Annexin A1 Dosage Regimen

Abstract

The present disclosure relates to annexin A1 (AnxA1) N-terminal peptides for use in the treatment of ischemic conditions and / or reperfusion injury, and pharmaceutical compositions comprising such annexin A1 (AnxA1) N-terminal peptides.

Description

[Technical Field]

[0001] The present disclosure relates to annexin A1 (AnxA1) N-terminal peptides for use in treating ischemic conditions and / or reperfusion injury, and pharmaceutical compositions comprising such annexin A1 (AnxA1) N-terminal peptides, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion. [Background technology]

[0002] The annexin superfamily consists of 13 calcium-phospholipid-binding proteins with significant biological and structural homology. Annexins are structurally divided into a highly conserved core domain and a variable N-terminal domain. Annexin A1 (ANXA1, 37 kDa, SEQ ID NO: 1) is an anti-inflammatory protein that inhibits the extravasation of blood-borne polymorphonuclear leukocytes (PMNs) into surrounding tissues. This protein binds to the N-formyl peptide receptor (FPR)2 or FPR-L1 receptor, where it initiates a series of signaling events. Following inflammatory stimuli, blood-borne PMNs migrate into surrounding tissues. PMN migration or extravasation is regulated by mediators such as adhesion molecules, cytokines, and proteases, which control pro- and anti-inflammatory processes. PMNs have a high destructive potential and potentially self-damage. Therefore, controlling PMN extravasation and inflammatory responses is important.

[0003] For therapeutic purposes as an anti-inflammatory agent, the complete annexin A1 protein has many drawbacks compared to its functional fragments or modified forms. When used to treat ocular inflammation, where the large size of the protein makes delivery by techniques (e.g., transdermal or transmucosal) more difficult than with smaller polypeptides, the smaller the molecular size, the better its penetration into the corneal epithelium is expected. Furthermore, susceptibility to proteolysis is a particular concern for all peptide pharmaceuticals, especially larger ones, and especially when oral delivery (preferred by many patients) is intended.

[0004] Although several annexin A1 derivatives lacking key N-terminal regions of the polypeptide have been shown to lack significant activity in several assays of inflammation and mediator release, full-length N-terminal N-acetyl annexin A1 has been shown to be biologically active in several systems. Several peptides derived primarily from the unique N-terminal portion of the annexin A1 protein have been shown to have anti-inflammatory properties. One of the most extensively studied annexin A1 peptides is peptide Ac2-26, which mimics amino acids 2 through 26 of the 54-amino acid N-terminal region. Annexin A1 and its N-terminal peptide (Ac2-26) have been shown to exert most of their anti-inflammatory effects via the FPR2 / lipoxin A4 (FPR2 / Alx) receptor. In vivo, Ac2-26 peptide has been shown to exert anti-inflammatory effects in models of myocardial ischemia-reperfusion (I / R), mesenteric I / R, glycogen peritonitis, and IL1 air pouch, and was reported to significantly reduce neutrophil recruitment to the site of injury / inflammation.

[0005] Shorter versions of the Ac2-26 peptide, such as peptides Ac2-12 and Ac2-6, have also been shown to elicit some anti-inflammatory effects in acute models of inflammation. Longer polypeptides with anti-inflammatory effects have been disclosed, such as polypeptides corresponding to amino acid residues 2-48, 2-50, and 11-48, including the protease-resistant V24L variant (WO2012 / 174397 and WO2022 / 038281).

[0006] Myocardial infarction, commonly known as a heart attack, occurs when blood flow to the coronary arteries of the heart is reduced or stopped, causing damage to the heart muscle. Further tissue damage in the form of reperfusion injury can occur during reperfusion, i.e., when blood supply returns to the heart after a period of ischemia or oxygen deprivation. Myocardial infarction is a severe condition, and the development of safe and effective treatments with minimal side effects is needed. Summary of the Invention

[0007] There is a need for the development of a safe and effective treatment for ischemic conditions and / or reperfusion injury with minimal side effects. The present inventors demonstrate that administration of three doses of AnxA1 N-terminal peptide for one or three days significantly improved cardiac output 14 days after ischemia. Surprisingly, administration of three doses of AnxA1 N-terminal peptide within 24 hours of reperfusion showed the greatest improvement in cardiac function. Therefore, administration of three doses of AnxA1 N-terminal peptide within 24 hours of the establishment of reperfusion (the onset of reperfusion) is sufficient to improve long-term cardiac function.

[0008] In some embodiments, the present disclosure relates to an annexin A1 (AnxA1) N-terminal peptide for use in treating ischemic conditions and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

[0009] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising an annexin A1 (AnxA1) N-terminal peptide and at least one pharmaceutically acceptable excipient for use in treating an ischemic condition and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion. [Brief explanation of the drawings]

[0010] [Figure 1] Figure 1 shows the effect of 1-day and 3-day Peptide 1 treatment on cardiac function in a rat model of acute myocardial infarction. Three doses of Peptide 1 administered during the first 24 hours at the time of establishment of reperfusion (start of reperfusion), 3 hours after establishment of reperfusion, and 6 hours after establishment of reperfusion significantly improved cardiac function over the long term. *p<0.05: One-way ANOVA vs. vehicle. [Figure 2A] 1 shows the effects of immediate and delayed administration of annexin A1 peptide in a rat model of acute myocardial infarction. Treatment regimens for Groups 1, 2, and 3 are shown. [Figure 2B] This figure shows the effects of immediate and delayed administration of annexin A1 peptide in a rat model of acute myocardial infarction. Peptide 1 significantly reduced infarct size when the first dose was administered at T=0 (the start of reperfusion) (Group 1), when the first dose was administered at T=1, one hour after the establishment of reperfusion (Group 2), or when the first dose was administered at T=2, two hours after the establishment of reperfusion (Group 3). *p<0.05: One-way ANOVA vs. vehicle. #p<0.05, ##p<0.01: t-test between each treatment group and vehicle. [Figure 3A] Figure 1 shows the effect of one day of peptide 1 treatment on prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction. Endothelial cell counts 72 hours after myocardial infarction (MI) are shown in sham-operated rats, rats treated with vehicle, and rats administered three doses of 30 μg / kg peptide 1. [Figure 3B] 1 shows the effect of one day of peptide 1 treatment on prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction. The presence of anti-inflammatory monocytes / macrophages 24 hours after MI is shown in sham-operated rats, rats treated with vehicle, and rats administered three doses of 30 μg / kg peptide 1.

[0011] definition The term "a" denotes at least one, i.e., one or more.

[0012] The terms "approximately" and "about" as referred to herein are synonymous. In some embodiments, "approximately" and "about" refer to ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, or ±0.1% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±10%, ±5%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±10% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±1% of the recited amount, value, or duration.

[0013] As used herein, the term "dosing interval" refers to the period between the administration of two doses.

[0014] As used herein, the term "time of administration" refers to the time at which administration or infusion, for example, iv infusion, begins.

[0015] A pharmaceutically acceptable excipient is understood to be any excipient that is acceptable for inclusion in a pharmaceutical composition, including, but not limited to, bulking agents, tonicity adjusting agents, stabilizers, surfactants, buffers, water, carbohydrates, and sugar alcohols.

[0016] Intravenous infusion is the direct injection of a fluid or medication into a vein via an intravenous line, needle, cannula, or catheter. Administering a drug via IV infusion is usually necessary when longer or continuous systemic exposure is required to elicit a therapeutic effect. Unlike injections, infusions often use a pump or natural gravity to deliver fluids into the body.

[0017] As used herein, the term "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest the clinical symptoms of a given disease or disorder and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount." The amount effective for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that determining the appropriate dosage can be achieved using routine experimentation by constructing a matrix of values ​​and testing different points within the matrix, all of which is within the ordinary skill of a trained physician or veterinarian.

[0018] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient for the purpose of combating a condition, disease, or disorder. The term is intended to encompass the full range of treatments for a given condition from which the patient is suffering. The patient to be treated is preferably a mammal, particularly a human. Patients receiving treatment may be of various ages.

[0019] Reperfusion refers to the restoration of blood flow to a previously ischemic tissue or organ.

[0020] Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is tissue damage that occurs when blood supply returns to tissue after a period of ischemia or oxygen deprivation (anoxia or hypoxia).

