, 1400, 1420, 1440, 1460, 1480, 1500, 1520, 1540, 1560, 1580, 1600, 1620, 1640, 1660, 1680, 1690, 1700, 1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830, 1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070, 2080, 2090, 3000, 3010, sTREM-1 levels, preferably blood, plasma or serum levels, of 0, 1620, 1640, 1660, 1680, 1700, 1720, 1740, 1760, 1780, 1800, 1820, 1840, 1860, 1880, 1900, 1920, 1940, 1960, 1980 or 2000 pg / mL, or the corresponding sTREM-1 levels, preferably blood, plasma or serum levels, when determined using another immunoassay such as ELISA or ECLIA.

[0236] Thus, in one embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value, preferably obtained from a reference population sTREM-1, wherein the predetermined sTREM-1 value is a blood sTREM-1 level in the range of about 350 pg / mL to about 600 pg / mL; c) identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having an sTREM-1 level measured in step a) higher than the predetermined sTREM-1 value of step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0237] In another embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value, preferably obtained from a reference population sTREM-1, wherein the predetermined sTREM-1 value is a blood sTREM-1 level in the range of about 300 pg / mL to about 800 pg / mL, preferably about 350 pg / mL to about 600 pg / mL, as determined using an enzyme-linked immunosorbent assay (ELISA), or a corresponding blood sTREM-1 level as determined using another immunoassay, such as an ECLIA or ELFA; c) identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having an sTREM-1 level measured in step a) higher than the predetermined sTREM-1 value of step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0238] In another embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value, preferably obtained from a reference population sTREM-1, wherein the predetermined sTREM-1 value is a blood sTREM-1 level in the range of about 20 pg / mL to about 6000 pg / mL, preferably about 30 pg / mL to about 3000 pg / mL, as determined using an electrochemiluminescence immunoassay (ECLIA), or a corresponding blood sTREM-1 level as determined using another immunoassay such as ELISA or ELFA; c) identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having an sTREM-1 level measured in step a) higher than the predetermined sTREM-1 value of step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0239] In another embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to therapy, in particular to the administration of a TREM-1 inhibitor, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with a predetermined sTREM-1 value, preferably obtained from a reference population sTREM-1, wherein the predetermined sTREM-1 value is a blood sTREM-1 level in the range of about 30 pg / mL to about 3000 pg / mL, preferably about 300 pg / mL to about 2000 pg / mL, as determined using an enzyme-linked fluorescent assay (ELFA), or a corresponding blood sTREM-1 level as determined using another immunoassay, such as an ELISA or ECLIA; c) identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having an sTREM-1 level measured in step a) higher than the predetermined sTREM-1 value of step b) as likely to respond to therapy, particularly administration of a TREM-1 inhibitor.

[0240] According to one embodiment, the therapy is an immunomodulatory or anti-inflammatory therapy.

[0241] Examples of immunomodulatory or anti-inflammatory therapies include, but are not limited to, checkpoint inhibitors such as anti-PD-1, anti-PD-L1 and anti-CTLA4, TLR (Toll-like receptor) inhibitors, cytokine inhibitors such as anti-cytokine or anti-cytokine receptors (e.g., IL-1RA, an interleukin-1 receptor antagonist), inhibitors of immunostimulants such as G-CSF (granulocyte colony-stimulating factor), GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-7 (interleukin-7), CD28 antagonist peptides and antibodies, particularly monoclonal antibodies against CD28, and cellular therapies such as adoptive cell therapy.

[0242] In one embodiment, the therapy is selected from the group consisting of a checkpoint inhibitor, a TLR (Toll-like receptor) inhibitor, a cytokine inhibitor such as an anti-cytokine or anti-cytokine receptor, G-CSF (granulocyte colony-stimulating factor), IL-7 (interleukin-7), an inhibitor of an immunostimulant, and a cell therapy. In other words, in one embodiment, the therapy comprises or consists of the administration of at least one of a checkpoint inhibitor, a TLR (Toll-like receptor) inhibitor, a cytokine inhibitor, G-CSF (granulocyte colony-stimulating factor), IL-7 (interleukin-7), GM-CSF (granulocyte-macrophage colony-stimulating factor), an inhibitor of an immunostimulant, or a cell therapy.

[0243] As used herein, checkpoint inhibitors (CPIs, also known as immune checkpoint inhibitors or ICIs) refer to compounds that block the interaction between inhibitory receptors expressed on T cells and their ligands.Checkpoint inhibitors include antibodies, particularly monoclonal antibodies, and non-antibody inhibitors such as small molecule inhibitors.

[0244] Examples of checkpoint inhibitors include, but are not limited to, inhibitors of the cell surface receptor PD-1 (programmed cell death protein 1), also known as CD279 (cluster of differentiation 279), inhibitors of the ligand PD-L1 (programmed death ligand 1), also known as CD274 (cluster of differentiation 274) or B7-H1 (B7 homolog 1), inhibitors of the cell surface receptor CTLA4 or CTLA-4 (cytotoxic T lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152), inhibitors of LAG-3 (lymphocyte activation gene 3), also known as CD223 (cluster of differentiation 223), inhibitors of HAVCR2 (hepatitis A virus inhibitors of TIGIT (T cell immunoreceptor with Ig and ITIM domains), also known as VSIG9 (V-set and immunoglobulin domain-containing protein 9) or VSTM3 (V-set and transmembrane domain-containing protein 3); inhibitors of BTLA (B and T lymphocyte attenuator), also known as CD272 (cluster of differentiation 272); and inhibitors of CEACAM-1 (carcinoembryonic antigen-related cell adhesion molecule 1), also known as CD66a (cluster of differentiation 66a).

[0245] As used herein, TLR inhibitors (sometimes referred to as TLR antagonists) refer to compounds that block TLR signal transduction. TLR inhibitors can act by blocking the binding of TLR ligands to receptors or by blocking intracellular signaling pathways to stop signal transduction (Gao et al., Front Physiol. 2017;8:508). TLR inhibitors include, but are not limited to, small molecule inhibitors, antibodies, particularly monoclonal antibodies, oligonucleotides, lipid A analogs, microRNAs, and nanoinhibitors.

[0246] As used herein, cytokine inhibitor refers to a compound that reduces the synthesis of cytokines, reduces their concentration in free active form, blocks their interaction with specific receptors, or interferes with the signal transduction of cytokine receptors.Cytokine inhibitors include, but are not limited to, antibodies, particularly monoclonal antibodies against cytokines (i.e., anti-cytokine antibodies), antibodies, particularly monoclonal antibodies against cytokine receptors (i.e., anti-cytokine receptor antibodies), cytokine receptor antagonists, and soluble receptors that act as decoy receptors.

[0247] According to one embodiment, the therapy is a therapy that seeks to inhibit or remove endotoxin, also referred to herein as anti-endotoxin therapy.

[0248] Examples of anti-endotoxin therapies include, but are not limited to, endotoxin inhibitors such as anti-endotoxin antibodies, particularly anti-endotoxin monoclonal antibodies, recombinant alkaline phosphatases such as human recombinant AP (recAP), and hemoperfusion, which allows for the removal of toxins by directly contacting the blood in the extracorporeal circulation with a material that adsorbs toxins, such as, for example, a polymyxin B-immobilized fiber cartridge (PMX-DHP).

[0249] According to one embodiment, the therapy is a vasopressor therapy, in other words, according to one embodiment, the therapy comprises or consists of the administration of a vasopressor.

[0250] Examples of vasopressor therapy include, but are not limited to, administering vasoactive catecholamine hormones such as norepinephrine, dopamine, epinephrine, vasopressin, and / or phenylephrine.

[0251] According to one embodiment, the therapy is an angiogenesis inhibitor, in particular an angiopoietin-2 (Ang-2 or Ang2) inhibitor. In other words, according to one embodiment, the therapy comprises or consists of the administration of an angiogenesis inhibitor, in particular an angiopoietin-2 (Ang-2 or Ang2) inhibitor.

[0252] The angiopoietin-Tie signaling pathway, particularly angiopoietin-1 (Ang-1) and Tie-2, is a vascular-specific receptor tyrosine kinase pathway essential for normal vascular development. Ang-2 was initially identified as an antagonist of Ang-1 and inhibited Ang-1-mediated activation of Tie-2. However, it remains unclear whether Ang-2 acts as an antagonist or agonist of Tie-2 in the context of vascular remodeling. Several studies have shown that Ang-2 plays a role in inflammation-induced vascular remodeling and tumor angiogenesis and growth (Thurston & Daly, Cold Spring Harb Perspect Med. 2012 Sept. 1;2(9):a006550).

[0253] As used herein, an Ang-2 inhibitor (sometimes referred to as an Ang-2 antagonist) refers to a compound that blocks Ang-2 signal transduction, particularly a compound that blocks the interaction between Ang-2 and Tie2. Thus, according to the present invention, an Ang-2 inhibitor includes an inhibitor that binds to Ang-2 and an inhibitor that binds to Tie2. Examples of Ang-2 inhibitors include, but are not limited to, antibodies against Ang-2, in particular monoclonal antibodies, Ang2-blocking antibodies, also called ABA (Han et al., Sci Transl Med. 2016 Apr 20;8(335):335ra55), Ang2-binding and Tie2-activating antibodies, also called ABTAA (Han et al., Sci Transl Med. 2016 Apr 20;8(335):335ra55), nanobodies against Ang-2, such as bispecific nanobodies that inhibit VEGF (vascular endothelial growth factor) and Ang-2, peptibodies against Ang-2 corresponding to a fusion of an inhibitory Ang-2-binding peptide with an IgFc domain, soluble decoy receptors, also called soluble ligand capture receptors, oligonucleotides such as antisense RNA, and aptamers, such as RNA aptamers that specifically block Ang-2.

[0254] According to one embodiment, the therapy is adrenomedullin (ADM) and adrenomedullin-targeted therapy.

[0255] Examples of adrenomedullin and adrenomedullin-targeted therapies include, but are not limited to, adrenomedullin (ADM), e.g., a bolus of ADM or continuous infusion of ADM, antibodies that recognize ADM (anti-AMD antibodies), e.g., antibodies that recognize biologically active ADM (anti-bio-ADM antibodies), particularly monoclonal antibodies such as non-neutralizing antibodies such as adrecizumab.

[0256] According to one embodiment, the therapy is a TREM-1 inhibitor, in other words, according to one embodiment, the therapy comprises or consists of the administration of a TREM-1 inhibitor.

[0257] According to the present invention, a TREM-1 inhibitor is an active agent capable of inhibiting the function, activity or expression of TREM-1.

[0258] In one embodiment, the TREM-1 inhibitor is selected from the group consisting of peptides that inhibit the function, activity or expression of TREM-1, antibodies directed against TREM-1 and / or sTREM-1, or TREM-1 and / or sTREM-1 ligands, small molecules that inhibit the function, activity or expression of TREM-1, siRNAs directed against TREM-1, shRNAs directed against TREM-1, antisense oligonucleotides directed against TREM-1, ribozymes directed against TREM-1 and aptamers directed against TREM-1.

