Anti-adrenomedullin (ADM) conjugate for use in the treatment of patients in shock.

Abstract

This invention provides an anti-adrenomedullin (ADM) antibody for use in the treatment of patients with septic shock. [Solution] An adrenomedullin antibody or antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients in a state of shock, particularly septic shock, wherein the patient: has been in shock, particularly septic shock, for no more than 10 hours at the start of treatment with the ADM antibody or antibody fragment or anti-ADM non-Ig scaffold, and / or has been admitted to the ICU for no more than 10 hours, and / or is not receiving any organ support or has been receiving organ support for no more than 10 hours, wherein the antibody or fragment or scaffold is an adrenomedullin antibody or antibody fragment or anti-ADM non-Ig scaffold for use in treatment, which binds to the N-terminal region (aa1~21) of ADM.

Description

[Technical Field]

[0001] The subject of the present invention is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients in shock and / or in the treatment of diseases requiring ICU admission. [Background technology]

[0002] A variety of diseases or illnesses may share common, partially nonspecific symptoms that can range from unpleasant to unbearable for the individual suffering from them. Individuals who frequently experience more than one symptom may need to take several medications to alleviate these symptoms. There is an ongoing need for new forms of treatment or prevention of symptoms associated with many different underlying diseases or illnesses. In particular, it would be helpful to provide pharmaceuticals or drugs that can be used in the treatment or prevention of more than one symptom associated with an underlying disease or illness. This invention addresses this need.

[0003] The peptide adrenomedullin (ADM) was first described in 1993 (Kitamura K. et al. 1993. Biochemical and Biophysical Research Communications Vol. 192 (2): 553-560) as a novel blood pressure-lowering peptide containing 52 amino acids and isolated from human pheochromocytoma. In the same year, a precursor peptide containing 185 amino acids and the cDNA encoding the complete amino acid sequence of this precursor peptide were also described. In particular, the precursor peptide containing a 21-amino acid signal sequence at the N-terminus is called "prepro-adrenomedullin" (prepro-ADM). In this specification, all specific amino acid positions are usually related to prepro-ADM containing 185 amino acids. Peptide adrenomedullin (ADM) is a peptide containing 52 amino acids (SEQ ID NO: 1) and contains amino acids 95-146 of prepro-ADM, which is produced by protein cleavage. To date, only a few peptide fragments generated by the cleavage of prepro-ADM have been investigated more accurately, particularly the bioactive peptide adrenomedullin (ADM) and "PAMP," a peptide containing 20 amino acids (22-41), which follows the 21-amino acid signal peptide in prepro-ADM. The discovery and characterization of ADM in 1993 triggered intensive research activities, and these results have been compiled into various reviews. In relation to this specification, please refer in particular to the articles found in publications of "Peptides" dedicated to ADM (Editorial, Takahashi K. 2001. Peptides 22:1691) and (Eto T. 2001. Peptides 22: 1693-1711). A further review is (Hinson et al. 2000. Endocrine Reviews 21(2):138-167). Scientific investigations to date have revealed that ADM, in particular, can be considered a multifunctional regulatory peptide. ADM is released into circulation in an inactivated state extended by glycine (Kitamura K. et al. 1998. Biochem. Biophys. Res. Commun. 244(2):551-555).There are also binding proteins that are specific to ADM and likely regulate the effects of ADM in a similar manner (Pio R. et al. 2001. The Journal of Biological Chemistry 276(15):12292-12300). The most important physiological effect of ADM and PAMP observed in research to date is its effect on blood pressure.

[0004] ADM is an effective vasodilator, and its antihypertensive effect can be linked to a specific peptide segment in the C-terminal region of ADM. Furthermore, it has been found that PAMP, an additional bioactive peptide generated from prepro-ADM, exhibits a similar antihypertensive effect even when it appears to have a different mechanism of action than ADM.

[0005] Furthermore, ADM concentrations, which can be measured in circulating and other biological fluids, have been found to be significantly higher in several pathological conditions than in healthy controls. Therefore, ADM levels are significantly increased, to varying degrees, in patients with congestive heart failure, myocardial infarction, renal disease, hypertension, diabetes, acute shock, sepsis, and septic shock. PAMP concentrations are also increased in some of the aforementioned pathological conditions, although plasma levels are lower compared to ADM (Eto, T., supra). Furthermore, abnormally high concentrations of ADM have been observed in sepsis, with the highest concentrations observed in septic shock (see (Eto, T., "supra) and (Hirata et al. Journal of Clinical Endocrinology and Metabolism 1996. 81(4): 1449-1453; Ehlenz K. et al. 1997. Exp Clin Endocrinol Diabetes 105: 156-162); Tomoda Y. et al. 2001. Peptides 22: 1783-1794; Ueda S. et al. 1999. Am. J. Respir. Crit. Care Med. 160: 132-136; and Wang P. Peptides 2001. 22: 1835-1840)).

[0006] International Publication No. 2004 / 097423(A1) describes the use of antibodies against adrenomedullin for the diagnosis, prognosis, and treatment of cardiovascular disorders. Treatment of diseases by blocking ADM receptors has also been described in the art (e.g., International Publication No. 2006 / 027147(A1), PCT European Patent Application Publication No. 2005 / 012844), where said diseases may include sepsis, septic shock, cardiovascular diseases, infections, skin diseases, endocrine diseases, metabolic diseases, gastrointestinal diseases, cancer, inflammation, hematological diseases, respiratory diseases, musculoskeletal diseases, neurological diseases, and urinary tract diseases.

[0007] In the early stages of sepsis, ADM has been reported to improve cardiac function and blood supply to the liver, spleen, kidneys, and small intestine. ADM-neutralizing antibodies neutralize the aforementioned effects during the early stages of sepsis (Wang, P., "Adrenomedullin and cardiovascular responses in sepsis", Peptides, Vol. 22, pp. 1835-1840 (2001)).

[0008] Blocking ADM may be beneficial to some extent for other diseases. However, when a certain amount of ADM may be necessary for certain physiological functions, blocking ADM may also be harmful if it is completely neutralized. Many reports have emphasized that ADM administration may be beneficial in certain diseases. In contrast, other reports have indicated that ADM can be fatal when administered in certain medical conditions.

[0009] The administration of ADM in combination with ADM-binding protein 1 has been described in the art for the treatment of sepsis and septic shock. Treatment of septic animals with ADM and ADM-binding protein 1 is expected to prevent progression to the later stages of sepsis. In living organisms, ADM-binding protein (complement factor H) is present in the circulation of early-stage organisms at high concentrations (Pio et al.: Identification, characterization, and physiological actions of factor H as an Adrenomedullin binding Protein present in Human Plasma; Microscopy Res. and Technique, 55:23-27 (2002) and Martinez et al.; Mapping of the Adrenomedullin-Binding domains in Human Complement factor H; Hypertens Res Vol. 26, Suppl (2003), S56-59).

[0010] The efficacy of non-neutralizing antibodies targeting the N-terminus of ADM was investigated in a survival study of CLP-induced sepsis in mice. Prior treatment with non-neutralizing antibodies resulted in reduced catecholamine infusion rates, renal dysfunction, and ultimately improved survival rates (Struck et al. 2013. Intensive Care Med Exp 1(1):22; Wagner et al. 2013. Intensive Care Med Exp 1(1):21).

[0011] Due to these positive results, a humanized version of the N-terminal anti-ADM antibody, named adrecizumab, was developed for further clinical development. The beneficial effects of adrecizumab on vascular barrier function and survival have recently been demonstrated in preclinical models of systemic inflammation and sepsis (Geven et al. 2018. Shock 50(6):648-654). In this study, prior treatment with adrecizumab attenuated renal vascular leakage in endotoxemia rats and CLP-induced sepsis mice, which was consistent with increased renal expression of the protective peptide Ang-1 and decreased expression of the harmful peptide vascular endothelial growth factor. Furthermore, prior treatment with adrecizumab improved 7-day survival in CLP-induced sepsis in 10-50% of mice with single doses and 0-40% with repeated doses. Of particular interest is the proposed mechanism of action of adrecizumab. Both animal and human data show a potent dose-dependent increase in circulating ADM after administration of this antibody. Based on pharmacokinetic data and the lack of increase in MR-proADM (an inactive peptide fragment derived from the same prohormone as ADM), higher circulating ADM levels cannot be explained by increased production.

[0012] A mechanistic explanation for this increase may be that, since ADM is small enough to cross the endothelial barrier while antibodies are not, excess antibodies in circulation may be able to flow from the interstitium into the circulation (Geven et al. 2018. Shock. 50(2):132-140 and Voors et al (J. Eur J Heart Fail. 2019 Feb;21(2):163-171)). In addition, the binding of antibodies to ADM results in an extended ADM half-life. Although NT-ADM antibodies partially inhibit ADM-mediated signaling, a substantial increase in circulating ADM results in an overall "net" increase in ADM activity in the blood compartment, expressing beneficial effects on EC (mainly barrier stabilization), while the ADM harmful effects on VSMC (vasodilation) in the interstitium are reduced.

[0013] However, it is an object of the present invention to identify the best timing for administering an antibody against ADM so that a patient optimally benefits from the above mechanism.

[0014] WO 2013 / 072510 describes a non-neutralizing anti-ADM antibody for use in the treatment of severe chronic or acute diseases or acute conditions of a patient in order to reduce the patient's risk of death.

[0015] WO 2013 / 072511 describes a non-neutralizing anti-ADM antibody for use in the treatment of chronic or acute diseases or acute conditions of a patient in order to prevent or reduce organ damage or organ failure.

[0016] WO 2013 / 072512 describes a non-neutralizing anti-ADM antibody that is an ADM-stabilizing antibody that enhances the half-life (t 1 / 2 half residence time) of adrenomedullin in serum, blood, plasma. This ADM-stabilizing antibody blocks the biological activity of ADM to less than 80%.

[0017] WO 2013 / 072513 shows that in patients with chronic or acute diseases or acute conditions requiring stabilization of circulation, anti - adrenomedullin (ADM) antibodies or anti - adrenomedullin antibody fragments or anti - ADM non - Ig scaffolds can stabilize the patient's blood circulation and reduce the need for vasopressors, for example, reduce catecholamines in said patients.

[0018] WO 2013 / 072514 shows that anti - adrenomedullin (ADM) antibodies or anti - adrenomedullin antibody fragments or anti - ADM non - Ig scaffolds can be effectively used to regulate fluid balance in patients with chronic or acute diseases or acute conditions, especially in ICU (intensive care unit) patients suffering from fluid balance disorders.

[0019] WO 2017 / 182561 describes a method for determining the total amount of active DPP3 in a patient sample for diagnosing diseases associated with a necrotic course. It further describes a method for treating necrosis - related diseases with antibodies against DPP3.

Summary of the Invention

[0020] The inventors have found that anti - adrenomedullin (ADM) antibodies or anti - adrenomedullin antibody fragments or anti - ADM non - Ig scaffolds can be particularly effective in the treatment of shocked patients, especially septic shock, when administered within a certain period.

[0021] Therefore, especially when a patient admitted to the ICU requires anti - ADM treatment, anti - ADM antibodies or anti - ADM antibody fragments or anti - ADM non - Ig scaffolds may be administered at that time. According to the present invention, all patients are treated at the optimal timing after shock and / or after ICU admission.

[0022] In addition to and / or in relation to the above - mentioned effects, it is also a surprising discovery of the present invention that when the DPP3 level in a body fluid sample is below a threshold value, shocked patients will have the highest treatment effect using anti - ADM antibodies.

[0023] definition Before describing the present invention in detail, it is convenient to define the specific technical terms used throughout this specification. Although the present invention is described in relation to specific embodiments, this specification should not be construed as restrictive. Before describing the exemplary embodiments of the present invention in detail, we will provide definitions that are important for understanding the present invention.

[0024] As used herein and in the appended claims, the singular forms of "a" and "an" also include their respective plural forms unless the context clearly indicates otherwise.

[0025] In relation to the present invention, the terms “about” and “approximately” indicate an interval of precision that a person skilled in the art would understand to still ensure the technical effect of the feature of the problem. The terms typically represent a deviation of ±20%, preferably ±15%, more preferably ±10%, and even more preferably ±5% from a specified numerical value.

[0026] The term “comprising” should be understood as non-limiting. For the purposes of this invention, the term “consisting of” is considered a preferred embodiment of the term “comprising of.” Hereafter, when a group is defined as including at least a certain number of embodiments, this is intended to also include groups consisting preferably only of these embodiments.

[0027] It should also be understood that the terminology used herein is for the purpose of describing only specific embodiments and is not intended to limit the scope of the invention, which is limited solely by the appended claims.

[0028] According to the present invention, ADM-binding protein 1 may also be called ADM-binding protein 1 (complement factor H).

[0029] As used herein, the term “shock” is characterized by reduced oxygen delivery and / or increased oxygen consumption or insufficient oxygen utilization resulting in cellular and tissue hypoxia. This is a fatal pathological condition of circulatory failure and most often presents as hypotension (systolic blood pressure <90 mmHg or MAP <65 mmHg). Shock is classified into four main types based on its underlying cause: hypovolemic shock, cardiogenic shock, occlusive shock, and distributive shock (Vincent and De Backer 2014. N. Engl. J. Med. 370(6): 583).

[0030] The term "cardiogenic shock" refers to a situation where a patient may have acute coronary syndrome (e.g., acute myocardial infarction), or where such a patient has heart failure (e.g., acute decompensated heart failure), myocarditis, arrhythmia, cardiomyopathy, valvular heart disease, aortic dissection with acute aortic stenosis, traumatic chordal rupture, or extensive pulmonary embolism. Cardiogenic shock (CS) is defined as a severe reduction in end-organ blood flow due to decreased cardiac output. Notably, CS forms a spectrum ranging from mild blood flow reduction to severe shock. The established diagnostic criteria for CS are: (i) systolic blood pressure > ≤ 90 mmHg in 30 minutes or vasopressors required to reach blood pressure ≥ 90 mmHg; (ii) pulmonary congestion or elevated left ventricular filling pressure; (iii) signs of organ perfusion impairment with at least one of the following diagnostic criteria: (a) altered mental state; (b) chills, cold sweats; (c) oliguria (<0.5 mL / kg / hour or <30 mL / hour); (d) elevated serum lactate (Reynolds and Hochman 2008. Circulation 117: 686-697). Acute myocardial infarction (AMI) with subsequent ventricular dysfunction is the most frequent cause of CS, accounting for approximately 80% of cases. Mechanical complications such as ventricular septal rupture (4%) or free wall rupture (2%), and acute severe mitral regurgitation (7%) are less frequent causes of CS after AMI. (Hochman et al. 2000. J Am Coll Cardiol 36: 1063-1070). Non-AMI-related CS can be caused by decompensated valvular heart disease, acute myocarditis, arrhythmias, and others, with heterogeneous treatment options. This accounts for 40,000–50,000 patients per year in the United States and 60,000–70,000 patients per year in Europe. Despite the benefits of treatment, mainly through early revascularization, along with a subsequent decrease in mortality, CS remains a leading cause of death in AMI, with a mortality rate still close to 40–50%, according to recent enrollment and randomized trials (Goldberg et al. 2009. Circulation 119: 1211-1219).

[0031] The term "hypovoluted shock" refers to a condition in which a patient may have spontaneous bleeding in the context of hemorrhagic disorders including gastrointestinal bleeding, trauma, vascular etiology (e.g., ruptured abdominal aortic aneurysm, tumors affecting major blood vessels), and anticoagulant use, or non-hemorrhagic disorders including vomiting, diarrhea, renal loss, skin loss / insensitivity loss (e.g., burns, heatstroke), or third-space loss in the context of pancreatitis, cirrhosis, bowel obstruction, or trauma. Hypovoluted shock is characterized by a decrease in intravascular volume and can be classified into two simplified subtypes: hemorrhagic and non-hemorrhagic. Common causes of hemorrhagic hypovoluted shock include spontaneous bleeding in the context of gastrointestinal bleeding, trauma, vascular etiology (e.g., ruptured abdominal aortic aneurysm, tumors affecting major blood vessels), and anticoagulant use. Common causes of non-hemorrhagic hypovolemic shock include loss of third space in the context of vomiting, diarrhea, renal loss, skin loss / insensitivity (e.g., burns, heatstroke), or pancreatitis, cirrhosis, bowel obstruction, and trauma. For a general overview, see Koya and Paul 2018. Shock. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019-2018 Oct 27.

[0032] The term "vascular occlusive shock" refers to a type of shock in which a patient may have cardiac tamponade, tension pneumothorax, pulmonary embolism, or aortic stenosis. Vascular occlusive shock is caused by a physical obstruction of the major blood vessels or the heart itself. Several conditions can lead to this form of shock (e.g., cardiac tamponade, tension pneumothorax, pulmonary embolism, aortic stenosis). For a general overview, see Koya and Paul 2018. Shock. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019-2018 Oct 27.

[0033] The term "distributive shock" refers to a type of shock in which a patient may be suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. Depending on the cause, there are four types of distributive shock: neurogenic shock (decreased sympathetic nerve stimulation leading to vagal hypotonia), anaphylactic shock, septic shock, and shock caused by an adrenal crisis. In addition to sepsis, distributive shock can be caused by systemic inflammatory response syndrome (SIRS) resulting from non-inflammatory conditions such as pancreatitis, burns, or trauma. Other causes include toxic shock syndrome (TSS), anaphylaxis (sudden, severe allergic reaction), adrenal insufficiency (acute exacerbation of chronic adrenal insufficiency, destruction or removal of the adrenal gland, suppression of adrenal function due to exogenous steroids, pituitary dysfunction, and metabolic dysfunction of hormone production), reactions to drugs or toxins, heavy metal poisoning, liver failure, and damage to the central nervous system. For an overview, see Koya and Paul 2018. Shock. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019-2018 Oct 27.