[0021] As used herein, the term "establishment of reperfusion" refers to the point in time when blood flow to an organ or tissue is restored after being interrupted. This may also be referred to as the "onset of reperfusion."

[0022] As used herein, the term "after the establishment of reperfusion" refers to a time point occurring after reperfusion is established. This may also be referred to as "after the onset of reperfusion." DETAILED DESCRIPTION OF THE INVENTION

[0023] One aspect of the present disclosure provides an annexin A1 (AnxA1) N-terminal peptide for use in treating an ischemic condition and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

[0024] One aspect of the present disclosure provides a pharmaceutical composition comprising an annexin A1 (AnxA1) N-terminal peptide and at least one pharmaceutically acceptable excipient for use in treating an ischemic condition and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

[0025] One aspect of the present disclosure provides an annexin A1 (AnxA1) N-terminal peptide for use in treating an ischemic condition and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

[0026] One aspect of the present disclosure provides a pharmaceutical composition comprising an annexin A1 (AnxA1) N-terminal peptide and at least one pharmaceutically acceptable excipient for use in treating an ischemic condition and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are to be administered to a human subject within 24 hours of reperfusion.

[0027] One aspect of the present disclosure also provides a method for treating an ischemic condition and / or reperfusion injury, comprising administering three doses of annexin A1 (AnxA1) N-terminal peptide to a human subject within 24 hours of reperfusion.

[0028] One aspect of the present disclosure also provides a method for treating an ischemic condition and / or reperfusion injury, comprising administering to a human subject a pharmaceutical composition comprising an annexin A1 (AnxA1) N-terminal peptide and at least one pharmaceutically acceptable excipient, wherein three doses of the AnxA1 N-terminal peptide are administered to the human subject within 24 hours of reperfusion.

[0029] One aspect of the present disclosure also provides a method for reducing necrosis caused by ischemic conditions and / or reperfusion injury, comprising administering three doses of annexin A1 (AnxA1) N-terminal peptide to a human subject within 24 hours of reperfusion.

[0030] One aspect of the present disclosure also provides a method for reducing infarct size of an infarct caused by an ischemic condition and / or reperfusion injury, comprising administering three doses of annexin A1 (AnxA1) N-terminal peptide to a human subject within 24 hours of reperfusion.

[0031] One aspect of the present disclosure also provides a method for reducing infarct size in a myocardial infarction caused by an ischemic condition and / or reperfusion injury, comprising administering three doses of annexin A1 (AnxA1) N-terminal peptide to a human subject within 24 hours of reperfusion.

[0032] In some embodiments, the present disclosure relates to the use of an annexin A1 (AnxA1) N-terminal peptide for the manufacture of a medicament for use in treating an ischemic and / or inflammatory condition, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

[0033] In some embodiments, the ischemic condition is followed by reperfusion.

[0034] In some embodiments, the AnxA1 N-terminal peptide is administered to the human subject no more than three times within 24 hours of reperfusion.

[0035] In some embodiments, three doses of AnxA1 N-terminal peptide are administered once, for example, once within 24 hours of reperfusion.

[0036] In some embodiments, the AnxA1 N-terminal peptide is administered to the human subject only within 24 hours of reperfusion.

[0037] In some embodiments, the three doses of AnxA1 N-terminal peptide are three doses per day and are administered to a human subject on only one day.

[0038] In some embodiments, no dose of AnxA1 N-terminal peptide is administered to the human subject 24 hours after reperfusion.

[0039] In some embodiments, the entire dose of the AnxA1 N-terminal peptide is administered to the human subject within 24 hours of reperfusion.

[0040] In some embodiments, the AnxA1 N-terminal peptide is administered to the human subject within 24 hours of the establishment of reperfusion, for example, within 24 hours after the establishment of reperfusion.

[0041] In some embodiments, the AnxA1 N-terminal peptide is administered at an interval of 1 to 6 hours. For example, at an administration interval of about 1 to about 2 hours, for example, at an administration interval of about 2 to about 3 hours, for example, at an administration interval of about 3 to about 4 hours, for example, at an administration interval of about 4 to about 5 hours, for example, at an administration interval of about 5 to about 6 hours, For example, administered to a human subject as three doses at about 1 hour intervals, for example, at about 2 hours intervals, for example, at about 3 hours intervals, for example, at about 4 hours intervals, for example, at about 5 hours intervals, for example, at about 6 hours intervals.

[0042] In some embodiments, the AnxA1 N-terminal peptide is administered to a human subject in three doses spaced apart by about 2 to 4 hours, e.g., about 2 hours 30 minutes to about 3 hours 30 minutes, e.g., about 2 hours 45 minutes to about 3 hours 15 minutes.

[0043] In some embodiments, the AnxA1 N-terminal peptide is administered to a human subject in three doses, with doses spaced about three hours apart.

[0044] In some embodiments, the first dose of the AnxA1 N-terminal peptide is administered within about 0 hours of the establishment of reperfusion, for example, within about 5 minutes of the establishment of reperfusion, for example, within about 10 minutes of the establishment of reperfusion, for example, within about 15 minutes of the establishment of reperfusion, for example, within about 20 minutes of the establishment of reperfusion, for example, within about 25 minutes of the establishment of reperfusion, for example, within about 30 minutes of the establishment of reperfusion, for example, within about 45 minutes of the establishment of reperfusion, for example, within about 1 hour ... The therapeutic agent is administered to a human subject within about 1 hour 30 minutes of establishment of reperfusion, for example, within about 1 hour 45 minutes of establishment of reperfusion, for example, within about 2 hours of establishment of reperfusion, for example, within about 2 hours 30 minutes of establishment of reperfusion, for example, within about 3 hours of establishment of reperfusion, for example, within about 3 hours 30 minutes of establishment of reperfusion, for example, within about 4 hours of establishment of reperfusion, for example, within about 4 hours 30 minutes of establishment of reperfusion, for example, within about 5 hours of establishment of reperfusion, for example, within about 6 hours of establishment of reperfusion.

[0045] In some embodiments, the first dose of the AnxA1 N-terminal peptide is administered to the human subject within 0 hours to 6 hours of the establishment of reperfusion, for example, within 0 hours to 5 hours of the establishment of reperfusion, for example, within 0 hours to 4 hours of the establishment of reperfusion, for example, within 0 hours to 3 hours of the establishment of reperfusion, for example, within 0 hours to 2 hours of the establishment of reperfusion, for example, within 0 hours to 1 hour 30 minutes of the establishment of reperfusion, for example, within 0 hours to 1 hour 1 hour of the establishment of reperfusion, for example, within 0 hours to 30 minutes of the establishment of reperfusion.

[0046] In some embodiments, the second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 2 hours of the establishment of reperfusion, for example, within about 2 hours and 30 minutes of the establishment of reperfusion, for example, within about 3 hours of the establishment of reperfusion, for example, within about 3 hours and 30 minutes of the establishment of reperfusion, for example, within about 4 hours of the establishment of reperfusion, for example, within about 4 hours and 30 minutes of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 5 hours and 30 minutes of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 6 hours and 30 minutes of the establishment of reperfusion, for example, within about 7 hours of the establishment of reperfusion, for example, within about 7 hours and 30 minutes of the establishment of reperfusion, for example, within about 8 hours of the establishment of reperfusion, for example, within about 8 hours and 30 minutes of the establishment of reperfusion.

[0047] In some embodiments, the second dose of the AnxA1 N-terminal peptide is administered to the human subject within 1 hour to 9 hours of the establishment of reperfusion, for example, within 1 hour 30 minutes to 8 hours of the establishment of reperfusion, for example, within 2 hours to 7 hours of the establishment of reperfusion, for example, within 2 hours to 6 hours of the establishment of reperfusion, for example, within 2 hours to 5 hours of the establishment of reperfusion, for example, within 2 hours to 4 hours of the establishment of reperfusion, for example, within 2 hours 30 minutes to 3 hours 30 minutes of the establishment of reperfusion.