[0259] Thus, in one embodiment, the present invention relates to an in vitro method for identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, that is susceptible to the administration of a TREM-1 inhibitor as defined above, said method comprising: a) measuring the level of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in a biological sample from a human subject; b) comparing the level of sTREM-1 measured in step a) with the predetermined sTREM-1 value described above; c) identifying a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, having an sTREM-1 level measured in step a) higher than the predetermined sTREM-1 value in step b) as being susceptible to administration of said TREM-1 inhibitor.

[0260] Examples of peptides that inhibit TREM-1 function, activity or expression include, but are not limited to, peptides that target TREM-1 ligands, such as, for example, TLT-1 peptides.

[0261] In one embodiment, the TREM-1 inhibitor is a peptide that inhibits TREM-1 through its binding to a TREM-1 ligand.

[0262] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide.

[0263]

[0023] In one embodiment, the TREM-1 inhibitor is the compound of SEQ ID NO: 7 (MGLTLLLLLLLGLEGQGIVGSLPEVLQAPVGSSILVQCHYRLQDVKAQKVWCRFLPEGCQPLVSSAVDRRAPAGRRTFLTDLGGGLLQVEMVTLQEEDAGEYGCMVDGARGPQILHRVSLNILPPEEEEETHKIGSLAENAFSDPAGSANPLEPSQDEKSIPLIWGAVLLVGLLVAAVVLFAVMAKRKQGNRLGVCGRFLSS RVSGMNPSSVVHHVSDSGPAAELPLDVPHIRLDSPPSFDNTTYTSLPLDSPSGKPSLPAPSSLPPLPPKVLVCSKPVTYATVIFPGGNKGGGTSCGPAQNPPNNQTPSS), or a sequence having at least 60, 65, 70, 75, 80, 85, or 90% identity to the amino acid sequence set forth in SEQ ID NO:7.

[0264] In one embodiment, the TREM-1 inhibitor is a short TLT-1 peptide consisting of 6 to 20 consecutive amino acids derived from human TLT-1 having the amino acid sequence set forth in SEQ ID NO: 7 or a function-conservative variant or derivative thereof.

[0265] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide consisting of 6 to 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids and comprising the amino acid sequence of SEQ ID NO: 8 (LQEEDAGEYGCMVDGAR), also referred to as LR17, the amino acid sequence of SEQ ID NO: 9 (LQEEDAGEYGCM), also referred to as LR12, the amino acid sequence of SEQ ID NO: 10 (LQEEDA), also referred to as LR6-1, the amino acid sequence of SEQ ID NO: 11 (EDAGEY), or the amino acid sequence of SEQ ID NO: 12 (GEYGCM), also referred to as LR6-2, or the amino acid sequence of SEQ ID NO: 12, respectively, or a sequence having at least 60, 65, 70, 75, 80, 85, or 90% identity to the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, respectively.

[0266] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide consisting of 6 to 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids and comprising the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, or a function-conservative variant or derivative thereof.

[0267] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, or a sequence having at least 60, 65, 70, 75, 80, 85, or 90% identity to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, respectively.

[0268] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, or a function-conservative variant or derivative thereof.

[0269] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide having an amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, or a sequence having at least 60, 65, 70, 75, 80, 85, or 90% identity to the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, respectively.

[0270] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide having the amino acid sequence set forth in SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, or SEQ ID NO:12, or a function-conservative variant or derivative thereof.

[0271] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide having the amino acid sequence set forth in SEQ ID NO:9 (also known as LR12 or nangibotide or motrem), or a sequence having at least 60, 65, 70, 75, 80, 85, or 90% identity to the amino acid sequence set forth in SEQ ID NO:9.

[0272] In one embodiment, the TREM-1 inhibitor is a TLT-1 peptide having the amino acid sequence set forth in SEQ ID NO: 9, also known as LR12 or nangibotide or motrem, or a function-conservative variant or derivative thereof.

[0273] As used herein, the term "function-conservative variant" refers to a peptide derived from the TLT-1 peptide as described above, in which a given amino acid residue in the peptide has been altered without changing the overall conformation and function of the TLT-1 peptide, including, but not limited to, substitution of an amino acid with one having similar properties (e.g., a similar polarity substituted with another acidic or basic amino acid, an acidic or basic amino acid of similar hydrogen-bonding ability, a hydrophobic amino acid substituted with another hydrophobic amino acid, an aromatic amino acid substituted with another aromatic amino acid).

[0274] Because amino acids other than those shown to be conserved may differ within a protein, the percentage of protein or amino acid sequence similarity between any two proteins with similar functions may vary, and it is generally known that, for example, similarity may be 70% to 99% when determined according to an alignment method such as the cluster method based on the MEGALIGN algorithm.

[0275] "Function-conservative variants" also include TLT-1 peptides that share at least 20%, 30%, 40%, 50%, or 60% amino acid identity with a TLT-1 peptide, as defined above, and have the same or substantially similar properties or functions as the TLT-1 peptides described above, as determined, for example, by BLAST or FASTA algorithms. Preferably, "function-conservative variants" include TLT-1 peptides that share at least 60%, 65%, 70%, 75%, 80%, 85%, or 90% amino acid identity with a TLT-1 peptide, as defined above, and have the same or substantially similar properties or functions as the TLT-1 peptides described above.

[0276] As used herein, the term "derivative" refers to a variation of a peptide or its function-conservative variants, or otherwise modified to change the conformation, activity, specificity, efficacy, or stability of the peptide in vitro or in vivo. For example, variations can include modification by the covalent attachment of any type of molecule to the peptide or by the addition of a compound(s) to any amino acid of the peptide.

[0277] In one embodiment, the TLT-1 peptide or function-conservative variant or derivative thereof as described above may have the D or L configuration.

[0278] In one embodiment, the amino acid from the amino terminus of the above TLT-1 peptides or function-conservative variants or derivatives thereof has an acetylated terminal amino group and the amino acid from the carboxyl terminus has an amidated terminal carboxy group.

[0279] Furthermore, the above-mentioned TLT-1 peptides or their function-conserving variants or derivatives can be subjected to reversible chemical modifications to enhance their bioavailability (e.g., stability and lipid solubility) and their ability to cross the blood-brain barrier and epithelial tissues. Examples of such reversible chemical modifications include esterification of the carboxyl groups of the amino acids glutamic acid and aspartic acid with alcohols, thereby removing the negative charge of the amino acid and increasing its hydrophobicity. This esterification is reversible because the formed ester bond is recognized by intracellular esterases, which hydrolyze the bond and restore the charge to the aspartic acid and glutamic acid residues. The net effect is intracellular accumulation of the peptide, as internalized, de-esterified peptides cannot cross the cell membrane.

[0280] Another example of such a reversible chemical modification is the addition of additional peptide sequences, which can increase membrane permeability, such as the TAT peptide or the penetratin peptide (see Charge-Dependent Translocation of the Trojan. A Molecular View on the Interaction of the Trojan Peptide Penetratin with the 15 Polar Interface of Lipid Bilayers. Biophysical Journal, Vol. 87, Issue 1, July 1, 2004, pp. 332-343).

[0281] The above TLT-1 peptides or their function-conservative variants or derivatives can be obtained by conventional methods of solid-phase chemical peptide synthesis according to Fmoc and / or Boc-based methodologies (see Pennington, M.W. and Dunn, B.N. (1994) Peptide synthesis protocols. Humana Press, Totowa.).

[0282] Alternatively, the above-mentioned TLT-1 peptide or its function-conserving variant or derivative can be obtained by conventional methods based on recombinant DNA technology, for example, in brief, the method comprises inserting the nucleic acid sequence encoding the peptide into a suitable plasmid or vector, transforming competent cells with the plasmid or vector, and growing the cells under conditions that allow the expression of the peptide, and, if desired, isolating and (optionally) purifying the peptide or the eukaryotic cells that express the peptide by conventional means known to those skilled in these matters.A review of the principles of recombinant DNA technology can be found, for example, in the textbook entitled "Principles of Gene Manipulation: An Introduction to Genetic Engineering" (R.W. Old & S.B. Primrose, Blackwell Scientific Publications, 4th edition (1989)).

[0283] According to one embodiment, the TREM-1 inhibitor is a TLT-1 peptide as described above, in particular a TLT-1 peptide having the amino acid sequence set forth in SEQ ID NO:9, or a sequence having at least 60, 65, 70, 75, 80, 85 or 90% identity to the amino acid sequence set forth in SEQ ID NO:9, also known as LR12 or nangibotide or motrem, wherein the TLT-1 peptide is administered to a human subject by continuous infusion, preferably by continuous intravenous infusion, at a dose ranging from about 0.1 mg / kg body weight per hour (mg / kg / h) to about 2.5 mg / kg / h, preferably from about 0.3 mg / kg / h to about 1 mg / kg / h, and even more preferably from about 0.3 mg / kg / h to about 0.9 mg / kg / h. In one embodiment, the TLT-1 peptide is administered to a human subject by continuous infusion, preferably by continuous intravenous infusion, at a dose ranging from about 0.15 g / 24 hours to about 4.5 g / 24 hours, preferably from about 0.5 g / 24 hours to about 2 g / 24 hours, and even more preferably from about 0.5 g / 24 hours to about 1.5 g / 24 hours.

[0284] In one embodiment, TLT-1 peptide is administered to a human subject by continuous infusion, preferably by continuous intravenous infusion, at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg / kg / h, preferably at a dose of about 0.3 mg / kg / h. In one embodiment, TLT-1 peptide is administered to a human subject by continuous infusion, preferably by continuous intravenous infusion, at a dose of about 0.3 mg / kg / h or about 1 mg / kg / h. In one embodiment, TLT-1 peptide is administered to a human subject by continuous infusion, preferably by continuous intravenous infusion, at a dose of about 0.15, 0.30, 0.45, 0.60, 0.75, 0.90, 1.05, 1.2, 1.35, 1.5, 1.65, 1.8, or 2 g / 24 hours.

[0285] In one embodiment, the TLT-1 peptide is administered to a human subject for at least 24 hours and / or up to 5 days. In one embodiment, the TLT-1 peptide is administered to a human subject for 24 hours, 48 ​​hours, 72 hours, 96 hours, or 120 hours. Thus, in one embodiment, the TLT-1 peptide is administered to a human subject for 1 day, 2 days, 3 days, 4 days, or 5 days.

[0286] In one embodiment, a loading dose of TLT-1 peptide is administered prior to the continuous administration of the TLT-1 peptide. In one embodiment, the loading dose of TLT-1 peptide is in the range of about 0.5 mg / kg to about 5 mg / kg. In one embodiment, the loading dose of TLT-1 is about 0.5, 0.75, 1, 1.25, 1.5, 1.665, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 mg / kg, preferably about 1.665 mg / kg or 5 mg / kg. In one embodiment, the loading dose of TLT-1 peptide is administered over about 15 minutes, preferably by intravenous infusion. Thus, in one embodiment, the loading dose of TLT-1 peptide is in the range of about 2 mg / kg / h to about 20 mg / kg / h. In one embodiment, the loading dose of TLT-1 peptide is at a dose of about 2, 3, 4, 5, 6, 6.66, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / kg / h, preferably 6.66 or 20 mg / kg / h.

