Anti-adrenomedullin (ADM) antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds for use in the treatment or prevention of shock

Abstract

The present application is directed to an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in treating or preventing shock in a patient, wherein the patient is characterized by having a level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid that is below a threshold, and the anti-ADM antibody or anti-ADM non-Ig scaffold binds to the N-terminal portion of ADM (amino acids 1-21): YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14).

Description

[Technical Field] 【0001】 The subject of the present invention is an anti-adrenomedullin (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, characterized in that the patient has a subthreshold level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid, and the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14). [Background technology] 【0002】 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). 【0003】 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. 【0004】 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. 【0005】 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 (Correa 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. 【0006】 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. 【0007】 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. in press). 【0008】 The peptide adrenomedullin (ADM) was first described in 1993 (Kitamura et al., 1993) as a novel blood pressure-lowering peptide containing 52 amino acids and isolated from a human pheochromocytoma cell line (SEQ ID NO: 20). 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 generally related to prepro-ADM containing 185 amino acids. Peptide adrenomedullin (ADM) is a peptide containing 52 amino acids (SEQ ID NO: 20) 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 precisely, particularly the bioactive peptide 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 (Takahashi 2001. Peptides 22: 1691; Eto 2001. Peptides 22: 1693-1711). A further review is by Hinson et al. 2000 (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 et al. 1998. Biochem Biophys Res Commun 244(2): 551-555).There are also binding proteins that are specific to ADM and likely similarly regulate the effects of ADM (Pio 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. 【0009】 Therefore, ADM is an effective vasodilator, and thus its antihypertensive effect can be linked to a specific peptide segment in the C-terminal region of ADM. Furthermore, the bioactive peptide PAMP, generated from prepro-ADM, has been found to exhibit a similar antihypertensive effect, even though it appears to have a different mechanism of action than ADM (in addition to the above review, see Eto et al. 2001 and Hinson et al. 2000, also Kuwasaki et al. 1997. FEBS Lett 414(1): 105-110; Kuwasaki et al. 1999. Ann. Clin. Biochem. 36: 622-628; Tsuruda et al. 2001 Life Sci. 69(2): 239-245 and EP-A2 0 622 458). 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 control subjects. 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 2001. Peptides 22: 1693-1711).Abnormally high concentrations of ADM are observed in sepsis, with the highest concentrations observed in septic shock (Eto 2001. Peptides 22: 1693-1711; Hirata et al. Journal of Clinical Endocrinology and Metabolism 81(4): 1449-1453; Ehlenz et al. 1997. Exp Clin Endocrinol Diabetes 105: 156-162; Tomoda et al. 2001. Peptides 22: 1783-1794; Ueda et al. 1999. Am. J. Respir. Crit. Care Med. 160: 132-136 and Wang et al. 2001. Peptides 22: 1835-1840). 【0010】 Plasma concentrations of ADM are elevated in heart failure patients and correlate with disease severity (Hirayama et al. 1999. J Endocrinol 160: 297-303; Yu et al. 2001. Heart 86: 155-160). High plasma ADM is an independent negative prognostic indicator in these patients (Poyner et al. 2002. Pharmacol Rev 54: 233-246). 【0011】 International Publication No. 2004 / 097423 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, 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. 【0012】 For the initial stage of sepsis, ADM has been reported to improve cardiac function and blood supply to the liver, spleen, kidney, and small intestine. Anti-ADM neutralizing antibodies neutralize the aforementioned effects during the initial stage of sepsis (Wang et al. 2001. Peptides 22: 1835-1840). 【0013】 For other diseases, blockade of ADM may be beneficial to some extent. However, when a certain amount of ADM may be required for some physiological functions, blockade of ADM may also be harmful if ADM is completely neutralized. Many reports have emphasized that administration of ADM may be beneficial in certain diseases. In contrast to these, other reports have reported that ADM is fatal when administered in certain pathological conditions. 【0014】 WO 2013 / 072510 describes non-neutralizing anti-ADM antibodies for use in the treatment of severe chronic or acute diseases or acute pathological conditions of a patient to reduce the patient's risk of death. 【0015】 WO 2013 / 072511 describes non-neutralizing anti-ADM antibodies for use in the treatment of chronic or acute diseases or acute pathological conditions of a patient to prevent or reduce organ damage or organ failure. 【0016】 WO 2013 / 072512 describes a non-neutralizing anti-ADM antibody which is an ADM-stabilizing antibody that enhances the half-life (t 1 / 2 half residence time) of adrenomedullin in serum, blood, and plasma. This ADM-stabilizing antibody blocks the biological activity of ADM to less than 80%. 【0017】 WO 2013 / 072513 describes non-neutralizing anti-ADM antibodies for use in the treatment of acute diseases or pathological conditions of a patient to stabilize the circulation. 【0018】 International Publication No. WO 2013 / 072514 describes non-neutralizing anti-ADM antibodies for regulating fluid balance in patients with chronic or acute diseases or acute conditions. 【0019】 International Publication No. 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 necrotic-related diseases with an antibody against DPP3. 【0020】 A number of markers are known in the prior art related to shock, but none specifically suggest DPP3 as a marker for shock. 【0021】 Examples of such biomarkers include MR-proADM, lactate, C-reactive protein (CRP), and procalcitonin (PCT) (Ana Maria Navio Serano,1 Joaquin Valle Alonso,2,* Gustavo Rene Pinero,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 cited in a recent review (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). 【0022】 Therefore, a remarkable finding of this invention is that in patients in shock, DPP3 levels in body fluid samples can be used for guidance or monitoring of treatment with anti-ADM antibodies. Furthermore, the results of this invention clearly demonstrate that patients in shock will benefit most from treatment with anti-ADM antibodies when DPP3 levels in body fluid samples are below a threshold. [Overview of the project] 【0023】 The subject of the present invention is an anti-adrenomedullin (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, characterized in that the patient has a subthreshold level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid, and the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14). 【0024】 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 or prevention of shock in a patient, wherein the shock is selected from the group including hypovolemic shock, cardiogenic shock, occlusive shock, and distributive shock, and in particular is cardiogenic shock or septic shock. 【0025】 Another embodiment of the present application is an anti-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, In cases of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or the patient may have 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 may be suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds. 【0026】 One preferred embodiment of the present application relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, wherein the threshold of DPP3 in a sample of the patient's body fluid is 20-120 ng / mL, more preferably 30-80 ng / mL, more preferably 40-90 ng / mL, even more preferably 40-60 ng / mL, and most preferably the threshold is 50 ng / mL. 【0027】 One particular embodiment of the present application relates to an anti-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, wherein the DPP3 level is determined by contacting the body fluid sample with a capture binder that specifically binds to DPP3. 【0028】 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, which determines either a DPP3 protein level and / or an active DPP3 level and compares it to a predetermined threshold. 【0029】 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 or prevention of shock in a patient, the patient being further characterized by having an ADM-NH2 level greater than a threshold. 【0030】 ADM-NH2 levels are measured to identify patients in shock. 【0031】 One preferred embodiment of the present application relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, wherein the threshold of ADM-NH2 in a sample of the patient's body fluid is 40-100 pg / mL, more preferably 50-90 pg / mL, even more preferably 60-80 pg / mL, and most preferably 70 pg / mL. 【0032】 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. 【0033】 Another preferred embodiment of the present application relates to an anti-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, wherein the body fluid sample of the patient is selected from the group consisting of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. 【0034】 Another specific embodiment of the present application relates to an anti-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, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminus (amino acid 1) of ADM-Gly and / or ADM-NH2. 【0035】 Further embodiments of the present application relate 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 antibody, antibody fragment, or non-Ig scaffold does not bind to the C-terminal portion of ADM having the sequence amino acids 43-52:PRSKISPQGY-NH2 (SEQ ID NO: 24). 【0036】 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 or prevention of shock in a patient, wherein the antibody, fragment, or scaffold blocks the biological activity of ADM by 80% or less, preferably 50% or less. 【0037】 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 or prevention of shock in a patient, wherein the antibody or fragment is a monoclonal antibody or fragment that conjugates to ADM or the antibody fragment thereof, and the heavy chain is sequence: CDR1: Sequence ID 1 GYTFSRYW CDR2: Sequence ID 2 ILPGSGST CDR3: Sequence ID 3 TEGYEYDGFDY The light chain includes the following arrangement: CDR4: Sequence ID 4 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 5 FQGSHIPYT This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds, including those mentioned above. 【0038】 Another embodiment of the present application is an anti-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, wherein the antibody or fragment has a VH region Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK The VL region includes sequences selected from the group containing the following: Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes sequences selected from a group that includes, This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds. 【0039】 Another embodiment of the present application is an anti-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, wherein the antibody or fragment has the following sequence as a heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or a sequence containing a sequence that is >95% identical to this, with the following sequence as the light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or including sequences that are >95% identical to this, This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds. 【0040】 The subject matter of this application is a pharmaceutical preparation for use in the treatment or prevention of shock in patients, further comprising an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold. 【0041】 One embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is a liquid, preferably a ready-to-use liquid. 【0042】 Another embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is in a lyophilized state. 【0043】 One embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is administered intramuscularly. 【0044】 One preferred embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is administered intravascularly. 【0045】 Another embodiment of the present application relates to a pharmaceutical preparation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical preparation is administered by infusion. 【0046】 Another specific embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation can be administered systemically. 【0047】 Another embodiment of the present application is a method for treating or preventing shock in a patient, the method comprising administering to the patient an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold, the method is The steps include determining the DPP3 level in the sample of the target body fluid, The steps include: comparing the determined DPP3 level with a predetermined threshold; If the determined DPP3 level is below the predetermined threshold, the patient is treated. The aforementioned anti-ADM antibody, anti-ADM fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14), Regarding the method. 【0048】 Another embodiment of the present application is a method for treating or preventing shock in a patient, the method comprising administering to the patient an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold, the method is The steps include determining the ADM-NH2 level in a sample of the body fluid of the subject, - A step of comparing the determined ADM-NH2 level with a predetermined threshold. The present invention further comprises a method for treating the patient if the determined ADM-NH2 level is greater than the predetermined threshold. 【0049】 The subject of the present invention is an anti-adrenomedullin (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, characterized in that the patient has a subthreshold level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid, and the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14). 【0050】 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 or prevention of shock in a patient, wherein the shock is selected from the group including hypovolemic shock, cardiogenic shock, occlusive shock, and distributive shock, and in particular is cardiogenic shock or septic shock. 【0051】 Another embodiment of the present application is an anti-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, In cases of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or the patient may have 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 may be suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds. 【0052】 One preferred embodiment of the present application relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, wherein the threshold of DPP3 in a sample of the patient's body fluid is 20-120 ng / mL, more preferably 30-80 ng / mL, more preferably 40-90 ng / mL, even more preferably 40-60 ng / mL, and most preferably the threshold is 50 ng / mL. 【0053】 One particular embodiment of the present application relates to an anti-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, wherein the DPP3 level is determined by contacting the body fluid sample with a capture binder that specifically binds to DPP3. 【0054】 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, which determines either a DPP3 protein level and / or an active DPP3 level and compares it to a predetermined threshold. 【0055】 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 or prevention of shock in a patient, the patient being further characterized by having an ADM-NH2 level greater than a threshold. 【0056】 One preferred embodiment of the present application relates to an anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in a patient, wherein the threshold of ADM-NH2 in a sample of the patient's body fluid is 40-100 pg / mL, more preferably 50-90 pg / mL, even more preferably 60-80 pg / mL, and most preferably 70 pg / mL. 【0057】 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. 