[0048] In some embodiments, the third dose of the AnxA1 N-terminal peptide is administered within about 4 hours of the establishment of reperfusion, for example, within about 4 hours and 30 minutes of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 5 hours and 30 minutes of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 6 hours and 30 minutes of the establishment of reperfusion, for example, within about 7 hours of the establishment of reperfusion, for example, within about 7 hours of the establishment of reperfusion. The therapeutic agent is administered to a human subject within about 8 hours of the establishment of reperfusion, for example, within about 8 hours and 30 minutes of the establishment of reperfusion, for example, within about 8 hours and 30 minutes of the establishment of reperfusion, for example, within about 9 hours of the establishment of reperfusion, for example, within about 9 hours and 30 minutes of the establishment of reperfusion, for example, within about 10 hours of the establishment of reperfusion, for example, within about 10 hours and 30 minutes of the establishment of reperfusion, for example, within about 11 hours of the establishment of reperfusion, for example, within about 11 hours and 30 minutes of the establishment of reperfusion, for example, within about 12 hours of the establishment of reperfusion.

[0049] In some embodiments, the third dose of the AnxA1 N-terminal peptide is administered to the human subject within 4 hours to 12 hours of the establishment of reperfusion, for example, within 4 hours 30 minutes to 11 hours of the establishment of reperfusion, for example, within 5 hours to 10 hours of the establishment of reperfusion, for example, within 4 hours to 9 hours of the establishment of reperfusion, for example, within 4 hours to 8 hours of the establishment of reperfusion, for example, within 4 hours to 9 hours of the establishment of reperfusion, for example, within 5 hours 30 minutes to 6 hours 30 minutes of the establishment of reperfusion.

[0050] In some embodiments, the AnxA1 N-terminal peptide is a. within 0 to 15 minutes of the establishment of reperfusion, within 3 hours to 3 hours 15 minutes of the establishment of reperfusion, and within 6 hours to 6 hours 3 hours 15 minutes of the establishment of reperfusion; or b. within 15 minutes to 30 minutes of the establishment of reperfusion, within 3 hours 15 minutes to 3 hours 30 minutes of the establishment of reperfusion, and within 6 hours 15 minutes to 6 hours 30 minutes of the establishment of reperfusion; or c. within 30 minutes to 45 minutes of the establishment of reperfusion, within 3 hours 30 minutes to 3 hours 45 minutes of the establishment of reperfusion, and within 6 hours 30 minutes to 6 hours 45 minutes of the establishment of reperfusion; or d. within 1 hour 30 minutes to 1 hour 45 minutes of the establishment of reperfusion, within 4 hours 30 minutes to 4 hours 45 minutes of the establishment of reperfusion, and within 7 hours 30 minutes to 7 hours 45 minutes of the establishment of reperfusion; or e. within 1 hour 45 minutes to 2 hours of the establishment of reperfusion, within 4 hours 45 minutes to 5 hours of the establishment of reperfusion, and within 7 hours 45 minutes to 8 hours of the establishment of reperfusion; or f. within 2 to 3 hours of the establishment of reperfusion, within 5 to 6 hours of the establishment of reperfusion, and within 8 to 9 hours of the establishment of reperfusion; or g. within 3 to 4 hours of the establishment of reperfusion, within 6 to 7 hours of the establishment of reperfusion, and within 9 to 10 hours of the establishment of reperfusion; or h. within 4 to 5 hours of the establishment of reperfusion, within 7 to 8 hours of the establishment of reperfusion, and within 10 to 11 hours of the establishment of reperfusion; or i. within 5 to 6 hours of the establishment of reperfusion, within 8 to 9 hours of the establishment of reperfusion, and within 11 to 12 hours of the establishment of reperfusion; or j. Administered to a human subject as three doses per day within 6 to 7 hours of the establishment of reperfusion, within 9 to 10 hours of the establishment of reperfusion, and within 12 to 13 hours of the establishment of reperfusion.

[0051] In some embodiments, the AnxA1 N-terminal peptide is a. within about 0 hours of the establishment of reperfusion, within about 3 hours of the establishment of reperfusion, and within about 6 hours of the establishment of reperfusion; or b. within about 15 minutes of the establishment of reperfusion, within about 3 hours and 15 minutes of the establishment of reperfusion, and within about 6 hours and 15 minutes of the establishment of reperfusion; or c. within about 30 minutes of the establishment of reperfusion, within about 3 hours and 30 minutes of the establishment of reperfusion, and within about 6 hours and 30 minutes of the establishment of reperfusion; or d. within about 1 hour and 30 minutes of the establishment of reperfusion, within about 4 hours and 30 minutes of the establishment of reperfusion, and within about 7 hours and 30 minutes of the establishment of reperfusion; or e. within about 1 hour and 45 minutes of the establishment of reperfusion, within about 4 hours and 45 minutes of the establishment of reperfusion, and within about 7 hours and 45 minutes of the establishment of reperfusion; or f. within about 2 hours of the establishment of reperfusion, within about 5 hours of the establishment of reperfusion, and within about 8 hours of the establishment of reperfusion; or g. within about 3 hours of the establishment of reperfusion, within about 6 hours of the establishment of reperfusion, and within about 9 hours of the establishment of reperfusion; or h. within about 4 hours of the establishment of reperfusion, within about 7 hours of the establishment of reperfusion, and within about 10 hours of the establishment of reperfusion; or i. within about 5 hours of the establishment of reperfusion, within about 8 hours of the establishment of reperfusion, and within about 11 hours of the establishment of reperfusion; or j. Administered to a human subject as three doses per day within about 6 hours of the establishment of reperfusion, within about 9 hours of the establishment of reperfusion, and within about 12 hours of the establishment of reperfusion.

[0052] In some embodiments, the AnxA1 N-terminal peptide is a. about 15 minutes after the establishment of reperfusion, about 3 hours and 15 minutes after the establishment of reperfusion, and about 6 hours and 15 minutes after the establishment of reperfusion; or b. about 30 minutes after the establishment of reperfusion, about 3 hours and 30 minutes after the establishment of reperfusion, and about 6 hours and 30 minutes after the establishment of reperfusion; or c. about 1 hour 30 minutes after the establishment of reperfusion, about 4 hours 30 minutes after the establishment of reperfusion, and about 7 hours 30 minutes after the establishment of reperfusion; or d. about 1 hour and 45 minutes after the establishment of reperfusion, about 4 hours and 45 minutes after the establishment of reperfusion, and about 7 hours and 45 minutes after the establishment of reperfusion; or e. about 2 hours after the establishment of reperfusion, about 5 hours after the establishment of reperfusion, and about 8 hours after the establishment of reperfusion; or f. about 3 hours after the establishment of reperfusion, about 6 hours after the establishment of reperfusion, and about 9 hours after the establishment of reperfusion; or g. about 4 hours after the establishment of reperfusion, about 7 hours after the establishment of reperfusion, and about 10 hours after the establishment of reperfusion; or h. about 5 hours after the establishment of reperfusion, about 8 hours after the establishment of reperfusion, and about 11 hours after the establishment of reperfusion; or i. Administered to a human subject as three doses per day at about 6 hours after the establishment of reperfusion, at about 9 hours after the establishment of reperfusion, and at about 12 hours after the establishment of reperfusion.

[0053] In some embodiments, a first dose of the AnxA1 N-terminal peptide is administered to the human subject within about 0 to 2 hours of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 2 to 5 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within about 4 to 8 hours of the establishment of reperfusion.

[0054] In some embodiments, a first dose of the AnxA1 N-terminal peptide is administered to the human subject within about 0 to 1 hour of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 2 to 4 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within about 5 and 7 hours of the establishment of reperfusion.

[0055] In some embodiments, a first dose of the AnxA1 N-terminal peptide is administered to the human subject within about 0 hours of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 3 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within about 6 hours of the establishment of reperfusion.

[0056] In some embodiments, the AnxA1 N-terminal peptide is administered to a human subject in more than three doses within 24 hours of reperfusion, for example, four, five, or six doses within 24 hours of reperfusion.

[0057] In some embodiments, the AnxA1 N-terminal peptide or pharmaceutical composition is administered as an intravenous (iv) infusion.

[0058] In some embodiments, the AnxA1 N-terminal peptide or pharmaceutical composition is administered as a 1 to 60 minute iv infusion, such as a 10 to 50 minute iv infusion, such as a 20 to 40 minute iv infusion, such as a 30 minute iv infusion.