[0287] According to one embodiment, such therapy is to be administered within the first 2 to 24 hours after initiation of patient care, particularly after initiation of vasopressor therapy.

[0288] In one embodiment, the above therapy is to be administered within the first 2, 3, 6, 9, 12, 15, 18, 21 or 24 hours after initiation of patient care, particularly after initiation of vasopressor therapy.

[0289] In one embodiment, the subject is a human patient who is awaiting or undergoing medical treatment, or has been / is / will be the subject of medical treatment, or is being monitored for the development or progression of an inflammatory disorder, preferably a disease such as SIRS, sepsis or septic shock.

[0290] In one embodiment, the subject is a human patient hospitalized with septic shock.

[0291] In one embodiment, the subject has a documented or suspected infection.

[0292] In one embodiment, the subject has a community-acquired infection. In one embodiment, the subject has a hospital-acquired infection.

[0293] Examples of infections include, but are not limited to, respiratory infections, abdominal infections, and urinary tract infections (UTIs), meningitis, endocarditis, skin infections, bone infections, wound infections, catheter-associated bloodstream infections, and device-associated infections.

[0294] In one embodiment, the subject is male. In another embodiment, the subject is female. In one embodiment, the subject is a pregnant woman.

[0295] In one embodiment, the subject is an adult. In one embodiment, the subject is an elderly person. In one embodiment, the subject is a child. In one embodiment, the subject is an infant. In one embodiment, the subject is a newborn.

[0296] In one embodiment, the subject is not immunocompromised, immunosuppressed, or immunodeficient. In another embodiment, the subject is immunocompromised, immunosuppressed, or immunodeficient. In another embodiment, the subject is undergoing immunosuppressive therapy.

[0297] In one embodiment, the subject suffers from a chronic medical condition such as atrial fibrillation, cancer, chronic kidney disease, chronic lung disease, cirrhosis, coronary artery disease, deep vein thrombosis, diabetes, dyslipidemia, endocarditis, hypertension, influenza, malaria, or any other protozoan parasitic disease, myocardial infarction, neurological disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), peripheral arterial disease, pulmonary fibrosis, severe obesity, and stroke.

[0298] According to one embodiment, the inflammatory disorder comprises or is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, sepsis-associated organ dysfunction, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), acute kidney injury (AKI), pancreatitis, inflammatory bowel disease, pneumonia, endotoxemia, and hemorrhagic shock.

[0299] According to one embodiment, the inflammatory disorder is an acute inflammatory disorder.

[0300] Examples of acute inflammatory disorders include, but are not limited to, systemic inflammatory response syndrome (SIRS), sepsis, septic shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), pancreatitis, and hemorrhagic shock.

[0301] In one embodiment, the acute inflammatory disorder comprises or is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), pancreatitis, and hemorrhagic shock.

[0302] According to one embodiment, the inflammatory disorder comprises or is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, septic shock, acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI).

[0303] In one embodiment, the inflammatory disorder is systemic inflammatory response syndrome (SIRS), sepsis, or septic shock.

[0304] In one embodiment, the inflammatory disorder is septic shock.

[0305] Systemic inflammatory response syndrome (SIRS) is characterized by systemic inflammation and widespread tissue damage. Clinically, SIRS is defined as meeting at least two of the following four criteria: fever >38.0°C or hypothermia <36.0°C, tachycardia >90 beats / min, tachypnea >20 breaths / min, and leukocytosis >12x10 9 / L or leukopenia <4x10 9 / L (Bone et al., Chest. 1992 June;101(6):1644-55). SIRS can occur as a response to nonspecific insults of either infectious or non-infectious origin. Examples of insults of non-infectious origin include, but are not limited to, trauma, burns, pancreatitis, autoimmune diseases, and surgery. Examples of insults of infectious origin include bacterial infections (e.g., respiratory infections, abdominal infections, and urinary tract infections (UTIs)), fungal infections (e.g., respiratory infections), and viral infections (e.g., respiratory infections).

[0306] As described above, sepsis is defined as life-threatening organ dysfunction caused by a dysregulated response of a human subject to infection (Singer et al., JAMA. 2016 Feb. 23; 315(8):801-10). A patient with sepsis can be clinically identified as a patient suffering from documented or suspected infection and organ dysfunction. In one embodiment, organ dysfunction in a human subject can be identified using an organ dysfunction score, i.e., a score used to assess organ dysfunction in human subjects, particularly upon admission to an ICU or emergency room. Examples of organ dysfunction scores include, but are not limited to, the SOFA score, qSOFA score, MODS (Multiple Organ Failure Score), P-MODS (Pediatric Multiple Organ Failure Score), and LODS (Logistic Organ Failure System). In one embodiment, organ dysfunction in a human subject can be identified as an acute change in the total SOFA score of 2 or more points as a result of infection (Singer et al., JAMA. 2016 Feb. 23; 315(8):801-10). The baseline SOFA score can be considered to be zero in patients who are not known to have pre-existing organ dysfunction (Singer et al., JAMA. 2016 Feb 23;315(8):801-10).

[0307] Septic shock is defined as a subset of sepsis, where severe cardiovascular, cellular, and metabolic abnormalities are associated with a higher mortality risk than sepsis alone. Therefore, sepsis encompasses septic shock. Patients with septic shock can be clinically identified as those with sepsis who (i) have persistent hypotension requiring vasopressors to maintain mean arterial pressure above 65 mmHg despite adequate volume resuscitation, and (ii) have serum lactate levels above 2 mmol / L (18 mg / dL) (Sepsis-3 definition as described in Singer et al., JAMA. 2016 Feb 23;315(8):801-10). These criteria result in hospital mortality rates exceeding 40% (Singer et al., JAMA. 2016 Feb 23;315(8):801-10).

[0308] In one embodiment, the infection that induces a dysregulated response in a human subject suffering from SIRS, sepsis or septic shock is a bacterial infection, a fungal infection, or a viral infection.

[0309] Examples of infections include, but are not limited to, respiratory infections, abdominal infections, and urinary tract infections (UTIs).

[0310] According to one embodiment, human subjects suffering from SIRS, sepsis or septic shock can be evaluated using a severity score, i.e., a score used to evaluate the severity and / or prognosis of illness at the time of admission to ICU or emergency room. Examples of severity scores include, but are not limited to, APACHE II score, APACHE III score, APACHE IV score, SAPS score, SAPS II score and SAPS 3 score.

[0311] In one embodiment, a human subject suffering from SIRS, sepsis, or septic shock can be evaluated using the APACHE II (see "Acute Physiology and Chronic Health Evaluation II") scoring system. APACHE II is commonly used to assess the severity of illness and determine prognosis in adult patients admitted to intensive care units. APACHE II provides a general measure of illness severity using a point score ranging from 0 to 71 based on an initial set of 12 routine physiological measurements, age, and previous health status (Knaus et al., Crit Care Med. 1985 Oct;13(10):818-29). The APACHE II score can be determined within the first 24 hours of admission to the intensive care unit (ICU) or emergency room. Higher scores are associated with higher predicted mortality, with a score of 25 representing a 50% predicted mortality rate and a score above 35 representing an 80% predicted mortality rate.

[0312] In one embodiment, the human subject suffering from SIRS, sepsis or septic shock has an APACHE II score of less than 34. In one embodiment, the human subject suffering from SIRS, sepsis or septic shock is not moribund.

[0313] In one embodiment, a human subject suffering from SIRS, sepsis, or septic shock can be evaluated using the APACHE III (see Acute Physiology and Chronic Health Evaluation III) scoring system. APACHE III is redefined from the APACHE II scoring system to more accurately predict the risk of hospital mortality in critically ill hospitalized adults (Knaus et al., Chest. 1991 December;100(6):1619-36).

[0314] In one embodiment, human subjects suffering from SIRS, sepsis, or septic shock can be evaluated using the APACHEIV (see "Acute Physiology and Chronic Health Evaluation IV") scoring system. APACHEIV is an improved and updated model for estimating the risk of short-term mortality and predicting the length of intensive care unit (ICU) stay (Zimmerman et al., Crit Care Med. 2006 May;34(5):1297-310). The APACHEIV scoring system takes into account more variables, particularly the effects of mechanical ventilation, thrombolysis, and sedation on the Glasgow Coma Scale, rescaled Glasgow Coma Scale, PaO2 / FiO2 ratio, and disease-specific subgroups. APACHEIV uses a point score ranging from 0 to 286.

[0315] In one embodiment, a human subject suffering from SIRS, sepsis, or septic shock can be evaluated using the SAPSII (see "Simplified Acute Physiological Score II") scoring system. The SAPSII is a scoring system for estimating in-hospital mortality in adult patients admitted to an intensive care unit (ICU). The SAPSII includes 17 variables: 12 physiological variables, age, type of admission, and three variables related to underlying disease (Le Gall et al., JAMA. 1993 Dec. 22-29;270(24):2957-63). The SAPSII uses a point score ranging from 0 to 163.

[0316] In one embodiment, a human subject suffering from SIRS, sepsis, or septic shock can be evaluated using the SAPS3 (see "Simplified Acute Physiology Score III") scoring system. SAPS3 is a scoring system for predicting hospital mortality in patients admitted to the intensive care unit (ICU) (Metnitz et al., Intensive Care Med. 2005 Oct;31(10):1336-1344 and Moreno et al., Intensive Care Med. 2005 Oct;31(10):1345-55). SAPS3 is based on 20 different variables.

[0317] As described above, the presence of organ dysfunction associated with sepsis or septic shock can be assessed using organ dysfunction scores such as the SOFA score, qSOFA score, MODS (Multiple Organ Failure Score), P-MODS (Pediatric Multiple Organ Failure Score), or LODS (Logistic Organ Failure System).

[0318] The Sequential Organ Failure Assessment (SOFA) score (originally called the Sepsis-Associated Organ Failure Assessment, Vincent et al., Intensive Care Med. 1996 July;22(7):707-10) is a commonly used scoring system for assessing organ dysfunction in human subjects, particularly upon admission to the ICU or emergency room. The SOFA scoring system (Vincent et al., Crit Care Med. 1998 November;26(11):1793-800) relies on assessment of the respiratory system (i.e., PaO2 / FiO2 (mmHg)), nervous system (i.e., Glasgow Coma Scale), cardiovascular system (i.e., mean arterial pressure or required vasopressor administration), liver function (i.e., bilirubin (mg / dL or μmol / L)), coagulation (i.e., platelet count), and renal function (i.e., creatinine (mg / dL or μmol / L) or urine output (mL / d)).

[0319] The baseline SOFA score can be considered zero in patients without known pre-existing (acute or chronic) organ dysfunction before the onset of infection. A SOFA score of at least 2 points reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection (Singer et al., JAMA. 2016 Feb 23;315(8):801-10).

[0320] In one embodiment, the human subject is suffering from SIRS, sepsis or septic shock associated with a SOFA score of at least 2 points.

[0321] In one embodiment, the human subject is suffering from SIRS, sepsis or septic shock associated with organ dysfunction defined as an acute change in SOFA score of at least 2 points.