[0034] Refractory shock was defined as the requirement for norepinephrine infusion >0.5 μg / kg / min despite adequate emergency fluid therapy. The mortality rate in these patients is high at 94%, and the assessment and management of these patients requires a much more aggressive approach to sustain life. The term “refractory shock” is used when intratissue perfusion cannot be restored with initial corrective measures (e.g., vasopressors) and may therefore be called “high vasopressor-dependent” or “vasopressor-resistant” shock (Udupa and Shetty 2018. Indian J Respir Care 7: 67-72). Patients with refractory shock may have features of hypotension (mean arterial pressure <65 mmHg), tachycardia, cold extremities, prolonged capillary refill time, and tachypnea resulting from hypoxia and acidemia. In septic shock, fever may be present. Other signs of decreased blood flow may also be present, such as sensory changes, hyperlactateemia, and oliguria. These well-known signs of shock are not helpful in determining whether the problem lies in the pump (heart) or the circulation (blood vessels and tissues). Different types of shock coexist, and all forms of shock can become refractory when demonstrated by unresponsiveness to high-dose vasopressors (Udupa and Shetty 2018. Indian J Respir Care 7: 67-72).

[0035] Preferred examples of shock include hypovolemic shock, cardiogenic shock, vasoocclusive shock, and distributive shock, particularly cardiogenic shock, septic shock, Covid-19-induced shock, burn-induced shock, and traumatic shock. These examples are defined in more detail below.

[0036] As used herein, the term “ICU admission” refers to a patient admitted to intensive care who has, or may have, one or more acute, directly fatal organ failures requiring the use of organ support. In the art, well-documented criteria for admission to an intensive care unit have been established (Nates et al. (2016), Critical Care Medicine 44: 1553-1602). The term “ICU admission” also encompasses admissions under these criteria.

[0037] Types of organ support include: ·Respiratory support therapy: • Includes advanced respiratory support therapies such as tubal intubation and mechanical ventilation. Basic respiratory support therapies such as oxygen supplementation, incentive spirometry, chest percussion nebulization therapy, and others. • Circulatory support therapies such as artificial circulatory support (e.g., intra-aortic balloon pumping and use of ventricular assist devices) and drug therapy including the use of angiotensin-converting enzyme and beta-blockers, and others. • Renal support therapies such as hemodialysis and peritonitis dialysis. • Hemodynamic monitoring or adjunctive therapy such as blood pressure, blood flow and blood oxygen content, fluid resuscitation or blood transfusion, and measurement of vasoactive agents, such as nitroglycerin, nitric oxide, and others. • Neurological monitoring or assistance such as intraventricular catheterization These are some examples.

[0038] Extracorporeal organ support is described in detail in the examples provided in ICU Management & Practice, Volume 18 - Issue 1, 2018.

[0039] The following clinical criteria for SIRS define sepsis, severe sepsis, and septic shock. 1) Systemic inflammatory host response (SIRS) characterized by at least two of the following symptoms: • The patient exhibits hypotension (mean arterial pressure <65 mmHg). • High serum lactate levels >4 mmol / L • Blood glucose > 7.7 mmol / L (if not diabetic) • Central venous pressure is not within the range of 8-12 mmHg • Urine volume is <0.5 mL × kg -1 x time -1 That is • Central venous (superior vena cava) oxygen saturation is <70% or mixed venous oxygen saturation is <65%. • Heart rate is >90 beats / minute • Body temperature is either <36°C or >38°C. • Respiratory rate is >20 breaths / minute • White blood cell count is <4 or>12 × 10 9 / L (white blood cells); >10% are immature neutrophils 2) Sepsis In addition to at least two of the symptoms mentioned in 1), the clinical suspicion of a new infection is as follows: ·Cough / phlegm / chest pain Abdominal pain / bloating / diarrhea Line infection ·Endocarditis • Urinary dysfunction • Headache accompanied by neck stiffness Cellulitis / wounds / joint infections • Positive microbiology related to any of the infectious diseases 3) Severe sepsis Given that sepsis is present in the patient, the following clinical indications of any organ dysfunction are also present: Systolic blood pressure <90 / average; <65 mmHg ·Lactic acid >2mmol / L Bilirubin >34 μmol / L • Urine output: <0.5 mL / kg / hour in 2 hours • Creatinine > 177 μmol / L Platelets <100 x 10 9 / L • Unless SpO2O2 is given, >90% 4) Septic shock Septic shock refers to a potentially fatal medical condition that occurs when sepsis, which is organ damage or injury in response to an infection, results in dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus on Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly severe circulatory, cellular, and metabolic abnormalities carry a greater risk of death than sepsis alone. Patients with septic shock can be clinically identified by the absence of hypovolemia, the need for vasopressors to maintain a mean arterial pressure of 65 mmHg or higher, and serum lactate levels greater than 2 mmol / L (>18 mg / dL). This combination is associated with an in-hospital mortality rate greater than 40% (Singer et al. 2016. JAMA. 315 (8): 801-10). Primary infection is usually bacterial, but may also be fungal, viral, or parasitic. It can be present in any part of the body, but is most commonly found in the lungs, brain, urinary tract, skin, or abdominal organs. It can lead to multiple organ failure syndrome (formerly known as multiple organ failure) and death. Often, people with septic shock are cared for in the intensive care unit. It usually develops in children, immunocompromised individuals, and the elderly because their immune systems cannot cope with infections as effectively as those of healthy adults. The mortality rate for septic shock is approximately 25–50%. “Septic shock” is also called a fatal organ failure caused by a dysregulated host response to evidence or suspected infection resulting in at least a mean arterial pressure (MAP) drop of <65 mmHg, ineffective fluid resuscitation, and requiring vasopressors. Resistance to fluid resuscitation is defined as a lack of response to the administration of 30 mL of fluid per kilogram of body weight or determined according to the clinician’s assessment of inadequate hemodynamic outcomes. In septic shock according to the present invention, at least one sign of terminal organ dysfunction appears, as mentioned in 3) above. Septic shock is suggested when there is refractory hypotension that does not respond to treatment and intravenous fluid administration alone is insufficient to maintain the patient's blood pressure to prevent hypotension, and according to the present invention, administration of an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is also provided.

[0040] An anti-adrenomedullin (ADM) antibody is an antibody that specifically binds to ADM, and an anti-adrenomedullin antibody fragment is a fragment of the anti-ADM antibody, which specifically binds to ADM. An anti-ADM non-Ig scaffold is a non-Ig scaffold that specifically binds to ADM.

[0041] In one embodiment, the anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold according to the present invention reduces the need for vasopressors, for example, the patient's need for catecholamines. The need for vasopressors, for example, the patient's need for catecholamines, is an indicator of the patient's circulatory status. The anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold may be administered at the time the patient requires vasopressors, for example, catecholamines.

[0042] In one embodiment of the present invention, the patient is a patient in shock who needs to have his blood pressure raised.

[0043] Some patients with septic shock-induced hypotension may remain hypotensive despite adequate fluid replacement. In these cases, vasopressors are necessary to raise MAP. Therefore, in one embodiment of the present invention, patients with chronic or acute diseases or acute conditions are patients who require vasopressors to raise MAP. Catecholamines such as dopamine, epinephrine (adrenaline), norepinephrine (noradrenaline), and phenylephrine have traditionally been used to raise blood pressure in patients with septic shock. More recently, vasopressin has been proposed as a potential vasopressor in patients in a state of shock who need to stabilize circulation.

[0044] Vasopressors such as catecholamines can stabilize circulation in patients with chronic or acute diseases or acute conditions. However, if the patient's condition (hypotension) is very dangerous, vasopressor administration alone, such as catecholamines, may not prevent circulatory failure. For example, the additional administration of anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds along with catecholamines may help stabilize circulation in patients whose condition is so dangerous that catecholamine administration without anti-ADM antibody fragments or anti-ADM non-Ig scaffolds is insufficient to stabilize the patient's circulation.

[0045] Furthermore, vasopressors can have serious side effects. Dopamine stimulates D1 receptors in the renal circulation, leading to vasodilation and increased blood flow. This is one reason why clinicians use low doses of dopamine to protect renal function. Regarding other vasopressors, despite their intuitive appeal as something beneficial, it has been suggested that elevated blood pressure with certain drugs may be associated with a worse prognosis.

[0046] Therefore, the subject of the present invention is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients in shock to replace all or part of the administration of vasopressors. This means that the patients according to the present invention may be patients who require or require treatment with vasopressors or patients who are receiving treatment with vasopressors.

[0047] Therefore, the circulatory stabilizing effect of anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds may be adjunct to the primary treatment of shock. In one embodiment, this means administering anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds in addition to first-line treatment. In the case of shock, e.g., septic shock or similar, the primary treatment would be, for example, antibody administration. Anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds stabilize circulation and may help prevent the patient's dangerous condition from worsening, for example, until antibiotic administration is effective. As stated above, anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds may be administered in a prophylactic or therapeutic method, if a circulatory problem exists in the patient, meaning to prevent or stabilize the circulatory problem.

[0048] It should be emphasized that the cyclical problems included in the present invention may be acute cyclical problems according to specific embodiments of the present invention.

[0049] In one embodiment of the present invention, an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is used in combination with a vasopressor, such as a catecholamine, for use in the treatment of a patient in shock to stabilize the patient's circulation.

[0050] In one embodiment of the present invention, the patient in shock who needs to have his circulation stabilized is characterized in that the patient needs to be administered a vasopressor, such as a catecholamine.

[0051] Accordingly, in one particular embodiment, the subject of the present invention is an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment that conjugates to ADM or an anti-ADM non-Ig scaffold that conjugates to ADM, for use in the treatment of patients who require administration of vasopressors, for example, catecholamines.

[0052] Furthermore, in one embodiment of the present invention, an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is used in combination with an intravenously administered fluid, the combination being used in the treatment of a patient in shock to stabilize the patient's circulation. In one embodiment of the present invention, the patient having shock and needing circulatory stabilization is characterized in that the patient needs to receive intravenous fluid administration.

[0053] Therefore, in one particular embodiment, the subject of the present invention is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients in shock and particularly those requiring intravenous fluid administration. [Modes for carrying out the invention]

[0054] Detailed description of embodiments of the invention Embodiments of the present invention are shown below. Generally speaking, embodiments can be combined with other embodiments of the same category (product, process, use, method).

[0055] One embodiment of the present invention relates to an adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient: • At the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, the patient is in shock, particularly septic shock, for 10 hours or less, and / or • The patient has been admitted to the ICU for 10 hours or less at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or • At the start of treatment with the aforementioned anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient was not receiving any organ support or had received organ support for 10 hours or less. The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0056] One embodiment of the present invention relates to an adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient: • At the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, the patient is in shock, particularly septic shock, and / or • The patient has been admitted to the ICU for 8.4 hours or less at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or • At the start of treatment with the aforementioned anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient was not receiving any organ support or had received organ support for 8.4 hours or less. The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0057] A preferred embodiment is for use in the treatment of patients with shock, particularly septic shock, where the patient: • At the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, the patient is in shock, particularly septic shock, for 10 hours or less, and / or • The patient has been admitted to the ICU for 10 hours or less at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or • At the start of treatment with the aforementioned anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient was not receiving any organ support or had received organ support for 10 hours or less. The antibody or fragment or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM, If a) the patient is suffering from shock lasting less than 10 hours, particularly septic shock, and b) is hospitalized for less than 10 hours, the earliest possible initiation point for treatment using the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is among a) and b).

[0058] In another embodiment, if a) the patient is admitted to the ICU for 10 hours or less and c) receives organ support for 10 hours or less, the starting point for treatment with anti-adrenomedullin (ADM) antibodies, anti-adrenomedullin antibody fragments, or anti-ADM non-Ig scaffolds is the shortest possible time among a) and c).

[0059] In another embodiment, if a patient is b) suffering from shock of less than 10 hours, particularly septic shock, and c) has received organ support for less than 10 hours, the starting point for treatment with anti-adrenomedullin (ADM) antibodies or anti-adrenomedullin antibody fragments or anti-ADM non-Ig scaffolds is the earliest of b) and c).

[0060] In another embodiment, if a) the patient is suffering from shock of 10 hours or less, particularly septic shock, b) the patient has been in shock for 10 hours or less, and c) the patient has received organ support for 10 hours or less, the starting point for treatment with anti-adrenomedullin (ADM) antibodies or anti-adrenomedullin antibody fragments or anti-ADM non-Ig scaffolds is the shortest of a), b), and c).

[0061] In another embodiment, the present invention relates to an adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient: • The patient has been in shock for 10 hours or less at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, and / or • The patient has been admitted to the ICU for 10 hours or less at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or • At the start of treatment with the aforementioned anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient was not receiving any organ support or had received organ support for 10 hours or less. The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0062] In a preferred embodiment, the patient is suffering from shock, particularly septic shock, at a time of 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), 5 hours, preferably 4 hours, or preferably 3 hours, at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0063] In a preferred embodiment, the patient has been in shock, particularly septic shock, for 8.4 hours or less, preferably 8.26 hours (0.344 days), at the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0064] In a preferred embodiment, the patient is admitted to the ICU for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0065] In a preferred embodiment, the patient is admitted to the ICU for 8.4 hours or less and 8.26 hours (0.344 days) or less at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0066] In a preferred embodiment, the patient receives organ support for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, and preferably 3 hours at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0067] In a preferred embodiment, the patient has received organ support for 8.4 hours or less and 8.26 hours (0.344 days) or less at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0068] In another embodiment, the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is for use in the treatment of patients suffering from shock, particularly septic shock, and the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is, • Within 10 hours after the onset of shock in the aforementioned patient, and / or • Within 10 hours of admission to the ICU, and / or • The patient in question is either before or within 10 hours of receiving organ support. Administer with, The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0069] In another embodiment, the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is for use in the treatment of patients suffering from shock, particularly septic shock, and the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is, • Within 8.4 hours after the onset of shock in the aforementioned patient, and / or • The patient is within 8.4 hours of admission to the ICU, and / or • The patient in question is either before or within 10 hours of receiving organ support. Administer with, The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0070] In preferred embodiments, the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is for use in the treatment of patients suffering from shock, particularly septic shock, and the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is used • Within 10 hours after the onset of shock in the aforementioned patient, and / or • Within 10 hours of admission to the ICU, and / or • The patient in question is either before or within 10 hours of receiving organ support. Administer with, The antibody or fragment or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM, Anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold may be administered a) within 10 hours after the onset of shock in the patient and b) within 10 hours after the patient's admission to the ICU, with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold being administered as soon as possible between a) and b).

[0071] In another embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold may be administered a) within 10 hours after the onset of shock in the patient and c) before the patient receives organ support or within 10 hours of organ support, with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold being administered at the earliest possible time among a) and c).

[0072] In another embodiment, an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold may be administered b) within 10 hours of the patient's admission to the ICU and c) before the patient receives organ support or within 10 hours of organ support, with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold being administered at the earliest possible time among b) and c).

[0073] In another embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold may be administered a) within 10 hours after the onset of shock in the patient, b) within 10 hours after the patient's admission to the ICU, and c) before the patient receives organ support or within 10 hours of organ support, with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold being administered at the shortest possible time among a), b), and c).

[0074] In another embodiment, the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is for use in the treatment of patients suffering from shock, particularly septic shock, and the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is, • Within 10 hours after the onset of shock in the aforementioned patient, and / or • Within 10 hours of admission to the ICU, and / or • The patient in question is either before or within 10 hours of receiving organ support. Administer with, The antibody or fragment or scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4) of ADM.

[0075] In a preferred embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the onset of shock and / or sepsis in the patient.

[0076] In a preferred embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold is administered within 8.4 hours, preferably 8.26 hours (0.344 days), after the onset of shock and / or sepsis in the patient.

[0077] In a preferred embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold is administered within 9 hours of the patient's admission to the ICU, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours.

[0078] In a preferred embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold is administered within 8.4 hours, preferably 8.26 hours (0.344 days), after the patient is admitted to the ICU.

[0079] In a preferred embodiment, the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient has received organ support at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0080] In a preferred embodiment, the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered 8.4 hours, preferably 8.26 hours (0.344 days), after the patient has received organ support at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold.

[0081] In another specific embodiment of the present invention, the shock is selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock and distributive shock, and in particular is cardiogenic shock or septic shock.

[0082] In a particular embodiment of the present invention, the shock is: In cases of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or heart failure (e.g., acute decompensated heart failure), myocarditis, arrhythmia, cardiomyopathy, valvular heart disease, aortic dissection with acute aortic stenosis, traumatic chordal rupture, or extensive pulmonary embolism, or In cases of hypovolemic shock, the patient may have a hemorrhagic disorder including gastrointestinal bleeding, trauma, vascular etiology (e.g., ruptured abdominal aortic aneurysm, tumors affecting major blood vessels), or a non-hemorrhagic disorder including spontaneous bleeding or vomiting, diarrhea, renal loss, skin loss / insensitivity (e.g., burns, heatstroke), or pancreatitis, cirrhosis, bowel obstruction, or third-space loss in the context of trauma, or In cases of vascular occlusive shock, the patient may have cardiac tamponade, tension pneumothorax, pulmonary embolism, or aortic stenosis, or In cases of distributive shock, the patient is suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. It is selected from the group that includes it.

[0083] In a more preferred embodiment, the shock is septic shock, shock caused by Covid-19, shock caused by burns, or traumatic shock.

[0084] In the most preferred embodiment, the shock was related to sepsis.

[0085] In further embodiments, the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or was admitted to the ICU within 10 hours or less at the initiation of treatment, and / or is a patient who has received no organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein a body fluid sample taken from the patient shows a bio-ADM level of >70 pg / mL, and the body fluid is selected from the group including whole blood, plasma, and serum.

[0086] While numerous markers are known in conventional technologies related to shock, none have specifically suggested DPP3 as a marker of shock. Examples of such biomarkers include MR-proADM, lactate, C-reactive protein (CRP), and procalcitonin (PCT) (Ana Maria Navio Serano,1 Joaqui'n Valle Alonso,2,* Gustavo Rene Piniero,3 Alejandro Rodriguez Camacho,4 Josefa Soriano Benet,5 and Manuel Vaquero6 Bull Emerg Trauma. 2019 Jul; 7(3): 232-239.), as well as pentraxin 3, heparin-binding protein, soluble trigger receptor, PARK7, and IL-8, which have been cited in recent reviews (Charalampos Pierrakos, Dimitrios Velissaris, Max Bisdorff, John C. Marshall & Jean-Louis Vincent Critical Care volume 24, Article number: 287 (2020) Biomarkers of sepsis: time for a reappraisal).