【0058】 Another preferred embodiment of the present application relates to an anti-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, wherein the body fluid sample of the patient is selected from the group consisting of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. 【0059】 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 human amidated adrenomedullin peptide (1-52), hereafter referred to as bio-ADM®, in human EDTA whole blood and plasma. 【0060】 Another specific embodiment of the present application relates to an anti-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, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminus (amino acid 1) of ADM-Gly and / or ADM-NH2. 【0061】 Further embodiments of the present application relate 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 antibody, antibody fragment, or non-Ig scaffold does not bind to the C-terminal portion of ADM having the sequence amino acids 43-52:PRSKISPQGY-NH2 (SEQ ID NO: 24). 【0062】 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 or prevention of shock in a patient, wherein the antibody, fragment, or scaffold blocks the biological activity of ADM by 80% or less, preferably 50% or less. 【0063】 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 or prevention of shock in a patient, wherein the antibody or fragment is a monoclonal antibody or fragment that conjugates to ADM or the antibody fragment thereof, and the heavy chain is sequence: CDR1: Sequence ID 1 GYTFSRYW CDR2: Sequence ID 2 ILPGSGST CDR3: Sequence ID 3 TEGYEYDGFDY The light chain includes the following arrangement: CDR1: Sequence ID 4 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 5 FQGSHIPYT This relates to anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds, including those mentioned above. 【0064】 Another embodiment of the present application is an anti-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, wherein the antibody or fragment has a VH region, Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK The VL region includes sequences selected from the group containing the following: Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC This relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold containing a sequence selected from the group including the above. 【0065】 Another embodiment of the present application is an anti-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, wherein the antibody or fragment comprises the following sequence as a heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or a sequence containing a sequence that is >95% identical to this, with the following sequence as the light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The present invention relates to an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold containing a sequence that is >95% identical thereto. 【0066】 Another embodiment of the present application relates to an anti-adrenomedullin (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 anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold conjugates to the N-terminal portion (amino acids 1-10): YRQSMNNFQG (SEQ ID NO: 26) of ADM. 【0067】 Another embodiment of the present application is an anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in therapy, wherein 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 relates to an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold that exhibits binding affinity of M to ADM. 【0068】 Another embodiment of the present application relates to an anti-adrenomedullin (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 anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is subjected to label-free surface plasmon resonance of 1 × 10⁻¹⁶ using the Biacore 2000 system. -9 ~3×10 -9 This relates to an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold that exhibits affinity for human ADM. 【0069】 Another embodiment of the present application relates to 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, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is an IgG1 antibody. 【0070】 The subject matter of this application is a pharmaceutical preparation for use in the treatment or prevention of shock in patients, further comprising an anti-ADM antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold. 【0071】 One embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is a liquid, preferably a ready-to-use liquid. 【0072】 Another embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is in a lyophilized state. 【0073】 One embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is administered intramuscularly. 【0074】 One preferred embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation is administered intravascularly. 【0075】 Another embodiment of the present application relates to a pharmaceutical preparation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical preparation is administered by infusion. 【0076】 Another specific embodiment of the present application relates to a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, wherein the pharmaceutical formulation can be administered systemically. 【0077】 Another embodiment of the present application is a method for treating or preventing shock in a patient, the method comprising administering to the patient an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold, the method is The steps include determining the DPP3 level in the sample of the target body fluid, - A step of comparing the determined DPP3 level with a predetermined threshold. Includes, If the determined DPP3 level is below the predetermined threshold, the patient is treated. The aforementioned anti-ADM antibody, anti-ADM fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (aa1-21):YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14), Regarding the method. 【0078】 Another embodiment of the present application is a method for treating or preventing shock in a patient, the method comprising administering to the patient an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM non-Ig scaffold, the method is The steps include determining the ADM-NH2 level in a sample of the body fluid of the subject, - A step of comparing the determined ADM-NH2 level with a predetermined threshold. It further includes, If the determined ADM-NH2 level is greater than the predetermined threshold, the patient is treated. Regarding the method. 【0079】 In one embodiment of the present invention, either the DPP3 protein level and / or the active DPP3 level is determined and compared to a threshold. 【0080】 In a particular embodiment of the present invention, the threshold for DPP3 in the patient's body fluid sample is 20-120 ng / mL, more preferably 40-90 ng / mL, more preferably 30-80 ng / mL, and even more preferably 40-60 ng / mL, with the most preferred threshold being 50 ng / mL. 【0081】 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. 【0082】 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. 【0083】 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). 【0084】 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, Barsun 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., Barsun et al. 2007), thin-layer chromatography (e.g., Dhanda et al. 2008), or reverse-phase chromatography (e.g., Mazocco et al. 2006). 【0085】 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-naphthylamides (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. 【0086】 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. 【0087】 In a preferred embodiment, DPP3 is measured by adding the fluorescence-generating substrate Arg-Arg-βNA, and fluorescence is monitored in real time. 【0088】 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. 【0089】 If present, the test sample passes through the immobile binder and 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” means that assays may be performed in or on it. Any of the following materials or vessels may be used, including but not limited to porous materials, non-porous materials, test tubes, wells, slides, agarose resins (e.g., Sepharose from GE Healthcare Life Sciences), magnetic particles (e.g., Dynabeads® or Pierce® magnetic beads from Thermo Fisher Scientific), and others. 【0090】 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. 【0091】 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. 【0092】 In a particular embodiment of the present invention, the capture and binding agent is an antibody. 【0093】 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: 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. 【0094】 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. 【0095】 3. Liquid-phase assay (LAA) for quantifying DPP3 activity (modified from Jones et al., Analytical Biochemistry, 1982). LAA is a liquid-phase assay using a black unbound polystyrene microtiter plate to measure DPP3 activity. 20 microliters of sample (e.g., serum, heparin-plasma, citrate-plasma) and a calibration sample are pipetted into an unbound black microtiter plate. After adding the fluorescent substrate, Arg2-βNA, to the assay buffer (200 μL), the initial βNA fluorescence (T=0) is measured using a fluorometer with an excitation wavelength of 340 nm, and the emission is detected at 410 nm. The plate is then incubated at 37°C for 1 hour. The final fluorescence (T=60) is measured. The difference between the final and initial fluorescence is calculated. DPP3 activity is determined using a 6-point calibration curve. The calibration sample and sample are preferably repeated twice. 【0096】 In certain embodiments, an assay is used to determine the DPP3 level, and the assay sensitivity of the assay is such that it can quantify CPP3 in healthy subjects and is <20 ng / ml, preferably <30 ng / ml, more preferably <40 ng / ml. 【0097】 4. Another immunoassay method for measuring DPP3 from whole blood plasma samples is the available IB10 sphingotest® DPP3 (https: / / www.nexus-dx.com / wp-content / uploads / 2020 / 11 / DPP3-022-00072-IFU-REV-B_8x11.pdf). IB10 sphingotest® DPP3 is a rapid point-of-care (POC) immunoassay for in vitro quantification of dipeptidyl peptidase 3 (DPP3) in human EDTA whole blood and plasma. The Nexus IB10 immunochemistry system combines chemistry with microfluidics and centrifugal flow to rapidly prepare cell-free plasma from whole blood, which can then proceed through channels for rehydration, lysis, and mixing with lyophilized immunocomplexes. 【0098】 In a particular embodiment, the binder is at least 10 7 M -1, preferably 10 8 M -1 shows binding affinity for DPP3 of, more preferably an affinity of 10 9 M -1 greater than, and most preferably an affinity of 10 10 M -1 greater than. Those skilled in the art know that it may be possible to compensate for lower affinity by applying higher doses of the compound, and this measurement is not outside the scope of the present invention. 【0099】 In another embodiment of the present invention, the body fluid sample is selected from the group consisting of whole blood, plasma, and serum. 【0100】 Throughout this specification, mature ADM, bioADM and ADM-NH2 are used as synonyms and are molecules according to SEQ ID NO: 20. 【0101】 In one particular embodiment, the body fluid according to the present invention is a blood sample. The blood sample may be selected from the group including whole blood, serum and plasma. In a particular embodiment of the method, the sample is selected from the group including human citrated plasma, heparin plasma and EDTA plasma. 【0102】 In a particular embodiment, an assay is used to determine ADM-NH2 levels, and the assay sensitivity of said assay is capable of quantifying mature ADM-NH2 in healthy subjects and is <70 pg / ml, preferably <40 pg / ml, more preferably <10 pg / ml. 【0103】 In a particular embodiment of the present invention, the threshold value of ADM-NH2 is 40 - 100 pg / mL, more preferably 50 - 90 pg / mL, even more preferably 60 - 80 pg / mL, and most preferably a threshold value of 70 pg / ml is applied. 【0104】 In a particular embodiment of the present invention, the threshold value of plasma ADM-NH2 is 5 times the median concentration of the healthy population, preferably 4 times the median concentration, more preferably 3 times the median concentration, and most preferably 2 times the median concentration. 【0105】 In a particular embodiment, the binder is at least 10 7 M -1 Preferably 10 8 M -1 It shows binding affinity to ADM-NH2, with a preferred affinity of 10 9 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. 【0106】 To determine the affinity of the antibody to adremedullin, the binding dynamics of the antibody-immobilized adremedullin 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). 【0107】 In certain embodiments, the binder is selected from the group comprising an antibody or antibody fragment that binds to ADM-NH2 or a non-Ig scaffold. 【0108】 In certain embodiments, an assay is used to determine ADM-NH2 levels, and such assay is a sandwich assay, preferably a fully automated assay. 【0109】 In one embodiment, such an assay for determining the level of a biomarker (DPP3 and / or ADM-NH2) is a sandwich immunoassay using any type of detection technique, including but not limited to enzymatic labeling, chemiluminescence labeling, and electrochemiluminescence labeling. In one embodiment of the diagnostic method, such an assay is an enzymatically labeled sandwich assay. Examples of automated or fully automated assays include assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, BiomerieuxVidas®, and Alere Triage®. 【0110】 Various immunoassays are known and may be used for the assays and methods of the present invention, including: radioimmunoassays ("RIA"), homogeneous enzyme immunoassays ("EMIT"), enzyme-linked immunosorbent assays ("ELISA"), apoenzyme reactivation immunoassays ("ARIS"), dipstick immunoassays, and immunochromatographic assays. 【0111】 In one embodiment of the present invention, such assay is a sandwich immunoassay using any type of detection technique, including but not limited to enzyme labeling, chemiluminescence labeling, and electrochemiluminescence labeling. In one embodiment of the present invention, such assay is an enzyme-labeled sandwich assay. Examples of automated or fully automated assays include assays that may be used for one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, Biomerieux Vidas®, and Alere Triage®. 【0112】 In one embodiment of the present invention, the test technique may be a so-called POC (point-of-care) test, which allows the test to be performed in the presence of the patient in less than one hour, without the need for a fully automated assay system. An example of this technique is immunochromatography testing. 【0113】 In a preferred embodiment, the label is selected from the group including chemiluminescent labels, enzyme labels, fluorescent labels, and radioactive iodine labels. 【0114】 The assay may be a homogeneous or heterogeneous assay, a competitive or non-competitive assay. In one embodiment, the assay is a non-competitive immunoassay in the form of a sandwich, in which the molecule to be detected and / or quantified is conjugated to a first antibody and a second antibody. The first antibody may be conjugated to a solid phase, such as beads, the surface of a well or other container, a tip or strip, and the second antibody may be an antibody labeled with, for example, a dye, a radioisotope, or a reactive or enzymatically active moiety. The amount of the labeled antibody conjugated to the analyte is then measured by an appropriate method. The general compositions and procedures related to the "sandwich assay" are established and known to those skilled in the art (The Immunoassay Handbook, Ed. David Wild, Elsevier LTD, Oxford; 3rd ed. (May 2005), ISBN-13: 978-0080445267; Hultschig C et al., Curr Opin Chem Biol. 2006 Feb;10(1):4-10. PMID:16376134). 【0115】 In another embodiment, the assay comprises two capture molecules, both antibodies, preferably present as dispersions in a liquid reaction mixture, wherein a first labeled component binds to the first capture molecule, the first labeled component being part of a labeling system based on fluorescence or chemiluminescence quenching or amplification, and a second labeled component of the marking system binds to the second capture molecule, resulting in a measurable signal generated by the binding of both capture molecules to the analyte, enabling detection of the resulting sandwich complex in a solution containing the sample. 