[0322] The presence of organ dysfunction associated with sepsis or septic shock can also be assessed using the Quick SOFA Score (also known as quickSOFA or qSOFA). The qSOFA scoring system relies on three criteria: respiratory rate ≥ 22 breaths / min, impaired consciousness (Glasgow Coma Scale < 15), and systolic blood pressure ≥ 100 mmHg (Seymour et al., JAMA. 2016 Feb 23;315(8):762-74).

[0323] In one embodiment, the human subject is suffering from SIRS, sepsis or septic shock associated with a qSOFA score of at least 2 points.

[0324] In one embodiment, the human subject is suffering from SIRS, sepsis or septic shock associated with organ dysfunction defined as an acute change in qSOFA score of at least 2 points.

[0325] According to one embodiment, the human subject is suffering from septic shock.

[0326] According to one embodiment, the human subject is suffering from SIRS, sepsis or septic shock, preferably septic shock, and is receiving standard treatment. Standard treatment, particularly standard treatment for septic shock, may include, but is not limited to, fluid therapy, the above-mentioned vasopressor therapy, cardiovascular support, respiratory support (such as mechanical ventilation), renal support, and / or sedation. Thus, in one embodiment, the human subject is suffering from SIRS, sepsis or septic shock, preferably septic shock, and is receiving fluid therapy, the above-mentioned vasopressor therapy, cardiovascular support, respiratory support (such as mechanical ventilation), renal support, and / or sedation.

[0327] According to the present invention, a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, identified by the above methods is likely to respond to therapy, particularly the administration of a TREM-1 inhibitor, as described above.

[0328] According to one embodiment, the aim of the above method is to identify a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, which human subject is a "responder", i.e. will respond or likely to respond to such a treatment, in particular the administration of a TREM-1 inhibitor.

[0329] Conversely, in the present invention, a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, who is a "non-responder" is a human subject who does not respond or is poorly responsive to therapy, in particular to the administration of a TREM-1 inhibitor as described above.

[0330] According to one embodiment, for a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, the response to a therapy as described above, in particular to the administration of a TREM-1 inhibitor, is characterized by at least one of the following occurring after administration of the TREM-1 inhibitor: - reversal of hypotensive shock, preferably during or after the administration period of therapy (preferably a TREM-1 inhibitor), e.g., for 6 hours, 12 hours, 18 hours or 24 hours after the end of administration, where reversal of shock is defined as the absence of any vasopressor therapy during the 24-hour period (i.e., no need to restart vasopressor therapy within 24 hours of the end of vasopressor therapy), - A reduction in a severity score (such as an APACHE II score, an APACHE III score, an APACHE IV score, an SAPS score, an SAPS II score, or an SAPS 3 score) used to assess the severity and / or prognosis of a human subject suffering from an inflammatory disorder, preferably SIRS, sepsis, or septic shock, upon admission to an ICU or emergency room, - A decrease in organ dysfunction score (such as SOFA score, qSOFA score, MODS (Multiple Organ Dysfunction Score), P-MODS (Pediatric Multiple Organ Dysfunction Score), or LODS (Logistic Organ Dysfunction System)) used to assess the presence of organ dysfunction in human subjects suffering from an inflammatory disorder, preferably SIRS, sepsis or septic shock, upon admission to an ICU or emergency room, - a decrease in the SOFA score and / or qSOFA score, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after initiation of administration of the therapy (preferably a TREM-1 inhibitor), and in one embodiment the decrease in the SOFA score is a decrease of at least 1 point (also referred to as delta-1 point or ΔSOFA-1 point), preferably at least 1.5 points, preferably with reference to the SOFA score and / or qSOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of the therapy, in particular on the 3rd or 5th day after initiation of administration of the therapy, - a reduction in the need for cardiovascular support, e.g., a reduction in the use of vasopressor therapy over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to the need for cardiovascular support upon admission to the ICU or emergency room or before initiation of therapy, - a reduction in the need for respiratory support, e.g. a reduction in the use of invasive mechanical ventilation (IMV), preferably with reference to the need for respiratory support at the time of admission to the ICU or emergency room or before the start of the administration of the therapy, in particular over 1, 2, 3, 4, 5, 6 or 7 days after the start of the therapy, preferably the administration of a TREM-1 inhibitor, - a reduced need for renal support, e.g., a reduced use of continuous or non-continuous renal replacement therapy, also called RRT (such as dialysis), preferably over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), with reference to the need for renal support at the time of admission to the ICU or emergency room or before initiation of therapy, - a reduced risk of reinfection, in particular 28, 90 or 365 days after the initial inflammatory disorder, in particular the initial infection causing the inflammatory disorder, - absence of reinfection, especially 28, 90 or 365 days after the initial inflammatory disorder, especially the initial infection causing the inflammatory disorder; - A reduced risk of re-hospitalization, particularly a reduced risk of re-infection 28, 90 or 365 days after the initial inflammatory disorder, particularly the initial infection causing the inflammatory disorder; - No readmission, especially no readmission 28, 90 or 365 days after the initial admission; - an increased chance of survival, in particular surviving 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years after initiation of administration of a therapy (preferably a TREM-1 inhibitor), in one embodiment survival chance, particularly in subjects with multiple comorbidities, is assessed with the Charlson Comorbidity Index (CCI), preferably with reference to the CCI assessed at the time of admission to the ICU or emergency room or before initiation of administration of the therapy, and an increased chance of 10-year survival corresponds to a decrease in the Charlson Comorbidity Index, - a reduced risk of sepsis-related death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - A reduction in the risk of all-cause death, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - a reduced risk of post-septic or post-shock morbidity, particularly at days 5, 28, 90 or 365 after initiation of therapy (preferably a TREM-1 inhibitor); - Improved quality of life, particularly post-sepsis or post-shock quality of life, which can be assessed, for example, by assessing survival and quality-adjusted life years (QALYs) estimated from the EQ5D. For example, the EQ5D5L Health-Related Quality of Life (HRQoL) score can be calculated and converted to a utility score, particularly at 3, 6, 9, 12, 18, 24 or 36 months after the start of treatment. - a decrease in the levels of inflammatory markers such as CRP or IL6, IL-8, IL-10, MCP-1 and TNF-α, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to levels assessed upon admission to the ICU or emergency room or before initiation of therapy, or - A decrease in levels of markers of endothelial damage such as, for example, Ang-2, VCAM-1, VGEFR-1 and E-selectin, particularly over 1, 2, 3, 4, 5, 6 or 7 days after initiation of therapy (preferably a TREM-1 inhibitor), preferably with reference to levels assessed upon admission to the ICU or emergency room or before initiation of therapy.

[0331] In one embodiment, a human subject as described above suffering from SIRS, sepsis or septic shock, preferably septic shock, and susceptible to the administration of a therapy, in particular a TREM-1 inhibitor, i.e. a responder, is a human subject suffering from SIRS, sepsis or septic shock, preferably septic shock, and susceptible to reversal of hypotensive shock, preferably within the administration period of a therapy (in particular a TREM-1 inhibitor) or after an administration period of, for example, 6 hours, 12 hours, 18 hours or 24 hours after the end of administration, wherein hypotensive shock reversal is defined as the absence of any vasopressor therapy within 24 hours (i.e. no need to resume vasopressor therapy 24 hours after the end of vasopressor therapy).

[0332] Conversely, in one embodiment, a human subject suffering from SIRS, sepsis or septic shock, preferably septic shock, who is unlikely to respond to a therapy, in particular the administration of a TREM-1 inhibitor as described above, i.e. a non-responder, is a human subject suffering from SIRS, sepsis or septic shock, preferably septic shock, in which reversal of hypotensive shock does not occur, preferably within the administration period of a therapy (in particular a TREM-1 inhibitor) or after a period of, for example, 6, 12, 18 or 24 hours after the end of administration, where hypotensive shock reversal is defined as the absence of any vasopressor therapy during the 24 hour period, or a human subject suffering from SIRS, sepsis or septic shock, preferably septic shock, who needs to resume vasopressor therapy within 6, 12, 18 or 24 hours after discontinuation of a therapy (in particular a TREM-1 inhibitor).

[0333] In one embodiment, the responder is a human subject suffering from SIRS, sepsis or septic shock, who is susceptible to a decrease in Sequential Organ Failure Assessment (SOFA) score following administration of a TREM-1 inhibitor, as described above.

[0334] In one embodiment, the responder is a human subject suffering from SIRS, sepsis or septic shock who is susceptible to a decrease in Sequential Organ Failure Assessment (SOFA) score following administration of a TREM-1 inhibitor, as described above, with reference to the SOFA score assessed at the time of admission to the ICU or emergency room or prior to initiation of administration of therapy.

[0335] As used herein, the difference in SOFA score after administration of a TREM-1 inhibitor may also be referred to as the delta SOFA score or ΔSOFA score, particularly with reference to the SOFA score assessed at the time of admission to the ICU or emergency room or before the start of administration of therapy.

[0336] In one embodiment, the responder is a human subject suffering from SIRS, sepsis or septic shock, who is likely to experience a reduction in SOFA score of at least 1 point, preferably at least 1.5 points, after administration of a TREM-1 inhibitor as described above, particularly with reference to the SOFA score assessed at the time of admission to the ICU or emergency room or before initiation of administration of therapy.

[0337] Thus, in one embodiment, the responder is a human subject suffering from SIRS, sepsis or septic shock and who is likely to have a delta SOFA score (ΔSOFA score) of at least -1 point (minus one point), preferably at least -1.5 points (minus one and a half points) after administration of a TREM-1 inhibitor as described above.

[0338] In one embodiment, the reduction in SOFA score, particularly a reduction of at least 1 point, preferably at least 1.5 points, is assessed on day 1, day 2, day 3, day 4, day 5, day 6 or day 7 after initiation of administration of the therapy, preferably day 3 or day 5 after initiation of administration of the therapy.

[0339] Thus, in one embodiment, the delta SOFA score (ΔSOFA score) is the delta SOFA score assessed on day 1, day 2, day 3, day 4, day 5, day 6 or day 7 after initiation of administration of the therapy, preferably on day 3 or day 5 after initiation of administration of the therapy.

[0340] Applicants demonstrate herein that by measuring levels of soluble TREM-1 (sTREM-1) in biological samples from human subjects suffering from septic shock and comparing those measured sTREM-1 levels to predetermined sTREM-1 values, human subjects suffering from septic shock who are likely to respond to TREM-1 inhibitors can be identified. In particular, Applicants demonstrate that human subjects suffering from septic shock who have circulating levels of sTREM-1 higher than a predetermined median sTREM-1 level in a reference population of human subjects suffering from septic shock are likely to respond to, and therefore benefit from, administration of a TLT-1 peptide that inhibits TREM-1 activity.

[0341] Prompt patient care is essential for the prognosis of subjects suffering from SIRS, sepsis or septic shock.