[0087] In preferred embodiments, bio-ADM is measured from plasma. However, in the improvement of the technical lifecycle of analyte measurement, it is typical that there is the possibility of measuring such analytes not only in plasma but also in other—at least blood-based—matrices. For example, in the case of bio-ADM, another technique has been developed that uses whole (EDTA-) blood, called IB10 sphingotest® bio-ADM (https: / / www.nexus-dx.com / wp-content / uploads / 2020 / 07 / bio-ADM-IFU-REV-A.pdf). IB10 sphingotest® bio-ADM® is a rapid point-of-care (POC) immunoassay for the in vitro quantitative determination of the human amidated adrenomedullin peptide (1-52), hereafter referred to as bioactive adrenomedullin (bio-ADM®), in human EDTA whole blood and plasma.

[0088] Dipeptidylaminopeptidase III, also known as dipeptidylarylamidase III, dipeptidylpeptidase III, enkephalinase B, or erythrocyte angiotensinase; abbreviated as DPP3 or DPPIII, is a metallopeptidase that removes dipeptides from physiologically active peptides such as enkephalins and angiotensins. DPP3 was first identified, and its activity was measured in an extract of purified bovine anterior pituitary gland by Ellis & Nuenke 1967. The enzyme, listed as EC3.4.14.4, has a molecular weight of approximately 83 kDa and is highly conserved in prokaryotes and eukaryotes (Prajapati & Chauhan 2011). The amino acid sequence of the human variant is shown in Sequence ID No. 1. Dipeptidylpeptidase III is a ubiquitous, primarily cytoplasmic peptidase. Despite the lack of a signal sequence, several studies have reported membrane activity (Lee & Snyder 1982).

[0089] DPP3 is a zinc-dependent exopeptidase belonging to the peptidase family M49. It has broad substrate specificity for oligopeptides from 3 / 4 to 10 amino acids in various compositions and can also cleave after proline. DPP3 is known to hydrolyze dipeptides from the N-terminus of its substrates, including angiotensin II, III, and IV; Leu- and Met-enkephalins; and endomorphin 1 and 2. The metallopeptidase DPP3 has optimal activity conditions at pH 8.0-9.0. 2+ and Mg 2+ It can be activated by the addition of divalent metal ions such as those mentioned above.

[0090] Structural analysis of DPP3 revealed the catalytic motifs HELLGH (hDPP3 450-455) and EECRAE (hDPP3 507-512), as well as the following amino acids important for substrate binding and hydrolysis: Glu316, Tyr318, Asp366, Asn391, Asn394, His568, Arg572, Arg577, Lys666, and Arg669 (Prajapati & Chauhan 2011; Kumar et al. 2016; numbering represents the sequence of human DPP3, see Sequence ID No. 1). Considering all known amino acids or sequence regions related to substrate binding and hydrolysis, the active site of human DPP3 can be defined as the region of amino acids 316-669.

[0091] The most prominent substrates of DPP3 are angiotensin II (AngII) and the renin-angiotensin system (RAS), which are tumor effectors. The RAS is activated in cardiovascular diseases (Dostal et al. 1997. J Mol Cell Cardiol;29:2893-902; Roks et al. 1997. Heart Vessels. Suppl 12:119-24), sepsis, and septic shock (Corre^a et al. 2015. Crit Care 2015;19:98). In particular, AngII is known to modulate many cardiovascular functions, including the control of blood pressure and cardiac remodeling.

[0092] Recently, two assays have been developed, characterized, and validated to specifically detect DPP3 in human bodily fluids (e.g., blood, plasma, serum): a luminescence immunoassay (LIA) for detecting DPP3 protein concentration and an enzyme capture activity assay (ECA) for detecting specific DPP3 activity (Rehfeld et al. 2019. JALM 3(6): 943-953). After removing all interfering substances by a washing step, the actual detection of DPP3 activity is performed. Both methods are highly specific and enable reproducible detection of DPP3 in blood samples.

[0093] Circulating DPP3 levels were found to be elevated in patients with cardiogenic shock and were associated with an increased risk of early mortality and severe organ failure (Deaniau et al. 2019. Eur J Heart Fail. in press). Furthermore, DPP3 was measured in comprehensively discriminatory cardiogenic shock patients who developed refractory shock compared to intractable shock, and DPP3 concentrations ≥ 59.1 ng / mL were associated with a higher risk of death (Takagi et al. Eur J Heart Fail. 2020 Feb;22(2):279-286).

[0094] In further embodiments, the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the start of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 9 hours or less at the start of treatment, and / or received no organ support or 9 hours or less at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein a fluid sample taken from the patient shows a DPP3 level below the threshold, and the fluid is selected from the group including whole blood, plasma, and serum.

[0095] In the most preferred embodiment, the patient has a DPP3 level in a body fluid sample below a threshold, wherein the threshold for the DPP3 level in the patient's body fluid sample is 20-120 ng / mL, more preferably 30-80 ng / mL, even more preferably 40-60 ng / mL, and most preferably 50 ng / mL.

[0096] In certain embodiments of the present invention, the DPP3 level threshold is a 5-fold median concentration, preferably a 4-fold median concentration, more preferably a 3-fold median concentration, and most preferably a 2-fold median concentration, compared to the healthy population.

[0097] The amount of DPP3 protein and / or DPP3 level as DPP3 activity in the aforementioned body fluid sample may be determined by different methods, such as immunoassay, activity assay, mass spectrometry, or the like.

[0098] b) A DPP3 enzyme assay that is specific to DPP3 by specifically capturing DPP3 from a sample using a specific binder (anti-DPP3 antibody or other type of binder) before determining enzyme activity, and several types of binding assays (immunoassays and similarity assays, using other types of antigen-specific binders instead of antibodies).

[0099] DPP3 activity can be measured by detecting the cleavage products of DPP3-specific substrates. Known peptide hormone substrates include Leu-enkephalin, Met-enkephalin, endomorphin 1 and 2, valorphin, β-casomorphin, dynorphin, proctrin, ACTH (adrenocorticotropic hormone), and MSH (melanocyte-stimulating hormone; Abramic' et al. 2000, Barshun et al. 2007, Dhanda et al. 2008). The cleavage of the mentioned peptide hormones and other untagged oligopeptides (e.g., Ala-Ala-Ala-Ala, Dhanda et al. 2008) can be monitored by detecting their respective cleavage products. Detection methods include, but are not limited to, HPLC analysis (e.g., Lee & Snyder 1982), mass spectrometry (e.g., Abramic' et al. 2000), H1-NMR analysis (e.g., Vandenberg et al. 1985), capillary zone electrophoresis (CE; e.g., Barshun et al. 2007), thin-layer chromatography (e.g., Dhanda et al. 2008), or reverse-phase chromatography (e.g., Mazocco et al. 2006).

[0100] Detection of fluorescence by hydrolysis of fluorescence-generating substrates by DPP3 is a standard procedure for monitoring DPP3 activity. These substrates are specific di- or tripeptides (Arg-Arg, Ala-Ala, Ala-Arg, Ala-Phe, Asp-Arg, Gly-Ala, Gly-Arg, Gly-Phe, Leu-Ala, Leu-Gly, Lys-Ala, Phe-Arg, Suc-Ala-Ala-Phe) conjugated to fluorophores. Examples of fluorophores include, but are not limited to, β-naphthylamides (2-naphthylamide, βNA, 2NA), 4-methoxy-β-naphthylamide (4-methoxy-2-naphthylamide), and 7-amide-4-methylcoumarin (AMC, MCA; Abramic' et al. 2000, Ohkubo et al. 1999). The cleavage of these fluorescence-generating substrates yields either fluorescent β-naphthylamine or 7-amino-4-methylcoumarin, respectively. In liquid-phase assays or ECAs, the substrate and DPP3 are incubated, for example, in a 96-well plate format, and fluorescence is measured using a fluorescence detector (Ellis & Nuenke 1967). In addition, DPP3-carrying samples can be immobilized and separated on a gel by electrophoresis. The gel is stained with a fluorescence-generating substrate (e.g., Arg-Arg-βNA) and fast garnet GBC, and the fluorescent protein bands are detected by a fluorescence reader (Ohkubo et al. 1999). The same peptides (Arg-Arg, Ala-Ala, Ala-Arg, Ala-Phe, Asp-Arg, Gly-Ala, Gly-Arg, Gly-Phe, Leu-Ala, Leu-Gly, Lys-Ala, Phe-Arg, Suc-Ala-Ala-Phe) can be bound to chromophores such as p-nitroanilidone acetate. DPP3 activity can be monitored by detecting the color change due to hydrolysis of the chromogenic substrate.

[0101] Another option for detecting DPP3 activity is the Protease-Glo® assay (commercially available from Promega). In this embodiment of the method, a DPP3-specific di- or tripeptide (Arg-Arg, Ala-Ala, Ala-Arg, Ala-Phe, Asp-Arg, Gly-Ala, Gly-Arg, Gly-Phe, Leu-Ala, Leu-Gly, Lys-Ala, Phe-Arg, Suc-Ala-Ala-Phe) is bound to aminoluciferin. Upon cleavage by DPP3, aminoluciferin is released and acts as a substrate for a binding luciferase reaction that emits detectable luminescence.

[0102] In a preferred embodiment, DPP3 is measured by adding the fluorescence-generating substrate Arg-Arg-βNA, and fluorescence is monitored in real time.

[0103] In a particular embodiment of the method for determining active DPP3 in a target bodily fluid sample, the scavenging agent that reacts with DPP3 is immobilized on a solid phase.

[0104] The test sample passes through the immobile binder, and if present, DPP3 binds to the binder and is immobilized for detection. A substrate may then be added, and the reaction product may be detected to indicate the presence or amount of DPP3 in the test sample. For the purposes of this specification, the term “solid phase” may be used to include any substance or vessel in which the assay may be performed or on which it may be performed, including but not limited to porous materials, non-porous materials, test tubes, wells, slides, agarose resin (e.g., Sepharose from GE Healthcare Life Sciences), magnetic particles (e.g., Dynabeads® or Pierce® magnetic beads from Thermo Fisher Scientific), and others.

[0105] In another embodiment of the present invention, the DPP3 level is determined by contacting the bodily fluid sample with a scavenging agent that specifically binds to DPP3.

[0106] In another preferred embodiment of the present invention, the capture and binding agent for determining the DPP3 level may be selected from the group consisting of antibodies, antibody fragments, or non-IgG scaffolds.

[0107] In a particular embodiment of the present invention, the capture and binding agent is an antibody. The amount of the DPP3 protein and / or DPP3 activity in the target body fluid sample may be determined, for example, by one of the following methods:

[0108] 1. Luminescent immunoassay (LIA) for quantifying DPP3 protein concentration (Rehfeld et al., 2019 JALM 3(6): 943-953). LIA is a one-step chemiluminescent sandwich immunoassay using white, highly binding polystyrene microtiter plates as the solid phase. These plates are coated with monoclonal anti-DPP3 antibody AK2555 (capture antibody). Tracer anti-DPP3 antibody AK2553 is labeled with MA70-acridinium NHS ester and used at a concentration of 20 ng per well. 20 microliters of sample (e.g., serum, heparin-plasma, citrate-plasma, or EDTA-plasma derived from patient blood) and a calibration sample are pipetteed into the coated white microtiter plates. After adding tracer antibody AK2553, the microtiter plates are incubated at room temperature and 600 rpm for 3 hours. Then, unbound tracers are removed by four washing steps (350 μL per well). The remaining chemiluminescence is measured for 1 second per well using a microtiter plate luminometer. The DPP3 concentration is determined using a 6-point calibration curve. The calibration sample and the sample are preferably repeated twice.

[0109] 2. Enzyme capture activity assay (ECA) for quantifying DPP3 activity (Rehfeld et al., 2019 JALM 3(6): 943-953). ECA is a DPP3-specific activity assay that uses black, highly binding polystyrene microtiter plates as the solid phase. These plates are coated with the monoclonal anti-DPP3 antibody AK2555 (capture antibody). 20 microliters of sample (e.g., serum, heparin-plasma, citrate-plasma, EDTA-plasma, cerebrospinal fluid, and urine) and a calibration sample are pipetted into the coated black microtiter plate. After adding assay buffer (200 μL), the microtiter plate is incubated at 22°C and 600 rpm for 2 hours. DPP3 present in the sample is immobilized by binding to the capture antibody. Unbound sample components are removed by four washing steps (350 μL per well). The specific activity of immobilized DPP3 is measured by adding a fluorescence-generating substrate and Arg-Arg-β-naphthylamide (Arg2-βNA) to the reaction buffer and incubating at 37°C for 1 hour. DPP3 specifically cleaves Arg2-βNA into Arg-Arg dipeptide and fluorescent β-naphthylamine. Fluorescence is measured using a fluorometer with an excitation wavelength of 340 nm, and emission is detected at 410 nm. The activity of DPP3 is determined using a 6-calibration curve. Calibration samples and test samples are preferably repeated twice.

[0110] 3. Liquid-phase assay (LAA) for quantifying DPP3 activity (modified from Jones et al., Analytical Biochemistry, 1982). The LAA is a liquid-phase assay that uses a black non-binding polystyrene microtiter plate to measure DPP3 activity. 20 microliters of a sample (e.g., serum, heparin-plasma, citrate-plasma) and a calibration sample are pipetted into a non-binding black microtiter plate. After adding the fluorogenic substrate, Arg2-βNA, into the assay buffer (200 μL), the initial βNA fluorescence (T = 0) is measured with a fluorometer using an excitation wavelength of 340 nm, and the emission is detected at 410 nm. Then, the plate is incubated at 37 °C for 1 hour. The final fluorescence at (T = 60) is measured. The difference between the final and initial fluorescence is calculated. The activity of DPP3 is determined using a six-point calibration curve. The calibration samples and the samples are preferably repeated twice. In certain embodiments, an assay is used to determine DPP3 levels, and the assay sensitivity of said assay is capable of quantifying DPP3 in healthy subjects, <20 ng / ml, preferably <30 ng / ml, more preferably <40 ng / ml.

[0111] Another immunoassay method for measuring DPP3 from plasma of whole blood samples is the commercially available IB10 sphingotest® DPP3 (https: / / www.nexus-dx.com / wp-content / uploads / 2020 / 11 / DPP3-022-00072-IFU-REV-B_8x11.pdf). The IB10 sphingotest® DPP3 is a rapid point-of-care (POC) immunoassay for the in vitro quantification of dipeptidyl peptidase 3 (DPP3) in human EDTA whole blood and plasma. The Nexus IB10 immunochemistry system can rapidly prepare cell-free plasma from whole blood by combining chemistry with microfluidics and centrifugal flow, and then proceed through channels and mix with rehydrated, lysed, and lyophilized immune complexes. In certain embodiments, the binder has a binding affinity for DPP3 of at least 10 7 M -1 , preferably 10 8 M -1 and a more preferred affinity is 109 M -1 The larger and most preferred affinity is 10 10 M -1 Larger. Those skilled in the art will know that it may be conceivable to compensate for lower affinity by applying higher doses of the compound, and this measurement is not outside the scope of the present invention.

[0112] In another embodiment of the present invention, the body fluid sample is selected from the group consisting of whole blood, plasma, and serum.

[0113] In certain embodiments, DPP3 levels are measured using an immunoassay. Immunoassays for determining DPP3 are known from the literature. More specifically, the immunoassay is used as described, for example, in International Publication No. 2017 / 182561. Immunoassays that may be useful for determining the levels of DPP3 or its fragments of at least five amino acids may be used in the examples and may include the steps described in the claims. All thresholds and values ​​should be viewed in correlation with the calibrations used according to the tests and examples. Those skilled in the art may know that the absolute value of a threshold may be affected by the calibration used. This means that all values ​​and thresholds shown herein should be understood in relation to the calibration used.

[0114] The threshold is predetermined by measuring the DPP3 concentration and / or DPP3 activity in healthy controls and calculating, for example, the corresponding 75th percentile, more preferably the 90th percentile, and even more preferably the 95th percentile. The upper boundary of the 75th percentile, more preferably the 90th percentile, and even more preferably the 95th percentile defines the health threshold for diseased patients. In relation to the percentile values, the threshold separating healthy and diseased patients may be 5-25 ng / ml, more preferably 7-20 ng / ml, more preferably 8-18 ng / ml, and most preferably 10-15 ng / ml in plasma using a sandwich-type anti-DPP3 immunoassay (see Example 3). In a plasma DPP3-specific enzyme capture activity assay, the threshold separating healthy and diseased patients is 0.5-2 nmol βNA -1 ml -1 , more preferably 0.7~1.8 nmol βNA fraction -1 ml -1 , more preferably 0.8~1.5 nmol βNA fraction -1 ml -1 Most preferably 1.0 to 1.3 nmol βNA fractions -1 ml -1 , more preferably (see Example 5).

[0115] Those skilled in the art know how to determine thresholds from previously conducted trials. Those skilled in the art understand that a particular threshold may depend on the cohort used to calculate predetermined thresholds that may be routinely used later. Those skilled in the art understand that a particular threshold may depend on the calibration used in the assay. Those skilled in the art understand that a particular threshold may depend on the sensitivity and / or specificity that is deemed acceptable to practitioners.

[0116] The sensitivity and specificity of a diagnostic test depend not only on the "quality" of the test analysis but also on the clarity of what constitutes an abnormal outcome. In practice, the patient operating characteristic curve (ROC curve) is typically calculated by plotting the values ​​of a variable against its relative frequency in the "normal" (i.e., clearly healthy) and "disease" populations (i.e., patients with infectious diseases). Depending on the specific interview being conducted, the reference group does not necessarily have to be "normal," but the disease group under consideration may be a group of patients with another disease or condition from which differentiation is being considered. For any particular marker, the distribution of marker levels in subjects with and without disease will likely overlap. Under such conditions, the test will not absolutely distinguish between normal and disease with 100% accuracy, and the overlapping region indicates where it cannot distinguish between normal and disease. A threshold is selected that is greater than (or lower than, depending on how the marker changes in disease) the test is considered abnormal, and less than the test is considered normal. The area under the ROC curve is a measure of the probability that a perceived measurement allows for accurate identification of a condition. ROC curves can be used even when test results do not necessarily provide exact numbers. ROC curves can be constructed as long as the results can be ranked. For example, test results for a “disease” sample may be ranked according to degree (e.g., 1=low, 2=normal, 3=high). This ranking can show the correlation with the results of the “normal” population and the resulting ROC curve. These methods are well known in the art (see, e.g., Hartley et al, 1982). Preferably, a threshold is selected to provide an ROC curve area greater than about 0.5, more preferably greater than about 0.7. In this context, the term “about” represents ±5% of a given measurement.