【0116】 In another embodiment, the labeling system includes a rare earth cryptate or rare earth chelate combined with a fluorescent dye or chemiluminescent dye, particularly a cyanine-based dye. 【0117】 In connection with the present invention, a fluorescence-based assay involves the use of dyes, such as cyanine dyes such as FAM (5- or 6-carboxyfluorescein), VIC, NED, fluorescein, fluorescein isothiocyanate (FITC), IRD-700 / 800, CY3, CY5, CY3.5, CY5.5, Cy7, xanthenes, and 6-carboxy-2',4',7',4,7-hexachlorofluorescein (HEX). You may select from the group including TET, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein (JOE), N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX), 5-carboxyrhodamine-6G (R6G5), 6-carboxyrhodamine-6G (RG6), rhodamine, rhodamine green, rhodamine red, rhodamine 110, BODIPY dyes such as BODIPY TMR, coumarins such as Oregon green and umbelliferone, benzimides such as Hoechst 33258; phenanthridines such as Texas red, Yakima Yellow, Alexa Fluor, PET, ethidium bromide, acridine dyes, carbazole dyes, phenoxazine dyes, porphyrin dyes, polymethine dyes, and similar dyes. 【0118】 In connection with the present invention, the chemiluminescent-based assay involves the use of dyes based on the physical principles described with respect to chemiluminescent substances in (Kirk-Othmer, Encyclopedia of Chemical Technology, 4th ed., executive editor, JI Kroschwitz; editor, M. Howe-Grant, John Wiley & Sons, 1993, vol.15, pp. 518-562, incorporated herein by reference, including citations on pages 551-562). Preferred chemiluminescent dyes are acridinium esters. 【0119】 Where used herein, “assay” or “diagnostic assay” may refer to any type applied in the diagnostic field. Such an assay may be based on binding the analyte to be detected with one or more capture probes having a specific affinity. Taking into account the interaction between the capture molecule and the target molecule or molecule of interest, the affinity constant is preferably 10 8 M -1 Larger. 【0120】 In certain embodiments, at least one of the two binders is labeled to be detectable. 【0121】 The ADM-NH2 levels of the present invention were determined using the ADM-NH2 assay described (Weber et al. 2017. JALM 2(2):1-4). The DPP3 levels of the present invention were determined using the DPP3 assay described as outlined in example (Rehfeld et al. 2019. JALM 3(6): 943-953). If these are calibrated differently from the assay systems used in the present invention, the above thresholds may differ in other assays. Therefore, the above cutoff values ​​should be applied to suit assays that are calibrated differently in this way, taking into account the differences in calibration. One possibility for quantifying the differences in calibration is a method-comparative analysis (correlation) of the assay in question using the respective biomarker assays used in the present invention by measuring each biomarker (e.g., bio-ADM, DPP3) in a sample using both methods. Another possibility, if this test has sufficient analytical sensitivity, is to use the assay in question to determine the median biomarker level in a representative normal population, compare the results with the median biomarker level described in the literature, and recalculate the calibration based on the difference obtained from this comparison. Using the calibration used in this invention, samples from normal (healthy) subjects were measured: the plasma bio-ADM median (mature ADM-NH2) was 24.7 pg / ml, with a minimum value of 11 pg / ml and a 99th percentile of 43 pg / ml (Marino et al. 2014. Critical Care 18:R34). Using the calibration used in this invention, samples from 5,400 normal (healthy) subjects (from a Swedish single-center prospective population-based study (MPP-RES)) were measured: the median (interquartile range) of plasma DPP3 was 14.5 ng / ml (11.3 ng / ml~19 ng / ml). 【0122】 Therefore, in this invention, ADM-NH2 levels are measured to identify patients who have an increased risk of developing shock. 【0123】 In certain embodiments of the present invention, the shock is selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock, and distributive shock. 【0124】 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. 【0125】 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. 【0126】 Shock is characterized by decreased oxygen delivery and / or increased oxygen consumption or insufficient oxygen utilization, resulting in cellular and tissue hypoxia. It is a fatal 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, vascular occlusive shock, and distributive shock (Vincent and De Backer 2014. N. Engl. J. Med. 370(6): 583). 【0127】 Hypovolemic 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 hypovolemic shock include gastrointestinal bleeding, trauma, vascular etiologies (e.g., ruptured abdominal aortic aneurysm, tumors affecting major blood vessels), and spontaneous bleeding in the context of anticoagulant use. Common causes of non-hemorrhagic hypovolemic shock include vomiting, diarrhea, renal loss / insensitivity loss (e.g., burns, heatstroke), or third-space loss in the context of 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. 【0128】 Cardiogenic shock (CS) is defined as a severe decrease in end-organ blood flow due to reduced cardiac output. Notably, CS forms a spectrum ranging from mild hypoflow loss to severe shock. Established diagnostic criteria for CS are: (i) systolic blood pressure > ≤ 90 mmHg in 30 minutes or requiring vasopressors to reach blood pressure ≥ 90 mmHg; (ii) pulmonary congestion or increased 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 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 continued decline in mortality and the benefits of treatment, primarily through early revascularization, CS remains a leading cause of death, with a mortality rate of nearly 40–50%, according to recent enrollment and randomized trials (Goldberg et al. 2009. Circulation 119: 1211-1219). 【0129】 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 an overview, see Koya and Paul 2018. Shock. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019-2018 Oct 27. 【0130】 Depending on the cause, there are four types of distributive shock: neurogenic shock (decreased sympathetic nerve stimulation leading to decreased vagus nerve tone), anaphylactic shock, septic shock, and shock caused by 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. 【0131】 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). 【0132】 Septic shock is 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. Children, immunocompromised individuals, and the elderly usually develop the disease 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%. 【0133】 As used herein, the term “prevention” or any of its grammatical variations (e.g., to prevent, the act of preventing, and prevention, etc.) includes, but is not limited to, delaying the onset of symptoms, preventing disease recurrence, increasing the latency period between symptomatic episodes, or a combination thereof. As used herein, prevention does not require complete absence of symptoms. 【0134】 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). 【0135】 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 a single dose and 0–40% with repeated doses. Furthermore, Phase I trials demonstrated excellent safety and tolerability (see Example 6): no serious adverse events were observed, no adverse events more frequently occurring in adrecizumab-treated patients were detected, and no associated changes in other safety parameters were observed (Geven et al. 2017. Intensive Care Med Exp 5 (Suppl 2): ​​0427). Of particular interest is the proposed mechanism of action of adrecizumab. Both animal and human data show a strong dose-dependent increase in circulating ADM after administration of this antibody. Based on pharmacokinetic data and the lack of increase for MR-proADM (an inactive peptide fragment derived from the same prohormone as ADM), higher circulating ADM levels cannot be explained by increased production. 【0136】 A possible mechanistic explanation for this increase is that while ADM is small enough to cross the endothelial barrier, antibodies are not, allowing excess antibodies in circulation to flow from the interstitial to 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, antibody binding to ADM results in an extension of the ADM half-life. Although NT-ADM antibodies partially inhibit ADM-mediated signaling, a significant increase in circulating ADM leads to an overall "net" increase in ADM activity in blood compartments, exhibiting beneficial effects on EC (primarily barrier stabilization) while reducing the adverse effects of ADM on VSMC (vasodilation) in the interstitial. 【0137】 The present invention is not particularly limited to the use of adrecizumab. There is no reason to doubt that what is correct for adrecizumab will also be correct 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.). 【0138】 Throughout this specification, the “antibody,” “antibody fragment,” or “non-Ig scaffold” according to the present invention can bind to ADM and therefore target ADM, and can therefore be referred to as “anti-ADM antibody,” “anti-ADM antibody fragment,” or “high-ADM non-Ig scaffold.” 【0139】 The term "antibody" generally includes monoclonal and polyclonal antibodies and their binding fragments, particularly Fc fragments, as well as so-called "single-chain antibodies" (Bird et al. 1988), chimeric, humanized, and especially CDR-grafted antibodies, and dia antibodies or tetra antibodies (Holliger et al. 1993). It also includes, for example, immunoglobulin-like proteins selected by techniques including phage display, which specifically binds to target molecules contained in a sample. In this context, the term "specific binding" refers to an antibody produced against a target molecule. An antibody is considered specific if its affinity for the target molecule or the aforementioned fragment is at least preferably 50 times higher, more preferably 100 times higher, and most preferably at least 1000 times higher than its affinity for other molecules in the sample containing the target molecule. Methods for producing antibodies and selecting antibodies with a given specificity are well known in the art. 【0140】 In embodiments of the present invention, the anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold is monospecific. 【0141】 A monospecific anti-adrenomedullin (ADM) antibody, monospecific anti-adrenomedullin antibody fragment, or monospecific anti-ADM non-Ig scaffold binds to a specific region containing at least five amino acids within the target ADM. A monospecific anti-adrenomedullin (ADM) antibody, monospecific anti-adrenomedullin antibody fragment, or monospecific anti-ADM non-Ig scaffold is an anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or anti-ADM non-Ig scaffold that all possess affinity for the same antigen. While monoclonal antibodies are monospecific, monospecific antibodies may be produced by means other than from common germ cells. 【0142】 The aforementioned anti-ADM antibody, antibody fragment that binds to ADM, or anti-ADM non-Ig scaffold that binds to ADM may be a non-neutralizing anti-ADM antibody, antibody fragment that binds to ADM, or anti-ADM non-Ig scaffold that binds to ADM. 【0143】 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%. 【0144】 In contrast, non-neutralizing anti-ADM antibodies, or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds block the biological activity of ADM to 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 biological activity of ADM is reduced to less than 100%, 95% or less, 90% or less, 80% or less, and 50% or less. This means that the remaining biological activity of ADM bound to a non-neutralizing anti-ADM antibody, or anti-ADM antibody fragment or anti-ADM non-Ig scaffold will be greater than 0%, preferably greater than 5%, preferably greater than 10%, more preferably greater than 20%, and more preferably greater than 50%. 【0145】 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%, - A single or multiple ADM-binding molecule that, upon 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), reduces the amount of cAMP produced by the cell line through the action of a parallel-added human synthetic ADM peptide, 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 occurs to an extent of 80% or less, even when the amount added is 10 times greater than the amount required to obtain the maximum reduction of cAMP synthesis obtainable by the non-neutralizing molecule that binds to ADM to be analyzed. It is defined as 【0146】 The same definition applies to other ranges; 95%, 90%, 50%, and others. 【0147】 The antibody or fragment 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 kd or 214 amino acids long. 【0148】 Full-length immunoglobulin heavy chains are generally about 50 kd 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. 【0149】 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 (Fab')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. Proc. Natl. Acad. Sci. USA, 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 immunoglobulin light chain or heavy chain variable region is a framework region 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. 1983, US Department of Health and Human Services). As described above, CDRs are primarily involved in binding to the antigen's epitope. Immune complexes are antibodies such as monoclonal antibodies, chimeric antibodies, humanized antibodies or human antibodies, or functional antibody fragments specifically bound to an antigen. 【0150】 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, gln;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 methods (see, for example, International Publication No. 91 / 17271; International Publication No. 92 / 001047; International Publication No. 92 / 20791) or selected from human combinatorial monoclonal antibody libraries (see Morphosys website). Human antibodies can also be prepared using transgenic animals that carry human immunoglobulin genes (see, for example, International Publication No. 93 / 12227; International Publication No. 91 / 10741). 【0151】 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. 【0152】 In addition to anti-ADM antibodies, other biomolecular scaffolds are well known in the field of combined target molecules and are used for the generation of highly targeted biomacromolecules. Examples include aptamers, Spiegelmers, antikalins, and conotoxins. See Figures 1a, 1b, and 1c for illustrations of antibody formats. 【0153】 In a preferred embodiment, the anti-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. 【0154】 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); transferrin scaffolds (e.g., described in U.S. Patent Publication No. 2004 / 0023334), protein A scaffolds (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 cysteine ​​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). 【0155】 In one embodiment of the present invention, the anti-ADM antibody according to the present invention may be produced by synthesizing an ADM fragment as an antigen, as outlined in Example 1. Subsequently, the binder for the fragment is identified by the following method or by other methods known in the art. 【0156】 Humanization of mouse anti-tau may be performed according to the following method: 【0157】 To humanize mouse-derived antibodies, antibody sequences are analyzed for structural interactions between the complementarity-determining region (CDR) and the antigen-containing framework region (FR). Based on structural modeling, an appropriate human-derived FR is selected, and the mouse CDR sequence is transplanted into the human FR. Mutations in the amino acid sequence of the CDR or FR may be induced to restore the structural interactions lost due to species transmutation with respect to the FR sequence. This restoration of structural interactions may be performed by a random approach using a phage display library or a direct approach guided by molecular modeling (Almagro and Fransson 2008. Humanization of antibodies. Front Biosci. 2008 Jan 1;13:1619-33). 【0158】 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. 【0159】 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. 【0160】 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 length contained in ADM. 【0161】 In a more preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold can target and bind to an epitope of at least 4 amino acid length contained in ADM. 