[0342] Measurement of sTREM-1 level, particularly sTREM-1 protein level, can be carried out very quickly, particularly by point-of-care testing (POCT) or bedside testing, or central laboratory assay (testing near patients).Therefore, sTREM-1 level can be measured immediately after the onset of SIRS, sepsis, or septic shock, after the diagnosis of SIRS, sepsis, or septic shock in human subjects, after the hospitalization of human subjects for SIRS, sepsis, or septic shock, particularly after admission to ICU or emergency room, or after the start of vasopressor therapy.Therefore, results can be available within the first 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 15 hours, 18 hours, 21 hours, or 24 hours, and treatment plan can be determined immediately thereafter. [Brief explanation of the drawings]

[0343] [Figure 1]This figure shows that sTREM-1 release depends on TREM-1 dimerization. (Figure 1A) Graph showing TREM-1 expression by flow cytometry in U937 (gray) and U937-vitD cells (dark gray) compared to isotype control (light gray). (Figure 1B) Series of photographs showing TREM-1 expression and cell nuclei staining by confocal microscopy. White arrows indicate TREM-1 clustering and dimerization at the membrane of U937-vitD cells after incubation with LPS. (Figure 1C) Graph showing sTREM-1 concentration in the supernatant of U937 and U937-vitD cells in the resting state or after 30 min of incubation with APMA, Pro-MMP9, Act-MMP9, or LPS (100 ng / mL, as indicated). LOQ: limit of quantification. [Figure 2] Figure 2A shows a series of graphs demonstrating that baseline TREM-1 correlates with 28-day mortality. Figure 2B shows a receiver operating characteristic (ROC) plot (Figure 2A) and a Kaplan-Meier plot (Figure 2B) of 28-day mortality by quartile. Mortality (day 28) per quartile is 12%, 30%, 37%, and 49% for Q1 to Q4, respectively. Overall mortality is 32%. The optimal cutpoint was determined to be 408 pg / mL. [Figure 3] Series of boxplots of sTREM-1 at baseline (day 1) for (A) 28-day mortality and (B) 90-day mortality. Kruskal-Wallis test chi-squared is 28.8 and 29.5, respectively (both p<0.0001). [Figure 4] Series of boxplots of sTREM-1 at day 2 for (A) 28-day mortality and (B) 90-day mortality. Kruskal-Wallis test chi-squared is 30.2 and 30.8, respectively (both p<0.0001). [Figure 5] Series of boxplots of sTREM-1 at day 3 for (A) 28-day mortality and (B) 90-day mortality. Kruskal-Wallis chi-squared is 16.9 (p=0.0001) and 19.1 (p=0.0002). [Figure 6] Series of boxplots of sTREM-1 on renal replacement therapy (RRT) at admission (RRT adm) and during ICU stay (post-RRT) on (A) day 1 (B) day 2 (C) day 3. Kruskal-Wallis test chi-square is 54.7 (p<0.0001), 68.7 (p<0.0001), and 44 (p<0.0001), respectively. [Figure 7] 1 is a scheme showing the two stages of a Phase IIa clinical trial evaluating administration of nangibotide (also known as Motrem) to patients with septic shock (NCT03158948). [Figure 8] 1 is a scheme showing the randomization of patients in each treatment group. [Figure 9] 1 is a series of graphs showing the pharmacokinetics of nangibotide. (A) Nangibotide kinetics in each group (i.e., patients receiving 0.3 mg / kg / h, patients receiving 1.0 mg / kg / h, and patients receiving 3.0 mg / kg / h) from the start of the infusion (day 0) to the end of the infusion (day 5) and (B) Nangibotide kinetics in each group (i.e., patients receiving 0.3 mg / kg / h, patients receiving 1.0 mg / kg / h, and patients receiving 3.0 mg / kg / h) after the end of the infusion. Circles: 0.3 mg / kg / h; Squares: 1 mg / kg / h; Triangles: 3 mg / kg / h. [Figure 10] A series of graphs showing the change in SOFA assessment over time relative to baseline (LOCF) in (A) the overall population, (B) patients with low sTREM-1 at baseline (median <433 pg / mL), and (C) patients with high sTREM-1 at baseline (median ≥433 pg / mL). [Figure 11] 1 is a series of graphs showing organ support-free days in patients with high levels of sTREM-1 (median >433 pg / mL) at baseline: (A) days alive without vasopressors, (B) days alive without invasive mechanical ventilation (IMV), and (C) days alive without renal failure and continuous renal replacement therapy (CRRT). [Figure 12]1 is a series of graphs showing the change in Ang-2 concentration from baseline on days 3 (A) and 5 (B) in the "All" (corresponding to the entire population), the "G1" subgroup (corresponding to patients with low sTREM-1 at baseline, i.e., <433 pg / mL median), and the "G2" subgroup (corresponding to patients with high sTREM-1 at baseline, i.e., >433 pg / mL median). [Figure 13] 1 is a series of graphs showing the change in IL-6 concentrations from baseline on day 3 (A) and day 5 (B) in the "All" (corresponding to the entire population), the "G1" subgroup (corresponding to patients with low sTREM-1 at baseline, i.e., <433 pg / mL median), and the "G2" subgroup (corresponding to patients with high sTREM-1 at baseline, i.e., >433 pg / mL median). [Figure 14] (A) A series of graphs showing the association between the change in sTREM-1 at day 5 / EOI (end of infusion) from baseline in the all population in subgroup G1 (patients with sTREM-1 baseline below the median) and subgroup G2 (patients with sTREM-1 baseline above the median), (B) delta SOFA at day 5 (delta between day 5 / EOI and baseline).

[0344] Example The present invention is further illustrated by the following examples. Example 1: material and method Cell culture and stimulation

[0345] The human myelomonocytic cell line U937 (Culture Collections, Public Health England No. 85011440) was cultured in RPMI 1640 Glutamax supplemented with 10% fetal bovine serum, 25 mM Hepes, 100 U / ml penicillin, and streptomycin (all from Thermo Fisher Scientific, USA). For some experiments, U937 cells were cultured under the same conditions supplemented with 100 nM 1,25-dihydroxyvitamin D3 (Sigma-Aldrich, USA) to induce upregulation of TREM-1 (U937-vitD cells). For release experiments, pro-MMP-9 was activated by preincubation with 1 mM APMA at 37°C for 24 hours. 0.5 x 10 cells were cultured. 6 Cells were seeded at 1000 cells / mL and stimulated with E. coli 0127:B8 LPS (10 μg / mL; Sigma-Aldrich), Pro-MMP-9 (1 μg / mL; R&D Systems, Abingdon, UK), ρ-aminophenylmercuric acetate (APMA; 1 mM; Sigma-Aldrich), and APMA-activated MMP-9 (1 μg / mL) for 30 min at 37°C. Cell supernatants were collected, and sTREM-1 was measured using the Human TREM-1 Quantikine ELISA Kit (Biotechne, R&D Systems) according to the manufacturer's instructions. FACS analysis

[0346] TREM-1 expression was detected by FACS after staining with 5 μL allophycocyanin (APC)-conjugated mouse monoclonal anti-human TREM-1 or the corresponding isotype APC antibody (Miltenyi Biotec, Germany) for 30 min at 4°C in the dark. After washing twice with PBS, cells were resuspended and fixed with 4% paraformaldehyde. Analysis was performed using an Accuri C6 flow cytometer (Becton Dickinson, San Jose, CA, USA). Confocal microscope

[0347] 0.3x10 cells 6Cells were seeded at 1000 x g / well and stimulated with E. coli 0127:B8 LPS (1 μg / mL; Sigma-Aldrich) for 1 h in a LabTek chamber (Thermo Fisher Scientific). After stimulation, cells were washed, fixed with paraformaldehyde (4%) for 20 min, permeabilized with Triton 0.1% for 30 min, and then incubated with primary antibody (anti-hTREM-1-AF488; Bioss, USA) overnight at 4 °C. Nuclei were stained with TO-PRO-3 (1 μg / mL; Invitrogen, USA) for 1 h at 37 °C. After washing, coverslips were mounted using Vectashield (Vector Laboratories, USA) solution. Confocal images were acquired using a Leica SP5 confocal laser scanning microscope system (Leica, Germany) equipped with appropriate filter sets in sequential scanning mode. result sTREM-1 is a marker of TREM-1 activation.

[0348] We have previously demonstrated that TREM-1 dimerization is essential for activation in innate immune cells (Carrasco et al., Cell Mol Immunol. March 22, 2018). This is triggered by initial TLR engagement. Indeed, stimulation of human primary monocytes and neutrophils was able to induce membrane recruitment and clustering of TREM-1. Thus, we confirmed that the dimeric configuration of TREM-1 represents the active conformation of the receptor, capable of binding its endogenous ligand and inducing activation of downstream intracellular pathways. It has previously been demonstrated that metalloproteinases are responsible for the release of the TREM-1 ectodomain via proteolytic cleavage of its long juxtamembrane linker (Gomez-Pina et al., J Immunol. September 15, 2007;179(6):4065-73). Here, we show that this release requires TREM-1 dimerization, suggesting that sTREM-1 release is possible only when the receptor is in its active conformation. TREM-1 is expressed at very low levels in resting U937 cells and is upregulated when vitamin D is added to the culture medium (Figure 1A). To investigate whether the proteolytic cleavage of TREM-1 and subsequent sTREM-1 release are related to its active conformation, sTREM-1 in the supernatants of U937 and U937-vitD cells was measured after a 15-minute incubation with LPS and / or Act-MMP9. TREM-1 expression was diffuse at the membrane of resting U937-vitD cells, and LPS could induce TREM-1 clustering and dimerization at the membrane (Figure 1B, white arrow). sTREM-1 was not detectable in the supernatant of U937 cells after stimulation with LPS or after the addition of activated MMP9 (Act-MMP9). Incubation of U937-vitD cells with LPS or Act-MMP9 alone was not associated with sTREM-1 release. Interestingly, sTREM-1 was released by U937-vitD cells only when they were co-stimulated with LPS and Act-MMP9 (Fig. 1C).These results confirm that MMP9-induced proteolytic cleavage of TREM-1 is possible only when TREM-1 is in the dimeric state, the active conformation of the receptor, and therefore sTREM-1 may be a reliable biomarker of TREM-1 receptor activation. Example 2: material and method sTREM-1 Measurement: A Validated ELISA Method for the Quantitative Measurement of sTREM-1 in Human K2-EDTA Plasma

[0349] For routine assays, quantitative measurements of sTREM-1 were performed using a commercially available kit (Human TREM-1 Quantikine ELISA, BioTechne, R&D Systems) and quality control (QC) samples at three concentration levels: QC Low (101 pg / mL), QC Mid (532 pg / mL), and QC High (1080 pg / mL).

[0350] A pre-study assay qualification run was conducted to determine the in-run precision and accuracy of the assay. The pre-study assay qualification run consisted of calibration standards and QC samples at five concentration levels (LLOQ (41.3 pg / mL), low, medium, high, and ULOQ (1440 pg / mL)), with each QC sample processed in six plates for each assay. For each concentration level, no more than five of the six values ​​should be used in the final calculation of in-run precision and imprecision. In-run precision should be ≤20% (25% at LLOQ and ULOQ), and in-run imprecision should be within ±20% (25% at LLOQ and ULOQ). Pre-study assays should be validated three times before commencing routine assays.

[0351] Standard (STD) samples were prepared fresh each day using Calibrator Diluent RD5-18 and the kit's human TREM-1 standard. The STD samples were adjusted to obtain 10 calibration points (3000, 2000, 1000, 750, 500, 250, 125, 62.5, 31.3, and 15.6 pg / mL). The 3000 pg / mL and 15.6 pg / mL calibration standards were used as anchor points (the lowest calibration standard (LCS) and highest calibration standard (HCS) of the calibration curve).