[0117] Once the threshold is determined by using the previous trial cohort and considering all of the above points, the physician will use the predetermined threshold for the disease diagnostic method according to the present invention to determine whether the subject has a value greater than or less than the predetermined threshold in order to make an appropriate diagnosis.

[0118] One embodiment of the present application relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the start of treatment with the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold and / or was admitted to the ICU within 10 hours or less at the start of treatment, and further characterized in that the patient has an ADM-NH2 level greater than a threshold in a body fluid sample, wherein the body fluid is selected from the group including whole blood, plasma, and serum.

[0119] One embodiment of the present application relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the start of treatment with the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold and / or was admitted to the ICU for 8.4 hours or less at the start of treatment, and further characterized in that the patient has an ADM-NH2 level greater than a threshold in a body fluid sample, wherein the body fluid is selected from the group including whole blood, plasma, and serum.

[0120] In one preferred embodiment of the present application, the threshold for ADM-NH2 in the patient's body fluid sample is 40 to 100 pg / mL, more preferably 50 to 90 pg / mL, even more preferably 60 to 80 pg / mL, and most preferably 70 pg / mL.

[0121] Another embodiment of the present application relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, wherein the ADM-NH2 level is determined by contacting the body fluid sample with a capture binder that specifically binds to ADM-NH2.

[0122] The aforementioned antibody or fragment or scaffold binds to the N-terminal ADM (SEQ ID NO: 4) as detailed below.

[0123] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein the antibody, antibody fragment or non-Ig scaffold is the central region of adremedullin, aa21~42: CTVQKLAHQIYQFTDKDKDNVA(Sequence ID 3) The present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, characterized by its binding with an anti-ADM antibody, for use in the treatment of shock, particularly septic shock patients.

[0124] Another embodiment of the present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or was admitted to the ICU within 8.4 hours at the initiation of treatment, and / or is a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation of treatment with the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold, wherein the antibody, antibody fragment, or non-Ig scaffold is the central region of adremedullin, aa21~42: CTVQKLAHQIYQFTDKDKDNVA(Sequence ID 3) The present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, characterized by its binding with an anti-ADM antibody, for use in the treatment of shock, particularly septic shock patients.

[0125] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or antibody fragment or non-Ig scaffold is monospecific, particularly monoclonal, and relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock.

[0126] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or antibody fragment or non-Ig scaffold is monospecific, particularly monoclonal, and relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock.

[0127] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein the patient is not receiving any organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein according to any of the preceding embodiments, the antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system for at least 10 -7This invention relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold exhibiting binding affinity for ADM, for use in the treatment of patients with shock, particularly septic shock. In a more preferred embodiment, the antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system, resulting in 1 × 10⁻¹⁶ -9 ~3×10 -9 It exhibits binding affinity to ADM. In a more preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is an IgG1 antibody.

[0128] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H).

[0129] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H).

[0130] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment or scaffold recognizes and binds to the N-terminus (aa1) of ADM.

[0131] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment or scaffold recognizes and binds to the N-terminus (aa1) of ADM.

[0132] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment, and / or a patient who is not receiving any organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment or scaffold has a half-life (t) of ADM in serum, blood, or plasma. 1 / 2 The present invention relates to an ADM-stabilized antibody or fragment or scaffold for use in the treatment of shock, particularly septic shock patients, which is an ADM-stabilized antibody or fragment or an anti-ADM non-Ig scaffold that extends the half-residence time by at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100%.

[0133] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the start of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or is admitted to the ICU within 10 hours or less at the start of treatment, and / or the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold The present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein, according to any of the previous embodiments, the antibody, antibody fragment, or non-Ig scaffold blocks the biological activity of ADM by 80% or less, preferably 50% or less, using hADM22-52 as a reference antagonist in CHO-K1 cells expressing the human recombinant ADM receptor.

[0134] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugating to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation point of treatment, and / or a patient who is not receiving any organ support or has received organ support for 10 hours or less at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment has the N-terminal region (aa1~21) (SEQ ID NO: 4) or heavy chain of ADM sequence: CDR1: Sequence ID 5 GYTFSRYW CDR2: Sequence ID 6 ILPGSGST CDR3: Sequence ID 7 TEGYEYDGFDY It includes, and the light chain is in sequence: CDR1: Sequence ID 8 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 9 FQGSHIPYT This relates to a human monoclonal antibody or fragment that conjugates to an antibody fragment, including ADM, for use in the treatment of patients with shock, particularly septic shock.

[0135] A preferred embodiment of the present invention is a human monoclonal antibody or fragment conjugating to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation point of treatment, and / or a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment has the N-terminal region (aa1~21) (SEQ ID NO: 4) or heavy chain of ADM sequence: CDR1: Sequence ID 5 GYTFSRYW CDR2: Sequence ID 6 ILPGSGST CDR3: Sequence ID 7 TEGYEYDGFDY It includes, and the light chain is in sequence: CDR1: Sequence ID 8 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 9 FQGSHIPYT This relates to a human monoclonal antibody or fragment that conjugates to an antibody fragment, including ADM, for use in the treatment of patients with shock, particularly septic shock.

[0136] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation point of treatment, and / or a patient receiving no organ support or organ support for 10 hours or less at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment has a VH region as: Sequence number 10 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGT TLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 11 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 12 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 13 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 14 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHH The VL region includes sequences selected from the group containing the following: Sequence ID 15 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 16 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 17 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to a human monoclonal antibody or fragment that conjugates to ADM, or to such antibody fragment for use in the treatment of patients with shock, particularly septic shock.

[0137] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation point of treatment, and / or a patient who is not receiving any organ support or has received organ support for 8.4 hours or less at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the previous embodiments, the antibody or fragment has a VH region as: Sequence number 10 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGT TLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 11 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 12 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 13 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 14 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH The VL region includes sequences selected from the group containing the following: Sequence ID 15 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 16 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 17 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to a human monoclonal antibody or fragment that conjugates to ADM, or to such antibody fragment for use in the treatment of patients with shock, particularly septic shock.

[0138] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein the patient is not receiving any organ support or has received organ support for 10 hours or less at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, and according to any of the previous embodiments, the antibody or fragment has a heavy chain as: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFScSVMHEALHNHYTQKSLSLSPGK The light chain includes a sequence selected from the group containing the following: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to a human monoclonal antibody or fragment that conjugates to ADM, or to such antibody fragment for use in the treatment of patients with shock, particularly septic shock.

[0139] In a particular embodiment of the present invention, the antibody has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or an array that is identical to this by >95%, preferably >98%, preferably >99%. It includes the following sequence as a light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or an array that is >95%, preferably >98%, preferably 99% identical to this. Includes.

[0140] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 8.4 hours or less at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold and / or admitted to the ICU within 8.4 hours or less at the initiation point of treatment, and / or a patient who has received no organ support or organ support for 8.4 hours or less at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, wherein, according to any of the preceding embodiments, the antibody or fragment has a heavy chain as: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFScSVMHEALHNHYTQKSLSLSPGK The light chain includes a sequence selected from the group containing the following: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to a human monoclonal antibody or fragment that conjugates to ADM, or to such antibody fragment for use in the treatment of patients with shock, particularly septic shock.

[0141] In a particular embodiment of the present invention, the antibody has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or an array that is identical to this by >95%, preferably >98%, preferably >99%. It includes the following sequence as a light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or an array that is >95%, preferably >98%, preferably 99% identical to this. Includes.

[0142] Pairwise alignment is performed to evaluate the identity between two amino acid sequences. Identity is defined as the percentage of directly matching amino acids in the alignment.

[0143] In another embodiment, the anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, and binds to the N-terminal portion (amino acids 1-10) of ADM: YRQSMNNFQG (SEQ ID NO: 25).

[0144] However, the present invention is not particularly limited to the use of adrecizumab. There is no reason to doubt that what is true for adrecizumab will also be true for antibodies that share the main essential characteristics (particularly affinity and epitope specificity). Antibodies targeting the same region should be expected to have the same technical effect if they have the same affinity and the same or very comparable structural characteristics (size, shape, etc.).

[0145] Pharmaceutical composition containing the antibody outlined above

[0146] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is not receiving any organ support or has received organ support for 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, and which can be used in combination with known pharmaceuticals or other interventions according to any of the preceding embodiments. In particular, anti-ADM antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds can be used in combination with antimicrobial therapies (antibiotics, antifungals, etc.), surgical or other mechanical sterilization of microbial sources, vasopressors / inotropes, colloids or crystalloids for fluid resuscitation, artificial respiration, ECMO (extracorporeal membrane oxygenation), extracorporeal circulation liver support, and renal replacement therapy. A preferred embodiment involves the use of anti-ADM antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds in combination with primary pharmaceuticals for use in the treatment of patients with shock, particularly septic shock. The primary pharmaceutical may be an antibiotic in the case of infection; a vasopressor, such as a catecholamine, and / or administered intravenously with an infusion. The subject of the present invention is further the anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold according to the present invention, used in combination with a TNFα antibody.

[0147] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold according to any of the previous embodiments, or has received no organ support at all or 10 hours or less, preferably 8.4 hours (0.35 days), and / or is a patient who has received organ support for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold according to any of the previous embodiments.

[0148] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and the pharmaceutical formulation is a liquid formulation, preferably a ready-to-use liquid formulation, according to the previous embodiment.

[0149] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and the pharmaceutical formulation is in a lyophilized state according to the previous embodiment.

[0150] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and the pharmaceutical formulation is administered intramuscularly according to the previous embodiment.

[0151] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and the pharmaceutical formulation is administered intravascularly according to the previous embodiment.

[0152] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and the pharmaceutical formulation is administered by infusion according to the previous embodiment.

[0153] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, and wherein the pharmaceutical formulation can be administered systemically according to the previous embodiment.

[0154] Furthermore, in embodiments of the present invention, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is monospecific. The monospecific anti-ADM antibody, monospecific anti-ADM antibody fragment, or monospecific anti-ADM non-Ig scaffold binds to a single specific region containing at least 5 amino acids within the target ADM. The monospecific anti-ADM antibody, monospecific anti-ADM antibody fragment, or monospecific anti-ADM non-Ig scaffold is an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold that all have affinity for the same antigen. In certain and preferred embodiments, the present invention provides a monospecific anti-ADM antibody, monospecific anti-ADM antibody fragment, or monospecific anti-ADM non-Ig scaffold characterized in that the antibody, antibody fragment, or non-Ig scaffold binds to a single specific region containing at least 4 amino acids within the target ADM. In another particular embodiment, the anti-ADM antibody or antibody fragment that binds to ADM is a monospecific antibody. Monospecificity means that the antibody or antibody fragment binds to a specific region within the target ADM that preferably comprises at least four or at least five amino acids. Monospecific antibodies or fragments are antibodies or fragments that all have affinity for the same antigen. While monoclonal antibodies are monospecific, monospecific antibodies may be produced by means other than from common germ cells.

[0155] Another embodiment of the present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the antibody, fragment, or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4), wherein the antibody, fragment, or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4).

[0156] Another embodiment of the present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the antibody, fragment, or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4), wherein the antibody, fragment, or scaffold binds to the N-terminal portion (aa1~21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 4).

[0157] Symptoms may be selected from a group of shocks that includes shock caused by hypovolemia, cardiogenic shock, vascular occlusive shock, and distributive shock.

[0158] In another specific embodiment of the present invention, the shock is selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock and distributive shock, and in particular is cardiogenic shock or septic shock.

[0159] In a particular embodiment of the present invention, the shock is: In cases of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or heart failure (e.g., acute decompensated heart failure), myocarditis, arrhythmia, cardiomyopathy, valvular heart disease, aortic dissection with acute aortic stenosis, traumatic chordal rupture, or extensive pulmonary embolism, or In cases of hypovolemic shock, the patient may have a hemorrhagic disorder including gastrointestinal bleeding, trauma, vascular etiology (e.g., ruptured abdominal aortic aneurysm, tumors affecting major blood vessels), or a non-hemorrhagic disorder including spontaneous bleeding or vomiting, diarrhea, renal loss, skin loss / insensitivity (e.g., burns, heatstroke), or pancreatitis, cirrhosis, bowel obstruction, or third-space loss in the context of trauma, or In cases of vascular occlusive shock, the patient may have cardiac tamponade, tension pneumothorax, pulmonary embolism, or aortic stenosis, or In cases of distributive shock, the patient is suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. It is selected from the group that includes it.

[0160] In a more preferred embodiment, the shock is septic shock, shock caused by Covid-19, shock caused by burns, or traumatic shock. In the most preferred embodiment, the shock is related to septic shock.

[0161] In a preferred embodiment, the present invention relates to an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, after the patient is admitted to the ICU. The present invention relates to an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of shock, particularly septic shock patients, characterized by being administered within 8.4 hours (0.35 days) or within 8.4 hours (0.35 days) and / or before the patient receives organ support or within 10 hours or less, preferably within 8.4 hours (0.35 days), wherein the patient has received no organ support or has received it for 10 hours or less, preferably within 8.4 hours (0.35 days).

[0162] In the most preferred embodiment, an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold is administered to the patient within 7 hours, preferably 6 hours, preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the onset of shock. In a further or alternative embodiment, the treatment is performed within 7 hours, preferably 6 hours, preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient is admitted to the ICU.

[0163] In further embodiments, the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the body fluid sample taken from the patient shows a bio-ADM level of 70 pg / mL, and the body fluid is selected from the group including whole blood, plasma, and serum.

[0164] The present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the body fluid sample taken from the patient shows a bio-ADM level of 70 pg / mL, and the body fluid is selected from the group including whole blood, plasma, and serum.

[0165] The present invention further relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the body fluid sample taken from the patient shows a DPP3 level below the threshold, and the body fluid is selected from the group including whole blood, plasma, and serum.

[0166] In the most preferred embodiment, the patient has a DPP3 level in a body fluid sample below a threshold, wherein the threshold for the DPP3 level in the patient's body fluid sample is 20-120 ng / mL, more preferably 30-80 ng / mL, even more preferably 40-60 ng / mL, and most preferably 50 ng / mL.

[0167] The aforementioned antibody or fragment or scaffold binds to mature ADM, for example, amino acids 1-52 (SEQ ID NO: 1), or to a fragment of mature ADM, for example, the central region ADM (MR-ADM) (SEQ ID NO: 3), or to the N-terminal ADM (SEQ ID NO: 4), as detailed below.

[0168] Accordingly, another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days), before or after organ support is provided to the patient, and the antibody or fragment or scaffold binds to mature ADM, for example, amino acids 1-52 (SEQ ID NO: 1), or the fragment as defined above, and the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock.

[0169] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody or fragment or scaffold is the N-terminal portion (aa1~21) of ADM: YRQSMNNFQGLRSFGCRFGTC (Sequence ID 4) The present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of shock, particularly septic shock, in patients.

[0170] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody, antibody fragment or non-Ig scaffold is the central portion of adrenomedullin, aa21~42: CTVQKLAHQIYQFTDKDKDNVA(Sequence ID 3) The present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, characterized by its binding with an anti-ADM antibody, for use in the treatment of shock, particularly septic shock patients.

[0171] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody, antibody fragment or non-Ig scaffold is monospecific in a specific monoclonal.

[0172] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support is administered, and according to any of the previous embodiments, the antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system for at least 10 -7 This invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold that exhibits binding affinity for ADM of M, for use in the treatment of patients with shock, particularly septic shock.

[0173] In a more preferred embodiment, the antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system, resulting in a 1 × 10⁻¹⁶ reaction. -9 ~3×10 -9 It exhibits binding affinity to ADM. In a more preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is an IgG1 antibody.

[0174] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H).

[0175] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support is administered, and according to any of the preceding embodiments, the antibody or fragment or scaffold recognizes and binds to the N-terminus (aa1) of ADM.

[0176] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody or fragment or scaffold has a half-life (t) of ADM in serum, blood, or plasma. 1 / 2 The present invention relates to an ADM-stabilized antibody or fragment or scaffold for use in the treatment of shock, particularly septic shock patients, which is an ADM-stabilized antibody or fragment or an anti-ADM non-Ig scaffold that extends the half-residence time by at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100%.

[0177] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or the patient is receiving organ support. The present invention relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the antibody, fragment, or scaffold is administered before receiving or within 10 hours or less, preferably 8.4 hours (0.35 days) of organ support, and according to any of the previous embodiments, the antibody, fragment, or scaffold blocks 80% or less, preferably 50% or less, of the biological activity of ADM using hADM22-52 as a reference antagonist in CHO-K1 cells expressing the human recombinant ADM receptor.

[0178] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) of organ support, wherein, according to any of the previous embodiments, the antibody or fragment has the N-terminal region (aa1~21) (SEQ ID NO: 4) or heavy chain of ADM sequenced: CDR1: Sequence ID 5 GYTFSRYW CDR2: Sequence ID 6 ILPGSGST CDR3: Sequence ID 7 TEGYEYDGFDY It includes, and the light chain is in sequence: CDR1: Sequence ID 8 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 9 FQGSHIPYT This relates to a human monoclonal antibody or fragment that conjugates to an antibody fragment, including ADM, for use in the treatment of patients with shock, particularly septic shock.

[0179] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugating to ADM or its antibody fragment for use in the treatment of sepsis and / or shock, particularly in patients with septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the antibody or fragment has a VH region as: Sequence number 10 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGT TLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 11 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 12 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 13 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 14 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH It includes the following sequence as the VL region: Sequence ID 15 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 16 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 17 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to a human monoclonal antibody or fragment that conjugates to ADM or its antibody fragment for use in the treatment of sepsis and / or shock, particularly in patients with septic shock, comprising a sequence selected from the group including the above.

[0180] Another embodiment of the present invention relates to a human monoclonal antibody or fragment conjugated to ADM or an antibody fragment thereof for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, wherein, according to any of the previous embodiments, the antibody or fragment has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFScSVMHEALHNHYTQKSLSLSPGK It includes the following sequence as a light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC This relates to a human monoclonal antibody or fragment that conjugates to ADM or its antibody fragment for use in the treatment of patients with shock, particularly septic shock.