【0162】 In one particular embodiment of the present invention, an anti-ADM antibody or an anti-ADM antibody fragment or an anti-ADM non-Ig scaffold that binds to adrenomedullin is provided for use in the treatment or prevention of shock in a patient, wherein the antibody or fragment or scaffold is not ADM-binding protein 1 (complement factor H). 【0163】 In one particular embodiment of the present invention, an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment conjugated to adremedullin or an anti-ADM non-Ig scaffold conjugated to adremedullin is provided for use in the treatment or prevention of shock in a patient, wherein the antibody or fragment or scaffold conjugates to a region of at least 4 or at least 5 amino acids within the sequence of amino acids 1 to 21 of ADM:YRQSMNNFQGLRSFGCRFGTC SEQ ID NO:22. 【0164】 In a preferred embodiment of the present invention, the anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold binds to the ADM region or epitope (amino acids 1-21) located at the N-terminal portion of adrenomedullin. 【0165】 In another preferred embodiment, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the region or epitope: YRQSMNNFQGLRSF (SEQ ID NO: 25), which is the region within amino acids 1-14 of adrenomedullin, relative to the N-terminal portion (amino acids 1-14) of adrenomedullin. 【0166】 In another preferred embodiment, the anti-ADM antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the region or epitope:YRQSMNNFQG (SEQ ID NO: 26) within amino acids 1-10 of adrenomedullin, which is the N-terminal portion (amino acids 1-10) of adrenomedullin. 【0167】 In another preferred embodiment, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to a region or epitope within amino acids 1-6 of adrenomedullin, meaning the N-terminal portion (amino acids 1-6) of adrenomedullin: YRQSMN (SEQ ID NO: 27). As described above, the region or epitope preferably comprises at least 4 or at least 5 amino acids in length. 【0168】 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 (amino acid 1) of adrenomedullin. The N-terminus is "Y" in SEQ ID NOs. 20, 22, or 23, respectively, and represents amino acid 1, which is essential for binding. The antibody or fragment or scaffold will not bind to an extended N-terminus, N-terminally modified adrenomedullin, or N-terminally cleaved adrenomedullin. In another preferred embodiment, this means that the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold will only bind to a region within the sequence of mature ADM when the N-terminus of ADM is free. In the above embodiment, the anti-ADM antibody or anti-ADM antibody fragment or non-Ig scaffold will not bind to a region within the sequence of mature ADM if the sequence is contained, for example, within pro-ADM. 【0169】 For clarity, the number in parentheses for a specific region of ADM, such as "N-terminus (amino acids 1-21)," indicates that a person skilled in the art will understand that the N-terminus of ADM consists of amino acids 1-21 of the mature ADM sequence. 【0170】 In another specific embodiment according to the present invention, the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold provided herein does not bind to the C-terminal portion of ADM, i.e., amino acids 43-52 of ADM:PRSKISPQGY-NH2 (SEQ ID NO: 24). 【0171】 Epitopes, also known as antigenic determinants, are the parts of an antigen that are recognized by the immune system, particularly antibodies. For example, an epitope is a specific fragment of an antigen to which an antibody binds. The part of the antibody that binds to the epitope is called a paratope. Epitopes of protein antigens are classified into two categories based on their structure and interaction with paratopes: three-dimensional epitopes and linear epitopes. 【0172】 Three-dimensional structures and linear epitopes interact with paratopes based on the 3D three-dimensional structure adopted by the epitope, which is determined by the surface features of the relevant epitope residues and the shape or tertiary structure of other segments of the antigen. Three-dimensional epitopes are formed by 3D three-dimensional structures adopted through the interaction of discontinuous amino acid residues. Linear or continuous epitopes are epitopes recognized by antibodies by their linear sequence of amino acids or primary structure, and are formed by 3D three-dimensional structures adopted through the interaction of continuous amino acid residues. 【0173】 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, which results in an increase of at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100% in serum, blood, or plasma ADM levels or ADM immunoreactivity. 【0174】 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 contains at least 10%, preferably at least 50%, more preferably >50%, and most preferably >100% of the half-life (t) of adrenomedullin in serum, blood, or blood. 1 / 2 This is an ADM-stabilized antibody, an ADM-stabilized antibody fragment, or an ADM-stabilized non-Ig scaffold that enhances the half-residence time. 【0175】 The half-life (half-residence time) of ADM may be determined using an immunoassay for ADM quantification in human serum, blood, or plasma, both in the absence and in the presence of an ADM-stabilized antibody, an ADM-stabilized antibody fragment, or an ADM-stabilized non-Ig scaffold. 【0176】 You may follow these steps: -ADM may be diluted in human citrated plasma in the absence and presence of ADM-stabilized antibody, adrenomedullin-stabilized antibody fragment, or adrenomedullin-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 denaturing agent (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, adrenomedullin-stabilized antibody fragment, or adrenomedullin-stabilized non-Ig scaffold, respectively. - The enhancement of half-life is calculated for stabilized ADM compared to ADM incubated in the absence of ADM-stabilized antibody, adrenomedullin-stabilized antibody fragment, or adrenomedullin-stabilized non-Ig scaffold. 【0177】 A doubling of the half-life of ADM is equivalent to a 100% enhancement of the half-life. 【0178】 Half-life (or half-residence time) is defined as the time it takes for a particular chemical or drug to fall to half of its baseline concentration in a particular body fluid or blood. 【0179】 An assay that may be used to determine the half-life (half-residence time) of adrenomedullin in serum, blood, and plasma is described in Example 3. 【0180】 In preferred embodiments, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is a non-neutralizing antibody, fragment, or 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%. In other words, this means that the non-neutralizing anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will block the biological activity of ADM to less than 100%, preferably less than 95%, and preferably less than 90%. In embodiments in which the non-neutralizing anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold blocks the biological activity of ADM to less than 95%, any anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold that would block the biological activity of ADM to more than 95% would be outside the scope of the embodiments. In one embodiment, this means that the biological activity is reduced to 95% or less, preferably 90% or less, more preferably 80% or less, and more preferably 50% or less. 【0181】 In one embodiment of the present invention, the non-neutralizing antibody is an antibody that binds to a region of at least 5 amino acids within the sequence of amino acids 1 to 21 (SEQ ID NO: 14) of mature human ADM, or an antibody that binds to a region of at least 5 amino acids within the sequence of amino acids 1 to 19 (SEQ ID NO: 17) of mature human ADM. 【0182】 In another preferred embodiment of the present invention, the non-neutralizing antibody is an antibody that binds to a region of at least four amino acids in the sequence of amino acids 1 to 21 of mature human ADM (SEQ ID NO: 14), or an antibody that binds to a region of at least five amino acids in the sequence of amino acids 1 to 19 of mature human ADM (SEQ ID NO: 17). 【0183】 In certain embodiments of the present invention, a non-neutralizing anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is used, wherein the anti-ADM antibody or anti-ADM antibody fragment blocks the biological activity of ADM to less than 80%, preferably less than 50%, of the baseline value. The limited blockade of the biological activity of ADM (meaning a reduction in biological activity) occurs even at excess concentrations of the antibody, fragment, or scaffold, and should be understood as meaning an excess of the antibody, fragment, or scaffold against ADM. The limited blockade is an inherent characteristic of the ADM conjugate in the particular embodiments. This means that the antibody, fragment, or scaffold has a maximum inhibition of 80% or 50%, respectively. In preferred embodiments, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold will block / reduce the biological activity of anti-ADM to at least 5%. The above means that approximately 20%, 50%, or even 95% of ADM biological activity remains present, respectively. 【0184】 Therefore, according to the present invention, the provided anti-ADM antibody, anti-ADM antibody fragment, and anti-ADM non-Ig scaffold do not neutralize the respective ADM biological activity. 【0185】 Biological activity is defined as the effect 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 μg / ml or less) are obtained using either an ADM-stabilized antibody, an ADM-stabilized antibody fragment, or an ADM-stabilized non-Ig scaffold, respectively. 【0186】 Maximum inhibition in the 50% 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 to 50% of the baseline value, respectively. Maximum inhibition in the 80% ADM bioassay means that the anti-ADM antibody, the anti-adrenomedullin antibody fragment, or the anti-adrenomedullin non-Ig scaffold blocks the biological activity of ADM to 80%, respectively. This means that the biological activity of ADM is blocked to 80% or less. This means that approximately 20% residual ADM biological activity remains. 【0187】 However, in connection with the foregoing, the expression “blocks the bioactivity of ADM” with respect to the anti-ADM antibodies, anti-ADM antibody fragments, and anti-ADM non-Ig scaffolds disclosed herein should be understood to mean that they merely reduce the bioactivity of ADM from 100% to at most 20% residual ADM bioactivity, preferably reducing the bioactivity of ADM from 100% to 50% residual ADM bioactivity; in any case, there should be some residual ADM bioactivity that can be determined as detailed above. 【0188】 The biological activity of ADM may be determined in a human recombinant adrenomedullin receptor cAMP function assay (adrenomedullin bioassay) according to Example 2. 【0189】 In preferred embodiments, the modification of anti-ADM antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds is used in the treatment or prevention of shock in patients. 【0190】 The "modulation" of anti-ADM antibodies, or the modification of anti-ADM antibody fragments or anti-ADM non-Ig scaffolds, affects the half-life (t) of adrenomedullin in serum, blood, and plasma. 1 / 2 An antibody or antibody fragment or non-Ig scaffold that enhances the half-residence time 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%, wherein 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 the 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 ADM biological activity, respectively. 【0191】 The 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 bioactivity and extension of the in vivo half-life (increase in ADM bioactivity) results in a beneficial simplification of anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold administration. In states of excess endogenous ADM (maximum stimulation, late sepsis, shock, and debilitation), 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 regulated anti-ADM antibodies or anti-ADM antibody fragments or anti-ADM non-Ig scaffolds act like ADM bioactivity buffers to maintain the bioactivity of ADM within a specific physiological range. 【0192】 In certain embodiments of the present invention, the antibody is a monoclonal antibody or a fragment thereof. In one embodiment of the present invention, the anti-ADM antibody or anti-ADM antibody fragment is a human or humanized antibody or derived therefrom. In one particular embodiment, one or more (mouse) CDRs are grafted onto a human antibody or antibody fragment. 【0193】 In one embodiment, the subject of the present invention is a human or humanized CDR-grafted antibody or antibody fragment thereof that conjugates to ADM, wherein the human or humanized CDR-grafted antibody or antibody fragment thereof is: GYTFSRYW (Sequence ID 1), ILPGSGST (Sequence ID 2) and / or TEGYEYDGFDY (Sequence ID 3) The antibody contains a heavy chain (H chain) and a light chain with the sequence: QSIVYSNGNTY (Sequence ID 4), RVS (not part of the sequence listing) and / or FQGSHIPYT(Sequence ID 5) Includes. 【0194】 In one particular embodiment of the present invention, the subject of the present invention is a human or humanized monoclonal antibody or an antibody fragment thereof that conjugates to ADM, wherein the heavy chain is: GYTFSRYW (Sequence ID 1), ILPGSGST (Sequence ID 2), TEGYEYDGFDY (Sequence ID 3) It includes at least one CDR selected from the group including the following, and the light chain is: QSIVYSNGNTY (Sequence ID 4), RVS (not part of the sequence listing), FQGSHIPYT(Sequence ID 5) It includes at least one CDR selected from the group that includes [the specified group]. 【0195】 In a more specific embodiment of the present invention, the subject of the present invention is a human monoclonal antibody or an antibody fragment thereof that binds to ADM, wherein the heavy chain is sequence: GYTFSRYW (Sequence ID 1), ILPGSGST (Sequence ID 2), TEGYEYDGFDY (Sequence ID 3) It includes, and the light chain is in sequence: QSIVYSNGNTY (Sequence ID 4), RVS (not part of the sequence listing), FQGSHIPYT(Sequence ID 5) Includes. 【0196】 In very specific embodiments, the anti-ADM antibody has a sequence selected from the group including SEQ ID NOs: 6, 7, 8, 9, 10, 11, 12, 13, 32, and 33. 【0197】 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 The affinity for human ADM 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. 【0198】 The subject of the present invention is a human or humanized monoclonal antibody or fragment that conjugates to ADM, or an antibody fragment thereof, for the treatment or prevention of shock in patients according to the present invention, wherein the antibody or fragment is: Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes sequences selected from the group that includes the following. 【0199】 Another embodiment of the present invention relates to a human or humanized monoclonal antibody or fragment conjugating to ADM, or an antibody fragment thereof, for use in the treatment or prevention of shock in patients, wherein the antibody or fragment has the following sequence as its heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFScSVMHEALHNHYTQKSLSLSPGK It includes the following sequence as a light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes. 【0200】 In a particular embodiment of the present invention, the antibody has the following sequence as its heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or a sequence having >95%, preferably >98%, preferably >99% identity with the above, with the following sequence as the light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or it includes an array that is >95%, preferably >98%, preferably >99% identical to the above. 【0201】 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. 【0202】 In certain embodiments of the present invention, the antibody has the following sequence as the heavy chain: SEQ ID NO: 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or comprises CDR sequences that are 100% identical to SEQ ID NO: 1, SEQ ID NO: 2, and / or SEQ ID NO: 3, and are >95%, preferably >98%, preferably >99% identical to SEQ ID NO: 32, and has the following sequence as the light chain: SEQ ID NO: 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or it contains a CDR sequence that is 100% identical to SEQ ID NO: 4 and / or SEQ ID NO: 5, and has >95%, preferably >98%, preferably >99% identity to SEQ ID NO: 33. 