[0059] In some embodiments, the AnxA1 N-terminal peptide or pharmaceutical composition is administered as a 30 minute iv infusion.

[0060] In some embodiments, the AnxA1 N-terminal peptide is selected from the group consisting of: AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 2, Annexin A1 2-50), b. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 3, Annexin A1 2-48); c. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 4, Annexin A1 2-46), d. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 5, Annexin A1 2-50 V24L), e. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6, Annexin A1 2-48 V24L), f. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 7, Annexin A1 2-46 V24L), and g. A functional variant of any one of SEQ ID NOs: 2-7, comprising 1 to 6 individual amino acid substitutions.

[0061] In some embodiments, a functional variant comprises one to three individual amino acid substitutions, for example, one individual amino acid substitution, two individual amino acid substitutions, or three individual amino acid substitutions.

[0062] In some embodiments, one or more individual amino acid substitutions are conservative amino acid substitutions.

[0063] In some embodiments, the functional variant is a ligand and / or agonist of one or more of formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), and formyl peptide receptor 3 (FPR3).

[0064] In some embodiments, the functional variant activates and / or stimulates one or more of formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), and formyl peptide receptor 3 (FPR3).

[0065] In some embodiments, the AnxA1 N-terminal peptide has a C-terminal amidation.

[0066] In some embodiments, the AnxA1 N-terminal peptide is AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6, Annexin A1 2-48 V24L), optionally with C-terminal amidation.

[0067] In some embodiments, the AnxA1 N-terminal peptide is administered at a dose of about 15 μg / kg, about 25 μg / kg, about 50 μg / kg, about 100 μg / kg, about 150 μg / kg, about 200 μg / kg, or about 400 μg / kg of the AnxA1 N-terminal peptide.

[0068] In some embodiments, the ischemic condition and / or reperfusion injury is myocardial ischemic condition and / or reperfusion injury of the heart.

[0069] In some embodiments, the ischemic condition and / or reperfusion injury is selected from the group consisting of coronary artery disease, such as angina and myocardial infarction; stroke, heart failure; peripheral arterial disease; thromboembolic disease; and venous thrombosis.

[0070] In some embodiments, the ischemic condition and / or reperfusion injury is coronary artery disease.

[0071] In some embodiments, the ischemic condition and / or reperfusion injury is a myocardial infarction.

[0072] In some embodiments, the ischemic condition and / or reperfusion injury is acute myocardial infarction.

[0073] In some embodiments, the ischemic condition and / or reperfusion injury is a myocardial infarction followed by reperfusion.

[0074] In some embodiments, the ischemic condition and / or reperfusion injury is selected from the group consisting of myocardial infarction due to myocardial ischemia / reperfusion, myocardial infarction due to myocardial ischemia, myocarditis, sepsis, sepsis-induced cardiomyopathy, and sepsis-induced myocardial inflammation.

[0075] In some embodiments, the ischemic condition and / or reperfusion injury is myocardial infarction resulting from myocardial ischemia or myocardial infarction resulting from myocardial ischemia / reperfusion.

[0076] In some embodiments, the myocardial infarction is selected from the group consisting of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

[0077] In some embodiments, the myocardial infarction is ST-elevation myocardial infarction (STEMI).

[0078] In some embodiments, the ischemic condition and / or reperfusion injury results in an inflammatory immune response and / or tissue destruction.

[0079] In some embodiments, administration of the AnxA1 N-terminal peptide reduces or prevents an inflammatory immune response in ischemic tissue.

[0080] In some embodiments, administration of the AnxA1 N-terminal peptide reduces necrosis caused by ischemic conditions and / or reperfusion injury.

[0081] In some embodiments, necrosis is reduced compared to necrosis caused by ischemic conditions and / or reperfusion injury in a human subject that has not received any AnxA1 N-terminal peptide.

[0082] In some embodiments, administration of the AnxA1 N-terminal peptide reduces infarct size of an infarct caused by ischemic conditions and / or reperfusion injury.

[0083] In some embodiments, the infarct size is reduced compared to the infarct size of an infarct caused by ischemic conditions and / or reperfusion injury in a human subject that has not received any administration of the AnxA1 N-terminal peptide.

[0084] In some embodiments, administration of the AnxA1 N-terminal peptide reduces myocardial infarct size in myocardial infarction caused by ischemic conditions and / or reperfusion injury.

[0085] In some embodiments, the myocardial infarction size is reduced compared to the myocardial infarction size of a myocardial infarction caused by ischemic conditions and / or reperfusion injury in a human subject that has not received any administration of the AnxA1 N-terminal peptide.

[0086] In some embodiments, the pharmaceutical composition is a liquid pharmaceutical composition comprising an AnxA1 N-terminal peptide and at least one pharmaceutically acceptable excipient.

[0087] In some embodiments, the liquid pharmaceutical composition comprises 0.5 to 10 mg / mL of AnxA1 N-terminal peptide, for example, 1 to 10 mg / mL, for example, 2 to 9 mg / mL, for example, 3 to 8 mg / mL, for example, 4 to 6 mg / mL.

[0088] In some embodiments, the liquid pharmaceutical composition comprises: i) 1 to 10 mg / mL of AnxA1 N-terminal peptide; ii) 3-5% (w / w) sugar alcohol, and iii) 0.5-1.5% (w / w) carbohydrates.

[0089] In some embodiments, the liquid pharmaceutical composition comprises: i) 1 to 10 mg / mL of AnxA1 N-terminal peptide; ii) 3-5% (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycol (PEG), and polypropylene / ethylene glycol copolymer; and iii) 0.5-1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose, and arabinose.

[0090] In some embodiments, the liquid pharmaceutical composition comprises: i) 1 to 10 mg / mL of AnxA1 N-terminal peptide; ii) 3-5% (w / w) sugar alcohol; iii) 0.5-1.5% (w / w) carbohydrates; iv) 0.005 to 0.015% (w / w) of a surfactant, and v) 5-15 mM buffer.

[0091] In some embodiments, the liquid pharmaceutical composition has a pH of 8.2 to 8.4. i) 1 to 10 mg / mL of AnxA1 N-terminal peptide; ii) 3-5% (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycol (PEG), and polypropylene / ethylene glycol copolymer; iii) 0.5 to 1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose, and arabinose; iv) 0.005 to 0.015% (w / w) of a surfactant selected from the group consisting of polysorbate-80 and polysorbate-20, and v) A buffer selected from the group consisting of 5-15 mM acetate buffer, TRIS, amine-containing buffer, amino acid-based buffer such as lysine, hydroxy-lysine histidine and glycylglycine, non-phosphate buffer, bicarbonate buffer, HEPES, and borate buffer.

[0092] In some embodiments, the liquid pharmaceutical composition is administered as more than three iv infusions per day, for example, four, five, or six iv infusions per day.

[0093] In some embodiments, multiple daily iv infusions correspond to administration of a dose of about 15 μg / kg, about 25 μg / kg, about 50 μg / kg, about 100 μg / kg, about 150 μg / kg, about 200 μg / kg, or about 400 μg / kg of AnxA1 N-terminal peptide.

[0094] In some embodiments, multiple daily iv infusions correspond to administration of a dose of about 15-400 μg / kg, about 25-400 μg / kg, about 50-400 μg / kg, about 100-400 μg / kg, about 150-400 μg / kg, or about 200-400 μg / kg of AnxA1 N-terminal peptide.

[0095] In some embodiments, multiple daily iv infusions correspond to administration of a dose of 15-400 μg / kg, about 25-400 μg / kg, about 25-200 μg / kg, about 25-150 μg / kg, about 25-100 μg / kg, or about 25-50 μg / kg of AnxA1 N-terminal peptide.

[0096] In some embodiments, multiple daily iv infusions correspond to administration of a dose of 25-200 μg / kg of AnxA1 N-terminal peptide.

[0097] In some embodiments, the liquid pharmaceutical composition is administered as an iv infusion three times daily.

[0098] In some embodiments, the liquid pharmaceutical composition is administered three times daily as an iv infusion of 20 to 40 minutes each, for example, as an iv infusion of 30 minutes each.

[0099] In some embodiments, each iv infusion corresponds to administration of a dose of about 25-200 μg / kg, about 25-150 μg / kg, about 25-100 μg / kg, or about 25-50 μg / kg of AnxA1 N-terminal peptide.