[0181] In a particular embodiment of the present invention, the antibody has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or an array that is identical to this by >95%, preferably >98%, preferably >99%. It includes the following sequence as a light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or an array that is >95%, preferably >98%, preferably 99% identical to this. Includes.

[0182] Pairwise alignment is performed to evaluate the identity between two amino acid sequences. Identity is defined as the percentage of directly matching amino acids in the alignment.

[0183] In certain embodiments of the present invention, the antibody has the following sequence as the heavy chain: SEQ ID NO: 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or a CDR sequence that is 100% identical to SEQ ID NO: 5, SEQ ID NO: 6, and / or SEQ ID NO: 7 and has >95%, preferably >98%, preferably >99% identity to SEQ ID NO: 22, and has the following sequence as the light chain: SEQ ID NO: 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or a CDR sequence that is 100% identical to SEQ ID NO: 8 and / or SEQ ID NO: 9 and is >95%, preferably >98%, preferably >99% identical to SEQ ID NO: 23.

[0184] In another embodiment, an anti - adrenomedullin (ADM) antibody or anti - ADM antibody fragment or anti - ADM non - Ig scaffold is an anti - adrenomedullin (ADM) antibody or anti - ADM antibody fragment or anti - ADM non - Ig scaffold for use in the treatment or prevention of shock in a patient and binds to the N - terminal portion of ADM (amino acids 1 - 10): YRQSMNNFQG (SEQ ID NO: 25).

[0185] A pharmaceutical composition comprising the antibody outlined above

[0186] Another embodiment of the present invention relates to an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support is administered, and which can be used in combination with known pharmaceuticals or other interventions according to any of the preceding embodiments. In particular, anti-ADM antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds can be used in combination with antimicrobial therapies (antibiotics, antifungals, etc.), surgical or other mechanical sterilization of microbial sources, vasopressors / inotropes, colloids or crystalloids for fluid resuscitation, artificial respiration, ECMO (extracorporeal membrane oxygenation), extracorporeal circulation liver support, and renal replacement therapy. A preferred embodiment involves the use of anti-ADM antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds in combination with primary pharmaceuticals for use in the treatment of patients with shock, particularly septic shock. The primary pharmaceutical may be an antibiotic in the case of infection; a vasopressor, such as a catecholamine, and / or administered intravenously with an infusion. The subject of the present invention is further the anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold according to the present invention, used in combination with a TNFα antibody.

[0187] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, comprising the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days) before or after organ support is provided to the patient, wherein the antibody or fragment or scaffold comprises any of the foregoing.

[0188] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) after organ support, and according to the previous embodiment, the pharmaceutical formulation is a liquid, preferably a ready-to-use liquid.

[0189] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) of organ support, and according to the previous embodiment, the pharmaceutical formulation is in a lyophilized state.

[0190] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) of organ support, and according to the previous embodiment, the pharmaceutical formulation is administered intramuscularly.

[0191] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) of organ support, and according to the previous embodiment, the pharmaceutical formulation is administered intravascularly.

[0192] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support, and according to any of the previous embodiments, the pharmaceutical formulation is administered by infusion.

[0193] Another embodiment of the present invention relates to a pharmaceutical formulation for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold can be administered systemically to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours or less, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or within 10 hours or less, preferably 8.4 hours (0.35 days) before or after organ support is provided to the patient.

[0194] The antibody according to the present invention is a protein comprising one or more polypeptides substantially encoded by an immunoglobulin gene that specifically binds to an antigen. Known immunoglobulin genes include the κ, λ, α (IgA), γ (IgG1, IgG2, IgG3, IgG4), δ (IgD), ε (IgE), and μ (IgM) constant region genes, as well as various immunoglobulin variable region genes. Full-length immunoglobulin light chains are generally about 25 kDa or 214 amino acids long. Full-length immunoglobulin heavy chains are generally about 50 kDa or 446 amino acids long. The light chain is encoded by a variable region gene (about 110 amino acids long) at the NH2 terminus and a κ or λ constant region gene at the COOH terminus. The heavy chain is similarly encoded by a variable region gene (about 116 amino acids long) and one of the other constant region genes.

[0195] The basic structural unit of an antibody is generally a tetramer consisting of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the variable regions of the light and heavy chains bind to the antigen, while the constant region mediates effector function. Immunoglobulins also exist in various other forms, including Fv, Fab, and F(ab')2, as well as bispecific hybrid antibodies and single-chain antibodies (e.g., Lanzavecchia et al. 1987. Eur. J. Immunol. 17: 105; Huston et al 1988. PNAS 85:5879-5883; Bird et al. 1988. Science 242:423-426; Hood et al. 1984. Immunology, Benjamin, NY, 2nd ed.; Hunkapiller and Hood, 1986. Nature 323: 15-16). The variable regions of the immunoglobulin light or heavy chain include framework regions interrupted by three high-frequency variable regions, also known as complementarity-determining regions (CDRs) (see Sequences of Proteins of Immunological Interest, E. Kabat et al, US Department of Health and Human Services, 1983). As described above, CDRs are primarily involved in binding to the epitope of the antigen. Immune complexes are antibodies such as monoclonal antibodies, chimeric antibodies, humanized antibodies or human antibodies, or functional antibody fragments specifically bound to an antigen.

[0196] Chimeric antibodies are antibodies whose light and heavy chain genes are typically constructed from immunoglobulin variable and constant region genes belonging to different species, usually through genetic engineering. For example, the variable segment of a gene derived from a mouse monoclonal antibody can be bound to human constant segments such as κ and γ1 or γ3. Thus, in one example, other mammalian species can be used, or the variable region can be produced by molecular technology, but therapeutic chimeric antibodies are hybrid proteins consisting of a variable or antigen-binding domain from a mouse antibody and a constant or effector domain from a human antibody. Methods for producing chimeric antibodies are well known in the art; see, for example, U.S. Patent No. 5,807,715. "Humanized: Immunoglobulin is an immunoglobulin containing a human framework region and one or more CDRs derived from non-human (mouse, rat, or synthetic, etc.) immunoglobulins. The non-human immunoglobulin providing the CDRs is called the “donor,” and the human immunoglobulin providing the framework is called the “acceptor.” In one embodiment, all CDRs are derived from the donor immunoglobulin in the humanized immunoglobulin." A constant region is not required, but if present, it must be substantially identical to the constant region of human immunoglobulin, i.e., at least 85-90% identical, or at least 95% identical. Therefore, except perhaps the CDR, the entire humanized immunoglobulin is substantially identical to the corresponding portion of the natural human immunoglobulin sequence. A "humanized antibody" is an antibody containing humanized light chain and humanized heavy chain immunoglobulins. A humanized antibody binds to the same antigen as the donor antibody that provides the CDR. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework. Humanized or other monoclonal antibodies may have further conserved amino acid substitutions that have substantially no effect on antigen-binding or other immunoglobulin functions. Exemplary conserved substitutions include those of gly, ala;val, ile, leu;asp, glu;asn, gin;ser, thr;lys, arg; and phe, tyr. Humanized immunoglobulins can be constructed using genetic engineering (see, for example, U.S. Patent No. 5,585,089).Human antibodies are antibodies whose light and heavy chain genes are of human origin. Human antibodies can be produced using methods known in the art. Human antibodies can also be produced by immortalizing human B cells that secrete the target antibody. For example, immortalization can be performed by EBV infection or by fusing human B cells with hybridoma cells that produce myeloma or trioma cells. Human antibodies can also be produced by phage display (see, e.g., Dower et al., International Publication No. 91 / 17271; McCafferty et al., International Publication No. 92 / 001047; and Winter, International Publication No. 92 / 20791) or selected from a human combinatorial antibody library (see Morphosys website). Human antibodies can also be prepared using transgenic animals carrying human immunoglobulin genes (see, e.g., International Publication Nos. 93 / 12227 and International Publication No. 91 / 10741).

[0197] Therefore, anti-ADM antibodies may have formats known in the art. Examples include human antibodies, monoclonal antibodies, humanized saccharomyces, chimeric antibodies, and CDR-grafted antibodies. In preferred embodiments, the antibodies according to the present invention are, for example, recombinant antibodies such as IgG, typical full-length immunoglobulins, for example, but not limited to Fab minibodies, single-chain Fab antibodies, monovalent Fab antibodies with epitope tags, e.g., Fab-V5Sx2; bivalent Fab (mini-antibodies) dimerized with the CH3 domain; for example, multimerization utilizing heterogeneous domains, e.g., dimerization of the dHLX domain, e.g., bivalent or multivalent Fab produced by Fab-dHLX-FSx2; F(ab')2 fragments, scFv fragments, multimerized multivalent and / or multispecific scFv fragments, bivalent and / or bispecific diabodies, BITE® (bispecific T cell engager), trifunctional antibodies, e.g., multivalent antibodies derived from different classifications other than G; single-domain antibodies, e.g., chemically bound antibodies (fragment antigen binding) containing at least a heavy and / or light chain F variable domain, such as Fab fragments containing nanobodies derived from camelid or fish immunoglobulins and a number of other things.

[0198] In addition to anti-ADM antibodies, other biomolecular scaffolds are well known in the field of combined target molecules and are used for the production of highly targeted biomolecules. Examples include aptamers, Spiegelmers, antikalins, and conotoxins. For illustrations of antibody formats, see Figures 1a, 1b, and 1c in International Publication No. 2013 / 072513.

[0199] The antibody fragment according to the present invention is an antigen-binding fragment of the antibody according to the present invention.

[0200] In a preferred embodiment, the ADM antibody format is selected from the group comprising Fv fragment, scFv fragment, Fab fragment, scFab fragment, F(ab)2 fragment, and scFv-Fc fusion protein. In another preferred embodiment, the antibody format is selected from the group comprising bioavailability-optimized complexes of these, such as scFab fragment, Fab fragment, scFv fragment, and PEGylated fragment. One of the most preferred formats is the scFab format.

[0201] Non-Ig scaffolds may be protein scaffolds, and these may be used as antibody mimetic models when they can bind to ligands or antigens. Non-Ig scaffolds include tetranectin-based non-Ig scaffolds (e.g., described in U.S. Patent Publication No. 2010 / 0028995), fibronectin scaffolds (e.g., described in European Patent No. 1266025); lipocalin-based scaffolds (e.g., described in International Publication No. 2011 / 154420); ubiquitin scaffolds (e.g., described in International Publication No. 2011 / 073214); transferling scaffolds (e.g., described in U.S. Patent Publication No. 2004 / 0023334), scaffold protein A (e.g., described in European Patent No. 2231860), ankyrin repeat-based scaffolds (e.g., described in International Publication No. 2010 / 060748), microproteins, preferably microproteins that form cystine knots (e.g., described in European Patent Publication No. 2314308), Fyn The scaffolding may be selected from the group including SH3 domain scaffolding (e.g., described in International Publication No. 2011 / 023685), EGFR-A domain scaffolding (e.g., described in International Publication No. 2005 / 040229), and Kunitz domain scaffolding (e.g., described in European Patent No. 1941867).

[0202] In one embodiment of the present invention, the antibody according to the present invention may be produced as follows: Balb / c mice were immunized with 100 μg of ADM peptide BSA conjugate (emulsified in 100 μl of Freund's complete adjuvant) on days 0 and 14, and with 50 μg (in 100 μl of Freund's incomplete adjuvant) on days 21 and 28. For three days prior to the fusion experiment, the animals received 50 μg of the conjugate dissolved in 100 μl of saline, given as one intraperitoneal injection and one intravenous injection. Splenocytes and myeloma cell line SP2 / 0 cells derived from immunized mice were fused with 1 ml of 50% polyethylene glycol for 30 seconds at 37°C. After washing, the cells were seeded in 96-well cell culture plates. Hybrid clones were selected by growth in HAT medium (RPMI1640 culture medium supplemented with 20% fetal bovine serum and HAT supplement). After two weeks, the HAT medium was replaced with HT medium for three passages, and then returned to normal cell culture medium. The cell culture supernatant was screened for antigen-specific IgG antibodies for three weeks after fusion. Positive test microcultures were transferred to 24 wells for growth. After retesting, selected cultures were cloned and re-cloned using limiting dilution techniques, and the isotype was determined (see also Lane, RD 1985. J. Immunol. Meth. 81: 223-228; Ziegler B. et al. 1996. Horm. Metab. Res. 28: 11-15).

[0203] Antibodies were produced using phage display according to the following procedure. The human naive antibody gene library HAL7 / 8 was used to isolate recombinant single-stranded F variable domains (scFv) against the ADM peptide. The antibody gene library was screened using a panning strategy that included the use of peptides containing biotin tags linked to the ADM peptide sequence by two different spacers. Background from nonspecific binders was minimized using a mixture of panning rounds with nonspecific binding antigens and streptavidin-binding antigens. Phages eluted from the third round of panning were used to produce monoclonal scFv expressing Escherichia coli (E. coli) strains. The supernatant from the cultures of these clone strains was used directly in antigen ELISA (see reference cited in International Publication No. 2013 / 072513, the full text of which is incorporated herein).

[0204] Humanization of the mouse anti-Tau may be carried out according to the following method: For humanization of an antibody of mouse origin, the antibody sequence is analyzed for the structural interaction of the complementarity-determining region (CDR) and the framework region (FR) containing the antigen. Based on the structural modeling, an appropriate FR of human origin is selected and the mouse CDR sequences are transplanted into the human FR. Mutations may be induced in the amino acid sequences of the CDR or FR to restore the structural interactions that were lost by class switching with respect to the FR sequence. This restoration of the structural interaction may be carried out using a phage display library or by a direct approach (Almagro and Fransson 2008. Front Biosci. 13: 1619-33) guided by molecular modeling. In a preferred embodiment, the ADM antibody format is selected from the group consisting of Fv fragment, scFv fragment, Fab fragment, scFab fragment, F(ab)2 fragment and scFv-Fc fusion protein. In another preferred embodiment, the antibody format is selected from the group consisting of these bioavailability-optimized complexes such as scFab fragment, Fab fragment, scFv fragment and PEGylated fragment. One of the most preferred formats is the scFab format. In another preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment or anti-ADM non-Ig scaffold is a full-length antibody, antibody fragment, or non-Ig scaffold.

[0205] In a preferred embodiment, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold targets at least a 5-amino acid long epitope contained in ADM and is capable of binding to the epitope.

[0206] In another preferred embodiment, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold targets at least a 4-amino acid long epitope contained in ADM and is capable of binding to the epitope.

[0207] In one particular embodiment of the present invention, an anti-ADM antibody, an anti-ADM antibody fragment conjugating to ADM, or an anti-ADM non-Ig scaffold conjugating to ADM is provided for use in the treatment of patients with shock, particularly septic shock, wherein the patient has been in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold, and / or has been admitted to the ICU for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment according to a previous embodiment, wherein the antibody, fragment, or scaffold comprises the sequence aa1-21 of mature human ADM: YRQSMNNFQGLRSFGCRFGTC (Sequence ID 4). It binds to a region of at least four or at least five amino acids within the molecule.

[0208] In one particular embodiment of the present invention, an anti-ADM antibody, an anti-ADM antibody fragment conjugating to ADM, or an anti-ADM non-Ig scaffold conjugating to ADM is provided for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, wherein, according to the previous embodiment, the antibody, fragment, or scaffold is the sequence aa1-21 of mature human ADM: YRQSMNNFQGLRSFGCRFGTC (Sequence ID 4). It binds to a region of at least four or at least five amino acids within the molecule.

[0209] In a preferred embodiment of the present invention, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold binds to a region or epitope (amino acids 1-21) of ADM located at the N-terminal portion of ADM.

[0210] In another preferred embodiment, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminus (aa1) of ADM. The N-terminus means that amino acid 1, which is "Y" in SEQ ID NO: 1 or 4, is essential for antibody binding. The antibody or fragment or non-Ig scaffold does not bind to N-terminal extension, N-terminal modification, or N-terminal degradation.

[0211] In preferred embodiments, an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold can target and bind to an epitope of at least 5 amino acids in ADM, preferably human ADM.

[0212] In preferred embodiments, an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold can target and bind to an epitope of at least 4 amino acids in ADM, preferably human ADM.

[0213] In one particular embodiment, it is preferable to use an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold according to the present invention, wherein the anti-ADM antibody or the anti-ADM antibody fragment or anti-ADM non-Ig scaffold constitutes at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100% of the half-life (t) of ADM in serum, blood, or plasma. 1 / 2 This refers to an ADM-stabilized antibody, an ADM-stabilized antibody fragment, or an ADM-stabilized non-Ig scaffold that enhances the half-life (half-residence time). The half-life (half-residence time) of ADM may be determined in human plasma in the absence and presence of the ADM-stabilized antibody, ADM-stabilized antibody fragment, or ADM-stabilized non-Ig scaffold, respectively, using an immunoassay for ADM quantification.

[0214] You may follow these steps: -ADM may be diluted in human citrated plasma in the absence and presence of ADM-stabilized antibody, ADM-stabilized antibody fragment, or ADM-stabilized non-Ig scaffold, respectively, and incubated at 24°C. - An aliquot may be taken at a selected time (for example, within 24 hours), and the decomposition of ADM may be stopped in the aliquot by freezing it at -20°C. - The amount of ADM may be determined directly by an hADM immunoassay if the selected assay is not affected by the stabilized antibody. Alternatively, aliquots may be treated with a denaturant (such as HCl), the sample may be cleaned (e.g., by centrifugation), the pH may be neutralized, and ADM may be quantified by an ADM immunoassay. Alternatively, non-immunoassay techniques (e.g., RP-HPLC) may be used for ADM quantification. -Calculate the half-life of ADM incubated in the absence of ADM-stabilized antibody, ADM-stabilized antibody fragment, or ADM-stabilized non-Ig scaffold, and in the presence of these, respectively.

[0215] The enhancement of half-life is calculated for stabilized ADM compared to ADM incubated in the absence of ADM-stabilized antibody, ADM-stabilized antibody fragment, or ADM-stabilized non-Ig scaffold.

[0216] A doubling of the half-life of ADM is a 100% half-life enhancement. Half-life (half-residence time) is defined as the time it takes for a particular chemical or drug to fall to half its baseline concentration in a particular body fluid or blood.