【0203】 In an embodiment of the present invention, an anti-ADM antibody or anti-ADM antibody fragment for use in treating or preventing shock in a patient may be administered at a dose of at least 0.5 mg / kg body weight, particularly at least 1.0 mg / kg body weight, more particularly 1.0 - 20.0 mg / kg body weight, for example, 2.0 - 10 mg / kg body weight, 2.0 - 8.0 mg / kg body weight, or 2.0 - 5.0 mg / kg body weight. 【0204】 As used herein, the term "pharmaceutical preparation" refers to a preparation that is in a form effective to effect the biological activity of the active ingredient contained therein and that does not contain additional ingredients that are unduly toxic to the subject to whom the preparation is administered. 【0205】 The present invention also relates to a pharmaceutical preparation comprising a therapeutically effective amount of an active ingredient in combination with at least one pharmaceutically acceptable excipient. 【0206】 "Pharmaceutically acceptable excipient" refers to an excipient that does not produce harmful, allergic or other undesirable reactions when administered to a subject. This includes, in addition to therapeutic proteins, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The characteristics of the carrier will depend on the route of administration. 【0207】 The subject of the present invention is a pharmaceutical preparation for use in treating or preventing shock in a patient comprising an antibody or fragment or scaffold according to the present invention. 【0208】 The subject of the present invention is a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, comprising an antibody or fragment or scaffold according to the present invention, wherein the shock is selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock and distributive shock, particularly cardiogenic shock or septic shock. 【0209】 The subject of the present invention is a pharmaceutical formulation for use in the treatment or prevention of shock in patients according to the present invention, wherein the pharmaceutical formulation is a liquid, preferably a ready-to-use liquid. 【0210】 The subject of the present invention is a pharmaceutical formulation for use in the treatment or prevention of shock in patients according to the present invention, wherein the pharmaceutical formulation is in a lyophilized state. 【0211】 The subject of the present invention is a pharmaceutical formulation for use in the treatment or prevention of shock in patients according to the present invention, wherein the pharmaceutical formulation is administered intramuscularly. 【0212】 The subject of the present invention is a pharmaceutical formulation for use in the intervention and treatment of congestion in patients according to the present invention, wherein the pharmaceutical formulation is administered intravascularly. 【0213】 The subject of the present invention is a pharmaceutical preparation for use in the intervention and treatment of congestion in patients according to the present invention, wherein the pharmaceutical preparation is administered by injection. 【0214】 The subject of the present invention is a pharmaceutical preparation for use in the treatment or prevention of shock in patients according to the present invention, wherein the pharmaceutical preparation is administered systemically. 【0215】 In connection with the above, the following sequentially numbered embodiments provide further specific aspects of the present invention. 【0216】 Embodiment 1. An 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, wherein the patient has a subthreshold level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid, and the anti-ADM antibody, anti-ADM antibody, or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14). 【0217】 Embodiment 2. 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, and is an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in the patient described in Embodiment 1. 【0218】 Embodiment 3. In cases of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or the patient may have 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 the case of distributive shock, the patient may be suffering from shock caused by septic shock, neurogenic shock, anaphylactic shock or adrenal crisis. 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 Embodiments 1 and 2. 【0219】 Embodiment 4. The threshold value of DPP3 in a sample of the patient's body fluid is 20 - 120 ng / mL, more preferably 30 - 90 ng / mL, more preferably 30 - 80 ng / mL, even more preferably 40 - 60 ng / mL, and most preferably the threshold value is 50 ng / mL. 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 - 3. 【0220】 Embodiment 5. The threshold value of DPP3 in a sample of the patient's body fluid is 40 - 60 ng / mL. 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 Embodiment 4. 【0221】 Embodiment 6. The body fluid is selected from whole blood, plasma and serum. 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 - 5. 【0222】 Embodiment 7. The body fluid is plasma. 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 Embodiment 6. 【0223】 Embodiment 8. An anti-adrenomedullin (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 according to any one of Embodiments 1 to 7, wherein the DPP3 level is determined by contacting the body fluid sample with a capture agent that specifically binds to DPP3. 【0224】 Embodiment 9. The aforementioned capture and binding agent is an antibody, an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in the patient described in Embodiment 8. 【0225】 Embodiment 10. 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 9, for determining either a DPP3 protein level and / or an active DPP3 level and comparing it to a predetermined threshold. 【0226】 Embodiment 11. The patient further characterized by having an ADM-NH2 level greater than a threshold, and 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 the patient according to any one of embodiments 1 to 10. 【0227】 Embodiment 12. The threshold for ADM-NH2 in a sample of the patient's body fluid is 40-100 pg / mL, more preferably 50-90 pg / mL, even more preferably 60-80 pg / mL, and most preferably 70 pg / mL, for use in the treatment or prevention of shock in the patient described in Embodiment 11. 【0228】 Embodiment 13. The threshold for ADM-NH2 in a sample of the patient's body fluid is 70 pg / mL, and the anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is for use in the treatment or prevention of shock in the patient described in Embodiment 12. 【0229】 Embodiment 14. The body fluid is an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold, selected from whole blood, plasma, and serum, for use in the treatment or prevention of shock in a patient according to any one of Embodiments 1 to 13. 【0230】 Embodiment 15. The body fluid is plasma, 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 Embodiment 14. 【0231】 Embodiment 16. An anti-adrenomedullin (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 according to any one of embodiments 11 to 15, wherein the ADM-NH2 level is determined by contacting the body fluid sample with a capture agent that specifically binds to ADM-NH2. 【0232】 Embodiment 17. The aforementioned capture and binding agent is an antibody, an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in the patient described in Embodiment 16. 【0233】 Embodiment 18. The body fluid sample from the patient is selected from the group consisting of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva, and is an anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in the patient according to any one of Embodiments 1 to 17. 【0234】 Embodiment 19. The anti-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 18, which recognizes and binds to the N-terminus (amino acid 1) of ADM-Gly and / or ADM-NH2. 【0235】 Embodiment 20. The antibody, antibody fragment, or non-Ig scaffold described above does not bind to the C-terminal portion of ADM having the sequence amino acids 43-52:PRSKISPQGY-NH2 (SEQ ID NO: 24), and is an 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 Embodiments 1 to 19. 【0236】 Embodiment 21. The antibody or fragment or scaffold blocks 80% or less, preferably 50% or less, of the biological activity of ADM, and is used in the treatment or prevention of shock in a patient according to any one of Embodiments 1 to 20. 【0237】 Embodiment 22. The antibody or fragment is a monoclonal antibody or fragment that binds to ADM or its antibody fragment, and the heavy chain is sequence: CDR1: Sequence ID 1 GYTFSRYW CDR2: Sequence ID 2 ILPGSGST CDR3: Sequence ID 3 TEGYEYDGFDY The light chain includes the following arrangement: CDR1: Sequence ID 4 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 5 FQGSHIPYT. including, An anti-adrenomedullin (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 described in any one of Embodiments 1 to 21. 【0238】 Embodiment 23. The antibody or fragment is defined as the VH region. Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK The VL region includes sequences selected from the group containing the following: Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC. Includes sequences selected from a group that includes, An anti-adrenomedullin (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 described in any one of Embodiments 1 to 22. 【0239】 Embodiment 24. The antibody or fragment has the following sequence as its heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Or a sequence containing a sequence that is >95% identical to this, with the following sequence as the light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Or including sequences that are >95% identical to this, An anti-adrenomedullin (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 described in any one of Embodiments 1 to 23. 【0240】 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: 26). 【0241】 Embodiment 26. 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-ADM antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in Embodiment 25, exhibiting binding affinity of M to ADM. 【0242】 Embodiment 27. The aforementioned anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold is subjected to label-free surface plasmon resonance (1 × 10⁻¹⁶) using the Biacore 2000 system. -9 ~3×10 -9 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 as described in Embodiment 26, exhibiting affinity for human ADM. 【0243】 Embodiment 28. 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 25 to 27. 【0244】 Embodiment 29. A pharmaceutical preparation for use in the treatment or prevention of shock in a patient, comprising an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold described in any one of Embodiments 1 to 28. 【0245】 Embodiment 30. The pharmaceutical formulation is a liquid, preferably a ready-to-use liquid, and is a pharmaceutical formulation for use in the treatment or prevention of shock in a patient, as described in Embodiment 29. 【0246】 Embodiment 31. The pharmaceutical preparation is in a lyophilized state and is a pharmaceutical preparation for use in the treatment or prevention of shock in patients according to Embodiments 29 and 30. 【0247】 Embodiment 32. The pharmaceutical preparation is a pharmaceutical preparation for use in the treatment or prevention of shock in patients according to Embodiments 29 and 31, which is administered intramuscularly. 【0248】 Embodiment 33. The pharmaceutical formulation is a pharmaceutical formulation for use in the treatment or prevention of shock in patients described in Embodiments 29 and 32, which is administered intravascularly. 【0249】 Embodiment 34. The pharmaceutical preparation is administered by infusion and is intended for use in the treatment or prevention of shock in patients according to Embodiments 29 and 33. 【0250】 Embodiment 35. The aforementioned pharmaceutical preparation is intended for systemic administration and is a pharmaceutical preparation for use in the treatment or prevention of shock in patients according to embodiments 29 and 34. [Brief explanation of the drawing] 【0251】 [Figure 1a] Figure 1a shows antibody format-Fv and scFv variants. [Figure 1b] Figure 1b shows antibody formats—heterofusion and bispecific antibodies. [Figure 1c] Figure 1c shows antibody formats—bivalent antibodies and bispecific antibodies. [Figure 2ab] Figure 2a shows the dose-response curve for human ADM. Maximum cAMP stimulation was adjusted to 100% activation. Figure 2b shows the dose / inhibition curve for human ADM22-52 (ADM receptor antagonist) in the presence of 5.63 nM hADM. [Figure 2cd] Figure 2c shows the dose / inhibition curve for CT-H in the presence of 5.63 nM hADM. Figure 2d shows the dose / inhibition curve for MR-H in the presence of 5.63 nM hADM. [Figure 2ef] Figure 2e shows the dose / inhibition curve of NT-H in the presence of 5.63 nM hADM. Figure 2f shows the dose-response curve of mouse ADM. Maximum cAMP stimulation was adjusted to 100% activation. [Figure 2gh] Figure 2g shows the dose / inhibition curve for human ADM22-52 (ADM receptor antagonist) in the presence of 0.67 nM mADM. Figure 2h shows the dose / inhibition curve for CT-M in the presence of 0.67 nM mADM. [Figure 2ij] Figure 2i shows the dose / inhibition curve for MR-M in the presence of 0.67 nM mADM. Figure 2j shows the dose / inhibition curve for NT-M in the presence of 0.67 nM mADM. [Figure 2kl] Figure 2k shows the inhibition of ADM by F(ab)2 NT-M and Fab NT-M. Figure 2l shows the inhibition of ADM by F(ab)2 NT-M and Fab NT-M. [Figure 3] Figure 3 shows a typical hADM dose / signal curve and an hADM dose / signal curve in the presence of 100 μg / mL antibody NT-H. [Figure 4] Figure 4 shows the stability of hADM in human plasma (citric acid) in the absence and presence of NT-H antibody. [Figure 5] Figure 5 shows the alignment of Fabs with the same human framework sequence. [Figure 6] Figure 6 shows the ADM concentrations in healthy human subjects after applying NT-H at different doses for 60 days or less. [Figure 7] Figure 7 shows Kaplan-Meier survival plots for low (<40.5 ng / mL) and high (≧40.5 ng / mL) DPP3 concentrations. (A) 7-day survival rate for sepsis patients relative to DPP3 plasma concentration; (B) 7-day survival rate for cardiogenic shock patients relative to DPP3 plasma concentration; (C) 7-day survival rate for septic shock patients relative to DPP3 plasma concentration. [Figure 8] Figure 8 shows the Kaplan-Meier survival plot for all patients (14-day mortality rate for patients treated with placebo (Plac) or the N-terminal ADM antibody adrecizumab (Adz)). [Figure 9] Figure 9 shows the Kaplan-Meier survival plot (14-day mortality rate for patients treated with placebo (Plac) or N-terminal ADM antibody adrecizumab (Adz)) for patients with DPP3 < 50 ng / mL. [Figure 10]Figure 10 shows the Kaplan-Meier survival plot (14-day mortality rate for patients treated with placebo (Plac) or N-terminal ADM antibody adrecizumab (Adz)) for patients with DPP3 > 50 ng / mL. [Figure 11] Figure 11 shows Kaplan-Meier plots for the effect of adrecizumab on 28-day mortality in patients with high and low concentrations of previously administered bio-ADM. Study population: PP and PP / DPP3 ≤ 70. Figure 11a shows patients with bio-ADM between PP / DPP3 ≤ 70 and 70 to 182 pg / mL (<median), and Figure 11b shows patients with bio-ADM greater than 182 pg / mL (greater than median). The HRs calculated using the 95% CI and log-rank p-value (two-sided) are as follows: PP less than median: HR = 0.630 [0.276~1.44], log-rank p = 0.270; PP greater than median: HR = 0.870 [0.499~1.52], log-rank p = 0.634; PP less than median / DPP3: HR = 0.607 [0.242~1.52], log-rank p = 0.284; PP greater than median / DPP3: HR = 0.623 [0.327~1.19], log-rank p = 0.151. [Examples] 【0252】 Example 1 - Production of antibodies and determination of their affinity constants Several human and mouse antibodies were produced, and their affinity constants were determined (see Tables 1 and 2). It should be emphasized that the exemplary antibodies, antibody fragments, and non-Ig scaffolds according to the present invention are bound to ADM and therefore should be considered as anti-ADM antibody / antibody fragment / non-Ig scaffolds. 【0253】 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. 【0254】 Mouse monoclonal antibody production: 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. For three days prior to the fusion experiment, the animals received 50 μg of the complex dissolved in 100 μl of saline, administered as a single intraperitoneal injection and a single intravenous injection. Splenocytes and myeloma cell line SP2 / 0 cells from immunized mice were fused at 37°C for 30 seconds using 1 ml of 50% polyethylene glycol. 