[0100] In some embodiments, the liquid pharmaceutical composition is administered by iv infusion at a flow rate of about 0.5-10 mL / min, such as 0.5-10 mL / min, for example, 0.5-5 mL / min, for example, 0.5-4 mL / min, for example, 0.5-3 mL / min, for example, 1-2 mL / min, for example, about 1.5 mL / min.

[0101] In some embodiments, the liquid pharmaceutical composition is administered by iv infusion at a flow rate of 1.5 mL / min. [Example]

[0102] In the examples below, references to "Peptide 1" are identified herein as AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6 (Annexin A1 2-48 V24L)) with C-terminal amidation.

[0103] Example 1: Effects of 1 and 3 days of Peptide 1 treatment on cardiac function in a rat model of acute myocardial infarction method: Myocardial infarction was induced in male Sprague-Dawley rats. On day 0, rats were anesthetized with a mixture of 2-2.2% isoflurane USP (Abbott Laboratories, Montreal, Canada) in oxygen and placed on a heating pad (set at 37°C) to maintain body temperature. The animals were intubated and immediately ventilated with a mixture of 2-2.2% isoflurane USP (Abbott Laboratories, Montreal, Canada) in oxygen using a positive-pressure rodent ventilator (CWE Model SAR-830 / P) set at approximately 10 mL / kg body weight at a respiratory rate of 70-80 breaths / min. The pericardium was opened to expose the heart, and a 5-0 wax-coated braided silk suture (Sofsilk™) was placed around the left anterior descending (LAD) coronary artery approximately 2-3 mm below the left atrium. The suture was briefly snare to confirm the size and location of myocardial ischemia based on color change and then tied off, creating a large anterolateral myocardial infarction (affecting approximately 45% of the LV). The suture was held in place for 30 minutes (30 minutes of ischemia) followed by reperfusion. A sham-operated group of rats was also included. Peptide 1 (or vehicle) was administered three times into the tail vein. The first dose was administered at the time of establishment of reperfusion (the beginning of reperfusion), the second dose was administered 3 hours after the establishment of reperfusion, and the third dose was administered 6 hours after the establishment of reperfusion. Group 1 received 3 x 10 μg / kg for 3 days, Group 2 received 3 x 30 μg / kg for 3 days, Group 4 received 3 x 100 μg / kg for 3 days, and Group 5 received 3 x 30 μg / kg for only 1 day. Fourteen days after ischemia, cardiac function was assessed by transthoracic echocardiography (echocardiogram model Q9 connected to a Chison 12.0 MHz probe, Chison Medical Imaging Co.).

[0104] result: As shown in Figure 1, vehicle treatment was associated with the development of cardiac dysfunction, resulting in a 25% reduction in cardiac output compared to sham animals. Peptide 1 administration for 1 or 3 days significantly improved cardiac output by 20–30% compared to vehicle treatment 14 days after ischemia. Only rats receiving 3 × 30 μg / kg of Peptide 1 per day showed the greatest improvement in cardiac function, with cardiac output comparable to sham animals (79.5 mL vs. 81.1 mL, respectively). Thus, three doses of Peptide 1 administered during the first 24 hours at the time of establishment of reperfusion (start of reperfusion), 3 hours after establishment of reperfusion, and 6 hours after establishment of reperfusion significantly improved long-term cardiac function.

[0105] Example 2: Effects of immediate and delayed administration of annexin A1 peptide in a rat model of acute myocardial infarction method: Myocardial infarction was induced by 30 minutes of ischemia via occlusion of the left coronary artery, followed by 24 hours of reperfusion. Sprague-Dawley rats were treated with three doses of peptide 1 (30 μg / kg). Treatment was initiated either at the time of establishment of reperfusion (the beginning of reperfusion) (T0 h, T3 h, T6 h) (Group 1) or delayed at either 1 hour (T1 h, T4 h, T7 h) after establishment of reperfusion (Group 2) or 2 hours (T2 h, T5 h, T8 h) after establishment of reperfusion (Group 3).

[0106] At the end of the 24-hour reperfusion period, the left coronary artery was reoccluded and Evans blue dye solution was injected. Hearts were excised from the rats, stored at -20°C, and then sliced ​​into 1-mm-thick transverse sections. Heart sections were incubated with triphenyltetrazolium chloride (TTC, 1%) at 37°C for 30 minutes to define viable and nonviable myocardium within the risk zone. The areas at risk and infarcted areas were identified using image software.

[0107] result: Peptide 1 significantly reduced infarct size when administered three times, with the first dose administered at the time of establishment of reperfusion (the beginning of reperfusion) (Group 1). Delaying the start of treatment with peptide 1 by 1 and 2 hours reduced infarct size to a similar extent as when peptide 1 was administered immediately at the time of establishment of reperfusion (Figure 2B). Thus, peptide 1 has cardioprotective effects when administered both at the time of establishment of reperfusion and at least 2 hours after the establishment of reperfusion.

[0108] Example 3: Effect of 1-day Peptide 1 treatment on prevention of cardiac inflammation and tissue healing in a rat model of acute myocardial infarction method: Myocardial infarction was induced in male Sprague-Dawley rats. On day 0, rats were anesthetized with a mixture of 2-2.2% isoflurane USP (Abbott Laboratories, Montreal, Canada) in oxygen and placed on a heating pad (set at 37°C) to maintain body temperature. The animals were intubated and immediately ventilated with a mixture of 2-2.2% isoflurane USP (Abbott Laboratories, Montreal, Canada) in oxygen using a positive-pressure rodent ventilator (CWE Model SAR-830 / P) set at approximately 10 mL / kg body weight at a respiratory rate of 70-80 breaths / min. The pericardium was opened to expose the heart, and a 5-0 wax-coated braided silk suture (Sofsilk™) was placed around the left anterior descending (LAD) coronary artery approximately 2-3 mm below the left atrium. The suture was briefly snare-tipped to confirm the size and location of myocardial ischemia based on color change and then tied off, creating a large anterolateral myocardial infarction (affecting approximately 45% of the LV). The suture was held in place for 30 minutes (30 minutes of ischemia), followed by reperfusion. A sham-operated group of rats was also included. Peptide 1 (30 μg / kg) or vehicle was administered three times via the tail vein. The first dose was administered at the onset of reperfusion, the second dose 3 hours after reperfusion, and the third dose 6 hours after reperfusion. On days 1 or 3, the animals were re-anesthetized, and the chest cavity was reopened to expose the heart. The heart was removed and perfused through the aorta with 10 mL of cold PBS, avoiding crossing the aortic valve, to flush the coronary arteries. The left ventricle plus septum was placed in a well of a 6-well plate containing 1 mL of cold PBS and cut into approximately 1-2 mm pieces. Cardiomyocytes were dispersed using a Neonatal Heart Dissociation Kit (Miltenyi Biotec, #130-098-373).

[0109] After cell dissociation, red blood cells were lysed with 2 mL of FACS lysing solution (BD Biosciences, #555899).

[0110] Super Bright Complete Staining Buffer (ThermoFisher Scientific, #SB-4401-42, 150 μL) was added to 1.5 × 10 cardiac cells to prevent nonspecific polymer interactions. Cells were stained with the antibody mix, and all samples were protected from light and kept at room temperature for 20 minutes (see Table 1). One unstained sample was added for each batch.

[0111] Finally, cells were fixed with PFA 2% for 10 min at room temperature and protected from light. [Table 1]

[0112] One or two days after cell staining, all samples were read on a flow cytometer (Sony ID7000), and absolute cell numbers were determined using Accucount Fluorescent Particles (Spherotech, ACFO-50-5, lot AP02).

[0113] result: Figure 3A shows endothelial cell counts 72 hours after myocardial infarction (MI) in sham-operated rats, vehicle-treated rats, and rats administered three doses of 30 μg / kg of peptide 1. Surprisingly, rats administered peptide 1 exhibited a significant 2.4-fold increase in endothelial cell count compared to vehicle. This increase in endothelial cell count in the early stages of MI suggests the possibility of angiogenesis in the damaged tissue. Angiogenesis plays an important role in supplying essential nutrients and oxygen to the healing infarct, thereby contributing to more robust cardiac recovery.