[0217] In certain embodiments, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is a non-neutralizing antibody, fragment, or non-Ig scaffold. A neutralizing anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will block the biological activity of ADM to almost 100%, at least more than 90%, and preferably at least more than 95%.

[0218] In contrast, non-neutralizing anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds block the biological activity of ADM by less than 100%, preferably less than 95%, preferably less than 90%, more preferably less than 80%, and even more preferably less than 50%. This means that the remaining biological activity of ADM bound to a non-neutralizing anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will be greater than 0%, preferably more than 5%, preferably more than 10%, more preferably more than 20%, and more preferably more than 50%. In connection with this, (a) whether it is an antibody, antibody fragment, or non-Ig scaffold having "non-neutralizing anti-ADM activity", the molecule is collectively referred to here for simplicity as a "non-neutralizing" anti-ADM antibody, antibody fragment, or non-Ig scaffold that blocks the biological activity of ADM to less than 80%, and is defined as follows: - Addition to the culture medium of a eukaryotic cell line expressing a functional human recombinant ADM receptor consisting of CRLR (calcitonin receptor-like receptor) and RAMP3 (receptor activity regulatory protein 3) through the action of parallel-added human synthetic ADM peptide A single or multiple ADM-binding molecule(s) that reduces the amount of cAMP produced by a cell line, wherein the added human synthetic ADM is added in an amount that stimulates up to half of cAMP synthesis in the absence of the non-neutralizing antibody to be analyzed, and the reduction of cAMP by the ADM-binding molecule(s) occurs to an extent of 80% or less, even when the amount added is 10 times greater than the amount of the non-neutralizing molecule(s) that binds to ADM to be analyzed required to obtain the maximum reduction of cAMP synthesis available with the non-neutralizing antibody to be analyzed. The same definition applies to other ranges; 95%, 90%, 50%, and others.

[0219] In certain embodiments of the present invention, an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold is used, wherein the antibody, antibody fragment, or non-Ig scaffold blocks the biological activity of ADM to less than 80%, preferably less than 50%, of the baseline value. This means that 80% or less or 50% or less of circulating ADM is blocked, respectively. The limited blockade of the biological activity of ADM occurs even at excess concentrations of the antibody, antibody fragment, or non-Ig scaffold, and is understood to mean an excess of the antibody, antibody fragment, or non-Ig scaffold against ADM. The limited blockade is an inherent characteristic of the ADM conjugate. This means that the antibody, antibody fragment, or non-Ig scaffold has a maximum inhibition of 80% or 50%, respectively. Implicitly, this means that even when an appropriate or excess amount of the antibody, antibody fragment, or non-Ig scaffold is administered, 20% or 50% of residual ADM biological activity remains.

[0220] In a preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will block at least 5% of the biological activity of ADM. Implicitly, this means that the remaining 95% of circulating ADM biological activity will remain. This is the lower threshold of the biological activity remaining after administration of the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold. Biological activity is defined as the effect that a substance exerts on a living organism, tissue, organ, or functional unit in vivo or in vitro (e.g., in an assay) after its interaction. In the case of ADM biological activity, this may be the effect of ADM in a human recombinant ADM receptor cAMP function assay. Therefore, according to the present invention, biological activity is defined by an ADM receptor cAMP function assay. To determine the biological activity of ADM in such an assay, the following steps may be taken: - The dose-response curve is performed using ADM in the human recombinant ADM receptor cAMP function assay. - You may calculate the ADM concentration under semi-maximal cAMP stimulation. - At a constant semi-maximal cAMP-stimulated ADM concentration, dose-response curves (final concentration of 100 μl or less) are obtained using either an ADM-stabilized antibody, an ADM-stabilized antibody fragment, or an ADM-stabilized non-Ig scaffold, respectively.

[0221] Maximum inhibition (at maximum dose) by the 50% ADM-stabilized antibody means that the ADM antibody, the ADM antibody fragment, or the ADM non-Ig scaffold blocks the biological activity of ADM up to 50% of the baseline value, respectively. Maximum inhibition in the 80% ADM bioassay means that the anti-ADM antibody, the anti-ADM antibody fragment, or the anti-ADM non-Ig scaffold blocks the biological activity of ADM up to 80%, respectively. This means that the biological activity of ADM is blocked to 80% or less.

[0222] In preferred embodiments, modification of an anti-ADM antibody, modification of an anti-ADM antibody fragment, or modification of an anti-ADM non-Ig scaffold is used. "Modification" of an anti-ADM antibody, modification of an anti-ADM antibody fragment, or modification of an anti-ADM non-Ig scaffold is an antibody, ADM antibody fragment, or non-Ig scaffold that enhances the half-life (t half-residence time) of ADM in serum, blood, or plasma by at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100%, and blocks the biological activity of ADM to less than 80%, preferably less than 50%, where the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will block the biological activity of ADM to at least 5%. These values ​​relate to half-life, and the blockade of biological activity must be understood in relation to the assay described above to determine these values. This means blocking 80% or less or 50% or less of circulating ADM, respectively. This means that either 20% residual ADM biological activity remains, or 50% residual ADM biological activity remains, respectively. Such modification of anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds offers the advantage of facilitating drug administration. A combination of partial blockade or reduction of ADM biological activity and extension of the in vivo half-life (increase in ADM biological activity) results in a beneficial simplification of anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold administration. In a state of excess endogenous ADM, the activity reduction effect is the primary effect of the antibody, fragment, or scaffold that limits the (negative) effects of ADM. In cases of low or normal concentrations of endogenous ADM, the biological effect of anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds is a combination of reduction (due to partial blockade) and increase due to extension of the ADM half-life. Therefore, non-neutralizing and modulated ADM antibodies or ADM antibody fragments or ADM non-Ig scaffolds act like ADM bioactivity buffers to maintain the biological activity of ADM within a specific physiological range.

[0223] The anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold according to the present invention has an affinity constant of 10 -7 M or more, preferably 10-8 M, and the preferred affinity is 10 -9 M or more, most preferably 10 -10 It exhibits an affinity for human ADM that is higher than M. Those skilled in the art know that it may be conceivable to compensate for lower affinity by applying higher doses of the compound, and this measurement is not outside the scope of the present invention. The affinity constant may be determined according to the method described in Example 1 of International Publication No. 2013 / 072513.

[0224] It should be emphasized that the term "ADM-binding protein" includes ADM-binding protein 1 (complement factor H). However, the ADM-binding protein as defined in this invention is neither a non-neutralizing anti-ADM antibody / antibody fragment / non-Ig scaffold nor a regulated anti-ADM antibody / antibody fragment / non-Ig scaffold. Furthermore, the subject of this invention is an anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of acute diseases or acute conditions in patients according to the present invention, and the antibody or antibody fragment or non-Ig scaffold may be used in combination with further active ingredients.

[0225] Furthermore, the subject of the present invention is a pharmaceutical formulation comprising an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold according to the present invention. Furthermore, the subject of the present invention is a pharmaceutical formulation according to the present invention, wherein the pharmaceutical formulation is a liquid, preferably a ready-to-use liquid. In another embodiment, the subject of the present invention is further a pharmaceutical formulation according to the present invention, wherein the pharmaceutical formulation is in a dry state that is redissolved before use. The pharmaceutical formulation may be administered intramuscularly. The pharmaceutical formulation may be administered intravascularly. The pharmaceutical formulation may be administered by injection. In another embodiment, the subject of the present invention is further a pharmaceutical formulation according to the present invention, wherein the pharmaceutical formulation is in a freeze-dried state before use.

[0226] In another more preferred embodiment of the present invention, the present invention provides a pharmaceutical formulation comprising an anti-ADM antibody or an anti-ADM antibody fragment conjugating ADM or an anti-ADM non-Ig scaffolding conjugating ADM for use in the treatment of patients with shock, particularly septic shock, wherein the patient is in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffolding, and / or is admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation point of treatment, and / or is a patient who has not received any organ support or has received organ support for 10 hours or less, preferably 8.4 hours (0.35 days) at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffolding comprising the antibody or fragment or scaffolding, wherein, according to the previous embodiment, the pharmaceutical formulation can be administered to a patient in need thereof.

[0227] In another embodiment of the present invention, the pharmaceutical formulation according to the present invention can be administered to a patient for treatment of shock, particularly septic shock, provided that the patient requires such treatment, the patient being defined as follows: the patient has been in a state of shock for 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, and / or has been admitted to the ICU within 10 hours or less, preferably 8.4 hours (0.35 days), at the initiation point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold containing the antibody or fragment or scaffold, or has received no organ support or organ support for 10 hours or less, preferably 8.4 hours (0.35 days).

[0228] In another, more preferred embodiment, the present invention provides a pharmaceutical formulation comprising an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment conjugating ADM, or an anti-ADM non-Ig scaffolding conjugating ADM, for use in the treatment of patients with shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffolding is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days), after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days), after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days), after organ support is administered, and according to the previous embodiment, the pharmaceutical formulation can be administered to patients who need it.

[0229] Another embodiment of the present invention allows the pharmaceutical formulation according to the present invention to be used in the treatment of patients with shock, particularly septic shock, and the pharmaceutical formulation can be administered to a patient for therapeutic purposes, provided that the patient requires such treatment, and the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered to the patient within 10 hours, preferably 8.4 hours (0.35 days) after the onset of shock, and / or within 10 hours, preferably 8.4 hours (0.35 days) after the patient is admitted to the ICU, and / or before the patient receives organ support or within 10 hours or less, preferably 8.4 hours (0.35 days) after organ support is administered.

[0230] In one embodiment, the ADM antibody, ADM antibody fragment, or ADM non-Ig scaffold according to the present invention is a non-neutralizing ADM antibody, a non-neutralizing ADM antibody fragment, or a non-neutralizing ADM non-Ig scaffold.

[0231] When used herein, antibody formats are selected from the group comprising Fv fragments, scFv fragments, Fab fragments, scFab fragments, F(ab)2 fragments, and scFv-Fc fusion proteins.

[0232] In embodiments of the present invention, the ADM antibody or ADM antibody fragment or ADM non-Ig scaffold according to any of the previous embodiments is for use in the treatment of a patient in need, and the antibody or fragment may be administered in doses of at least 0.5 mg / kg body weight, particularly at least 1.0 mg / kg body weight, more particularly 1.0 to 20.0 mg / kg body weight, for example, 2.0 to 10 mg / kg body weight, 2.0 to 8.0 mg / kg body weight, or 2.0 to 5.0 mg / kg body weight.

[0233] In preferred embodiments of the present invention, the symptoms of shock treated or prevented using either an ADM antibody or ADM antibody fragment or a non-Ig scaffold according to any of the previous embodiments are associated with a viral infection, the virus being selected from the group including Hepadnaviridae, Adenoviridae, Herpesviridae, Influenza virus, Arenaviridae, Filoviridae, Togaviridae, Norovirus, Flaviviridae, Retroviridae, Measles virus, Reoviridae, Enteroviridae, Picornaviridae, Caliciviridae, and others.

[0234] In preferred embodiments of the present invention, the symptoms of shock treated or prevented using either an ADM antibody or ADM antibody fragment or a non-Ig scaffold according to any of the preceding embodiments are associated with drug therapy for the primary disease, such as chemotherapy, treatment with biological agents (e.g., antibodies or fragments thereof), antibiotics, or any drug that causes any of the above symptoms of the disease.

[0235] Further preferred embodiments of the present invention relate to a method for treating (e.g., curing, alleviating, improving, or relieving) or preventing a condition defined in any of the preceding embodiments, comprising administering an ADM antibody or ADM antibody fragment or non-Ig scaffold according to any of the preceding embodiments to a patient in need thereof. The subject is preferably a human.

[0236] Administration of ADM antibodies, ADM antibody fragments, or non-Ig scaffolds may be carried out by any means known in the art, including oral administration, intravenous administration, subcutaneous administration, intra-arterial administration, intramuscular administration, intracardiac administration, intrathecal administration, intraperitoneal administration, intraventricular administration, sublingual administration, transdermal administration, and / or inhalation administration. Administration may be systemic, for example, intravenous or local administration.

[0237] When used herein, the “effective dose” or “effect amount” of a drug, compound, or pharmaceutical composition is an amount sufficient to obtain a beneficial or desired result. For prophylactic use, beneficial or desired results include the elimination or reduction of risk, reduction of severity, or delay in the onset of the disease, including its biochemical, histological, and / or behavioral symptoms, its complications, and pathological intermediate phenotypes exhibited during the onset of the disease. For therapeutic use, beneficial or desired results include clinical outcomes such as a decrease in the pain intensity, duration, or frequency of headache attacks, and a reduction in one abnormal symptom obtained from headache (biochemical, histological, and / or behavioral), including its complications and pathological intermediate phenotypes exhibited during the onset of the disease, a decrease in the quality of life of the person suffering from the disease, a reduction in the dose of other medicines necessary for the treatment of the disease, an enhancement of the effect of another medicine, and / or a delay in the progression of the patient's disease. The effective dose may be administered in one or more doses. For the purposes of this invention, the effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a prophylactic or therapeutic measure, either directly or indirectly. As understood in clinical contexts, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Therefore, the “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective dose if, in combination with one or more other agents, the desired result may or may not be achieved.

[0238] The following embodiments are the subject of the present invention.

[0239] Embodiment 1. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients with shock, particularly septic shock, wherein the patient: • At the time of initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, the patient is suffering from shock of 10 hours or less, particularly septic shock, and / or • The patient has been admitted to the ICU for 10 hours or less at the time of initiation of treatment using the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or • At the start of treatment with the aforementioned anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient was not receiving any organ support or had received organ support for 10 hours or less. The antibody or fragment or scaffold binds to the N-terminal portion (aa1~21) of ADM (SEQ ID NO: 4), Adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in therapeutic purposes.

[0240] Embodiment 2. The patient is suffering from shock, particularly septic shock, at a time of 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), 5 hours, preferably 4 hours, preferably 3 hours, at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, preferably 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), 5 hours, preferably 4 hours, preferably 3 hours, and is in a state of shock, particularly septic shock, as described in Embodiment 1.

[0241] Embodiment 3. The patient is admitted to the ICU for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, preferably 3 hours, at the start of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, for use in the treatment described in Embodiment 1 or 2, wherein the patient is admitted to the ICU for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, at the start of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold.

[0242] Embodiment 4. The patient is receiving organ support for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours at the start of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment according to any one of Embodiments 1 to 3, wherein the patient is receiving organ support for 9 hours or less, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours at the start of treatment with the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold.

[0243] Embodiment 5. An anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment of patients suffering from shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is provided. • Within 10 hours after the onset of shock in the aforementioned patient, and / or • Within 10 hours of admission to the ICU, and / or • Before the patient receives organ support or within 10 hours of receiving organ support. Administer with, The antibody or fragment or scaffold binds to the N-terminal portion (aa1~21) of ADM (SEQ ID NO: 4), Anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in therapeutic purposes.

[0244] Embodiment 6. The anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold according to Embodiment 5, for use in the treatment of patients suffering from shock, particularly septic shock, the anti-adrenomedullin (ADM) ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the onset of shock in the patient.

[0245] Embodiment 7. The anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from shock, particularly septic shock, according to Embodiment 5 or 6, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient is admitted to the ICU.

[0246] Embodiment 8. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from shock, particularly septic shock, according to any one of Embodiments 5 to 7, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient has received organ support at the starting point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

[0247] Embodiment 9. The patient has shock selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock and distributive shock, particularly cardiogenic shock, septic shock, shock caused by Covid-19, shock caused by burns and traumatic shock, and the patient is provided with an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that conjugates to ADM or an anti-ADM non-Ig scaffold that conjugates to adrenomedullin for use in the treatment described in any one of Embodiments 1 to 8.

[0248] Embodiment 10. The patient has septic shock and is an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to ADM or an anti-ADM non-Ig scaffold that binds to adrenomedullin, for use in the treatment described in Embodiment 9.

[0249] Embodiment 11. A body fluid sample taken from the patient exhibits a bio-ADM level of >70 pg / mL, and the body fluid is selected from the group including whole blood, plasma, or serum, and is an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from shock, particularly septic shock, as described in any one of Embodiments 1 to 10.

[0250] Embodiment 12. A body fluid sample taken from the patient exhibits a DPP3 level of <50 ng / mL, and the body fluid is selected from the group including whole blood, plasma, or serum, for use in the treatment of a patient suffering from shock, in particular septic shock, as described in any one of Embodiments 1 to 11, and comprising an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold.

[0251] Embodiment 13. The antibody or antibody fragment or non-Ig scaffold is a monospecific anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 12.

[0252] Embodiment 14. The antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system for at least 10 -7 An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 13, exhibiting binding affinity of M to ADM.

[0253] Embodiment 15. The aforementioned antibody or fragment or scaffold is subjected to label-free surface plasmon resonance (1 × 10⁻¹⁶) using the Biacore 2000 system. -9 ~3×10 -9An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in Embodiment 14, exhibiting binding affinity to ADM.

[0254] Embodiment 16. The anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is an IgG1 antibody, and is used in the treatment or prevention of shock in a patient according to any one of Embodiments 13 to 15.

[0255] Embodiment 17. The antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H), and is an anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 16.

[0256] Embodiment 18. The antibody or fragment or scaffold is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 17, which recognizes and binds to the N-terminus (aa1) of ADM.

[0257] Embodiment 19. The antibody or fragment or scaffold is an ADM that stabilizes the antibody or fragment or scaffold, which extends the half-life (t1 / 2 half-residence time) of ADM in serum, blood, or plasma by at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100%, for use in the treatment according to any one of Embodiments 1 to 18.

[0258] Embodiment 20. The antibody or fragment or scaffold is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 19, which blocks 80% or less, preferably 50% or less, of the biological activity of ADM using hADM22-52 as a reference antagonist in CHO-K1 cells expressing human recombinant ADM receptor.

[0259] Embodiment 21. The subject is an anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold for use in any one of Embodiments 1 to 20, which involves treatment with chemotherapy, vasopressors, biologics, antibiotics, or antiviral compounds.

[0260] Embodiment 22. The antibody or fragment is a human monoclonal antibody or fragment that binds to ADM or its antibody fragment, and the heavy chain is sequence: CDR1: Sequence ID 5 GYTFSRYW CDR2: Sequence ID 6 ILPGSGST CDR3: Sequence ID 7 TEGYEYDGFDY It includes, and the light chain is in sequence: CDR1: Sequence ID 8 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 9 FQGSHIPYT including, An anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment described in any one of Embodiments 1 to 21.