[0352] 100 μL of Assay Diluent RD1-27 was added to each well. Next, 50 μL of standard, QC, or sample was added per well. The plate was incubated at 450 rpm on a microplate shaker at room temperature for 2 hours. After the 2-hour incubation, the plate was manually washed three times with wash buffer, and 200 μL of human TREM-1 conjugate was added to each well. The plate was then incubated at 450 rpm on a microplate shaker for an additional 2 hours at room temperature. After washing, 200 μL of substrate solution was added to each well. The plate was incubated in the dark at room temperature for 30 minutes. The optical density (OD) was read at 650 nm (pre-read), and when the OD (650 nm) of the HCS was approximately 1.0, 50 μL of stop solution was added to each well. The OD (450 nm) of each well was then measured within 30 minutes.

[0353] Calibration curves were obtained by plotting the optical density and concentration of the calibration standards using a logistic curve (4-PL) and a 1 / y2 weighting factor.

[0354] Calibration standards between 2000 and 31.3 pg / mL were excluded from the final calibration curve only if their back-calculated imprecision was outside the ±20% range (±25% for LCS and HCS), or if there was a documented problem during preparation or assay, or if the coefficient of variation (CV%) of the concentrations in replicates (n = 2 wells per calibration standard) exceeded 20%. No more than 30% of these calibration standards could be excluded from each series of calibration standards, and the final calibration curve must include at least six non-zero calibration concentration levels, including LCS and HCS. A blank (0.00 pg / mL) composed of Calibrator Diluent RD5-18 was not used in the calibration curve calculation.

[0355] Each routine run included six QC samples (n=2 replicates at three concentration levels). At least four of the six QC samples must be within the acceptance criteria (at least one value within the acceptance criteria for each concentration level). The acceptance criteria were defined as follows: The calculated individual imprecision of the replicate concentrations (n=2 wells per sample) must be within ±20% compared to the nominal value. The coefficient of variation (CV%) of the replicate concentrations must be ≤20%.

[0356] The coefficient of variation (CV%) of replicate concentrations of test samples (n=2 wells per test sample) must also be 20% or less. Evaluation of sTREM-1 in the AdrenOSS cohort (NCT02393781)

[0357] This study was an ancillary investigation of septic shock patients from the AdrenOSS study (NCT02393781), a European prospective, observational, multinational study conducted at 24 centers in five countries (France, Belgium, the Netherlands, Italy, and Germany). Patients were recruited from June 2015 to May 2016. The study protocol was approved by the local ethics committee and conducted in accordance with Directive 2001 / 20 / EC, Good Clinical Practices (ICH version 4 of May 1, 1996, and Decision of November 24, 2006), and the Declaration of Helsinki. Enrolled patients were aged 18 years or older and either (i) admitted to the ICU for sepsis or septic shock or (ii) transferred from another ICU for sepsis and septic shock less than 24 hours after primary admission. If patients were treated with vasopressors, they were considered eligible only if treatment was initiated within a maximum of 24 hours of primary admission before ICU admission. Once eligible, patients were stratified by severe sepsis and septic shock based on the definitions of sepsis and organ failure since 2001. Exclusion criteria included pregnancy, vegetative state coma, and participation in an interventional trial within the previous month. Informed consent was obtained from all patients or their legal representatives before enrollment in the study. Patients were treated according to current guidelines, and all treatments and procedures were registered. sTREM-1 was measured in blood samples collected at baseline (also called day 1 or d1), day 2 (d2), and day 3 (d3). Statistical analysis of the AdrenOSS cohort

[0358] Analysis was performed on 293 patients with septic shock. Demographic and baseline characteristics were summarized descriptively within each population, and categorical variables were summarized by contingency tables (frequency and proportions (percentages)). Continuous variables were summarized by mean, standard deviation, standard error, median, quartiles and range, minimum and maximum. Day 1 sTREM-1 levels (referred to separately as baseline or ICU admission) were also described (mean, standard deviation, standard error, median, quartiles and range, minimum and maximum) and separately within defined populations and subgroups. 28-day mortality was estimated within each quartile of the distribution of day 1 sTREM-1 levels. Time to death was analyzed using a proportional hazards Cox regression model. The area under the receiver operating characteristic curve (AUC) with 95% CI for predicting 28-day mortality from day 1 sTREM-1 levels was calculated. The optimal sTREM-1 cutoff was estimated based on i) minimizing the distance between the upper left corner point (0,1) of the receiver operating characteristic curve and any point on the ROC curve, and ii) the Youden index. Boxplots of sTREM-1 by survivor / non-survivor and RRT (renal replacement therapy) were plotted. Where appropriate, sTREM-1 data were log-transformed. The association of sTREM-1 levels with day 1 and 28-day mortality was assessed using univariate and multivariate logistic regression models adjusted for sTREM-1 at baseline (day 1) and other prognostic factors: age, sex, cardiac comorbidities, non-cardiac comorbidities, lactate (maximum or minimum on day 1), SOFA at day 1, APACHE II at day 1, and SAPS II at day 1. result sTREM-1 is a prognostic marker in patients with septic shock: results from the AdrenOSS cohort

[0359] The demographics and general baseline characteristics of patients in the overall population and in each sTREM-1 quartile are shown in Table 1. No significant differences were observed among the four sTREM-1 quartile groups (Q1, Q2, Q3, and Q4) for baseline characteristics, age, sex, body mass index (BMI), type of ICU admission, source of sepsis, medical history, and physiological values ​​at admission. The first quartile group, Q1, includes patients with sTREM-1 levels lower than the first quartile (299 pg / mL), i.e., patients with sTREM-1 levels between 42 and 299 pg / mL. The second quartile group, Q2, includes patients with sTREM-1 levels between the first quartile (299 pg / mL) and the second quartile (497 pg / mL), i.e., patients with sTREM-1 levels between 299 pg / mL and 497 pg / mL. The third quartile, Q3, included patients with sTREM-1 levels between the second (497 pg / mL) and third (809 pg / mL) quartiles, i.e., patients with sTREM-1 levels between 497 pg / mL and 809 pg / mL. The fourth quartile, Q4, included patients with sTREM-1 levels higher than the third quartile, i.e., patients with sTREM-1 levels between 809 pg / mL and 5540 pg / mL. At baseline, sTREM-1 levels were significantly correlated with lactate, arterial pH, creatinine, urea, and PCT levels. sTREM-1 levels were also correlated with renal replacement therapy (RRT), baseline SOFA, SAPS II, and APACHE II scores, and 28- and 90-day mortality. The 28-day mortality rates were 12.2%, 30.1%, 37%, and 49.3% in quartiles Q1, Q2, Q3, and Q4, respectively. Overall mortality was 32%. These results confirm that the level of TREM-1 pathway activation at ICU admission, assessed by measurement of plasma sTREM-1, is associated with a more complicated outcome in patients with septic shock. [Table 1] TIFF0007800938000002.tif230163TIFF0007800938000003.tif229162

[0360] Figure 2A shows the ROC plot. Figure 2B shows patient survival over time in the form of a Kaplan-Meier curve. Patients with the lowest sTREM-1 values ​​(Q1 quartile) had a higher 28-day survival rate than patients with the highest sTREM-1 values ​​(Q2-Q4 quartiles). Survival rates within sTREM-1 quartiles were 87.8%, 69.9%, 63%, and 50.7%, respectively, from Q1 to Q4. The optimal cutoff value for predicting mortality from the data presented in Table 2 below was calculated at 408 pg / mL. [Table 2] TIFF0007800938000005.tif80162

[0361] No interactions were observed between sTREM-1 levels and age, sex, lactate, cardiac comorbidities, non-cardiac comorbidities, SOFA, SOFA.4, APACHE2, or SAPS2 (all interactions p>0.1). sTREM-1 was an independent predictor of 28-day mortality, providing additional information to all covariates examined (all p<0.001).

[0362] Non-survivors at 28 and 90 days showed significantly elevated sTREM-1 levels at baseline compared with survivors at 28 and 90 days (Figure 3A-B). Interestingly, sTREM-1 levels on day 1 correlated with those on days 2 and 3 (Spearman's rank correlation r = 0.91 (CI: 0.88, 0.93; p < 0.001; n = 260), and Spearman's rank correlation r = 0.86 (CI: 0.81, 0.9); p < 0.001; n = 219)), and sTREM-1 levels on day 2 correlated with those on day 3 (Spearman's r = 0.96 (CI: 0.95, 0.97; p < 0.001; n = 213)). sTREM-1 levels on days 2 and 3 were found to remain elevated in non-survivors at 28 and 90 days compared with those of survivors at 28 and 90 days (Figures 4A-B and 5A-B). sTREM-1 levels on days 1, 2, and 3 were also associated with renal replacement therapy (RRT) at admission and throughout the stay (Figures 6A-C).

[0363] Of all the parameters examined, sTREM-1 was shown to correlate better with SOFA scores (Spearman's rank correlation r=0.42, p<0.001; n=254).

[0364] All these results tend to indicate that sTREM-1 levels are associated with severity, renal replacement therapy, and mortality, thus confirming that sTREM-1 levels can be used as a reliable biomarker to identify patients at risk for complicated outcomes. Example 3: material and method sTREM-1 Measurement: A Validated ELISA Method for the Quantitative Measurement of sTREM-1 in Human K2-EDTA Plasma

[0365] Quantitative measurement of sTREM-1 was carried out using the method described in Example 2. Evaluating sTREM-1 in a Phase IIa clinical trial of nangibotide in patients with septic shock (NCT03158948)

[0366] This was a European, prospective, observational, multinational study involving 14 centers in four countries (France, Belgium, the Netherlands, and Spain). Patients were recruited from July 2017 to June 2018. The study was conducted in accordance with the principles set forth in the Declaration of Helsinki and its subsequent amendments, the guidelines of the International Conference on Harmonisation on Good Clinical Practice (GCP), and the requirements of national drug and data protection laws, as well as other applicable regulatory requirements.

[0367] This was a randomized, double-blind, two-stage, placebo-controlled trial. As described in Figure 7, the study consisted of two stages with a similar treatment regimen: 0.3 mg / kg / h, 1.0 mg / kg / h, or 3.0 mg / kg / h of nangibotide (corresponding to the peptide LR12, having the amino acid sequence set forth in SEQ ID NO: 9, also known as Motrem) compared with placebo. All patients diagnosed with septic shock were considered for study participation. All potential study patients underwent standard care management procedures. Patients with evidence of septic shock according to the Sepsis-3 definition (Singer et al., JAMA 2016) (i.e., patients with sepsis and (i) persistent hypotension requiring vasopressors to maintain a mean arterial pressure ≥ 65 mmHg, and (ii) serum lactate levels above 2 mmol / L (18 mg / dL) despite adequate volume resuscitation) were considered eligible for inclusion.