[0114] Furthermore, we assessed the presence of anti-inflammatory monocytes / macrophages in the heart 24 hours after MI after peptide 1 treatment. These cell types play important roles in resolving inflammation, promoting scar formation, and promoting angiogenesis. As shown in Figure 3B, there is an observable increase in anti-inflammatory monocytes / macrophages in vehicle-treated animals. Interestingly, administration of peptide 1 further increases the number of anti-inflammatory monocytes / macrophages by 1.9-fold compared to the vehicle-treated group. This unexpected enhancement suggests that peptide 1 may contribute to promoting inflammation resolution in the myocardium.

[0115] Array Overview Full-length annexin A1 (Homo sapiens) has the following sequence: >sp|P04083|ANXA1_HUMAN Annexin A1 OS=Homo sapiens GN=ANXA1 PE=1 SV=2 MAMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAALHKAIMVKGVDEATIIDILTKRNNAQRQQIKAAYLQETGKPLDETLKKALTGHLEEVVLALLKTPAQFDADELRAAMKGLGTDEDTLIEILASRTNKEIRDINRVYREELKRDLAKDITSDTSGDFRNALLSLakGDRSEDFGVNEDLADSDARALYEAGERRKGTDVNVFNTILTTRSYPQLRRVFQKYTKYSKHDMNKVLDLELKGDIEKCLTAIVKCATSKPAFFAEKLHQAMKGVGTRHKALIRIMVSRSEIDMNDIKAFYQKMYGISLCQAILDETKGDYEKILVALCGGN (SEQ ID NO: 1). AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 2, Annexin A1 2-50) AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 3, Annexin A1 2-48) AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 4, Annexin A1 2-46) AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 5, Annexin A1 2-50 V24L) AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6, Annexin A1 2-48 V24L) AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 7, Annexin A1 2-46 V24L) AMVSEFLKQAWFIENEEQEYVQTVK (SEQ ID NO: 8, Annexin A1 2-26), AMVSEFLKQAWFIENEEQEYVQTLK (SEQ ID NO: 9, Annexin A1 2-26 V24L) All peptides may be amidated (-NH2) at the C-terminus.

Claims

1. An annexin A1 (AnxA1) N-terminal peptide for use in the treatment of ischemic conditions and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

2. A pharmaceutical composition comprising an annexin A1 (AnxA1) N-terminal peptide and at least one pharmaceutically acceptable excipient for use in the treatment of ischemic conditions and / or reperfusion injury, wherein three doses of the AnxA1 N-terminal peptide are administered to a human subject within 24 hours of reperfusion.

3. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject no more than three times within 24 hours of reperfusion.

4. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the three doses of the AnxA1 N-terminal peptide are administered once, for example once within 24 hours of reperfusion.

5. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject only within 24 hours of reperfusion.

6. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the three doses of the AnxA1 N-terminal peptide are three doses per day and are administered to the human subject for only one day.

7. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said dose of AnxA1 N-terminal peptide is not administered to a human subject 24 hours after reperfusion.

8. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the entire dose of the AnxA1 N-terminal peptide is administered to a human subject within 24 hours of reperfusion.

9. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject within 24 hours of the establishment of reperfusion, for example within 24 hours after the establishment of reperfusion.

10. The AnxA1 N-terminal peptide is administered at an interval of 1 to 6 hours. For example, at an administration interval of about 1 to about 2 hours, for example, at an administration interval of about 2 to about 3 hours, for example, at an administration interval of about 3 to about 4 hours, for example, at an administration interval of about 4 to about 5 hours, for example, at an administration interval of about 5 to about 6 hours, The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, administered to the human subject as three doses, for example at an interval of about 1 hour, for example at an interval of about 2 hours, for example at an interval of about 3 hours, for example at an interval of about 4 hours, for example at an interval of about 5 hours, for example at an interval of about 6 hours.

11. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject in three doses with an interval between doses of about 2 to 4 hours, such as from about 2 hours 30 minutes to about 3 hours 30 minutes, such as from about 2 hours 45 minutes to about 3 hours 15 minutes.

12. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject in three doses with an interval of about three hours between doses.

13. The first dose of the AnxA1 N-terminal peptide is administered within about 0 hours of the establishment of reperfusion, for example, within about 5 minutes of the establishment of reperfusion, for example, within about 10 minutes of the establishment of reperfusion, for example, within about 15 minutes of the establishment of reperfusion, for example, within about 20 minutes of the establishment of reperfusion, for example, within about 25 minutes of the establishment of reperfusion, for example, within about 30 minutes of the establishment of reperfusion, for example, within about 45 minutes of the establishment of reperfusion, for example, within about 1 hour of the establishment of reperfusion, for example, within about 1 hour 15 minutes of the establishment of reperfusion, for example, within about 1 hour 30 minutes of the establishment of reperfusion. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide or pharmaceutical composition is administered to the human subject within about 1 hour and 45 minutes of the establishment of reperfusion, for example within about 2 hours of the establishment of reperfusion, for example within about 2 hours and 30 minutes of the establishment of reperfusion, for example within about 3 hours of the establishment of reperfusion, for example within about 3 hours and 30 minutes of the establishment of reperfusion, for example within about 4 hours of the establishment of reperfusion, for example within about 4 hours and 30 minutes of the establishment of reperfusion, for example within about 5 hours of the establishment of reperfusion, for example within about 6 hours of the establishment of reperfusion.

14. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the first dose of the AnxA1 N-terminal peptide is administered to the human subject within 0 to 6 hours of the establishment of reperfusion, such as within 0 to 5 hours of the establishment of reperfusion, for example within 0 to 4 hours of the establishment of reperfusion, for example within 0 to 3 hours of the establishment of reperfusion, for example within 0 to 2 hours of the establishment of reperfusion, for example within 0 to 1 hour 30 minutes of the establishment of reperfusion, for example within 0 to 1 hour 1 hour of the establishment of reperfusion, for example within 0 to 30 minutes of the establishment of reperfusion.

15. The second dose of the AnxA1 N-terminal peptide is administered within about 2 hours of the establishment of reperfusion, for example, within about 2 hours and 30 minutes of the establishment of reperfusion, for example, within about 3 hours of the establishment of reperfusion, for example, within about 3 hours and 30 minutes of the establishment of reperfusion, for example, within about 4 hours of the establishment of reperfusion, for example, within about 4 hours and 30 minutes of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide or pharmaceutical composition is administered to the human subject within about 5 hours and 30 minutes of the establishment of reperfusion, for example within about 6 hours of the establishment of reperfusion, for example within about 6 hours and 30 minutes of the establishment of reperfusion, for example within about 7 hours of the establishment of reperfusion, for example within about 7 hours and 30 minutes of the establishment of reperfusion, for example within about 8 hours of the establishment of reperfusion, for example within about 8 hours and 30 minutes of the establishment of reperfusion.

16. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the second dose of the AnxA1 N-terminal peptide is administered to the human subject within 1 hour to 9 hours of the establishment of reperfusion, such as within 1 hour 30 minutes to 8 hours of the establishment of reperfusion, for example within 2 hours to 7 hours of the establishment of reperfusion, for example within 2 hours to 6 hours of the establishment of reperfusion, for example within 2 hours to 5 hours of the establishment of reperfusion, for example within 2 hours to 4 hours of the establishment of reperfusion, for example within 2 hours 30 minutes to 3 hours 30 minutes of the establishment of reperfusion.

17. the third dose of the AnxA1 N-terminal peptide is administered within about 4 hours of the establishment of reperfusion, for example, within about 4 hours and 30 minutes of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 5 hours of the establishment of reperfusion, for example, within about 5 hours and 30 minutes of the establishment of reperfusion, for example, within about 6 hours of the establishment of reperfusion, for example, within about 6 hours and 30 minutes of the establishment of reperfusion, for example, within about 7 hours of the establishment of reperfusion, for example, within about 7 hours and 30 minutes of the establishment of reperfusion, for example, 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide or pharmaceutical composition is administered to the human subject within about 8 hours of the establishment of reperfusion, for example within about 8 hours and 30 minutes of the establishment of reperfusion, for example within about 9 hours of the establishment of reperfusion, for example within about 9 hours and 30 minutes of the establishment of reperfusion, for example within about 10 hours of the establishment of reperfusion, for example within about 10 hours and 30 minutes of the establishment of reperfusion, for example within about 11 hours of the establishment of reperfusion, for example within about 11 hours and 30 minutes of the establishment of reperfusion, for example within about 12 hours of the establishment of reperfusion.

18. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the third dose of the AnxA1 N-terminal peptide is administered to the human subject within 4 hours to 12 hours of the establishment of reperfusion, such as within 4 hours 30 minutes to 11 hours of the establishment of reperfusion, for example within 5 hours to 10 hours of the establishment of reperfusion, for example within 4 hours to 9 hours of the establishment of reperfusion, for example within 4 hours to 8 hours of the establishment of reperfusion, for example within 4 hours to 9 hours of the establishment of reperfusion, for example within 5 hours 30 minutes to 6 hours 30 minutes of the establishment of reperfusion.

19. The AnxA1 N-terminal peptide is a. within 0 to 15 minutes of the establishment of reperfusion, within 3 hours to 3 hours 15 minutes of the establishment of reperfusion, and within 6 hours to 6 hours 3 hours 15 minutes of the establishment of reperfusion; or b. within 15 minutes to 30 minutes of the establishment of reperfusion, within 3 hours 15 minutes to 3 hours 30 minutes of the establishment of reperfusion, and within 6 hours 15 minutes to 6 hours 30 minutes of the establishment of reperfusion; or c. within 30 to 45 minutes of the establishment of reperfusion, within 3 hours 30 to 3 hours 45 minutes of the establishment of reperfusion, and within 6 hours 30 to 6 hours 45 minutes of the establishment of reperfusion; or d. within 1 hour 30 minutes to 1 hour 45 minutes of the establishment of reperfusion, within 4 hours 30 minutes to 4 hours 45 minutes of the establishment of reperfusion, and within 7 hours 30 minutes to 7 hours 45 minutes of the establishment of reperfusion; or e. within 1 hour 45 minutes to 2 hours of the establishment of reperfusion, within 4 hours 45 minutes to 5 hours of the establishment of reperfusion, and within 7 hours 45 minutes to 8 hours of the establishment of reperfusion, or f. within 2 to 3 hours of the establishment of reperfusion, within 5 to 6 hours of the establishment of reperfusion, and within 8 to 9 hours of the establishment of reperfusion; or g. within 3 to 4 hours of the establishment of reperfusion, within 6 to 7 hours of the establishment of reperfusion, and within 9 to 10 hours of the establishment of reperfusion; or h. within 4 to 5 hours of the establishment of reperfusion, within 7 to 8 hours of the establishment of reperfusion, and within 10 to 11 hours of the establishment of reperfusion; or i. within 5 to 6 hours of the establishment of reperfusion, within 8 to 9 hours of the establishment of reperfusion, and within 11 to 12 hours of the establishment of reperfusion, or j. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, administered to said human subject as a dose three times a day within 6 to 7 hours of the establishment of reperfusion, within 9 to 10 hours of the establishment of reperfusion, and within 12 to 13 hours of the establishment of reperfusion.

20. The AnxA1 N-terminal peptide is a. within about 0 hours of the establishment of reperfusion, within about 3 hours of the establishment of reperfusion, and within about 6 hours of the establishment of reperfusion; or b. within about 15 minutes of the establishment of reperfusion, within about 3 hours and 15 minutes of the establishment of reperfusion, and within about 6 hours and 15 minutes of the establishment of reperfusion; or c. within about 30 minutes of the establishment of reperfusion, within about 3 hours and 30 minutes of the establishment of reperfusion, and within about 6 hours and 30 minutes of the establishment of reperfusion; or d. within about 1 hour 30 minutes of the establishment of reperfusion, within about 4 hours 30 minutes of the establishment of reperfusion, and within about 7 hours 30 minutes of the establishment of reperfusion; or e. within about 1 hour 45 minutes of the establishment of reperfusion, within about 4 hours 45 minutes of the establishment of reperfusion, and within about 7 hours 45 minutes of the establishment of reperfusion; or f. within about 2 hours of the establishment of reperfusion, within about 5 hours of the establishment of reperfusion, and within about 8 hours of the establishment of reperfusion; or g. within about 3 hours of the establishment of reperfusion, within about 6 hours of the establishment of reperfusion, and within about 9 hours of the establishment of reperfusion; or h. within about 4 hours of the establishment of reperfusion, within about 7 hours of the establishment of reperfusion, and within about 10 hours of the establishment of reperfusion; i. within about 5 hours of the establishment of reperfusion, within about 8 hours of the establishment of reperfusion, and within about 11 hours of the establishment of reperfusion; or j) The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide or pharmaceutical composition is administered to the human subject as three doses per day within about 6 hours of the establishment of reperfusion, within about 9 hours of the establishment of reperfusion, and within about 12 hours of the establishment of reperfusion.

21. The AnxA1 N-terminal peptide is a. about 15 minutes after the establishment of reperfusion, about 3 hours and 15 minutes after the establishment of reperfusion, and about 6 hours and 15 minutes after the establishment of reperfusion; or b. about 30 minutes after the establishment of reperfusion, about 3 hours and 30 minutes after the establishment of reperfusion, and about 6 hours and 30 minutes after the establishment of reperfusion; or c. about 1 hour 30 minutes after the establishment of reperfusion, about 4 hours 30 minutes after the establishment of reperfusion, and about 7 hours 30 minutes after the establishment of reperfusion; or d. about 1 hour and 45 minutes after the establishment of reperfusion, about 4 hours and 45 minutes after the establishment of reperfusion, and about 7 hours and 45 minutes after the establishment of reperfusion; or e. about 2 hours after the establishment of reperfusion, about 5 hours after the establishment of reperfusion, and about 8 hours after the establishment of reperfusion; or f. about 3 hours after the establishment of reperfusion, about 6 hours after the establishment of reperfusion, and about 9 hours after the establishment of reperfusion; or g. about 4 hours after the establishment of reperfusion, about 7 hours after the establishment of reperfusion, and about 10 hours after the establishment of reperfusion; or h. about 5 hours after the establishment of reperfusion, about 8 hours after the establishment of reperfusion, and about 11 hours after the establishment of reperfusion; or i. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide or pharmaceutical composition is administered to the human subject as three doses per day at about 6 hours after the establishment of reperfusion, at about 9 hours after the establishment of reperfusion, and at about 12 hours after the establishment of reperfusion.

22. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a first dose of the AnxA1 N-terminal peptide is administered to the human subject within about 0 to 2 hours of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 2 to 5 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within about 4 to 8 hours of the establishment of reperfusion.

23. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a first dose of the AnxA1 N-terminal peptide is administered to the human subject within about 0 to 1 hour of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within about 2 to 4 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within about 5 and 7 hours of the establishment of reperfusion.

24. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein a first dose of the AnxA1 N-terminal peptide is administered to the human subject within approximately 0 hours of the establishment of reperfusion, a second dose of the AnxA1 N-terminal peptide is administered to the human subject within approximately 3 hours of the establishment of reperfusion, and a third dose of the AnxA1 N-terminal peptide is administered to the human subject within approximately 6 hours of the establishment of reperfusion.

25. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered to the human subject in more than three doses within 24 hours of reperfusion, for example in four, five, or six doses within 24 hours of reperfusion.

26. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, administered as an intravenous (iv) infusion.

27. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, administered as a 1 to 60 minute iv infusion, such as a 10 to 50 minute iv infusion, such as a 20 to 40 minute iv infusion, such as a 30 minute iv infusion.

28. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, administered as a 30 minute iv infusion.

29. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal peptide is selected from the group consisting of: AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 2, Annexin A1 2-50); b. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 3, Annexin A1 2-48); c. AMVSEFLKQAWFIENEEQEYVQTVKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 4, Annexin A1 2-46); d. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDVAA (SEQ ID NO: 5, Annexin A1 2-50 V24L); e. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6, Annexin A1 2-48 V24L); f. AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSS (SEQ ID NO: 7, Annexin A1 2-46 V24L), and g. A functional variant of any one of SEQ ID NOs: 2-7, comprising from 1 to 6 individual amino acid substitutions.

30. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 29, wherein the functional variant comprises one to three individual amino acid substitutions, for example one individual amino acid substitution, two individual amino acid substitutions, or three individual amino acid substitutions.

31. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of claims 29 to 30, wherein said one or more individual amino acid substitutions are conservative amino acid substitutions.

32. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of claims 29 to 31, wherein the functional variant is a ligand and / or agonist of one or more of formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), and formyl peptide receptor 3 (FPR3).

33. 33. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of claims 29 to 32, wherein the functional variant activates and / or stimulates one or more of formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), and formyl peptide receptor 3 (FPR3).

34. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal peptide has C-terminal amidation.

35. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said AnxA1 N-terminal peptide is AMVSEFLKQAWFIENEEQEYVQTLKSSKGGPGSAVSPYPTFNPSSDV (SEQ ID NO: 6, Annexin A1 2-48 V24L), optionally with C-terminal amidation.

36. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the AnxA1 N-terminal peptide is administered at a dose of about 15 μg / kg, about 25 μg / kg, about 50 μg / kg, about 100 μg / kg, about 150 μg / kg, about 200 μg / kg, or about 400 μg / kg of the AnxA1 N-terminal peptide.

37. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or reperfusion injury is a myocardial ischemic condition and / or reperfusion injury of the heart.

38. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the ischemic condition and / or reperfusion injury is selected from the group consisting of coronary artery disease such as angina pectoris and myocardial infarction; stroke, heart failure; peripheral arterial disease; thromboembolic disease; and venous thrombosis.

39. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or reperfusion injury is coronary artery disease.

40. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or reperfusion injury is myocardial infarction.

41. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or reperfusion injury is acute myocardial infarction.

42. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein said ischemic condition and / or reperfusion injury is myocardial infarction followed by reperfusion.

43. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the ischemic condition and / or reperfusion injury is selected from the group consisting of myocardial infarction due to myocardial ischemia / reperfusion, myocardial infarction due to myocardial ischemia, myocarditis, sepsis, sepsis-induced cardiomyopathy, and sepsis-induced myocardial inflammation.

44. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the ischemic condition and / or reperfusion injury is myocardial infarction caused by myocardial ischemia or myocardial infarction caused by myocardial ischemia / reperfusion.

45. 41. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 40, wherein the myocardial infarction is selected from the group consisting of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

46. 41. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 40, wherein the myocardial infarction is ST-elevation myocardial infarction (STEMI).

47. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein the ischemic condition and / or reperfusion injury results in an inflammatory immune response and / or tissue destruction.

48. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N-terminal peptide reduces or prevents an inflammatory immune response in ischemic tissue.

49. 10. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of said AnxA1 N-terminal peptide reduces necrosis caused by said ischemic condition and / or reperfusion injury.

50. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 49, wherein the necrosis is reduced compared to necrosis caused by ischemic conditions and / or reperfusion injury in a human subject that has not received any administration of the AnxA1 N-terminal peptide.

51. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of the AnxA1 N-terminal peptide reduces the infarct size of an infarct caused by the ischemic condition and / or reperfusion injury.

52. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 51, wherein the infarct size is reduced compared to the infarct size of an infarct caused by an ischemic condition and / or reperfusion injury in a human subject that has not received any administration of the AnxA1 N-terminal peptide.

53. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to any one of the preceding claims, wherein administration of the AnxA1 N-terminal peptide reduces the size of myocardial infarction caused by the ischemic condition and / or reperfusion injury.

54. The AnxA1 N-terminal peptide or pharmaceutical composition for use according to claim 53, wherein the size of the myocardial infarction is reduced compared to the size of the myocardial infarction caused by ischemic conditions and / or reperfusion injury in a human subject who has not received any administration of the AnxA1 N-terminal peptide.

55. 10. The pharmaceutical composition for use according to any one of the preceding claims, which is a liquid pharmaceutical composition comprising said AnxA1 N-terminal peptide and at least one pharmaceutically acceptable excipient.

56. 10. A liquid pharmaceutical composition for use according to any one of the preceding claims, comprising 0.5 to 10 mg / mL of said AnxA1 N-terminal peptide, such as 1 to 10 mg / mL, for example 2 to 9 mg / mL, for example 3 to 8 mg / mL, for example 4 to 6 mg / mL.

57. 10. A liquid pharmaceutical composition for use according to any one of the preceding claims, comprising: i) 1 to 10 mg / mL of the AnxA1 N-terminal peptide; ii) 3-5% (w / w) sugar alcohol, and iii) 0.5-1.5% (w / w) carbohydrates.

58. 10. A liquid pharmaceutical composition for use according to any one of the preceding claims, comprising: i) 1 to 10 mg / mL of the AnxA1 N-terminal peptide; ii) 3-5% (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycol (PEG), and polypropylene / ethylene glycol copolymer; and iii) 0.5-1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose, and arabinose.

59. 10. A liquid pharmaceutical composition for use according to any one of the preceding claims, comprising: i) 1 to 10 mg / mL of the AnxA1 N-terminal peptide; ii) 3-5% (w / w) sugar alcohol; iii) 0.5-1.5% (w / w) carbohydrates; iv) 0.005-0.015% (w / w) of a surfactant, and v) 5-15 mM buffer.

60. 10. A liquid pharmaceutical composition for use according to any one of the preceding claims, having a pH of 8.2 to 8.4 and comprising: i) 1 to 10 mg / mL of the AnxA1 N-terminal peptide; ii) 3-5% (w / w) of a sugar alcohol selected from the group consisting of mannitol, sorbitol, inositol, glycerol, xylitol, propylene glycol, polyethylene glycol (PEG), and polypropylene / ethylene glycol copolymer; iii) 0.5-1.5% (w / w) of a carbohydrate selected from the group consisting of sucrose, trehalose, mannose, ribose, maltose, glucose, lactose, galactose, and arabinose; iv) 0.005-0.015% (w / w) of a surfactant selected from the group consisting of polysorbate-80 and polysorbate-20, and v) A buffer selected from the group consisting of 5-15 mM acetate buffer, TRIS, amine-containing buffer, amino acid-based buffer such as lysine, hydroxy-lysine histidine and glycylglycine, non-phosphate buffer, bicarbonate buffer, HEPES, and borate buffer.

61. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, administered as more than three iv infusions per day, for example four, five or six iv infusions per day.

62. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the multiple daily iv injections correspond to administration of a dose of about 15 μg / kg, about 25 μg / kg, about 50 μg / kg, about 100 μg / kg, about 150 μg / kg, about 200 μg / kg, or about 400 μg / kg of the AnxA1 N-terminal peptide.

63. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said multiple daily iv infusions correspond to administration of a dose of about 15-400 μg / kg, about 25-400 μg / kg, about 50-400 μg / kg, about 100-400 μg / kg, about 150-400 μg / kg, or about 200-400 μg / kg of said AnxA1 N-terminal peptide.

64. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said multiple daily iv infusions correspond to administration of a dose of 15-400 μg / kg, about 25-400 μg / kg, about 25-200 μg / kg, about 25-150 μg / kg, about 25-100 μg / kg, or about 25-50 μg / kg of said AnxA1 N-terminal peptide.

65. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein said multiple daily iv infusions correspond to the administration of a dose of about 25-200 μg / kg of said AnxA1 N-terminal peptide.

66. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, administered as an iv infusion three times daily.

67. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, to be administered three times a day as an iv infusion of 20 to 40 minutes each, for example as an iv infusion of 30 minutes each.

68. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein each iv injection corresponds to administration of a dose of about 25-200 μg / kg, about 25-150 μg / kg, about 25-100 μg / kg, or about 25-50 μg / kg of said AnxA1 N-terminal peptide.

69. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, wherein the liquid pharmaceutical composition is administered by iv infusion at a flow rate of about 0.5 to 10 mL / min, such as 0.5 to 10 mL / min, for example 0.5 to 5 mL / min, such as 0.5 to 4 mL / min, for example 0.5 to 3 mL / min, such as 1 to 2 mL / min, for example about 1.5 mL / min.

70. 10. The liquid pharmaceutical composition for use according to any one of the preceding claims, administered by iv infusion at a flow rate of 1.5 mL / min.

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