[0261] Embodiment 23. The antibody or fragment has the following VH region: Sequence number 10 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGT TLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 11 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 12 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 13 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH Sequence ID 14 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHH The VL region includes sequences selected from the group containing the following: Sequence ID 15 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 16 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 17 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC. Includes sequences selected from a group that includes, A human monoclonal antibody or fragment that conjugates to ADM or its antibody fragment for use in the treatment described in Embodiment 22.

[0262] Embodiment 24. The antibody or fragment has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or an array that is >95% identical to this one. It includes the following sequence as a light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or an array that is >95% identical to this one. including, A human monoclonal antibody or fragment that conjugates to ADM or its antibody fragment for use in the treatment described in Embodiment 22 or 23.

[0263] Embodiment 25. The anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient according to any one of Embodiments 1 to 24, wherein the anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-10) of ADM: YRQSMNNFQG (SEQ ID NO: 25).

[0264] Embodiment 26. A pharmaceutical preparation for use in the treatment or prevention of disease symptoms, or for use in the treatment described in any one of Embodiments 1 to 25. [Brief explanation of the drawing]

[0265] [Figure 1] Figure 1 shows the time-course mortality rate in patients treated with adrecizumab compared to placebo, when treatment was administered 0–10 hours after diagnosis of shock (Figure 1A) and 10–12.2 hours after shock. The HR [95% CI] and log-rank p-values ​​were as follows: 0–10 hours after diagnosis of shock: HR = 0.439 [0.174–1.11], log-rank p = 0.072; 10–12.2 hours after diagnosis of shock: HR = 0.711 [0.326–1.55], log-rank p = 0.387. [Figure 2] Figure 2 shows the change in SOFA score when adrecizumab treatment was administered within 10 hours of shock diagnosis (Figure 2A) compared to treatment administered more than 10 hours after shock diagnosis (Figure 2B). The SOFA score was determined immediately before administration and the following day. The difference in SOFA score at each time point compared to the pre-administration / placebo SOFA score was calculated for each patient, and the average of the obtained values ​​is shown in the graph. The analysis included only patients for whom recorded values ​​for all SOFA components were available. "SOFA+" was defined by handling missing data as follows: SOFA was set to 0 for discharged patients at each time point, and SOFA was set to 24 for patients who died. [Figure 3]Figure 3 shows the 28-day mortality rate over time in patients treated with adrecizumab compared to placebo, when treatment was administered between 0 and 0.344 days (8.3 hours) after ICU admission (Figure 3A) and between 0.344 and 29 days after ICU admission (Figure 3B). The HR [95% CI] and log-rank p-values ​​were as follows: 28-day mortality rate for patients who stayed in the ICU for 0 to 0.34 days before treatment: HR = 0.263 [0.077 to 0.898], log-rank p = 0.22; 28-day mortality rate for patients who stayed in the ICU for 0.34 to 29 days before treatment: HR = 0.734 [0.358 to 1.5], log-rank p = 0.399. [Figure 4] Figure 4 shows the 90-day mortality rate over time in patients treated with adrecizumab compared to placebo, when treatment was administered between 0 and 0.344 days (8.3 hours) after ICU admission (Figure 4A) and between 0.344 and 29 days after ICU admission (Figure 4B). 90-day mortality rate for the group with 0 to 0.34 days of ICU stay before treatment: HR = 0.364 [0.137 to 0.97], log-rank p = 0.035; 90-day mortality rate for the group with 0.34 to 29 days of ICU stay before treatment: HR = 0.826 [0.469 to 1.45], log-rank p = 0.51. [Figure 5] Figure 5 shows the change in SOFA score when adrecizumab treatment was administered within 0.344 days after ICU admission (Figure 5A) compared with treatment administered more than 0.344 days after ICU admission (Figure 5B). The SOFA score was determined immediately before and the day after administration. The difference in SOFA score at each time point compared to the pre-administration / placebo SOFA score was calculated for each patient, and the average of the obtained values ​​is shown in the graph. The analysis included only patients for whom recorded values ​​for all SOFA components were available. "SOFA+" was defined by handling missing data as follows: SOFA was set to 0 for discharged patients at each time point, and SOFA was set to 24 for patients who died. [Figure 6]Figure 6 shows the mean fluid balance at day 7 after the start of treatment when adrecizumab treatment was administered at 0.344 days after ICU admission (Figure 6A), compared to treatment administered more than 0.344 days after ICU admission (Figure 6B). Fluid balance (fluid input - fluid output) was recorded every 24 hours in the ICU. The mean fluid balance at 7 days or less after adrecizumab / placebo infusion was calculated for each patient. For example, days when fluid balance was lost due to discharge from the ICU or death were not considered. Median + IQR is shown as a bar graph. [Figure 7] Figure 7 shows the mean fluid balance at day 7 after the start of treatment when adrecizumab treatment was administered within 10 hours of shock diagnosis (Figure 7A), compared to treatment administered more than 10 hours after shock diagnosis (Figure 7B). The mean fluid balance at 7 days or less after adrecizumab / placebo infusion was calculated for each patient. For example, days when fluid balance was lost due to discharge from the ICU or death were not considered. Median + IQR is shown as a bar graph. [Figure 8] Figure 8 shows the DPP3 concentrations from patients in septic shock on the day of ICU admission and the following day. [Figure 9] Figure 9 shows the individual trajectory of DPP3 concentration from patients with septic shock. The x-axis represents the number of days after admission to the ICU (day 1 is the admission day). [Examples]

[0266] Examples Antibody production and determination of their affinity constants We produced several human and mouse antibodies and determined their affinity constants (see Table 1).

[0267] Peptides / complexes for immunization Peptides for immunization were synthesized using an additional N-terminal cysteine ​​residue (if cysteine ​​was not present in the selected ADM sequence) for peptide binding to bovine serum albumin (BSA), see Table 1 (JPT Technologies, Berlin, Germany). The peptides were covalently bonded to BSA using a sulfolink coupling gel (Perbio Science, Bonn, Germany). The coupling procedure was performed according to the Perbio manual.

[0268] Mouse antibodies were produced according to the following method. Balb / c mice were immunized with 100 μg of peptide-BSA complex (emulsified in 100 μl of Freund's complete adjuvant) on days 0 and 14, and with 50 μg of peptide-BSA complex (in 100 μl of Freund's incomplete adjuvant) on days 21 and 28. Three days prior to the fusion experiment, the animals received 50 μg of the complex dissolved in 100 μl of saline, administered as one intraperitoneal injection and one intravenous injection.

[0269] Splenocytes from immunized mice and cells from the myeloma cell line SP2 / 0 were fused at 37°C for 30 seconds using 1 ml of 50% polyethylene glycol. After washing, the cells were seeded into 96-well cell culture plates. Hybrid clones were selected by growth in HAT medium (RPMI1640 culture medium supplemented with 20% fetal bovine serum and HAT supplement). After 2 weeks, the HAT medium was replaced with HT medium for 3 passages, and then returned to normal cell culture medium.

[0270] Cell culture supernatants were screened for antigen-specific IgG antibodies for 3 weeks after fusion. Positive test microcultures were transferred to 24 wells for growth. After retesting, selected cultures were cloned and re-cloned using limiting dilution techniques, and the isotype was determined (see also Lane, RD 1985. J. Immunol. Meth. 81: 223-228; Ziegler et al. 1996. Horm. Metab. Res. 28: 11-15).

[0271] Mouse monoclonal antibody production: Antibodies were produced using a standard antibody production method (Marx et al, 1997. Monoclonal Antibody Production, ATLA 25, 121) and purified with protein A. Antibody purity was >95% based on SDS gel electrophoresis analysis.

[0272] Human antibodies: Human antibodies were produced using phage display according to the following procedure. The human naive antibody gene library HAL7 / 8 was used to isolate recombinant single-stranded F variable domains (scFv) against the ADM peptide. The antibody gene library was screened using a panning strategy that included the use of peptides containing biotin tags linked to the ADM peptide sequence by two different spacers. Background from nonspecific binders was minimized using a mixture of panning rounds with nonspecific binding antigens and streptavidin-binding antigens. Phages eluted from the third round of panning were used to produce monoclonal scFv expressing Escherichia coli (E. coli) strains. Supernatants from the cultures of these clone strains were used directly for antigen ELISA (see also Hust et al. 2011. Journal of Biotechnology 152, 159-170; Schuette et al. 2009. PLoS One 4, e6625).

[0273] Positive clones were selected based on a positive ELISA signal for the antigen and negativity on streptavidin-coated microtiter plates. For further characterization, scFv open reading frames were cloned into the expression plasmid pOPE107 (Hust et al. 2011. Journal of Biotechnology 152, 159-170), captured from the culture supernatant by immobilized metal ion affinity chromatography, and purified by size exclusion chromatography.

[0274] Affinity constant To determine the affinity of the antibody to ADM, the binding dynamics of the ADM immobilized on the antibody were determined by label-free surface plasmon resonance using the Biacore 2000 system (GE Healthcare Europe GmbH, Freiburg, Germany). This was performed using anti-mouse Fc antibody covalently bound at high density to the surface of the CM5 sensor, according to the antibody manufacturer's instructions (mouse antibody capture kit; GE Healthcare) (Lorenz et al. 2011. Antimicrob Agents Chemother. 55 (1): 165-173).

[0275] Each antibody produces monoclonal antibodies against the following ADM regions of human and mouse ADM. The following table shows the selection of the obtained antibodies used in further experiments. The selection is based on the target region. [Table 1]

[0276] Production of antibody fragments by enzymatic digestion Fab and F(ab)2 fragments were produced by enzymatic digestion of mouse full-length antibody NT-M. Antibody NT-M was digested using a) a pepsin-based F(ab)2 preparation kit (Pierce 44988) and b) a papain-based Fab preparation kit (Pierce 44985). The fragmentation procedure was carried out according to the instructions provided by the supplier. Digestion for F(ab)2 fragmentation was performed at 37°C for 8 hours. Digestion for Fab fragmentation was performed for 16 hours in each case.

[0277] Procedure for Fab production and purification The immobilized papain was equilibrated by washing the resin with 0.5 ml of digestion buffer, and the column was centrifuged at 5000 x g for 1 minute. The buffer was then discarded. A desalted column was prepared by removing the storage solution, washing with digestion buffer, and then centrifuging at 1000 x g for 2 minutes each time. 0.5 ml of the prepared IgG sample was added to a spin column tube containing the equilibrated immobilized papain. The digestion reaction was incubated for 16 hours on a tabletop locker at 37°C. The digested product was separated from the immobilized papain by centrifuging the column at 5000 x g for 1 minute. The resin was then washed with 0.5 ml of PBS and centrifuged at 5000 x g for 1 minute. The washing fraction was added to a digestion antibody with a total sample volume of 1.0 ml. The NAb protein A column was equilibrated with PBS and IgG elution buffer at room temperature. The column was centrifuged for 1 minute to remove the storage solution (containing 0.02% sodium azide), equilibrated with 2 ml of PBS, centrifuged again for 1 minute, and the flow-through was discarded. The sample was applied to the column and resuspended by inversion. The mixture was mixed by inversion for 10 minutes and incubated at room temperature. The column was centrifuged for 1 minute and the flow-through was stored with the Fab fragment. (References: Coulter and Harris 1983. J. Immunol. Meth. 59, 199-203.; Lindner et al. 2010. Cancer Res. 70, 277-87; Kaufmann et al. 2010. PNAS. 107, 18950-5.; Chen et al. 2010. PNAS. 107, 14727-32; Uysal et al. 2009 J. Exp. Med. 206, 449-62; Thomas et al. 2009. J. Exp. Med. 206, 1913-27; Kong et al. 2009 J. Cell Biol. 185, 1275-840).

[0278] Procedure for the production and purification of the F(ab')2 fragment The immobilized pepsin was equilibrated by washing the resin with 0.5 ml of digestion buffer, and the column was centrifuged at 5000 x g for 1 minute. The buffer was then discarded. A desalted column was prepared by removing the storage solution, washing with digestion buffer, and then centrifuging at 1000 x g for 2 minutes each time. 0.5 ml of the prepared IgG sample was added to a spin column tube containing the equilibrated immobilized pepsin. The digestion reaction was incubated on a tabletop locker at 37°C for 16 hours. The digest was separated from the immobilized papain by centrifuging the column at 5000 x g for 1 minute. The resin was then washed with 0.5 ml of PBS and centrifuged at 5000 x g for 1 minute. The washing fraction was added to a digestion antibody with a total sample volume of 1.0 ml. The NAb protein A column was equilibrated with PBS and IgG elution buffer at room temperature. The column was centrifuged for 1 minute to remove the storage solution (containing 0.02% sodium azide), equilibrated with 2 mL of PBS, centrifuged again for 1 minute, and the flow-through was discarded. The sample was applied to the column and resuspended by inversion. The mixture was mixed by inversion for 10 minutes and incubated at room temperature. The column was centrifuged for 1 minute and the flow-through was stored with the Fab fragment.(References: Mariani et al. 1991. Mol. Immunol. 28: 69-77; Beale 1987. Exp Comp Immunol 11:287-96; Ellerson et al. 1972. FEBS Letters 24(3):318-22; Kerbel and Elliot 1983. Meth Enzymol 93:113-147; Kulkarni et al. 1985. Cancer Immunol Immunotherapy 19:211-4; Lamoyi 1986. Meth Enzymol 121:652-663; Parham et al. 1982. J Immunol Meth 53:133-73; Raychaudhuri et al. 1985. Mol Immunol 22(9):1009-19; Rousseaux et al. 1980. Mol Immunol 17:469-82; Rousseaux et al. 1983. J Immunol Meth 64:141-6; Wilson et al. 1991. J Immunol Meth 138:111-9).

[0279] NT-H antibody fragment humanization: Antibody fragments were immobilized using the CDR grafting method (Jones et al. 1986. Nature 321, 522-525).

[0280] The following steps were taken to obtain a humanized sequence: -Total RNA extraction: Total RNA was extracted from NT-H hybridomas using the Qiagen kit. - First round RT-PCR: QIAGEN® OneStep RT-PCR kit (catalog no. 210210) was used. RT-PCR was performed using primer sets specific to the heavy and light chains. For each RNA sample, 12 individual heavy chain and 11 light chain RT-PCR reactions were set up using a degenerate forward primer mixture covering the variable region leader sequence. Reverse primers were placed in the constant regions of the heavy and light chains. Restriction enzyme sites were not incorporated into the primers. - Reaction setup: 5.0 μl of 5×QIAGEN® OneStep RT-PCR buffer, 0.8 μl of dNTP mixture (containing 10 mM of each dNTP), 0.5 μl of primer set, 0.8 μl of QIAGEN® OneStep RT-PCR enzyme mixture, 2.0 μl of template RNA, 20.0 μl of RNase-free water, total volume 20.0 μl PCR conditions: Reverse transcription: 50°C, 30 min; Initial PCR activation: 95°C, 15 min; Cycles: 94°C, 25 sec; 54°C, 30 sec; 72°C, 30 sec for 20 cycles; Final extension: 72°C, 10 min. Second round seminested PCR: The RT-PCR product from the first round reaction was further amplified in the second round. 12 individual heavy chain and 11 light chain RT-PCR reactions were set up using a seminested primer set specific to the antibody variable region. - Reaction setup: 10 μl of 2× PCR mixture; 2 μl of primer set; 8 μl of first-round PCR product; total volume 20 μl; hybridoma antibody cloning report PCR conditions: initial denaturation at 95°C for 5 minutes; 25 cycles of 95°C for 25 seconds, 57°C for 30 seconds, and 68°C for 30 seconds; final extension at 68°C for 10 minutes. -After PCR was completed, electrophoresis of the PCR reaction sample was performed on an agarose gel to visualize the amplified DNA fragments. After sequencing of more than 15 cloned DNA fragments amplified by nested RT-PCR, several mouse antibody heavy and light chains were cloned and deemed accurate. Protein sequence alignment and CDR analysis identified one heavy chain and one light chain. The amino acids at positions 26, 40, and 55 in the variable heavy chain and the amino acid at position 40 in the variable light chain are extremely important for binding properties, so these may be returned to mouse origin. The obtained candidate products are shown below. (Padlan 1991. Mol. Immunol. 28, 489-498; Harris and Bajorath. 1995. Protein Sci. 4, 306-310).

[0281] Annotation of antibody fragment sequences (SEQ ID NOs. 10-17): Bold and underlined text indicates CDR1, 2, and 3 in numerical order from the N-terminus to the C-terminus; italics indicate the constant region; hinge regions are highlighted with bold and underlined text, and the C-terminal histidine tag is highlighted with bold and italicized text.

[0282] Sequence number 10 (AM-VH-C) [ka] Sequence ID 11 (AM-VH1) [ka] Sequence ID 12 (AM-VH2-E40) [ka] Sequence ID 13 (AM-VH3-T26-E55) [ka] Sequence ID 14 (AM-VH4-T26-E40-E55) [ka] Sequence ID 15 (AM-VL-C) [ka] Sequence ID 16 (AM-VL1) [ka] Sequence ID 17 (AM-VL2-E40) [ka] Sequence ID 22 (adrecizumab heavy chain) [ka] Sequence ID 23 (adrecizumab light chain) [ka] Sequence ID 24 (aa1-14 of human ADM) YRQSMNNFQGLRSF Sequence ID 25 (aa1-10 of human ADM) YRQSMNNFQG

[0283] Example 2 method plan The AdrenOSS-2 trial was a double-blind, placebo-controlled, randomized, multicenter, demonstration, biomarker, and dose-finding Phase II trial investigating the safety, tolerability, and efficacy of adrecizumab in patients with early septic shock and elevated bio-ADM. The trial was conducted at 30 hospitals in Belgium, France, Germany, and the Netherlands that had medical, surgical, and / or mixed ICUs. Further details of the trial setting were initially reported by Geven et al. (Geven C, Blet A, Kox M, Hartmann O, Scigalla P, Zimmermann J, Marx G, Laterre PF, Mebazaa A, Pickkers P, (2019) A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2). BMJ Open 0: e024475).