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 to determine the isotype (see also Lane, RD 1985. J. Immunol. Meth. 81: 223-228; Ziegler et al. 1996. Horm. Metab. Res. 28: 11-15). 【0255】 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. 【0256】 Human antibodies: Human antibodies were produced using phage display according to the following procedure: The human naive antibody gene library HAL7 / 8 was used for the isolation of recombinant single-stranded F variable domains (scFv) against the adrenomedullin peptide. The antibody gene library was screened using a panning strategy that included the use of peptides containing biotin tags linked to the adrenomedullin 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 for the production of 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; Schutte et al. 2009. PLoS One 4, e6625). 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., J. Biotechn. 2011), captured from the culture supernatant by immobilized metal ion affinity chromatography, and purified by size exclusion chromatography. 【0257】 Affinity constant: To determine the affinity of the antibody to ADM, the binding dynamics of the ADM immobilized with 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). 【0258】 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 for use in further experiments. The selection is based on the target region. 【0259】 [Table 1] 【0260】 The following is a list of further monoclonal antibodies obtained. 【0261】 [Table 2-1] [Table 2-2] 【0262】 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) 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. 【0263】 Fab Production and Purification Procedure: 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 equilibrated immobilized papain. 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: 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) 【0264】 Procedure for production and purification of F(ab')2 fragment: 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 equilibrated immobilized pepsin. The digestion reaction was incubated on a tabletop locker at 37°C for 16 hours. The digest was separated from 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). 【0265】 NT-H antibody fragment humanization: Antibody fragments were immobilized using the CDR grafting method (Jones et al. 1986. Nature 321, 522-525). 【0266】 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: The 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 sequences. Reverse primers were placed in the constant regions of the heavy and light chains. Restriction enzyme sites were not incorporated into the primers. 【0267】 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 semi-nested 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 semi-nested primer set specific to the antibody variable region. 【0268】 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. 【0269】 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. After alignment with allogeneic human framework sequences, the humanized sequence obtained for the variable heavy chain is as follows: see Figure 5. 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 and may be returned to their 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). 【0270】 Notes on antibody fragment sequences (SEQ ID NOs. 6-13; 32 and 33): Bold and underlined text indicates CDRs; italicized 1, 2, and 3 are constant regions; hinge regions are highlighted in bold; and framework point mutations have a gray background. 【0271】 Sequence number 6 (AM-VH-C) [ka] 【0272】 Sequence ID 7 (AM-VH1) [ka] 【0273】 Sequence ID 8 (AM-VH2-E40) [ka] 【0274】 Sequence ID 9 (AM-VH3-T26-E55) [ka] 【0275】 Sequence ID 10 (AM-VH4-T26-E40-E55) [ka] 【0276】 Sequence ID 11 (AM-VL-C) [ka] 【0277】 Sequence ID 12 (AM-VL1) [ka] 【0278】 Sequence ID 13 (AM-VL2-E40) [ka] 【0279】 Sequence ID 32 (adrecizumab heavy chain) [ka] 【0280】 Sequence ID 33 (adrecizumab light chain) [ka] 【0281】 Example 2 - Effect of selected anti-ADM antibodies on anti-ADM biological activity The effect of selected ADM antibodies on ADM biological activity was tested using a human recombinant adrenomedullin receptor cAMP function assay (adrenomedullin bioassay). 【0282】 Testing of antibodies targeting human or mouse adrenomedullin in the human recombinant adrenomedullin receptor cAMP function assay (adrenomedullin bioassay) 【0283】 Substances: Cell line CHO-K1, receptor adrenomedullin (CRLR+RAMP3), receptor confidence plate cell line: CRLR: U17473; RAMP3: AJ001016 【0284】 CHO-K1 cells (FAST-027C) expressing human recombinant adrenomedullin receptors, cultured in antibiotic-free medium prior to the test, were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation, and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA). 【0285】 Dose-response curves were developed in parallel with those of a reference agonist (hADM or mADM). 【0286】 Antagonist test (96 wells): For the antagonist test, 6 μl of reference agonist (human (5.63 nM) or mouse (0.67 nM) adrenomedullin) was mixed with 6 μl of test sample in different antagonist dilutions; or with 6 μl of buffer. After incubation at room temperature for 60 minutes, 12 μl of cells (2,500 cells / well) were added. The plates were incubated at room temperature for 30 minutes. After the addition of lysis buffer, the DeltaF percentage was estimated according to the manufacturer's specifications, and hADM22-52 was used as the reference antagonist using the Cis-Bio International (catalog No. 62AM2PEB) HTRF kit. 【0287】 Antibody assay cAMP-HTRF assay Anti-hADM antibodies (NT-H, MR-H, CT-H) were tested for antagonist activity in a human recombinant adrenomedullin receptor (FAST-027C) cAMP function assay in the presence of 5.63 nM human ADM1-52 at the following final antibody concentrations: 100 μg / ml, 20 μg / ml, 4 μg / ml, 0.8 μg / ml, and 0.16 μg / ml. 【0288】 Anti-mADM antibodies (NT-M, MR-M, CT-M) were tested for antagonist activity in a human recombinant ADM receptor (FAST-027C) cAMP function assay at the following final antibody concentrations: 100 μg / ml, 20 μg / ml, 4 μg / ml, 0.8 μg / ml, and 0.16 μg / ml, in the presence of 0.67 nM mouse ADM1-50. Relative inhibition against antagonist concentration was plotted (see Figures 2a-2l). The maximum inhibition by individual antibodies is shown in Table 3. 【0289】 [Table 3] 【0290】 Example 3 - Stabilization of hADM with anti-ADM antibody The stabilizing effect of anti-ADM antibodies on hADM was tested using an hADM immunoassay. 【0291】 Immunoassay for the Quantification of Human Adrenomedullin The technique used was an acridinium ester-based sandwich-coated tube luminescence immunoassay. 【0292】 A labeled compound (tracer): 100 μg (100 μl) of CT-H (1 mg / ml in PBS, pH 7.4, AdrenoMed AG, Germany) was mixed with 10 μl of acridinium NHS ester (1 mg / ml in acetonitrile, InVent GmbH, Germany) (European Patent No. 0353971) and incubated at room temperature for 20 minutes. Labeled CT-H was purified by gel filtration HPLC using Bio-Sil® SEC 400-5 (Bio-Rad Laboratories, Inc., USA). The purified CT-H was diluted in (300 mmol / L potassium phosphate, 100 mmol / L NaCl, 10 mmol / L Na-EDTA, 5 g / L bovine serum albumin, pH 7.0). The final concentration was approximately 800,000 relative light units (RLU) per 200 μL of the labeled compound (approximately 20 ng of labeled antibody). Acridinium ester chemiluminescence was measured using AutoLumat LB 953 (Berthold Technologies GmbH & Co. KG). 【0293】 Solid phase: Polystyrene tubes (Greiner Bio-One International AG, Austria) were coated with MR-H (AdrenoMed AG, Germany) (1.5 μg MR-H / 0.3 mL 100 mmol / L NaCl, 50 mmol / L Tris / HCl, pH 7.8) (at room temperature for 18 hours). After blocking with 5% bovine serum albumin, the tubes were washed with PBS, pH 7.4, and vacuum-dried. 【0294】 Calibration: The assay was calibrated using a dilution of hADM (BACHEM AG, Switzerland) in a protease inhibitor cocktail (Roche Diagnostics AG, Switzerland) containing 250 mmol / L NaCl, 2 g / L Triton X-100, and 50 g / L bovine serum albumin (20 tablets / L). 【0295】 hADM immunoassay: 50 μl of sample (or calibration sample) was added to a coated tube by pipette after adding labeled CT-H (200 μl), and the tube was incubated at 4°C for 4 hours. Unbound tracers were removed by washing five times (1 ml each) with washing solution (20 mM PBS, pH 7.4, 0.1% Triton X-100). 【0296】 Tube-bound chemiluminescence was measured using LB953: Figure 3 shows a typical hADM dose / signal curve and an hADM dose / signal curve in the presence of 100 μg / mL antibody NT-H. NT-H did not affect the described hADM immunoassay. 【0297】 Stability of human adrenomedullin: Human adrenomedullin was diluted in human citrated plasma (final concentration 10 nM) and incubated at 24°C. At selected time points, the degradation of hADM was stopped by freezing at -20°C. Incubation was performed in and without NT-H (100 μg / ml). The remaining hADM was quantified using the above hADM immunoassay. 【0298】 Figure 4 shows the stability of hADM in human plasma (citric acid) in the absence and presence of NT-H antibody. The half-life of hADM alone was 7.8 hours, while in the presence of NT-H, the half-life was 18.3 hours (2.3 times higher stability). 【0299】 Example 4 - Sepsis Mortality a) Initial treatment of sepsis Animal model: 12-15 week old male C57B1 / 6 mice (Charles River Laboratories, Germany) were used for the study. Peritonitis was surgically induced under light isoflurane anesthesia. An incision was made in the upper left quarter of the peritoneal cavity (normal location of the cecum). The cecum was exposed, and a firm ligament was placed around it with a suture distal to the small bowel insertion. A single puncture wound was made in the cecum using a 24-gauge needle, and a small amount of cecal contents were exposed through the wound. The cecum was returned to the peritoneal cavity, and the abdominal incision was closed. The animals were then returned to cages with free access to food and water. 500 μl of saline solution was administered subcutaneously for hydration. 【0300】 Application and dosage of compounds (NT-M, MR-M, CT-M): Mice were treated immediately after CLP (initial treatment). CLP is an abbreviation for cecal ligation and puncture. 【0301】 Test Groups: Three compounds were tested against treatment with a medium and a control compound. Each group contained 5 mice for blood collection one day later to determine BUN (blood urea nitrogen). Additional mice from each group were followed over a period of 4 days. 【0302】 Treatment group (10 μl / body weight g) Dosage / Follow-up: 1 NT-M, 0.2 mg / ml: Survived for 4 days 2 MR-M, 0.2 mg / ml, survived for 4 days. 3 CT-M, 0.2 mg / ml: Survived for 4 days. 4. Nonspecific mouse IgG, 0.2 mg / ml: Survived for 4 days. 5. Control - PBS 10 μl / g body weight - Survived for 4 days 【0303】 Clinical Chemistry: Blood urea nitrogen (BUN) concentrations were measured at baseline and 1 day after CLP to assess renal function. Blood samples were obtained from cavernous sinuses with capillaries under shallow ether anesthesia. Measurements were performed using an Olympus AU400 multianalyzer. Table 4 shows the 4-day mortality rate and mean BUN concentration. 【0304】 [Table 4] 【0305】 Table 4 shows that NT-M antibodies significantly reduced mortality. After 4 days, 70% of mice treated with NT-M antibodies survived. 30% of animals treated with MR-M antibodies survived, and 10% of animals treated with CT-M antibodies survived after 4 days. In contrast, all mice treated with nonspecific mouse IgG died after 4 days. The same results were obtained in the control group administered PBS (phosphate-buffered saline). Blood urea nitrogen (BUN) tests are used to assess renal function, aid in the diagnosis of renal disease, and monitor patients with acute or chronic renal impairment or failure. S-BUN test results revealed that NT-M antibodies were most effective in protecting the kidneys. 【0306】 b) Late-stage treatment of sepsis Animal model: 12-15 week old male C57B1 / 6 mice (Charles River Laboratories, Germany) were used for the study. Peritonitis was surgically induced under light isoflurane anesthesia. An incision was made in the upper left quarter of the peritoneal cavity (normal location of the cecum). The cecum was exposed, and a firm ligament was placed around it with a suture distal to the small bowel insertion. A single puncture wound was made in the cecum using a 24-gauge needle, and a small amount of cecal contents were exposed through the wound. The cecum was returned to the peritoneal cavity, and the abdominal incision was closed. The animals were then returned to cages with free access to food and water. 500 μl of saline solution was administered subcutaneously for hydration. 【0307】 Application and Dosage of Compound (NT-M FAB2): NT-M FAB2 was tested against treatment with a medium and a control compound. Treatment was administered 6 hours after the full onset of sepsis following CLP (late treatment). Each group consisted of 4 mice, followed for 4 days. 【0308】 Treatment group (10 μl / body weight g) Dosage / Follow-up: 1 NT-M, FAB2 0.2 mg / ml: Survived for 4 days. 2. Control nonspecific mouse IgG, 0.2 mg / ml: Survived for 4 days. 3. Medium: PBS 10 μl / g body weight. Survival for 4 days. 【0309】 [Table 5] 【0310】 Table 5 shows that the NT-M FAB2 antibody significantly reduced mortality. After 4 days, 75% of mice treated with the NT-M FAB2 antibody survived. In contrast, all mice treated with nonspecific mouse IgG died after 4 days. The same results were obtained in the control group, which received PBS (phosphate-buffered saline). 【0311】 Example 5 - Administration of NT-H in healthy humans In a randomized, double-blind, placebo-controlled trial, a single dose of NT-H antibody was administered intravenously (iv) to eight healthy male subjects (n=6 active, n=2 placebo in each group) in three sequential groups: Group 1 (0.5 mg / kg), Group 2 (2 mg / kg), and Group 3 (8 mg / kg). The primary eligibility criteria were written informed consent, including age 18–35 years, agreement to use a reliable method of contraception, and agreement to use a BMI of 18–30 kg / m2. Subjects received a single intravenous infusion of NT-H antibody (0.5 mg / kg; 2 mg / kg; 8 mg / kg) or placebo over a 1-hour period within the study unit. There were no differences in baseline ADM levels among the four groups. The median ADM level was 7.1 pg / mL in the placebo group, 6.8 pg / mL in the first treatment group (0.5 mg / kg), 5.5 pg / mL in the second treatment group (2 mg / kg), and 7.1 pg / mL in the third treatment group (8 mg / mL). The results showed that in healthy human subjects, ADM levels increased rapidly within the first 1.5 hours after administration of NT-H antibody, then leveled off and slowly decreased (Figure 6). 【0312】 Example 6 - Method for measuring DPP3 protein and DPP3 activity Antibody production and determination of DPP3 binding ability: Several mouse antibodies were produced and screened based on their ability to bind to human DPP3 in specific binding assays (see Table 6). 【0313】 Peptides / complexes for immunization: Peptides for immunization were synthesized using an additional N-terminal cysteine ​​residue (if cysteine ​​was not present in the selected DPP3 sequence) for peptide binding to bovine serum albumin (BSA), see Table 6 (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. Recombinant GST-hDPP3 was produced by USBio (United States Biological, Salem, Massachusetts, USA). 【0314】 Mouse immunization, immune cell induction, and screening: On day 0, Balb / c mice were intraperitoneally (ip) injected with 84 μg of GST-hDPP3 or 100 μg of DPP3 peptide BSA complex (emulsified in TiterMax Gold adjuvant), on day 14 with 84 μg or 100 μg (emulsified in Freund's complete adjuvant), and on days 21 and 28 with 42 μg or 50 μg (emulsified in Freund's incomplete adjuvant). On day 49, the animals received intravenous (iv) injection of 42 μg of GST-hDPP3 or 50 μg of DPP3 peptide BSA complex dissolved in physiological saline. Three days later, the mice were euthanized and immunocell fusion was performed. 