[0368] Exclusion criteria were a previous episode of septic shock (vasopressor administration) during the current hospitalization, concurrent immunosuppression as an underlying disease, solid organ transplant requiring immunosuppressive therapy, known pregnancy, long QT syndrome (QTc ≥ 440 ms), shock due to any other cause, e.g., hypotension related to gastrointestinal bleeding, ongoing documented or suspected endocarditis, history of prosthetic heart valves, end-stage neurological disease, end-stage liver cirrhosis (Child-Pugh class C), Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥ 34, end-stage chronic kidney disease requiring chronic dialysis, home oxygen therapy regularly exceeding 6 hours / day, severe obesity (body mass index [BMI] ≥ 40), recent cardiopulmonary resuscitation (within the current hospitalization), moribund patients, and a decision to limit complete care taken before obtaining informed consent.

[0369] After screening for eligibility, patients were randomized to one of the treatment groups. Patients then received a loading dose of 5 mg / kg nangibotide over 15 minutes, followed by a continuous intravenous (iv) infusion of nangibotide or matching placebo in addition to standard of care. Treatment with the study drug was initiated as soon as possible, but no later than 24 hours after the onset of septic shock, defined by the initiation of vasopressor therapy. Patients were treated until 12 (± 2) hours after resolution of septic shock (defined as discontinuation of vasopressors), with a maximum treatment duration of 5 days (120 hours).

[0370] Phase 1 was conducted to investigate ascending doses of nangibotide or placebo in a sequential design in cohorts of four patients (3:1 randomization). After cohort completion, safety and PK data were reviewed by an independent Data Safety Monitoring Board (DSMB) and the study could proceed to the next cohort / phase. Phase 2 investigated three doses of nangibotide in a randomized, balanced, parallel-group design with up to three doses of nangibotide and a placebo arm. Only doses of nangibotide deemed safe and well-tolerated during Phase 1 were administered in Phase 2. Pharmacokinetic analysis method for phase IIa using nangibotide

[0371] Nangibotide blood concentrations were determined by a validated LC-MS / MS method in accordance with the European Medicines Agency's (EMA) guideline for the validation of analytical methods for drug concentrations in biological samples, EMEA / CHMP / EWP / 192217 / 2009, version EMA / 275542 / 2014. The peptide was stabilized in blood samples by treatment with 10% trichloroacetic acid solution (1500 mg / mL, 4°C) and centrifugation (3500 g, 10 min, 4°C), with the supernatant collected and frozen prior to analysis. The lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ) were 5 ng / mL and 1000 ng / mL, respectively. The standard curve was linear in the range of 5 ng / mL to 1000 ng / mL, with a correlation coefficient greater than 0.995. During three quality control (QC) validations of nangibotide, intra- and inter-run precision and accuracy of + / -20% LLOQ and + / -15% (other levels up to ULOQ) were achieved. Immunogenicity assessment

[0372] Anti-nangibotide antibodies in serum were assessed at baseline, day 8, and day 28 by an indirect ELISA method validated according to the method described by Shankar et al. (J Pharm Biomed Anal. 2008 Dec 15;48(5):1267-81) and the EMA guidance on immunogenicity assessment of therapeutic proteins of biotechnology origin (EMEA / CHMP / BMWP / 14327 / 2006, issued April 2008). Screening samples that tested positive were further evaluated using a confirmatory assay in which a cutpoint was established to have 0.1% false-positive samples (Shankar et al., J Pharm Biomed Anal. 2008 Dec 15;48(5):1267-81). Validation of the method showed no drug interference. The sensitivity of the assay was established to be 0.3125 μg / mL. Statistical analysis of phase IIa with nangibotide

[0373] Adverse events (AEs) were coded using the MedDRA dictionary version 18.1. Treatment-emergent adverse events (TEAEs) were summarized and enumerated. Analysis was performed on 49 patients with septic shock. Demographic and baseline characteristics were summarized descriptively within each population. Categorical variables were summarized using contingency tables (frequency and percentage). sTREM-1 levels on day 1 were also described (mean, standard deviation, standard error, median, quartiles, and range, minimum and maximum). Mortality was reported as frequency and percentage. For continuous endpoints, i.e., sequential organ failure assessment (SOFA), missing data were imputed using the last observation carry-forward method (LOCF). Time-to-event analyses, i.e., duration of invasive mechanical ventilation (IMV), duration of continuous renal replacement therapy (CRRT), and survival, utilized censoring techniques. Additionally, sensitivity analyses of time-to-event data (excluding survival) were performed using censoring at the upper limit of the corresponding observation period (i.e., day 28 or day 90). The number of days alive and free of any vasopressor, IMV (invasive mechanical ventilation), or CRRT (continuous renal replacement therapy) use was calculated as the total number of calendar days from treatment initiation (day 0) to visit day 28 when subjects were alive and free of any vasopressor, IMV, or CRRT treatment. The following comparisons were performed: each nangibotide dose group versus placebo, all nangibotide dose combinations versus placebo, and dose-response using ordinal trend tests. The incidence (number and percentage) of exploratory composite endpoints: patients alive and free of vasopressors, IMV, and CRRT at day 28 was summarized by treatment and compared between treatments using Fisher's exact test. For pharmacodynamic markers, log-transformed data were expressed as percent change from baseline at day 5 or end of infusion (EOI) if the infusion was stopped before day 5. High and low sTREM-1 patients were defined as those who had sTREM-1 blood concentrations above and below the population median (i.e., 433 pg / mL, respectively) at the time of ICU admission (baseline or day 0)."All nangibotide" refers to the analysis obtained by pooling data from the 0.3 mg / kg / h, 1 mg / kg / h, and 3 mg / kg / h nangibotide treatment groups. result Patient demographics and baseline characteristics

[0374] Fifty patients were randomized, and 49 were treated (one patient died before dosing). As shown in Figure 8, 12 patients were randomized in each group, with one additional patient in the 0.3 mg / kg / h group. All discontinuations were due to death. Thirty-six patients survived to day 90. All groups were well balanced with respect to baseline characteristics (age, sex, race, weight, height, and BMI not shown). The mean age was 64 years (±13 years). On average, patients were on vasopressors for 15 hours (range 3 to 24 hours) before initiating treatment, with no significant differences between groups. 15 of 49 patients (30.6%) were treated after receiving vasopressors between 3 and 12 hours. Patient demographics and general baseline characteristics are shown in Table 3 below. [Table 3] safety

[0375] No adverse events (AEs) led to treatment discontinuation. The number of serious adverse events / AEs (SAEs / AEs) and the number of patients with SAEs / AEs were similar between the nangibotide and placebo groups. Proportionally, the number of SAEs and the number of patients with SAEs were higher in the placebo group. The number of AEs and the number of patients with high severity AEs were similar between treatment groups but proportionally higher in the placebo group. The number of AEs by system organ class was similar between treatment groups. AEs related to infections and cardiac disorders were proportionally higher in the nangibotide group. The most common AEs (>10%) were atrial fibrillation, anemia, pleural effusion, and thrombocytopenia. The incidence of atrial fibrillation and thrombocytopenia was proportionally higher in the nangibotide group. Two suspected unexpected serious adverse reactions (SUSARs) without clear explanation were reported, both in the nangibotide group. No clear explanation was found to indicate a relationship to nangibotide treatment. As shown in Table 4 below, nangibotide was safe and well tolerated up to 3 mg / kg / h. [Table 4] Pharmacokinetics

[0376] For all subjects in all groups, predose samples (blood samples taken before the start of the nangibotide infusion, i.e., baseline samples) contained no quantifiable nangibotide. The mean nangibotide blood concentrations over time obtained from each group (i.e., patients receiving 0.3 mg / kg / h, 1.0 mg / kg / h, and 3.0 mg / kg / h) from the start of the intravenous infusion are shown in Figure 9A. Nangibotide exhibited linear behavior from the start to the end of the intravenous infusion. Nangibotide blood concentrations were found to be dose-proportional. After the end of the infusion, the product was rapidly eliminated (Figure 9B), demonstrating a pharmacokinetic pattern similar to that previously observed in healthy volunteers. Because no drug was detected in the blood 2 hours after the end of the infusion, no sustained pharmacological effects are predicted after this period. mortality rate

[0377] There was a consistent trend in the proportion of patients who died favoring the nangibotide treatment group compared with placebo. Indeed, the pooled all-cause mortality rate at day 28 was 14% (5 / 37) in the nangibotide group and 25% (3 / 12) in the placebo group (see Table 5 below). [Table 5]

[0378] In the subgroup with baseline sTREM-1 levels above the median, i.e., above 433 pg / mL, all deaths were sepsis-related. In this group, all deaths occurred during the first week of the study. Mortality at day 5 was calculated as 40% (2 / 5) and 20% (4 / 20) in the placebo and nangibotide groups, respectively (see Table 6 below). [Table 6] Organ failure parameters

[0379] Although no statistically significant differences in clinical parameters were observed between the nangibotide treatment groups compared to the placebo group, a consistent numerical trend favoring nangibotide was observed in the reduction of SOFA scores over the first 5 days (with a greater reduction in treatment groups compared to the placebo group). For example, as shown in Table 7 below, the difference in SOFA scores for the "all nangibotide" group compared to the "placebo" group was -0.70 (95% CI: -2.41, 1.01), and ranged from -1.66 (95% CI: -3.73, 0.40) to 0.34 (95% CI: -1.76, 2.44) for doses of 0.3-3 mg / kg / h. [Table 7]

[0380] Interestingly, these differences were more significant in the baseline high sTREM-1 subgroup (patients with baseline sTREM-1 levels above the median, i.e., above 433 pg / mL). Indeed, as shown in Table 8 below, the difference in SOFA scores for the "all nangibotide" group compared to the "placebo" group was -1.5 (95% CI: -3.83, 0.84), and ranged from -2.85 (95% CI: -5.68, -0.02; p=0.0487) to -0.16 (95% CI: -2.80, 2.48) for doses of 0.3 to 3 mg / kg / h. [Table 8]

[0381] Conversely, these differences were less significant in the baseline low sTREM-1 subgroup (patients with sTREM-1 levels below the median at baseline, i.e., less than 433 pg / mL). Indeed, as shown in Table 9 below, the difference in SOFA scores for the "all nangibotide" group compared to the "placebo" group on day 5 was -0.18 (95% CI: -2.95, 2.59), and ranged from -0.71 (95% CI: -3.97, 2.54) to 0.12 (95% CI: -3.70, 3.94) for doses of 0.3 to 3 mg / kg / h. [Table 9]

[0382] Unexpectedly, as shown in Figure 10, an inverse dose response was observed, with a more significant difference in the low dose group 0.3 mg / kg / h (-2.85, p=0.0487) compared to the high dose group 3 mg / kg / h (-0.16, p=0.9007).

[0383] These results indicate that the overall treatment-related decrease in SOFA score observed in the entire population was driven by a decrease in SOFA score in patients with the highest baseline sTREM-1 values ​​(above the median, i.e., above 433 pg / mL), and no between-group differences were observed in the group of patients with low baseline sTREM-1 values ​​(below the median, i.e., below 433 pg / mL).

[0384] Similarly, no statistically significant differences in clinical parameters were observed between the nangibotide treatment groups compared with the placebo group, but consistent numerical trends favoring nangibotide were observed for vasopressor use, invasive mechanical ventilation (IMV) use, and renal replacement therapy (RRT) use.