[0284] Code of ethics The clinical trial procedures and informed consent form (ICF) processes, approved by each independent ethics committee (IEC), followed international standards and the national regulations of each participating country.

[0285] participants Male and female patients (>18 years old) diagnosed with early septic shock (<12 hours) and elevated bioADM levels (>70 pg / mL) who met the inclusion and exclusion criteria were screened at ICU admission and at the initiation of vasopressor therapy. The list of inclusion and exclusion criteria was previously published in Geven et al. (Geven C, Blet A, Kox M, Hartmann O, Scigalla P, Zimmermann J, Marx G, Laterre PF, Mebazaa A, Pickkers P, (2019) A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2). BMJ Open 0: e024475). [Table 2]

[0286] After the written ICF was submitted by the patient or their legal representative (IEC-accredited local procedure), and the plasma bio-ADM concentration was >70 pg / mL (sphingotest®, sphingotec GmbH, Hennigsdorf, Germany), the Clinical Coordination Center (CCC) confirmed the patient's eligibility. All trial-related data were obtained anonymously.

[0287] Intervention Patients were randomly assigned in a 1:1:2 ratio to either treatment group A (adrecizumab 2 mg / kg), treatment group B (adrecizumab 4 mg / kg), or placebo. Patients received their assigned investigational drug as a single intravenous dose (approximately 1 hour) within 12 hours of initiating vasopressor therapy. A detailed description of the application scheme has already been published by Geven et al.[2].

[0288] Evaluation Criteria Among other endpoints, we recorded 7-day, 28-day, and 90-day mortality, as well as the daily change in SOFA score compared to the SOFA score at enrollment (SOFA = Assessment of Critical Organ Dysfunction). Another endpoint was mean fluid balance 7 days or less after adrecizumab / placebo infusion.

[0289] Of particular interest were the effects of the time from shock diagnosis to treatment and the time from ICU admission to treatment on the outcome scales.

[0290] Statistics and data analysis The analysis method in this embodiment included a comparison of the combined adrecizumab dose to placebo. Perprotocol (PP) analysis included all patients who received the investigational drug according to the protocol with minimal deviation and who met all major enrollment criteria. The patient population was further enriched by excluding patients with circulating dipeptidyl peptidase 3 (DPP3) concentrations higher than 50 ng / mL.

[0291] Continuous data were analyzed using the median, which included patient count, averaging, standard deviation (SD), or interquartile range. Exploratory comparisons between treatment and placebo were performed using the Kruskal-Wallis test, where necessary. Categorical variables were grouped by category, presented as numbers and percentages, and compared using the chi-squared test for contingency tables. Both treatment groups (2 mg / kg and 4 mg / kg) were combined for efficacy analysis. The log-rank test was chosen to show differences in mortality within the treatment groups, and Kaplan-Meier plots were used for illustration. Unadjusted and adjusted hazard ratios (HRs) were estimated using the Cox proportional hazards model. Missing SOFA scores due to death or ICU discharge were imputed (e.g., as proposed by de Grooth et al. (de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM, (2017) in randomized controlled trials, where SOFA and mortality endpoints were set to either 24 or 0, respectively) *Systematic Review and Meta-Regression Analysis*. *Critical Care 21: 38*). All reported p-values ​​are two-sided. P-values ​​less than 0.05 were considered significant. Statistical analysis was performed using SAS version 9.3 and R version 3.4.3 (http: / / www.r-project.org).

[0292] Patients and experimental treatments The first patient was randomized on December 8, 2017. The last patient was enrolled on September 25, 2019. A total of 459 patients were screened. In addition to these, 158 patients were ineligible and therefore not randomized (bio-ADM <70 pg / mL, n=91; did not meet selection / exclusion criteria, n=67). A total of 301 patients were randomized in four countries to either placebo (n=152), adrecizumab 2 mg / kg (n=72), or adrecizumab 4 mg / kg (n=77) to determine the intended-to-treat (ITT) population. For per protocol analysis (PP), n=7 patients were excluded. Finally, n=50 patients with pre-treatment DPP3 levels >50 ng / mL were excluded, resulting in an analysis of the entire patient population of n=244. Elevated plasma DPP3 levels trigger an adverse pathway that is mechanistically different from the ADM pathway and therefore cannot be addressed by adrecizumab.

[0293] result One crucial aspect of narrowing down the patient population for which a drug would be beneficial is defining the therapeutic range for specific clinical symptoms in patients. This is particularly important in acute changes and life-threatening conditions or other acute circulatory disorders such as sepsis, septic shock, and other life-threatening conditions. We investigated the efficacy of adrecizumab as a function of disease progression in septic shock. Operationally, disease progression is a change in the requirements for organ support, time since the onset of septic shock, and time since ICU admission.

[0294] To evaluate the above problem, the inventors examined a subpopulation of the AdrenOSS-2 clinical trial.

[0295] To investigate the effect of the time between shock diagnosis and the initiation of adrecizumab treatment, the population was divided into two groups based on the median time between shock diagnosis and treatment initiation, i.e., 8.4 hours, and the two groups were compared. When treatment was administered 0 to 10 hours after shock diagnosis, adrecizumab treatment resulted in a lower 28-day mortality rate compared to placebo (HR 0.439 (0.174 to 1.11)) (Figure 1A). When the time between shock diagnosis and treatment was 10 to 12.2 hours, the difference in mortality between adrecizumab treatment and placebo was not very clear (HR 0.711 (0.326 to 1.55)) (Figure 1B).

[0296] Figure 2 shows the change in SOFA score when adrecizumab treatment was administered within 8.4 hours after shock diagnosis (Figure 2A) compared to treatment administered later than 8.4 hours after shock diagnosis (Figure 2A), supporting the remarkable beneficial effects of the antibody of the present invention.

[0297] To investigate the effect of the length of time between patient ICU admission and the initiation of adrecizumab treatment, the population was divided into two groups based on the median of the time between patient ICU admission and the initiation of treatment, i.e., 0.344 days (8.3 hours), and the two groups were compared. When treatment was administered between 0 and 0.344 days (8.3 hours) after ICU admission, the 28-day mortality rate was significantly lower with adrecizumab treatment compared to placebo (HR 0.263 (0.077~0.898), log-rank p-value 0.022) (Figure 3A). When the time between ICU admission and treatment was between 0.344 days and 29 days, the difference in mortality between adrecizumab treatment and placebo was not very clear (HR 0.734 (0.358~1.50)) (Figure 3B). The hyperproportional beneficial therapeutic effect in patients treated within 0.344 days (8.3 hours) or less after ICU admission was consistent throughout the entire 90-day observation period: when treated between 0 and 0.344 days (8.3 hours) after ICU admission, adrecizumab treatment resulted in a significantly lower 90-day mortality rate compared to placebo (HR 0.364 (0.137~0.970), log-rank p-value 0.035) (Figure 4A). When the time between ICU admission and treatment was between 0.344 and 29 days, the difference in mortality between adrecizumab treatment and placebo was not very clear (HR 0.826 (0.469~1.45)) (Figure 4B).

[0298] Figure 5 shows the change in SOFA score when adrecizumab treatment was administered at 0.344 days after ICU admission (Figure 5A) compared to treatment administered more than 0.344 days after ICU admission (Figure 5B). When adrecizumab treatment was administered within 0.344 days after ICU admission, the SOFA score decreased rapidly and sustainably, supporting the remarkable beneficial effects of the antibody of the present invention.

[0299] Figure 6 shows the mean fluid balance at day 7 after the start of treatment when adrecizumab treatment was administered within 0.344 days after ICU admission (Figure 6A) compared with treatment administered more than 0.344 days after ICU admission (Figure 6B). Fluid balance (fluid input - fluid output) was recorded every 24 hours in the ICU. The mean fluid balance at 7 days or less after adrecizumab / placebo infusion was calculated for each patient. For example, days when fluid balance was lost due to discharge from the ICU or death were not considered. When adrecizumab treatment was administered within 0.344 days after ICU admission, fluid balance decreased significantly by 70.2%, but this decrease did not occur when treatment was administered later after ICU admission, supporting the remarkable beneficial effect of the antibody of this invention.

[0300] Figure 7 shows the mean fluid balance at day 7 after the start of treatment when adrecizumab treatment was administered within 8.4 hours after diagnosis of shock (Figure 8A), compared to treatment administered more than 8.4 hours after diagnosis of shock (Figure 8B). Fluid balance (fluid input - fluid output) was recorded every 24 hours in the ICU. The mean fluid balance for 7 days or less after adrecizumab / placebo infusion was calculated for each patient. For example, days when fluid balance was lost due to discharge from the ICU or death were not considered. When adrecizumab treatment was administered within 10 hours after diagnosis of shock, fluid balance decreased by 58.2%, but when treatment was administered later after diagnosis of shock, the decrease was not as significant (30.4%), supporting the remarkable beneficial effect of the antibody of this invention.

[0301] Patients who received adrecizumab or placebo infusion early after a shock diagnosis or ICU admission showed a more severe clinical state at the time of adrecizumab or placebo infusion initiation than those treated later, as indicated by higher APACHE II scores and other severity-related variables. This was expected, as the standard of care treatment typically results in short-term, but not sustained, improvement in the patient's clinical state.

[0302] A comparison of patients who received adrecizumab with those who received placebo did not reveal any relevant differences regarding these baseline characteristics, suggesting that the observed beneficial effects of adrecizumab are not conflated by other factors.

[0303] The beneficial effects of adrecizumab were more evident when treatment was initiated earlier. In an illustrative analysis, the population was divided into three groups after ranking patients according to the time from ICU admission to treatment initiation. 28-day mortality was analyzed for combinations of the first, second, third, and fourth quartiles of this population. Quartile 1 encompassed the time frame of 0–0.24 days after ICU admission, quartile 2 encompassed the time frame of 0.25–0.34 days after ICU admission, and quartile 3 / 4 encompassed the time frame of >0.35 days after ICU admission. Mortality was most clearly reduced in quartile 1 (85%), clearly detectable but less clearly in quartile 2 (53%), and hardly clear but still clearly in quartile 3 / 4 (23%) (Table 2). [Table 3]

[0304] Example 3 From the AdrenOSS-1 clinical trial, ICU-admitted septic shock patients with bio-ADM concentrations higher than 70 pg / mL and DPP3 concentrations below 50 ng / mL were selected and further analyzed. The following day, an increase in DPP3 levels above 70 ng / mL was observed. The median concentration increased from 41.0 ng / mL to 129.7 ng / mL (see Figure 8 and Table 3). [Table 4]

[0305] This is further illustrated in Figure 9 with an example of an individual patient's progress.

[0306] The data demonstrate that patients with septic shock treatable with adrecizumab upon ICU admission may pathologically exhibit elevated plasma levels of DPP3. These, in turn, can induce shock and death, as described in the literature (Blet et al., Crit Care. 2021 Feb 15;25(1):61). Therefore, this supports the concept of initiating treatment with adrecizumab early rather than late in patients with septic shock to avoid the increase in DPP3 and subsequent fatal developments such as shock and death.

Claims

1. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of patients in shock, particularly in patients with septic shock, wherein the patient: - The patient has been suffering from shock, particularly septic shock, for no more than 10 hours prior to the initiation of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold, and / or - The patient was admitted to the ICU within 10 hours of the initiation of treatment using the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, and / or - At the start of treatment using the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, the patient is either not receiving any organ support or has received organ support for no more than 10 hours. And here, the antibody or fragment or scaffold binds to the N-terminal portion (aa1-21) of ADM: YRQSMNNNFQGLRSFGCRFGTC (SEQ ID NO: 4), Adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in therapeutic purposes.

2. The patient is in a state of shock, particularly septic shock, for use in the treatment according to claim 1, wherein the patient is in a state of shock, particularly septic shock, for a period of time not exceeding 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), 5 hours, preferably 4 hours, preferably 3 hours, with an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment that binds to ADM, or an anti-ADM non-Ig scaffold that binds to adremedullin.

3. An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment that binds to ADM or an anti-ADM non-Ig scaffold that binds to adremedullin, for use in the treatment according to claim 1 or 2, wherein the patient is admitted to the ICU for no more than 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

4. An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment that binds to ADM or an anti-ADM non-Ig scaffold that binds to adremedullin, for use in the treatment according to any one of claims 1 to 3, wherein the patient receives organ support for not more than 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.24 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, at the start of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

5. An anti-adrenomedullin (ADM) antibody, an anti-adrenomedullin antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment of patients suffering from shock, particularly septic shock, wherein the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is - Within 10 hours after the onset of shock in the aforementioned patient, and / or - Within 10 hours of the patient's admission to the ICU, and / or - Before the patient receives organ support or within 10 hours of receiving organ support. It is administered as follows: And here, the antibody or fragment or scaffold binds to the N-terminal portion (aa1-21) of ADM: YRQSMNNNFQGLRSFGCRFGTC (SEQ ID NO: 4), Anti-adrenomedullin (ADM) antibodies, anti-adrenomedullin antibody fragments, or anti-ADM non-Ig scaffolds for use in the treatment of patients in shock, particularly those suffering from septic shock.

6. The anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold according to claim 5, for use in the treatment of a patient suffering from shock, particularly septic shock, with an antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold, which is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the onset of shock in the patient.

7. The anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from a shock condition, particularly septic shock, according to claim 5 or 6, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient is admitted to the ICU.

8. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from a shock condition, particularly septic shock, according to any one of claims 5 to 7, wherein the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold is administered within 9 hours, preferably 8.4 hours, preferably 8.26 hours (0.344 days), preferably 8 hours, preferably 7 hours, preferably 6 hours, preferably 5.76 hours (0.25 days), preferably 5.75 hours (0.25 days), preferably 5 hours, preferably 4 hours, or preferably 3 hours, after the patient has received organ support at the starting point of treatment with the anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold.

9. An anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to ADM or an anti-ADM non-Ig scaffold that binds to adrenomedullin, for use in the treatment according to any one of claims 1 to 8, wherein the patient has shock selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock and distributive shock, particularly cardiogenic shock, septic shock, shock caused by Covid-19, shock caused by burns and traumatic shock.

10. An anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to ADM or an anti-ADM non-Ig scaffold that binds to adrenomedullin, for use in the treatment according to claim 9, wherein the patient has septic shock.

11. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from a shock condition according to any one of claims 1 to 10, particularly septic shock, wherein a body fluid sample taken from the patient exhibits a bio-ADM level of >70 pg / mL, and the body fluid is selected from the group including whole blood, plasma, or serum.

12. An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment of a patient suffering from a shock condition, particularly septic shock, according to any one of claims 1 to 11, wherein a body fluid sample taken from the patient exhibits a DPP3 level of <50 ng / mL, and the body fluid is selected from the group including whole blood, plasma, or serum.

13. An anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment according to any one of claims 1 to 12, wherein the antibody or antibody fragment or non-Ig scaffold is monospecific.

14. The antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore2000 system, resulting in at least 10 -7 An anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment according to any one of claims 1 to 13, exhibiting binding affinity of M to ADM.

15. The antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore2000 system, resulting in 1 × 10⁻¹⁶ -9 ~3 x 10 -9 An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment according to claim 14, exhibiting binding affinity to ADM.

16. The anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient according to any one of claims 13 to 15, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is an IgG1 antibody.

17. An anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment according to any one of claims 1 to 16, wherein the antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H).

18. An anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment according to any one of claims 1 to 17, wherein the antibody or fragment or scaffold recognizes and binds to the N-terminus (aa1) of ADM.

19. The antibody or fragment or scaffold is an ADM-stabilizing antibody or fragment or scaffold for use in the treatment according to any one of claims 1 to 18, wherein the antibody or fragment or scaffold extends the half-life (t1 / 2 half-residence time) of ADM in serum, blood, or plasma by at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100%.

20. The anti - adrenomedullin (ADM) antibody or fragment or scaffold for use in the treatment according to any one of claims 1 to 19, wherein the antibody or fragment or scaffold blocks 80% or less, preferably 50% or less, of the biological activity of ADM, using hADM22 - 52 as a reference antagonist in CHO - K1 cells expressing human recombinant ADM receptor.

21. The anti - adrenomedullin (ADM) antibody or fragment or scaffold for use in the treatment according to any one of claims 1 to 20, wherein the subject has experienced treatment with chemotherapy, vasopressor agents, treatment with biologics, antibiotics, or antiviral compounds.

22. The antibody or fragment is a human monoclonal antibody or fragment that binds to ADM or its antibody fragment, where the heavy chain has the sequence: CDR1: SEQ ID NO: 5 GYTFSRYW CDR2: SEQ ID NO: 6 ILPGSGST CDR3: SEQ ID NO: 7 TEGYEYDGFDY and the light chain has the sequence: CDR1: SEQ ID NO: 8 QSIVYSNGNTY CDR2: RVS CDR3: SEQ ID NO: 9 FQGSHIPYT and The anti - adrenomedullin (ADM) antibody or fragment or scaffold for use in the treatment according to any one of claims 1 to 21.

23. The antibody or fragment has, as the VH region: SEQ ID NO: 10 (AM - VH - C) QVQLQQSGAE LMKPGASVKISC KATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQ LSSLTS EDSAVYYCTEGYEYDGFDYWGQGTTLTVSSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LS S VVT VPS S SLGTQTYICNVNHKPSNTKV DKRVEPKH HHHHHH SEQ ID NO: 11 (AM - VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHHHH Sequence ID 12 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHHHH Sequence ID 13 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHHHH Sequence ID 14 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKHHHHHHHH Includes sequences selected from the group containing, And the following sequence as the VL region: Sequence ID 15 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 16 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 17 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes sequences selected from a group that includes, A human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof for use in the treatment described in claim 22.

24. The antibody or fragment has the following sequence as its heavy chain: Sequence ID 22 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or including a sequence that is >95% identical to the said sequence, And the following sequence as the light chain: Sequence ID 23 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or including a sequence that is >95% identical to the said sequence, A human monoclonal antibody or fragment that conjugates to ADM or an antibody fragment thereof for use in the treatment described in claim 22 or 23.

25. An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient according to any one of claims 1 to 24, wherein the anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1 to 10) of ADM: YRQSMNNNFQG (SEQ ID NO: 25).

26. A pharmaceutical preparation for use in the treatment or prevention of disease symptoms, or for use in the treatment described in any one of claims 1 to 25.

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