【0315】 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 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 1 week, the HAT medium was replaced with HT medium for 3 passages, and then returned to normal cell culture medium. The cell culture supernatant was screened for recombinant DPP3-conjugated IgG antibody 2 weeks after fusion. Recombinant GST-tagged hDPP3 (USBiologicals, Salem, USA) was immobilized in 96-well plates (100 ng / well) and incubated at room temperature for 2 hours with 50 μl of cell culture supernatant per well. After washing the plates, 50 μl / well of POD rabbit anti-mouse IgG was added and incubated at room temperature for 1 hour. After the next washing step, 50 μl of the dye stock solution (o-phenylenediamine in 3.7 mM citrate / hydrogen phosphate buffer, 0.012% H2O2) was added to each well, incubated at room temperature for 15 minutes, and the color reaction was stopped by adding 50 μl of 4N sulfuric acid. Absorption was detected at 490 mm. 【0316】 The positive test microcultures were transferred to 24 wells for growth. After retesting, the selected cultures were cloned, re-cloned using the limiting dilution method, and the isotype was determined. 【0317】 Mouse monoclonal antibody production Antibodies produced against GST-tagged human DPP3 or DPP3 peptide were produced using a standard antibody production method (Marx et al. 1997) and purified with protein A. Antibody purity was >90% based on SDS gel electrophoresis analysis. 【0318】 Antibody Characterization - Binding to hDPP3 and / or Immunotherapy Peptides To analyze the ability of different antibodies and antibody clones to bind DPP3 / immunolytic peptides, binding assays were performed: 【0319】 Solid phase: Recombinant GST-tagged hDPP3 (SEQ ID NO: 34) or DPP3 peptide (immunotherapy peptide, SEQ ID NO: 35) was immobilized on the surface of a high-binding microtiter plate (96-well polystyrene microplate, Greiner Bio-One international AG, Austria, 1 μg / well in coupling buffer [50 mM Tris, 100 mM NaCl, pH 7,8], at room temperature for 1 hour). After blocking with 5% bovine serum albumin, the microplate was vacuum-dried. 【0320】 Labeling procedure (tracer): 100 μg (100 μl) ml of different anti-DPP3 antibodies (detection antibody, 1 mg / ml in PBS, pH 7.4) were mixed with 10 μl of acridinium NHS ester (1 mg / ml in acetonitrile, InVent GmbH, Germany; European Patent No. 0353971) and incubated at room temperature for 30 minutes. The labeled anti-DPP3 antibodies were purified by gel filtration HPLC using a 5 μm Shodex protein KW-803 (Showa Denko, Japan). The purified labeled antibodies were diluted in assay buffer (50 mmol / l potassium phosphate, 100 mmol / l NaCl, 10 mmol / l Na2-EDTA, 5 g / l bovine serum albumin, 1 g / l mouse IgG, 1 g / l bovine IgG, 50 μmol / l astatin, 100 μmol / l leupeptin, pH 7.4). The final concentration is approximately 5-7 × 10⁻¹⁶ per 200 μl. 6 The relative light unit (RLU) was a labeled compound (approximately 20 ng of labeled antibody). Acridinium ester chemiluminescence was measured using a Centro LB 960 (Berthold Technologies GmbH & Co. KG) luminometer. 【0321】 hDPP3 binding assay: Plates were packed with 200 μl of labeled and diluted detection antibody (tracer) and incubated at 2–8°C for 2–4 hours. Unbound tracers were removed by four washes with 350 μl of washing solution (20 mM PBS, pH 7.4, 0.1% Triton X-100). Sufficiently bound chemiluminescence was measured using a Centro LB 960 luminometer (Berthold Technologies GmbH & Co. KG). 【0322】 Antibody Characterization - hDPP3 Inhibition Analysis To analyze the DPP3 inhibitory ability of different antibodies and antibody clones, a DPP3 activity assay (Jones et al., 1982) was performed using a known procedure. Recombinant GST-tagged hDPP3 was diluted in assay buffer (25 ng / ml GST-DPP3 in 50 mM Tris-HCl, pH 7.5, and 100 μM ZnCl2), and 200 μl of this solution was incubated with 10 μg of each antibody at room temperature. After 1 hour of pre-incubation, the fluorescence-generating substrate Arg-Arg-βNA (20 μl, 2 mM) was added to the solution, and the generation of free βNA was monitored over time at 37°C using a Twinkle LB 970 microplate fluorometer (Berthold Technologies GmbH & Co. KG). βNA fluorescence was detected by excitation at 340 nm and emission at 410 nm. The slope of fluorescence increase (RFU / min) for different samples was calculated. The slope of GST-hDPP3 in the buffer control was defined as 100% activity. The inhibitory ability of a potential scavenging agent is defined as the percentage decrease in GST-hDPP3 activity upon incubation with the scavenging agent. 【0323】 The following table shows the selection of obtained antibodies, their binding kinetics in relative light units (RLU), and their relative inhibitory activity (%) (Table 6). Monoclonal antibodies produced against the DPP3 region described below were selected based on recombinant DPP3 and / or immunized peptides, and their inhibitory potential. 【0324】 All antibodies produced against the GST-tagged full-length recombinant hDPP3 show strong binding to immunized GST-tagged hDPP3. Antibodies produced against the SEQ ID NO: 35 peptide similarly bind to GST-hDPP3. The SEQ ID NO: 35 antibody also strongly binds to the immunized peptide. 【0325】 [Table 6] 【0326】 The development of a luminescence immunoassay (DPP3-LIA) for the quantification of DPP3 protein concentration and an enzyme capture activity assay (DPP3-ECA) for the quantification of DPP3 activity have been described in recent years (Rehfeld et al. 2019. JALM 3(6): 943-953), which is incorporated herein by reference to the full text. 【0327】 Example 7 - DPP3 in shock This study determines plasma DPP3 concentrations in patients with sepsis / septic shock and cardiogenic shock, and relates them to short-term mortality in these patients. 【0328】 a) Study cohort - Sepsis / Septic shock DPP3 was measured in 574 patient-derived plasma samples from adrenomedullin and in the prognosis of the AdrenOSS-1 trial for severe sepsis and septic shock. AdrenOSS-1 is a prospective observational multinational trial including 583 patients admitted to the intensive care unit with sepsis or septic shock (Hollinger et al., 2018 Aug 22;3(6):1424-1433). 292 patients were diagnosed with septic shock. 【0329】 b) Study cohort - cardiogenic shock Plasma samples from 108 patients diagnosed with cardiogenic shock were screened for DPP3. Blood samples were collected within 6 hours of detection of cardiogenic shock. Mortality was followed for 7 days. 【0330】 hDPP3 immunoassay: Immunoassays (LIA) or activity assays (ECA) detecting the amount of human DPP3 (LIA) or the activity of human DPP3 (ECA), respectively, were used to determine DPP3 levels in patient plasma. Antibody immobilization, labeling, and incubation were performed as described in Rehfeld et al. (Rehfeld et al. 2019. JALM 3(6): 943-953). 【0331】 Results: Short-term patient survival in sepsis patients was associated with DPP3 plasma concentration at admission. Patients with DPP3 plasma concentrations greater than 40.5 ng / mL (third quartile) had an increased risk of death compared to patients with DPP3 plasma concentrations below this threshold (Figure 7A). Applying this cutoff to a subcohort of septic shock patients revealed a more evident risk of short-term mortality for high DPP3 plasma concentrations (Figure 7B). When the same cutoff was applied to patients with cardiogenic shock, an increased risk of short-term mortality within 7 days was observed in patients with anti-DPP3 (Figure 7C). 【0332】 Example 8 - NT-ADM antibody (AdrenOSS-2) in a patient with septic shock AdrenOSS-2 is a double-blind, placebo-controlled, randomized, multicenter, validation and dose-finding Phase II clinical trial investigating the safety, tolerability, and efficacy of an N-terminal ADM antibody named adrecizumab in patients with septic shock and elevated adrenomedullin (Geven et al. BMJ Open 2019;9:e024475). Overall, 301 patients with septic shock and bio-ADM concentrations >70 pg / mL were randomly assigned to receive either placebo (n=152), adrecizumab 2 ng / kg (n=72), or adrecizumab 4 ng / kg (n=77) via a single intravenous infusion over approximately 1 hour. The all-cause mortality rate within 28 (90) days after selection was 25.8% (34.8%). The mean age was 68.4 years, and 61% were male. For per protocol analysis, n=294 patients remained eligible, and the 14-day cause-unspecified all-cause mortality rate was 18.5%. 【0333】 In patients treated with adrecizumab (total of both doses, per protocol population), a trend toward lower short-term mortality (14 days after admission) was observed compared to placebo (hazard ratio (HR) 0.701 [0.408-1.21], p=0.100) (Figure 8). Surprisingly, the treatment effect was more pronounced in patients with admission DPP3 concentrations of less than 50 ng / mL (n=244, HR 0.426, p=0.007) (Figure 9), but in patients with high DPP3 (≥50 ng / mL, n=44), the prognosis was similar between adrecizumab and placebo (HR 1.69, p=0.209) (Figure 10). 【0334】 Table 7 summarizes the treatment effects (14-day mortality) for different DPP3 thresholds. 【0335】 [Table 7] 【0336】 Example 9: To demonstrate that anti-ADM therapy is effective even in patients with bio-ADM levels lower than 70 pg / mL, we investigated whether patients exhibited different therapeutic effects depending on their pre-administration bio-ADM concentration in a selected patient population (all patients with bio-ADM > 70 pg / mL). No such interactions were detected; in other words, beneficial therapeutic effects were detected in all patients regardless of their pre-administration bio-ADM concentration. This finding strongly suggests that the treatment is effective even in patients with bio-ADM levels lower than 70 pg / mL, with the possible (and acceptable) limitation that such effects may not be expected in patients with healthy, normal-range bio-ADM concentrations. 【0337】 P-values ​​for the interaction between treatment and pre-administration bio-ADM: • Per protocol group: p=0.279 • Perprotocol population / pre-administration DPP3 < 70 ng / mL: p = 0.150 【0338】 This was further illustrated in a Kaplan-Meier plot, where the patient population was separated by their pre-administration bio-ADM concentration (bio-ADM < / greater than median) (see Figures 11a and 11b). 【0339】 Sequence List Sequence ID 1 GYTFSRYW Sequence ID 2 ILPGSGST Sequence ID 3 TEGYEYDGFDY Sequence ID 4 QSIVYSNGNTY Sequence "RVS" (not part of the sequence listing): RVS Sequence ID 5 FQGSHIPYT Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 14 (Human ADM1-21) YRQSMNNFQGLRSFGCRFGTC Sequence ID 15 (Human ADM 21-32) CTVQKLAHQIYQ Sequence ID 16 (Human ADM C-42-52) CAPRSKISPQGY-CONH2 Sequence ID 17 (Mouse ADM 1-19) YRQSMNQGSRSNGCRFGTC Sequence ID 18 (Mouse ADM 19-31) CTFQKLAHQIYQ Sequence ID 19 (Mouse ADM C-40-50) CAPRNKISPQGY-CONH2 Sequence ID No. 20 (Mature Human Adrenomedullin (Mature ADM); Amidated ADM; Bio-ADM): Amino Acids 1-52 or 95-146 of pro-ADM YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-CONH2 Sequence ID 21 (Mouse ADM 1-50) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGMAPRNKISPQGY-CONH2 Sequence ID 22 (Human ADM 1-21): YRQSMNNFQGLRSFGCRFGTC Sequence ID 23 (Human ADM 1-42): YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA Sequence ID No. 24 (Amino acids 43-52 of human ADM) PRSKISPQGY-NH2 Sequence ID No. 25 (Amino acids 1-14 of human ADM) YRQSMNNFQGLRSF Sequence ID No. 26 (Amino acids 1-10 of human ADM) YRQSMNNFQG Sequence ID No. 27 (Amino acids 1-6 of human ADM) YRQSMN Sequence ID No. 28 (Amino acids 1-32 of human ADM) YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQ Sequence ID No. 29 (Amino Acids 1-40 Mouse ADM) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGMA Sequence ID No. 30 (Amino Acids 1-31 Mouse ADM) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQL Sequence ID 31 (proADM: 164 amino acids (22-185 of preproADM)) ARLDVASEF RKKWNKWALS RGKRELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RVKRYRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGYGRRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL Sequence ID 32 (Adrecizumab heavy chain) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGY EYDGFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK Sequence ID 33 (Adrecizumab light chain) DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 34 - Human DPP3 (amino acids 1-737) MADTQYILPNDIGVSSLDCREAFRLLSPTERLYAYHLSRAWYGGLAVLLQTSPEAPYIYALLSRLFRAQDPDQLRQHALAEGLTEEEYQAFLVYAAGVYSNMGNYKSFGDTKFVPNLPKEKLERVILGSEAAQQHPEEVRGLWQTCGELMFSLEPRLRHLGLGKEGITTYFSGNCTMEDAKLA QDFLDSQNLSAYNTRLFKEVDGEGKPYYEVRLASVLGSEPSLDSEVTSKLKSYEFRGSPFQVTRGDYAPILQKVVEQLEKAKAYAANSHQGQMLAQYIESFTQGSIEAHKRGSRFWIQDKGPIVESYIGFIESYRDPFGSRGEFEFGFVAVVNKAMSAKFERLVASAEQLLKELPWPPTFEKDKF LTPDFTSLDVLTFAGSGIPAGINIPNYDDLRQTEGFKNVSLGNVLAVAYATQREKLTFLEEDDKDLYILWKGPSFDVQVGLHELLGHGSGKLFVQDEKGAFNFDQETVINPETGEQIQSWYRSGETWDSKFSTIASSYEECRAESVGLYLCLHPQVLEIFGFEGADAEDVIYVNWLNMVRAGLL ALEFYTPEAFNWRQAHMQARFVILRVLLEAGEGLVTITPTTGSDGRPDARVRLDRSKIRSVGKPALERFLRRLQVLKSTGDVAGGRALYEGYATVTDAPPECFLTLRDTVLLRKESRKLIVQPNTRLEGSDVQLLEYEASAAGLIRSFSERFPEDGPELEEILTQLATADARFWKGPSEAPSGQA Sequence ID 35 - Human DPP3 (amino acids 474-493 (N-Cys)) - Immunopeptide with N-terminal cysteine ​​added CETVINPETGEQIQSWYRSGE Sequence ID 36 - IGHV1-69*11 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGRIIPILGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARYYYYYGMDVWGQGTTVTVSS Sequence ID 37 - HB3 QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSS Some aspects of the present invention are described below. 1. An 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, wherein the patient has a subthreshold level of dipeptidyl peptidase 3 (DPP3) in a sample of body fluid, and the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNFQGLRSFGCRFGTC (SEQ ID NO: 14). 2. An anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in the patient described in item 1, selected from the group including hypovolemic shock, cardiogenic shock, vascular occlusive shock, and distributive shock, and in particular cardiogenic shock or septic shock. 3. In the case of cardiogenic shock, the patient may have acute coronary syndrome (e.g., acute myocardial infarction), or the patient may have 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 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, or a non-hemorrhagic disorder including 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 may be suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. Anti-adrenomedullin (ADM) antibodies, anti-ADM antibody fragments, or anti-ADM non-Ig scaffolds for use in the treatment or prevention of shock in patients described in items 1 and 2. 4. 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 items 1 to 3, wherein the threshold of DPP3 in a sample of the patient's body fluid is 20 to 120 ng / mL, more preferably 30 to 80 ng / mL, even more preferably 40 to 60 ng / mL, and most preferably the threshold is 50 ng / mL. 5. 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 the patient described in item 4, wherein the threshold for DPP3 in a sample of the patient's body fluid is 40-60 ng / mL. 6. 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 described in any of items 1 to 5, wherein the body fluid is selected from whole blood, plasma, and serum. 7. 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 the patient described in item 6, wherein the body fluid is plasma. 8. 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 any of the patients described in items 1 to 7, wherein the DPP3 level is determined by contacting the body fluid sample with a capture agent that specifically binds to DPP3. 9. The capture and binding agent is an antibody, 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 the patient described in item 8. 10. 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 any of the patients described in items 1 to 9, for determining either DPP3 protein levels and / or active DPP3 levels and comparing them to a predetermined threshold. 11. An anti-adrenomedullin (ADM) antibody, an anti-ADM antibody fragment, or an anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in any of the patients described in items 1 to 10, further characterized in that the patient has an ADM-NH2 level greater than a threshold. 12. 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 the patient described in item 11, wherein the threshold of ADM-NH2 in a sample of the patient's body fluid is 40-100 pg / mL, more preferably 50-90 pg / mL, even more preferably 60-80 pg / mL, and most preferably the threshold is 70 pg / mL. 13. 