[0385] In the baseline low sTREM-1 subgroup, the difference in vasopressor-free days alive in the "all nangibotide" group compared with the "placebo" group was 0.64 (95% CI: -5.78, 7.07; p = 0.8368) for doses of 0.3 to 3 mg / kg / h, ranging from 2.29 (95% CI: -5.30, 9.87; p = 0.5369) to 0.07 (95% CI: -8.83, 8.97; p = 0.9868). In the baseline high sTREM-1 subgroup, the difference in vasopressor-free days alive in the "all nangibotide" group compared with the "placebo" group was 2.94 (95% CI: -9.36, 15.25; p = 0.6243) at doses of 0.3 to 3 mg / kg / h, ranging from 4.07 (95% CI: -10.81, 18.94; p = 0.5757) to -0.48 (95% CI: -14.48, 13.53; p = 0.9444).

[0386] In the overall population, the difference in days alive without IMV (invasive mechanical ventilation) in the "all nangibotide" group compared with the "placebo" group was 1.33 (95% CI: -6.20, 8.89; p=0.7240) for doses of 0.3 to 3 mg / kg / h, ranging from 2.32 (95% CI: -6.75, 11.40; p=0.6091) to -2.08 (95% CI: -11.34, 7.17; p=0.6524). In the baseline low sTREM-1 subgroup, the difference in days alive without IMV (invasive mechanical ventilation) in the "all nangibotide" group compared with the "placebo" group was -1.30 (95% CI: -9.92, 7.32; p=0.7568) for doses of 0.3 to 3 mg / kg / h, ranging from 3 (95% CI: -7.18, 13.18; p=0.5455) to -6.32 (95% CI: -18.25, 5.61; p=0.2823). In the baseline high sTREM-1 subgroup, the difference in days alive without IMV (invasive mechanical ventilation) in the "all nangibotide" group compared with the "placebo" group was 5.63 (95% CI: -7.24, 18.51; p=0.3732) at doses of 0.3-3 mg / kg / h, ranging from 2.63 (95% CI: -12.93, 18.20; p=0.7285) to 4.30 (95% CI: -10.35, 18.95; p=0.5483).

[0387] In the overall population, the difference in days alive free of CRRT (continuous renal replacement therapy) in the "all nangibotide" group compared with the "placebo" group was 2.70 (95% CI: -4.46, 9.86; p=0.4516) for doses of 0.3-3 mg / kg / h, ranging from 4.10 (95% CI: -4.53, 12.73; p=0.3435) to 1.50 (95% CI: -7.30, 10.30; p=0.7330). In the baseline low sTREM-1 subgroup, the difference in days alive free of CRRT (continuous renal replacement therapy) in the "all nangibotide" group compared with the "placebo" group was 0.77 (95% CI: -4.72, 6.25; p=0.7738) for doses of 0.3 to 3 mg / kg / h, ranging from 1.43 (95% CI: -5.04, 7.90; p=0.6502) to 0.89 (95% CI: -6.70, 8.48; p=0.8086). In the baseline high sTREM-1 subgroup, the difference in days alive without CRRT (continuous renal replacement therapy) in the "all nangibotide" group compared with the "placebo" group was 7.85 (95% CI: -5.22, 20.91; p=0.2254) for doses of 0.3-3 mg / kg / h, ranging from 8.67 (95% CI: -7.13, 24.46; p=0.2666) to 7.37 (95% CI: -7.49, 22.24; p=0.3140).

[0388] These trends were magnified in patients with high levels of circulating sTREM-1 at baseline (above the median, i.e., above 433 pg / mL), as shown in Figure 11. Furthermore, in the "all nangibotide" group, the proportion of patients alive and not receiving any medical support at 28 days was 70% compared with 40% in the "placebo" group. marker

[0389] A trend toward a decrease in circulating levels of endothelial damage markers (Ang-2, VCAM-1, VGEFR-1, and E-selectin), inflammatory markers (IL-8, IL-10, MCP-1, TNF-α, and IL-10), and sTREM-1 during treatment was observed in patients treated with nangibotide. This trend was more pronounced in patients with higher baseline sTREM-1 levels for Ang-2, IL-6, and sTREM-1. For example, while no clear treatment effect was observed for Ang-2 levels in the overall population, a more pronounced decrease was observed in the "G2" subgroup (i.e., patients with baseline sTREM-1 levels greater than 433 pg / mL) compared with the "All" and "G1" subgroups (i.e., patients with baseline sTREM-1 levels less than 433 pg / mL) in the overall population (see Figure 12). The same trend was observed for IL-6 levels, as shown in Figure 13. sTREM-1 as an efficacy marker

[0390] In addition to its value as a qualified biomarker, sTREM-1 was also evaluated as a marker of nangibotide efficacy in this Phase IIa study. The effect of nangibotide treatment on sTREM-1 kinetics over time was assessed. As shown in Figure 14A, no clear changes were observed over time in the overall population, but a trend toward decreased sTREM-1 was observed in the subgroup of patients with higher baseline sTREM-1 levels. Interestingly, patients with the greatest changes in sTREM-1 also had the greatest decrease in SOFA at day 5 / EOI (end of infusion) (Figure 14B). conclusion

[0391] Nangibotide was shown to be safe and well-tolerated in patients with septic shock. In this small exploratory study, a non-significantly lower mortality rate was observed in the nangibotide group. Surprisingly, clinical parameters and mortality showed a clear trend toward a beneficial effect of nangibotide in patients with higher circulating levels of sTREM-1 at baseline.

[0392] Highly variable and controversial results have been published regarding the use of sTREM-1 as a prognostic marker in patients with septic shock. This may be due, in part, to the lack of a validated, reproducible quantitative assay. We validated such a method in accordance with the European Medicines Agency's (2011) Guidelines for the Validation of Analytical Methods for Drug Concentrations in Biological Samples (EMEA / CHMP / EWP / 192217 / 2009 Rev.1 Corr.2). The validated method, described above (see Materials and Methods), was used to retrospectively measure sTREM-1 levels in two independent clinical cohorts: the AdrenOSS cohort and a cohort from a phase IIa clinical trial using nangibotide.

[0393] Interestingly, comparable data were obtained in these two independent European cohorts of 293 and 49 patients, as shown below. [Table 10]

[0394] Baseline sTREM-1 levels were associated with 28-day mortality: 12% and 8% mortality rates were observed in the sTREM-1 Q1 subgroup, and 49% and 42% mortality rates were observed in the sTREM-1 Q4 subgroup. The median values ​​were 497 pg / mL in the AdrenOSS cohort and 433 pg / mL in the phase IIa cohort with nangibotide, with minimum and maximum values ​​(pg / mL) of 42 / 5540 pg / mL and 154 / 1960 pg / mL, respectively, suggesting a similar distribution between the two cohorts.

[0395] These results confirm the need for validated methods to collect reliable data across different cohorts, and that such methods allow reference values ​​from reference populations to be used to derive predetermined sTREM-1 values ​​that can be used in further studies.

[0396] Overall, this study aimed to evaluate the value of sTREM-1 level assessment for patient selection prior to nangibotide administration. Indeed, literature data demonstrating that high baseline sTREM-1 levels are associated with complex outcomes (Charles et al., BMC Infect Dis. 2016 Oct 12;16(1):559) are inconsistent with previous clinical data showing that low baseline sTREM-1 levels are associated with complex outcomes (Gibot et al., Crit Care Med. 2005 Apr;33(4):792-6). Therefore, it remained unclear whether sTREM-1 levels were associated with disease severity and clinical outcomes. The mechanism of sTREM-1 release was also unclear.

[0397] This study demonstrated for the first time that sTREM-1 release depends on TREM-1 activation. Therefore, sTREM-1 can be used as a reliable surrogate for TREM-1 pathway activation. This may therefore enable us to identify patients most likely to benefit from anti-TREM-1 therapeutic approaches, such as nangibotide (corresponding to the peptide LR12, which has the amino acid sequence set forth in SEQ ID NO: 9).

[0398] Furthermore, using a guideline-based validated methodology, we demonstrated in two independent cohorts that high sTREM-1 levels correlated with severity and mortality in patients with septic shock. This confirms that sTREM-1 is a reliable biomarker of severity and may enable the identification of patients at risk for complicated outcomes. Indeed, baseline sTREM-1 blood levels, i.e., within 24 hours after diagnosis of septic shock, were found to correlate with severity.

[0399] A subgroup analysis was also conducted in a Phase IIa clinical trial evaluating the safety and tolerability of nangibotide in patients with septic shock. This study compared the efficacy of nangibotide between patients whose baseline sTREM-1 levels were below a predetermined sTREM-1 value, defined herein as the median, and those whose baseline sTREM-1 levels exceeded this predetermined sTREM-1 value. The efficacy of nangibotide was more pronounced in patients whose baseline sTREM-1 levels exceeded the predetermined sTREM-1 value, i.e., above the median (>433 pg / mL). This was observed in pharmacodynamic parameters (endothelial and inflammatory biomarkers), medical support use (IMV, CRRT, vasopressors), and the SOFA score.

[0400] The low pharmacological activity of nangibotide in patients with baseline sTREM-1 levels below the specified sTREM-1 value cannot be explained by toxicity or side effects, as nangibotide was well tolerated at all doses tested and no adverse events related to nangibotide treatment were observed at the highest dose. Anti-nangibotide antibodies were not found in the patient serum, indicating that this apparent low pharmacological activity in these patients cannot be related to the presence of anti-nangibotide neutralizing antibodies that could have inhibited nangibotide. Nangibotide blood concentrations were dose-proportional and within the same range as previously observed in healthy volunteers, meaning that there was no unusual pharmacokinetic profile of nangibotide in the patients, which could explain the differences between groups. The product was rapidly eliminated after the end of the infusion, which also means that these differences cannot be explained by any sustained pharmacological activity.

[0401] Overall, these results confirm that sTREM-1 is a reliable companion diagnostic marker for patient eligibility and administration of TREM-1 inhibitors (e.g., nangibotide).

Claims

1. 1. A pharmaceutical composition comprising nangibotide for use in treating septic shock in a human subject in need thereof, wherein the human subject has a level of soluble Triggering Receptors Expressed on Myeloid cells-1 (sTREM-1) greater than 433 pg / mL, and nangibotide is a TREM-like transcript-1 (TLT-1) peptide having the amino acid sequence set forth in SEQ ID NO:

9.

2. 2. The pharmaceutical composition of claim 1, wherein the level of sTREM-1 is a blood level of sTREM-1.

3. 3. The pharmaceutical composition of claim 2, wherein the blood level of sTREM-1 is a serum level of sTREM-1 or a plasma level of sTREM-1.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the level of sTREM-1 is measured by enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA), or enzyme-linked fluorescence assay (ELFA).

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein nangibotide is for administration for at least 24 hours.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein nangibotide is administered by continuous infusion at a dose ranging from 0.1 mg per kilogram of body weight per hour (mg / kg / h) to 2.5 mg / kg / h.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein nangibotide is administered by continuous infusion at a dose ranging from 0.3 mg / kg / h to 1 mg / kg / h.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein nangibotide is administered by continuous infusion at a dose of 1 mg / kg / h.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein nangibotide is administered by continuous intravenous infusion.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition induces a decrease in the Sequential Organ Failure Assessment (SOFA) score of the subject.

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