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 the patient described in item 12, wherein the threshold for ADM-NH2 in a sample of the patient's body fluid is 70 pg / mL. 14. 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 any of the patients described in items 1 to 13, wherein the body fluid is selected from whole blood, plasma, and serum. 15. 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 the patient described in item 14, wherein the body fluid is plasma. 16. 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 of items 11 to 15, wherein the ADM-NH2 level is determined by contacting the body fluid sample with a capture agent that specifically binds to ADM-NH2. 17. The capture and binding agent is an antibody, 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 patients as described in item 16. 18. 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 described in any of items 1 to 17, wherein the body fluid sample of the patient is selected from the group consisting of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. 19. An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in any of the patients described in items 1 to 18, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold recognizes and binds to the N-terminus (amino acid 1) of ADM-Gly and / or ADM-NH2. 20. An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in patients described in any of items 1 to 19, wherein the antibody, antibody fragment, or non-Ig scaffold does not bind to the C-terminal portion of ADM having the sequence amino acids 43-52:PRSKISPQGY-NH2 (SEQ ID NO: 24) of ADM. 21. An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in patients described in any of items 1 to 20, wherein the antibody or fragment or scaffold blocks 80% or less, preferably 50% or less, of the biological activity of ADM. 22. The antibody or fragment is a monoclonal antibody or fragment that binds to ADM or its antibody fragment, wherein the heavy chain is sequence: CDR1: Sequence ID 1 GYTFSRYW CDR2: Sequence ID 2 ILPGSGST CDR3: Sequence ID 3 TEGYEYDGFDY Includes, and the light chains are arranged: CDR1: Sequence ID 4 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 5 FQGSHIPYT including, An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in any of the patients described in items 1 to 21. 23. The antibody or fragment, as a VH region Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Includes sequences selected from the group containing, And the following sequence as the VL region: Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes sequences selected from a group that includes, An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in any of the patients described in items 1 to 22. 24. The antibody or fragment has the following sequence as its heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK or including a sequence that is >95% identical to the said sequence, And the following sequence as the light chain: Sequence ID 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or including a sequence that is >95% identical to the said sequence, An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in any of the patients described in items 1 to 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 patients described in any of items 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: 26). 26. The antibody or fragment or scaffold is subjected to label-free surface plasmon resonance using the Biacore 2000 system for at least 10 -7 Anti-adrenomedullin (ADM) antibody or anti-adrenomedullin antibody fragment or anti-ADM non-Ig scaffold for use in the treatment described in item 25, exhibiting binding affinity of M to ADM. 27. The anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is subjected to label-free surface plasmon resonance of 1 × 10⁻¹⁶ using the Biacore 2000 system. -9 ~3×10 -9 An anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold exhibiting affinity for human ADM, for use in the treatment or prevention of shock in patients as described in item 26. 28. An anti-adrenomedullin (ADM) antibody, anti-ADM antibody fragment, or anti-ADM non-Ig scaffold for use in the treatment or prevention of shock in patients as described in any of items 25 to 27, wherein the anti-ADM antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold is an IgG1 antibody. 29. A pharmaceutical preparation for use in the treatment or prevention of shock in patients, comprising an anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment or anti-ADM non-Ig scaffold described in any of items 1 to 28. 30. A pharmaceutical preparation for use in the treatment or prevention of shock in a patient as described in item 29, wherein the pharmaceutical preparation is a liquid, preferably a ready-to-use liquid. 31. A pharmaceutical preparation for use in the treatment or prevention of shock in patients as described in items 29 and 30, wherein the pharmaceutical preparation is in a lyophilized state. 32. A pharmaceutical preparation for use in the treatment or prevention of shock in patients as described in items 29 and 31, which is administered intramuscularly. 33. A pharmaceutical preparation for use in the treatment or prevention of shock in patients described in items 29 and 32, which is administered intravascularly. 34. A pharmaceutical preparation to be administered by infusion for use in the treatment or prevention of shock in patients as described in items 29 and 33. 35. A pharmaceutical preparation intended for use in the treatment or prevention of shock in patients as described in items 29 and 34, which is intended for systemic administration.

Claims

[Claim 1] A pharmaceutical composition for use in the treatment or prevention of shock in a patient, comprising an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment, wherein the patient has a dipeptidyl peptidase 3 (DPP3) concentration below a threshold in a body fluid sample, and the anti-ADM antibody or anti-ADM antibody fragment binds to the N-terminal portion (amino acids 1-21) of ADM: YRQSMNNNFQGLRSFGCRFGTC (SEQ ID NO: 14), comprising an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment, for use in the treatment or prevention of shock in a patient. [Claim 2] The pharmaceutical composition according to claim 1, wherein the shock is selected from the group including shock caused by decreased blood volume, cardiogenic shock, vascular occlusive shock, and distributive shock. [Claim 3] The pharmaceutical composition according to claim 2, wherein the shock is cardiogenic shock or septic shock. [Claim 4] - In the case of cardiogenic shock, the patient may have acute coronary syndrome, or the patient may have 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 spontaneous bleeding in the context of gastrointestinal bleeding, trauma, vascular etiology, and anticoagulant use, or a non-hemorrhagic disorder including vomiting, diarrhea, renal loss, skin loss / insensitivity, 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 may be suffering from septic shock, neurogenic shock, anaphylactic shock, or shock caused by an adrenal crisis. A pharmaceutical composition according to any one of claims 1 to 3. [Claim 5] The pharmaceutical composition according to claim 4, wherein in the case of cardiogenic shock, the patient may be suffering from acute myocardial infarction. [Claim 6] In the case of cardiogenic shock, the patient has acute decompensated heart failure, according to claim 4 of the pharmaceutical composition. [Claim 7] The pharmaceutical composition according to claim 4, wherein in cases of hypovolemic shock, the patient may be suffering from a ruptured abdominal aortic aneurysm or a tumor affecting major blood vessels. [Claim 8] The pharmaceutical composition according to claim 4, wherein in the case of hypovolemic shock, the patient may be suffering from burns or heatstroke. [Claim 9] The pharmaceutical composition according to any one of claims 1 to 8, wherein the threshold value of DPP3 in the patient's body fluid sample is 20 to 120 ng / mL. [Claim 10] The pharmaceutical composition according to claim 9, wherein the threshold value of DPP3 in the patient's body fluid sample is 30 to 80 ng / mL. [Claim 11] The pharmaceutical composition according to claim 9, wherein the threshold value of DPP3 in the patient's body fluid sample is 40 to 60 ng / mL. [Claim 12] The pharmaceutical composition according to claim 9, wherein the threshold value of DPP3 in the patient's body fluid sample is 50 ng / mL. [Claim 13] The pharmaceutical composition according to any one of claims 1 to 12, wherein the DPP3 concentration is determined by contacting the body fluid sample with a scavenging agent that specifically binds to DPP3. [Claim 14] The pharmaceutical composition according to claim 13, wherein the capture and binding agent is an antibody. [Claim 15] A pharmaceutical composition according to any one of claims 1 to 14, comprising determining either the DPP3 protein concentration and / or the active DPP3 concentration and comparing it with the threshold. [Claim 16] The aforementioned patient had ADM-NH levels greater than the threshold. 2 A pharmaceutical composition according to any one of claims 1 to 15, further characterized by having a concentration. [Claim 17] ADM-NH in the body fluid sample of the aforementioned patient 2 The pharmaceutical composition according to claim 16, wherein the threshold concentration is 40 to 100 pg / mL. [Claim 18] ADM-NH in the body fluid sample of the aforementioned patient 2 The pharmaceutical composition according to claim 17, wherein the threshold concentration is 50 to 90 pg / mL. [Claim 19] ADM-NH in the body fluid sample of the aforementioned patient 2 The pharmaceutical composition according to claim 17, wherein the threshold concentration is 60 to 80 pg / mL. [Claim 20] ADM-NH in the body fluid sample of the aforementioned patient 2 The pharmaceutical composition according to claim 17, wherein the threshold concentration is 70 pg / mL. [Claim 21] Said ADM-NH 2 The concentration of the body fluid sample is ADM-NH 2 A pharmaceutical composition according to any one of claims 16 to 20, determined by contacting it with a scavenging agent that specifically binds to it. [Claim 22] The pharmaceutical composition according to claim 21, wherein the capture and binding agent is an antibody. [Claim 23] The pharmaceutical composition according to any one of claims 1 to 22, wherein the bodily fluid sample of the patient is selected from the group consisting of blood, serum, plasma, urine, cerebrospinal fluid (CSF), and saliva. [Claim 24] The pharmaceutical composition according to claim 23, wherein the body fluid sample is selected from blood, plasma, and serum. [Claim 25] The pharmaceutical composition according to claim 23, wherein the bodily fluid sample is plasma. [Claim 26] The anti-ADM antibody or anti-ADM antibody fragment is the N-terminus (amino acid 1) of ADM-Gly and / or ADM-NH 2 A pharmaceutical composition according to any one of claims 1 to 25, which recognizes and binds to the N-terminus (amino acid 1) of [Claim 27] The anti-ADM antibody or anti-ADM antibody fragment does not bind to the C-terminal portion of ADM having the sequence amino acids 43 to 52 of ADM: PRSKISPQGY-NH 2 The pharmaceutical composition according to any one of claims 1 to 26, which does not bind to the C-terminal portion of ADM having (SEQ ID NO: 24). [Claim 28] The pharmaceutical composition according to any one of claims 1 to 27, wherein the anti-ADM antibody or anti-ADM antibody fragment blocks 80% or less of the biological activity of ADM, meaning that the remaining biological activity of ADM bound to the anti-ADM antibody or anti-ADM antibody fragment is more than 20%. [Claim 29] The pharmaceutical composition according to claim 28, wherein the anti-ADM antibody or anti-ADM antibody fragment blocks 50% or less of the biological activity of ADM, meaning that the remaining biological activity of ADM bound to the anti-ADM antibody or anti-ADM antibody fragment is greater than 50%. [Claim 30] The anti-ADM antibody or anti-ADM antibody fragment is a monoclonal antibody or fragment that binds to ADM, where the heavy chain is sequenced as follows: CDR1: Sequence ID 1 GYTFSRYW CDR2: Sequence ID 2 ILPGSGST CDR3: Sequence ID 3 TEGYEYDGFDY Includes, and light chains are arranged: CDR1: Sequence ID 4 QSIVYSNGNTY CDR2: RVS CDR3: Sequence ID 5 FQGSHIPYT including, A pharmaceutical composition according to any one of claims 1 to 29. [Claim 31] The anti-ADM antibody or anti-ADM antibody fragment is defined as the VH region. Sequence number 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWG QGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Sequence ID 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK Includes sequences selected from the group consisting of, And the following sequence as the VL region: Sequence ID 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Sequence ID 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Includes sequences selected from the group consisting of, A pharmaceutical composition according to any one of claims 1 to 30. [Claim 32] The anti-ADM antibody or anti-ADM antibody fragment has the following sequence as its heavy chain: Sequence ID 32 QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWIGEILPGSGSTNYNQKFQGRVTITADTSTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGT 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 33 DVVLTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWYLQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGGGTKL EIKRTVAAPSVFIFPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC or including a sequence that is >95% identical to the said sequence, The pharmaceutical composition according to claim 30. [Claim 33] The pharmaceutical composition according to any one of claims 1 to 32, wherein the anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment is bound to the N-terminal portion (amino acids 1 to 10) of ADM: YRQSMNNNFQG (SEQ ID NO: 26). [Claim 34] The anti-ADM antibody or anti-ADM antibody fragment is subjected to label-free surface plasmon resonance using the Biacore 2000 system, at least 10 -7 The pharmaceutical composition according to claim 33, which exhibits binding affinity of M to ADM. [Claim 35] The anti-ADM antibody or anti-ADM antibody fragment is subjected to label-free surface plasmon resonance using the Biacore 2000 system, resulting in a reaction of 1 × 10⁻¹⁶. -9 ~3 x 10 -9 The pharmaceutical composition according to claim 34, which exhibits affinity for human ADM. [Claim 36] The pharmaceutical composition according to any one of claims 33 to 35, wherein the anti-ADM antibody or anti-ADM antibody fragment is an IgG1 antibody. [Claim 37] A pharmaceutical formulation for use in the treatment or prevention of shock in a patient, comprising the pharmaceutical composition according to any one of claims 1 to 36. [Claim 38] The pharmaceutical preparation for use in the treatment or prevention of shock in a patient, as described in claim 37, wherein the pharmaceutical preparation is a liquid preparation. [Claim 39] The pharmaceutical preparation for use in the treatment or prevention of shock in a patient, according to claim 38, wherein the pharmaceutical preparation is a liquid preparation that can be used immediately. [Claim 40] A pharmaceutical preparation for use in the treatment or prevention of shock in a patient, according to any one of claims 37 to 39, wherein the pharmaceutical preparation is in a freeze-dried state. [Claim 41] A pharmaceutical preparation for use in the treatment or prevention of shock in a patient according to claim 37 or 40, wherein the pharmaceutical preparation is administered intramuscularly. [Claim 42] A pharmaceutical preparation for use in the treatment or prevention of shock in a patient according to claim 37 or 41, wherein the pharmaceutical preparation is administered intravascularly. [Claim 43] A pharmaceutical preparation for use in the treatment or prevention of shock in a patient according to claim 37 or 42, wherein the pharmaceutical preparation is administered by injection. [Claim 44] A pharmaceutical preparation for use in the treatment or prevention of shock in a patient according to claim 37 or 43, wherein the pharmaceutical preparation is intended for systemic administration.

Images